Key words borocyclopropanes - heterocycles - Simmons–Smith reaction - zinco-cyclopropanation
- cross-coupling
Cyclopropane motifs are ubiquitous in Nature[1 ] and are widely employed in pharmaceutically and agrochemically relevant compounds.[2 ] Cyclopropylboronic acids and derivatives are excellent synthons for the rapid introduction
of the cyclopropyl motif into complex molecules.[3 ] Suzuki cross-coupling of these cyclopropylboronic acids with heteroaryls provide
heteroaryl-substituted cyclopropanes, which serve as chiral cores in many natural
products and biologically active drug candidates.[4 ] For example, thiazolopyrimidinones comprising the cyclopropane group (Figure [1, 1 ]) serve as N -methyl-d -aspartate (NMDA) receptor activity modulators and rely on racemic borocyclopropylmethanols
as optimal synthons for the introduction of cyclopropane groups in a racemic fashion.[5 ] Similarly, borocyclopropane building blocks have been employed in the synthesis
of cyclopropane-containing drug candidates (Figure [1, 2–4 ]), where the products are delivered as racemates requiring chiral HPLC separation.[6 ] Although an array of methodologies to access substituted borocyclopropane subunits
in a diastereoselective manner are available,[7 ] access to optically active borocyclopropane subunits is often limited. Thus far,
asymmetric cyclopropanation methodologies to access enantioenriched borocyclopropanes
include palladium-catalyzed cyclopropanation of chiral vinylboronates via diazo decomposition,[8 ] and copper-catalyzed carbene transfer of ethyldiazoacetate to alkenylboronates for
the preparation of chiral 1,2,3-trisubstituted cyclopropanes (Scheme [1 ], part i).[9 ] The in situ preparation of enantioenriched borocyclopropanes via the zinco-cyclopropanation
of substituted allylic alcohols is an alternative to the use of stoichiometric quantities
of diazo compounds (Scheme [1 ], part ii).[10 ] The Simmons–Smith reaction has also been employed for the synthesis of chiral vinylpinacolboronates
as separable racemic diastereomeric mixtures.[8b ]
Figure 1 Selected cyclopropane-containing biologically active drug candidates
Scheme 1 Synthesis of enantioenriched cyclopropylboronates
The Simmons–Smith cyclopropanation mediated by dioxaborolane 11 is a versatile methodology for the conversion of allylic alcohols and allylic ethers
into an array of diversely substituted cyclopropane motifs in high enantioselectivities.[11 ] We report herein the first enantioselective Simmons–Smith cyclopropanation of boronate-bearing
allylic alcohols for the preparation of enantioenriched borocyclopropane building
blocks.[12 ] Pinacolate analogues have often been used in borocyclopropanation methodologies.[4 ]
[5 ]
[6 ]
,
[13 ] Many of these derivatives are oils and are prone to decomposition through protodeboronation,
and are hence recurrently deemed ‘unstable’ boronic acids.[14 ] In contrast, cyclopropyltrifluoroborates are solids and display a reduced propensity
to undergo protodeboronation, but have limited solubility in moderately polar solvents.[15 ]
[16 ]
N -Methyliminodiacetic acid (MIDA) boronates have emerged as efficient building blocks
due to their air stability, crystallinity, monomeric constitution, and compatibility
with silica gel chromatography. The most attractive properties of MIDA boronates are
their reversibly attenuated reactivity towards anhydrous cross-coupling conditions
and compatibility with a wide range of reagents, which make them ideal coupling candidates
for late-stage functionalization.[3 ] For these reasons, we envisioned the use of enantioselective Simmons–Smith cyclopropanation
of MIDA boronate bearing allylic alcohol to prepare the corresponding cyclopropylmethanol,
which could serve as a robust building block for diversification reactions and the
synthesis of cyclopropane-containing chiral cores in complex molecules discussed previously
(Figure [1 ]). Our initial Simmons–Smith cyclopropanation attempt was thwarted by two aspects
of the reaction: (a) the insolubility of the vinyl MIDA boronate bearing the (E )-allylic alcohol in the solvents typically used for dioxaborolane-mediated cyclopropanations,
such as dichloromethane, chloroform, and chlorobenzene and (b) decomposition of the
boronate under the oxidative conditions used for the removal of dioxaborolane.[11 ]
To improve solubility, we proposed the replacement of the N -methyl substituent in MIDA boronates with a cyclohexyl group to prepare N -cyclohexyliminodiacetic acid (CIDA) protected boronates. The CIDA-bearing boronate
allylic alcohol 15a (Scheme [2 ]) can be synthesized on a multigram scale in three steps starting from TBS-protected
vinyl-Bpin-bearing (E )-allylic alcohol in 80% overall yield. During the synthesis of the free allylic alcohol
15a , we were pleased to find orthogonal deprotection conditions for boronate substrates
bearing silyl protecting groups. The in situ deprotection of the TBS group was a result
of a mixture of DMSO, used as a cosolvent, and minimal amounts of water, generated
during the CIDA protection, which provided the CIDA boronate allylic alcohol in 20%
yield and the TBS-protected allylic alcohol in 60% yield. Heating the crude reaction
mixture in DMSO/water (5:1) enhanced the overall yield to 80%.[17 ] Once obtained, we were pleased to find that the CIDA allylic alcohol 15a was readily soluble in dichloromethane.
Scheme 2 Enantioselective borocyclopropanation of borosubstituted allylic alcohols 15a and 15b
The cyclopropanation reaction with 15a using Zn(CH2 I)2 (2.2 equiv) and dioxaborolane 11 (1.1 equiv) proceeded smoothly with full conversion of the starting material. However,
isolation of the cyclopropylmethanol by decomplexation of the chiral dioxaborolane
ligand using hydrogen peroxide and sodium hydroxide led to the complete hydrolysis
of the product (Scheme [2 ]). Attempts to use less equivalents of peroxide did not prevent the hydrolysis of
the product. The traditional workup conditions for the dioxaborolane-mediated cyclopropanation
involves the use of 30% hydrogen peroxide and 2 M sodium hydroxide[29 ] or the use of highly basic 5 M aqueous potassium hydroxide to decomplex the dioxaborolane
from the cyclopropyl methoxide species 16 formed in the reaction. Indeed, the hydrolysis of alkyltriolborates is known to involve
harsh oxidative conditions,[18 ] resulting in narrow functional group compatibility and challenging purifications.[19 ]
Considering that MIDA boronates are highly labile to aqueous basic conditions and
the presence of strong oxidants, we investigated a non-oxidative process for selective
decomplexation of the tartaramide–boronate complex in the presence of the CIDA group
in intermediate 16 . Diethanolamine (DEA) and ethanolamine have been used for the transesterification
of certain pinacolboronate esters bearing electron-withdrawing groups.[20 ] However, Szabò recently observed that the diethanolamine cyclic boronate deprotection
protocol is unsuccessful for transesterification of some electron-deficient vinylpinacolate
analogues.[21 ] To the best of our knowledge, DEA has not been used for the transesterification
of alkyltriolborates. We investigated the use of DEA for the transesterification of
the (cyclopropylmethanol)boronate complexes. After extensive screening for isolation
conditions, the decomplexation of the boron-ligated intermediate 16 was achieved by direct addition of DEA (5 equiv) to the reaction mixture and stirring
for 3 hours at room temperature. Purification of the decomplexed crude product by
silica gel chromatography afforded 13 in 92% yield and 95.6:4.4 er (Scheme [2 ]).
For comparative purposes, BPin-substituted allylic alcohol 15b was subjected to the Simmons- Smith cyclopropanation conditions. After optimization,
the pinacol-protected borocyclopropane 14 was obtained in 21% yield with a reproducible 90.9:9.1 er (Scheme [2 ]). The low yield of the pinacol derivative is likely due to the transesterification
of the pinacol ligand with excess DEA or due to decomposition by flash chromatography
of pinacolboronates. We evaluated the robustness of the DEA decomplexation process
using Glorius’s intermolecular screening tool[22 ] for the cyclopropanation of allylic alcohol 17
[11 ] with five substrates containing base-sensitive functionalities, such as esters and
carbamates, as well as indole, to study an example of an oxidizable group (Scheme
[3 ]).
Scheme 3 Cyclopropanation of allylic alcohol 17 . Workup conditions : a Diethanolamine (5 equiv), rt, 3 h; b H2 O2 (30% in water), 2 M aq NaOH, rt, 10 min; c N -Methyldiethanolamine (5 equiv), rt, 3 h.
The recovery of the additives is consistently higher with the use of the non-oxidative
conditions. The superiority is striking in the case of substrate 19c (Scheme [3 ]) bearing the acetate functionality, where the non-oxidative decomplexation allows
isolation in 98% yield in comparison to no recovery when using the traditional procedure.
The base-sensitive Fmoc-group-containing compound 19d was found to be labile toward both oxidative and non-oxidative protocols, allowing
only 35% isolated yield. We investigated the use of a more hindered DEA such as N -methyl DEA, and were pleased to find an improved recovery of 87% in comparison to
the 15% yield isolated using the oxidative conditions. For highly base-sensitive groups,
the N -methyl DEA workup is recommended for better yields. Indole was recovered in 96% yield
when using the DEA decomplexation, in comparison to 68% recovered when using the traditional
decomplexation procedure, demonstrating the use of DEA-promoted cleavage of dioxaborolane
to obtain oxidation-sensitive N-heterocycle-substituted cyclopropanes, which are typically
incompatible with the traditional conditions.[23 ]
Based on the robustness screen of DEA, cyclopropanation of substrate 20 bearing the sensitive O -acetyl group was attempted (Scheme [4 ]). Cyclopropylmethanol 21 bearing the acetate group was obtained in 76% isolated yield. During analysis of
the byproducts, it was determined that the moderate yield was not a result of the
decomposition of the acetyl allylic alcohol, but due to the lower reactivity of the
substrate, evidenced by the recovery of the starting material in 24% isolated yield.
Thus, the DEA-promoted decomplexation procedure proved to be quite versatile, and
functional groups such as esters, carbamates, and others were shown to be compatible
under the new non-oxidative conditions for the decomplexation of 11 .
