Highly regio- and stereoselective synthesis of polysubstituted cyclopropane compounds via the Pd(0)-catalyzed coupling-cyclization reaction of 2-(2′,3′-allenyl)malonates with organic halides

Article abstract of DOI:10.1021/jo049323u

A new method for highly regio- and stereoselective synthesis of polysubstituted cyclopropane compounds via the Pd(0)-catalyzed coupling-cyclization reaction of 2-(2′,3′-allenyl)malonates with organic halides is described. In these reactions, the starting

Full text of DOI:10.1021/jo049323u

SCHEME 1
High ly Regio- a n d Ster eoselective
Syn th esis of P olysu bstitu ted Cyclop r op a n e
Com p ou n d s via th e P d (0)-Ca ta lyzed
Cou p lin g-Cycliza tion Rea ction of
2-(2′,3′-Allen yl)m a lon a tes w ith Or ga n ic
Ha lid es
Shengming Ma,* Ning J iao, Qing Yang, and
Zilong Zheng
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. China
masm@mail.sioc.ac.cn
Received April 22, 2004
allenyl)malonates with organic halides was developed for
the regioselective synthesis of cyclopropane or cyclopen-
tene derivatives via a π-allyl palladium intermediate.10
It is a challenge to control both the regio- and stereo-
selectivity of the reactions if there is a substitutent R2
at the 2′-position of the allenic compounds (Scheme 1).
Here, we wish to report our recent observation on the
highly regio- and stereoselective synthesis of polysubsti-
tuted cyclopropane derivatives.
Abstr a ct: A new method for highly regio- and stereoselec-
tive synthesis of polysubstituted cyclopropane compounds
via the Pd(0)-catalyzed coupling-cyclization reaction of
2-(2′,3′-allenyl)malonates with organic halides is described.
In these reactions, the starting materials are easily available
and the operation is convenient. The ratios of trans-isomer/
cis-vinylic cyclopropanes are up to 98:2.
Syn th esis of 2-(2′,3′-a lk a d ien yl)m a lon a tes 2. Com-
pounds 2a -e were prepared from the Pd(PPh3)4-cata-
lyzed alkylation reaction of malonates in ClCH2CH2Cl
with the corresponding 2,3-alkadienyl acetates 1a -e,
which, in turn, were prepared from the corresponding 2,3-
allenols11 and acetic anhydride (Scheme 2).12
The cyclopropyl group has been playing a prominent
role in organic chemistry.1 This smallest cycloalkane is
found as a basic structural element in a wide range of
naturally occurring compounds2 and has also been used
as a versatile synthetic intermediate in organic syn-
thesis.3-5 Thus, it still is of current interest to develop
efficient methods for the stereoselective synthesis of
polysubstituted functionalized cyclopropanes.
Cycliza tion Rea ction of 2-(2′,3′-Allen yl)m a lon a tes
w ith Or ga n ic Ha lid es. When the reaction of dimethyl
Recently, palladium-catalyzed reactions of allenes have
been most extensively investigated to achieve numerous
transformations.6,7 On the basis of our previous work,8,9
a Pd(0)-catalyzed coupling-cyclization reaction of 2-(2′,3′-
(6) (a) For a review on the palladium-catalyzed chemistry of allenes,
see: Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem. Rev.
2000, 100, 3067. (b) For a recent highlight, see: Hashmi, A. S. K.
Angew. Chem. Int. Ed. 2000, 39, 3590. (c) Ma, S. Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E.-i., Ed.;
J ohn Wiley & Sons: Hoboken, NJ , 2002; Vol. 1, pp 1491-1521. (d)
Ma, S. Acc. Chem. Res. 2003, 36, 701.
(7) (a) Ohno, H.; Toda, A.; Miwa, Y.; Taga, T.; Osawa, E.; Yamaoka,
Y.; Fujii, N.; Ibuka, T. J . Org. Chem. 1999, 64, 2992. (b) J eong, I.-Y.;
Nagao, Y. Tetrahedron Lett. 1998, 39, 8677. (c) Nemoto, H.; Yoshida,
M.; Fukumoto, K. J . Org. Chem. 1997, 62, 6450. (d) Oppolzer, W.;
Pimm, A.; Stammen, B.; Hume, W. E. Helv. Chim. Acta 1997, 80, 623.
