An X- (X = I, Br)-triggered ring-opening cyclization of cyclopropenyl-substituted alkyl halides or mesylates: An efficient and highly regioand stereoselective approach to (E)-haloalkylidene 4-7-membered cyclic compounds

Article abstract of DOI:10.1021/jo900389m

(Chemical Equation Presented) Polyfunctionalized (E)-haloalkylidene cyclic products were efficiently synthesized in moderate to excellent yields via a regio- and stereoselective X^- (X = I or Br)-triggered ring-opening intramolecular trapping of

Full text of DOI:10.1021/jo900389m

pubs.acs.org/joc
An X- (X=I, Br)-Triggered Ring-Opening
Cyclization of Cyclopropenyl-Substituted Alkyl
Halides or Mesylates: An Efficient and Highly Regio-
and Stereoselective Approach to (E)-Haloalkylidene
4-7-Membered Cyclic Compounds
allenes have been developed as a class of powerful starting
materials for the construction of cyclic compounds.4 As two
classes of very similar analogues to allenes, alkylidenecyclo-
propanes5,6 and even cyclopropenes5t,5u,7,8 have also caught
the attention of organic chemists.
In 2003, we described a regioselective cycloisomerization
of cyclopropenyl ketones leading to 2,3,4-trisubstituted fur-
ans or 2,3,5-trisubstituted furans by using CuI or
PdCl2(CH3CN)2 as the catalysts, respectively.9 In the same
year, we noticed an X- (X=I, Br)-triggered ring-opening
Jie Chen and Shengming Ma*
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032, People’s
Republic of China
(5) For some representative reports on the ring-opening reactions of
alkylidenecyclopropanes, see: (a) Brandi, A.; Cicchi, S.; Cordero, F. M.;
Goti, A. Chem. Rev. 2003, 103, 1213. (b) Noyori, R.; Odagi, T.; Takaya, H. J.
€
Am. Chem. Soc. 1970, 92, 5780. (c) Binger, P.; Buch, H. M. Top. Curr. Chem.
masm@mail.sioc.ac.cn
1987, 135, 77. (d) Motherwell, W. B.; Shipman, M. Tetrahedron Lett. 1991,
32, 1103 and references cited therein. (e) Corlay, H.; Motherwell, W. B.;
Pennell, A. M. K.; Shipman, M.; Slawin, A. M. Z.; Williams, D. J.; Binger, P.;
Stepp, M. Tetrahedron 1996, 52, 4883. (f) Delgado, A.; Rodriguez, J. R.;
Received February 22, 2009
~
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Org. Chem. 2008, 73, 4702. For some reviews of alkylidenecyclopropanes,
see: (s) Nakamura, I.; Yamamoto, Y. Adv. Synth. Catal. 2002, 344, 111. (t)
Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117. (u) Ma,
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(6) For reports on the ring-opening reactions of alkylidenecyclopro-
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€
Kozhushkov, S.; Spath, T.; Fiebig, T.; Galland, B.; Ruasse, M.-F.; Vavier,
Polyfunctionalized (E)-haloalkylidene cyclic products were
efficiently synthesized in moderate to excellent yields via a
regio- and stereoselective X- (X = I or Br)-triggered ring-
opening intramolecular trapping of cyclopropenes 1. The
reaction can be used for construction of 4-7-membered
products. The E-stereoselectivity of the exo-CdC bond is
very high. The carbon-halogen bond in the exo-CdC
bond may further be elaborated to prepare differently
substituted cyclic products with a stereodefined CdC bond.
P.; Apeloig, Y.; de Meijere, A. J. Org. Chem. 2002, 67, 4100. (c) Huang, J.;
Shi, M. J. Org. Chem. 2005, 70, 3859. (d) Ma, S.; Lu, L. J. Org. Chem. 2005,
70, 7629. (e) Chen, J.; Lu, L.; Ma, S. Tetrahedron 2008, 64, 8899.
(7) For some representative reports on the reactions CdC bond on
cyclopropenes, see: (a) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am.
