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DOI: 10.1055/s-0028-1087810
Synthesis and Evaluation of Chiral Dibenzazepinium Halide Phase-Transfer Catalysts
Publikationsverlauf
Publikationsdatum:
16. Februar 2009 (online)
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Abstract
Two complimentary routes to chiral dibenzazepinium halides have been developed. This has enabled the synthesis and evaluation of a range of potential phase-transfer catalysts (PTC) for asymmetric alkylation and Michael addition reactions involving glycine imine esters.
Key words
amino acids - asymmetric alkylation - phase-transfer catalysis - quaternary ammonium salts - Michael addition
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-
1a
Lygo B. Phase-Transfer Reactions, In Rodd’s Chemistry of Carbon Compounds Vol. V: Elsevier Science Ltd.; Oxford: 2001. p.101-150 -
1b
O’Donnell MJ. Asymmetric Phase-Transfer Reactions in Catalytic Asymmetric Synthesis 2nd ed.:Ojima I. Verlag Chemie; New York: 2000. -
1c
Shioiri T. Chiral Phase-Transfer Catalysts, In Handbook of Phase-Transfer CatalysisSasson Y.Neumann R. Blackie Academic and Professional; London: 1997. - For reviews covering recent developments in asymmetric phase-transfer catalysis, see:
-
2a
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3a
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3b
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enrichment of scalemic amino acid derivatives by crystallisation,
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References and Notes
Representative
Procedures for Route APreparation of 6-
tert
-Butyl-2-bromo-3-methylphenol
N-Bromosuccinimide (77.6 g, 0.44 mol)
was added in batches to a solution of 4 (68.2
g, 0.42 mol) in PE (1.5 L). The resulting mixture stirred for 3
h at r.t., then filtered through silica gel, and concentrated under
reduced pressure. The residue was distilled (140-145 ˚C,
1.3˙10-³ bar) to afford the
product (83.1 g, 83%) as a pale yellow oil. The residue
could also be purified by chromatography on silica gel (R
f
= 0.5,
PE) to give the product in similar yield.
IR (neat): νmax = 3497,
1602 cm-¹. ¹H NMR
(400 MHz, CDCl3): δ = 7.09 (1 H, d, J = 8.0 Hz, ArH), 6.72 (1 H,
d, J = 8.0 Hz, ArH), 5.90 (1
H, s, OH), 2.34 (3 H, s, CH3), 1.38 [9 H, s,
C(CH3)3]. ¹³C
NMR (100 MHz, CDCl3): δ = 150.4 (C), 136.0
(C), 134.7 (C), 125.5 (CH), 121.6 (CH), 115.4 (C), 35.1 (C), 29.5
(CH3), 23.1 (CH3). MS (EI): m/z calcd
for C11H15O79Br: 242.0301; found:
242.0303 [M]+.
Preparation of 3,3′-Dibromo-5,5′-di-
tert
-butyl-2,2′-dimethyl-4,4′-dihydroxybiphenyl
Copper(I)
chloride (2.40 g, 24.0 mmol) was added to a solution of TMEDA (3.84
mL, 25.0 mmol) in MeOH (600 mL). After stirring for 20 min, 6-tert-butyl-2-bromo-3-methylphenol (58.9
g, 240 mmol) was added, the mixture stirred under an air atmosphere
for 3 d, then concentrated under reduced pressure. The residue was
dissolved in Et2O and filtered through silica gel. The
solution was again concentrated under reduced pressure and the residue
purified by chromatography on silica gel to afford unreacted starting material
(36%) followed by the product (33.5 g, 58%, R
f
= 0.4;
PE-EtOAc, 9:1) as a colourless solid.
Mp 183-184 ˚C.
IR (neat): νmax = 3494 cm-¹. ¹H
NMR (400 MHz, CDCl3): δ = 6.95 (2 H,
s, ArH), 5.96 (2 H, s, OH), 2.09 (6 H, s, CH3), 1.40 [18
H, s, C(CH3)3]. ¹³C
NMR (100 MHz, CDCl3): δ = 149.5 (C),
134.2 (C), 134.1 (C), 134.0 (C), 127.6 (CH), 116.0 (C), 35.2 (C),
29.6 (CH3), 20.9 (CH3). MS (EI): m/z calcd for C22H28O2
8¹Br2:
482.0450; found: 482.0456 [M]+.