Scheme 4 Cyclopropanation of highly base-sensitive substrate
With the two borocyclopropane derivatives in hand, we turned our attention to the
cross-coupling conditions for the Suzuki–Miyaura reaction, which is arguably the most
effective method to integrate the cyclopropyl moiety into aromatic or heteroaromatic
systems.[24 ] Heterocycles are the most widely used motifs in medicinal chemistry, and to aid
introduction of the cyclopropane motif into heterocycles, we evaluated a series of
cross-couplings of heteroaryl halides with 13 and 14 to obtain enantioenriched heteroaryl-substituted cyclopropanes. Methods for the cross-coupling
of cyclopropylboronic acids and their pinacol analogues have been previously exploited.[3 ]
[25 ] Cross-coupling of cyclopropyl MIDA boronates has been achieved using SPhos and Pd(OAc)2 to afford excellent yields of the coupled products while the cross-coupling of racemic
trans -2-(trifluoromethyl)cyclopropyl MIDA boronates in the presence of Pd(OAc)2 and PCy3 provides the cyclopropyl adducts in only 17–32% yields.[26 ] After screening various cross-coupling conditions, we found the use of PCy3 and Pd2 (dba)3 as a suitable combination for the cross-coupling of the CIDA-boronate-bearing cyclopropylmethanol
13 (Scheme [5 ]). It should be noted that cyclopropylboronic acids prepared immediately prior to
the reaction can be as effective as the MIDA boronates.
Scheme 5 Suzuki cross-coupling of borocyclopropanes. a Yields obtained when using borocyclopropane 13 . b Yields obtained when using borocyclopropane 14 .
The cross coupling of 13 (95.6:4.4 er) with five heteroaryl bromides in the presence of Pd2 (dba)3 (5 mol%), PCy3 (10 mol%) and aqueous potassium triphosphate afforded the cross-coupled cyclopropylmethanols
23a –e in excellent yields (Scheme [5 ]). When the same coupling reactions were performed with the Bpin-substituted cyclopropane
14 (90.9:9.1 er), lower yields were obtained even though cyclopropane 14 was freshly prepared. The higher cross-coupling efficiency of the CIDA borocyclopropane
compared to that of the Bpin-borocyclopropanes can be attributed to stability and
controlled the hydrolytic character of tetracoordinate boronates in cross-coupling
reactions.[19 ] Moreover, enantioenriched cyclopropane 13 exhibited benchtop air-stability even after 5 months, while borocyclopropane 14 partially decomposed (by about 20%) over 3 weeks.
Having evaluated an approach to access trans -N-heterocycle-substituted cyclopropanes, we turned our attention to the cis analogues. Attempts to synthesize the CIDA-bearing cis -boronate allylic alcohols failed due to lack of stability. To overcome these challenges,
we took to an in situ approach to obtain the disubstituted borocyclopropylmethanol
via the enantioselective zinco-cyclopropanation reaction of allyl alcohol followed
by cross-coupling with N-heterocycles to prepare cis -N-heterocycle-substituted cyclopropanes (Scheme [6 ]). A modified procedure was employed to enhance the yield of the zinco-cyclopropanation
of the non-substituted allylic alcohol substrate. Treatment of allyl alcohol 24 with the gem -dizinc carbenoid in the presence of chiral ligand 11 led to the cyclic boronate 12 , which was subjected to Suzuki cross-coupling. In the case of allyl alcohol, the
product often contained residual dioxaborolane or complexed dioxaborolane, affecting
the yield of the reaction. To overcome the lower yield arising from the residual complexed
dioxaborolane, the non-oxidative DEA-promoted decomplexation was applied to the crude
reaction mixture to obtain the completely decomplexed cis isomer. Purification of the crude reaction mixture provided the desired N-heterocycle-substituted
cyclopropanes in good yields and excellent enantioselectivity (Scheme [6 ]).
Scheme 6 Synthesis of cis -heteroaryl-substituted cyclopropanes
In conclusion, a non-oxidative and enantioselective methodology has been developed
that not only allows for the preparation of enantiopure borocyclopropane building
blocks, but also provides a tool for the decomplexation of boron-ligated intermediates
in the zinco-cyclopropanation reaction. Using this methodology, a novel air-stable
enantioenriched CIDA borocyclopropane 13 building block was obtained in 92% yield and 95.6:4.4 er compared to the pinacolborocyclopropane
14 obtained in 21% yield and 90.9:9.1 er. Efficient cross-coupling conditions for the
CIDA borocyclopropane allowed access to enantioenriched trans -N-heterocycle-substituted cyclopropanes in excellent yields. The non-oxidative DEA
decomplexation was also applied in the zinco-cyclopropanation reaction to allow access
to the fully decomplexed cis -N-heterocycle-substituted cyclopropanes, resulting in higher yields. This work demonstrates
a robust and mild alternative for dioxaborolane-mediated cyclopropanations, broadening
compatibility with highly base-sensitive and oxidizable substrates.
Unless otherwise stated, all glassware was oven-dried and/or was flame-dried prior
to use and all reactions were set up and carried out under an argon atmosphere[27 ] with the exclusion of moisture. Anhydrous solvents were obtained either by filtration
through drying columns on a GlassContour system (Irvine, CA) (benzene and THF) or
by distillation over calcium hydride (Et3 N, pyridine, CH2 Cl2 ) or sodium (THF). Absolute EtOH, glacial acetic acid, and Ac2 O were used as is from commercial bottles. Unless otherwise noted, all solutions are
aqueous solutions. Analytical TLC was performed on pre-coated, glass-backed silica
gel (Merck 60 F254). Visualization of the developed chromatogram was aided by UV absorbance
(254 nm), UV fluorescence (350 nm), or by using aq potassium permanganate (KMnO4 ), p -anisaldehyde, and ninhydrin. Flash column chromatography was performed on silica
gel (pore size 60 Å, 230–400 mesh particle size, 40–63 μm particle size) in glass
columns for the separation of products. Melting points were obtained on a Buchi melting
point B-540 apparatus and are uncorrected. Specific rotations, [α]D values, were calculated from optical rotations measured at 25 °C in MeOH at the specified
concentrations (c in g/100 mL) using a 0.5-dm cell length (l) on a Perkin-Elmer Polarimeter 241 at
589 nm, using the general formula: [α]D
25 = (100 × α)/(l × c ). 1 H and 13 C NMR spectra were recorded on Bruker AV400, AV500, and AV700 MHz spectrometers. The
corresponding chemical shifts for 1 H NMR and 13 C NMR spectra are recorded in CDCl3 or acetone-d
6 , and reported in ppm relative to the chemical shift of tetramethylsilane or the residual
CHCl3 (1 H: δ = 7.26, 13 C: δ = 77.2), residual (CD3 )2 CO (1 H: δ = 2.09, 13 C: δ = 205.9), or residual (CD3 )2 SO (1 H: δ = 2.54, 13 C: δ = 40.5) as reference. All 13 C NMR spectra were obtained with complete proton decoupling. IR spectra were obtained
on a Bruker Vertex Series FTIR (neat). High resolution mass spectra were recorded
on an LC-MSD instrument from Agilent technologies 1200 series in positive electrospray
ionization (ESI) and atmospheric-pressure chemical ionization (APCI) modes and analytical
Supercritical Fluid Chromatography (SFC) were performed by the Centre régional de
spectroscopie de masse de l’Université de Montréal. SFC data are reported as follows:
(column type, eluent, flow rate, pressure: retention time (t
R )). All organic extracts were dried over sodium sulfate and concentrated under vacuum.
Et2 Zn was purchased neat from AkzoNobel and used without further purification. Diethanolamine
and N -methyldiethanolamine were purchased from Aldrich and were used without further purification.
Fmoc-Val-OH was purchased from AAPPTec and used without further purification. Unless
specified otherwise, all reagents for Suzuki cross-coupling reactions were used without
further purification and catalysts were handled in the glovebox. All reagents used
were purified using standardized protocols.
(E )-6-Cyclohexyl-2-(3-hydroxyprop-1-en-1-yl)-1,3,6,2-dioxazaborocane-4,8-dione (15a)
(E )-6-Cyclohexyl-2-(3-hydroxyprop-1-en-1-yl)-1,3,6,2-dioxazaborocane-4,8-dione (15a)
To a dry microwave vial, (E )-2-{3-[(tert -butyldimethylsilyl)oxy]prop-1-en-1-yl}-6-cyclohexyl-1,3,6,2-dioxazaborocane-4,8-dione
(15aa ; 440 mg, 1.10 mmol) was added, followed by DMSO (14 mL) and H2 O (2.8 mL). The vial was sealed and placed under microwave irradiation for 1 h at
130 °C. The reaction mixture was cooled, transferred into a 40 mL flask, diluted with
H2 O (10 mL) and lyophilized until dryness; this gave 15a .
Yield: 313 mg (99%); white solid; Rf
= 0.3 (CH2 Cl2 /MeCN, 1:1); mp 117–118 °C.
IR (neat): 2939, 2860, 1740, 1644, 1448, 1326, 1290, 1244 cm–1 .
1 H NMR (400 MHz, acetone-d
6 ): δ = 6.27 (dd, J = 13.5, 4.1 Hz, 1 H), 5.82 (d, J = 17.8 Hz, 1 H), 4.20–4.13 (m, 2 H), 3.94 (d, J = 16.8 Hz, 2 H), 3.74 (s, 1 H), 3.26 (td, J = 12.1, 6.1 Hz, 1 H), 2.81 (s, 2 H), 1.89 (d, J = 12.5 Hz, 2 H), 1.71–1.49 (m, 4 H), 1.44–1.25 (m, 4 H).
13 C NMR (126 MHz, CDCl3 ): δ = 169.5 (2 C), 146.3 (2 C), 123.9, 67.0, 64.5, 56.5 (2 C), 27.4 (2 C), 25.51,
25.46.
11 B NMR (400 MHz, acetone-d
6 ): δ = 10.7.
HRMS (ESI): m /z [M + H]+ calcd for C13 H20 BNO5 : 282.1507; found: 282.1509.
