1,6-Conjugate Addition of Boronic Acids to 2-Allylidenemalonates

Abstract

The addition of boronic acids to 2-allylidenemalonates under Rh^I or Pd^²+ catalysis shows an enhanced selectivity for the 1,6-addition reaction in comparison with diunsaturated monoesters. In the case of the Rh^I-catalyzed addition, the position of the new C=C double bond in the final product can be tuned with the choice of the base to give vinylmalonates of alkylidenemalonates.

addition reactions - catalysis - boron - rhodium - palladium

References and Notes

See, for example:

1a Perlmutter P. In Conjugate Addition Reactions in Organic Synthesis   Pergamon; Oxford: 1992. 

1b Tomioka K. Nagaoka Y. In Comprehensive Asymmetric Catalysis   Vol. 3:  Jacobsen EN. Pfaltz A. Yamamoto H. Springer; Berlin: 1999.  Ch. 31.1.

1c Kanai M. Shibasaki M. In Catalytic Asymmetric Synthesis   2nd ed.:  Ojima I. Wiley; New York: 2000.  p.569 

1d Sibi MP. Manyem S. Tetrahedron  2000,  56:  8033 

1e Krause N. Hoffmann-Röder A. Synthesis  2001,  171 

1f Lipshutz BH. In Organometallics in Organic Synthesis. A Manual   2nd ed.:  Schlosser M. Wiley; Chichester: 2002.  p.665 ; and references cited therein

2 First report: Sakai M. Hayashi H. Miyaura N. Organometallics  1997,  16:  4229 

Reviews:

3a Hayashi T. Synlett  2001,  879 

3b Fagnou K. Lautens M. Chem. Rev.  2003,  103:  169 

3c Hayashi T. Yamasaki K. Chem. Rev.  2003,  103:  2829 

3d Hayashi T. Pure Appl. Chem.  2004,  76:  465 

3e Hayashi T. Bull. Chem. Soc. Jpn.  2004,  77:  13 

3f Yoshida K. Hayashi T. In Modern Rhodium-Catalyzed Organic Reactions   Evans PA. Wiley-VCH; Weinheim: 2005.  Chap. 3. p.55 

For recent leading references, see:

4a Fredrick MA. Hulce M. Tetrahedron  1997,  53:  10197 

4b Krause N. Gerold A. Angew. Chem., Int. Ed. Engl.  1997,  36:  186 

4c Krause N. Thorand S. Inorg. Chim. Acta  1999,  296:  1 

4d Fukuhara K. Urabe H. Tetrahedron Lett.  2005,  46:  603 

4e Yoshikai N. Yamashita T. Nakamura E. Angew. Chem. Int. Ed.  2005,  44:  4721 

4f Fillion E. Wilsily A. Liao ET. Tetrahedron: Asymmetry  2006,  17:  2957 

4g Bernardi L. López-Cantarero J. Niess B. Jørgensen KA. J. Am. Chem. Soc.  2007,  129:  5772 

4h Hartog T. Harutyunyan SR. Font D. Minnaard AJ. Feringa BL. Angew. Chem. Int. Ed.  2008,  47:  398 

4i Okada S. Arayama K. Murayama R. Ishizuka T. Hara K. Hirone N. Hata T. Urabe H. Angew. Chem. Int. Ed.  2008,  47:  6860 ; and references cited therein

5 For a recent example of the 1,6-addition to related diunsaturated nitrodienes, see: Belot S. Massaro A. Tenti A. Mordini A. Alexakis A. Org. Lett.  2008,  10:  4557 

6a Hayashi T. Yamamoto S. Tokunaga N. Angew. Chem. Int. Ed.  2005,  44:  4224 

6b For an intramolecular version using related pinacol boronate esters, see: Tseng N.-W. Mancuso J. Lautens M. J. Am. Chem. Soc.  2006,  128:  5338 

7 De la Herrán G. Murcia C. Csákÿ AG. Org. Lett.  2005,  7:  5629 

8 For a related Ir^I-catalyzed conjugate addition of boroxines to diunsaturated carbonyl compounds, see: Nishimura T. Yasuhara Y. Hayashi T. Angew. Chem. Int. Ed.  2006,  45:  5164 

9 The synthesis of 1a was carried out by reaction of diethyl malonate with acrolein (LiBr, Ac₂O) by a literature procedure: Sylla M. Joseph D. Chevallier E. Camara C. Dumas F. Synthesis  2006,  1045 ; compound 1b was prepared similarly using cinnamaldehyde (80%).