Preparation of 3,3′-Dibromo-5,5′-di-
tert
-butyl-4,4′-dimethoxy-2,2′-dimethylbiphenyl
(5)
Methyl iodide (3.8 mL, 60.9 mmol) was added dropwise
to a mixture of 3,3′-dibromo-5,5′-di-tert-butyl-2,2′-dimethyl-4,4′-dihydroxybiphenyl
(11.8 g, 24.4 mmol) and anhyd K2CO3 (10.1
g, 73.1 mmol) in dry DMF (300 mL). The mixture was stirred at r.t.
for 18 h, then H2O (350 mL) added, and the solution extracted
with EtOAc (2 × 200 mL). The combined extracts were washed
with brine (2 × 200 mL), dried (MgSO4), and
concentrated under reduced pressure. The residue was purified by
chromatography on silica gel (R
f
= 0.3;
PE-EtOAc, 49:1) to give the product (12.2 g, 98%)
as a colourless solid.
Mp 105-107 ˚C.
IR (neat): νmax = 3048, 2960, 2868,
2841 cm-¹. ¹H NMR
(400 MHz, CDCl3): δ = 7.00 (2 H, s,
ArH), 3.96 (6 H, s, OCH3), 2.10 (6 H, s, CH3),
1.39 [18 H, s, C(CH3)3]. ¹³C
NMR (100 MHz, CDCl3): δ = 155.8 (C),
141.6 (C), 137.7 (C), 135.8 (C), 127.5 (CH), 122.0 (C), 61.5 (CH3), 35.3
(C), 31.1 (CH3), 21.0 (CH3). MS (EI): m/z calcd for C24H32O2
79Br8¹Br:
512.0743; found: 512.0752[M]+.
Preparation of 5,5′-Di-
tert
-butyl-4,4′-dimethoxy-2,2′-dimethyl-3,3′-(3,5-bistrifluoromethylphenyl)biphenyl
3,5-Bistrifluoromethylphenylboronic
acid (7.56 g, 29.3 mmol) was added to a solution of 5 (5.00
g, 9.76 mmol) in degassed THF (175 mL), then degassed 2 M aq K2CO3 (115 mL)
and Pd(PPh3)4 (1.13 g, 0.98 mmol) were added.
The mixture was heated at 70 ˚C for 24 h under
a nitrogen atmosphere, then cooled to r.t., acidified with 2 M HCl,
and extracted with Et2O (2 × 100 mL). The combined
extracts were washed with brine (2 × 100 mL), dried (MgSO4),
and concentrated under reduced pressure. The residue was recystallised
(Et2O-MeOH) to afford the product (4.71 g, 62%)
as a colourless solid.
Mp 183-184 ˚C.
IR (neat): νmax = 2963 cm-¹. ¹H
NMR (400 MHz, CDCl3): δ = 7.89 (4 H,
s, ArH), 7.86 (2 H, s, ArH), 7.18 (2 H, s, ArH), 3.16 (6 H, s, OCH3),
1.76 (6 H, s, CH3), 1.42 [18 H, s, C(CH3)3]. ¹³C
NMR (125 MHz, CDCl3): δ = 156.4 (C),
141.1 (C), 140.6 (C), 137.6 (C), 133.3 (C), 133.1 (C), 131.5 (q, J = 33.5 Hz, C), 131.1 (CH),
129.2 (CH), 123.5 (q, J = 271.0
Hz, CF3), 120.8 (q, J = 7.7
Hz, CH), 60.7 (CH3), 35.1 (C), 31.1 (CH3),
18.2 (CH3). MS (EI): m/z calcd
for C40H38F12O2: 778.2675;
found: 778.2667 [M]+.
Preparation of 5,5′-Di-
tert
-butyl-4,4′-dimethoxy-2,2′-bisbromomethyl-3,3′-(3,5-bistrifluoromethylphenyl)-biphenyl
(6b)
To a solution of 5,5′-di-tert-butyl-4,4′-dimethoxy-2,2′-dimethyl-3,3′-(3,5-bistrifluoromethylphenyl)biphenyl
(1.85 g, 2.37 mmol) in CCl4 (30 mL) was added NBS (0.88
g, 4.97 mmol) and AIBN (5 mg). The mixture was placed under an argon
atmosphere and heated at reflux for 20 min using a 60 W light bulb
(1 cm from flask). The mixture was then cooled to r.t., filtered
through silica gel, and concentrated under reduced pressure to give
the product (2.11 g, 95%) as a colourless solid.
