Functionalized alkenylzinc reagents bearing carbonyl groups: Preparation by direct metal insertion and reaction with electrophiles

Article abstract of DOI:10.1002/anie.201302058

Highly functionalized cyclic and acyclic alkenylzinc reagents bearing functional groups such as aldehyde, keto, and ester groups were readily prepared by either direct zinc insertion in the presence of LiCl or by magnesium insertion in the presence of LiC

Full text of DOI:10.1002/anie.201302058

Angewandte
Chemie
DOI: 10.1002/anie.201302058
Organozinc Reagents
Functionalized Alkenylzinc Reagents Bearing Carbonyl Groups:
Preparation by Direct Metal Insertion and Reaction with
Electrophiles**
Christoph Sꢀmann, Matthias A. Schade, Shigeyuki Yamada, and Paul Knochel*
Dedicated to the Bayer company on the occasion of its 150th anniversary
Functionalized alkenes bearing aldehyde, keto, or ester
functions are found in a plethora of natural products as well
as in pharmaceutically active substances.[1] Consequently,
functionalized alkenyl organometallic compounds bearing
such sensitive carbonyl groups are important intermediates in
organic synthesis. In particular, alkenylzinc halides would be
useful targets due to their high functional-group tolerance
and their excellent reactivity in the presence of an appro-
Scheme 1. LiCl-mediated zinc insertion in 1a leading to 2a.
priate catalyst.[2] Functionalized alkenyl organometallic com-
pounds are mostly prepared by halogen–metal exchange
reactions of the corresponding iodoalkenes.[3] The major
drawbacks of this method are the low reaction temperatures
required and the use of expensive alkenyl iodides as the
starting material. Furthermore, only a few direct insertion
reactions for the synthesis of unfunctionalized alkenyl
organometallics have been reported.[4] For instance, Rieke
et al. described the use of highly active zinc (Zn*), which was
prepared by reduction of ZnCl2 with lithium naphthalide, for
the synthesis of styrylzinc bromide.[5]
Recently, we have developed a practical and useful
method for the synthesis of alkyl-,[6] aryl-,[6b,7] and benzylzinc
halides[8] by the LiCl-mediated metal-insertion reaction of the
corresponding chlorides and bromides. Herein, we now report
the convenient, mild, and atom-economical[9] preparation of
highly functionalized alkenylzinc reagents starting from read-
ily available alkenyl bromides bearing, for the first time,
sensitive functional moieties such as aldehyde, keto, and ester
groups.
transfer from the zinc to the organohalide through conjuga-
tion and enables therefore this exceptionally fast insertion
reaction. A subsequent Pd-catalyzed Negishi cross-coupling
reaction[11,12] with 4-bromobenzonitrile (3a) using 2 mol%
[Pd(PPh3)4][13] affords the highly functionalized benzonitrile
4a in 82% yield. Moreover, the CuI-catalyzed allylation
reaction[14] with ethyl 2-(bromomethyl)acrylate (3b) leads to
the desired product 4b in 94% yield (Table 1, entry 1). The
copper-catalyzed reaction[14,15] of 2a with bromoacetylene
3c[16] affords the highly functionalized acetylene 4c in 80%
yield (Table 1, entry 2). Furthermore, the acylation reac-
tion[13] using 2-bromobenzoyl chloride (3d) affords ketone 4d
in 51% yield (Table 1, entry 3). Additionally, the Pd-cata-
lyzed cross-coupling reaction with 5-bromo-3-cyanopyridine
(3e) furnishes the highly functionalized cyclohexenyl deriv-
ative 4e in 65% yield (Table 1, entry 4). Finally, the reaction
of 2a with the Tietze immonium reagent 3 f[17] leads to the
aminoaldehyde 4 f (68% yield; Table 1, entry 5). The hetero-
cyclic dihydropyranylzinc derivative 2b can also be prepared
by direct zinc insertion using zinc powder (1.5 equiv) in the
presence of LiCl (1.5 equiv, 258C, 1 h, 77% yield). After
reaction with the immonium salt 3 f, the N,N-dimethylami-
nomethyl-substituted dihydropyran derivative 4g was iso-
lated in 88% yield (Table 1, entry 6).
Furthermore, alkenyl bromides bearing a keto function,
such as 3-bromocyclohexenone (1c), react readily with zinc
powder (2 equiv) and LiCl (2 equiv) at 258C within 30 min to
give the corresponding zincated cyclohexenone 2c (86%).[18]
The subsequent Pd-catalyzed cross-coupling reaction with 4-
bromobenzonitrile (3a) affords the 3-substituted cyclohexe-
none derivative 4h in 88% yield (Table 1, entry 7). CuI-
mediated reactions of 2c with 3-bromocyclohexene (3g) and
bromoacetylene 3c furnish the unsaturated ketones 4i and 4j,
respectively, in 71–76% yield (Table 1, entries 8 and 9).