(E )-3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-ol (15b)
(E )-3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-ol (15b)
To a stirred solution of (E )-tert -butyldimethyl{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl]oxy}silane[28 ] (12.0 g, 40.2 mmol) in EtOH (201 mL) was added dropwise a 3 M solution of trichloroacetic
acid in EtOH (46.9 mL). The reaction mixture was stirred for 12 h. The reaction mixture
was concentrated, and the residue was diluted with EtOAc (20 mL) and washed with sat.
aq NaHCO3 (2 × 15 mL). The organic layer was dried with Na2 SO4 and concentrated under reduced pressure to provide a crude brown oil, which was purified
by flash chromatography (silica gel, EtOAc/hexanes, 3:7).
Yield: 4.20 g (57%); yellow oil; Rf
= 0.4 (EtOAc/hexane, 3:7).
IR (neat): 3420, 2977, 2929, 1643, 1358, 1317, 1411, 1004, 970 cm–1 .
1 H NMR (400 MHz, CDCl3 ): δ = 6.74 (dt, J = 18.2, 4.2 Hz, 1 H), 5.70 (dt, J = 18.2, 1.9 Hz, 1 H), 4.24 (dd, J = 4.2, 1.9 Hz, 2 H), 1.79 (br, 1 H), 1.27 (s, 12 H).
13 C NMR (126 MHz, CDCl3 ): δ = 151.9, 117.3, 83.5, 64.8 (2 C), 25.0 (4 C).
HRMS (ESI): m /z [M + H]+ calcd for C9 H17 BO3 : 185.1343; found: 185.1344.
6-Cyclohexyl-2-[(1R ,2R )-2-(hydroxymethyl)cyclopropyl]-1,3,6,2-dioxazaborocane-4,8-dione (13)
6-Cyclohexyl-2-[(1R ,2R )-2-(hydroxymethyl)cyclopropyl]-1,3,6,2-dioxazaborocane-4,8-dione (13)
A 10 mL flame-dried flask was charged with 15a (48.3 mg, 0.17 mmol), 11 (51.1 mg, 0.19 mmol), and CH2 Cl2 (2 mL). The mixture was sonicated for 1 min to provide a homogeneous solution. In
another flame-dried flask, neat Et2 Zn (40.3 μL, 0.4 mmol) was added to CH2 Cl2 (2 mL) at 0 °C; dropwise addition of diiodomethane (63.6 μL, 0.8 mmol) followed.
The mixture was stirred at 0 °C for 10 min. The mixture of dioxaborolane 11 and 15a was cannulated slowly into the reaction flask. After complete addition, the reaction
mixture was allowed to stir for 8 h. The mixture remained homogeneous throughout.
Upon completion of the reaction, the mixture was quenched with NH4 Cl (2 mL), and diluted with EtOAc (5 mL) and brine (5 mL). The organic layer was separated
and the aqueous layer was washed with EtOAc (2 × 5 mL). The organic layers were combined,
dried with Na2 SO4 , and concentrated under reduced pressure. To the resulting residue was added a solution
of diethanolamine (93.5 mg, 0.9 mmol) in CH2 Cl2 (750 μL) and the mixture was allowed to stir for 3 h. After this, the mixture was
saturated with silica gel, dried, and directly loaded for flash chromatography (silica
gel, EtOAc/hexanes (1:1) then MeCN); this gave product 13 .
Yield: 48.3 mg (92%); 95.6:4.4 er; SFC (Chiralpak OD-H 25cm, 30 °C, 150 bar, 10% MeOH,
3 mL/min): t
R(major) : 9.76 min; t
R(minor) : 8.63 min; white solid; mp 132–133 °C; Rf
= 0.3 (MeCN); [α]D
25 +10.8 (c 0.83, MeOH).
IR (neat): 2936, 2861, 1741, 1449, 1292, 1247, 1000, 898 cm–1 .
1 H NMR (500 MHz, acetone-d
6 ): δ = 4.13 (dd, J = 25.9, 16.9 Hz, 2 H), 3.92–3.83 (m, 3 H), 3.67 (dd, J = 11.1, 5.9 Hz, 1 H), 3.22 (dd, J = 10.6, 7.6 Hz, 1 H), 2.83 (s, 1 H) 2.12 (ddd, J = 19.0, 11.3, 8.0 Hz, 2 H), 1.86 (dd, J = 13.8, 7.5 Hz, 2 H), 1.65 (d, J = 13.0 Hz, 1 H), 1.58 (dd, J = 12.2, 3.6 Hz, 1 H), 1.56–1.40 (m, 3 H), 1.28 (tt, J = 12.8, 3.7 Hz, 1 H), 0.88 (dd, J = 12.4, 7.5 Hz, 1 H), 0.42–0.36 (m, 2 H), –0.26 to –0.30 (m, 1 H).
13 C NMR (176 MHz, acetone-d
6 ): δ = 168.8, 168.0, 72.3, 66.4, 65.4, 57.0, 55.1, 27.1, 26.6, 24.7, 24.5, 17.3, 5.9,
1.9.
HRMS (ESI): m /z [M + H]+ calcd for C14 H22 BNO5 : 296.1664; found: 296.1672.
Larger-Scale Preparation of 13 (5.6 mmol)
Larger-Scale Preparation of 13 (5.6 mmol)
In a 250 mL flame-dried flask, 15a (1.56 g, 5.6 mmol) and 11 (51.7 g, 6.10 mmol) were dissolved in CH2 Cl2 (25 mL). Sonication for 1 min allowed 15a to dissolve in the CH2 Cl2 . In another flame-dried flask, Et2 Zn (1.26 mL, 12.2 mmol) was added to CH2 Cl2 (50 mL) and DME (1 mL) at 0 °C; dropwise addition of diiodomethane (1.9 mL, 24.2
mmol) followed. The mixture was stirred at 0 °C for 10 min. The mixture of dioxaborolane
11 and 15a was cannulated slowly into the cooled reaction flask. After complete addition, the
reaction mixture was allowed to stir for 12 h. The reaction remained homogeneous throughout.
Upon completion, the mixture was quenched with NH4 Cl (5 mL), and diluted with EtOAc (20 mL) and brine (10 mL). The organic layer was
separated, and the aqueous layer was washed with EtOAc (2 × 20 mL). The organic layers
were combined, dried with Na2 SO4 , and concentrated under reduced pressure. To the resulting residue was added a solution
of diethanolamine (2.92 g, 27.8 mmol) in CH2 Cl2 (21 mL), and the mixture was allowed to stir for 3 h. The crude reaction mixture
was loaded directly for flash chromatography (silica gel, EtOAc/ hexanes (1:1) then
MeCN). This gave product 13 as a white solid spectroscopically identical to 13 obtained at a 0.2 mmol scale.
Yield: 1.52 g (93%); 92.9:7.3 er; SFC (Chiralpak OD-H 25cm, 30 °C, 150 bar, 10% MeOH,
3 mL/min): t
R(major) : 10.11 min, t
R(minor) : 8.41 min; [α]D
25 +9.3 (c 1.0, MeOH).
[(1R ,2R )-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]methanol (14)
[(1R ,2R )-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]methanol (14)
Neat Et2 Zn (169 μL, 1.64 mmol) was added to stirred CH2 Cl2 (3 mL) in a flame-dried flask at rt. The solution was cooled to 0 °C and diiodomethane
(264 μL, 3.28 mmol) was added dropwise over 5 min while maintaining the temperature
at –5 to 0 °C. Once the addition was complete, the mixture was allowed to stir for
10 min, after which a solution of premixed 15b (137 mg, 0.74 mmol) and 11 (221 mg, 0.82 mmol) in CH2 Cl2 (2 mL) was added dropwise over 1 min. The resulting mixture was stirred for 6 h at
rt. The reaction mixture was diluted with NH4 Cl (1 mL) and EtOAc (3 mL). The organic layer was separated and washed with brine
(2 mL). The aqueous layer was extracted with EtOAc (2 × 3 mL) and the organic layers
were combined, dried with Na2 SO4 , and concentrated under reduced pressure. To the residue was added diethanolamine
(2.85 g, 27.1 mmol) in CH2 Cl2 (21 mL) and the mixture was allowed to stir for 3 h. The the crude reaction mixture
was loaded directly onto a column for chromatography (silica gel, EtOAc/hexanes, 1:3).
After purification the pure product was obtained as a yellow oil.
Yield: 31 mg (21%); 90.9:9.1 er; TOF (6224) (Chiralpak OJ-RH, 13% MeCN, 0.4 mL/min):
t
R(major) : 20.19 min, t
R(minor) : 17.74 min; Rf
= 0.3 (EtOAc/hexane, 1:3); [α]D
25 +7.4 (c 0.83, MeOH).
IR (neat): 2977, 2932, 1644, 1425, 1371, 1314, 1141, 1042, 854 cm–1 .
1 H NMR (400 MHz, CDCl3 ): δ = 3.45 (d, J = 6.8 Hz, 2 H), 1.65 (s, 1 H), 1.30–1.34 (m, 1 H), 1.21 (s, 12 H), 0.76–0.73 (ddd,
J = 7.7, 6.3, 3.7 Hz, 1 H), 0.56–0.54 (m, 1 H), –0.23 (dt, J = 9.8, 5.8 Hz, 1 H).
13 C NMR (101 MHz, CDCl3 ): δ = 83.2, 68.0, 24.8 (2 C), 20.5 (4 C), 9.3, –1.6.
11 B NMR (400 MHz, CDCl3 ): δ = 33.1.
HRMS (ESI): m /z [M + H – H2 O]+ calcd for C10 H19 BO3 : 180.1431; found: 180.1423.
