Arylation and vinylation of α-diazocarbonyl compounds with boroxines

Article abstract of DOI:10.1021/ol900362d

An alternative approach for α-arylation and α-vinylation of carbonyl compounds is described: reaction between aryl-or vinylboroxines with α-diazocarbonyl compounds leads to the formation of α-arylated or α-vinylated carbonyl compounds under mild conditions.

Full text of DOI:10.1021/ol900362d

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1667-1670
Arylation and Vinylation of
r-Diazocarbonyl Compounds with
Boroxines
Cheng Peng,† Wei Zhang,† Guobing Yan,‡ and Jianbo Wang*,†,‡
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of
Chemistry, Peking UniVersity, Beijing 100871, China, and Department of Chemistry,
Tongji UniVersity, Shanghai 200092, China
wangjb@pku.edu.cn
Received February 19, 2009
ABSTRACT
An alternative approach for r-arylation and r-vinylation of carbonyl compounds is described: reaction between aryl- or vinylboroxines with
r-diazocarbonyl compounds leads to the formation of r-arylated or r-vinylated carbonyl compounds under mild conditions.
R-Arylation and R-vinylation of carbonyl compounds are
very important in organic synthesis. Although various
approaches have been developed for these purposes, they
usually suffer drawbacks in one way or another. Recently,
palladium-catalyzed R-arylation and R-vinylation of carbonyl
compounds, which are mostly developed by Buchwald and
Hartwig, have been shown to provide simple and efficient
methods to introduce aryl and vinyl groups to the R carbon
of carbonyl compounds.1,2 However, these catalytic processes
have to be carried out under strong basic conditions. An
indirect approach toward R-arylated carbonyl compounds
would be the arylation of the corresponding R-diazocarbonyl
compounds, which could be easily available through diazo-
tization of the corresponding carbonyl compounds under mild
conditions (Scheme 1). In this paper, we report an alternative
Scheme 1. R-Arylation of Carbonyl Compounds
† Peking University.
‡ Tongji University.
(1) For seminal reports, see: (a) Palucki, M.; Buchwald, S. L. J. Am.
Chem. Soc. 1997, 119, 11108. (b) Hamann, B. C.; Hartwig, J. F. J. Am.
Chem. Soc. 1997, 119, 12382. (c) Satoh, T.; Kawamura, Y.; Miura, M.;
Nomura, M. Angew. Chem., Int. Ed. 1997, 36, 1740
.
(2) For selected recent publications, see: (a) Hama, T.; Culkin, D. A.;
Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 4976. (b) Takemiya, A.;
Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 14800. (c) Mart´ın, R.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 7236. (d) Huang, J.;
Bunel, E.; Faul, M. M. Org. Lett. 2007, 9, 4343. (e) Liao, X.; Weng, Z.;
Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 195. (f) Durbin, M. J.; Willis,
M. C. Org. Lett. 2008, 10, 1413. (g) Vo, G. D.; Hartwig, J. F. Angew.
R-arylation method by the reaction of R-diazocarbonyl
compounds with easily accessible arylboroxines. This ap-
proach also applies to R-vinylation by using the correspond-
ing vinylboroxines.
Chem., Int. Ed. 2008, 47, 2127
.
10.1021/ol900362d CCC: $40.75
Published on Web 03/04/2009
2009 American Chemical Society

