Catalytic tandem C-C bond formation/cleavage of cyclopropene for allylzincation of aldehydes or aldimine using organozinc reagents

Article abstract of DOI:10.1021/ol500208r

The tandem allylation of aldehydes or an aldimine with allylzinc intermediates derived from organozinc reagents and cyclopropenes is described. The present three-component reaction involves carbozincation of cyclopropene and sequential cleavage of a cyclopropylzinc intermediate in situ without a transition-metal catalyst. The allylzinc intermediates generated in situ, which is an α,β-unsaturated acylanion equivalent, gave the corresponding homoallylic alcohols or amine in good yields.

Full text of DOI:10.1021/ol500208r

Letter
pubs.acs.org/OrgLett
Catalytic Tandem C−C Bond Formation/Cleavage of Cyclopropene
for Allylzincation of Aldehydes or Aldimine Using Organozinc
Reagents
Takeo Nakano,† Kohei Endo,†,*,‡ and Yutaka Ukaji†
†Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa
920-1192, Japan
‡PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
S
* Supporting Information
ABSTRACT: The tandem allylation of aldehydes or an aldimine
with allylzinc intermediates derived from organozinc reagents and
cyclopropenes is described. The present three-component reaction
involves carbozincation of cyclopropene and sequential cleavage of a
cyclopropylzinc intermediate in situ without a transition-metal
catalyst. The allylzinc intermediates generated in situ, which is an
α,β-unsaturated acylanion equivalent, gave the corresponding
homoallylic alcohols or amine in good yields.
Scheme 1. Allylzincation via Sequential Carbozincation and
C−C Bond Cleavage of Cyclopropylzinc Intermediate
ctivation of a C−C single bond in highly strained
molecules is a powerful approach to the construction of
A
structurally complex molecules in a single operation. However,
previous reports have typically achieved C−C bond cleavage
with the use of an expensive transition-metal catalyst, such as
Pt, Rh, Ru, or Ir.1 We previously reported the cleavage of
cyclopropylzinc intermediates without a transition-metal
catalyst to give allylzinc intermediates, which can take part in
the allylzincation of β-hydrazoneamide derivatives in a single
operation.2 The transition-metal-free carbozincation of cyclo-
propene in the presence of β-hydrazoneamide derivatives is a
key factor in our approach to the tandem C−C bond cleavage
in cyclopropylzinc intermediates.
Nucleophilic addition to electronically unactivated cyclo-
propene typically requires a transition metal as a catalyst.3,4
Marek and co-workers reported the Cu-catalyzed carbometa-
lation of cyclopropene, oxidation, and retro aldol-type C−C
bond cleavage.5 In contrast, our strategy using cyclopropenone
acetal (CPA)6 as a cyclopropene for the carbozincation
proceeded without any metal catalyst to give a cyclopropylzinc
intermediate in the presence of a β-hydrazoneamide, and
subsequent C−C bond cleavage of a cyclopropylzinc
intermediate took place in situ.7 Our previous report showed
that the carbozincation2,8 of CPA proceeded to give cyclo-
propylzinc intermediate A, the subsequent ring-opening of
which generated allylzinc intermediate B for the chemoselective
allylzincation of hydrazone (Scheme 1, a). Chemoselective C−
C bond cleavage without a transition-metal catalyst gave the
sterically congested hydrazine in a single operation. Although
we have described the allylation of benzaldehyde in the
presence of a stoichiometric amount of β-hydrazoneamide, the
yield of the desired product was low. Since β-hydrazoneamides
take part in the reaction as ligands as well as electrophiles, the
allylation to other electrophiles may be difficult to control. We
report here the β-hydrazoneamide-catalyzed tandem carbozin-
cation of cyclopropene and the subsequent allylzincation of
Received: January 21, 2014
Published: February 24, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
additional aldehydes and an aldimine as 3-component reactions
in a single operation (Scheme 1, b).
ligands L2 or L3 promoted unidentified side reactions (entries
2−4). The ligands gradually gave a trace amount of byproducts
via allylation to hydrazone and/or cyclopropylation, as reported
previously.2 The use of acyclic β-hydrazoneamide L4 or L5
gave the desired product 2a in lower yields (entries 5 and 6).
On the other hand, β-ketoamide L6, β-hydroxyhydrazone L7,
amino alcohol L8, and N,N,N′,N′-tetramethylethylenediamine
(TMEDA) did not give the product 2a (entries 7−10).
Therefore, the amounts of L1, diethylzinc, and CPA were
examined. The reaction in the presence of a catalytic amount of
L1 (15 mol %) gave 2a in 56% yield (entry 11). When the
reaction was carried out at 0 °C, the yield of 2a decreased
(entry 12). Further screening of the reaction conditions in the
presence of L1 (25 mol %) showed that the reaction using
diethylzinc (1.3 equiv) and CPA (1.3 equiv) gave the desired
product 2a in 76% yield (entries 13−17). The use of a
coordinative solvent slowed the reaction (entries 18−23).
Under the optimized conditions, a catalytic tandem allylation
reaction was performed using various aromatic and aliphatic
aldehydes (Table 2). The reaction typically gave the (E)-isomer
