Highly stereoselective radical carbonylations of gem-dihalocyclopropane derivatives with CO

Article abstract of DOI:10.1021/ol062673d

A couple of radical carbonylations of gem-dihalocyclopropanes 1 using CO and Bu₃SnH (formylation) or Bu₃Sn(CH₂CH=CH ₂) (allylacylation) successfully proceeded to give trans and cis adducts (2 and 3) with good to

Full text of DOI:10.1021/ol062673d

ORGANIC
LETTERS
2007
Vol. 9, No. 4
563-566
Highly Stereoselective Radical
Carbonylations of
gem-Dihalocyclopropane Derivatives
with CO
Yoshinori Nishii,* Takao Nagano, Hideki Gotoh,† Ryohei Nagase,†
Jiro Motoyoshiya, Hiromu Aoyama, and Yoo Tanabe*,†
Department of Chemistry, Faculty of Textile Science and Technology, Shinshu
UniVersity, Ueda, Nagano 386-8567, Japan, and Department of Chemistry, School of
Science and Technology, Kwansei Gakuin UniVersity, Sanda, Hyogo 669-1337, Japan
nishii@shinshu-u.ac.jp
Received November 2, 2006
ABSTRACT
A couple of radical carbonylations of gem-dihalocyclopropanes 1 using CO and Bu3SnH (formylation) or Bu3Sn(CH2CH
successfully proceeded to give trans and cis adducts (2 and 3) with good to excellent stereoselectivity (trans/cis >99/1
1/99). The formylation of 2,3-cis-disubstituted 1,1-dihalocyclopropanes enhanced trans selectivity (trans/cis >99/1 95/5), whereas both 2,3-
cis-disubstituted and 2-monosubstituted 1,1-dihalocyclopropanes underwent allylacylation with nearly complete trans selectivity (trans/cis
>99/1). Inherently less reactive gem-dichloro- and bromochlorocyclopropanes than gem-dibromocyclopropanes served as favorable substrates.
d
CH2) (allylacylation)
)
−
−
75/25 or 17/83
−
)
)
Intermolecular carbonylation of various organic radical
intermediates using CO is recognized as a useful transforma-
tion.1 The addition of certain radical species to CO generates
the corresponding acyl radicals, which undergo hydroformyl-
ation (-CHO) or acylation through the consecutive trap with
olefins (-COR).2 Recently, Zard’s group reported that
cyclopropylacyl radicals derived from S-cyclopropylacyl-
xanthates add to external olefins without loss of the labile
cyclopropane ring.3
occurrence in nature and potential synthetic utility.4 Trans-
formations of gem-dihalocyclopropanes into functionalized
cyclopropanes are useful because of the preparative acces-
sibility of gem-dihalocyclopropanes and the unique reaction
mode.5 Several efficient methods have been exploited for
the carbon elongation on the gem-dihalogenocarbons,6 but
(4) (a) Patai, S.; Rappoport, Z. The Chemistry of the Cyclopropyl Group;
Wiley: London, 1987. (b) Reissig, H.-U. Top. Curr. Chem. 1988, 144, 73.
(c) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-Y.; Yip, Y.-C.; Tanko, J.; Hudlicky,
T. Chem. ReV. 1989, 89, 165. For recent reviews: (d) Lebel, H.; Marcoux,
J.-F.; Molinaro, C.; Charette, A. B. Chem. ReV. 2003, 103, 977. (e) Reissig,
H.-U.; Zimmer, R. Chem. ReV. 2003, 103, 1151. (f) Wessjohann, L. A.;
Brandt, W. Chem. ReV. 2003, 103, 1625. (g) Liu, X.; Fox, J. M. J. Am.
Chem. Soc. 2006, 128, 5600.
Cyclopropyl carbonyls and methanols are an important
chemical class in organic synthesis due to their widespread
† Kwansei Gakuin University.
(1) For reviews of radical reactions of CO, see: (a) Ryu, I.; Sonoda, N.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1050. (b) Ryu, I.; Sonoda, N.;
Curran, D. P. Chem. ReV. 1996, 96, 177. (c) Ryu, I. Chem. Soc. ReV. 2001,
30, 16. For a review of acyl radicals, see: (d) Chatgilialogu, C.; Crich, D.;
Komatsu, M.; Ryu, I. Chem. ReV. 1999, 99, 1991.
(2) (a) Ryu, I.; Kusano, K.; Ogawa, A.; Kambe, N.; Sonoda, N. J. Am.