10

General Procedure for the Rh ^I -Catalyzed Addition of Boronic Acids to 1a with NaHCO ₃ as Base (Table 1, Entries 1-7)
To a mixture of boronic acid (2.0 equiv, 0.32 mmol) and [Rh(cod)Cl]₂ (5% Rh, 2.0 mg, 0.004 mmol) under Ar was added a solution of 1a (1.0 equiv, 34 mg, 0.16 mmol) in dioxane-H₂O (6:1, 0.5 mL) followed by NaHCO₃ (0.1 equiv, 2.7 mg, 0.032 mmol). The mixture was stirred at
50 ˚C for 18 h. Evaporation under vacuum afforded the crude reaction products, which were purified by column chromatography (hexane-EtOAc, 85:15).

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General Procedure for the Rh ^I -Catalyzed Addition of Boronic Acids to 1a and 2a with Et ₃ N as Base (Table 1, Entries 8-15)
To a mixture of boronic acid (2.0 equiv, 0.32 mmol) and [Rh(cod)Cl]₂ (5% Rh, 2.0 mg, 0.004 mmol) under Ar was added a solution of 1a or 2a (1.0 equiv, 0.16 mmol) in dioxane-H₂O (10:1, 0.5 mL) followed by Et₃N (1.0 equiv, 16.2 mg, 22 µL, 0.16 mmol). The mixture was stirred at
25 ˚C for 18 h. Evaporation under vacuum afforded the crude reaction products, which were purified by column chromatography (hexane-EtOAc, 85:15).

12

We have confirmed that isomerization of compounds 3 to 4 is a base-promoted process: treatment of compound (E)-3d in dioxane-H₂O (10:1) with Et₃N (1.0 equiv) at r.t. (18 h) afforded 4d (90% isolated yield).

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General Procedure for the Rh ^I -Catalyzed Addition of Boronic Acids to 1b,c and 2b with Ba(OH) ₂ as Base (Table 1, Entries 16-19)
To a mixture of boronic acid (2.0 equiv, 0.34 mmol) and [Rh(cod)₂BF₄] (5% Rh, 3.5 mg, 0.008 mmol) under Ar was added a solution of 1b or 2b (1.0 equiv, 0.17 mmol) in dioxane-H₂O (10:1, 0.5 mL) followed by Ba(OH)₂˙H₂O (1.0 equiv, 32.2 mg, 0.17 mmol). The mixture was stirred at
25 ˚C for 18 h. Evaporation under vacuum afforded the crude reaction products, which were purified by column chromatography (hexane-EtOAc, 85:15).

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Compound 1c was prepared by cross-metathesis reaction between 1a and 1-octene (5% Grubbs II catalyst, CH₂Cl₂, r.t., 18 h, 60% yield).

Reviews:

15a Yamamoto Y. Nishikata T. Miyaura N.
J. Synth. Org. Chem., Jpn.  2006,  64:  1112 

15b Gutnov A. Eur. J. Org. Chem.  2008,  4547 

15c Yamamoto Y. Nishikata T. Miyaura N. Pure Appl. Chem.  2008,  80:  807 ; and references cited therein

16 Horiguchi H. Tsurugi H. Satoh T. Miura M. J. Org. Chem.  2008,  73:  1590 

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General Procedure for the Pd ^²+ -Catalyzed Addition of Boronic Acids to 1a and 2a (Table 2)
To a mixture of Pd(acac)₂ (5% Pd, 2,6 mg, 0.008 mmol), 1,2-diphenylphosphinobenzene (dppben, 3.8 mg, 0.008 mmol), Cu(BF₄)₂˙6H₂O (12 mg, 0.034 mmol), and boronic acid (0.34 mmol) under Ar was added a solution of the starting material (0.17 mmol) in dioxane-H₂O (10:1, 0.5 mL). The mixture was stirred at 25 ˚C for 18 h. Evaporation under vacuum afforded the crude reaction products, which were purified by column chromatography (hexane-EtOAc, 95:05).

