Synthesis of lactones and lactams from vinylcyclopropane by palladium-catalyzed nucleophilic allylation

Article abstract of DOI:10.1055/s-0034-1378566

A palladium-catalyzed nucleophilic allylation of aldehydes with vinylcyclopropane in the presence of diethylzinc proceeded to provide homoallyl alcohols with anti stereoselectivity. Aldimines prepared from aldehyde and primary amines in situ underwent a s

Full text of DOI:10.1055/s-0034-1378566

2306▌
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cluster
Synthesis of Lactones and Lactams from Vinylcyclopropane by Palladium-
Catalyzed Nucleophilic Allylation
Lactones and Lactams from Vinylcyclopropane
Goki Hirata, Gen Onodera, Masanari Kimura*
Graduate School of Engineering, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Fax +81(95)8192677; E-mail: masanari@nagasaki-u.ac.jp
Received: 18.05.2014; Accepted after revision: 15.07.2014
dehydes and aldimines to afford homoallyl alcohols and
Abstract: A palladium-catalyzed nucleophilic allylation of alde-
homoallylamines, respectively (Scheme 2).6
hydes with vinylcyclopropane in the presence of diethylzinc pro-
ceeded to provide homoallyl alcohols with anti stereoselectivity.
Aldimines prepared from aldehyde and primary amines in situ un-
OH
R1
R2
Pd catalyst
Et3B or Et2Zn
derwent a similar nucleophilic allylation to give homoallylamines
with syn stereoselectivity. The resulting homoallyl alcohols and ho-
moallylamines could be converted by treatment with a tetranuclear
zinc cluster into γ-vinyl-δ-valerolactones and γ-vinyl-δ-valerolact-
ams, respectively.
+
R1
O
OH
R2
anti/syn = 18:1–2:1
NHR1
R2
OH
Ph
Pd catalyst
Key words: palladium, vinylcyclopropane, nucleophilic allylation,
aldehyde, aldimine
+
Ph
NR1
Et3
B
R2
anti/syn = 8:1 to 1:1
Activated cyclopropanes are important and efficient key
intermediates in modern organic synthesis.1 In particular,
cycloaddition and ring expansion reactions of vinylcyclo-
propanes are powerful tools for the construction of highly
functionalized heterocycles and unsaturated hydrocar-
bons.2 Recently, we developed a multicomponent cou-
pling reaction of alkynes and dimethylzinc with
vinylcyclopropane promoted by a Ni catalyst (Scheme
1).3 In this case, vinylcyclopropane served as an allylnick-
el species, undergoing insertion of alkynes followed by
transmetalation with dimethylzinc to construct octadiene
frameworks with high regio- and stereoselectivity.
Scheme 2 Pd-catalyzed nucleophilic allylation of aldehydes or aldi-
mines with allyl alcohols
The combination of Pd(0) catalyst and diethylzinc or tri-
ethylborane accelerates amphiphilic allylations with allyl
alcohols as allyl cation and allyl anion equivalents, de-
pending on the nucleophiles and electrophiles in situ.
Herein, we demonstrate a successful extension of the
Pd(0) catalyst and diethylzinc system to nucleophilic al-
lylation of aldehydes and aldimines with vinylcyclopro-
pane derived from dimethyl malonate and 1,4-dihalo-2-
butene to form homoallyl alcohols and homoallylamines
(Scheme 3). Furthermore, these products can be converted
into γ-vinyl-δ-valerolactones and γ-vinyl-δ-valerolactams
by treatment with a tetranuclear zinc cluster.
R
R
Ni catalyst
Me2Zn
R
E
+
E
E
E
R
E = CO2Me
OH
R1CHO
or
NHR2
Pd cat.