(e) Okuro, K.; Alper, H. J . Org. Chem. 1997, 62, 1566. (f) Grigg, R.;
Xu, L. Tetrahedron Lett. 1996, 37, 4251. (g) Grigg, R.; Rasul, R.;
Redpath, J .; Wilson, D. Tetrahedron Lett. 1996, 37, 4609. (h) Larock,
R. C.; Zenner, J . M. J . Org. Chem. 1995, 60, 482. (i) Ma, S.; Negishi,
E. J . Org. Chem. 1994, 59, 4730. (j) Walkup, R. D.; Guan, L.; Mosher,
M. D.; Kim, S. W.; Kim, Y. S. Synlett 1993, 88. (k) Larock, R. C.;
Berrios-Pena, N. G.; Fried, C. A. J . Org. Chem. 1991, 56, 2615.
(8) (a) Ma, S.; Zhao, S. Org. Lett. 2000, 2, 2495. (b) Ma, S.; J iao, N.;
Zhao, S.; Hou, H. J . Org. Chem. 2002, 67, 2837.
(9) (a) Ahmar, M.; Cazes, B.; Gore, J . Tetrahedron Lett. 1985, 26,
3795. (b) Ahmar, M.; Cazes, B.; Gore, J . Tetrahedron 1987, 43, 3453.
(c) Cazes, B. Pure Appl. Chem. 1990, 62, 1867. (d) Besson, L.; Bazin,
J .; Gore, J .; Cazes. B. Tetrahedron Lett. 1994, 35, 2881. (e) Gamez, P.;
Ariente, C.; Gore, J .; Cazes, B. Tetrahedron 1998, 54, 14835. (f)
Yamamoto, Y.; Almasum, M.; Fujiwara, N. Chem. Commun. 1996, 381.
(g) Oh, C. H.; Rhim, C. Y.; Song, C. H.; Ryu, J . H. Chem. Lett. 2002,
1140.
(10) (a) Shimizu, I.; Tsuji, J . Chem. Lett. 1984, 233. (b) Ahmar, M.;
Cazes, B.; Gore, J . Tetrahedron Lett. 1984, 25, 4505.
(11) Xu, D.; Li, Z.; Ma, S. Chem. Eur. J . 2002, 8, 5012.
(12) Fleming, I.; Higgins, D.; Lawrence, N. I.; Thomas, A. P. J . Chem.
Soc., Perkin Trans. 1 1992, 24, 3331.
* Address correspondence to this author. Fax: (+86)21-64167510.
(1) For some reviews, see: (a) Special thematic issue on cyclopro-
panes and related rings: de Meijere, A. Chem. Rev. 2003, 103, 931-
1648. (b) Taylor, R. E.; Engelhardt, F. C.; Schmitt, M. J . Tetrahedron
2003, 59, 5623. (c) de Meijere, A.; Kozhushkov, S. I.; Fokin, A. A.;
Emme, I.; Redlich, S.; Rchreiner, P. R. Pure Appl. Chem. 2003, 75,
549. (d) Donaldson, W. A. Tetrahedron 2001, 57, 8589.
(2) (a) Faust, R. Angew. Chem. Int. Ed. 2001, 40, 2251. (b) Salau¨n,
J . Top. Curr. Chem. 2000, 207, 1. (c) Salau¨n, J . Curr. Med. Chem. 1995,
2, 511. (d) Djerassi, C.; Doss, G. A. New J . Chem. 1990, 14, 713.
(3) For reviews on the divinylcyclopropane rearrangements leading
to more functionalized alkanes, see: (a) Davies, H. M. L. Tetrahedron
1993, 49, 5203. (b) Hudlicky, T.; Fan, R.; Reed, J .; Gadamasetti, K. G.
Org. React. 1992, 41, 1. (c) Piers, E. In Comprehensive Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, UK, 1991; Vol.
5, p 971. (d) Mann, J . Tetrahedron 1986, 42, 4611.
(4) For reviews on the vinylcyclopropane rearrangements leading
to functionalized alkanes, see: (a) Hudlicky, T.; Reed, J . W. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, UK, 1991; Vol. 5, p 899. (b) Goldschmidt,
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(5) For reviews on ring-opening reactions of cyclopropane leading
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J .; Hudlicky, T. Chem. Rev. 1989, 89, 165. (c) Salau¨n, J . R. Y. Top.
Curr. Chem. 1988, 144, 1. (d) Reissig, H. U. Top. Curr. Chem. 1988,
144, 73.
