Highly stereoselective synthesis of trisubstituted vinylcyclopropane derivatives via arsonium ylides

Article abstract of DOI:10.1021/jo051782n

Alkylidene or arylidene malonates reacted with arsonium allylides to give trans-disubstituted cyclopropane-1,1-dicarboxylates with high stereoselectivity in high yields. The mechanism of the cyclopropanation reactions has also been investigated.

Full text of DOI:10.1021/jo051782n

SCHEME 1. Synthesis of Disubstituted
Cyclopropane-1,1-dicarboxylates via Telluronium
Ylides
Highly Stereoselective Synthesis of
Trisubstituted Vinylcyclopropane
Derivatives via Arsonium Ylides
Hong Jiang, Xianming Deng, Xiuli Sun,
Yong Tang,* and Li-Xin Dai
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry,
354 Fenglin Lu, Shanghai 200032, China
tangy@mail.sioc.ac.cn
addition/cyclization5 such as ylide cyclopropanation6 of
alkylidene malonates is one of the most convenient ways.
In a previous study on the synthesis and application of
cyclopropane derivatives,7 we described a cyclopropana-
tion reaction of arylidene malonates with telluronium
ylides to afford disubstituted cyclopropane 1,1-dicarboxy-
lic esters with good stereoselectivity in high yields
(Scheme 1).8 However, attempts to extend the substrates
to propylidene malonate using telluronium cinnamylide
gave only a trace amount of the desired cyclopropane
(Scheme 1) under the same reaction conditions. There-
fore, we are interested in developing a highly diastereo-
selective ylide cyclopropanation suitable for both alky-
lidene and arylidene malonates. In this paper, we wish
to report the results of our studies on this subject.
Initial study showed that the reaction of telluronium
cinnamylide with propylidene malonate gave a trace
amount of the desired cyclopropane (Scheme 1). Consid-
ering that the match between ylide and substrate is
crucial to the yields as well as the control of stereoselec-
tivity in ylide cyclopropanation,9 we tried to use the
corresponding arsonium ylide10 instead to continue the
study.
Received August 24, 2005
Alkylidene or arylidene malonates reacted with arsonium
allylides to give trans-disubstituted cyclopropane-1,1-dicar-
boxylates with high stereoselectivity in high yields. The
mechanism of the cyclopropanation reactions has also been
investigated.
Vinylcyclopropane 1,1-dicarboxylic esters are very use-
ful synthetic intermediates in construction of cyclopen-
tane skeleton and heterocyclic compounds.1 Although the
cyclopropanation reactions of olefins using the transition-
metal-catalyzed decomposition of diazoalkanes is well-
studied,2 only a few examples were reported for the
preparation of these cyclopropanes, probably because the
regioselectivity control is difficult and the diazoalkanes
bearing two electron-withdrawing groups are substan-
tially less reactive than diazoalkanes both without
electron-withdrawing groups and with one electron-
withdrawing group.3 Of the methods developed for direct
synthesis of these compounds,2a,4 the tandem nucleophilic
Fortunately, we found that the reaction of ethyl pro-
pylidene malonate with arsonium cinnamylide, prepared
in situ by deprotonation of the corresponding arsonium
bromide with KN(Me3Si)2 (0.5 M in THF) at room
temperature, proceeded well in THF to give the desired
cyclopropane with high stereoselectivity in 71% yield
(entry 3, Table 1).
(1) (a) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am. Chem. Soc. 2005,
127, 5764. (b) Pohlhaus, P. D.; Johnson, J. S. J. Org. Chem. 2005, 70,
1057. (c)Young, I. S.; Kerr, M. A. Org. Lett. 2004, 6, 139. (d) Ganton,
M. D.; Kerr, M. A. J. Org. Chem. 2004, 69, 8554. (e) Young, I. S.; Kerr,
M. A. Angew. Chem., Int. Ed. 2003, 42, 3023. (f) England, D. B.; Kuss,
T. D. O.; Keddy, R. G.; Kerr, M. A. J. Org. Chem. 2001, 66, 4704. (g)
Kotsuki, H.; Arimura, K.; Maruzawa, R.; Ohshima, R. Synlett 1999,
650. (h) Beal, R. B.; Dombrowski, M. A.; Snider, B. B. J. Org. Chem.
1986, 51, 4391.
(2) For reviews, see: (a) Lebel, H.; Marcoux, J.-F.; Molinaro, C.;
Charette, A. B. Chem. Rev. 2003, 103, 977. (b) Davies, H. M. L.;
Antoulinakis, E. Org. React. 2001, 57, 1. (c) Doyle, M. P.; Forbes, D.