Mp
90-92 ˚C. IR (neat): νmax = 2964
cm-¹. ¹H NMR (400 MHz,
CDCl3): δ = 8.15 (2 H, s, ArH), 7.98
(2 H, s, ArH), 7.96 (2 H, s, ArH), 7.40 (2 H, s, ArH), 3.95 (2 H,
d, J = 10.0 Hz, CH
a
Hb),
3.89 (2 H, d, J = 10.0 Hz, CHa
H
b
),
3.22 (6 H, s, OCH3), 1.44 [18 H, s, C(CH3)3]. ¹³C
NMR (100 MHz, CDCl3): δ = 157.4 (C),
143.9 (C), 138.9 (C), 135.8 (C), 134.1 (C), 132.8 (C), 131.7 (C,
q, J = 33.5 Hz), 131.6 (C, q, J = 33.5 Hz), 131.1 (CH), 130.8
(CH), 130.3 (CH), 123.3 (C, q, J = 273.0
Hz), 123.3 (C, q, J = 273.0
Hz), 121.7 (CH, m), 60.9 (CH3), 35.4 (C), 30.8 (CH3),
30.3 (CH2). MS (EI):
m/z calcd
for C40H36O2F12
8¹Br2:
938.0845; found: 938.0815[M]+.
Preparation of (
R
)-2,10-Di-
tert
-butyl-3,9-dimethoxy-6-methyl-6-(1-naphthalen-1-ylethyl)-4,8-bis(3,5-bistri-fluoromethylphenyl)-6,7-dihydro-5
H
-dibenzo[
c
,
e
]-azepinium
Bromide (1g)
Dibromide 6b (0.57
g, 0.61 mmol) was dissolved in MeCN (15 mL) and CH2Cl2 (3
mL), then (R)-α-methylnaphth-1-ylamine
(0.13 g, 0.67 mmol) and anhyd K2CO3 (0.50
g 3.60 mmol) added. The mixture was stirred at 60 ˚C for
16 h then filtered, and concentrated under reduced pressure. The residue
purified by recrystallisation (PhMe) to afford the product 1g (0.45 g, 70%) as a colourless
solid.
Mp 102-104 ˚C. [α]D +78
(c 0.4, CHCl3). IR (neat): νmax = 2964
cm-¹. ¹H NMR (400
MHz, CDCl3): δ = 8.28 (1 H, s, ArH),
8.07 (2 H, s, ArH), 8.04 (1 H, s, ArH), 7.95 (1 H, d, J = 8.0 Hz,
ArH), 7.91 (1 H, dd, J = 8.0,
1.0 Hz, ArH), 7.85 (1 H, s, ArH), 7.55 (1 H, s, ArH), 7.54 (1 H,
s, ArH), 7.49 (1 H, dd, J = 7.5,
7.0 Hz, ArH), 7.39-7.28 (3 H, m, ArH), 7.07 (1 H, d, J = 8.5 Hz, ArH), 6.80 (1 H,
s, ArH), 5.51 (1 H, d,
J = 15.0
Hz, NCH
a
Hb),
5.20 (1 H, q, J = 6.5 Hz, CHCH3), 4.19 (1 H, d, J = 15.0 Hz, NCHa
H
b
),
3.38 (1 H, d, J = 13.0 Hz, NCH
a
Hb),
3.19 (3 H, s, OCH3), 3.02 (3 H, s, OCH3),
2.98 (3 H, s, NCH3), 2.81 (1 H, d, J = 13.0
Hz, NCHa
H
b
), 1.60 [9 H, s, C(CH3)3],
1.46 [9 H, s, C(CH3)3],
1.09 (3 H, d, J = 6.5 Hz, NCHCH
3
). ¹³C
NMR (100 MHz, CDCl3): δ = 158.3 (C), 128.1
(C), 147.9 (C), 147.8 (C), 137.8-119.4 (complex CAr and
CF3), 62.3 (CH), 61.2 (CH3), 61.0 (CH3),
59.7 (CH2), 57.9 (CH2), 43.2 (CH3),
36.0 (C), 35.8 (C), 30.9 (CH3), 30.8 (CH3),
15.9 (CH3). ¹9F NMR (282 MHz, CDCl3,
referenced to CFCl3 = 0 ppm): δ = -62.1, -62.9, -63.2, -63.3.