The reaction conditions were examined for the β-
hydrazoneamide-mediated or -catalyzed tandem allylzincation
of benzaldehyde (1a) using diethylzinc and CPA (Table 1,
Figure 1). The reaction without a ligand gave product 2a in
poor yield (entry 1).9 The use of cyclic hydrazoneamide L1 as a
ligand gave the desired product 2a in moderate yield; other
Table 1. Optimization of Reaction Conditions
entry
ligand
L1
solvent
X
Y
yield (%)
1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
benzene
hexane
THF
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.2
1.3
1.4
1.5
1.3
1.3
1.3
1.3
1.3
1.3
0
<10
44
2
110
110
110
110
110
110
110
110
110
15
3
L2
nd
20
4
L3
Table 2. Scope of Substrates
5
L4
41
6
L5
trace
nd
nd
nd
nd
56
7
L6
8
L7
9
L8
b
10
11
TMEDA
L1
entry
R1, X
Ph, O (1a)
R2
Et
yield (%)
a
12
L1
15
<33
47
13
14
15
16
17
18
19
20
21
22
23
L1
25
1
2
3
4
5
6
7
8
76 (2a)
48 (2a-Me)
63 (2a-iPr)
62 (2b)
68 (2c)
71 (2d)
70 (2e)
52 (2f)
L1
25
70
Ph, O (1a)
Me
i-Pr
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
L1
25
76
Ph, O (1a)
L1
25
65
2-MeC6H4, O (1b)
3-MeC6H4, O (1c)
4-MeC6H4, O (1d)
4-CF3C6H4, O (1e)
4-MeOC6H4, O (1f)
4-FC6H4, O (1g)
1-naphthyl, O (1h)
2-naphthyl, O (1i)
2-furyl, O (1j)
L1
25
61
L1
25
63
L1
25
65
L1
25
<7
14
a
L1
Et2O
25
9
56 (2g)
48 (2h)
trace (2i)
74 (2j)
L1
MTBE
CH2Cl2
25
38
10
11
12
13
14
15
16
17
L1
25
19
a
b
The reaction was performed at 0 °C. TMEDA is N,N,N′,N′-
2-phenylethyl, O (1k)
2-phenylethenyl, O (1l)
c-Hex, O (1m)
73 (2k)
68 (2l)
tetramethylethylenediamine.
77 (2m)
b
t-Bu, O (1n)
35 (2n)
Ph, NTs (1o)
41 (2o)
a
b
L1 (2 equiv), Et2Zn (2 equiv), and CPA (2 equiv) were used. The
product was isolated as a ketone after deprotection of acetal moiety.
as a sole or major product along with less than 5% of the (Z)-
isomer. When Me2Zn or i-Pr2Zn was used instead of Et2Zn, the
allylation reaction of benzaldehyde (1a) proceeded to give the
desired products 2a-Me or 2a-iPr (entries 2 and 3). When
Ph2Zn was used, the desired product was obtained in low yield,
but the reaction was not reproducible. The reactions of 2-, 3-,
or 4-methylbenzaldehyde (1b−d) gave the desired products
2b−d in good yields (entries 4−6). When aromatic aldehydes
1e−g bearing an electron-donating or -withdrawing group on
the benzene ring were used, the corresponding products 2e−g
were obtained in moderate to good yields, respectively (entries
7−9). The use of 1- or 2-naphthaldehyde (1h or 1i) decreased
the yields of products 2h or 2i (entries 10 and 11). A
Figure 1. List of ligands.
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Letter
heteroaromatic aldehyde, 2-furfural (1j), was available (entry
12). The use of aliphatic aldehydes, such as dihydrocinna-
maldehyde (1k), cinnamaldehyde (1l), and cyclohexanecarbox-
aldehyde (1m), gave the products 2k−m in good yields (entries
13−15). The reaction of bulky pivalaldehyde (1n) diminished
the yield of product; the acetal moiety partially decomposed on
silica gel to give 2n. The acidic deprotection after the reaction
gave the product 2n as a ketone (entry 16). The use of N-
tosylimine (1o) gave the corresponding amine 2o in moderate
yield (entry 17). The reaction of ketone derivatives was
examined, and the use of acetophenone gave the products in
poor yield as a nonisolable mixture. In contrast, the use of 2,2,2-
trifluoroacetophenone (1p) gave the desired product 2p in 28%
yield (eq 1). The reaction using simple cyclopropene gave the
Figure 2. Plausible mechanism.
The allylzinc intermediates in the present report prepared in
situ from stable cyclopropenes and commercially available
dialkylzinc reagents would be useful for synthetic organic
chemistry via an allylation reaction to give densely function-
alized molecules in a one-pot procedure. Further studies on the
chemoselective C−C bond cleavage are currently underway in
our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedure and physical properties of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: kendo@se.kanazawa-u.ac.jp.
Notes
product 2q in low yield as a nonisolable diastereomeric mixture
(eq 2). We tentatively examined the use of bisoxazoline L9 as a
chiral ligand for the asymmetric allylation reaction.10 The
desired product 2a was obtained, but the enantioselectivity was
poor (eq 3). Deprotection of the acetal moiety of product 2a
proceeded in the presence of p-toluenesulfonic acid (PTSA) to
give the corresponding α-hydroxy ketone 3 in almost
quantitative yield (eq 4).
A plausible mechanism for the present reaction is shown in
Figure 2. Initial carbozincation of cyclopropene in the presence
of L1 results in the formation of cyclopropylzinc intermediate
A. Subsequent ring-opening generates the allylzinc intermediate
B. The allylzincation of aldehyde proceeds to give the desired
product, while the elimination of L1 might occur. The oxygen
atoms in CPA seem to play an important role in obtaining the
desired products in good yields, since 3-methyl-3-phenyl-
cyclopropene gave the desired product in low yield along with
the generation of unidentified byproducts.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the JST PRESTO program and a
Grant-in-Aid for Scientific Research (B).
■
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