Synergistic effect of additives on cyclopropanation of olefins

Article abstract of DOI:10.1039/c3ob40751a

An efficient cyclopropanation of olefins with Zn(CH₂I) ₂, a catalytic amount of CCl₃CO₂H, and 1,2-dimethoxyethane at room temperature is described. A wide variety of olefins, including acid-sensitive substrates,

Full text of DOI:10.1039/c3ob40751a

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Synergistic effect of additives on cyclopropanation of
olefins†
Cite this: Org. Biomol. Chem., 2013, 11,
588
5
a
a
a,b
Donghao Cheng, Deshun Huang and Yian Shi*
Received 15th April 2013,
Accepted 21st June 2013
DOI: 10.1039/c3ob40751a
www.rsc.org/obc
8
An efficient cyclopropanation of olefins with Zn(CH
amount of CCl CO H, and 1,2-dimethoxyethane at room temp- However, one of the drawbacks of our earlier procedures is
erature is described. A wide variety of olefins, including acid- that stoichiometric amounts of CF CO H are usually used. For
2 2
I) , a catalytic and have found a variety of applications in synthesis.
3
2
3
2
sensitive substrates, can be cyclopropanated in 71–99% yield.
3 2
some unreactive substrates such as stilbenes, excess CF CO H
8
is frequently needed to obtain high conversions. Therefore,
the development of a cyclopropanation procedure requiring
Cyclopropanes are present in many biological and medicinal
1
2
molecules, and are synthetically useful intermediates. The
9,10
only substoichiometric amounts of RXH is highly desirable.
Simmons–Smith reaction is a very effective method to syn-
Herein, we wish to report our preliminary studies on this
subject.
Initial studies were carried out with relatively unreactive
trans-stilbene (1a) as the substrate. As shown in Fig. 1, a poor
conversion of trans-stilbene was observed with no additive
3
thesize cyclopropanes from olefins (Scheme 1). Since the
4
initial report of the Simmons–Smith reaction, lots of modifi-
5
cations have been reported. A variety of strategies have also
been developed to generate various zinc species, including
6
a,b
6c–g
6h
XZnCH X,
RZnCH2I or Zn(CH I) ,
Zn(CH Cl) ,
2 2
2
2
2
(
Fig. 1, curve A). The conversion only slightly increased with
6
i,j
6k
6l–n
RCO CH ZnR, ArOZnCH2I, and (RO) P(O)OZnCH I.
In
7b,11
2
2
2
2
the addition of 0.2 equiv. of CF
3
CO
2
H or CCl
3
CO
2
H
(Fig. 1,
1
998, we reported a novel class of tunable cyclopropanation
curves B and C). However, in the case of CCl CO H, the conver-
3
2
zinc species (RXZnCH I) generated by reacting appropriate zinc
2
sion greatly increased when 1 equiv. of 1,2-dimethoxyethane
reagents with RXH ranging from alcohols to acids
7,8
(
3 2
Scheme 2). The zinc species, derived from acids like CF CO H,
display very high reactivities for the cyclopropanation of olefins
Scheme 1
Scheme 2
Fig. 1 Plot of the conversion of trans-stilbene against time (h). All reactions
a
Beijing National Laboratory of Molecular Sciences, CAS Key Laboratory of Molecular
were carried out with trans-stilbene (0.50 mmol), Et
n-hexane), CH (2.0 mmol), and additives in CH Cl (2.5 mL) at 30 °C for 24 h.
The conversions were determined using GC analysis. The curves presented are:
(A) no additive, (B) CF CO H (0.10 mmol), (C) CCl CO H (0.10 mmol), (D)
CF CO H (0.10 mmol), DME (0.50 mmol), (E) CCl CO H (0.10 mmol), DME
(0.50 mmol), (F) DME (0.50 mmol), (G) CCl CO H (1.0 mmol), (H) MeCOCO
(0.10 mmol), DME (0.50 mmol), (I) 2,4,6-trichlorophenol (0.10 mmol), DME
2
Zn (1.0 mmol, 1.0 M in
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, China
2
I
2
2
2
b
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523,
3
2
3
2
USA. E-mail: yian@lamar.colostate.edu; Fax: +001-970-4911801;
Tel: +001-970-4917424
†
3
2
3
2
3
2
2
H
Electronic supplementary information (ESI) available: Experimental procedures,
characterization data, and NMR spectra. See DOI: 10.1039/c3ob40751a
(0.50 mmol), (J) CF
3
CH
2
OH (0.10 mmol), and DME (0.50 mmol).