C. Chem. Rev. 1998, 98, 911.
As shown in Table 1, the reaction was base-dependent.
When LiHMDS was used as a base, both the yield and
(5) (a) Wang, Y.; Zhao, X.; Li, Y.; Lu, L. Tetrahedron Lett. 2004,
7775. (b) Yamazaki, S.; Kataoka, H.; Yamabe, S. J. Org. Chem. 1999,
64, 2367. (c) Trost, B. M.; Tanimori, S.; Dunn, P. T. J. Am. Chem. Soc.
1997, 119, 2735. (d) Funaki, I.; Roel, P. L. B.; Lambertus, T.;
Zwanenburg, B. Tetrahedron 1996, 52, 12253. (e) Kasatkin, A. N.;
Kulak, A. N.; Biktimirov, R. Kh.; Tolstikov, G. A. Tetrahedron Lett.
1990, 31, 4915.
(6) (a) Krief, A.; Provins, L.; Froidbise, A. Synlett 1999, 1936. (b)
Dauben, W. G.; Lewis, T. A. Synlett 1995, 857.
(3) For cyclopropanation with a diazalkanes bearing two electron-
withdrawing groups, see: (a) Wurz, R. P.; Charette, A. B. Org. Lett.
2003, 5, 2327. (b) Mueller, P.; Allenbach, Y.; Robert, E. Tetrahedron:
Asymmetry 2003, 779. (c) Doyle, M. P.; Davies, S. B.; Hu, W. Org. Lett.
2000, 2, 1145. (d) Koskinen, A. M. P.; Munoz, L. J. Org. Chem. 1993,
58, 879. (e) Koskinen, A. M. P.; Hassila, H. J. Org. Chem. 1993, 58,
4479. (f) Taber, D. F.; Amedio, J. C.; Raman, K. J. Org. Chem. 1988,
53, 2984.
(7) (a) Zheng, J.-C.; Liao, W.-W.; Tang, Y.; Sun, X.-L.; Dai, L.-X. J.
Am. Chem. Soc. 2005, 127, 12222. (b) Liao, W.-W.; Li, K.; Tang, Y. J.
Am. Chem. Soc. 2003, 125, 13030. (c) Ye, S.; Huang, Z. Z.; Xia, C. A.;
Tang, Y.; Dai, L.-X. J. Am. Chem. Soc. 2002, 124, 2432. (d) Ye, S.;
Yuan, L.; Huang, Z. Z.; Tang, Y.; Dai, L.-X. J. Org. Chem. 2000, 65,
6257.(e) Ye, S.; Tang, Y.; Dai, L.-X. J. Org. Chem. 2001, 66, 5757. (f)
Ye, S.; Tang, Y.; Dai, L.-X. J. Org. Chem. 2000, 65, 6257.
(8) Tang, Y.; Chi, Z.-F.; Huang, Y.-Z.; Dai, L.-X.; Yu, Y.-H. Tetra-
hedron 1996, 8747.
(4) (a) Ma, S.; Jiao, N.; Yang, Q.; Zheng, Z. J. Org. Chem. 2004, 69,
6463. (b) Ma, S.; Jiao, N.; Zhao, S.; Hou, H. J. Org. Chem. 2002, 67,
2837.
(9) Tang, Y.; Huang, Y.-Z.; Dai, L.-X.; Sun, J.; Xia, W. J. Org. Chem.
1997, 62, 954.
10.1021/jo051782n CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/01/2005
10202
J. Org. Chem. 2005, 70, 10202-10205

TABLE 1. Effects of Reaction Conditions on the
Cycloprapanation Reaction of Propylidene Malonatea
TABLE 2. Stereoselective Synthesis of
trans-Disubstituted Cyclopropane-1,1-dicarboxylates via
Arsonium Ylides
en-
try
(trans/ yield
cis)b (%)c
base
solvent
X-
T (°C)
1
2
3
4
5
6
LiHMDS THF
NaHMDS THF
KHMDS THF
KHMDS THF
KHMDS THF
KHMDS THF+
Br- (4a) -78 to rt 1.5/1 30
Br- (4a) -78 to rt 11/1
Br- (4a) -78 to rt 13/1
BPh4- (5) -78 to rt 7/1
BF4- (6) -78 to rt 10/1
Br- (4a) -78 to rt 11/1
82
71
80
74
75
entry
R1
R2
Me (2b)
i-Pr (2c)
i-Bu (2d)
Ph (2e)
R′ (trans/cis)a yield (%)b
10% HMPA
KHMDSd THF
1
2
Ph (4a)
Ph (4a)
Ph (4a)
Ph (4a)
Ph (4a)
Ph (4a)
H (4b)
H (4b)
TMS (4c) Ph (2e)
TMS (4c) Et (2a)
Et
Et
16/1 (3b)
5/1 (3c)
88
89
91
93
93
94
88
83
89
86
7
8
9
Br- (4a) -78 to rt 16/1
88
KHMDSd THF + LiBre Br- (4a) -78 to rt 1.5/1 37f
KHMDSg THF
Br- (4a) -78
Br- (4a) rt
24/1
7/1
77(89f)
76
3
Me 16/1 (3d)
Et 14/1 (3e)
4
10 KHMDS THF
5
p-CH3-C6H4 (2f) Me 25/1 (3f)
a With stirring for a further 6 h after the cooling bath was
removed. b Determined by 1H NMR. c Isolated yields. d With stir-
ring for further 5 min after the cooling bath was removed. e 2.5
equiv added. f Conversion based on ester by 1H NMR. g Quenched
at -78 °C.
