An efficient stereoselective synthesis of 1-iodo- or 1-phenyl selenenyl-2-aryl-3-azabicyclo[3.1.0]hexane via electrophilic cyclization of benzyl-2-arylmethylidenecyclopropylmethyl-amines

Article abstract of DOI:10.1016/j.tetlet.2007.11.068

The reaction of benzyl-2-arylmethylidenecyclopropylmethyl-amine 1 with iodine in the presence of potassium carbonate or PhSeBr stereoselectively gives ring-closure product 1-iodo-2-aryl-3-azabicyclo[3.1.0]hexane or 1-phenylselenenyl-2-aryl-3-azabicyclo[3.

Full text of DOI:10.1016/j.tetlet.2007.11.068

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 562–565
An efficient stereoselective synthesis of 1-iodo- or 1-phenyl
selenenyl-2-aryl-3-azabicyclo[3.1.0]hexane via electrophilic
cyclization of benzyl-2-arylmethylidenecyclopropylmethyl-amines
Weijun Fua and Xian Huanga,b,
*
aDepartment of Chemistry, Zhejiang University (Xixi Campus), Hangzhou 310028, PR China
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, PR China
Received 26 July 2007; revised 7 November 2007; accepted 13 November 2007
Available online 17 November 2007
Abstract—The reaction of benzyl-2-arylmethylidenecyclopropylmethyl-amine 1 with iodine in the presence of potassium carbonate
or PhSeBr stereoselectively gives ring-closure product 1-iodo-2-aryl-3-azabicyclo[3.1.0]hexane or 1-phenylselenenyl-2-aryl-3-azabi-
cyclo[3.1.0]hexane in good yields at room temperature. A plausible reaction mechanism has been proposed.
Ó 2007 Elsevier Ltd. All rights reserved.
3-Azabicyclo[3.1.0]hexanes are important structural
motifs frequently found in pharmacologically interesting
structures. They are present in a large number of biolog-
ical active compounds, which exhibit activity against a
broad range of Grampositive pathogens, including
methicillin-resistant Staphylococcus aureus (MRSA)
and Staphylococcus epidermidis (MRSE) and vanco-
mycin-resistant Enteroccocus faecium (VRE).1 The cur-
rent approach toward 3-azabicyclo[3.1.0]hexanes mainly
involves rhodium(II) acetate-mediated cyclopropana-
tion of an N-protected pyrroline with ethyl diazoace-
tate.2 This method is obviously limited to small-scale
synthesis because of the expensive catalytic system.
Thus, a general and practical method to prepare 3-aza-
bicyclo[3.1.0]hexanes is still required.
from MCPs have been developed.4 The electrophilic
cyclization of methylenecyclopropanes has been well
documented.5 Recently, we have found cyclizations of
cyclopropylideneacetic acids and cyclopropylidene alco-
hols to afford 5,6-dihydro-2H-pyran-2-ones or dihydro-
pyrans in good yields under different reaction
conditions.6 In our continual efforts on the application
of MCPs in organic synthesis, we wish to report our
recent studies on the reaction of benzyl-2-arylmethyl-
idene-cyclopropylmethyl-amine 17 with iodine or PhSeBr
to give the corresponding 1-iodo-2-aryl-3-azabicyclo-
[3.1.0]hexanes 2 or 1-phenylselenenyl-2-aryl-3-azabi-
cyclo[3.1.0]hexanes
conditions.
3 in good yields under mild
At the first attempt, we conducted the reaction of ben-
zyl-2-benzylidenecyclo-propylmethyl-amine 1a (1 mmol)
with iodine (1.5 equiv) in THF at room temperature in
the presence of potassium carbonate (1.7 equiv).8 The
desired product 2a was obtained in 63% yield with excel-
lent stereoselectivity (Table 1, entry 1). With this encour-
aging result, a systematic study was undertaken to
screen various solvents for the cyclization process. The
results are summarized in Table 1. We found that the
ring-closure reactions promoted by iodine proceeded
smoothly at room temperature to give the corres-
ponding trans-1-iodo-2-phenyl-3-azabicyclo[3.1.0]hex-
ane (2a) in moderate to good yields in all cases (Table
1, entries 1–5). In CH3CN, this reaction proceeded
Methylenecyclopropanes (MCPs), highly strained but
readily accessible molecules, have been proven to be use-
ful synthetic intermediates because the relief of ring
strain provides a potent thermodynamic driving force.3
In the past several years, a number of methods for con-
struction of complex and interesting organic molecules
Keywords: Benzyl-2-arylmethylidenecyclopropylmethyl-amine; Ring-
closure; 1-Iodo-2-aryl-3-azabicyclo[3.1.0]hexane; 1-Phenylselenenyl-2-
aryl-3-azabicyclo-[3.1.0] hexane.