Et2Zn
Scheme 1 Ni-catalyzed multicomponent coupling of vinylcyclopro-
pane, alkyne, and Me2Zn
R1
E
R1
E
+
E
E
R1
E = CO2Me
N
E
Pd-catalyzed allylation is one of the most useful and con-
venient methods for the synthesis of important complex
molecules containing physiologically active scaffolds.4
We previously demonstrated that a combination of a Pd(0)
catalyst and diethylzinc or triethylborane effectively pro-
motes oxidative addition of allyl alcohols to form a π-al-
R2
E
Scheme 3 Pd-catalyzed nucleophilic allylation of aldehydes or aldi-
mines with vinylcyclopropane
Table 1 shows the results of nucleophilic allylation of al-
dehydes with dimethyl 2-ethenylcyclopropane-1,1-dicar-
boxylate in the presence of a Pd(0) catalyst promoted by
diethylzinc at room temperature under a nitrogen atmo-
sphere.7 Among the various Pd catalysts, and using dieth-
ylzinc and triethylborane as promoters, the combination
of Pd(acac)2 and PPh3 with diethylzinc gave the best re-
sults. Table 1 shows the results of allylation of various al-
dehydes, such as aromatic, α,β-unsaturated, and aliphatic
aldehydes. Benzaldehyde underwent nucleophilic allyla-
lylpalladium
intermediate.5
Interestingly,
π-
allylpalladium can undergo umpolung upon addition of
diethylzinc and triethylborane to serve as an allyl anion
equivalent in situ, allowing nucleophilic allylation of al-
SYNLETT 2014, 25, 2306–2310
Advanced online publication: 11.08.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1378566; Art ID: st-2014-s0433-c
© Georg Thieme Verlag Stuttgart · New York

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Lactones and Lactams from Vinylcyclopropane
2307
tion with dimethyl 2-ethenylcyclopropane-1,1-dicarbox- diethylzinc with stirring at room temperature. As was the
ylate to provide homoallyl alcohol 1a in 72% yield as a case for aldimines prepared from benzaldehyde and aro-
single isomer with anti stereoselectivity along with the cy- matic amines, the reaction was compatible with both elec-
clized product 2a as a by-product in a 2:1 ratio (entry 1, tron-donating and electron-withdrawing aromatic rings of
Table 1). p-Chlorobenzaldehyde participated in nucleop- primary amines.
hilic allylation to afford the homoallyl alcohol 1b in ex-
cellent yield with high stereoselectivity (entry 2, Table 1).
p-Tolualdehyde and 2-naphthylaldehyde showed similar
Table 2 Pd/Et2Zn-Promoted Nucleophilic Allylation of Aldimines
with Vinylcyclopropanea
Pd(acac)2
Ph3P
results and gave the desired products in good to reason-
able yields (entries 3 and 4, Table 1). Dihydrocinnamalde-
+ R1CHO
+
R2NH2
hyde gave the desired product 1e in 39% yield, but lactone
2e was obtained in 60% yield as a major product. sec-Al-
kylaldehyde participated in the similar nucleophilic al-
lylation to afford homoallyl alcohol 1f in 54% yield along
with lactone 2f in 36% yield. Pivalaldehyde provided a
trace amount of homoallyl alcohol 1g, instead, lactone 2g
was obtained in 62%, exclusively (entry 7, Table 1). The
nucleophilicity of the alkoxides of homoallyl alcohols de-
rived from aliphatic aldehydes seems to enhance the intra-
molecular esterification leading to γ-vinyl-δ-lactones 2.
E
E
Et2Zn
NHR2
E = CO2Me
R1
NR2
R
E
O
E
E
4
3
Entry
Aldehyde
R1
Amine
R2
Yield (%) [ratio]
3 [syn/anti]
4
Table 1 Pd/Et2Zn-Promoted Nucleophilic Allylation of Aldehyde
1
2
3
4
5
6
7
Ph
PMP
Ph
3a: 42 [4:1]
3b: 44 [3:1]
3c: 36 [2:1]
none
4a: 47
4b: 27
4c: 21
4d: 62
4e: 50
4f: 51
none
with Vinylcyclopropanea
Ph
OH
R
E
Pd(acac)2
Ph3P
Ph
p-ClC6H4
Bn
R
E
O
RCHO
+
Ph
E
Et2Zn
E
O
E = CO2Me
Ph
n-C6H13
PMP
PMP
none
E
1
2
p-ClC6H4
n-C5H11
3f: 27 [3:1]
3g: 32 [single]
Entry
R
Time (h)
Yield (%) [ratio]
1
2
3
4
5
6
7
Ph
48
18
3
1a: 72, 2a: 21 [1:1]
1b: 78, 2b: 21 [1:1]
1c: 71, 2c: 28 [1:1]
1d: 69, 2d: 17 [1:1]
1e: 39, 2e: 60 [2:1]
1f: 54, 2f: 36 [1:1]
1g: trace, 2g: 62 [1:1]
a The reaction was carried out in the presence of aldimine which was
prepared from aldehyde (1 mmol) and amine (1.05 mmol) in THF (1
mL) at reflux (removal of H2O by azeotropic distillation), 2-vinylcy-
clopropane (1.2 mmol), Pd(acac)2 (0.05 mmol), Ph3P (0.1 mmol), and
Et2Zn (2.4 mmol; 1 M hexane solution) in anhyd THF (1 mL) at r.t.