10.1021/jo049323u CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/20/2004
J . Org. Chem. 2004, 69, 6463-6466
6463

SCHEME 2
SCHEME 3
TABLE 1. Th e P d (P P h 3)4-Ca ta lyzed
2-(1′-methyl-2′-butyl-2′,3′-butadienyl)malonate (2a ) and
PhI (3a ) was carried out in the presence of 5 mol % of
Pd(PPh3)4, 10 mol % of n-Bu4NBr as the phase transfer
catalyst, and 4.0 equiv of K2CO3 in the CH3CN under
reflux, it was very interesting to find that the cyclopro-
pane derivative 4a a was formed as the sole product in
94% yield with the ratio of trans-4a a /cis-4a a as high as
96:4 (Scheme 3). The stereochemistry of 4a a was deter-
mined by the 1H-1H NOESY spectra (Figure 1). The
formation of the cyclopentene derivative 5a a was not
observed.
The Pd(PPh3)4-catalyzed coupling-cyclization reaction
of dimethyl 2-(1′-methyl-2′-hexyl-2′,3′-butadienyl)ma-
lonate (2b) and PhI in different solvents was studied
(Table 1). The reaction in CH3CN gave 4ba in 86% yield
(trans-4ba :cis-4ba ) 95:5) (entry 1, Table 1). When the
reaction was carried out in DMSO, low yield and stereo-
selectivity of 4ba were observed (entry 3, Table 1). The
reactions in DMF and toluene gave similar results;
however, they were slower (entries 4 and 5, Table 1).
Therefore, we defined Conditions A (5 mol % of Pd(PPh3)4,
10 mol % of n-Bu4NBr, 4.0 equiv of K2CO3, CH3CN,
reflux) for the highly regio- and stereoselective prepara-
tion of cyclopropane derivative 4ba . If the reaction was
conducted in the absence of n-Bu4NBr (Conditions B: 5
mol % of Pd(PPh3)4, K2CO3 (4.0 equiv), CH3CN, reflux)
the ratio of trans-4ba /cis-4ba decreased slightly while
the yield was higher (compare entry 2 with entry 1, Table
1).
Cou p lin g-Cycliza tion Rea ction of Dim eth yl
2-(1′-Meth yl-2′-h exyl-2′,3′-bu ta d ien yl)m a lon a te (2b) w ith
P h I in Differ en t Solven tsa
entry
solvent
time (h)
yield of 4ba (%)
cis:trans
1
CH3CN
CH3CN
DMSO
DMF
17
16
16
34
60
86
93
81
85
85
5:95
6:94
8:92
6:94
6:94
2c
3
4
5
toluene
a
b
PhI (1.2 equiv) was used. The first letter refers to the allene
while the second letter refers to the halide. c The reaction was
carried out in the absence of Bu4NBr.
results of these reactions leading to cyclopropane deriva-
tives 4 as the sole products are summarized in Table 2.
The results of the Pd(PPh3)4-catalyzed coupling-cy-
clization reactions of 2b and 2c with different organic
halides under Conditions A and B were summarized in
Table 3. It should be noted that the configuration of the
CdC bond in 1-alkenyl iodide remained unchanged
during the reaction (entries 2, 4, and 6, Table 3).
In summary, we have developed a new protocol for the
highly regio- and stereoselective synthesis of polysubsti-
tuted cyclopropane compounds. Further studies in this
area are being pursued in our laboratory.
On the basis of these preliminary results, we extended
this reaction to different 2-(2, 3-allenyl)malonates. The
Exp er im en ta l Section
St a r t in g Ma t er ia ls. (1) Syn t h esis of (3-n -Bu t yl)p en t a -
3,4-d ien -2-yl Aceta te (1a ). Typ ica l p r oced u r e A: Acetic
anhydride (1.1 mL, 11.2 mmol) was added to the mixture of (3-
n-butyl)penta-3,4-dien-2-ol (1.12 g, 8 mmol), Et3N (1.52 mL, 11
mmol), and DMAP (97 mg, 0.8 mmol) in Et2O (25 mL). The
solution was stirred at room temperature for 1 h as monitored
by TLC. Evaporation and purification via flash chromatography
F IGURE 1.