The reactions of R-diazocarbonyl compound with orga-
noboron compounds have been previously reported to form
a C-C bond between alkyl or aryl and an R carbon of
carbonyl group.3-7 Pioneering work by Hooz and co-workers
established the alkylation of diazonitrile, ethyl diazoacetate,
and diazoketones by means of trialkylboranes.3 The reactions
reported by Hooz are only limited to alkylboranes, and the
reaction is sluggish with poor yields for organoboranes
containing relatively bulky alkyl groups. Further improve-
ment was made by Brown, Hooz, and co-workers by using
dialkylchloroboranes and alkyl- or aryldichloroboranes,
which are more reactive boron reagents toward diazo
compounds.4 The drawback of Brown’s modification is that
chlorinated byproducts are formed in some cases due to the
competing 1,2-chloro migration. Particularly notable in this
modification is that arylation can occur with high yields by
using aryldichloroboranes,4b and most recently, Brown and
Salunkhe have extended this reaction by using alkenyldi-
chloroboranes.6 However, these otherwise very attractive
arylation and vinylation reactions have so far received limited
attention, presumably because toxic and unstable boron
compounds are used, and the reactions have to be carried
out at low temperature. Moreover, in Brown’s report, only
ethyl diazoacetate is applied as a diazo substrate.
At the outset of this investigation, we examined the
reaction of methyl R-diazopropionate 1a with phenylboronic
acid 2 (eq 1). The R-arylation product 3a was isolated, albeit
in low yield. Subsequent efforts to optimize this reaction
proved fruitless. When phenyl pinacolborane 4 was used
instead of boronic acid, 3a was not observed, and most
starting materials remained unchanged after stirring at 80
°C for 24 h. To our delight, when phenylboronic acid 2 was
replaced by phenylboroxine 5a, the reaction under the same
conditions was found to be faster and the yield was slightly
higher.
Further optimization of the reaction conditions was carried
out. The results are summarized in Table 1. Changing solvent
Table 1. Optimization of Reaction Conditions with Methyl
R-Diazopropionate 1a and Phenylboroxine 5aa
Mechanistically, it is reasonable to consider that these
reactions are initiated by the nucleophilic attack of diazo
substrate to boron. Thus, increasing the electronegativity in
the boron should enhance the reaction. This explains the high
reactivity with dialkylchloroboranes and alkydichloroboranes
in Brown’s reaction, as compared with the original trialky-
lboranes in Hooz’s system. In view of the fact that orga-
noboronic acids and their derivatives, which are stable,
nontoxic, and easily available, are gaining popularity within
the synthetic organic chemistry community,8,9 we have
conceived that it is worthwhile to investigate the reaction of
diazo compounds with boronic acids and their derivatives.10
additive
(3 equiv)
entry
solvent
T (°C)
yieldb (%)
1
2
3
4
5
6
7
8
non
non
non
non
non
Non
Et3N
pyridine
morpholine
iPr2EtN
iPr2NH
iPr2NH
iPr2NH
iPr2NH
iPr2NH
PhMe
PhMe
PhH
n-hexane
DCE
80
40
60
60
60
60
60
60
60
60
60
60
60
60
60
50
33
31
24
30
38
72
68
60
49
82
88
91
85
79
Et3N
(3) (a) Hooz, J.; Linke, S. J. Am. Chem. Soc. 1968, 90, 5936. (b) Hooz,
J.; Linke, S. J. Am. Chem. Soc. 1968, 90, 6891. (c) Hooz, J.; Morrison,
G. F. Can. J. Chem. 1970, 48, 868. (d) Hooz, J.; Gunn, D. M. J. Chem.
Soc., Chem. Commun. 1969, 139. (e) Hooz, J.; Gunn, D. M. Tetrahedron
Lett. 1969, 3455. (f) Hooz, J.; Gunn, D. M. J. Am. Chem. Soc. 1969, 91,
PhMe
PhMe
PhMe
PhMe
PhMe
DCE
DCE
THF
DCE
9
10
11
12
13c
14c
15d
6195
.
(4) (a) Brown, H. C.; Midland, M. M.; Levy, A. B. J. Am. Chem. Soc.
1972, 94, 3662. (b) Hooz, J.; Bridson, J. N.; Calzada, J. G.; Brown, H. C.;
Midland, M. M.; Levy, A. B. J. Org. Chem. 1973, 38, 2574
.
(5) For further applications of the Hooz reaction, see: (a) Pasto, D. J.;
Wojtkowski, P. W. Tetrahedron Lett. 1970, 215. (b) Pasto, D. J.;
Wojtkowski, P. W. J. Org. Chem. 1971, 36, 1790. (c) Newman, H. J. Org.
Chem. 1974, 39, 100. (d) Hooz, J.; Bridson, J. N. J. Am. Chem. Soc. 1973,
95, 602. (e) Hooz, J.; Oudenes, J.; Roberts, J. L.; Benderly, A. J. Org.
a If otherwise indicated, the reaction was carried out with 1.0 equiv of
diazo compound, 1.5 equiv of (PhBO)3. b Yields calculated from GC using
mesitylene as an internal standard. c 1.0 equiv of (PhBO)3 was used. d 0.6
equiv of (PhBO)3 was used.
Chem. 1987, 57, 1347
.
(6) Brown, H. C.; Salunkhe, A. M. Synlett 1991, 684
.
(7) For comprehensive reviews on diazo compounds, see: (a) Doyle,
M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds; Wiley-Interscience: New York, 1998.
(b) Ye, T.; McKervey, M. A. Chem. ReV. 1994, 94, 1901. (c) Zhang, Z.;
and temperature seemed not improve the yields (entries 1-6).
It was then observed that the reaction could be significantly
improved by adding base as additives, among which diiso-
propylamine afforded the best results (entry 11). The reaction
Wang, J. Tetrahedron 2008, 64, 6577
.
(8) For reviews on Suzuki-Miyaura coupling, see: (a) Suzuki, A. Acc.
Chem. Res. 1982, 15, 178. (b) Miyaura, N.; Suzuki, A. Chem. ReV. 1995,
95, 2457. (c) Miyaura, N. J. Organomet. Chem. 2002, 653, 54. (d) Miyaura,
N. In AdVances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI:
London, 1998; Vol. 6, pp 187
(9) For use of arylboroxines in organic synthesis, see: (a) Hayashi, T.;
.
(10) For a recent report on Pd-catalyzed coupling of arylboronic acids
with R-diazocarbonyl compounds, see: Peng, C.; Wang, Y.; Wang, J. J. Am.
Chem. Soc. 2008, 130, 1566.
Senda, T.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 1999, 121, 11591.
(b) Chen, F.-X.; Kina, A.; Hayashi, T. Org. Lett. 2006, 8, 341
.
1668
Org. Lett., Vol. 11, No. 7, 2009