6
p-Br-C6H4 (2g)
Ph (2e)
Et (2a)
Et
Et
Et
Et
Et
27/1 (3g)
43/1 (3h)
13/1 (3i)
13/1 (3j)
13/1 (3k)
7
8
9
10
a Determined by 1H NMR. b Isolated yields.
stereoselectivity decreased greatly (entry 3 versus entry
1, Table 1). NaHMDS gave good stereoselectivity in 82%
yield (entry 2 in Table 1). The anions of the arsonium
salts influenced both the yields and the selectivity
(entries 3-5, Table 1).11 Further studies showed that
lowering the reaction temperature increased the diaste-
reoselectivity. For instance, the ratio of trans-isomer and
cis-isomer could be improved from 7/1 to 24/1 by lowering
the reaction temperature from room temperature to -78
°C (entry 9 versus entry 10, Table 1). Noticeably, lithium
ion decreased both the yields and diastereoselectivity
greatly. In our screening conditions, the best result was
achieved using KHMDS as a base and THF as a solvent.
In this case, the reaction gave the cyclopropane in 88%
yield with high diastereoselectivity (trans/cis ) 16/1,
entry 7).
highly stereoselectively converted to the corresponding
cyclopropane in excellent yields (entries 4-6, Table 2).
Other arsonium ylides, such as simple allylide and
3-trimethylsilylallylide, could react well with both alky-
lidene and arylidene malonates to give the desired
cyclopropane with high stereoselectivity in high yields
(entries 7-10). For example, the reactions of the arso-
nium allylide with benzylidene malonate and propylidene
malonate gave 88% and 83% yields, respectively, with
high selectivity. It is worth noting that the triphenyl-
arsine could be recovered with high yield as shown in eq
1.
The high diastereoselectivity and yield obtained with
propylidene malonate encouraged us to further explore
the cyclopropanation of arylidene and alkylidene mal-
onates. As shown in Table 2, ethylene, isobutylene, and
isopentylene malonates gave good to high stereoselecivity
as well as excellent yields (entries 1-3, Table 2). Com-
pared with the ethylene and isopentylene malonates,
isobutylene malonate took longer to react and the selec-
tivity decreased slightly, probably as a result of the steric
hindrance (entry 2). Arylidene malonates could also be
(10) Selected references on the reactions of arsonium ylides: (a) Dai,
W.-M.; Wu, A.-X.; Wu, H.-F. Tetrahedron: Asymmetry 2002, 2187. (b)
Chen, Y.-L.; Ding, W.-Y.; Cao, W.-G.; Lu, C. Synth. Commun. 2002,
1953. (c) Shen, Y.-C.; Wang, T.-L. J. Fluorine Chem. 1997, 82, 139. (d)
Moorhoff, C. M. J. Chem. Res., Synop.1997, 130. For reviews, see: (e)
He, H. S.; Chung, C. W. Y.; But, T. Y. S.; Toy, P. H. Tetrahedron 2005,
1385. (f) Huang, Y.-Z.; Shi, L.-L.; Zhou, Z.-L. Triphenylarsine. In
Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.;
Wiley: New York, 1995; p 5339. The arsenic compounds described here
should be handled with caution. Although triphenylarsine has been
used for years as a ligand by inorganic chemists and seems to have
only moderate acute toxicity, repeated exposure should be avoided by
working with care in an efficient hood. Because the compounds
described in this paper are nonvolatile, actual danger is minimal.
(11) A similar “salt effect” was reported in the epoxidation of
arsonium ylides, Still, W. C.; Novack, V. J. J. Am. Chem. Soc. 1981,
103, 1283.