*
Corresponding author. Fax: +86 571 88807077; e-mail: huangx@
mail.hz.zj.cn
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.068

W. Fu, X. Huang / Tetrahedron Letters 49 (2008) 562–565
563
Table 1. Reaction of MCPs E-1a with iodine in a variety of solvents
NHBn
I
H
I2
Ph
K2CO3, r.t.
N
Ph
H
H
Bn
1a
2a
Entry
Solvent
Time (h)
Yield of 2aa (%)
1
2
3
4
5
THF
DMF
CH3CN
CH2Cl2
MeC6H5
4
24
2
24
24
63
51
88
45
56
a Isolated yields, I2 (1.5 equiv), K2CO3 (1.7 equiv).
efficiently to give 2a in 88% yield for 2 h (Table 1, entry
3). Therefore, the reaction conditions chosen to carry
out this reaction were in CH3CN with iodine (1.5 equiv)
and K2CO3 (1.7 equiv) at room temperature.
Figure 1. The crystal structure of 2b.
Table 3. Reactions of benzyl-2-arylmethylidene cyclopropylmethyl-
amines 1 with PhSeCl in CH2Cl2
Then, we carried out the electrophilic cyclization of a
variety of benzyl-2-arylmethylidenecyclopropylmethyl-
amines E-1 with iodine under the optimized conditions.
The results are summarized in Table 2. It is obvious that
both electron-donating and electron-withdrawing sub-
stituents on the benzene ring of 1 can be applied to
afford 3-azabicyclo[3.1.0]hexanes 2 in fairly good yields.
For MCPs E-1, trans-1-iodo-2-aryl-3-azabicyclo[3.1.0]-
hexanes 2 were obtained stereoselectively in all cases
within 2 h (Table 2, entries 1–7). The cis isomers were
not detected in the crude products. The configuration
of 2b was determined by X-ray diffraction. The X-ray
crystal structure of 2b is shown in Figure 1.9
NHBn
PhSeBr
PhSe
Ar
H
N
CH2Cl2, r.t.
Ar
H
H
Bn
1
3
Entry
Ar
Time (h)
Yieldsa (%)
1
2
3
4
5
C6H5(1a)
1
1
1
1
1
3a, 85
3b, 76
3c, 80
3d, 72
3e, 77
p-CH3OC6H4(1c)
p-BrC6H4(1d)
o-CH3OC6H4(1f)
o-BrC6H4(1g)
a Isolated yields based on MCPs 1.
Moreover, we examined a similar electrophilic cycliza-
tion reaction of benzyl-2-benzylidenecyclopropylmethyl-
amine 1a with PhSeBr. We found that the corresponding
cyclization product 3a was obtained in 89% yield when
the reaction was carried out at room temperature in
CH2Cl2 with 1.2 equiv of PhSeBr.10 Then, the scope of
this reaction was investigated. Some typical results are
summarized in Table 3. From Table 3, it can be con-
cluded that in the presence of 1.2 equiv of PhSeBr, this
reaction proceeded efficiently to give the cyclization
products 3 in good yields in all cases. For MCPs 1,
trans-1-phenylselenenyl-2-aryl-3-azabicyclo[3.1.0]hexanes
3 were formed exclusively (Table 3, entries 1–5).11
Based on the above results, a plausible mechanism for
this electrophilic cyclization reaction of MCPs 1 with
iodine in the presence of K2CO3 and PhSeBr is depicted
in Scheme 1. The addition of I+ or PhSe+ to the double
bond of MCPs 1 would form the bridged intermediate
Table 2. Iodocyclization of benzyl-2-arylmethylidenecyclopropylmeth-
yl-amines 1
X
X
Ar
X+
Ar
Ar
H
H
NHBn
H
I
H
I2
Ar
BnHN
BnHN
BnHN
K2CO3, r.t.
N
Ar
H
H
Bn
4A
4
1
1
2
Ar>>H
Entry
Ar
C6H5(1a)
p-CH3C6H4(1b)
p-CH3OC6H4(1c)
p-BrC6H4(1d)
p-ClC6H4(1e)
o-CH3OC6H4(1f)
o-BrC6H4(1g)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
2
2
2
2
2
2
2
2a, 88
2b, 92
2c, 89
2d, 85
2e, 91
2f, 78
2g, 75
X
X
H
H
- H+
Ar
Ar
N
H
Bn
BnHN
2 X=I
3 X=PhSe
4B
a Isolated yields based on MCPs 1.