Larger-Scale Preparation of 14 (5.4 mmol)
Larger-Scale Preparation of 14 (5.4 mmol)
Neat Et2 Zn (1.23 mL, 12.0 mmol) was added to a flame-dried flask containing a stir bar, CH2 Cl2 (25.0 mL), and DME (1.13 mL). The solution was cooled to 0 °C, after which diiodomethane
(1.93 mL, 23.9 mmol) was added dropwise over 5 min, while maintaining the temperature
at –5 to 0 °C. Once the addition was complete, the mixture was allowed to stir for
10 min, after which a solution of premixed 15b (1.00 g, 5.43 mmol) and 11 (1.61 g, 5.98 mmol) in CH2 Cl2 (25 mL) was added dropwise over 1 min. The resulting mixture was stirred for 15 h
at rt. The reaction mixture was diluted with NH4 Cl (10 mL) and EtOAc (20 mL). The organic layer was separated and washed with brine
(10 mL). The aqueous layer was extracted with EtOAc (2 × 10 mL). The organic layers
were combined, dried with Na2 SO4 and concentrated under reduced pressure. To the residue was added warm diethanolamine
(2.85 g, 27.1 mmol) in CH2 Cl2 (21 mL) and the mixture was allowed to stir for 3 h. Once the reaction was complete,
the crude reaction mixture was loaded directly for chromatography (silica gel, EtOAc/hexanes,
1:3). After purification the pure product was obtained as a yellow oil spectroscopically
identical to 14 at the 1.64 mmol scale.
Yield: 452 mg (42%); 89.6:10.3 er; TOF (6224) (Chiralpak OJ-RH, 9% MeCN, 0.4 mL/min):
t
R(major) : 25.24 min; t
R(minor) : 21.86; [α]D
25 +7.6 (c 1.0, MeOH).
Products 19a–e by Rapid Assessment of Functional Groups: Intermolecular Screening
Protocol for Non-oxidative Workup; General Procedure D
Products 19a–e by Rapid Assessment of Functional Groups: Intermolecular Screening
Protocol for Non-oxidative Workup; General Procedure D
To a solution of Et2 Zn (113 μL, 1.10 mmol) in CH2 Cl2 (2.5 mL) at 0 °C was added diiodomethane (177 μL, 2.20 mmol). The mixture was stirred
at 0 °C for 10 min to give a white precipitate, to which was added a solution of alcohol
17 (67.1 mg, 0.50 mmol), additive 19 (0.50 mmol), and dioxaborolane 11 (149 mg, 1.1 mmol) in CH2 Cl2 (2.5 mL) via a cannula. The resulting mixture was stirred for 2 h at rt and was quenched
by the addition of sat. aq NH4 Cl (5 mL). The mixture was transferred into a separatory funnel and the reaction flask
was rinsed with Et2 O (5 mL). The two layers were separated, and the aqueous layer was extracted with
Et2 O (3 × 5 mL). The combined organic layers were dried and concentrated to afford a
colorless residue. Warm diethanolamine (263 mg, 2.50 mmol), weighed into a vial and
dissolved in CH2 Cl2 (2.5 mL), was transferred to the flask containing the reaction mixture. Additional
CH2 Cl2 (2.5 mL) was used to rinse the diethanolamine and transferred to the flask containing
the reaction mixture. The mixture was stirred at rt for 3 h. Silica gel was added
to the reaction mixture, which was concentrated, resulting in dry silica gel saturated
with the crude reaction mixture. Purification by column chromatography afforded cyclopropane
18 as a colorless oil, which was identical in all aspects to the reported compound,[29 ] and additives 19a –e .
Products 18 and 19a–e by Rapid Assessment of Functional Groups: Intermolecular Screening
Protocol for Oxidative Workup; General Procedure E
Products 18 and 19a–e by Rapid Assessment of Functional Groups: Intermolecular Screening
Protocol for Oxidative Workup; General Procedure E
To a solution of Et2 Zn (113 μL, 1.10 mmol) in CH2 Cl2 (2.5 mL) at 0 °C was added diiodomethane (177 μL, 2.20 mmol). The mixture was stirred
at 0 °C for 10 min to give a white precipitate, to which was added a solution of alcohol
17 (67.1 mg, 0.50 mmol), additive (0.50 mmol), and dioxaborolane 11 (149 mg, 1.1 mmol) in CH2 Cl2 (2.5 mL) via a cannula. The resulting mixture was stirred for 2 h at rt and was quenched
by the addition of sat. aq NH4 Cl (5 mL). The mixture was transferred into a separatory funnel and the reaction flask
was rinsed with Et2 O (5 mL). The two layers were separated, and the aqueous layer was extracted with
Et2 O (3 × 5 mL). The combined organic layers were transferred into an Erlenmeyer flask,
and a solution containing 2 N aq NaOH (8.7 mL) and 30% aq H2 O2 (1.5 mL) was added in one portion. The resulting biphasic solution was vigorously
stirred for 10 min, after which the two layers were separated. The aqueous layer was
extracted with Et2 O (3 × 5 mL) and the combined organic layers were washed with 10% aq HCl (10 mL).
The aqueous layer was extracted with Et2 O (3 × 5 mL) and the combined organic layers were successively washed with sat. aq
Na2 SO3 (10 mL), sat. aq NaHCO3 (10 mL), and brine (10 mL), dried over Na2 SO4 , filtered, and concentrated under reduced pressure. Purification by column chromatography
afforded cyclopropane 18 and additive 19a –e .
Benzyl 3,3-Dimethylbutanoate (19a)
Benzyl 3,3-Dimethylbutanoate (19a)
General Procedure D : Purification by column chromatography (silica gel, EtOAc/hexanes, 1:9) resulted
in the recovered additive 19a (95.9 mg, 93%) and the desired cyclopropane 18 (70.4 mg, 95%).
General Procedure E : Recovered additive 19a (85.6 mg, 83%) and the desired cyclopropane 18 (67.4 mg, 91%).
Benzyl Phenethylcarbamate (19b)
Benzyl Phenethylcarbamate (19b)
General Procedure D : Purification by column chromatography (silica gel, EtOAc/hexanes, 1:9) resulted
in the recovered additive 19b (125 mg, 97%) and the desired cyclopropane 18 (69.7 mg, 94%).
General Procedure E : Recovered additive 19b (97.0 mg, 76%) and the desired cyclopropane 18 (70.4 mg, 95%).
4-Bromobenzyl Acetate (19c)
4-Bromobenzyl Acetate (19c)
General Procedure D : Purification by column chromatography (silica gel, EtOAc/hexanes, 1:3) resulted
in the recovered additive 19c (83.7 mg, 98%) and the desired cyclopropane 18 (51.9 mg, 94%).
General Procedure E : No recovery of 19c and the desired cyclopropane 18 (51.9 mg, 94%).
{[(9H -Fluoren-9-yl)methoxy]carbonyl}-l -valine (19d)
{[(9H -Fluoren-9-yl)methoxy]carbonyl}-l -valine (19d)
General Procedure D : Purification by column chromatography (silica gel, MeOH/CH2 Cl2 , 1:9) resulted in the recovered additive 19d (59.4 mg, 35%) and the desired cyclopropane 18 (68.9 mg, 93%).
General Procedure E : Recovered additive 19d (25.5 mg, 15%) and the desired cyclopropane 18 (69.7 mg, 94%).
1H -Indole (19e)
General Procedure D : Purification by column chromatography (silica gel, MeOH/CH2 Cl2 , 1:9) resulted in the recovered additive 19e (58.0 mg, 99%) and the desired cyclopropane 18 (68.9 mg, 93%).
General Procedure E : Recovered additive 19e (39.8 mg, 68%) and the desired cyclopropane 18 (69.7 mg, 94%).
N -Methyldiethanolamine Workup for Fmoc-Containing Additive 19d
N -Methyldiethanolamine Workup for Fmoc-Containing Additive 19d
To a solution of Et2 Zn (113 μL, 1.1 mmol) in CH2 Cl2 (2.5 mL) at 0 °C was added diiodomethane (179 μL, 2.2 mmol). The mixture was stirred
at 0 °C for 10 min to give a white precipitate, to which was added a solution of alcohol
17 (67 mg, 0.5 mmol), 19d (0.5 mmol), and dioxaborolane 11 (162 mg, 0.6 mmol) in CH2 Cl2 (2.5 mL) via a cannula. The resulting mixture was stirred for 2 h at rt and was quenched
by the addition of sat. aq NH4 Cl (5 mL). The mixture was transferred into a separatory funnel and the reaction flask
was rinsed with Et2 O (5 mL). The two layers were separated and the aqueous layer was extracted with Et2 O (3 × 5 mL). The combined organic layers were dried and concentrated to afford a
colorless residue. N -Methyldiethanolamine (298 mg, 2.5 mmol) was weighed into a vial, dissolved in CH2 Cl2 (2.5 mL), and transferred to the flask containing the reaction mixture. Additional
CH2 Cl2 (2.5 mL) was used to rinse the diethanolamine and transferred to the flask containing
the reaction mixture. The mixture was stirred at rt for 3 h and was then adsorbed
onto silica gel. Purification by column chromatography (silica gel, MeOH/CH2 Cl2 , 1:9) resulted in the recovered additive 19d (148 mg, 87%) and the desired cyclopropane 18 (68.9 mg, 93%).
4-[(1R ,2S )-2-(Hydroxymethyl)cyclopropyl]benzyl Acetate (21)
4-[(1R ,2S )-2-(Hydroxymethyl)cyclopropyl]benzyl Acetate (21)
To a solution of Et2 Zn (233 μL, 2.26 mmol) in CH2 Cl2 (3.7 mL) at 0 °C was added diiodomethane (365 μL, 4.52 mmol). The mixture was stirred
at 0 °C for 10 min to give a white precipitate, to which was added a solution of allylic
alcohol 20 (212 mg, 1.03 mmol) and dioxaborolane 11 (306 mg, 1.13 mmol) in CH2 Cl2 (5.5 mL) via a cannula. The resulting mixture was stirred for 15 h at rt and was
quenched by the addition of sat. aq NH4 Cl (15 mL). The mixture was transferred into a separatory funnel and the reaction
flask was rinsed with Et2 O (15 mL). The two layers were separated, and the aqueous layer was extracted with
Et2 O (3 × 4 mL). The combined organic layers were dried and concentrated to afford a
colorless residue. Warm diethanolamine (541 mg, 5.15 mmol), weighed into a vial and
dissolved in CH2 Cl2 (4 mL), was transferred to the flask containing the reaction mixture. Additional
CH2 Cl2 (4 mL) was used to rinse the diethanolamine and transferred to the flask containing
the reaction mixture. The mixture was stirred at rt for 3 h. The mixture was stirred
at rt for 3 h. Silica gel was added to the reaction mixture, which was concentrated,
resulting in dry silica gel saturated with the crude reaction mixture. Purification
of the saturated silica by column chromatography (silica gel, EtOAc/hexanes, 1:4)
afforded 21 .
