1,6-Conjugate addition of boronic acids to 2-allylidenemalonates

Article abstract of DOI:10.1055/s-0028-1087560

The addition of boronic acids to 2-allylidenemalonates under Rh^I or Pd²⁺ 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. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087560

LETTER
585
1,6-Conjugate Addition of Boronic Acids to 2-Allylidenemalonates
1, 6-Conjugate
A
dd
a
ition of Bo
b
ronic
A
cids
t
r
o 2-Ally
i
lidenem
e
a
lonate
s
la de la Herrán, Aurelio G. Csákÿ*
Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, 28040 Madrid, Spain
Fax +34(91)3945030; E-mail: csaky@quim.ucm.es
Received 24 October 2008
acids to a,b,g,d-diunsaturated carbonyl compounds may
give rise to the formation of the 1,4- or the 1,6-conjugate
addition products and Heck-type products (Scheme 1) de-
pending on the substitution pattern of the starting material
Abstract: The addition of boronic acids to 2-allylidenemalonates
under RhI or Pd2+ catalysis shows an enhanced selectivity for the
1,6-addition reaction in comparison with diunsaturated monoesters.
In the case of the RhI-catalyzed addition, the position of the new
C=C double bond in the final product can be tuned with the choice and the boronic acid (aryl- or alkenylboronic acid).6–8
of the base to give vinylmalonates of alkylidenemalonates.
We report herein our results on the addition of boronic
acids to 2-allylidenemalonates 1, which show an en-
hanced selectivity for the 1,6-addition reaction in compar-
Key words: addition reactions, catalysis, boron, rhodium, palladi-
um
ison with a,b,g,d-diunsaturated esters 2 (Scheme 2).
The results of the RhI-catalyzed addition of aryl- and
Conjugate addition reactions of organometallic reagents
alkenylboronic acids to compound 1a,9 unsubstituted in
to a,b-unsaturated carbonyl compounds are one of the
d-position (R2 = H), are given in Table 1 (entries 1–14).
main synthetic methods for C–C bond formation.1 Among
We observed that the 1,6-conjugate addition reaction was
the different procedures reported, the reaction of boronic
favored in all cases when the reaction was carried out with
acids under RhI catalysis has become increasingly popu-
[(cod)RhCl]2 as catalyst in dioxane–H2O as solvent in the
lar.2,3 Compared with other more traditional methods,
presence of NaHCO3 or Et3N as bases. Opposite to
such as organocuprate chemistry, the RhI-catalyzed conju-
a,b,g,d-diunsaturated ester 2a (entry 15) the reactions of
gate addition of organoboronic acids is highly functional-
malonate 1a with alkenylboronic acids did not give rise to
group tolerant and enjoys more environmentally benign
the Heck-type products 6.7
conditions, as the reactions can be carried out in water-
In addition, it was possible to control the position of the
new C=C bond formed in the final products. Thus, vinyl-
malonates 3 (E-isomers) were obtained when the reaction
was carried out with NaHCO3 (entries 1–7).10 It is worth
mentioning that the 1,6-conjugate addition to linear
a,b,g,d-dienoates has been reported to give rise to Z-al-
kenes.4a,7 On the other hand, the alkylidenemalonates 4
were obtained when the reaction was carried out with
Et3N (entries 8–14).11,12
containing organic solvents, the heavy metal is used in
catalytic amounts, and the boron reagents and subproducts
are of low toxicity. This becomes specially relevant in
large-scale operations. Additionally, many aryl- and alke-
nylboronic acids are commercially available or can be
easily prepared by a wide variety of methods.
R3
O
R2
R1
In a similar fashion, the reaction of compound 1b,9 substi-
tuted in d-position (R2 = Ph), afforded the corresponding
1,6-addition products 3 (E-isomers) instead of the 20:80
mixture of 1,6- and 1,4-addition products observed for 2b
(Table 1, entries 16–18). In this case, no reaction was ob-
served when using [(cod)RhCl]2 as catalyst, either in the
presence of NaHCO3 or Et3N as bases. Optimization of
reaction conditions led to the use of [(cod)2Rh]BF4 as cat-
alyst in dioxane–H2O as solvent in the presence of
Ba(OH)2 as base.13 Similarly, the reaction of PhB(OH)2
with 1c,14 alkyl-substituted in d-position (R2 = nC6H13),
afforded (E)-3k (entry 19).
1,6-conjugate addition
R3
O
O
R3B(OH)2
RhI (cat.)
R2
R1
R2
R1
1,4-conjugate addition
R3
O
R2
R1
Heck-type products
Scheme 1
Among the various kinds of carbonyl compounds used as
starting materials in conjugate addition reactions, dienic
substrates have not been amply investigated, as a result of
the difficulties in controlling the 1,4- or 1,6-regioselectiv-
ity.4,5 In particular, the RhI-catalyzed addition boronic
It has been shown recently that the conjugate addition of
boronic acids to electron-deficient alkenes can be cata-
lyzed by cationic Pd2+ species.15 In general a,b-unsaturat-
ed esters do not perform well in these type of reactions,
and the formation of Heck-type products is normally ob-
served.16 However, the Pd2+-catalyzed conjugate addition
reaction of boronic acids to a,b,g,d-dienoates has not been
reported.
SYNLETT 2009, No. 4, pp 0585–0588
Advanced online publication: 16.02.2009
x
x.
x
x.
2
0
0
9
DOI: 10.1055/s-0028-1087560; Art ID: G35508ST
© Georg Thieme Verlag Stuttgart · New York

