Olefination of carbonyl compounds through reductive coupling of alkenylboronic acids and tosylhydrazones

Article abstract of DOI:10.1002/anie.201200683

The partners decide: The C-C bond-forming reductive cross-coupling of alkenylboronic acids and tosylhydrazones takes place under mild reaction conditions without the need of a metal catalyst, thus giving rise to olefination-type products (see scheme). The position of the double bond in the product is determined by the structure of the coupling partners. Copyright

Full text of DOI:10.1002/anie.201200683

Angewandte
Chemie
DOI: 10.1002/anie.201200683
Synthetic Methods
Olefination of Carbonyl Compounds through Reductive Coupling of
Alkenylboronic Acids and Tosylhydrazones**
M. Carmen Pꢀrez-Aguilar and Carlos Valdꢀs*
À
The formation of C C bonds is a fundamental transformation
scope.[9] The mechanism proposed for this reaction comprises
the following steps (Scheme 1b): 1) decomposition of the
hydrazone in the presence of the base to form the diazo
compound A, 2) formation of the boronate intermediate B by
interaction of the boronic acid with the diazo compound,
À
of organic synthesis. Among the enormous variety of C C
bond-forming reactions currently available, metal-catalyzed
cross-couplings stand as some of the more versatile and
reliable methodologies.[1] In spite of this, the need of
a transition-metal catalyst is a drawback because of the high
cost and toxicity of the most popular metals. For these
À
3) C C bond formation by migration of the R group with loss
of nitrogen to give the intermediate boronic acid C, and
4) protodeboronation to give the final product.
À
reasons, C C bond-forming reactions that might work with
the same levels of efficiency and selectivity as transition metal
catalyzed reactions, but that do not need the addition of
a transition metal, so called metal-free cross-couplings, are
highly desirable, and indeed, have attracted increasing
attention in the recent years.[2]
These reactions proceed very efficiently with aryl and
alkylboronic acids. However, preliminary investigation of the
reactions with alkenylboronic acids gave a less satisfactory
result because of the formation of a mixture of isomers arising
from the position of the double bond. This result could be
rationalized considering that the initially formed allylboronic
acid could suffer a direct g-protodeboronation or a 1,3-
borotropic rearrangement/a-protodeboronation sequence.[10]
Taking into consideration the interest of these metal-free
reductive couplings, we initiated a study to investigate in more
detail the reactions with alkenylboronic acids, with the aim to
develop reaction conditions or combinations of reagents
which might lead to a single isomer of the reductive coupling
alkene, and therefore, convert these transformations into
more relevant synthetic processes.
In the context of our interest on sulfonylhydrazones as
versatile intermediates in organic synthesis,[3] we have
À
recently described
a new C C bond-forming reaction
between tosylhydrazones 1 and boronic acids 2, which gives
rise to the reductive coupling products 3 (Scheme 1a).[4–6] This
process takes place without the need for a metal catalyst[7–8]
under extremely simple reaction conditions (just in the
presence of K2CO3), and exhibits
a remarkably wide
We initially focused on the reaction between the hydra-
zone 1a, and 2-phenylvinylboronic acid (2a; Scheme 2a). An
extensive study of bases and reaction conditions was carried
out,[11] and although a moderate influence of the base
employed was found, the process could not be driven to
give a single compound. The best results in terms of yield and
selectivity were obtained by employing K2CO3 or NaOH as
Scheme 1. Reductive coupling of tosylhydrazones with aryl and alkyl-
boronic acids and mechanism proposed. Ts=4-toluenesulfonyl.
[*] M. C. Pꢀrez-Aguilar, Dr. C. Valdꢀs
Instituto Universitario de Quꢁmica Organometꢂlica “Enrique
Moles”, Universidad de Oviedo
c/Juliꢂn Claverꢁa 8, 33006 Oviedo (Spain)
E-mail: acvg@uniovi.es
[**] Financial support of this work from the DGI of Spain (CTQ-2010-
16790) and Consejerꢁa de Educaciꢃn y Ciencia of Principado de
Asturias (IB08-088) is acknowledged. A FPI predoctoral fellowship
to M.C.P.-A. is gratefully acknowledged. We wish to thank Prof. Josꢀ
Barluenga for his constant encouragement and support.
Scheme 2. Preliminary experiments of reductive couplings of tosylhydra-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200683.
zones with alkenylboronic acid 2a. Influence of the base and the structure
of the hydrazone on the ratio of isomers.