Chem. Soc. 2000, 122, 978 and references cited therein. (b) Kubota, K.; Mori,
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Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2002, 124, 11566.
(i) Trofimov, A.; Rubina, M.; Rubin, M.; Gevorgyan, V. J. Org. Chem. 2007,
72, 8910. (j) Masarwa, A.; Stanger, A.; Marek, I. Angew. Chem., Int. Ed.
2007, 46, 8039. (k) Fordyce, E. A. F.; Wang, Y.; Luebbers, T.; Lam, H. W.
Chem. Commun. 2008, 1124. (l) Sherrill, W. M.; Rubin, M. J. Am. Chem. Soc.
2008, 130, 13804. (m) Yan, N.; Liu, X.; Fox, J. M. J. Org. Chem. 2008, 73,
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(o) Fordyce, E. A. F.; Luebbers, T.; Lam, H. W. Org. Lett. 2008, 10, 3993. (p)
Simaan, S.; Marek, I. Chem. Commun. 2009, 292. (q) Tarwade, V.; Liu, X.;
Yan, N.; Fox, J. M. J. Am. Chem. Soc. 2009, 131, 5382. For some reviews of
cyclopropenes, see: (r) Nakamura, M.; Isobe, H.; Nakamura, E. Chem. Rev.
2003, 103, 1295. (s) Fox, J. M.; Yan, N. Curr. Org. Chem. 2005, 9, 719. (t)
Rubin, M.; Rubina, M.; Gevorgyan, V. Synthesis 2006, 1221. (u) Marek, I.;
Simaan, S.; Masarwa, A. Angew. Chem., Int. Ed. 2007, 46, 7364.
(8) For reports on the ring-opening reactions of cyclopropenes, see: (a)
Giudici, R. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2007, 129, 3824. (b) Smith,
M. A.; Richey, H. G. Organometallics 2007, 26, 609. (c) Nakamura, I.;
Bajracharya, C. B.; Yamamoto, Y. J. Org. Chem. 2003, 68, 2297. (d) Binger,
P.; Biedenbach, B. Chem. Ber. 1987, 120, 601. (e) Bauer, J. T.; Hadfield, M.
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F.; Chen, F. Y.; Lam, H. W. Angew. Chem., Int. Ed. 2009, 48, 7350.
(9) Ma, S.; Zhang, J. J. Am. Chem. Soc. 2003, 125, 12386.
Efficient synthesis of carbocycles and heterocycles is one
of the main themes in organic synthesis due to the impor-
tance of cyclic compounds.1-3 Recently functionalized
(1) Topics in Heterocyclic Chemistry; Eychen, D., Van, E., Oliver, K. C.,
Eds.; Springer: Berlin, Germany, 2006; Vol. 1.
(2) (a) Li, C.; Liu, R. Chem. Rev. 2000, 100, 3127. (b) Miura, T.;
Murakami, M. Chem. Commun. 2007, 217. (c) Schaumann, E.; Kirschning,
A. Synlett 2007, 177.
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D.; Fujiwara, T.; Kataoka, H. J. Org. Chem. 2008, 73, 249. (b) Tsuji, H.;
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Masuda, M. J. Org. Chem. 2007, 72, 9114.
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2003, 36, 701. (c) Modern Allene Chemistry; Krause, N., Hashmi, A. S. K.,
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DOI: 10.1021/jo900389m
r
Published on Web 06/22/2009
J. Org. Chem. 2009, 74, 5595–5598 5595
2009 American Chemical Society

Chen and Ma
JOCNote
TABLE 1. Reaction of 1a with MI under Different Reaction Conditions
TABLE 2. Reaction of 1b with NaI under Different Reaction Conditions
entry
MI
solvent
temp (°C)
yield of E-2aa (%)
1b
2b,c
3
4
5
6
7
8
9
NaI
NaI
NaI
AgI
CuI
LiI
NaI
NaI
NaI
NaI
NaI
acetone
acetone
acetone
acetone
acetone
acetone
CH3CN
THF
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
80
78
70
80
0d
NaI
entry (equiv)
yield of
Mb (mol/L) time (h) E-2bc (%)
additivea
none
Na2CO3 (0.6)
Na2CO3 (0.7)
Na2CO3 (0.6)
0e
1
2
3
4
1.5
1.5
1.7
1.6
0.067
0.067
0.05
18
16.5
20
9
23
57
47
58
74
74
71
73
67
0.025
20
a Equiv of Na2CO3 used. b M=the concentration of 1b. c Isolated
yield.