5
588 | Org. Biomol. Chem., 2013, 11, 5588–5591
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Communication
a
a
Table 1 Studies on reaction conditions
Table 2 Cyclopropanation of olefins
b
Entry
Additive
Solvent
Conv. (%)
b
c
Entry Substrate
Time (h) Conv. (%) Yield (%)
1
2
3
4
5
6
7
None
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
29
6
52
64
55
82
84
1
2
3
4
5
48
18
2
86
100
100
100
99
77
77
97
95
94
TMEDA (1.0 equiv.)
2,2′-Bipyridine (1.0 equiv.)
2
Et O (1.0 equiv.)
t
BuOMe (1.0 equiv.)
THF (1.0 equiv.)
18
18
Dioxane (1.0 equiv.)
8
CH
Cl
2 2
77
9
CH
Cl
2 2
70
6
18
100
88
7
18
97
96
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
DME (1.0 equiv.)
DME (0.2 equiv.)
DME (0.5 equiv.)
DME (2.0 equiv.)
DME (5.0 equiv.)
DME (1.0 equiv.)
DME (1.0 equiv.)
DME (1.0 equiv.)
CH
CH
CH
CH
CH
DCE
Toluene
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
85
64
73
56
8
75
47
66
8
9
18
24
100
87
84
71
n-Hexane
10
4
100
99
a
All reactions were carried out with trans-stilbene (1a) (0.50 mmol),
Zn (1.0 mmol, 1.0 M in n-hexane), CH (2.0 mmol), CCl CO
0.10 mmol), and additive in solvent (2.5 mL) at 30 °C for 18 h. 11
Et
2
2
I
2
3
2
H
(
18
18
100
100
77
94
b
The conversions were determined using GC analysis.
12
6
l,9,12
(
DME)
parable to the conversion obtained with 2 equiv. of CCl
Fig. 1, curve G). A similar synergistic effect of additives on the
cyclopropanation of olefins was also observed with
MeCOCO H (Fig. 1, curve H).
was added (Fig. 1, curve E). This result was com-
3
CO
2
H
1
1
1
3
4
5
18
18
18
100
99
72
71
82
(
100
2
The observed beneficial effect of DME on the cyclopropana-
tion prompted us to systematically examine various other addi-
tives. As shown in Table 1, TMEDA was found to be
detrimental to the reaction (Table 1, entry 2). The ether-type
additives were favorable for the reaction, with DME being the
best (Table 1, entries 4–10). Further studies showed that the
amount of DME was important for the reaction conversion,
with 1 equiv. being optimal (Table 1, entries 10–14). While a
precise understanding of the beneficial effect of additives like
1
1
6
7
18
18
100
100
76
93
1
3
1
1
8
9
20
100
90
18
3
100
100
91
90
DME on the cyclopropanation awaits further study, the addi- 20
tives could coordinate with the zinc carbenoids to increase
12
their stabilities and/or disrupt inactive aggregates. At the 21
same time, the additives could also reduce the reactivity of the
zinc carbenoids. As a result, the reaction conversion is depen-
3
100
84
dent on the amount of the additives added. Among the sol-
vents examined (Table 1, entries 10 and 15–17), the highest
conversion was obtained with CH Cl .