Chem. Soc. 1990, 112, 1295. (b) Ryu, I.; Yamazaki, H.; Kusano, K.; Ogawa,
A.; Sonoda, N. J. Am. Chem. Soc. 1991, 113, 8558. (c) Ryu, I.; Yamazaki,
H.; Ogawa, A.; Kambe, N.; Sonoda, N. J. Am. Chem. Soc. 1993, 115, 1187.
(3) Heinrich, M. R.; Zard, S. Z.; Org. Lett. 2004, 6, 4969.
(5) For a recent review: Fedorynski, M. Chem. ReV. 2003, 103, 1099.
(6) (a) Vu, V. A.; Marek, I.; Polborn, K.; and Knochel, P. Angew. Chem.,
Int. Ed. 2002, 41, 351. (b) Inoue, R.; Shinokubo, H.; Oshima, K. Tetrahedron
Lett. 1996, 37, 5377. (c) Harada, T.; Kastuhira, T.; Hattori, K.; Oku, A. J.
Org. Chem. 1993, 58, 2958. (d) Danheiser, R. L.; Savoca, A. C. J. Org.
Chem. 1985, 50, 2401. (e) Kitatani, K.; Hiyama, T.; Nozaki, H. J. Am.
Chem. Soc. 1975, 97, 949; Bull. Chem. Soc. Jpn. 1977, 50, 1600. (f) Scott,
F.; Mafunda, B. G.; Normant, J. F.; Alexakis, A. Tetrahedron Lett. 1983,
24, 5767. (g) Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1967, 89, 3911;
1968, 90, 5615.
10.1021/ol062673d CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/17/2007

most of them were applied to gem-dibromo derivatives,
which have higher reactivity than gem-dichloro derivatives
during such reactions. For example, a Giese-type radical-
mediated reaction of 2,3-disubstituted gem-dibromocyclo-
propanes successfully proceeds with electron-deficient olefins
such as acrylonitrile and methyl acrylate, whereas the related
reaction using less reactive gem-dichlorocyclopropanes gave
a disappointing result: a competitive hydrostannylation of
olefins with Bu3SnH mainly occurred (Scheme 1).7a
Table 1. Stereoselective Radical-Type Formylation of
gem-Dihalocyclopropanes 1a
yieldb ratioc
entry substrate X1 X2
R1
R2 R3 R4 (%)
of 2/3
1
2
3
4
5
1a
1b
1c
1d
1e
1f
Cl Cl Ph
Cl Cl Hex
Cl Cl CH2OH
Cl Cl CH2OH
Cl Cl CH2OH
Cl Cl CH2OH
H
H
H
H
H
H
H
H
H
Me H
H
H
H
H
51
48
54
60
75:25
75:25
75:25
17:83
20:80
<1:99
Scheme 1
Ph 48
6
Me Ph 42
7
8
9
10
11
12
13
14
15
1g
1h
1i
1j
1k
1l
1m
1n
1o
Cl Cl
Cl Cl
Br Br
Br Cl Ph
Br Cl Hex
-(CH2)4-
-(CH2)6-
-(CH2)4-
H
H
H
H
H
H
H
H
H
H
H
H
H
H
55 >99:1
47 95:5
14 >99:1
H
H
60
63
75:25
75:25
Br Cl
Br Cl
-(CH2)4-
-(CH2)6-
73 >99:1
67
62
95:5
17:83
<1:99
Br Cl CH2OH H H Me H
Br Cl CH2OH H H Me Ph 41
Consistent with our ongoing study on useful transforma-
tions of gem-dihalocyclopropanes,7-9 we disclose herein a
few highly stereoselective radical-type carbonylations of
gem-dihalocyclopropane derivatives with CO, utilizing Bu3-
SnH or Bu3Sn(CH2CHdCH2)/catalytic AIBN.
The initial investigation was guided by the formylation
of inherently less reactive, but synthetically more accessible,
gem-dichlorocyclopropanes 1a-h (Table 1).10a The salient
a Reactions were carried out under CO pressure (80 atm) at 80 °C. 0.4
equiv (0.2 equiv added twice) of AIBN was used for 1a-h, 0.2 equiv (added
1
once) for 1i-o. b Isolated. c Determined by H NMR measurement.
features are as follows. (i) R1-Monosubstituted 1,1-dichlo-
rocyclopropanes 1a and b underwent the desired formylation
to give trans and cis adducts 2a,b and 3a,b, respectively,
with moderate stereoselectivity (t/c ) 75/25) (entries 1, 2).
(ii) Surprisingly, although the reaction using 1c bearing the
CH2OH group (R1) showed moderate trans selectivity (t/c
) 75/25) (entry 3), Me (R3) and/or Ph (R4) substituted
analogues 1d-f resulted in an apparent switch of the
stereoselectivity to give lactols 3d-f that were derived from
cis-formyl radicals (t/c ) 17/83 to <1/99) (entries 4-6).