CH3NO2
dioxane
DCE
10
11
80
80
yield (entry 6, Table 1); study on the solvent effect implied
that acetone is the best solvent for this transformation
(compare entries 7-11 with entry 3, Table 1).
a Isolated yield. b 0.5 equiv of Na2CO3 was used. c 1.2 equiv of NaI was
used. d 89% of 1a was recovered. e 83% of 1a was recovered.
However, when we applied the optimized reaction condi-
tions to the reaction of 5-(30,30-bis(methoxycarbonyl)-
cyclopropenyl)pentyl bromide 1b, the yield of the 7-
membered product E-2b was only 9% (entry 1, Table 2).
It was observed that the reaction with the addition of
0.6 equiv of Na2CO3 afforded E-2b in a slightly higher
yield (entry 2, Table 2). Thus, further study for the effect
of concentration of 1b was conducted (Table 2). When
the concentration of 1b was adjusted to 0.05 M, we
were pleased to find that the reaction of 1b in the presence
of 0.7 equiv of Na2CO3 occurred smoothly to give the
product E-2b in 57% yield (entry 3, Table 2). The stereo-
chemistry was also established by its X-ray diffraction study
(Figure S2, Supporting Information).13 Here again, the
regioselectivity is very high with I- attacking the less sub-
stituted sp2 carbon atom, which is the same as reported in our
previous studies.10
coupling reaction of cyclopropenyl carboxylates with organ-
ic halides providing an efficient and highly regio- and
stereoselective route to a series of polyfunctionalized (1E)-
alkenyl halides.10 However, in the presence of imines, the
NaI-catalyzed reaction of cyclopropenyl carboxylates pro-
vided a highly regio- and stereoselective route to a series of
polyfunctionalized vinyl aziridines.11 Herein, we wish to
report an X- (X=I, Br)-triggered ring-opening cyclization
of cyclopropenyl-substituted alkyl halides or mesylates,
providing a highly regio- and stereoselective approach to
the synthesis of (E)-haloalkylidene 4-7-membered cyclic
compounds.
The reaction of dimethyl 2-(3-bromopropyl)-3-phenylcy-
cloprop-2-ene-1,1-dicarboxylate 1a with 1.5 equiv of NaI in
the presence of 0.5 equiv of Na2CO3 in acetone under reflux
was studied. To our delight, the reaction smoothly led to the
formation of (E)-iodobenzylidenecyclopentane derivative
E-2a in 78% yield with excellent regio- and stereoselectivity,
which was established by the X-ray diffraction study of E-2a
(Figure S1, Supporting Information).12 It should be noted
that in all the cases the formation of six-membered ring 3a
was not observed, which indicated that the iodide anion
attacked regioselectively at the sp2-carbon atom connected
to the phenyl group in 1a.
With the optimized reaction conditions in hand, the scope
of the reaction of the mesylates was studied with some of the
typical results being summarized in Table 3. R1 or R2 may
be COCH3, CO2Me, CO2Et, and SO2Ph. Besides NaI,
LiBr H2O may also be used as the metallic halide to give
3
the corresponding (E)-bromomethylene 5-membered pro-
ducts in moderate to excellent yields (entries 2, 4, 6, and 8,
Table 3). Even the 4-membered product E-2l was prepared in
27% yield from the ring-opening reaction of 1h (entry 10,
Table 3).