could be further improved by using 1,2-dichloroethane (DCE)
as solvent (entry 13). Since three phenyl groups in one
phenylboroxine can be theoretically transferred to the
product, we proceeded to reduce the amount of phenylborox-
ine. One equivalent of boroxine afforded satifactory results
(entry 13). When the phenylboroxine was further reduced,
the reaction became sluggish and the yield was diminished
due to the side reactions of diazo substrate (entry 15).
In Hooz and Brown’s reports, only the diazo compounds
without R-substitution (N2CHA, A ) CN, CO2Et, COMe,
COPh, etc.), in most cases the ethyl diazoacetate, were
investigated. As a general R-arylation method, more diazo
substrates with structural diversity have to be employed.
Thus, the optimized reaction conditions were applied to the
reaction of 5a with various R-diazocarbonyl compounds
(Table 2). The R-phenylation products were obtained in
(entry 12). Since the R-aryl-R-diazoacetates are easily
available from the corresponding R-arylacetates,11 this
process constitutes a practical access to R,R-diaryl-substituted
acetates.
Furthermore, a series of arylboroxines were examined
through the reaction with p-tolyldiazoacetate 6 under the
same conditions at 100 °C. As shown in Table 3, the
Table 3. Reaction of Arylboroxine 5b-h with 6a
entry
5, Ar′
time (h)
yield (7, %)b
1
2
3
4
5
6c
7
8
5b, p-CH3C6H4
5c, m-CH3C6H4
5d, m-ClC6H4
5e, m,p-Cl2C6H3
5f, m-NO2C6H4
5g, m-CHOC6H4
5h, p-CH3OC6H4
5i, 1-naphthyl
13
14
14
4
2
5
7a, 73
7b, 79
7c, 86
7d, 87
7e, 87
7f, 60
7g, 56
7h, 56
Table 2. Reaction of 1a-m with Phenylboroxine 5aa
13
11
a Reaction conditions: 5b-i (1.0 equiv), 6 (1.0 equiv). b Isolated yield.
diazo
substrate (1, R, R′)
c i-Pr2NH was replaced by Et3N.
entry
time (h)
yieldb (%)
1
2
3
4
5
6
7
8
1a, Me, OMe
1b, nPr, OMe
1c, Pr, OMe
4
9
3a, 84
3b, 84
3c, 65
3d, 91
3f, 90
3e, 96
3g, 68
3h, 61
3i, 64
3j, 78
3k, 81
3l, 61
3m, 56
reactions all proceeded well to afford diaryl-substituted
acetate products 7a-h. It was noted that the reaction was
significantly accelerated by electron-withdrawing substituents
of arylboroxines (entries 4-6).
i
10
12
49
48
43
48
48
16
2
1d, Bn, OMe
1e, H, OEt
1f, H, NiPr2
It is worthwhile to note that both the arylboroxine substrate
and the diazo substrate in this reaction can bear halide
substituents (Table 2, entries 8, 9, and 13; Table 3, entries 3
and 4). To introduce an aryl group bearing halide substituent
to the R-position of carbonyl group would be difficult with
the Pd-catalyzed reaction due to the anticipated side reactions.
The scope of this R-arylation approach was further
explored by using cyclic R-diazocarbonyl substrates (eqs 2
and 3). The reaction with cyclic R-diazoketone 8 and cyclic
R-diazo amide 9 under the same conditions provided the
corresponding R-arylation products in moderate yields.
1g, Me, C6H
1h, Me, p-ClC6H4
1i, Me, p-BrC6H4
1j, C6H5, OMe
1k, p-MeOC6H4,OMe
1l, p-BrC6H4, OMe
1m, 1-naphthyl, OMe
9
10
11
12
13
2
17
a The reaction was carried out with diazo compound (1.0 equiv) and
phenylboroxine (1.0 equiv) at 60 °C (for entries 1-4, 6-10) or 100 °C
(entries 5, 11-13). b Isolated yield.
moderate to high yields in all cases. Reaction with R-alkyl
substituted diazo esters gave the R-phenyl-substituted ali-
phatic esters in good yields (entries 2-4). When the alkyl
group was replaced by hydrogen, the reaction became
sluggish but the yield remained high (entries 5). Reaction
with R-diazoamide also worked well (entry 6), thus providing
an efficient way for R-arylation of amides.
The results for the reaction with R-diazoketones are also
summarized in Table 2 (entries 7-9). The slightly diminished
yields in these cases as compared with R-diazoesters might
be attributed to the decreased reactivity of the substrates
under the reaction conditions, which resulted in 1, 2-H shift
side reactions. Finally, the R-aryl-R-diazoacetates were also
studied (entries 10-13). Reactions with these substrates
needed a higher temperature to reach completion. The
electron-donating group was found to facilitate the reaction
Compared with R-arylation, R-vinylation of carbonyl
compounds has only been sparsely reported.2d,12 Encouraged
by the success of the R-arylation with arylboroxines, we
turned our attention to investigate the corresponding R-vi-
Org. Lett., Vol. 11, No. 7, 2009
1669