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Table 1: Olefination of tosylhydrazones 1 by reaction with alkenylboronic
acids 2.[a]
the base, and incorporating 2 equivalents of CsF into the
reaction mixture (Scheme 2a). In all cases, the stereoisomeric
compounds 5a and 5a’, wherein the double bond has
migrated, are obtained as the major product. Notably, by
employing an equimolar amount of NaOH and CsF, the
formation of the isomer 4a, which retains the double bond in
the original position, is reduced to only 6%.
Entry Product
Ar (5)
Method[b] Yield
[%][c]
Interestingly, when the same reaction was conducted by
employing the hydrazone 1b, derived from cyclohexanone,
the isomer 5b was the only product detected in the reaction
mixture (Scheme 2b). After some optimization,[11] the best
reaction conditions found employed of a combination of
K2CO3 (2 equiv) and CsF (2 equiv) in 1,4-dioxane at 1108C .
These reaction conditions were then applied to a set of
structurally diverse hydrazones to evaluate the scope of the
process. In the course of the study, we found that the use of
microwave heating under similar reaction conditions (K2CO3,
CsF, 1,4-dioxane; Method B) or in the absence of CsF but
employing a 1:1 mixture of 1,4-dioxane/MeOH as the solvent
(Method C), not only reduces dramatically the reaction times
(12 h to 30 min), but also increases the yields in many of the
examples. Moreover, some reactions that failed under ther-
mal conditions gave rise to the desired olefination product
with satisfactory yields under microwave irradiation. The
most relevant results of this study are presented in Table 1.[11]
First of all, it must be pointed that in all the reactions with
hydrazones derived from dialkyl ketones, the trisubstitued
alkene 5 was the only product detected in the crude reaction
mixture (Table 1, entries 1–27). The reaction is very general
with regard to the structure of the dialkyl ketone, and can be
applied to a wide variety of systems, including hydrazones
derived from carbocyclic, heterocyclic (entries 7–10, 21), and
acyclic ketones (entries 25–27). Interestingly, the reactions
with nonsymmetrically substituted hydrazones provide,
depending on the size of the substituents, a single isomer
(entries 20, 24, and 27) or a mixture of Z/E steroisomers
(entries 18, 19, and 21) in which the major isomer has the
benzyl group on the side opposite to the bulkier substituent.
The reaction was extended also to other styrylboronic
acids, featuring either electron-withdrawing or electron-
donating substituents, and proceeded with similar yields
(Table 1, entries 2–5, 8, 9, 14–17, and 26). The regioselective
reaction is not restricted to dialkyl hydrazones, as diaryl-
substituted hydrazones also exclusively provided the olefina-
tion isomer 5 (entries 28 and 29). Another challenging
example is the olefination of the hydrazone derived from
carvone (entry 30) as a representative of a a,b-unsaturated
carbonyl compound. Again the reaction gives rise to a single
positional isomer, and moreover, to a single stereoisomer,
because of the presence of the methyl substituent, which
determines the configuration of the new double bond.
However, the reaction with the hydrazone derived from
methyl pyruvate led to a 1:1 mixture of the two double bond
regioisomers (entry 31), and as in the example presented in
Scheme 2, reactions of hydrazones derived from alkyl aryl
ketones participate in a reaction leading to Z/E mixtures of
the two possible olefination products 5 and 5’, and in some
cases small amounts of the regioisomer 4.[11,12]
1
2
3
4
5
Ph (5b)
B
B
B
B
B
88 (78)[e]
4-MeOC6H4 (5bb)
4-CF3C6H4 (5bc)
3-FC6H4 (5bd)
4-ClC6H4 (5be)
92
52 (51)[e]
89
76 (59)[e]
6
Ph (5c)
B
86
7
8
9
Ph (5da)
4-MeOC6H4 (5db)
4-CF3C6H4 (5dc)
B
A
B
82 (57)[e]
57
68
10
11
Ph (5e)
Ph (5 f)
B
B
82
77
12
Ph (5g)
C
80
13
14
15
16
17
Ph (5ha)
C
C
C
C
C
81
70
83
93
79
4-MeOC6H4 (5hb)
4-CF3C6H4 (5hc)
3-FC6H4 (5hd)
4-ClC6H4 (5he)
18[d]
Ph (5i)
A
93
19[d]
Ph (5j)
Ph (5k)
A
A
50
49
20[d]
21[d]
Ph (5l)
B
78
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Table 1: (Continued)
The reactions of cyclic tosylhydrazones are noteworthy
Entry Product
Ar (5)
Method[b] Yield
[%][c]
for various reasons: 1) cyclic tosylhydrazones provide
extremely poor yields in the reductive couplings with
arylboronic acids, however, perform very well with alkenyl-
boronic acids; 2) the products obtained are the thermody-
namically unstable isomers which feature an exocyclic double
bond and are not conjugated with the aromatic ring. More-
over, from a synthetic point of view, these transformations can
be envisioned as a new type of olefination reaction of
carbonyl compounds,[14] a key transformation in organic
synthesis, and is achieved in a very simple manner—no
metal catalyst, no inert atmosphere or dry solvents are
needed—and from readily available starting materials.