for 48 h under nitrogen. All of the lactams 4 were obtained as a dia-
stereoisomeric mixture in a 2:1 ratio.
p-ClC6H4
p-MeC6H4
2-naphthyl
PhCH2CH2
c-C6H11
48
48
48
24
Homoallylamines 3a–3c were produced with syn stereo-
selectivity along with lactams 4a–4c in a 2:1 ratio (entries
1–3, Table 2). Aldimines from aliphatic amines such as
benzylamine and n-hexylamine could be used as sub-
strates for a similar nucleophilic allylation reaction. How-
ever, homoallylamines 3 were not obtained at all; instead,
lactams 4d and 4e were produced exclusively (entries 4
and 5, Table 2). Homoallylamines derived from aliphatic
amines could be readily converted into lactams 4 by intra-
molecular lactamization under the reaction conditions
owing to the greater nucleophilicity of the amino groups.
Although p-chlorobenzaldehyde and aliphatic aldehyde
could be also used as aldehydes for nucleophilic allyla-
tion, aldimine prepared from n-hexanal and p-anisidine
selectively afforded homoallylamine 3g as a sole product
(entries 6 and 7, Table 2).
t-Bu
a The reaction was carried out in the presence of aldehyde (1 mmol),
vinylcyclopropane (1.2 mmol), Pd(acac)2 (0.05 mmol), Ph3P (0.1
mmol), and Et2Zn (2.4 mmol; 1 M hexane solution) in anhyd THF (1
mL) at r.t. for 48 h under nitrogen. All of the homoallyl alcohols 1
were obtained as a single isomer, whereas lactones 2 were obtained as
diastereomeric mixture in 1:1 to 2:1 ratios.
A similar nucleophilic allylation reaction could be used
for the synthesis of homoallylamines and δ-lactams. The
result of reactions using various kinds of aromatic and al-
iphatic aldimines prepared from aldehydes and primary
amines are summarized in Table 2. The reaction was con-
ducted as follows: in situ formation of aldimines from pri-
mary amines and aldehyde by two azeotropic distillations
of a mixture of THF–water (30 min reflux in 1 mL of
THF), exposure of the aldimines to a mixture of
Pd(acac)2, Ph3P, and vinylcyclopropane, and addition of
The homoallyl alcohols 1 and homoallylamines 3 result-
ing from Pd-catalyzed nucleophilic allylation with vinyl-
cyclopropane could be converted into lactones and
© Georg Thieme Verlag Stuttgart · New York
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2308
G. Hirata et al.
CLUSTER
lactams (Table 3).8 Mashima and Ohshima reported excel- radiation at the protons indicated in bold face are illustrat-
lent conversion of esters from a mixture of alcohols and ed in Figure 1. The configurations of the lactones 5 and
carboxylic acids promoted by a tetranuclear zinc cluster.9 lactams 6 were complementary to each other; that is, the
Under similar conditions for esterification by a zinc clus- nucleophilic allylation of aldehydes and aldimines with
ter, homoallyl alcohols and homoallylamines isolated vinylcyclopropane showed the opposite stereoselectivity,
from the reactions detailed in Tables 1 and 2 could be cy- providing anti-homoallyl alcohols and syn-homoallyl-
clized to afford lactones and lactams under xylene reflux amines.
conditions accompanied by decarboxylation. Homoallyl
alcohols as single isomers of 1a and 1b led to γ-vinyl-δ-
lactones 5a and 5b as single isomers (entries 1 and 2, Ta-
ble 3). Homoallylamines 3a, 3b, and 3g also underwent
the intramolecular cyclization to construct lactams 6a, 6b,
and 6g in reasonable ways (entries 3–5, Table 3).