2 2
a
2
All reactions were carried out with olefins (0.50 mmol), Et Zn
(
1.0 mmol, 1.0
0.10 mmol), and DME (0.50 mmol) in CH
M
in n-hexane), CH
2
I
2
Cl
(2.0 mmol), CCl
(2.5 mL) at 25 °C unless
3 2
CO H
(
2
2
The cyclopropanation procedure with 0.2 equiv. of otherwise noted. For entries 1 and 2, reactions were carried out with
olefins (1.0 mmol), Et Zn (2.0 mmol), CH (4.0 mmol), CCl CO
2 2
0.20 mmol), and DME (1.0 mmol) in CH Cl (5.0 mL). The
2
2
I
2
3
2
H
CCl CO H and 1 equiv. of DME can be extended to a wide
variety of olefins, giving the corresponding cyclopropanes in
7
b
3
2
(
conversions were determined from the crude reaction mixture either
1–99% yield (Table 2). The effective substrates include trans-, using GC or H NMR analysis. Isolated yield.
1
c
cis-, terminal, and trisubstituted olefins. Various functional
groups, such as OH, OTBS, and CO R, can be tolerated
Table 2, entries 3, 4, 6, 7, 10, and 11). For acid-sensitive silyl
2
(
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 5588–5591 | 5589

View Article Online
Communication
Organic & Biomolecular Chemistry
Acknowledgements
The authors gratefully acknowledge the National Basic
Research Program of China (973 program, 2011CB808600) and
the Chinese Academy of Sciences for financial support.
Scheme 3
Notes and references
1
For leading reviews, see: (a) J. Salaün, in Topics in Current
Chemistry, ed. A. de Meijere, Springer-Verlag, Berlin, 2000,
vol. 207, ch. 1, pp. 1–67; (b) W. A. Donaldson, Tetrahedron,
2
2
001, 57, 8589; (c) R. Faust, Angew. Chem., Int. Ed., 2001, 40,
251; (d) J. Pietruszka, Chem. Rev., 2003, 103, 1051;
Scheme 4
(
4
e) A. Reichelt and S. F. Martin, Acc. Chem. Res., 2006, 39,
33; (f) D. Y.-K. Chen, R. H. Pouwer and J.-A. Richard,
Chem. Soc. Rev., 2012, 41, 4631.
2
For leading reviews, see: (a) H. N. C. Wong, M.-Y. Hon,
C.-W. Tse, Y.-C. Yip, J. Tanko and T. Hudlicky, Chem. Rev.,
1989, 89, 165; (b) J. Salaün, Chem. Rev., 1989, 89, 1247;
(
c) The Chemistry of the Cyclopropyl Group, ed. Z. Rappoport,
Wiley, Chichester, 1995; (d) H.-U. Reissig and R. Zimmer,
Chem. Rev., 2003, 103, 1151; (e) M. Yu and B. L. Pagenkopf,
Tetrahedron, 2005, 61, 321; (f) C. A. Carson and M. A. Kerr,
Chem. Soc. Rev., 2009, 38, 3051; (g) S. R. Goudreau and
A. B. Charette, Angew. Chem., Int. Ed., 2010, 49, 486;
Scheme 5 Synthesis of a key intermediate for Roflumilast.
(
h) T. P. Lebold and M. A. Kerr, Pure Appl. Chem., 2010, 82,
797; (i) M.-N. Roy, V. N. G. Lindsay and A. B. Charette, in
1
Science of Synthesis, Stereoselective Synthesis, ed. J. G. de
Vries, Thieme, 2011, vol. 1, ch. 14, pp. 731–817;
( j) D. Zhang, H. Song and Y. Qin, Acc. Chem. Res., 2011, 44,
enol ethers 1t and 1u, the cyclopropane products were
obtained in high yields without desilylation (Table 2, entries
7
b
2
0 and 21). The cyclopropanation of dienol 1v afforded the
447; (k) P. Tang and Y. Qin, Synthesis, 2012, 2969;
corresponding bicyclopropane 2v in 82% yield with good
1
4
(l) Z. Wang, Synlett, 2012, 2311; (m) D. J. Mack and
J. T. Njardarson, ACS Catal., 2013, 3, 272.
3 For leading reviews, see: (a) H. E. Simmons, T. L. Cairns,
S. A. Vladuchick and C. M. Hoiness, Org. React., 1973, 20, 1;
diastereoselectivity (dr = 87 : 13) (Scheme 3). For geraniol 1w,
the allylic alcohol can be selectively cyclopropanated in 93%
1
5
yield along with bicyclopropane 2w (Scheme 4).