Analogously, 3-bromocyclopentenone (1d) was converted to
the alkenylzinc reagent 2d in 94% yield (258C, 5 h). The
subsequent Pd-catalyzed cross-coupling with 4-(trifluoro-
methyl)bromobenzene (3h) leads to the substituted cyclo-
Thus, 2-bromocyclohex-1-enecarbaldehyde (1a) under-
goes a smooth zinc insertion using commercially available
zinc powder (1.5 equiv, 258C, 1 h) in the presence of LiCl
(1.5 equiv), leading to the zinc reagent 2a (86% yield,
Scheme 1).[10] The presence of the electron-withdrawing
formyl group on the double bond accelerates the electron
[*] C. Sꢀmann, Dr. M. A. Schade, Dr. S. Yamada, Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
E-mail: Paul.Knochel@cup.uni-muenchen.de
[**] We thank the European Research Council under the European
Community’s Seventh Framework Programme (FP7/2007–2013,
ERC grant agreement no. 227763) and the Deutsche Forschungs-
gemeinschaft (DFG) for financial support. We also thank BASF SE
(Ludwigshafen), W. C. Heraeus (Hanau), and Chemetall GmbH
(Frankfurt) for generous gifts of chemicals.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302058.
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Table 1: Reactions of alkenylzinc reagents of type 2 with electrophiles.
Table 1: (Continued)
Entry Organozinc reagent Electrophile
(yield [%])[a]
Product
Yield
[%][b]
Entry Organozinc reagent Electrophile
(yield [%])[a]
Product
Yield
[%][b]
94[c]
80[d]
14
15
2 f
3g
3b
4o
4p
96[c,f]
1
2
2a (86)
3b
3c
4b
4c
2a
2g (35)
95[d,f]
3
2a
3d
4d
51[d]
16
17
2h (41)
2i (62)
3b
3b
4q
4r
89[d,f]
4
5
2a
2a
3e
3 f
4e
4 f
65[e]
68
79[d,f]
85[d,f]
6
2b (77)
3 f
4g
88
18
2i
3k
4s
[a] Determined by titration with I2. [b] Yield of isolated, analytically pure
product. [c] 3 mol% CuCN·2LiCl was used. [d] 1 equiv CuCN·2LiCl was
used. [e] 2 mol% [Pd(PPh3)4] was used and the reaction was performed
at 508C. [f] Z/E>99:1.
7
2c (86)
3a
3g
3c
3h
4h
4i
88[e]
76[c]
71[d]
74[e]
pentenone 4k in 74% yield (Table 1, entry 10). Moreover, (2-
bromocyclopent-1-en-1-yl)(phenyl)methanone (1e) readily
undergoes metal insertion in the presence of zinc powder
(1.5 equiv) and LiCl (1.5 equiv; 258C, 1 h) to give the
corresponding zinc reagent 2e in 62% yield. The CuI-
catalyzed allylation reaction of 2e with ethyl 2-(bromo-
methyl)acrylate (3b) furnishes the desired product 4l in 79%
yield (Table 1, entry 11). The Pd-catalyzed cross-coupling of
2e with ethyl 4-bromobenzoate (3i) leads to 4m in 70% yield
(Table 1, entry 12).
Acyclic alkenylzinc reagents bearing a vicinal aldehyde
were also prepared without losing the stereochemical infor-
mation of the alkenyl precursors due to the chelation of the
zinc center with the carbonyl group. In general, the formation
of a five-membered-ring chelate stabilizes the corresponding
organometallic compound by several kcalmolÀ1 [19] and
reduces the nucleophilicity of the carbonyl group. Thus, (Z)-
3-bromo-4,4-dimethylpent-2-enal (1 f) reacts with zinc
powder (1.5 equiv) in the presence of LiCl (1.5 equiv) to
give the alkenylzinc reagent 2 f (67%, 258C, 1 h). Its Pd-
catalyzed cross-coupling with 2-bromobenzaldehyde (3j) and
CuI-catalyzed allylation using 3-bromocyclohexene (3g) fur-
nish the unsaturated aldehydes 4n and 4o, respectively, in 92–
96% yield (Table 1, entries 13 and 14). Moreover, the 4-
fluoro- and the 4-methoxy-substituted derivatives 1g and 1h
of (Z)-3-bromo-3-phenylprop-2-enal react to the correspond-
ing zinc species 2g and 2h in 35–41% yield. The subsequent
CuI-catalyzed allylation reaction with ethyl 2-(bromomethyl)-
8
2c
9
2c
4j
10
2d (94)
4k
11
2e (62)
3b
4l
79[d]
12
13
2e
3i
3j
4m
4n
70[e]
2 f (67)
92[e,f]
2
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acrylate (3b) furnishes the cinnamyl aldehydes 4p and 4q in
89–95% yield (Z/E > 99:1; Table 1, entries 15 and 16).