A plausible reaction mechanism for Pd-catalyzed nucleo-
philic allylation of aldehydes and aldimines with vinylcy-
clopropane is illustrated in Scheme 4. An allyl anion
equivalent generated from vinylcyclopropane and dieth-
ylzinc via umpolung of π-allylpalladium intermediate re-
acts with the aldehyde via the six-membered transition
state I to avoid steric repulsion between the aldehyde sub-
stituents and the Et group or ligands on the Zn atom. Thus,
Table 3 Decarboxylative Lactonization and Lactamization of Ho-
moallylic Alcohols and Homoallylamines by Tetranuclear Zinc Clus-
tera
homoallyl alcohols 1 are obtained with anti stereoselec-
tivity. In contrast to the results obtained for aldehydes, al-
dimines undergo nucleophilic allylation through the
intermediate II to avoid steric repulsion between substitu-
ents on the nitrogen atom and the Et group or the ligands
on the zinc atom, resulting predominantly in the selective
formation of syn-isomer 3. An alternative structural fea-
ture associated with the six-membered allylzinc species
which affects its interaction with aldehydes and aldimines
is likely to rationalize the opposite stereoselectivity as
well as the nucleophilic allylation of aldehydes and aldi-
mines with allylmetal species.10
NHR2
OH
Zn4(OCOCF3)6
R1
E
R1
E
xylene, reflux, 24 h
R1
R1
E
or
E
1
3
NR2
O
or
O
O
6
5
Entry
1 or 3 [ratio]
Yield (%) of 5 or 6 [ratio]
1
2
3
4
5
1a
5a: 75
1b
5b: 70
Pd catalyst
3a: [4:1]
3b: [3:1]
3g: [single]
6a: 80 [4:1]
6b: 76 [4:1]
6g: 89 [single]
oxidative
addition
Pd
E
E
E
E
umpolung
E
Ph
Et2Zn
RCHO
NR
a The reaction was carried out in the presence of homoallyl alcohol 1
or homoallylamine 3 (0.3 mmol), and Zn4(OCOCF3)6O (0.0038
mmol) in xylene (1 mL) at reflux under nitrogen for 24 h.
E
ZnEt
E
H
Ph
E
H
R
N
O
R
E
The structures of the products were determined based on
coupling constants from 1H NMR spectral data and NOE
experiments. Selected data for the nOe observed by the ir-
L
E
L
Zn
Zn
H
H
L
L
I (L = Et or solvent)
II (L = Et or solvent)
0%
Ph
E
H
Hc
R
N
E
H
OH
Ph
anti-selectivity
Ph
O
O
E
E
L
Hb
H
Zn
L
O
7.1%
O
III
Ph
Ha
Hc
JHaHb = 3.4 Hz
5a
4.0%
n-C5H11
2.9%
Ha
PMP
O
N
E
H
Ha
Hb
NPMP
PMP
NHR
N
E
n-C5H11
13.8%
Hb
O
H
Ph
syn-selectivity
O
6g
n-C5H11
0%
JHaHb = 5.3 Hz
Scheme 4 Plausible reaction mechanism for Pd/Et2Zn-promoted nu-
cleophilic allylation of aldehyde and aldimine with vinylcyclopro-
pane
Figure 1 Structure determination for NOE data of lactone 5a and
lactam 6g
Synlett 2014, 25, 2306–2310
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Lactones and Lactams from Vinylcyclopropane
2309
Chem. 2005, 2647. (e) Muzart, J. Eur. J. Org. Chem. 2007,
3077. (f) Bras, J. L.; Muzart, J. Chem. Rev. 2011, 111, 1170.
(5) (a) Horino, Y.; Naito, M.; Kimura, M.; Tanaka, S.; Tamaru,
Y. Tetrahedron Lett. 2001, 42, 3113. (b) Kimura, M.;
Horino, Y.; Mukai, R.; Tanaka, S.; Tamaru, Y. J. Am. Chem.
Soc. 2001, 123, 10401. (c) Kimura, M.; Futamata, M.;
Shibata, K.; Tamaru, Y. Chem. Commun. 2003, 234.
(d) Kimura, M.; Mukai, R.; Tanigawa, N.; Tanaka, S.;
Tamaru, Y. Tetrahedron 2003, 59, 7767. (e) Mukai, R.;
Horino, Y.; Tanaka, S.; Tamaru, Y.; Kimura, M. J. Am.