Yield: 172 mg (76%); 93.4:6.6 er; SFC (Chiralpak AD-H 25cm, 30 °C, 150 bar, 10% MeOH,
3 mL/min): t
R(major) : 5.65 min; t
R(minor) : 9.73 min; colorless oil; [α]D
25 –20.0 (c 0.20, MeOH).
IR (neat): 3389, 2931, 2871, 1734, 1376, 1226, 1026, 1016 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 7.28–7.24 (m, 4 H), 5.07 (s, 2 H), 3.47 (dd, J = 15.7, 6.3 Hz, 1 H), 3.26 (dd, J = 11.6, 8.5 Hz 1 H), 2.28 (td, J = 8.5, 6.2 Hz 1 H), 2.09 (s, 3 H), 1.54–1.47 (m, 1 H), 1.06 (td, J = 8.4, 5.4 Hz, 1 H), 0.89–0.85 (m, 1 H).
13 C NMR (126 MHz, CDCl3 ): δ = 171.1, 138.7, 134.0, 129.3 (2 C), 128.6 (2 C), 66.3, 63.9, 21.23, 21.22, 20.7,
8.0.
HRMS (ESI): m /z [M + Na]+ calcd for C13 H16 O3 : 243.0991; found: 243.0987.
(2-Heterylcyclopropyl)methanol Compounds 23a–e by Suzuki Cross-Coupling of 13; General
Procedure A
(2-Heterylcyclopropyl)methanol Compounds 23a–e by Suzuki Cross-Coupling of 13; General
Procedure A
To a dried round-bottom flask equipped with a stir bar was added HetArBr 22a –e (0.28 mmol), 13 (0.14 mmol), Pd2 (dba)3 (6.4 mg, 5 mol%), and Cy3 P (3.9 mg, 10 mol%). The vial was sealed with a septum and flushed with argon. To
the vial was added dioxane (500 μL), and the resulting mixture was stirred at 23 °C
for 20 min. To the mixture was then added 3.0 M aq K3 PO4 (280 μL), and the mixture was degassed by sparging with argon for 20 min. The vial
was placed in an oil bath and heated at 110 °C while stirring for 20 h. After completion,
the reaction mixture was cooled and diluted with EtOAc (4 mL) and brine (2 mL) and
the organic layer was separated. The aqueous layer was washed with EtOAc (2 × 2 mL),
dried, and concentrated. Purification by column chromatography provided the coupled
products 23a –e .
(2-Heterylcyclopropyl)methanol Compounds 23a–e by Suzuki Cross-Coupling of 14; General
Procedure B
(2-Heterylcyclopropyl)methanol Compounds 23a–e by Suzuki Cross-Coupling of 14; General
Procedure B
To a dried flask equipped with a stir bar was added HetArBr 22a –e (0.28 mmol), 14 (0.14 mmol), Pd2 (dba)3 (6.4 mg, 5 mol %), and Cy3 P (3.93 mg, 10 mol%). The vial was sealed with a septum and flushed with argon. To
the vial was added dioxane (500 μL) and the resulting mixture was stirred at 23 °C
for 20 min. To the mixture was then added 3.0 M aq K3 PO4 (280 μL, degassed with argon for 20 min). The vial was placed in an oil bath and
heated at 110 °C while stirring for 20 h. After completion, the reaction mixture was
cooled and diluted with EtOAc (4 mL) and brine (2 mL) and the organic layer was separated.
The aqueous layer was washed with EtOAc (2 × 2 mL), dried, and concentrated. Purification
by column chromatography provided the coupled products 23a –e .
[(1S ,2S )-2-(Pyridin-3-yl)cyclopropyl]methanol (23a)
[(1S ,2S )-2-(Pyridin-3-yl)cyclopropyl]methanol (23a)
General Procedure A : 3-Bromopyridine (47.1 mg, 0.29 mmol) and 13 (41.3 mg, 0.14 mmol) were used.
Yield: 19.8 mg (95%); pale yellow oil; Rf
= 0.3 (MeOH/CH2 Cl2 , 1:9); [α]D
25 +25.6 (c 0.83, MeOH).
General Procedure B : 3-Bromopyridine (47.1 mg, 0.29 mmol) and 14 (27.7 mg, 0.14 mmol) were used.
Yield: 18.6 mg (89%); pale yellow oil.
IR (neat): 3352, 3269, 3002, 2926, 2853, 11642, 1472, 1426, 1109 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 8.39 (s, J = 5.7 Hz, 2 H), 7.30 (d, J = 7.8 Hz, 1 H), 7.17 (dd, J = 7.8, 4.8 Hz, 1 H), 3.66 (ddd, J = 35.5, 11.3, 6.5 Hz, 2 H), 2.03 (br, 1 H), 1.83–1.79 (m, 1 H), 1.48 (dd, J = 13.4, 6.1 Hz, 1 H), 1.03–0.97 (m, 2 H).
13 C NMR (126 MHz, CDCl3 ): δ = 148.5, 147.2, 138.2, 132.9, 123.4, 66.2, 25.4, 19.0, 13.8.
HRMS (ESI): m /z [M + H]+ calcd for C9 H11 NO: 150.0913; found: 150.0910.
[(1S ,2S )-2-(Quinolin-3-yl)cyclopropyl]methanol (23b)
[(1S ,2S )-2-(Quinolin-3-yl)cyclopropyl]methanol (23b)
General Procedure A : 5-Bromoquinoline, 98% (58.3 mg, 0.28 mmol) and 13 (41.3 mg, 0.14 mmol) were used.
Yield: 26.2 mg (94%); pale yellow oil.
General Procedure B : 5-Bromoquinoline, 98% (58.3 mg, 0.28 mmol) and 14 (27.7 mg, 0.14 mmol) were used.
Yield: 24.5 mg (88%); pale yellow oil; Rf
= 0.3 (MeOH/CH2 Cl2 , 1:9); [α]D
25 +36.3 (c 0.87, MeOH).
IR (neat): 3352, 3303, 3001, 2922, 2854, 1706, 1495, 1332, 1028 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 8.72 (d, J = 2.2 Hz, 1 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.70 (s, 2 H), 7.64–7.62 (m, 1 H), 7.52–7.50 (m, 1 H), 3.77 (dd,
J = 11.3, 6.3 Hz, 1 H), 3.68 (dd, J = 11.3, 6.9 Hz, 1 H), 2.02–1.99 (m, 1 H), 1.62–1.58 (m, 1 H), 1.13–1.08 (m, 2 H).
13 C NMR (126 MHz, CDCl3 ): δ = 150.6, 146.9, 135.5, 131.3, 129.3, 128.7, 128.2, 127.4, 126.9, 66.3, 25.6,
19.3, 13.9.
HRMS (ESI): m /z [M + H]+ calcd for C13 H13 NO: 200.1069; found: 200.1067.
[(1S ,2S )-2-(4-Methylpyridin-2-yl)cyclopropyl]methanol (23c)
[(1S ,2S )-2-(4-Methylpyridin-2-yl)cyclopropyl]methanol (23c)
General Procedure A : 2-Bromo-4-methylpyridine, 98% (48.2 mg, 0.28 mmol) and 13 (41.3 mg, 0.14 mmol) were used.
Yield: 21.3 mg (93%); clear oil.
General Procedure B : 2-Bromo-4-methylpyridine, 98% (48.2 mg, 0.28 mmol) and 14 (27.7 mg, 0.14 mmol) were used.
Yield: 16.5 mg (72%); clear oil; Rf
= 0.4 (MeOH/CH2 Cl2 , 1:9); [α]D
25 +44.0 (c 0.56, MeOH).
IR (neat): 3350, 2923, 2850, 1608, 1447, 1376, 1024, 848 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 8.28 (d, J = 5.1 Hz, 1 H), 6.95 (d, J = 11.8 Hz, 1 H), 6.86 (d, 1 H), 3.70 (dd, J = 11.3, 6.4 Hz, 1 H), 3.58 (dd, J = 11.3, 7.1 Hz, 1 H), 2.30 (s, 3 H), 1.95–1.91 (m, 1 H), 1.74 (tdd, J = 10.6, 5.3, 3.2 Hz, 1 H), 1.64 (s, 1 H), 1.27–1.24 (m, 1 H), 0.94 (ddd, J = 8.6, 5.7, 4.4 Hz, 1 H).
13 C NMR (126 MHz, CDCl3 ): δ = 161.3, 149.1, 147.2, 122.4, 121.9, 66.4, 25.7, 23.0, 21.1, 14.0.
HRMS (ESI): m /z [M + H]+ calcd for C13 H13 NO: 164.1069; found: 164.1069.
[(1S ,2S )-2-(6-Aminopyridin-2-yl)cyclopropyl]methanol (23d)
[(1S ,2S )-2-(6-Aminopyridin-2-yl)cyclopropyl]methanol (23d)
General Procedure A : 2-Amino-6-bromopyridine, 98% (48.4 mg, 0.28 mmol) and 13 (41.3 mg, 0.14 mmol) were used.
Yield: 21.1 mg (92%); yellow oil.
General Procedure B : 2-Amino-6-bromopyridine, 98% (27.7 mg, 0.14 mmol) and 14 (41.3 mg, 0.14 mmol) were used.
Yield: 18.6 mg (81%); yellow oil; Rf
= 0.3 (MeOH/CH2 Cl2 , 1:9); [α]D
25 +37.5 (c 0.85, MeOH).
IR (neat): 3337, 3206, 2927, 2851, 1574, 1464, 1025, 791 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 7.29 (t, J = 7.8 Hz, 1 H), 6.43 (d, J = 7.4 Hz, 1 H), 6.27 (d, J = 8.1 Hz, 1 H), 3.67 (dd, J = 11.3, 6.3 Hz, 1 H), 3.52 (dd, J = 11.2, 7.3 Hz, 1 H), 1.85–1.82 (m, 1 H), 1.64 (d, J = 6.0 Hz, 1 H), 1.18–1.15 (m, 1 H), 0.88–0.85 (m, 1 H).