The reactions of arylidene and alkylidene malonates
with arsonium allylides afforded trans-2,3-disubstituted
1,1-dialkoxylcarbonylcyclopropanes with high stereo-
selectivity. A possible mechanism as shown in Scheme 2
can rationalize the trans-selectivity produced.12 Arsonium
ylides 1 took a “transoid approach” in which the triphen-
ylarsonium group and carbon carbon double bond of
malonate 2 are located in an anti-like orientation to form
intermediates A or B, followed by trans-elimination to
provide cyclopropanes. In accordance with the mecha-
(12) Aggarwal, V. K.; Harvey, J. N.; Richardson, J. J. Am. Chem.
Soc. 2002, 124, 5747.
J. Org. Chem, Vol. 70, No. 24, 2005 10203

SCHEME 2. Possible Mechanism for the Cyclopropanation of Arsonium Ylide
SCHEME 3. Proposed Cisoid Approach Mechanism
SCHEME 4. Effect of Lithium Ion on
Stereochemistry
SCHEME 5
shown in Scheme 3, the presence of lithium ion should
destroy the formation of intermediates C and D as a
result of the strong interaction of lithium ion with oxygen
anion14 and will influence the diastereoselectivity. Thus,
we investigated the effect of lithium bromide as an
additive on this reaction. As expected, we found that
lithium ion had a strong effect on both the yield and
stereoselectivity (Scheme 4). This mechanism is also
consistent with the experimental results shown in Scheme
5. Increasing the steric interaction between the R2 group
and the R1 group or the size of the ester group decreases
the selectivity. For instance, when R2 is changed from
phenyl to isopropyl, the ratio for trans- and cis-isomers
is reduced from 5/1 to 1/1. Although both the proposed
mechanisms could explain the stereochemistry, a clear
mechanistic understanding awaits further investigation.
nism proposed in Scheme 2, it appears that intermediate
A is more stable than intermediate B and thus the trans-
disubstituted cyclopropane 1,1-dicarboxylic esters forms
preferably as the major product.
Considering a possible interaction between the arso-
nium cation and ester oxygen,13 an alternative mecha-
nism is shown in Scheme 3. The ylide may approach the
malonate in a manner such that the triphenylarsonium
cation and carbon carbon double bond of malonate 2 are
in a cis-like orientation to form intermediates C and D,
which allows for an interaction between the triphenyl-
arsonium cation and one of the ester oxygen atoms.
Intermediates C and D can give the observed cyclopro-
panes by an elimination reaction. Formation of proposed
intermediate C is disfavored on steric grounds relative
to intermediate D and thus the trans-isomer is proposed
to be the major product. According to the mechanism
(14) (a)Maryanoff, B. E.; Reitz, A. B.; Mutter, M. S.; Inners, R. R.;
Almond, H. R., Jr.; Whittle, R. R.; Olofson, R. A. J. Am. Chem. Soc.
1986, 108, 7664. (b) Ousset, J. B.; Mioskowski, C.; Solladie, G. Synth.
Commun. 1983, 13, 1193.
(13) (a) Mitsumoto, Y.; Nitta, M. J. Chem. Soc., Perkin Trans. 1
2002, 2268. (b) Boubia, B.; Mann, A.; Bellamy, F. D.; Mioskowski, C.
Angew. Chem. Int. Ed. Engl. 1990, 29, 1454.
10204 J. Org. Chem., Vol. 70, No. 24, 2005

General Experimental Procedure for Cyclopropanation
of Allyltriphenyl (3-Trimethylsilylallyltriphenyl) Arso-
nium Bromide with Alkylidene (or Arylidene) Malonic
Acid Esters. Synthesis of Diethyl trans-2-Ethyl-3-vinylcy-
clopropane-1,1-dicarboxylate (3i). A dried vial was charged
with triphenylallyl arsonium bromide (172 mg, 0.403 mmol), 2.5
mL of THF, and a solution of potassium bis(trimethylsilyl) amide
(0.5 M in THF, 0.7 mL, 0.35 mmol) via a syringe at -78 °C. The
resulting mixture was stirred for 30 min, and then diethyl
propylidene malonic acid ester (64 mg, 0.32 mmol) in THF (1
mL) was added. After 1 h, the cooling bath was removed, and
the mixture was stirred for a further 5 min and filtered rapidly
through a glass funnel with a thin layer of silica gel (CH2Cl2 as
the elutant, 60 mL). The filtrate was concentrated and the
residue was subjected to 1H NMR analysis (δ5.07 vs δ5.20) to
determine the ratio of isomers (trans/cis ) 16/1). The pure
product was obtained by flash chromatography (EtOAc/30-60
°C petroleum ether ) 1/100, v/v). Yield: 61 mg (83%). 1H NMR
(300 MHz, CDCl3) for trans-isomer δ 5.52-5.39 (m, 1H), 5.26
(dd, J ) 17.1, 1.8 Hz, 1H), 5.07 (dd, J ) 10.2, 1.8 Hz, 1H), 4.30-
4.06 (m, 4H), 2.42 (t, J ) 8.1 Hz, 1H), 2.01 (q, J ) 7.5 Hz, 1H),
1.46-1.35 (m, 2H), 1.30-1.18 (m, 6H), 0.97 (t, J ) 7.2 Hz, 3H);
13C NMR (300 MHz, CDCl3) δ 168.0, 167.9, 133.3, 117.8, 61.4,
61.3, 41.7, 35.7, 33.9, 20.8, 14.2, 14.1, 13.0; MS (EI) m/z (rel
intensity) 241 (MH+, 26), 211 (100), 137 (79), 93 (77), 195 (73),
149 (62), 148 (34), 77 (34), 183 (32); IR (thin film)/cm-1 2980
(m), 2936 (m), 1726 (s), 1368 (m), 1290 (m), 1204 (m), 1149 (m),
415 (m), 401 (s); HRMS (EI) calcd for C13H20O4 [M+] 240.1362,
found 240.1350.