586
G. de la Herrán, A. G. Csákÿ
LETTER
R3
R3
Z
Z
Z
Z
R2
R2
R1
R1
R3B(OH)2
4
6
3
5
Z
R2
RhI (cat.)
base
dioxane–H2O
R3
R1
R3
1, 2
R2
R2
1 Z = R1 = CO2Et
R1
R1
2 Z = CO2R, R1 = H
Scheme 2
Table 1 RhI-Catalyzed Addition of R2B(OH)2 to 1 and 2
Entry 1, 2
Z
R1
R2
R3
RhI
Base
Solventb Temp Product,
catalysta (equiv)
(°C)
50
50
50
50
50
50
50
25
25
25
25
25
25
25
25
25
25
25
25
yield (%)c
(E)-3a 80
(E)-3b 70
(E)-3c 70d
(E)-3d 80
(E)-3e 70
(E)-3f 70
(E)-3g 65d
4a 80
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
2a
1b
1b
2b
1c
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Bn
CO2Et
CO2Et
CO2Me
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
NaHCO3 (0.1)
6:1
6:1
4-BrC6H4
NaHCO3 (0.1)
NaHCO3 (0.1)
NaHCO3 (0.1)
NaHCO3 (0.1)
NaHCO3 (0.1)
NaHCO3 (0.1)
Et3N (1.0)
3
4-MeOC6H4
C6H5CH=CH
4-MeC6H4CH=CH
4-MeOC6H4CH=CH
4-FC6H4CH=CH
Ph
6:1
4
6:1
5
6:1
6
6:1
7
6:1
8
10:1
10:1
10:1
10:1
10:1
10:1
10:1
10:1
10:1
10:1
10:1
10:1
9
4-BrC6H4
Et3N (1.0)
4b 60
10
11
12
13
14
15
16
17
18
19
4-MeOC6H4
C6H5CH=CH
4-MeC6H4CH=CH
4-MeOC6H4CH=CH
p-F-C6H4CH=CH
C6H5CH=CH
Ph
Et3N (1.0)
4c 60d
Et3N (1.0)
4d 75
Et3N (1.0)
4e 75e
Et3N (1.0)
4f 65
Et3N (1.0)
4g 60e
Et3N (1.0)
6a 60f
CO2Et
CO2Et
H
Ba(OH)2 (1.0)
Ba(OH)2 (1.0)
Ba(OH)2 (1.0)
Ba(OH)2 (1.0)
(E)-3h 85
(E)-3i 60e
(Z)-3j, 5a 85f,g
(E)-3k 75
4-MeC6H4
Ph
CO2Et
n-C6H13 Ph
a Conditions: RhI (5 mol%). A = [(cod)RhCl]2. B = [(cod)2Rh]BF4.
b Ratio of dioxane to H2O.
c Isolated yield after silica gel chromatography.
d Unreacted starting material (15%) was observed in the 1H NMR (200 MHz, CDCl3) spectra of the reaction crudes.
e Unreacted starting material (20%) was observed in the 1H NMR (200 MHz, CDCl3) spectra of the reaction crudes.
f See ref. 7.
g Mixture (Z)-3j/5a = 20:80 (85% overall yield).
We observed that, in the case of 2a (Table 2, entries 1, 2), yields were lower in comparison with the same reaction
the addition of boronic acids under Pd2+ catalysis gave rise under RhI catalysis.
to the Heck reaction products 5 (Scheme 3).17 On the other
In conclusion, we have shown that the reaction of boronic
hand, when the reaction was carried out on the malonate
acids with allylidenemalonates favors the 1,6-addition
derivative 1a (Table 2, entries 3–5), the corresponding
products with respect to a,b,g,d-diunsaturated esters
1,6-addition products 3 (E-isomers) were obtained, albeit
either under RhI or Pd2+ catalysis. In the case of the RhI-
Synlett 2009, No. 4, 585–588 © Thieme Stuttgart · New York