Furthermore, the acyclic alkenyl bromide (Z)-ethyl 3-
bromo-3-phenylacrylate (1i) bearing an ester function was
converted into the corresponding zinc reagent 2i with zinc
powder (1.5 equiv) and LiCl (1.5 equiv; 258C, 1 h) in 62%
yield. The copper-mediated reaction of 2i with ethyl 2-
(bromomethyl)acrylate (3b) and 4-chlorobenzoyl chloride
(3k) affords the highly functionalized cinnamyl esters 4r and
4s, respectively, in 79–85% yield (Z/E > 99:1; Table 1,
entries 17 and 18).
Unsaturated 1,4-dicarbonyl compounds are highly reac-
tive and undergo condensation reactions with hydrazine
providing tetrahydrophthalazines.[20] Thus, zinc reagent 2a
was acylated with benzoyl chloride using 3 mol% CuCN·2
LiCl as the catalyst to afford the 1,4-dicarbonyl derivative 4v.
After aqueous workup, the crude unsaturated 1,4-dicarbonyl
compound undergoes a smooth condensation reaction with
hydrazine hydrate (NH2NH2·H2O) in methanol to afford the
1-substituted tetrahydrophthalazine 5a in 54% yield
(Scheme 2).[21]
Scheme 3. Selective insertion of Mg in the presence of ZnCl2 and LiCl
in the ester-substituted alkenyl bromides 6a and b (additional com-
plexed salts are not shown for the sake of clarity).
cyclopentene derivative 6c was converted to its correspond-
ing zinc reagent 7c and submitted to CuI-mediated allylation
with 3b affording the unsaturated product 8d in 86% yield
(Table 2, entry 1). Its Pd-catalyzed cross-coupling with the
bromothiophene 3m leads to the substituted thiophene 8e in
79% yield (Table 2, entry 2).
Although 1,2-dibromocyclopentene (6d) can be con-
verted to the corresponding magnesium reagent by Br/Mg
exchange with iPrMgCl·LiCl,[23] a more atom-economical
approach using Mg/ZnCl2/LiCl is possible. Thus, the treat-
ment of 6d with magnesium in the presence of ZnCl2 and LiCl
leads to the desired alkenylzinc reagent 7d in quantitative
yield. Its CuI-catalyzed acylation reaction using 2-bromoben-
zoyl chloride (3d) affords the unsaturated ketone 8 f in 64%
yield (Table 2, entry 3). Additional CuI-mediated reactions
with cyclohexenone (3n), 3-iodocyclohexenone (3o), and
bromoacetylene 3c lead to the expected products 8g–8i,
respectively, in 65–78% yield (Table 2, entries 4–6). Finally,
the Pd-catalyzed cross-coupling reaction of 7d with 3-bromo-
5-cyanopyridine (3e) furnishes the substituted pyridine 8j in
54% yield (Table 2, entry 7).
Functionalization of the related 1,2-dibromocyclohexene
by using this method was not possible. As the six-membered
ring has lower ring strain, the initially formed organometallic
reagent presumably eliminates MgBr2 leading to cyclohexyne
which undergoes side reactions. However, the increased ring
strain in the dibromonorbornadiene 6e prevents this elimi-
nation reaction and the corresponding zinc reagent 7e was
obtained within 1 h in 70% yield using Mg (2.5 equiv) in the
presence of LiCl (1.5 equiv) and ZnCl2 (1.1 equiv). The CuI-
catalyzed allylation reaction of 7e with ethyl 2-(bromo-
methyl)acrylate (3b) leads to the desired product 8k in 61%
yield (Table 2, entry 8). The Pd-catalyzed cross-coupling of 7e
with ethyl 4-iodobenzoate (3p) furnishes the arylated nor-
bornadiene 8l in 60% yield (Table 2, entry 9).
Scheme 2. Synthesis of substituted tetrahydrophthalazines of type 5.
The direct insertion of zinc into alkenyl bromides requires
the presence of adjacent electron-withdrawing groups.