As illustrated in the case of compound 5, the cyclopropana-
tion is amenable to the gram scale, giving cyclopropane 6 in
(
b) A. H. Hoveyda, D. A. Evans and G. C. Fu, Chem. Rev.,
1
1
993, 93, 1307; (c) A. B. Charette and J.-F. Marcoux, Synlett,
995, 1197; (d) M. Lautens, W. Klute and W. Tam, Chem.
8
9% yield (Scheme 5). Compound 6 is a key intermediate
towards Roflumilast, a selective long-acting PDE-4 inhibitor for
1
6
Rev., 1996, 96, 49; (e) A. B. Charette and A. Beauchemin,
Org. React., 2001, 58, 1; (f) S. E. Denmark and G. Beutner,
in Cycloaddition Reactions in Organic Synthesis, ed.
S. Kobayashi and K. A. Jørgensen, Wiley-VCH, Weinheim,
the treatment of inflammatory conditions of lungs.
2
002, ch. 3, pp. 85–150; (g) H. Lebel, J.-F. Marcoux,
Conclusion
C. Molinaro and A. B. Charette, Chem. Rev., 2003, 103, 977;
(h) A. B. Charette, in The Chemistry of Organozinc Com-
pounds, ed. Z. Rappoport and I. Marek, John Wiley & Sons,
West Sussex, UK, 2006, ch. 7, pp. 237–286; (i) H. Pellissier,
Tetrahedron, 2008, 64, 7041; ( j) A. Maleki, Synlett, 2009,
1690; (k) H. Y. Kim and P. J. Walsh, Acc. Chem. Res., 2012,
45, 1533; (l) M. Pasco, N. Gilboa, T. Mejuch and I. Marek,
Organometallics, 2013, 32, 942.
In summary, we have developed an efficient cyclopropanation
procedure for olefins with a catalytic amount of CCl CO H and
one equiv. of DME. A wide variety of olefins including acid-
sensitive substrates have been cyclopropanated in 71–99%
3 2
yield. The synergistic effect of CCl CO H and DME dramati-
cally reduces the amount of acid used, which makes this cyclo-
propanation procedure milder and more practical. Further
understanding the mechanism and developing more effective
catalytic systems with high reactivity and selectivity are cur-
rently under way.
3
2
4 (a) H. E. Simmons and R. D. Smith, J. Am. Chem. Soc.,
1958, 80, 5323; (b) H. E. Simmons and R. D. Smith, J. Am.
Chem. Soc., 1959, 81, 4256.
5
590 | Org. Biomol. Chem., 2013, 11, 5588–5591
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Communication
5
For leading references on modifications of Simmons–
Smith cyclopropanations, see: (a) R. S. Shank and
H. Shechter, J. Org. Chem., 1959, 24, 1825; (b) E. LeGoff,
J. Org. Chem., 1964, 29, 2048; (c) R. J. Rawson and
I. T. Harrison, J. Org. Chem., 1970, 35, 2057; (d) J. M. Denis,
C. Girard and J. M. Conia, Synthesis, 1972, 549;
B. L. Christenson, D. M. Coe and S. P. O’Connor, Tetra-
hedron Lett., 1995, 36, 2215; (e) S. E. Denmark,
B. L. Christenson and S. P. O’Connor, Tetrahedron Lett.,
1995, 36, 2219; (f) H. Takahashi, M. Yoshioka,
M. Shibasaki, M. Ohno, N. Imai and S. Kobayashi, Tetra-
hedron, 1995, 51, 12013; (g) A. B. Charette and C. Brochu,
J. Am. Chem. Soc., 1995, 117, 11367; (h) S. E. Denmark and
S. P. O’Connor, J. Org. Chem., 1997, 62, 584; (i) N. Imai,
K. Sakamoto, M. Maeda, K. Kouge, K. Yoshizane and
J. Nokami, Tetrahedron Lett., 1997, 38, 1423;
( j) S. E. Denmark and S. P. O’Connor, J. Org. Chem., 1997,
62, 3390; (k) S. E. Denmark, S. P. O’Conner and S. R. Wilson,
Angew. Chem., Int. Ed., 1998, 37, 1149; (l) J. Balsells and
P. J. Walsh, J. Org. Chem., 2000, 65, 5005; (m) A. B. Charette,
C. Molinaro and C. Brochu, J. Am. Chem. Soc., 2001, 123,
12168; (n) T. Miura, Y. Murakami and N. Imai, Tetrahedron:
Asymmetry, 2006, 17, 3067; (o) H. Shitama and T. Katsuki,
Angew. Chem., Int. Ed., 2008, 47, 2450.