LETTER
1,6-Conjugate Addition of Boronic Acids to 2-Allylidenemalonates
587
R2B(OH)2
Z
Z
Z
R2
R2
Pd(acac)2
Cu(BF4)2
dppben
R1
1a, 2a
R1
R1
6
3
1a Z, R1 = CO2Et
2a Z = CO2Bn, R1 = H
Scheme 3
Chem. Int. Ed. 2005, 44, 4721. (f) Fillion, E.; Wilsily, A.;
Liao, E. T. Tetrahedron: Asymmetry 2006, 17, 2957.
(g) Bernardi, L.; López-Cantarero, J.; Niess, B.; Jørgensen,
K. A. J. Am. Chem. Soc. 2007, 129, 5772. (h) Hartog, T.;
Harutyunyan, S. R.; Font, D.; Minnaard, A. J.; Feringa, B. L.
Angew. Chem. Int. Ed. 2008, 47, 398. (i) 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.
catalyzed addition, the position of the new C=C double
bond in the final product can be tuned with the choice of
the base, allowing the synthesis of either vinylmalonates
or alkylidenemalonates.18
Table 2 Pd2+-Catalyzed Addition of R2B(OH)2 to 1 and 2
Entry 1, 2
Z
R1
R2
Yield of 3 and 5
(%)a
(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.
(6) (a) Hayashi, T.; Yamamoto, S.; Tokunaga, N. Angew. Chem.
Int. Ed. 2005, 44, 4224. (b) For an intramolecular version
using related pinacol boronate esters, see: Tseng, N.-W.;
Mancuso, J.; Lautens, M. J. Am. Chem. Soc. 2006, 128,
5338.
1
2
3
4
5
2a
2a
1a
1a
1a
CO2Bn
CO2Bn
H
H
C6H5CH=CH 5a 45
Ph
5b 40
CO2Et CO2Et Ph
(E)-3a 70
(E)-3c 55
CO2Et CO2Et 4-MeOC6H4
(7) De la Herrán, G.; Murcia, C.; Csákÿ, A. G. Org. Lett. 2005,
7, 5629.
CO2Et CO2Et C6H5CH=CH (E)-3d 60
a Isolated yield after silica gel chromatography.
(8) For a related IrI-catalyzed conjugate addition of boroxines to
diunsaturated carbonyl compounds, see: Nishimura, T.;
Yasuhara, Y.; Hayashi, T. Angew. Chem. Int. Ed. 2006, 45,
5164.
Acknowledgment
(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%)..
Projects UCM-BSCH PR34-07-15878, UCM GR74/07-910815,
and CTQ2006-15279-C03-01 are gratefully acknowledged for
financial support. Prof. J. Plumet (UCM) is thanked for his valuable
discussions about the paper.
(10) General Procedure for the RhI-Catalyzed Addition of
Boronic Acids to 1a with NaHCO3 as Base (Table 1,
Entries 1–7)
References and Notes
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).
(1) See, for example: (a) Perlmutter, P. In Conjugate Addition
Reactions in Organic Synthesis; Pergamon: Oxford, 1992.
(b) Tomioka, K.; Nagaoka, Y. In Comprehensive
Asymmetric Catalysis, Vol. 3; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer: Berlin, 1999, Ch. 31.1.
(c) Kanai, M.; Shibasaki, M. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley: New York, 2000,
569. (d) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56,
8033. (e) Krause, N.; Hoffmann-Röder, A. Synthesis 2001,
171. (f) Lipshutz, B. H. In Organometallics in Organic
Synthesis. A Manual, 2nd ed.; Schlosser, M., Ed.; Wiley:
Chichester, 2002, 665; and references cited therein.
(2) First report: Sakai, M.; Hayashi, H.; Miyaura, N.
Organometallics 1997, 16, 4229.
(3) Reviews: (a) Hayashi, T. Synlett 2001, 879. (b) Fagnou, K.;
Lautens, M. Chem. Rev. 2003, 103, 169. (c) Hayashi, T.;
Yamasaki, K. Chem. Rev. 2003, 103, 2829. (d) Hayashi, T.
Pure Appl. Chem. 2004, 76, 465. (e) Hayashi, T. Bull.
Chem. Soc. Jpn. 2004, 77, 13. (f) Yoshida, K.; Hayashi, T.
In Modern Rhodium-Catalyzed Organic Reactions; Evans,
P. A., Ed.; Wiley-VCH: Weinheim, 2005, Chap. 3, 55.
(4) For recent leading references, see: (a) Fredrick, M. A.;
Hulce, M. Tetrahedron 1997, 53, 10197. (b) Krause, N.;
Gerold, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 186.
(c) Krause, N.; Thorand, S. Inorg. Chim. Acta 1999, 296, 1.
(d) Fukuhara, K.; Urabe, H. Tetrahedron Lett. 2005, 46,
603. (e) Yoshikai, N.; Yamashita, T.; Nakamura, E. Angew.
(11) General Procedure for the RhI-Catalyzed Addition of
Boronic Acids to 1a and 2a with Et3N 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 mL, 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).
(13) General Procedure for the RhI-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
Synlett 2009, No. 4, 585–588 © Thieme Stuttgart · New York