22
Ph (5m)
Ph (5n)
Ph (5o)
C
C
C
78
89
86
23
24[d]
We next turned our attention to 2-alkyl-substituted
alkenylboronic acids 6 (Table 2). The reactions proceeded
with moderate yields, and in general, the microwave-pro-
moted reactions provided better results. Quite surprisingly,
the regioselectivity of the reactions was completely reversed
from the reactions with styrylboronic acids 2. Now, in most of
the examples studied, the regioisomer 7, in which the double
bond in the original position is preserved, was obtained as the
major isomer. Remarkable regioselectivity was obtained for
the reactions of dialkyl hydrazones (entries 1–3). Moreover,
25
26
Ph (5pa)
4-MeOC6H4 (5pb)
B
A
88
87
27[d]
Ph (5q)
A
96
28
29
Ph (5r)
Ph (5s)
B
A
63
55
Table 2: Reductive alkenylation of tosylhydrazones 1 by reaction with
alkenyl boronic acids 6.[a]
30
31
Ph (5t)
B
A
70
73
Entry
1
Product
R (7)
Yield [%][b]
57(94:6)[c]
Ph (5u/4u)
Bn (7a)
2[e]
3[e]
nC3H7 (7ba)
Bn (7bb)
62 (91:9)[c]
69 (94:6)[c]
[a] Method A: N-tosylhydrazone 1, (1.0 equiv); boronic acid 2, (2 equiv);
K2CO3, (2 equiv); CsF, (2 equiv), 1,4-dioxane, 1108C, 12–14h. Method B:
N-tosylhydrazone 1, (1.0 equiv); boronic acid 2, (2 equiv); K2CO3,
(2 equiv); CsF, (2 equiv), 1,4-dioxane, MW, 1508C, 30min. Method C:
N-tosylhydrazone 1, (1.0 equiv); boronic acid 2, (2 equiv); K2CO3,
(2 equiv); 1,4-dioxane/methanol (1:1 v/v) MW, 1508C, 30min. [b] Data
for the highest yielding method (see the Supporting Information for
a more detailed table). [c] Yields of isolated products after column
chromatography. [d] The stereochemistry of the major isomer was
established based on two-dimensional and selective nOe experiments.
[e] The yield for the one-pot reaction is indicated within parentheses.
Reaction conditions: ketone, (1 equiv); tosylhydrazide, (1 equiv), 1,4-
dioxane, MW, 468C, 30 min; then, boronic acid 2 (2 equiv); K2CO3,
(2 equiv); CsF, (2 equiv), MW, 1508C, 30 min. Bn=benzyl,
4
Bn (7c)
68 (50:50)[c]
5
6
7
Bn (7da)
nC6H13 (7 db)
Cy (7dc)
61
49
35
8
Bn (7e)
61
9
10
11
Bn (7 fa)
nC6H13 (7 fb)
Cy (7 fc)
63
58
40
MW=microwave, PMP=para-methoxyphenyl.
12
nC6H13 (7 fd)
35
Finally, like in many other processes involving tosyl-
hydrazones, the reductive couplings can be conducted in
[a] Reaction conditions: N-tosylhydrazone 1, (1.0 equiv); boronic acid 6,
(2 equiv); K2CO3, (2 equiv); CsF, (2 equiv); 1,4-dioxane, MW, 1508C,
30 min. [b] Yields of isolated products after column chromatography.
a
one-pot fashion directly from the carbonyl com-
pounds,[4,8e,13] thus providing the olefination products 5 with
complete regioselectivity albeit in yields slightly lower than
the reactions from the recrystallized tosylhydrazones
(Table 1, entries 1, 3, 5, and 7).
1
[c] The ratio of double bond regioisomers determined by H NMR
spectroscopy of the crude reaction mixture is indicated within paren-
1
theses. [e] The stereochemistry was established based on the H NMR
spectra.