MS (ES+): m/z calcd
for C53H50F12NO2: 960.3644;
found: 960.3682 [M - Br]+.
Representative
Procedures for Route BPreparation of 3,3′-Dibromo-5,5′-di-
tert
-butyl-4,4′-dimethoxy-2,2′-bisbromomethylbiphenyl
Bromination
of 5 was performed as described for 6b, to give the product (100%)
as a colourless solid.
Mp 206-207 ˚C.
IR (neat): νmax = 3054, 2966, 2869
cm-¹. ¹H NMR (400
MHz, CDCl3): δ = 7.24 (2 H, s, ArH),
4.49 (2 H, d, J = 10.0 Hz, CHaHb), 4.19 (2 H, d, J = 10.0
Hz, CHaHb), 4.01 (6 H, s, OCH3),
1.42 [18 H, s, C(CH3)3]. ¹³C
NMR (100 MHz, CDCl3): δ = 157.3 (C),
145.1 (C), 136.3 (C), 134.6 (C), 128.5 (CH), 122.4 (C), 61.8 (CH),
35.8 (C), 33.2 (CH2), 30.9 (CH3). MS (EI): m/z calcd for C24H30O2
79Br2
8¹Br2: 669.8930;
found: 669.8893[M]+.
Preparation of (
R
)-4,8-Bisbromo-2,10-di-
tert
-butyl-3,9-dimethoxy-6-(1-phenylethyl)-6,7-dihydro-5
H
-dibenzo-[
c
,
e
]azepine
(7a)
To a stirred solution of 3,3′-dibromo-5,5′-di-tert-butyl-4,4′-dimethoxy-2,2′-bisbromomethylbiphenyl
(221 mg, 0.33 mmol) in CHCl3 (10 mL) was added (R)-1-phenylethyl-amine (38.7 µL,
0.30 mmol) and anhyd K2CO3 (0.27 g, 1.98 mmol).
The mixture was stirred at 60 ˚C for 18 h then filtered
and concentrated under reduced pressure. The residue was purified
by chromatography on silica gel (R
f
= 0.6; Et2O-PE,
1:4) to yield the product (160 mg, 85%) as colourless crystals.
Mp
88-92 ˚C. [α]D
²² +14
(c 0.7, CHCl3). IR (neat): νmax = 2957
cm-¹. ¹H NMR (400
MHz, CDCl3): δ = 7.55 (1 H, s, ArH),
7.53 (1 H, s, ArH), 7.39-7.32 (4 H, m, ArH), 7.30-7.23
(1 H, m, ArH), 4.10-3.00 (5 H, m, 2 × CH2 and
CH), 3.99 (6 H, s, OCH3), 1.47 [18 H, s, C(CH3)3],
0.90 (3 H, m, CH3). ¹³C
NMR (100 MHz, CDCl3): δ = 156.4 (C),
146.1 (C), 144.0 (C), 137.6 (C) 135.0 (C), 128.2 (CH), 127.7 (CH), 126.8
(CH), 125.5 (CH), 122.0 (C), 61.7 (CH3), 52.4 (CH2), 35.5
(C), 31.0 (CH3), 23.3 (CH3). MS (ES+): m/z calcd for C32H40NO2
79Br2:
628.1420; found: 628.1456 [M + H]+.
Preparation of (
R
)-2,10-di-
tert
-butyl-3,9-dimethoxy-6-(1-phenylethyl)-4,8-bis(3,5-bistrifluoromethylphenyl)-6,7-dihydro-5
H
-dibenzo[
c
,
e
]azepine
(8a)
Reaction of (R)-4,8-dibromo-2,10-di-tert-butyl-3,9-dimethoxy-6-(1-phenylethyl)-6,7-dihydro-5H-dibenzo-[c,e]azepine with 3,5-bistrifluoromethylphenylboronic
acid was performed using the coupling procedure described above.