6464 J . Org. Chem., Vol. 69, No. 19, 2004

TABLE 2. Th e P d (P P h 3)4-Ca ta lyzed
sulfate. After evaporation, the residue was purified by flash
chromatography on silica gel (eluent: petroleum ether:ethyl
acetate ) 20:1) to afford 53 mg (83%) of 2a ; liquid; IR (neat)
2956, 1955, 1760, 1739, 1435 cm-1; 1H NMR (300 MHz, CDCl3)
δ 4.63-4.78 (m, 2 H), 3.73 (s, 3 H), 3.70 (s, 3 H), 3.48 (d, J )
10.4 Hz, 1 H), 2.62-2.77 (m, 1 H), 1.92-2.02 (m, 2 H), 1.24-
1.45 (m, 4 H), 1.07 (d, J ) 6.60 Hz, 3 H), 0.89 (t, J ) 7.15 Hz, 3
H); 13C NMR (75.4 MHz, CDCl3) δ 204.7, 169.2, 168.9, 106.8,
78.5, 57.2, 52.6, 52.5, 36.4, 30.8, 29.8, 22.5, 17.9, 14.1; MS m/z
(%) 254 (M+, 12.20), 93 (100); HRMS m/z (EI) calcd for C14H22O4
254.15181, found 254.15498.
Cou p lin g-Cycliza tion Rea ction s of 2 w ith P h I in CH3CNa
yield (c/t)d
2
entry
R1/R2/(2)
time (h)b 4c
Cond. A
Cond. B
1
2
3
4
n-C6H13/Me/(2b) 17 (10) 4ba 86 (5:95)
93 (6:94)
91 (4:96)
72 (5:95)
P d (0)-Ca t a lyzed Cou p lin g-Cycliza t ion R ea ct ion of
Allen ylm a lon a tes w ith Or ga n ic Ha lid es. Con d ition s A:
P r ep a r a t ion of 1,1-Bis(m et h oxyca r b on yl)-2-b u t yl-2-(1′-
p h en yl-eth en yl)-3-m eth ylcyclop r op a n e (4a a ). Typ ica l p r o-
ced u r e: To a mixture of potassium carbonate (112 mg, 0.8
mmol), n-Bu4NBr (6.4 mg, 10 mol %), and Pd(PPh3)4 (12 mg, 5
mol %) in CH3CN (2 mL) was added dimethyl 2-(1′-methyl-2′-
butyl-2′,3′-butadienyl) malonate 2a (51 mg, 0.2 mmol) and
iodobenzene (49 mg, 1.2 equiv, 0.24 mmol) subsequently under
nitrogen. The resulting mixture was refluxed for 24 h as
monitored by TLC. After filtration, washing with ether, and
evaporation, the residue was purified by flash chromatography
on silica gel (eluent: petroleum ether:ethyl acetate ) 20:1) to
afford 62 mg (94%) of 4a a (cis-4a a :trans-4a a ) 4:96); liquid; IR
n-C6H13/Ph/(2c)
Me/Me/(2d )
Bn/Me(2e)
36 (13) 4ca 86 (4:96)
21 (25) 4d a 93 (6:94)
42 (25) 4ea 88 (20:80) 80 (13:87)
a
b
PhI (1.2 equiv) was used. The reaction time for Conditions
A. The reaction time for Conditions B is given in parentheses.c The
first letter refers to the allene while the second letter refers to
d
the halide. c/t ) cis/trans.
on silica gel (eluent: petroleum ether:ethyl acetate ) 20:1)
afforded 1.455 g (100%) of 1a .11 The analytical data are the same
as what were reported by us in ref 11.