13 C NMR (126 MHz, CDCl3 ): δ = 148.5, 147.2, 138.2, 132.9, 123.4, 66.2, 25.4, 19.0, 13.8.
HRMS (ESI): m /z [M + H]+ calcd for C9 H11 NO: 165.1027; found: 165.1022.
[(1S ,2S )-2-(Pyrimidin-5-yl)cyclopropyl]methanol (23e)
[(1S ,2S )-2-(Pyrimidin-5-yl)cyclopropyl]methanol (23e)
General Procedure A : 5-Bromopyrimidine, 97% (44.5 mg, 0.28 mmol) and 13 (41.3 mg, 0.14 mmol) were used.
Yield: 19.8 mg (94%); yellow oil.
General Procedure B : 5-Bromopyrimidine, 97% (44.5 mg, 0.28 mmol) and 14 (27.7 mg, 0.14 mmol) were used.
Yield: 18.7 mg (89%); pale yellow oil; Rf
= 0.3 (MeOH/CH2 Cl2 , 1:9); [α]D
25 +38.9 (c 0.87, MeOH).
IR (neat): 3335, 3003, 2925, 2853, 1721, 1559, 1416, 1076, 1025 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 9.01 (s, 1 H), 8.46 (s, 2 H), 3.74 (dd, J = 11.3, 6.1 Hz, 1 H), 3.63 (dd, J = 11.3, 6.7 Hz, 1 H), 2.01 (s, 1 H), 1.83– 1.79 (m, 1 H), 1.54–1.50 (m, 1 H), 1.05
(ddt, J = 24.4, 8.7, 5.4 Hz, 2 H).
13 C NMR (126 MHz, CDCl3 ): δ = 156.4 (2 C), 154.8, 136.0, 65.6, 25.2, 16.6, 13.5.
HRMS (ESI): m /z [M + H]+ calcd for C8 H10 N2 O: 151.0865; found: 151.0859.
cis -Cyclopropylmethanol Derivatives 25a–f; General Procedure C
cis -Cyclopropylmethanol Derivatives 25a–f; General Procedure C
A solution of 24 (66.5 μL, 1.1 mmol) in CH2 Cl2 (4.6 mL) was added to Et2 Zn (115 μL, 1.1 mmol) in a 50 mL round-bottom flask at 0 °C. Gas evolution was observed.
After 5 min, a solution of dioxaborolane 11 (371 mg, 1.37 mmol) in CH2 Cl2 (7 mL) was added. The reaction mixture was stirred for 10 min at 0 °C.
In a 50 mL round-bottom flask at –40 °C, neat Et2 Zn (507 μL, 4.92 mmol) was added dropwise to a mixture of I2 (1.22 g, 4.81 mmol), Et2 O (0.98 mL, 9.33 mmol), and CH2 Cl2 (4.7 mL). Once the I2 was completely consumed, the reaction mixture was cooled to –78 °C and a solution
of CHI3 (951 mg, 2.42 mmol) in CH2 Cl2 (14 mL) was slowly added to the IZnEt solution. The mixture was stirred at –78 °C
for 10 min.
The alkoxide solution was quickly cannulated over the carbenoid solution and the reaction
mixture was allowed to reach –40 °C (cryostat bath). The reaction mixture was stirred
24 h at this temperature. The reaction mixture was quenched with sat. aq NH4 Cl. The aqueous layer was extracted with Et2 O (3 × 10 mL). The organic layers were gathered and dried over MgSO4 and the solvents were removed until 500 μL under reduced pressure. The intermediate
is unstable and highly volatile and care must be taken to avoid loss of the volatile
boronate.
The residue was taken up in degassed THF (4.4 mL) and added to a sealed tube containing
Pd(PPh3 )4 (68.7 mg, 5 mol%) in THF (2.2 mL). Then 3 N aq degassed KOH (2.2 mL) was added followed
by the desired coupling partner 22a –e (2.2 mmol). The reaction mixture was heated at 65 °C overnight (16 h). After the
mixture had cooled down, H2 O was added to it. The aqueous layer was extracted with Et2 O (3 × 7 mL). The combined organic layers were dried over MgSO4 . The solvents were removed under reduced pressure. The residue was stirred in diethanolamine
(602 mg, 5.72 mmol) in CH2 Cl2 (3 mL) for 1 h to remove any dioxaborolane bound to the cyclopropane. The residue
was taken up in CH2 Cl2 and purified by flash chromatography (silica gel, MeOH/CH2 Cl2 , 5:95, unless stated otherwise) to provide the desired coupled products 25a –f .
[(1R ,2S )-2-(Pyridin-3-yl)cyclopropyl]methanol (25a)
[(1R ,2S )-2-(Pyridin-3-yl)cyclopropyl]methanol (25a)
The product was prepared according to general procedure C using 3-bromopyridine (217
μL, 2.28 mmol).
Yield: 92 mg (72%); light yellow oil; Rf
= 0.23 (MeOH/CH2 Cl2 , 1:9); [α]D
25 –45.2 (c 1.0, MeOH).
IR (neat): 3264, 3005, 2866, 1573, 1573, 1480, 1418, 1167, 1025 cm–1 .
1 H NMR (400 MHz, CDCl3 ): δ = 8.53 (s, 1 H), 8.42 (d, J = 4.5 Hz, 1 H), 7.56 (d, J = 7.9 Hz, 1 H), 7.21 (dd, J = 7.8, 4.8 Hz, 1 H), 3.47 (dd, J = 11.5, 6.4 Hz, 1 H), 3.25 (dd, J = 11.5, 8.3 Hz, 1 H), 2.25 (dd, J = 14.7, 8.4 Hz, 1 H), 1.93 (s, 1 H), 1.56 (qt, J = 8.5, 6.1 Hz, 1 H), 1.13 (td, J = 8.4, 5.4 Hz, 1 H), 0.87 (q, J = 5.7 Hz, 1 H).
13 C NMR (126 MHz, CDCl3 ): δ = 151.0, 147.7, 137.0, 134.6, 123.5, 62.9, 21.17, 18.7, 8.0.
HRMS (ESI): m /z [M + H]+ calcd for C9 H11 NO: 150.0913; found: 150.0912.
[(1R ,2S )-2-(Quinolin-3-yl)cyclopropyl]methanol (25b)
[(1R ,2S )-2-(Quinolin-3-yl)cyclopropyl]methanol (25b)
The product was prepared according to general procedure C using 3-bromoquinoline (308
μL, 2.28 mmol).
Yield: 162 mg (71%); light yellow oil; Rf
= 0.26 (MeOH/CH2 Cl2 , 1:9); [α]D
25 +38.6 (c 1.0, MeOH).
IR (neat): 3262, 3064, 3005, 2872, 1571, 1493, 1464, 1417 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 8.86 (d, J = 2.1 Hz, 1 H), 8.01 (d, J = 8.6 Hz, 1 H), 7.88 (s, 1 H), 7.71 (d, J = 8.1 Hz, 1 H), 7.61 (ddd, J = 8.4, 5.1, 1.4 Hz, 1 H), 7.50–7.46 (m, 1 H), 3.49 (dd, J = 11.5, 6.3 Hz, 1 H), 3.26 (dd, J = 11.5, 8.4 Hz, 1 H), 2.39 (dd, J = 14.7, 8.3 Hz, 1 H), 1.89 (br, 1 H), 1.62 (qt, J = 8.5, 6.0 Hz, 1 H), 1.19 (td, J = 8.4, 5.5 Hz, 1 H), 0.97 (q, J = 5.7 Hz, 1 H).
13 C NMR (126 MHz, CDCl3 ): δ = 152.7, 146.7, 134.7, 131.6, 129.0, 128.9, 127.8, 127.4, 126.8, 62.3, 21.2,
18.6, 7.7.
HRMS (ESI): m /z [M + H]+ calcd for C13 H13 NO: 200.1069; found: 200.1066.
[(1R ,2S )-2-(4-Methylpyridin-2-yl)cyclopropyl]methanol (25c)
[(1R ,2S )-2-(4-Methylpyridin-2-yl)cyclopropyl]methanol (25c)
The product was prepared according to general procedure C using 2-bromo-4-methylpyridine
(252 μL, 2.28 mmol).
Yield: 136 mg (873%); light yellow oil; Rf
= 0.32 (MeOH/CH2 Cl2 , 1:9); [α]D
25 +31.1 (c 1.0, MeOH).
IR (neat): 3350, 3053, 3003, 2849, 1606, 1543, 1480, 1032 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 8.23 (d, J = 5.1 Hz, 1 H), 7.16 (d, J = 0.7 Hz, 1 H), 6.92 (d, J = 5.1 Hz, 1 H), 3.93 (dd, J = 12.1, 3.6 Hz, 1 H), 3.34 (dd, J = 12.1, 8.6 Hz, 1 H), 2.31 (s, 3 H), 2.15 (td, J = 8.6, 6.0 Hz, 1 H), 1.69–1.50 (m, 1 H), 1.13 (td, J = 8.7, 4.7 Hz, 1 H), 1.00 (dd, J = 10.8, 6.0 Hz, 1 H).
13 C NMR (126 MHz, CDCl3 ): δ = 160.3, 148.0, 147.9, 126.1, 122.2, 61.3, 22.5, 22.4, 21.0, 10.5.
HRMS (ESI): m /z [M + H]+ calcd for C10 H13 NO: 164.1069; found: 164.1071.
[(1R ,2S )-2-(6-Aminopyridin-2-yl)cyclopropyl]methanol (25d)
[(1R ,2S )-2-(6-Aminopyridin-2-yl)cyclopropyl]methanol (25d)
The product was prepared according to general procedure C using 2-amino-6-bromopyridine
(392 mg, 2.28 mmol).
Yield: 141 mg (75%); bright yellow oil; Rf
= 0.22 (MeOH/CH2 Cl2 , 1:9); [α]D
25 –57.7 (c 1.0, MeOH).