Alkenyl bromides without such electronic activation either
do not undergo an insertion reaction or react only at elevated
temperatures and require long reaction times. To avoid these
drawbacks, we have used a more strongly reducing metal,
magnesium. Thus, a LiCl-mediated Mg insertion in the
presence of ZnCl2 allows an efficient synthesis of alkenylzinc
halides starting from weakly activated alkenyl bromides.[22]
Whereas a vicinal ethyl ester does not sufficiently activate the
alkenyl bromide 6a for a LiCl-mediated zinc insertion, it
undergoes selective magnesium insertion in the presence of
ZnCl2 and LiCl furnishing the alkenylzinc reagent 7a in 70%
yield (Scheme 3). The subsequent Pd-catalyzed cross-cou-
pling with (5-bromothiophen-2-yl)trimethylsilane (3l) leads
to the substituted thiophene 8a in 71% yield. Remarkably,
the zinc insertion also proceeds well with the acyclic
unsaturated bromoester 6b. The LiCl-mediated Mg insertion
in the presence of ZnCl2 furnished the corresponding zinc
reagent 7b in 50% yield without any loss of stereochemical
information due to the chelation of the zinc center with the
carbonyl group. The subsequent copper-catalyzed reaction of
7b with 4-chlorobenzoyl chloride (3k) and ethyl 2-(bromo-
methyl)acrylate (3b) affords the functionalized acyclic com-
pounds 8b and 8c, respectively, in 77–86% yield (Z/E > 99:1,
Scheme 3).
Also (2-bromocyclopent-1-en-1-yl)(phenyl)sulfane (6 f)
does not undergo a direct zinc insertion. However, the use
of Mg (2.5 equiv) in the presence of LiCl (1.5 equiv) and
ZnCl2 (1.1 equiv) furnishes 7 f within 1 h in 68% yield. The
This method turned out to be general and the preparation
of several new functionalized alkenylzinc reagents are
described in Table 2. In analogy to 6a, the ester-substituted
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Table 2: Reactions of alkenylzinc reagents of type 7 with electrophiles.
In summary, we have demonstrated that alkenylzinc
reagents bearing sensitive carbonyl groups can readily be
generated by direct metal insertion. In the case of activated
substrates a direct zinc insertion in the presence of LiCl
proceeds well,[6b,8a] whereas for less activated alkenyl bro-
mides the use of magnesium in the presence of LiCl and ZnCl2
is required for the insertion.[6a,8c] Functional groups, such as
aldehydes, ketones, and esters are well tolerated. Further-
more, acyclic alkenylzinc reagents could be prepared from the
corresponding acyclic bromides without losing their stereo-
chemistry due to the chelating effect of the vicinal carbonyl
group; in this way trisubstituted olefins could be synthesized
with excellent Z selectivity (Z/E > 99:1). Subsequent func-
tionalization reactions like Negishi cross-couplings, acyla-
tions, and allylations have been performed, readily furnishing
polyfunctional compounds in excellent yields. Further exten-
sions of this work are currently underway in our laboratories.
Entry Organozinc reagent[a] Electrophile
(Yield [%])[b]
Product
Yield
[%][c]
1
2
3
7c (84)
7c
3b
3m
3d
8d
8e
8 f
86[d]
79[e]
64[f]
7d (98)
4
5
6
7d
7d
7d
3n
3o
3c
8g
8h
8i
70[f]
65[f]
78[d]
Received: March 11, 2013
Published online: && &&, &&&&
Keywords: aldehydes · lithium chloride · magnesium ·
.
organozinc reagents · zinc
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60[e]
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3p
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8m
8n
81[e]
86[f]
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carbonyl functionalities has been described in: A. Metzger, S.
Bernhardt, G. Manolikakes, P. Knochel, Angew. Chem. 2010,
122, 4769; Angew. Chem. Int. Ed. 2010, 49, 4665. In our case, no
addition has been observed due to reduced nucleophilicity of the
chelated carbonyl groups.
[13] More sophisticated catalyst systems have been tested furnishing
similar results.
[23] C. Despotopoulou, A. Krasovskiy, P. Mayer, P. Knochel, R. C.
Bauer, J. M. Stryker, Chem. Eur. J. 2008, 14, 2499.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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.
Angewandte
Communications
Communications
Organozinc Reagents
C. Sꢁmann, M. A. Schade, S. Yamada,
P. Knochel*
&&&& — &&&&
Functionalized Alkenylzinc Reagents
Bearing Carbonyl Groups: Preparation by
Direct Metal Insertion and Reaction with
Electrophiles
Highly functionalized cyclic and acyclic
alkenylzinc reagents bearing functional
groups such as aldehyde, keto, and ester
groups were readily prepared by either
direct zinc insertion in the presence of
LiCl or by magnesium insertion in the
presence of LiCl and ZnCl2. Subsequent
functionalization reactions like Negishi
cross-couplings, acylations, and allyla-
tions were performed, furnishing poly-
functional compounds in excellent yields.
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!