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Representative Data
( E )-2-(3-Phenylpropenyl)malonic Acid Diethyl Ester (3a) ^¹H NMR (200 MHz, C₆D₆): δ = 7.08 (m, 5 H), 5.98 (dd, J = 7.7, 15.3 Hz, 1 H), 5.62 (dt, J = 7.1, 15.2 Hz, 1 H) 4.03 (d, J = 7.9 Hz, 1 H), 3.92 (q, J = 7.2 Hz, 4 H), 3.12 (d, J = 7.1 Hz, 2 H), 0.89 (t, J = 7.2 Hz, 6 H) ppm. ^¹³C NMR (50.5 MHz, CDCl₃): δ = 168.5, 139.7, 135.3, 128.8, 128.7, 126.4, 123.2, 61.8, 55.8, 39.0, 14.2 ppm.
( E )-2-(5-Phenylpenta-1,4-dienyl)malonic Acid Diethyl Ester (3d) ^¹H NMR (300 MHz, C₆D₆): δ = 7.21 (m, 5 H), 6.35 (d, J = 15.9 Hz, 1 H), 6.18 (dd, J = 8.9, 15.5 Hz, 1 H), 6.09 (dt, J = 6.6, 15.9 Hz, 1 H), 5.68 (dt, J = 6.8, 15.5 Hz, 1 H), 4.22 (d, J = 8.9 Hz, 1 H), 4.05 (q, J = 7.0 Hz, 4 H), 2.79 (m, 2 H), 1.00 (t, J = 7.1 Hz, 6 H) ppm. ^¹³C NMR (50.5 MHz, CDCl₃): δ = 168.3, 137.4, 134.3, 131.2, 128.5, 127.5, 127.1, 126.1, 122.8, 61.6, 55.6, 35.7, 14.0 ppm.
( E )-2-(3,3-Diphenylpropenyl)malonic Acid Diethyl Ester (3h)
^¹H NMR (200 MHz, CDCl₃): δ = 7.20 (m, 5 H), 7.12 (m,
5 H), 6.08 (dd, J = 7.8, 15.7 Hz, 1 H), 5.64 (dd, J = 8.9, 15.7 Hz, 1 H), 4.70 (d, J = 7.7 Hz, 1 H), 4.12 (q, J = 7.3 Hz, 4), 4.02 (d, J = 8.9 Hz, 1 H), 1.18 (t, J = 7.1 Hz, 6 H) ppm. ^¹³C NMR (75.5 MHz, CDCl₃): δ = 168.7, 143.4, 139.1, 129.0, 128.9, 126.9, 124.0, 52.1, 55.9, 54.1, 14.5 ppm.
2-(3-Phenylpropylidene)malonic Acid Diethyl Ester (4a)
^¹H NMR (200 MHz, CDCl₃): δ = 7.21 (m, 5 H), 7.03 (t, J = 7.5 Hz, 1 H), 4.28 (q, J = 7.2 Hz, 2 H), 4.23 (q, J = 7.0 Hz, 2 H), 2.82 (m, 2 H), 2.62 (m, 2 H), 1.31 (t, J = 7.0 Hz,
3 H), 1.28 (t, J = 7.0 Hz, 3 H) ppm. ^¹³C NMR (50.5 MHz, CDCl₃): δ = 165.4, 164.0, 148.1, 140.5, 132.5, 128.6, 128.3, 126.3, 61.2, 34.4, 31.4, 14.1, 14.07 ppm.
2-(5-Phenylpent-4-enylidene)malonic Acid Diethyl Ester (4d)
^¹H NMR (200 MHz, CDCl₃): δ = 7.28 (m, 5 H), 7.03 (t, J = 7.5 Hz, 1 H), 6.44 (d, J = 15.8 Hz, 1 H), 6.18 (dt, J = 6.6, 15.8 Hz, 1 H), 4.3 (q, J = 7.3 Hz, 2 H), 4.24 (q, J = 7.1 Hz,
2 H), 2.46 (m, 4 H), 1.31 (t, J = 7.2 Hz, 3 H), 1.29 (t, J = 7.2 Hz, 3 H) ppm. ^¹³C NMR (50.5 MHz, CDCl₃): δ = 165.6, 163.8, 148.2, 137.5, 131.3, 1292, 128.5, 128.4, 127.2, 126.1, 61.3, 31.6, 29.5, 14.1 ppm.