IR (neat): 3332, 3202, 3002, 2860, 1616, 1594, 1324, 1020 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 7.35 (dd, J = 8.1, 7.5 Hz, 1 H), 6.67 (d, J = 7.4 Hz, 1 H), 6.31 (d, J = 8.2 Hz, 1 H), 4.41 (s, 2 H), 3.93 (dd, J = 12.0, 3.8 Hz, 1 H), 3.33 (dd, J = 12.0, 8.8 Hz, 1 H), 2.10 (td, J = 8.6, 6.0 Hz, 1 H), 1.59–1.51 (m, 1 H), 1.08 (td, J = 8.7, 4.8 Hz, 1 H), 0.98–0.95 (m, 1 H).
13 C NMR (126 MHz, CDCl3 ): δ = 158.4, 157.1, 138.3, 114.8, 105.9, 61.5, 22.3, 21.8, 9.8.
HRMS (ESI): m /z [M + H]+ calcd for C9 H12 N2 O: 165.1022; found: 165.1022
[(1R ,2S )-2-(Pyrimidin-5-yl)cyclopropyl]methanol (25e)
[(1R ,2S )-2-(Pyrimidin-5-yl)cyclopropyl]methanol (25e)
The product was prepared according to general procedure C using 5-bromopyrimidine
(360 mg, 2.28 mmol).
Yield: 127 mg (74%); light yellow oil; Rf
= 0.27 (MeOH/CH2 Cl2 , 1:9); [α]D
25 –11.2 (c 1.0, MeOH).
IR (neat): 3329, 3009, 2872, 1556, 1415, 1239, 1168, 1026 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 9.03 (s, 1 H), 8.65 (s, 2 H), 3.57 (dd, J = 11.4, 6.0 Hz, 1 H), 3.17 (dd, J = 11.4, 8.6 Hz, 1 H), 2.17 (dd, J = 14.6, 8.3 Hz, 1 H), 1.78 (s, 1 H), 1.59 (qt, J = 8.6, 5.9 Hz, 1 H), 1.18 (td, J = 8.4, 5.5 Hz, 1 H), 0.87 (q, J = 5.8 Hz, 1 H).
13 C NMR (126 MHz, CDCl3 ): δ = 157.6 (2 C), 156.6, 132.3, 62.0, 20.5, 16.0, 7.4.
HRMS (ESI): m /z [M + H]+ calcd for C8 H10 N2 O: 151.0866; found: 151.0860.
[(1R ,2S )-2-Phenylcyclopropyl]methanol (25f)
[(1R ,2S )-2-Phenylcyclopropyl]methanol (25f)
The product was prepared according to general procedure C using bromobenzene (238
μL, 2.28 mmol).
Yield: 120 mg (71%); 95.2:4.7 er; SFC (Chiralpak AD-H 25cm, 30 °C, 150 bar, 10% MeOH,
3 mL/min): t
R(major) : 6.76 min, t
R(minor) : 4.25 min; light yellow oil; Rf
= 0.45 (EtOAc/hexanes, 1:4); [α]D
25 –22.4 (c 1.0, MeOH).
IR (neat): 3330, 2962, 2865, 1638, 1603, 1496, 1451, 1019 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ =7.32–7.23 (m, 4 H), 7.23–7.17 (m, 1 H), 3.48 (dd, J = 11.7, 6.3 Hz, 1 H), 3.27 (dd, J = 11.7, 8.5 Hz, 1 H), 2.30 (td, J = 8.5, 6.2 Hz, 1 H), 1.54–1.47 (m, 1 H), 1.13 (s, 1 H), 1.05 (td, J = 8.4, 5.3 Hz, 1 H), 0.89 (dd, J = 11.4, 5.6 Hz, 1 H).
13 C NMR (126 MHz, CDCl3 ): δ = 138.4, 129.0 (2 C), 128.5 (2 C), 126.4, 63.1, 21.1, 20.9, 7.8;
HRMS (ESI): m /z [M + NH4 ]+ calcd for C10 H12 O: 1661226; found: 166.1219.
Synthesis of Starting Materials
Synthesis of Starting Materials
2,2′-(Cyclohexylazanediyl)diacetic Acid (CIDA)
2,2′-(Cyclohexylazanediyl)diacetic Acid (CIDA)
To a stirred solution of chloroacetic acid (6.94 mL, 116 mmol) and H2 O (9 mL) was added dropwise aq NaOH (9.28 g, 232 mmol in 30 mL of H2 O) maintaining the temperature below 30 °C by using an ice bath. The mixture was stirred
for 5 min after the addition, and the ice bath was removed. Cyclohexylamine was added
dropwise, keeping the temperature below 50 °C. After addition was complete, the reaction
mixture was heated at 80 °C for 3 h. A solution of barium chloride dihydrate (12.9
g, 52.9 mmol), dissolved in hot H2 O (24 mL), was added in one portion and the mixture was heated for 30 min. A heavy
precipitate of the barium salt of the amino acid separated at once. The stirring was
continued, keeping the heating bath at 100 °C, and then the mixture was cooled down
and kept in an ice bath. The precipitate was then filtered off. The dry barium salt
was placed in a flask into which boiling H2 O (24 mL) was added and heated to boiling; 5 M sulfuric acid (9 mL) was added gradually
over 30 min. Once the addition was complete, the mixture was stirred for 10 min and
then concentrated under reduced pressure to 5 mL. The solution was filtered on Celite
and concentrated.
Yield: 7.38 g (68%); yellow crystalline solid; mp 198–199 °C.
IR (neat): 3012, 2979, 2941, 2856, 1716 1584, 1400, 1240 cm–1 .
1 H NMR (500 MHz, DMSO): δ = 3.44 (s, 4 H), 2.58 (d, J = 7.6 Hz, 1 H), 1.72 (dd, J = 17.6, 14.0 Hz, 4 H), 1.52 (d, J = 12.2 Hz, 1 H), 1.21–1.10 (m, 4 H), 1.10–1.00 (m, 1 H).
13 C NMR (126 MHz, DMSO): δ = 173.9, 62.4, 54.1, 29.9, 26.2, 26.0.
HRMS (ESI): m /z [M + H]+ calcd for C10 H17NO4: 216.1230; found: 216.1227.
(E )-2-{3-[(tert -Butyldimethylsilyl)oxy]prop-1-en-1-yl}-6-cyclohexyl-1,3,6,2-dioxazaborocane-4,8-dione
(15aa)
(E )-2-{3-[(tert -Butyldimethylsilyl)oxy]prop-1-en-1-yl}-6-cyclohexyl-1,3,6,2-dioxazaborocane-4,8-dione
(15aa)
To a stirred solution of (E )-tert -butyldimethyl{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl]oxy}silane[28 ] (4.18 g, 14 mmol) in a mixture of acetone/H2 O (1:1; 94 mL) was added in one portion, sodium periodate (15.0 g, 70.1 mmol) and
ammonium acetate (5.57 g, 70.1 mmol). The mixture was stirred at rt for 24 h. The
flask was fitted with a short-path distillation setup and at rt the acetone and H2 O were removed to dryness. The resulting white solid was suspended in acetone and
stirred for 15 min and then filtered. The filtrate was then concentrated to almost
dryness. The crude boronic acid was used immediately for the next step. The crude
boronic acid (3.03 g, 14.0 mmol) and 2,2′-(cyclohexylazanediyl)diacetic acid (6.00
g, 27.9 mmol) were dissolved in a mixture of DMSO (14 mL) and benzene (85 mL), and
the mixture was refluxed using a Dean–Stark condenser for 6 h at 95 °C (internal temperature).
The reaction mixture was cooled and concentrated to remove benzene. The residue was
diluted with EtOAc (20 mL) and brine (10 mL). The organic layer was washed with H2 O (3 × 10 mL), dried with Na2 SO4 , and concentrated under reduced pressure to afford a light brown solid. Following
column chromatography (silica gel, CH2 Cl2 /MeCN, 1:1), the protected allylic alcohol 15aa was isolated.
Yield: 3.33 g (60%); white solid; Rf
= 0.5 (CH2 Cl2 /MeCN, 1:1); mp 132–133 °C.
IR (neat): 2931, 2856, 1747, 1648, 1449, 1252, 1104, 956 cm–1 .
1 H NMR (400 MHz, acetone-d
6 ): δ = 6.21 (dt, J = 17.5 Hz, 1 H), 5.87 (dt, J = 17.9 1 H), 4.28 (dd, J = 3.8, 2.0 Hz, 2 H), 4.15 (d, J = 16.8 Hz, 2 H), 3.93 (d, J = 16.8 Hz, 2 H), 3.22 (t, J = 11.9 Hz, 1 H), 1.89 (m, 2 H), 1.71–1.49 (m, 4 H), 1.44–1.24 (m, 4 H), 0.95 (s,
9 H), 0.11 (s, 6 H).
13 C NMR (126 MHz, CDCl3 ): δ = 169.1 (2 C), 146.3 (2 C), 67.2, 62.6, 56.6 (2 C), 27.4, 26.3 (2 C), 25.5 (2
C), 25.4 (3 C), 18.7, –5.0 (2 C).
HRMS (ESI): m /z [M + H]+ calcd for C19 H34 BNO5 Si: 395.2408; found: 395.2416.
Base-Sensitive Allylic Alcohol (Z )-4-(3-Hydroxyprop-1-en-1-yl)benzyl Acetate (20)
Base-Sensitive Allylic Alcohol (Z )-4-(3-Hydroxyprop-1-en-1-yl)benzyl Acetate (20)
(4-{3-[(tert -Butyldimethylsilyl)oxy]prop-1-yn-1-yl}phenyl)-methanol (20a)
(4-{3-[(tert -Butyldimethylsilyl)oxy]prop-1-yn-1-yl}phenyl)-methanol (20a)
To a dry sealed tube was added [Pd(PPh3 )2 Cl2 ] (304 mg, 0.433 mmol) and copper iodide (82.3 mg, 0.433 mmol). Et3 N (10.5 mL) was added to the sealed tube and the mixture was flushed with argon while
stirring for 5 min. To this was added 4-bromobenzyl alcohol (540 mg, 2.89 mmol), followed
by the immediate addition of the TBS-protected propargyl alcohol[30 ] (1.96 g, 11.5 mmol). The reaction mixture was then stirred for 15 h at 77 °C under
an argon atmosphere. The reaction mixture was diluted with EtOAc and washed with 10%
HCl solution (2 × 15 mL) and brine (2 × 15 mL). The layers were separated, and the
aqueous layer was extracted with EtOAc (3 × 15 mL). The organic layers were combined,
dried with Na2 SO4 , and concentrated. Purification by column chromatography (silica gel, MeOH/CH2 Cl2 , 1:9) afforded the coupled product 20a .