(iii) Note that similar reactions of 2,3-cis-disubstituted cyclic
substrates 1g,h gave almost the corresponding trans adduct
(t/c ) >99/1-95/5) (entries 7 and 8). This result is consistent
with that of a relevant radical addition.7a (iv) Unexpectedly,
inherently higher reactive dibromocyclopropane 1i underwent
mainly an undesirable (competitive) side hydrodebromination
(entry 9). (v) Notably, the use of gem-bromochloro analogues
1j-o consistently increased the reactivity and yield while
maintaining the stereoselectivity spectrum (entries 10-15).10b
(vi) The main side reaction was a competitive hydrodeha-
logenation of substrates by Bu3SnH, which may somewhat
decrease the yields. (vii) The gem-dichloro substrate required
0.4 equiv of AIBN catalyst, whereas only 0.2 equiv of AIBN
was required for the gem-bromochloro substrate. We specu-
late that the rate-determining step is not the initial debro-
mination, but rather the second carbonylation: the R-chlo-
rocyclopropyl radical is more reactive than the R-boromocyclo-
propyl radical.
(7) Radical type reactions: (a) Tanabe, Y.; Wakimura, K.; Nishii, Y.
Tetrahedron Lett. 1996, 37, 1837.(b) Tanabe, Y.; Nishii, Y.; Wakimura,
K. Chem. Lett. 1994, 1757. (c) Nishii, Y.; Fujiwara, A.; Wakasugi, K.;
Miki, M.; Yanagi, K.; Tanabe, Y. Chem. Lett. 2002, 30.
(8) Cationic-type reactions: (a) Tanabe, Y.; Seko, S.; Nishii, Y.; Yoshida,
T.; Utsumi, N.; Suzukamo, G. J. Chem. Soc., Perkin Trans. 1 1996, 2157.
(b) Nishii, Y.; Tanabe, Y. J. Chem. Soc., Perkin Trans. 1 1997, 477. (c)
Nishii, Y.; Wakasugi, K.; Koga, K.; Tanabe, Y. J. Am. Chem. Soc. 2004,
126. 5358. (d) Nishii, Y.; Yoshida, T.; Asano, H.; Wakasugi, K.; Morita,
J.; Aso, Y.; Yoshida, E.; Motoyoshiya, J.; Aoyama, H.; Tanabe, Y. J. Org.
Chem. 2005, 70, 2667 and other references cited therein.
(9) Anionic-type reactions and their application: (a) Nishii, Y.; Wakasugi,
K.; Tanabe, Y. Synlett 1998, 67. (b) Nishii, Y.; Wakimura, K.; Tsuchiya,
T.; Nakamura, S.; Tanabe, Y. J. Chem. Soc., Perkin Trans. 1 1996, 1243.
(c) Nishii, Y.; Maruyama, N.; Wakasugi, K.; Tanabe, Y. Bioorg. Med. Chem.
2001, 9, 33.
(10) Typical Procedure. (a) 7,7-Dichlorobicyclo[4.1.0]heptane (1g) (165
mg, 1.00 mmol), AIBN (33 mg, 0.20 mmol), Bu3SnH (349 mg, 1.20 mmol),
and benzene (50 mL) were placed in a 100-mL stainless steel autoclave
with a inserted glass tube. The mixture was stirred under CO pressure (80
atm) at 80 °C for 3 h. After temporary release of CO pressure, AIBN (33
mg, 0.20 mmol) was added to the mixture. Then, the mixture was stirred
under CO pressure (80 atm) at 80 °C for 3 h. After evacuation of excess
CO at room temperature, benzene was removed under reduced pressure.
The residue was stirred for 1 h with Et2O (10 mL) and aqueous satd KF
solution (10 mL). After Celite filtration, the separated organic phase was
washed with water and brine, dried (Na2SO4), and concentrated. The
obtained crude product was purified by SiO2 column chromatography
(hexane) to give the desired product 2g (87 mg, 55 %). (b) Following the
procedure mentioned above, the reaction of 1-bromo-1-chlorobicyclo[4.1.0]-
heptane (1l) (210 mg, 1.00 mmol) with 0.2 equiv of AIBN (33 mg, 0.20
mmol, added once) instead of the procedure using 0.2 equiv added twice
gave the desired product 2g (108 mg, 73%): 1H NMR (400 MHz, CDCl3)
δ 1.24-1.35 (m, 2H), 1.39-1.47 (m, 2H), 1.62-1.69 (m, 2H), 1.90-1.94
(m, 2H), 1.97-2.06 (m, 2H), 9.43 (s, 1H, CHO); 13C NMR (100 MHz,
CDCl3) δ 18.7, 20.8, 25.9, 58.7, 198.5; IR (neat) 2939, 2858, 1709, 1447
cm-1; HRMS (EI) calcd for C8H11ClO (M+) 158.0498, found 158.0498.