Scheme 1.

564
W. Fu, X. Huang / Tetrahedron Letters 49 (2008) 562–565
5. For brief investigations of halo lactonization of MCPs see:
(a) Ettlinger, M. G. J. Am. Chem. Soc. 1952, 74, 5805; (b)
Meinwald, J.; Wheeler, J. W.; Nimetz, A. A.; Liu, J. S. J.
Org. Chem. 1965, 30, 1038; (c) Herriott, A. W.; Jones, W.
M. Tetrahedron Lett. 1967, 2387; (d) Wichmann, J.;
Adam, G. Eur. J. Org. Chem. 1999, 3131; (e) Goldschmidt,
Z.; Finkel, D. J. Chem. Soc., Perkin Trans. 1 1983, 45.
6. (a) Huang, X.; Zhou, H. W. Org. Lett. 2002, 4, 4419; (b)
Huang, X.; Zhou, H. W.; Chen, W. L. J. Org. Chem. 2004,
69, 839; (c) Fu, W. J.; Huang, X.; Lin, Y. Synlett 2007,
321.
cation 4. The intermediate cation 4 would open up to
generate a carbocation 4A, which is stabilized by the
cyclopropyl and aryl rings.12 Due to the steric hindrance
of groups Ar and H, 4A would adopt conformation 4B
by the rotation of bond C4–C5, in which the bulkier
group Ar is trans to the I or PhSe group.13 Then, the
subsequent intramolecular nucleophilic attack of the
NH group would lead to the stereoselective formation
of cyclization product 2 or 3.
7. Synthesis of methylenecyclopropanols and their mesyl
intermediates: (a) Shao, L.-X.; Li, Y.-X.; Shi, M. Chem.
Eur. J. 2007, 13, 862; (b) Okuma, K.; Tanaka, Y.;
Yoshihira, K.; Ezaki, A.; Koda, G.; Otha, H.; Hara, K.;
Kashimura, S. J. Org. Chem. 1993, 58, 5915; (c) Lautens,
M.; Delanghe, P. H. M. J. Org. Chem. 1993, 58, 5037; (d)
Corre, M. L.; Hercouet, A.; Bessieres, B. J. Org. Chem.
1994, 59, 5483. General procedure for the synthesis of 1: To
a solution of 20 mmol of E-methylenecyclopropylcarbinol,
30 mmol of methanesulfonyl chloride in 50 mL CH2Cl2
was added 60 mmol of triethylamine. After stirring at
room temperature for 1 h, the reaction was quenched with
50 mL of water. Then the organic phase was washed with
1 M HCl, saturated NaHCO3 and brine, and dried over
anhydrous MgSO4. After filtration and removal of the
solvent under reduced pressure, the residues without any
further purification were dissolved in 30 mL of DMSO
with an external ice bath. Catalytic amount of NaI was
added. To the above mixture was then added 60 mmol of
phenylmethanamine. The mixture was stirred at room
temperature over night. After the reaction was complete,
the reaction was quenched with 50 mL of water and
extracted with ether. The combined organic layers were
then washed with saturated brine and dried over anhy-
drous MgSO4. After filtration and removal of the solvent
in vacuo, the residues were purified with flash chromato-
graphy (silica/petroleum ether–ethyl acetate 4:1 v/v) to
afford 1. Selected spectrum data of 1d: 1H NMR
(400 MHz, CDCl3) 7.42 (d, J = 8.4 Hz, 2H), 7.36 (d,
J = 8.4 Hz, 2H), 7.33–7.31 (m, 4H), 7.26–7.23 (m, 1H),
6.70 (d, J = 1.2 Hz, 1H), 3.84 (dd, J = 13.6, 8.8 Hz, 2H),
2.74–2.64 (m, 2H), 1.80–1.62 (m, 1H), 1.63 (br, 1H), 1.61–
1.57 (m, 1H), 1.18–1.14 (m, 1H); 13C NMR (100 MHz,
CDCl3) 140.2, 136.7, 131.5, 128.6, 128.4, 128.1, 128.0,
126.9, 120.5, 117.4, 53.6, 52.2, 13.7, 10.0; MS (EI): m/z
(%) = 329 (10, [M+ (81Br)], 327 (10, [M+ (79Br)], 91 (100);
In conclusion, we have developed a highly stereoselec-
tive iodocyclization and selenidocyclization reaction of
MCPs 1 with iodine in the presence of K2CO3 or
PhSeBr, leading to the formation of 1-iodo-2-aryl-3-aza-
bicyclo[3.1.0]hexanes 2 or 1-phenylselenenyl-2-aryl-3-
azabicyclo[3.1.0]hexanes 3 in good yields under mild
conditions. The stereoselectivity may be controlled by
the steric effects of the substituent group of the C@C
bond. As the easy availability of starting materials, the
convenient operation and the usefulness of the products,
the reaction may have potential utilities in organic
synthesis.