(2) Syn t h esis of Dim et h yl 2-(1′-m et h yl-2′-b u t yl-2′,3′-
bu ta d ien yl)m a lon a te (2a ). Typ ica l p r oced u r e B: To a
mixture of NaH (60% dispersion in mineral oil, 11 mg, 1.1 equiv)
and Pd(PPh3)4 (14.5 mg, 5 mol %) in dry ClCH2CH2Cl (2.0 mL)
was added subsequently dimethyl malonate (0.09 mL, 3.0 equiv)
and (3-n-butyl)penta-3,4- dien-2-yl acetate 1a 11 (46 mg, 0.25
mmol) under nitrogen. The resulting mixture was stirred at room
temperature for 24 h as monitored by TLC. Then the solution
was quenched with an aqueous solution of saturated NaCl (2
mL) and extracted with ether (20 mL). The organic layer was
washed with brine (3 × 8 mL) and dried over anhydrous sodium
1
(neat) 2955, 1733, 1626, 1576, 1435, 1229 cm-1; H NMR (400
MHz, CDCl3) trans-4a a , δ 7.51 (d, J ) 8.80 Hz, 2 H), 7.11-7.26
(m, 3 H), 5.62 (s, 1 H), 5.12 (s, 1 H), 3.73 (s, 3 H), 3.36 (s, 3 H),
2.21 (q, J ) 6.80 Hz, 1 H), 1.82-1.96 (m, 1 H), 1.01-1.32 (m, 8
H), 0.71 (t, J ) 7.05 Hz, 3 H); 13C NMR (75.4 MHz, CDCl3) δ
168.7, 167.9, 145.5, 138.5, 128.4, 127.7, 126.5, 116.5, 52.6, 52.5,
43.9, 43.5, 30.2, 29.8, 29.1, 23.1, 14.3, 10.6; the following data
were discernible for the cis isomer, cis-4a a , 7.62 (d, J ) 8.60
Hz, 2 H), 5.80 (s, 1 H), 4.98 (s, 1 H), 3.77 (s, 3 H), 3.29 (s, 3 H),
TABLE 3. Th e P d (P P h 3)4-Ca ta lyzed Cou p lin g-Cycliza tion Rea ction s of 2 w ith Or ga n ic Ha lid es in CH3CNa
a
b
RI (1.2 equiv) was used. The reaction time for Conditions A. The reaction time for Conditions B is given in parentheses. c The first
d
letter refers to the allene while the second letter refers to the halide. c/t ) cis/trans.
J . Org. Chem, Vol. 69, No. 19, 2004 6465

0.82 (t, J ) 6.96 Hz, 3 H); MS m/z (%) 330 (M+, 3.35), 270 (100).
Anal. Calcd for C20H26O4: C 72.73, H 7.88. Found: C 72.70, H
7.71.
data were discernible for the cis isomer, cis-4ba , δ 7.64 (d, J )
9.0 Hz, 2 H), 7.28-7.17 (m, 3 H), 5.81 (s, 1 H), 4.98 (s, 1 H),
3.78 (s, 3 H), 3.31 (s, 3 H); MS m/z (%) 358 (M+, 7.03), 298 (100).
Anal. Calcd for C22H30O4: C 73.74, H 8.38. Found: C 73.43, H
8.23.
Con d ition s B: P r ep a r a tion of 1,1-Bis(m eth oxyca r bo-
n yl)-2-h exyl-2-(1′-p h en ylet h en yl)-3-m et h ylcyclop r op a n e
(4ba ). Typ ica l p r oced u r e: To a mixture of potassium carbon-
ate (140 mg, 1.0 mmol) and Pd(PPh3)4 (15 mg, 5 mol %) in CH3-
CN (2 mL) was added dimethyl 2-(1′-methyl-2′-hexyl-2′,3′-
butadienyl)malonate 2b (70 mg, 0.25 mmol) and iodobenzene
(61 mg, 1.2 equiv, 0.3 mmol) subsequently under nitrogen. The
resulting mixture was refluxed for 16 h as monitored by TLC.
After filtration, washing with ether, and evaporation, the residue
was purified by flash chromatography on silica gel (eluent:
petroleum ether:ethyl acetate ) 20:1) to afford 83 mg (93%) of
4ba (trans-4ba :cis-4ba ) 94:6). 4ba viscous liquid; IR (neat)
Ack n ow led gm en t. Financial support from the Ma-
jor State Basic Research Development Program (Grant
No. G2000077500), the National Natural Science Foun-
dation of China, and Shanghai Municipal Committee
of Science and Technology is greatly appreciated.
Su p p or tin g In for m a tion Ava ila ble: Typical experimen-
tal procedures, analytical data for compounds not listed in the
2954, 1736, 1623, 1575, 1435, 1222 cm-1 1H NMR (300 MHz,
;
1
text, H NMR and 13C NMR spectra of those compounds, and
CDCl3) trans-4ba , δ 7.52 (d, J ) 9.70 Hz, 2 H), 7.15-7.28 (m, 3
H), 5.64 (s, 1 H), 5.13 (s, 1 H), 3.75 (s, 3 H), 3.36 (s, 3 H), 2.17-
2.27 (m, 1 H), 1.83-1.98 (m, 1 H), 1.20 (d, J ) 6.75 Hz, 3 H),
1.02-1.29 (m, 9 H), 0.74 (t, J ) 7.03 Hz, 3 H); the following
the NOSEY spectra of 4a a . This material is available free of
charge via the Internet at http://pubs.acs.org.
J O049323U
6466 J . Org. Chem., Vol. 69, No. 19, 2004