These successful results led us to investigate the reaction
utilizing Bu3Sn(CH2CHdCH2) instead of Bu3SnH. As ex-
564
Org. Lett., Vol. 9, No. 4, 2007

pected, allylacylation (sequential carbonylation and allyla-
tion) proceeded smoothly using 1a,b,d,g,h-o (Table 2).11
Scheme 3
Table 2. Stereoselective Radical-Type Allylacylation of
gem-Dihalocyclopropanes 1a
yieldb ratioc
entry substrate X1 X2
R1
R2 R3 R4 (%)
of 4/5
1
2
3
4
5
6
7
8
9
1a
1b
1d
1g
1h
1i
1j
1k
1l
Cl Cl Ph
Cl Cl Hex
Cl Cl CH2OH
Cl Cl -(CH2)4-
Cl Cl -(CH2)6-
Br Br -(CH2)4-
Br Cl Ph
Br Cl Hex
Br Cl -(CH2)4-
Br Cl -(CH2)6-
Br Cl CH2OH
Br Cl CH2OH
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
51
47
38
54
48
>99:1
>99:1
<1:99
>99:1
>99:1
17d >99:1
H
H
58
53
64
54
68
>99:1
>99:1
>99:1
>99:1
<1:99
<1:99
10
11
12
1m
1n
1o
H
Me
H
H
Me Ph 35
a Reactions were carried out under CO pressure (40 atm) at 80 °C. 0.4
equiv (0.2 equiv added twice) of AIBN was used for 1a-h, 0.2 equiv (added
7 to give mainly 2 because of the stereocongestion between
R1 (and/or R2) and CO. Hydroxymethyl substrate 1d
undergoes cyclization to give cis-lactol 3d through sterically
unfavorable cis radical 9d and stable lactol radical 10d. This
irreversible process from 9d to 10d drives an equilibrium
shift from 6d to 7d, eventually giving 3d as the major
product.12,13 The case of allylacylation amplifies the stereo-
selectivity due to the additional stereocongestion in the final
product-determining allylation step.
1
once) for 1j-o. b Isolated yield. c Determined by H NMR measurement.
d An unidentified complex byproduct was obtained.
The most notable feature is that the present reaction was
performed with nearly complete trans as well as cis selectiv-
ity (t/c ) >99/1 for 1a,b,d,g-m and t/c ) <1/99 for 1d,n,o)
for every case examined. The present protocol can be applied
for not only 2,3-disubstituted substrates but also 2-mono-
substituted analogues, which are unfavorable substrates with
regard to stereoselectivity.7a On this exclusive selectivity
switch, we speculate that the final allylation step markedly
enhances the trans selectivity. Similar to the preceding
formylation, bromochloro analogues 1j-n underwent the
allylacylation more smoothly than the dichloro analogues
(entries 1-5,7-11).
As the literature showed, lithium halocarbenoid on 2,3-
cis disubstituted or 2-monosubstituted cyclopropane rings
favors conformation 12 rather than 11, wherein lithium
(11) Typical Procedure. (a) 1,1-Dichloro-2-phenylcyclopropane (1a)
(187 mg, 1.00 mmol), AIBN (33 mg, 0.20 mmol), Bu3Sn(CH2CHdCH2)
(662 mg, 2.00 mmol), and benzene (30 mL) were placed in a 100-mL
stainless steel autoclave with a insert glass tube. The mixture was stirred
under CO pressure (40 atm) at 80 °C for 12 h. After temporary release of
CO pressure, AIBN (33 mg, 0.20 mmol) was added to the mixture. Then,
the mixture was stirred under CO pressure (40 atm) at 80 °C for 12 h.