The residue was purified by chromatography on silica gel (R
f
= 0.2;
CH2Cl2-PE, 1:4) to give the product
(63%) as colourless crystals.
Mp 101 ˚C; [α]D +1
(c 0.1, CHCl3). IR (neat): νmax = 2977 cm-¹. ¹H
NMR (400 MHz, CDCl3): δ = 8.40-8.20
(2 H, m, ArH), 7.83 (2 H, s, ArH), 7.80-7.70 (1 H, m, ArH),
7.55 (2 H, s, ArH), 7.36 (1 H, s, ArH), 7.02-6.98 (3 H,
m, ArH), 6.81-6.79 (2 H, m, ArH), 3.80-3.55 (2
H, m, CH2), 3.20-3.05 (3 H, m, CH and CH2),
3.09 (6 H, s, OCH3), 1.51 [18 H, s, C(CH3)3],
0.95-0.80 (3 H, m, CH3). ¹³C
NMR (100 MHz, CDCl3): δ = 156.9 (C),
142.8 (C), 139.6 (C), 137.5 (C), 133.2-121.1 (complex C,
CH, CF3), 61.1 (CH), 60.5 (CH3), 48.5 (CH2),
35.3 (C), 31.0 (CH3). MS (ES+): m/z calcd for C48H46NO2F12:
896.3331; found: 896.3455 [M + H]+.
Preparation of (
R
)-2,10-Di-
tert
-butyl-3,9-dimethoxy-6-methyl-6-(1-phenylethyl)-4,8-bis(3,5-bistrifluoromethyl-phenyl)-6,7-dihydro-5
H
-dibenzo[
c
,
e
]azepinium
Iodide (2a)
Methyl iodide (200 µL, 3.2 mmol)
was added to a solution of tertiary amine 8a (16
mg, 24 µmol) in CHCl3 (1.5 mL). The mixture
stirred at 60 ˚C in a sealed tube for 2 h. After
cooling to r.t., the solution was concentrated under reduced pressure. The
residue was purified by chromatography on silica gel (R
f
= 0.2;
CHCl3-MeOH, 19:1) to give the product as a pale yellow
solid (20.4 mg, 82%).
Mp 151-153 ˚C. [α]D +25
(c 0.2, CHCl3). IR (neat): νmax = 2924
cm-¹. ¹H NMR (400
MHz, CDCl3): δ = 8.29 (1 H, s, ArH),
7.97-7.94 (2 H, m, ArH), 7.90 (1 H, s, ArH), 7.82 (1 H,
s, ArH), 7.61 (1 H, s, ArH), 7.57 (1 H, s, ArH), 7.42-7.22 (3
H, m, ArH), 7.13-7.11 (1 H, m, ArH), 6.97 (2 H, d, J = 7.5 Hz, ArH), 5.32 (1 H,
d, J = 15.5 Hz, CH
a
Hb),
4.08 (1 H, d, J = 15.5
Hz, CHa
H
b
),
4.00-3.96 (1 H, m, CH), 3.38 (1 H, d, J = 11.5
Hz, CH
a
Hb),
3.16 (3 H, s, OCH3), 3.12 (3 H, s, OCH3),
2.93-2.85 (4 H, m, NCH3 and CHa
H
b
),
1.54 [9 H, s, C(CH3)3],
1.50 [9 H, s, C(CH3)3],
0.90 (3 H, m, CH3). ¹³C NMR
(125 MHz, CDCl3): δ = 158.2 (C), 158.1
(C), 147.9 (C), 147.6 (C), 137.9 (C), 137.7 (C), 137.5 (C), 136.8
(C), 135.2 (C), 133.3 (C, q, J = 34.0
Hz), 132.6 (C, q, J = 33.5 Hz),
132.6 (C, q, J = 33.5 Hz), 131.9
(CH), 131.8 (CH), 131.7 (C, m, obscured), 131.6 (CH), 130.9 (C),
130.1 (CH), 129.6 (CH), 129.4 (CH), 129.3 (C), 129.2 (CH), 124.7
(C), 123.3 (C), 122.9 (C, q, J = 273.0
Hz), 122.7 (C, q, J = 273.0 Hz),
122.7 (C, q, J = 274.0 Hz),
122.5 (CH), 122.4 (C, q, J = 273.0
Hz), 121.8 (CH), 70.7 (CH), 61.3 (CH3), 61.1 (CH3), 59.6
(CH2), 59.3 (CH2), 43.1 (CH3),
35.8 (C), 35.7 (C), 30.7 (CH3), 30.7 (CH3),
15.3 (CH3). MA (ES+): m/z calcd for C49H48NO2F12:
910.3488; found: 910.3453[M - I]+.