nylation by using vinylboroxine. With R-diazo amide 1f,
vinylboroxines 12a-f were applied to the similar reaction
conditions, and the results are summarized in Table 4. In all
Scheme 2. Mechanistic Rationale
Table 4. Reaction of Vinylboroxines 12a-f with 1fa
entry
12, R
12a, C6H5
12b, p-CH3C6H4
12c, p-ClC6H4
12d, 1-naphthyl
12e, n-pentyl
12f, BnOCH2CH2-
time (h)
yield (13, %)b
boron to carbon to give B. Hydrolysis of B leads to the
product. The additive of diisopropylamine has been found
to significantly improve the yield of the reaction. It was
observed that adding diisopropylamine could markedly slow
down the reaction. Since diazo compounds are generally
sensitive to acids, we speculate that the role of diisopropy-
lamine is to neutralize the reaction system by interact with
boroxine or acidic species generated during the reactions,
thus preventing the diazo substrate from decomposition.
In summary, we have developed a general approach for
R-arylation and R-vinylation by the reaction of R-diazocar-
bonyl compounds with boroxines. Since the reaction condi-
tions are mild and both diazo compounds and boroxines are
easily available, this reaction should find an application in
organic synthesis.
1
2
3
4
5
6
12
11
10
13
24
22
13a, 65
13b, 88
13c, 77
13d, 74
13e, 45
13f, 61
a Reaction conditions: 1f (1 equiv), 12a-f (1 equiv). b Isolated yield.
cases, the reaction occurred smoothly, giving R-vinylation
products in moderate to good yields. The byproduct attributed
from the shift of the double bond to the R,ꢀ position were
not detected in these cases. The same R-vinylation reaction
has also been tested with diazo ester 1a. In that case, the
major product of ꢀ,γ-unsaturated ester was accompanied by
small amount of R,ꢀ unsaturated ester as minor product.
The mechanism of this R-arylation and R-vinylation is
thought to be similar to the reaction of R-diazo compounds
with alkylborane (Scheme 2).3,4 The reaction is initiated by
nucleophilic attack of the diazo carbon to boroxine, generat-
ing intermediate A, followed by 1,2-migration of R′′ from
Acknowledgment. The project is generously supported
by the Natural Science Foundation of China (Grant Nos.
20832002, 20772003, and 20821062), the National Basic
ResearchProgramofChina(973Program,No.2009CB825300),
and the MOE of China (Cheung Kong Scholars Program).
Supporting Information Available: Experiment proce-
dure, characterization data, 1H and 13C NMR spectra for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(11) (a) Davies, H. M. L.; Townsend, R. J. J. Org. Chem. 2001, 66,
6595. (b) Zhang, X.; Qu, Z.; Ma, Z.; Shi, W.; Jin, X.; Wang, J. J. Org.
Chem. 2002, 67, 5621.
(12) For examples, see: (a) Ooi, T.; Goto, R.; Maruoka, K. J. Am. Chem.
Soc. 2003, 125, 10494. (b) Kim, H.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2008, 130, 398.
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