Acknowledgments
This work was supported by the National Natural Sci-
ence Foundation of China (20332060, 20472072) and
Academic Foundation of Zhejiang Province.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.11.068.
References and notes
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Cicchi, S.; Cordero, F. M.; Goti, A. Chem. Rev. 2003, 103,
1213; (c) Nakamura, I.; Yamamoto, Y. Adv. Synth. Catal.
2002, 2, 111.
IR (KBr): 3027, 2923, 1487, 1453, 1102 cmÀ1
.
8. (a) Wang, B. Y.; Huang, J. W.; Liu, L. P.; Shi, M. Synlett
2005, 421; (b) Ma, S.; Wu, S. Tetrahedron Lett. 2001, 42,
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Ma, S.; Shi, Z. Chem. Commun. 2002, 540, and references
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9. General procedure for the synthesis of 2a–g: To a solution
of 1 (1 mmol) in 8 mL CH3CN was added I2 (1.5 mmol),
and K2CO3 (1.7 mmol) and the resulting mixture were
stirred at room temperature for 2 h. The reaction mixture
was then diluted with ethyl acetate, washed with saturated
Na2S2O3 solution, dried (Mg2SO4), and filtered. The
solvent was evaporated under reduced pressure, and the
product was isolated by column chromatography on silica
gel (petroleum ether/ethyl acetate = 30:1) to afford 2a–g.
Selected spectrum data of 2a: Solid; mp 104–106 °C; 1H
NMR (400 MHz, CDCl3) 7.56–7.58 (m, 2H), 7.36–7.44
(m, 3H), 7.21–7.32 (m, 5H), 3.95 (s, 1H), 3.80 (d,
J = 12 Hz, 1H), 3.16 (d, J = 12 Hz, 1H), 2.98 (d,
J = 8.8 Hz, 1H), 2.65 (dd, J = 8.8 Hz, J = 3.6 Hz, 1H),
1.72–1.82 (m, 2H), 0.86–0.89 (m, 1H); 13C NMR
(100 MHz, CDCl3) 138.6, 138.5, 128.5, 128.3, 128.2,
4. (a) Suginome, M.; Matsuda, T.; Ito, Y. J. Am. Chem. Soc.
2000, 122, 11015; (b) Itazaki, M.; Nishihara, Y.; Osakada,
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W. Fu, X. Huang / Tetrahedron Letters 49 (2008) 562–565
565
128.1, 128.0, 126.9, 75.9, 56.2, 52.6, 25.7, 16.3, 9.9; MS
gel (petroleum ether/ethyl acetate = 30:1) to afford 3a–e.
Selected spectrum data of 3a: Solid; mp 95–96 °C; 1H
NMR (400 MHz, CDCl3) 7.52 (d, J = 6.4, 2H), 7.20–7.33
(m, 8H), 7.07–7.85 (m, 5H), 3.80 (s, 1H), 3.75 (d,
J = 13.2 Hz, 1H), 3.07–3.12 (m, 2H), 2.53–2.56 (m, 1H),
1.75–1.78 (m, 2H), 0.78–0.79 (m, 1H); 13C NMR
(100 MHz, CDCl3) 139.4, 138.8, 131.7, 130.5, 128.7,
128.5, 128.3, 128.2, 128.1, 127.6, 126.8, 126.4, 72.8, 59.5,
53.2, 32.6, 25.7, 14.3; MS (EI): m/z (%) = 405 (25, [M+]);
(EI): m/z (%) = 375 (31, [M+]); IR (KBr) 2918, 2795, 1598,
1450, 699 cmÀ1
. CCDC-666438 contains the supple-
mentary crystallographic data for 2b. These data can
be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
10. Chen, G. F.; Fu, C. L.; Ma, S. Tetrahedron 2006, 62,
4444.
11. General procedure for the synthesis of 3a–e: To a solution
of 1 (1 mmol) in 8 mL CH2Cl2 was added PhSeBr
(1.2 mmol) and the resulting mixture was stirred at room
temperature for 1 h. The mixture was then evaporated
directly and purified by column chromatography on silica
IR (neat) 2923, 1493, 734, 699 cmÀ1
.
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