Chem. Soc. 2004, 126, 11138. (f) Kimura, M.; Fukasaka, M.;
Tamaru, Y. Heterocycles 2006, 67, 535. (g) Kimura, M.;
Fukasaka, M.; Tamaru, Y. Synthesis 2006, 3611.
In summary, we have demonstrated the Pd-catalyzed nuc-
leophilic allylation of aldehydes and aldimines with di-
methyl
2-ethenylcyclopropane-1,1-dicarboxylate
promoted by diethylzinc to form homoallyl alcohols and
homoallylamines, respectively.11 Furthermore, these
products were converted into γ-vinyl-δ-valerolactones
and γ-vinyl-δ-valerolactams, accelerated by condensation
with a tetranuclear zinc cluster as a Lewis acid. This trans-
formation is useful for efficient medicinal synthesis of
physiologically active molecules such as hydroxy acids,
amino acids, δ-valerolactones, and δ-valerolactams.
(h) Kimura, M.; Mukai, R.; Tamaki, T.; Horino, Y.; Tamaru,
Y. J. Am. Chem. Soc. 2007, 129, 4122. (i) Kimura, M.;
Tamaki, T.; Nakata, M.; Tohyama, K.; Tamaru, Y. Angew.
Chem. Int. Ed. 2008, 47, 5803. (j) Kimura, M.; Kohno, T.;
Toyoda, K.; Mori, T. Heterocycles 2010, 82, 281.
Acknowledgment
This work was supported by Grants-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and Tech-
nology (MEXT).
(k) Fukushima, M.; Takushima, D.; Satomura, H.; Onodera,
G.; Kimura, M. Chem. Eur. J. 2012, 18, 8019.
(l) Takushima, D.; Fukushima, M.; Satomura, H.; Onodera,
G.; Kimura, M. Heterocycles 2012, 86, 171.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
(6) (a) Kimura, M.; Tomizawa, T.; Horino, Y.; Tanaka, S.;
Tamaru, Y. Tetrahedron Lett. 2000, 41, 3627. (b) Kimura,
M.; Shimizu, M.; Shibata, K.; Tazoe, M.; Tamaru, Y.
Angew. Chem. Int. Ed. 2003, 42, 3392. (c) Shimizu, M.;
Kimura, M.; Tamaru, Y. Chem. Eur. J. 2005, 11, 6629.
(d) Shimizu, M.; Kimura, M.; Watanabe, T.; Tamaru, Y.
Org. Lett. 2005, 7, 637. (e) Kimura, M.; Shimizu, M.;
Tanaka, S.; Tamaru, Y. Tetrahedron 2005, 61, 3709.
(f) Yamaguchi, Y.; Hashimoto, M.; Tohyama, K.; Kimura,
M. Tetrahedron Lett. 2011, 52, 913.
10.1055/s-00000083.SunpfgIpi
o
o
nr
i
References and Notes
(1) (a) He, Z.; Yudin, A. K. Org. Lett. 2006, 8, 5829.
(b) Matsuda, T.; Tsuboi, T.; Murakami, M. J. Am. Chem.
Soc. 2007, 129, 12596. (c) Aïssa, C.; Fürstner, A. J. Am.
Chem. Soc. 2007, 129, 14836. (d) Pohlhaus, P. D.; Sanders,
S. D.; Parsons, A. T.; Li, W.; Johnson, J. S. J. Am. Chem.
Soc. 2008, 130, 8642. (e) Shi, M.; Tang, X.-Y.; Yang, Y.-H.
J. Org. Chem. 2008, 73, 5311. (f) Rao, W.; Chan, P. W. H.
Chem. Eur. J. 2008, 14, 10486. (g) Mauleón, P.; Krinsky, J.
L.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 4513.
(h) Taniguchi, H.; Ohmura, T.; Suginome, M. J. Am. Chem.
Soc. 2009, 131, 11298. (i) Sapeta, K.; Kerr, M. A. Org. Lett.
2009, 11, 2081. (j) Saya, L.; Bhargava, G.; Navarro, M. A.;
Gulías, M.; López, F.; Fernández, I.; Gastedo, L.;
(7) See the Supporting Information.
(8) In the absence of Zn cluster catalyst, no lactonization and
lactamization proceeded at all. These cyclizations required
Zn cluster catalyst as a promoter to provide lactones and
lactams from homoallyl alcohols and homoallylamines,
respectively. Simple lactonization or lactamization
conditions using acid catalysts and dehydration–
condensation agents were ineffective.