In summary, we have developed an efficient cyclopro-
panation reaction of alkylidene and arylidene malonates
with arsonium allylides. This methodology provides an
easy access to trans-2,3-disubstituted cyclopropane 1,1-
dicarboxylic esters. The readily available starting mate-
rial, high selectivity, and high yield make this protocol
potentially useful in organic synthesis. Efforts to develop
its catalytic and asymmetric version are in progress in
our laboratory.
Experimental Section
General Procedure for Cyclopropanation of Alkylidene
(or Arylidene) Malonic Acid Esters with Triphenylcin-
namyl Arsonium Bromide. A. For Diethyl trans-2-Ethyl-
3-styrylcyclopropane-1,1-dicarboxylate (3a). A dried vial
was charged with triphenylcinnamyl arsonium bromide (160 mg,
0.318 mmol) and 2.5 mL of THF, followed by a solution of
potassium bis(trimethylsilyl) amide (0.5 M in THF, 0.6 mL, 0.3
mmol) via a syringe at room temperature under N2 atmosphere.
The resulting mixture was cooled to -78 °C and stirred for 30
min, and then diethyl propylidene malonic acid ester (50 mg,
0.250 mmol) in THF (1 mL) was added. After 1 h, the cooling
bath was removed. The mixture was stirred for a further 5 min
and filtered rapidly through a glass funnel with a thin layer of
silica gel (ethyl acetate as the elutant, 50 mL). The filtrate was
concentrated and the residue was subjected to 1H NMR analysis
(δ 5.89 vs δ 6.10) to determine the ratio of isomers (trans/cis )
16/1). The pure product was obtained by flash chromatography
1
(EtOAc/petroleum ether ) 1/100, v/v). Yield: 70 mg (88%). H
Acknowledgment. We are grateful for the financial
support from the Natural Sciences Foundation of China
and The Science and Technology Commission of Shang-
hai Municipality.
NMR for trans-isomer (300 MHz, CDCl3) δ 7.32-7.19 (m, 5H),
6.63 (d, J ) 15.9 Hz, 1H), 5.89 (dd, J ) 15.9, 9.0 Hz, 1H), 4.29-
4.10 (m, 4H), 2.58 (t, J ) 8.1 Hz, 1H), 2.13 (q, J ) 7.8 Hz, 1H),
1.51-1.40 (m, 2H), 1.28 (t, J ) 7.2 Hz, 3H), 1.21 (t, J ) 7.2 Hz,
3H), 1.00 (t, J ) 7.2 Hz, 3H); 13C NMR (300 MHz, CDCl3) δ 168.1,
167.8, 136.8, 132.8, 128.5, 127.3, 125.9, 125.1, 61.4, 42.1, 35.6,
34.6, 21.0, 14.1, 13.0; MS (EI) m/z (rel intensity) 316 (M+, 11),
169 (100), 242 (77), 115 (73), 270 (66), 91 (60), 168 (58), 141 (58),
213 (58); IR (thin film)/cm-1 2979 (m), 1723 (s), 1368 (m), 1290
(m), 1201(m), 1146 (m), 964 (m), 693(m). Anal. Calcd for
C19H24O4: C, 72.13; H, 7.65. Found: C, 72.18; H, 7.76.
Supporting Information Available: Characterization
data for all compounds and experimental procedure. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO051782N
J. Org. Chem, Vol. 70, No. 24, 2005 10205