After evacuation of excess CO at room temperature, benzene was removed
under reduced pressure. The residue was stirred for 1 h with Et2O (10 mL)
and aqueous satd KF solution (10 mL). The residue was stirred for 1 h
with Et2O (10 mL) and aqueous satd KF solution (10 mL). After Celite
filtration, the separated organic phase was washed with water and brine,
dried (Na2SO4), and concentrated. The obtained crude product was purified
by SiO2 column chromatography (hexane/EtOAc ) 3/1) to give the desired
product 4a (113 mg, 51%). (b) Following the procedure mentioned above,
the reaction of 1-bromo-1-chloro-2-phenylcyclopropane (1j) (210 mg, 1.00
mmol) with 0.2 equiv of AIBN (33 mg, 0.20 mmol, added once) instead of
the procedure using 0.2 equiv added twice gave the desired product 4a
(126 mg, 58%). 4a: colorless oil; 1H NMR (400 MHz, CDCl3) δ 1.73 (dd,
J ) 7.0 Hz, J ) 10.1 Hz, 1H), 2.21 (dd, J ) 7.0 Hz, J ) 10.1 Hz 1H), 3.01
(dd, J ) 7.0 Hz, J ) 10.1 Hz, 1H) 3.68 (m, 2H), 5.16-5.26 (m, 2H),
5.94-6.04 (m, 1H), 7.20-7.24 (m, 2H), 7.29-7.37 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 25.0, 36.3, 44.8, 52.5, 119.0, 127.6, 128.1, 129.3,
130.2, 134.6, 204.5; IR (neat) 2843, 1716, 1640, 1497 cm-1; HRMS (EI)
calcd for C13H13ClO (M+) 220.0655, found 220.0656.
Scheme 2
(12) Intra- and intermolecular traps of acyl radicals by amino groups
were reported: (a) Tojino, M.; Uenoyama, Y.; Fukuyama, T.; Ryu, I. Chem.
Commun. 2004, 2482. (b) Uenoyama, Y.; Fukuyama, T.; Nobuta, O.;
Matsubara, H.; Ryu, I. Angew. Chem., Int. Ed. 2005, 44, 1075.
We propose the following mechanism to explain the
stereoselectivity issue (Schemes 2 and 3). Initially generated
trans radical 6 more preferentially adds to CO than cis radical
(13) Baird, M. S.; Huber, F. A. M. Tetrahedron Lett. 1998, 39, 9081.
Org. Lett., Vol. 9, No. 4, 2007
565

Scheme 4
Table 3. Stereoselective Anionic Carbonylation and
Carboxylation of gem-Dihalocyclopropanes 1a
entry substrate methoda X1 X2 R1
R2
Br Br -(CH2)4-
Br Br -(CH2)4- OMe
Br Cl -(CH2)4-
Br Cl -(CH2)4- OMe
R
yield (%)
1
2
3
4
5
6
7
1i
1i
1l
1l
1p
1p
1q
A
B
A
B
A
B
B
H
65
64
43
47
64
57
36
H
locates in the concave site (Scheme 4).14 Therefore, this
anionic carbonylation (method A) and carboxylation (method
B) is anticipated to proceed to give cis adduct 14 more
preferentially than trans adduct 13. Indeed, either method
(A or B) utilizing the BuLi-DMF reagent or the BuLi-
CO2 reagent (followed by methylation using MeI-K2CO3)
successfully afforded the desired product 14 with nearly
complete selectivity in every case examined (Table 3).
The stereocomplemented result of the present radical
carbonylations vs the reported anionic method demonstrates
the utility from a synthetic viewpoint.
In conclusion, we developed a few stereoselective syn-
theses of cyclopropane derivatives utilizing highly stereo-
selective radical carbonylations (formylation and allylacyl-
ation) of gem-dihalocyclopropanes. The present method is a
new avenue for the stereoselective synthesis of cyclopropyl-
carbonyl compounds.
Br Br Ph
Br Br Ph
Br Br Bu
H
H
H
H
OMe
OMe
a Method A: BuLi, DMF. Method B: (i) BuLi, CO2, (ii) K2CO3, MeI.
Acknowledgment. We thank Prof. Ilhyong Ryu of Osaka
Prefecture University for his helpful discussions. This
research was partially supported by Grants-in-Aid for Young
Scientists (B) “17750036”, Scientific Research on Basic
Areas (B) “18350056”, Priority Areas (A) “17035087” and
“18037068”, Exploratory Research “17655045”, and for 21st
Century COE Program from MEXT.
Supporting Information Available: Experimental de-
tails, analytical data, and characterization data for reactions
in Tables 1-3. This material is available free of charge via
the Internet at http://pubs.acs.org.
(14) (a) Oku, A.; Harada, T.; Homoto, Y.; Iwamoto, M. J. Chem. Soc.,
Chem. Commun. 1988, 1490. (b) Seyferth, D.; Lambert, R. L.; Massol, M.
J. Organomet. Chem. 1975, 88, 255. (c) Banwell, M. G.; Reumin, M. E.
AdVances in Strain in Organic Chemistry; Halton. B., Ed.; JAI Press:
Greenwich, CT, 1991; Vol. 1, p 19.
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