(9) (a) Iwasaki, T.; Maegawa, Y.; Hayashi, Y.; Ohshima, T.;
Mashima, K. J. Org. Chem. 2008, 73, 5147. (b) Ohshima, T.;
Iwasaki, T.; Maegawa, Y.; Yoshiyama, A.; Mashima, K.
J. Am. Chem. Soc. 2008, 130, 2944. (c) Sniady, A.; Durham,
A.; Morreale, M. S.; Marcinek, A.; Szafert, S.; Lis, T.;
Brzezinska, K. R.; Iwasaki, T.; Ohshima, T.; Mashima, K.;
Dembinski, R. J. Org. Chem. 2008, 73, 5881.
(10) (a) Hirabayashi, R.; Ogawa, C.; Sugiura, M.; Kobayashi, S.
J. Am. Chem. Soc. 2001, 123, 9493. (b) Kobayashi, S.;
Ogawa, C.; Konishi, H.; Sugiura, M. J. Am. Chem. Soc.
2003, 125, 6610.
(11) General Procedure for the Nucleophilic Allylation of
Aldehyde with Vinylcyclopropane (Entry 1, Table 1): To
a solution of Pd(acac)2 (15.2 mg, 0.05 mmol), and Ph3P (26.2
mg, 0.1 mmol) in anhyd THF (2 mL) were successively
added vinylcyclopropane (221.0 mg, 1.2 mmol),
Mascareñas, J. L. Angew. Chem. Int. Ed. 2010, 49, 9886.
(k) Masarwa, A.; Marek, I. Chem. Eur. J. 2010, 16, 9712.
(l) Jiang, G.-J.; Fu, X.-F.; Li, Q.; Yu, Z.-X. Org. Lett. 2012,
14, 692. (m) Zhu, W.; Fang, J.; Liu, Y.; Ren, J.; Wang, Z.
Angew. Chem. Int. Ed. 2013, 52, 2032. (n) Bonderoff, S. A.;
Grant, T. N.; West, F. G.; Tremblay, M. Org. Lett. 2013, 15,
2888. (o) Schinkel, M.; Wallbaum, J.; Kozhushkov, J.;
Kozhushkov, S. I.; Marek, I.; Ackermann, L. Org. Lett.
2013, 15, 4482.
(2) (a) Brownman, R. K.; Johnson, J. S. Org. Lett. 2006, 8, 573.
(b) Sumida, Y.; Yorimitsu, H.; Oshima, K. Org. Lett. 2008,
10, 4677. (c) Ikeda, S.-I.; Obata, H.; Tsuchida, E.; Shirai, N.;
Odashima, K. Organometallics 2008, 27, 1645. (d) Li, C.-F.;
Xiao, W.-J.; Alper, H. J. Org. Chem. 2009, 74, 888.
(e) Moran, J.; Smith, A. G.; Carris, R. M.; Johnson, J. S.;
Krische, M. J. J. Am. Chem. Soc. 2011, 133, 18618.
(f) Tombe, R.; Kurahashi, T.; Matsubara, S. Org. Lett. 2013,
15, 1791.
(3) (a) Mori, T.; Nakamura, T.; Kimura, M. Org. Lett. 2011, 13,
2266. (b) Mori, T.; Nakamura, T.; Kimura, M. Org. Lett.
2011, 13, 3552. (c) Mori, T.; Nakamura, T.; Onodera, G.;
Kimura, M. Synthesis 2012, 44, 2333.
benzaldehyde (106.1 mg, 1 mmol), and diethylzinc (2.4
mmol, 1.0 M hexane solution) via syringe under a nitrogen
atmosphere. The mixture was stirred at r.t. for 48 h. The
mixture was diluted with EtOAc (30 mL) and washed with 2
M HCl, and then brine. The extract was dried (MgSO4) and
concentrated in vacuo and the residual oil was subjected to
column chromatography over silica gel (hexane–EtOAc,
2:1) to give 1a (210.5 mg, 72%; Rf 0.63; hexane–EtOAc,
2:1) and 2a (54.8 mg, 21%; Rf 0.5; hexane–EtOAc, 2:1).