Yield: 670.4 mg (84%); yellow oil. Rf
= 0.5 (MeOH/CH2 Cl2 , 1:9).
IR (neat): 3369, 2923, 2857, 1736, 1720, 1231, 1045, 1033, 1017 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 7.42 (d, J = 8.2 Hz, 2 H), 7.28 (d, J = 8.2 Hz, 2 H), 4.68 (s, 2 H), 4.54 (s, 2 H), 0.94 (s, 9 H), 0.17 (s, 6 H).
13 C NMR (126 MHz, CDCl3 ): δ = 141.2, 132.0 (2 C), 127.0 (2 C), 122.4, 88.2, 85.0, 65.1, 52.5, 26.1 (3 C),
18.6, –5.0 (2 C).
HRMS (ESI): m /z [M + H]+ calcd for C16 H24 O2 Si: 277.2; found: 277.7.
(Z )-(4-{3-[(tert -Butyldimethylsilyl)oxy]prop-1-en-1-yl}phenyl)-methanol (20b)
(Z )-(4-{3-[(tert -Butyldimethylsilyl)oxy]prop-1-en-1-yl}phenyl)-methanol (20b)
To a stirred solution of nickel(II) acetate tetrahydrate (883 mg, 3.55 mmol) in EtOH
(19.7 mL) under an argon atmosphere was added sodium borohydride (134 mg, 3.55 mmol),
resulting in a black amorphous precipitate. After 5 min of stirring, ethylenediamine
was added (237 mg, 3.94 mmol). The mixture was then allowed to stir for 30 min under
an argon atmosphere. The flask was purged with hydrogen, and alkyne 20a (1.09 g, 3.94 mmol) was rapidly added to the reaction mixture. The reaction was monitored
by NMR. Upon completion, the reaction mixture was filtered over Celite, and the Celite
was washed with Et2 O. The filtrate was washed with brine and extracted with Et2 O (3 × 10 mL). The filtrate was dried with Na2 SO4 and concentrated under reduced pressure to provide the desired pure product 20b . The solids along with the Celite were quenched in a 10% HCl solution.
Yield: 1.07 g (97%); Rf
= 0.5 (EtOAc/hexane, 1:4).
IR (neat): 2952, 2927, 2855, 1737, 1378, 1227, 1028, 835 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 7.34 (d, J = 8.1 Hz, 2 H), 7.19 (d, J = 8.1 Hz, 2 H), 6.48 (d, J = 11.8 Hz, 1 H), 5.83 (dt, J = 12.0, 6.1 Hz, 1 H), 4.69 (s, 2 H), 4.44 (dd, J = 6.1, 1.8 Hz, 2 H), 0.90 (s, 9 H), 0.06 (s, 6 H).
13 C NMR (126 MHz, CDCl3 ): δ = 139.8, 136.5, 133.0, 129.4, 129.2 (2 C), 127.0 (2 C), 65.3, 60.6, 25.1 (3 C),
18.5, –5.0 (2 C).
HRMS (ESI): m /z [M + NH4 ]+ calcd for C16 H26 O2 Si: 296.2; found: 296.2.
(Z )-4-{3-[(tert -Butyldimethylsilyl)oxy]prop-1-en-1-yl}benzyl Acetate (20c)
(Z )-4-{3-[(tert -Butyldimethylsilyl)oxy]prop-1-en-1-yl}benzyl Acetate (20c)
Anhyd pyridine (12 mL) was added to 20b (1.19 g, 4.27 mmol) in a dried flask. The mixture was allowed to stir for 10 min
and cooled to 0 °C. Upon cooling, acetic anhydride (12 mL) was added dropwise to the
mixture. The mixture was allowed to stir for 12 h. Upon completion of the reaction,
the mixture was diluted with Et2 O and washed with 10% HCl (2 × 20 mL), brine (2 × 20 mL), and NaHCO3 (2 × 20 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL), dried with Na2 SO4 , and concentrated. Purification by column chromatography (silica gel, EtOAc/hexanes,
1:4) afforded product 20c .
Yield: 985 mg (72%); yellow oil; Rf
= 0.6 (EtOAc/hexanes, 1:4).
IR (neat): 3022, 2953, 2928, 2888, 2855, 2070, 2040, 2031 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 7.33 (d, J = 8.1 Hz, 2 H), 7.20 (d, J = 8.1 Hz, 2 H), 6.48 (d, J = 11.8 Hz, 1 H), 5.85 (dt, J = 12.0, 6.1 Hz, 1 H), 5.10 (s, 2 H), 4.44 (dd, J = 6.1, 1.8 Hz, 2 H), 2.11 (s, 3 H), 0.90 (s, 9 H), 0.06 (s, 6 H).
13 C NMR (126 MHz, CDCl3 ): δ = 171.0, 137.0, 134.8, 133.2, 129.2, 129.1 (2 C), 128.3 (2 C), 66.2, 60.4, 26.1
(3 C), 21.2, 18.4, –5.0 (2 C).
HRMS (ESI): m /z [M + NH4 ]+ calcd for C18 H28 O3 Si: 338.2; found: 338.2.
(Z )-4-(3-Hydroxyprop-1-en-1-yl)benzyl Acetate (20)
(Z )-4-(3-Hydroxyprop-1-en-1-yl)benzyl Acetate (20)
Acetate 20c (330 mg, 1.03 mmol) was loaded into a dried flask containing THF (4.20 mL). The mixture
was cooled to 0 °C and TBAF (1.13 mL, 1.13 mmol) was added dropwise. The cooling bath
was removed and the mixture was stirred and monitored by TLC until completion. Upon
completion, the reaction mixture was quenched with NH4 Cl (5 mL) and diluted with EtOAc (8 mL). The aqueous layer was extracted with EtOAc
(3 × 8 mL), dried with Na2 SO4 , and concentrated. Purification by column chromatography (silica gel, EtOAc/hexanes,
1:1) afforded the desired product 20 .
Yield: 210 mg (99%); yellow oil; Rf
= 0.4 (EtOAc/hexanes, 1:1).
IR (neat): 3389, 3021, 2931, 2871, 1734, 1226, 1026, 1016 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 7.33 (d, J = 8.1 Hz, 2 H), 7.21 (d, J = 8.1 Hz, 2 H), 6.56 (d, J = 11.8 Hz, 1 H), 5.92–5.87 (m, 1 H), 5.10 (s, 2 H), 4.43 (dd, J = 6.5, 1.6 Hz, 2 H), 2.11 (s, 3 H), 1.86 (s, 1 H).
13 C NMR (126 MHz, CDCl3 ): δ = 171.1, 136.7, 135.2, 131.8, 130.8, 129.2 (2 C), 128.4 (2 C), 66.2, 59.8, 21.2.
HRMS (ESI): m /z [M + NH4 ]+ calcd for C12 H14 O3 : 224.1; found: 224.1.
Benzyl 3,3-Dimethylbutanoate (19a)
Benzyl 3,3-Dimethylbutanoate (19a)
To a suspension of NaH (88.8 mg, 3.70 mmol) in THF (13 mL) at 0 °C was added a solution
of benzyl alcohol (385 μL, 3.70 mmol) in THF (5.3 mL). The reaction mixture was stirred
at rt for 30 min. The mixture was then cooled to 0 °C and tert -butylacetyl chloride (488 μL, 3.51 mmol) was added dropwise. The reaction mixture
was allowed to stir at rt for 6 h. The mixture was quenched with sat. aq NH4 Cl (13 mL) and H2 O (7 mL) and diluted with EtOAc (13 mL). The layers were separated and the aqueous
layer was washed with EtOAc (3 × 13 mL). The organic layers were combined, dried with
Na2 SO4 , and concentrated. Purification by flash chromatography (silica gel, hexanes/CH2 Cl2 , 8:2 to 6:4) resulted in the desired product 19a . The NMR spectra matched those in the literature.[31 ]
Yield: 650 mg (85%).
Benzyl Phenethylcarbamate (19b)
Benzyl Phenethylcarbamate (19b)
To a reaction flask containing anhyd THF (16.5 mL) was added 2-phenethylamine (400
mg, 3.30 mmol) and 4-dimethylaminopyridine (20.2 mg, 5 mol%). Benzyl chloroformate
was added dropwise to the solution and the reaction mixture was allowed to stir for
6 h. The mixture was quenched with H2 O (10 mL) and diluted with Et2 O (13 mL). The aqueous layer was washed with Et2 O (3 × 20 mL). The organic layers were combined, dried with Na2 SO4 , and concentrated under reduced pressure and the white solid was washed with hexanes
to result in the desired product 19b . The spectra matched those reported in the literature.[32 ]
Yield: 758 mg (90%)
4-Bromobenzyl Acetate (19c)
4-Bromobenzyl Acetate (19c)
Additive 19c was synthesized according to the literature.[8 ] In a dried flask, 4-bromobenzyl alcohol (600 mg, 3.21 mmol) was dissolved in anhyd
pyridine (9 mL). The mixture was allowed to stir for 10 min and cooled down to 0 °C.
Upon cooling, acetic anhydride (9.10 mL, 96.2 mmol) was added dropwise to the mixture.
The mixture was allowed to stir for 12 h. Upon completion of the reaction, the mixture
was diluted with Et2 O and washed with 10% HCl (2 × 20 mL), brine (2 × 20 mL), and NaHCO3 (2 × 20 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL), dried with Na2 SO4 , and concentrated under reduced pressure. Purification by column chromatography (silica
gel, EtOAc/hexanes, 1:20) afforded product 19c . The spectra matched those reported in the literature.[33 ]
Yield: 640 mg (87%); yellow oil.