(
(
e) J. M. Conia, Pure Appl. Chem., 1975, 43, 317;
f) R. D. Rieke, P. T.-J. Li, T. P. Burns and S. T. Uhm, J. Org.
Chem., 1981, 46, 4323; (g) O. Repič and S. Vogt, Tetrahedron
Lett., 1982, 23, 2729; (h) E. C. Friedrich, J. M. Domek and
R. Y. Pong, J. Org. Chem., 1985, 50, 4640; (i) E. C. Friedrich,
S. E. Lunetta and E. J. Lewis, J. Org. Chem., 1989, 54, 2388;
(
2
(
1
j) E. C. Friedrich and E. J. Lewis, J. Org. Chem., 1990, 55,
491; (k) Y. Stenstrøm, Synth. Commun., 1992, 22, 2801;
l) K. Takai, T. Kakiuchi and K. Utimoto, J. Org. Chem.,
994, 59, 2671.
6
For leading references, see: XZnCH X: (a) G. Wittig and
2
K. Schwarzenbach, Angew. Chem., 1959, 71, 652;
(
b) G. Wittig and K. Schwarzenbach, Justus Liebigs Ann. 11 L. F. Frey, K. M. Marcantonio, C.-Y. Chen, D. J. Wallace,
Chem., 1961, 650, 1. RZnCH2I or Zn(CH I) :
J. A. Murry, L. Tan, W. Chen, U. H. Dolling and
2
2
(
c) J. Furukawa, N. Kawabata and J. Nishimura, Tetrahedron
E. J. J. Grabowski, Tetrahedron, 2003, 59, 6363.
Lett., 1966, 7, 3353; (d) J. Furukawa, N. Kawabata and 12 For leading references on ether-coordinated Simmons–
J. Nishimura, Tetrahedron, 1968, 24, 53; (e) S. Sawada and
Y. Inouye, Bull. Chem. Soc. Jpn., 1969, 42, 2669;
Smith cyclopropanation reagents, see: (a) S. E. Denmark,
J. P. Edwards and S. R. Wilson, J. Am. Chem. Soc., 1991,
113, 723; (b) S. E. Denmark, J. P. Edwards and S. R. Wilson,
J. Am. Chem. Soc., 1992, 114, 2592; (c) A. B. Charette,
S. Prescott and C. Brochu, J. Org. Chem., 1995, 60, 1081;
(d) A. B. Charette and J.-F. Marcoux, J. Am. Chem. Soc.,
1996, 118, 4539; (e) A. B. Charette, J.-F. Marcoux and
F. Bélanger-Gariépy, J. Am. Chem. Soc., 1996, 118, 6792;
(f) A. B. Charette, H. Juteau, H. Lebel and C. Molinaro,
J. Am. Chem. Soc., 1998, 120, 11943; (g) A. B. Charette,
E. Jolicoeur and G. A. S. Bydlinski, Org. Lett., 2001, 3, 3293;
(h) A. B. Charette and N. Wilb, Synlett, 2002, 176.
(
f) J. Nishimura, J. Furukawa, N. Kawabata and
M. Kitayama, Tetrahedron, 1971, 27, 1799;
g) A. B. Charrete, A. Beauchemin and J.-F. Marcoux, Tetra-
hedron Lett., 1999, 40, 33. Zn(CH Cl) : (h) S. E. Denmark
and J. P. Edwards, J. Org. Chem., 1991, 56, 6974.