Dimethyl 2-[2-(Hydroxyphenylmethyl)but-3-en-1-
yl]malonate (1a): IR (neat): 3524 (br), 3064 (m), 3030 (m),
(4) For recent reviews, see: (a) Trost, B. M. Chem. Pharm. Bull.
2002, 50, 1. (b) Trost, B. M. J. Org. Chem. 2004, 69, 5813.
(c) Tsuji, J. In Palladium Reagents and Catalysts; John
Wiley & Sons: Chichester, 2004. (d) Tamaru, Y. Eur. J. Org.
© Georg Thieme Verlag Stuttgart · New York
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G. Hirata et al.
CLUSTER
(MgSO4) and concentrated in vacuo to give a brown oil,
which was subjected to column chromatography over silica
gel (hexane–EtOAc, 70:30) to give 3a (167 mg, 42%; Rf 0.5;
hexane–EtOAc, 2:1) and 4a (172 mg, 47%; Rf 0.27; hexane–
EtOAc, 2:1).
1750 (s), 1732 (s), 1640 (m), 921 (m), 765 (m) cm–1. 1H
NMR (400 MHz, CDCl3): δ = 1.80 (ddd, J = 14.3, 11.8, 5.0
Hz, 1 H), 1.94 (ddd, J = 14.3, 10.0, 3.7 Hz, 1 H), 2.11 (d, J =
2.5 Hz, 1 H), 2.38 (dddd, J = 11.8, 9.3, 7.1, 3.7 Hz, 1 H), 3.38
(dd, J = 10.0, 5.0 Hz, 1 H), 3.67 (s, 6 H), 4.50 (d, J = 7.1 Hz,
1 H), 5.13 (dd, J = 17.5, 1.7 Hz, 1 H), 5.26 (dd, J = 10.2, 1.7
Hz, 1 H), 5.63 (ddd, J = 17.5, 10.2, 9.3 Hz, 1 H), 7.27–7.34
(m, 5 H). 13C NMR (100 MHz, CDCl3): δ = 29.7, 30.9, 49.6,
50.3, 52.4, 52.5, 120.0, 126.8, 127.9, 128.4, 137.2, 141.7,
169.4, 169.9. HRMS: m/z [M] calcd for C16H20O5: 292.1311;
found: 292.1311.
Methyl Tetrahydro-2-oxo-6-phenyl-5-vinyl-2H-pyran-3-
carboxylate (2a): obtained as a mixture of diastereomers in
a 2:1 ratio. IR (neat): 3035 (w), 2954 (m), 1732 (s), 1643
(m), 1263 (m), 1070 (m), 1002 (m), 925 (m), 702 (s) cm–1.
1H NMR (400 MHz, CDCl3: δ (major isomer) = 2.15 (ddd,
J = 13.9, 9.8, 7.3 Hz, 1 H), 2.44 (ddd, J = 13.9, 11.3, 5.9 Hz,
1 H), 2.80–2.89 (m, 1 H), 3.80 (dd, J = 7.3, 5.9 Hz, 1 H), 3.83
(s, 3 H), 4.99 (d, J = 17.2 Hz, 1 H), 5.08 (d, J = 10.5 Hz, 1
H), 5.09 (d, J = 3.7 Hz, 1 H), 5.56 (ddd, J = 17.2, 10.5, 7.0
Hz, 1 H) 7.26–7.36 (m, 5 H). 13C NMR (100 MHz, CDCl3):
δ (2:1 mixture of diastereomers) = 28.2, 29.4, 41.7, 43.6,
45.8, 47.8, 52.9, 85.9, 86.5, 118.2, 118.3, 127.1, 127.3,
128.5, 128.8, 128.9, 134.9, 135.1, 137.3, 137.6, 166.2,
166.7, 169.4, 169.5. HRMS: m/z [M] calcd for C15H16O4:
260.1049; found: 260.1047.