General Procedure
for the Alkylation of Glycine Imine 9 with Benzyl Bromide
A
mixture of the catalyst (1 mol%) and imine 9 (50
mg, 0.17 mmol) in PhMe (2 mL) was degassed, placed under nitrogen, and
cooled to 0 ˚C. Benzyl bromide (35 mg, 0.20 mmol)
was added followed by 15 M aq KOH (1 mL) and the mixture stirred
at 0 ˚C for 3 h. The mixture was then diluted
with H2O (10 mL) and extracted with EtOAc (3 × 10
mL). The combined extracts were dried (Na2SO4),
concentrated under reduced pressure, and purified by chromatography
on silica gel (R
f
= 0.5;
PE-EtOAc-Et3N, 89:10:1) to give 10 as a colourless oil.
¹H
NMR (400 MHz, CDCl3): δ = 7.59-7.56
(2 H, m, ArH), 7.38-7.26 (6 H, m, ArH), 7.20-7.14
(3 H, m, ArH), 7.06-7.03 (2 H, m, ArH), 6.61 (2 H, d, J = 6.5 Hz, ArH), 4.11 (1 H,
dd, J = 9.0, 4.5 Hz, CH), 3.23
(1 H, dd, J = 13.5, 4.5 Hz, CH
a
Hb),
3.16 (1 H, dd, J = 13.5, 9.0
Hz, CHa
H
b
),
1.44 [9 H, s, C(CH3)3].
These ¹H NMR data are in agreement with those previously
recorded.4d HPLC: Chiralcel OD-H (25 × 0.46 cm + guard)
hexane-2-PrOH (100:1), 0.5 mL min-¹; t
R = 14.8 min (R)-isomer; t
R = 28.2
min (S)-isomer.
General Procedure
for the Michael Addition of Glycine Imine 11 to MVK
A
mixture of imine 11 (0.12 mmol) and catalyst
(1 mol%) in i-Pr2O
(4 mL) was cooled to 0 ˚C. MVK (0.24 mmol) was added
followed by anhyd Cs2CO3 (0.06 mmol) and the mixture
stirred at 0 ˚C for 2
h. The mixture was then filtered and concentrated under reduced
pressure. The residue was purified by chromatography on silica gel
(R
f
= 0.2;
PE-EtOAc-Et3N, 89:10:1) to give 12 as a colourless oil.
IR (CHCl3): νmax = 1739,
1715, 1622 cm-¹. ¹H
NMR (400 MHz, CDCl3): δ = 7.67-7.63
(2 H, m, ArH), 7.43-7.26 (16 H, m, ArH), 7.10-7.06
(2 H, m, ArH), 6.89 (1 H, s, CHPh2), 4.19 (1 H, app.
t, J = 6.0 Hz, NCH), 2.58-2.50
(1 H, m), 2.44-2.36 (1 H, m), 2.23-2.18 (2 H,
m), 2.05 (3 H, s, Me). ¹³C NMR (100
MHz, CDCl3): δ = 208.0 (C), 171.0
(C), 170.7 (C), 140.0 (2 × C), 139.3 (C), 136.1 (C), 130.5
(CH), 128.8 (CH), 128.7 (CH), 128.6 (CH), 128.5 (2 × CH),
128.1 (CH), 128.0 (CH), 127.9 (CH), 127.7 (CH), 127.4 (CH), 127.0
(CH), 77.2 (CH), 64.1 (CH), 39.5 (CH2), 29.9 (CH3), 27.5
(CH2). MS (CI): m/z calcd
for C32H30NO3: 476.2226; found:
476.2241[M + H]+.
HPLC: Chiralpak AD (25 × 0.46 cm + guard),
hexane-2-PrOH (95:5), 1.0 mL min-¹; t
R = 23.7 min (R)-isomer; t
R = 29.5
min (S)-isomer.