RCO CH ZnR: (i) G. Wittig and M. Jautelat, Justus Liebigs
(
2
2
2
2
Ann. Chem., 1967, 702, 24; ( j) A. B. Charette,
A. Beauchemin and S. Francoeur, J. Am. Chem. Soc., 2001,
1
23, 8139. ArOZnCH
2
I: (k) A. B. Charette, S. Francoeur,
J. Martel and N. Wilb, Angew. Chem., Int. Ed., 2000, 39,
4
539. (RO) P(O)OZnCH I: (l) M.-C. Lacasse, C. Poulard and 13 For a leading reference on amine-coordinated Simmons–
2 2
A. B. Charette, J. Am. Chem. Soc., 2005, 127, 12440;
m) A. Voituriez and A. B. Charette, Adv. Synth. Catal., 2006,
48, 2363; (n) A. Voituriez, L. E. Zimmer and A. B. Charette,
Smith cyclopropanation reagents, see: A. B. Charette,
J.-F. Marcoux, C. Molinaro, A. Beauchemin, C. Brochu and
É. Isabel, J. Am. Chem. Soc., 2000, 122, 4508.
(
3
J. Org. Chem., 2010, 75, 1244.
(a) Z. Yang, J. C. Lorenz and Y. Shi, Tetrahedron Lett., 1998,
14 (a) A. G. M. Barrett and G. J. Tustin, J. Chem. Soc., Chem.
Commun., 1995, 355; (b) A. G. M. Barrett, W. W. Doubleday
and G. J. Tustin, Tetrahedron, 1996, 52, 15325.
7
8
9
3
9, 8621; (b) J. C. Lorenz, J. Long, Z. Yang, S. Xue, Y. Xie
and Y. Shi, J. Org. Chem., 2004, 69, 327.
For a leading review, see: R. G. Cornwall, O. A. Wong,
H. Du, T. A. Ramirez and Y. Shi, Org. Biomol. Chem., 2012,
15 (a) K. Maruoka, Y. Fukutani and H. Yamamoto, J. Org.
Chem., 1985, 50, 4414; (b) H. Sakauchi, H. Asao, T. Hasaba,
S. Kuwahara and H. Kiyota, Chem. Biodiversity, 2006, 3, 544;
(c) G. Brunner, L. Eberhard, J. Oetiker and F. Schröder,
J. Org. Chem., 2008, 73, 7543; (d) G. Brunner, S. Elmer and
F. Schröder, Eur. J. Org. Chem., 2011, 4623.
1
0, 5498.
For leading references on catalytic asymmetric cyclopropa-
nations with chiral dipeptide, see: (a) J. Long, H. Du, K. Li
and Y. Shi, Tetrahedron Lett., 2005, 46, 2737; (b) H. Du, 16 For leading references on the synthesis of Roflumilast, see:
J. Long and Y. Shi, Org. Lett., 2006, 8, 2827; (c) J. Long,
L. Xu, H. Du, K. Li and Y. Shi, Org. Lett., 2009, 11, 5226.
0 For leading references on catalytic asymmetric cyclopropa-
nations, see: (a) H. Takahashi, M. Yoshioka, M. Ohno and
S. Kobayashi, Tetrahedron Lett., 1992, 33, 2575; (b) N. Imai,
H. Takahashi and S. Kobayashi, Chem. Lett., 1994, 177;
(a) E. L. Williams and T.-C. Wu, PCT Int. Appl. WO
2004033430, 2004; (b) B. Kohl, B. Mueller and W. Palosch,
PCT Int. Appl. WO 2004080967, 2004; (c) P. Bose,
Y. P. Sachdeva, R. S. Bathore and Y. Kumar, PCT Int. Appl.
WO 2005026095, 2005; (d) M. Liao, R. Li, S. Yang, L. Zhang
and L. Ding, Faming Zhuanli Shenqing CN 102093194, 2011;
(e) Y. Zhong, G. Chen, A. Li and S. Li, Chin. J. Pharm., 2011,
42, 884; (f) F. Ni and J. Li, Synthesis, 2012, 3598.
1
(c) N. Imai, K. Sakamoto, H. Takahashi and S. Kobayashi,
Tetrahedron Lett., 1994, 35, 7045; (d) S. E. Denmark,
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 5588–5591 | 5591