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in the reactions with hydrazones derived from ethyl pyruvate
and pyruvic amides, the disubstitued alkenes are obtained as
a unique positional isomer (entries 5–12).[15] Only the reaction
with an aryl-substituted hydrazone (entry 4) led to a 1:1
mixture of regioisomers. Furthermore, the E stereochemistry
of the boronic acid is retained in the final product. The high
functional-group tolerance of the reaction must be noted, that
is, it can be carried out in the presence of a carboxylic ester
and even NH- or NH2 unprotected amides.
The complete diastereoselectivity observed in the reac-
tions with the hydrazone derived from 4-phenylcyclohexa-
none (Table 2, entries 2 and 3) is also worth noting. Only one
of the two possible diastereoisomers was detected in the
reaction, and thus corresponds to the incorporation of the
new R group in the equatorial position.[16] These are examples
of facial diasteresoselectivity in the reactions between a tosyl-
hydrazone and a boronic acid, a new feature that enhances the
respectively. Mechanistic and theoretical studies are under-
way.
In conclusion, we have presented a very general and
efficient reductive coupling between tosylhydrazones and
alkenylboronic acids, a coupling that can be envisoned as
a new type of olefination of carbonyl compounds though
À
tosylhydrazones. This C C bond-forming reaction takes place
under very simple reaction conditions without the need of
metal catalysts or inert atmosphere, and tolerates a variety of
functional groups. Depending on the nature of the substitu-
ents, and in a predictable manner, the reaction gives rise to
different isomers that differ in the position of the double
bond. For the reasons above, and taking into consideration
the generality of the process, and the ready availability of
both types of coupling partners, we believe that these
reactions may be very useful in organic synthesis.
À
Received: January 25, 2012
synthetic value of this C C bond-forming reaction.
Considering the results presented in Table 1 and Table 2,
the dramatic influence of the substituents of both coupling
partners in the outcome of these reactions is apparent. Table 3
Keywords: alkenes · boron · cross-coupling · hydrazones ·
.
synthetic methods
Table 3: Summary of the expected product distribution depending on the
substituents of the coupling partners.
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R1
R2
R3
g
a
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alkyl
alkyl
aryl
alkyl
alkyl
alkyl
alkyl
aryl
aryl
95–90
100
100
50
50
5–10
0
5–10
0
0
50
50
alkyl
aryl
aryl
aryl
aryl
alkyl
alkyl
alkyl
EWG]
aryl
akyl
EWG
95–90
100
EWG=electron-withdrawing group.
summarizes our observations, and allow one to predict the
particular isomer that is expected depending on the nature of
the reactants. An explanation of these observations will
probably depend on the relative rate of a and g protodeboro-
nations of the allylboronic intermediate D, which will be
affected by the substitution.[17] As suggested by one of the
referees, in the reactions with styrylboronic acids (R3 = Ar)
the stabilization of an incipient negative charge at the
benzylic position may favor the g protodeboronation, and
therefore the alternation of the double bond. This effect is not
present in the reactions with alkyl-substituted boronic acids
(R3 = Ar), and consequently a-protodeboronation, with pres-
ervation of the stereochemistry of the double bond, might
take place. In contrast, and for similar reasons, electron-
withdrawing groups in the hydrazone fragment (R2 = CO2Me,
CONHR) may favor the a protodeboronation, thus either
decreasing or enhancing the regioselectivity of the reactions
with styrylboronic acids and alkyl-substituted boronic acids,
[6] For a related reactions of boroxines with a-diazocarbonyl
compounds, see: C. Peng, W. Zhang, G. Yan, J. Wang, Org.
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vinylboroxines has been reported by Wang and co-workers
(Ref. [6]), thus giving rise to the corresponding nonconjugated
vinylation products as unique isomers, regardless of the alkyl or
aryl substitution of the boroxine, while the reactions with a-
diazoesters provide a mixture of regioisomers.
[16] The relative stereochemistry was determined based on the
analysis of the 1H NMR spectra. See the Supporting Information
for details.
[9] The application of this reaction in the parallel synthesis of
druglike molecules has been recently addressed: S. Nakagawa,
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[11] See the Supporting Information for more details.
[12] No regioselectivity was observed in reactions with hydrazones
derived from aromatic aldehydes, which gave rise to a 1:1
mixture of positional isomers of the double bond.
[17] A mechanistic pathway involving a [1,3]-borotropic rearrange-
ment cannot be excluded. For studies on [1,3]-borotropic
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Brown, M. V. Rangaishenvi, Tetrahedron Lett. 1990, 31, 7115;
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metallics 1992, 11, 1948; d) H. C. Brown, A. S. Phadke, N. G.
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