Dimethyl 2-[(p-Methoxyphenylamino)phenylmethylbut-
3-en-1-yl]malonate (3a): obtained as a mixture of
diastereomers in a 4:1 ratio. IR (neat): 3404 (m), 3001 (m),
2953 (m), 2833 (m), 1750 (s), 1732 (s), 1508 (s), 1435 (s),
1159 (br), 1038 (s), 925 (m), 704 (s) cm–1. 1H NMR (400
MHz, CDCl3): δ (major isomer) = 1.69 (ddd, J = 13.7, 11.3,
4.4 Hz, 1 H), 2.32 (ddd, J = 13.7, 10.5, 2.9 Hz, 1 H), 2.42–
2.49 (m, 1 H), 3.37 (dd, J = 10.5, 4.4 Hz, 1 H), 3.67 (s, 6 H),
3.72 (s, 3 H), 4.30 (d, J = 5.1 Hz, 1 H), 5.09 (dd, J = 17.1, 1.5
Hz, 1 H), 5.17 (dd, J = 10.2, 1.5 Hz, 1 H), 5.46 (ddd, J = 17.1,
10.2, 9.8 Hz, 1 H), 6.45 (d, J = 8.9 Hz, 2 H), 6.65 (d, J = 8.9
Hz, 2 H), 7.18–7.31 (m, 5 H). 13C NMR (100 MHz, CDCl3):
δ (4:1 mixture of diastereomers) = 29.6, 30.4, 48.4, 49.1,
49.4, 49.5, 52.4, 52.5, 52.53, 55.56, 55.59, 51.0, 51.4, 114.6,
114.7, 114.74, 119.6, 127.8, 128.4, 128.6, 128.7, 128.8,
129.0, 132.8, 136.3, 137.2, 139.2, 140.5, 140.7, 141.1,
152.1, 152.3, 169.4, 169.6, 169.7, 169.8. HRMS: m/z [M]
calcd for C23H27NO5: 397.1889; found: 397.1899.
Methyl 1-(p-Methoxyphenyl)-2-oxo-6-phenyl-5-
vinylpiperidine-3-carboxylate (4a): obtained as a mixture
of diastereomers in a 2:1 ratio. IR (neat): 2955 (m), 2839
(m), 1738 (s), 1693 (s), 1514 (s), 1250 (s), 1033 (m), 833 (m)
cm–1. 1H NMR (400 MHz, CDCl3): δ (major isomer) = 2.09
(dt, J = 13.9, 7.0 Hz, 1 H), 2.40–2.47 (m, 1 H), 2.74–2.84 (m,
1 H), 3.70 (s, 3 H), 3.76–3.81 (m, 1 H), 3.84 (s, 3 H), 4.69 (d,
J = 5.6 Hz, 1 H), 5.18 (dt, J = 17.3, 1.2 Hz, 1 H), 5.21 (dd,
J = 10.5, 1.2 Hz, 1 H), 5.92 (ddd, J = 17.3, 10.5, 6.6 Hz, 1
H), 6.72 (d, J = 9.0 Hz, 2 H), 6.97 (d, J = 9.0 Hz, 2 H), 7.16–
7.35 (m, 5 H). 13C NMR (100 MHz, CDCl3; 2:1 mixture of
diastereomers): δ = 26.7, 29.1, 42.7, 45.3, 47.2, 49.5, 52.3,
52.5, 55.11, 55.14, 70.0, 70.5, 113.9, 114.1, 117.1, 117.2,
127.6, 127.7, 127.8, 127.9, 128.3, 128.35, 128.43, 128.7,
133.4, 134.3, 137.1, 137.3, 139.5, 140.1, 158.0, 158.1,
166.3, 167.1, 170.7, 171.8. HRMS: m/z [M] calcd for
C22H23NO4: 365.1627; found: 366.1663.
Nucleophilic Allylation of Aldimine with
Vinylcyclopropane (Entry 1, Table 2): A solution of
benzaldehyde (106.1 mg, 1 mmol) and p-anisidine (129.3
mg, 1.05 mmol) in anhyd THF (1 mL) was refluxed for 30
min under nitrogen. The solvent was removed by distillation
under atmospheric pressure of nitrogen (azeotropic removal
of H2O). The azeotropic distillation of THF (1 mL)/H2O was
repeated twice. A mixture of Pd(acac)2 (15.2 mg, 0.05
mmol) and triphenylphoshine (26.2 mg, 0.1 mmol) in anhyd
THF (2 mL) and vinylcyclopropane (221.0 mg, 1.2 mmol)
dissolved in THF (1 mL) and diethylzinc (2.4 mmol, 1.0 M
hexane solution) were successively added to the aldimine
residue. The mixture was stirred at r.t. for 48 h. The reaction
mixture was diluted with EtOAc (30 mL) and washed with
sat. NaHCO3, and brine. The organic phase was dried
Synlett 2014, 25, 2306–2310
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