With 1.2 equiv of NaI, the yield of E-2a is lower (entry 2,
Table 1); control experiment indicated that the addition of
Na2CO3 is not necessary in this case (entry 3, Table 1); no
reaction was observed with AgI or CuI (entries 4 and 5,
Table 1); the reaction with LiI afforded E-2a in much lower
It should also be noted that 3,3-bis(methoxycarbonyl)-2-
alkyl or aryl-substituted cyclopropenylalkyl bromides 1i, 1j,
and 1k also smoothly afforded the corresponding products
E-2m, E-2n, and E-2o with the excellent regioselectivity
directing the X to the sp2 carbon atom at the 1-position
(Scheme 1).
(10) Ma, S.; Zhang, J.; Cai, Y.; Lu, L. J. Am. Chem. Soc. 2003, 125, 13954.
(11) Ma, S.; Zhang, J.; Lu, L.; Jin, X.; Cai, Y.; Hou, H. Chem. Commun.
2005, 909.
(12) Crystal data for compound E-2a: C16H17O4I, MW=400.20, mono-
clinic, space group P2(1)/c, final R indices [I > 2σ(I )], R1=0.0332, wR2=
(13) Crystal data for compound E-2b: C12H17O4I, MW=352.16, mono-
clinic, space group P2(1)/c, final R indices [I > 2σ(I )], R1=0.0416, wR2=
˚
0.0847, R indices (all data), R1=0.0394, wR2=0.0878, a=9.1568 (7) A, b=
˚
0.1048, R indices (all data), R1=0.0460, wR2=0.1075, a=8.2163(9) A, b=
˚
˚
˚
˚
19.9575 (16) A, c=9.6108 (7) A, R=90°, β=114.2340(1)°, γ=90°, V=1601.6
(2) A , T=293(2) K, Z=4, reflections collected/unique: 9277/3483 (R(int)=
13.1526(15) A, c=12.5835(14) A, R = 90°, β = 95.994(2)°, γ=90°, V=1352.4
(3) A , T=293(2) K, Z=4, reflections collected/unique: 7777/2944 (R(int)=
3
3
˚
˚
0.0446), number of observations [>2σ(I)] 2984, parameters 193. Supple-
mentary crystallographic data have been deposited at the Cambridge Crys-
tallographic Data Center as supplementary publication no. CCDC 694977.
Copies of the data can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (Fax: þ 44-1223/336- 033; E-mail:
deposit@ccdc.cam.ac.uk).
0.0900), number of observations [>2σ(I )] 2565, parameters 157. Supple-
mentary crystallographic data have been deposited at the Cambridge Crys-
tallographic Data Center as supplementary publication no. CCDC 694978.
Copies of the data can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (Fax: þ 44-1223/336- 033; E-mail:
deposit@ccdc.cam.ac.uk).
5596 J. Org. Chem. Vol. 74, No. 15, 2009

Chen and Ma
JOCNote
SCHEME 2. The Reactions of Cyclopropenes 1a and 1l with a
Catalytic Amount of LiBr H2O
TABLE 3. Scope of the Ring-Opening Cyclization Reaction
3
1
entry
R1
R2
m
MXa time (h) yield of 2b,c (%)
1
2
3
4
5
6
7
8
9
10
CO2Me CO2Me 3 (1c)
CO2Me CO2Me 3 (1c)
A
B
A
B
A
B
A
B
A
A
0.8
2.7
0.5
1
3
3
4
16
1
10
81 (61) (E-2c)d
96 (86) (E-2d)
82 (65) (E-2e)
84 (87) (E-2f)
76 (92) (E-2g)
77 (85) (E-2h)
79 (75) (E-2i)
71 (81) (E-2j)e
69 (76) (E-2k) f
22 (27) (E-2l)
CH3CO CO2Et
CH3CO CO2Et
CH3CO SO2Ph
CH3CO SO2Ph
CO2Me SO2Ph
CO2Me SO2Ph
3 (1d)
3 (1d)
3 (1e)
3 (1e)
3 (1f)
3 (1f)
SCHEME 3. The Synthetic Utilities of the Product E-2c
CO2Me CO2Me 4 (1g)
CO2Me CO2Me 2 (1h)
a A = NaI, B = LiBr H2O. b Isolated yield. c The numbers in
parentheses are isolated yields for the reactions carried out in the absence
3
of Na2CO3. d 2.4 equiv of NaI were used. e 2.4 equiv of LiBr H2O
3
were used. f When 1l was applied to the reaction with 0.6 equiv of
Na2CO3 as the additive, the yield of E-2k was 78%.