588
G. de la Herrán, A. G. Csákÿ
LETTER
[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).
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): d = 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):
d = 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.
(14) Compound 1c was prepared by cross-metathesis reaction
between 1a and 1-octene (5% Grubbs II catalyst, CH2Cl2,
r.t., 18 h, 60% yield).
(15) Reviews: (a) Yamamoto, Y.; Nishikata, T.; Miyaura, N.
J. Synth. Org. Chem., Jpn. 2006, 64, 1112. (b) Gutnov, A.
Eur. J. Org. Chem. 2008, 4547. (c) Yamamoto, Y.;
Nishikata, T.; Miyaura, N. Pure Appl. Chem. 2008, 80, 807;
and references cited therein.
(E)-2-(3,3-Diphenylpropenyl)malonic Acid Diethyl Ester
(3h)
1H NMR (200 MHz, CDCl3): d = 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): d = 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): d = 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): d = 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.
(16) Horiguchi, H.; Tsurugi, H.; Satoh, T.; Miura, M. J. Org.
Chem. 2008, 73, 1590.
(17) General Procedure for the Pd2+-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).
2-(5-Phenylpent-4-enylidene)malonic Acid Diethyl Ester
(4d)
1H NMR (200 MHz, CDCl3): d = 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): d = 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.
(18) Representative Data
(E)-2-(3-Phenylpropenyl)malonic Acid Diethyl Ester (3a)
1H NMR (200 MHz, C6D6): d = 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): d = 168.5, 139.7, 135.3, 128.8, 128.7, 126.4,
Synlett 2009, No. 4, 585–588 © Thieme Stuttgart · New York

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