SCHEME 1. The Reactions of Cyclopropenes 1i, 1j, and 1k with
NaI
SCHEME 4. The Plausible Mechanism for the Ring-Opening
Cyclization Reaction
attacked regioselectively the sp2 carbon atom at the 1-posi-
tion of cyclopropenes 1 to give a stereodefined carbanion 7,
which would undergo intramolecular nucleophilic substitu-
tions to afford E-2.
In conclusion, we have developed an X- (X=I, Br)-
triggered ring-opening intramolecular trapping of cyc-
lopropenyl-substituted alkyl bromides or mesylates pro-
viding an efficient highly regio- and stereoselective
approach to the synthesis of (E)-haloalkylidene cyclic com-
pounds. Further studies on the scope of the reaction and
the synthetic application are now being carried out in our
laboratory.
As expected, the reactions of 1a and 1l with LiBr H2O
occurred smoothly with only a catalytic amount of LiBr
H2O (Scheme 2).
3
3
The synthetic utilities of the product E-2 were demon-
strated by the transformation of the representative product
E-2c (Scheme 3). Treatment of E-2c with phenyl boronic acid
or diethyl zinc gave the coupling products E-4a and E-5a in
76% and 73% yields, respectively. Phenylacetylene and
1-hexyne underwent the Sonogashira coupling reaction with
E-2c to afford stereodefined conjugated enynes E-6a and
E-6b in excellent yields.
Experimental Section
General Procedure for the Ring-Opening Cyclization Reaction.
To a reaction tube were added sequentially NaI (35 mg, 0.23 mmol),
1.5 mL of acetone, 1a (54 mg, 0.15 mmol), and 1.5 mL of acetone.
The resulting mixture was refluxed for 2 days as monitored by TLC.
Evaporation and column chromatography on silica gel (eluent:
petroleum ether/Et2O = 10/1) afforded E-2a14 (49 mg, 80%): solid,
The plausible mechanism for this transformation is
depicted in Scheme 4. The nucleophile X- (I- and Br-)
(14) Kitagawa, O.; Inoue, T.; Hirano, K.; Taguchi, T. J. Org. Chem.
1993, 58, 3106.
J. Org. Chem. Vol. 74, No. 15, 2009 5597

Chen and Ma
JOCNote
m.p. 90-91 °C (petroleum ether/ethyl acetate); 1HNMR(300MHz,
CDCl3) δ 7.35-7.30 (m, 2H), 7.27-7.13 (m, 3H), 3.38 (s, 6H), 2.67
Acknowledgment. Financial support from the Major State
Basic Research & Development Program (2009CB825300) is
greatly appreciated.
(t, J= 7.5 Hz, 2H), 2.55 (t, J= 6.9 Hz, 2H), 1.78-1.65 (m, 2H); 13
C
NMR (75.4 MHz, CDCl3)δ 170.0, 146.2, 142.9, 128.8, 127.9, 127.6,
98.2, 64.9, 52.5, 42.7, 40.9, 22.8; MS (ESI) m/z 455 (M þ CH3OH þ
Naþ), 423 (M þ Naþ), 401 (M þ Hþ); IR (KBr) 2951, 1731, 1433,
1267 cm-1. Anal. Calcd for C16H17O4I: C 48.02; H 4.28. Found:
C 48.22; H 4.51.
Supporting Information Available: Experimental proce-
dures, characterization of the products, and the CIF files of
E-2a and E-2b. This material is available free of charge via the
Internet at http://pubs.acs.org.
5598 J. Org. Chem. Vol. 74, No. 15, 2009