3-Oxa- and 3-azabicyclo[3.1.0]hexan-2-ones via tandem radical cyclization - Intramolecular S(N)2 reactions

Full text of DOI:10.1021/jo952099b

J . Org. Chem. 1996, 61, 3205-3208
3205
volves hypervalent iodine. Mn(III)-mediated oxidative
cyclization of malonic esters was also shown to lead to
3-oxa-2-oxobicyclo[3.1.0]hexanes,1a,8 but this procedure is
restricted to ethylenic esters bearing a monosubstituted
double bond.
3-Oxa - a n d 3-Aza bicyclo[3.1.0]h exa n -2-on es
via Ta n d em Ra d ica l
Cycliza tion -In tr a m olecu la r SN2 Rea ction s
N. Baldovini, M.-P. Bertrand,* A. Carrie`re,
R. Nouguier,* and J .-M. Plancher
Resu lts a n d Discu ssion
Laboratoire de Chimie Mole´culaire Organique-URA 1412,
Faculte´ des Sciences St J e´roˆme, Av. Escadrille
Normandie-Niemen, 13397 Marseille Cedex 20, France
Ethyl 3-oxa- and 3-aza-2-oxobicyclo[3.1.0]hexane-1-
carboxylates are key intermediates in the synthesis of
strained amino acids.9 We first investigated the CuCl-
catalyzed cyclizations of amide 1 with the goal of a two-
step synthesis (from 1) of the above-mentioned strategic
bicyclic structure. When 1 was allowed to react, under
catalytic conditions in the presence of 0.1 equiv of Cu-
(bpy)Cl in isobutyronitrile, at reflux for 16 h (Scheme 1),
the two diastereomeric lactams 2a ,b were isolated in 58%
yield (77% with respect to converted starting material)
in a 6:4 ratio. However, 25% of the starting material was
recovered unchanged. Similar reactions reported in the
literature are often conducted in the presence of 0.3 equiv
of catalyst. We have observed that both the yield and of
course the rate of the reaction were sensitive to the
stoichiometry of Cu(I). Furthermore, a third product
appeared as the ratio of catalyst to substrate increased.
Not only was the relative proportion of the isomeric
lactams time dependent, but it was also sensitive to the
amount of catalyst. As an example, as reported in
Scheme 1, when 1 was treated with 1 equiv of Cu(bpy)-
Cl complex, the ratio of 2a :2b was reversed (4:6) and the
isomeric lactams accounted for only 70% of the products
(the bicyclic lactam 3 accounted for the remaining 30%).
The Cu(I)-catalyzed cyclizations are generally rational-
ized according to Scheme 2. The three-step process
involves the reduction of the substrate A into radical B
followed by a 5-exo cyclization leading to C and C′. The
last step is a ligand transfer oxidation leading to the
isomeric chlorides D and D′ and regenerating the cata-
lyst.
Our experimental observations suggested that with
greater than 10-20% of the reducing mediator the
mechanism should be complemented, as presented in
Scheme 3, by the cleavage of D and D′ by CuCl (possibly
reversible) and the reduction of the intermediate radical
E into the Cu(II) enolate F , responsible for the cyclopro-
panation. If this mechanistic proposal is correct, then
the reaction should lead to 3-azabicyclo[3.1.0]hexanes,
provided that 2 equiv of the Cu(I) complex was used
instead of a catalytic amount.
In order to confirm this last proposal, the two isomeric
lactams 2a and 2b were submitted separately to heating
in the presence of a catalytic amount (0.1 equiv) of Cu-
(bpy)Cl. No isomerization occurred, which clearly dem-
onstrated that Cu(I) is not able to reversibly cleave the
C-Cl bond.10 Therefore, the observed dependence of
their ratio on the Cu(I) stoichiometry must result from
Received November 28, 1995
In connection with our studies of radical cyclizations
leading to bicyclic lactones and lactams,1 we have inves-
tigated the behavior of δ-ethylenic R,R-dichloromalonates
and malonamides on treatment with CuCl. The reducing
metal-catalyzed inter- and intramolecular additions of
perchlorocarbonyl compounds to double bonds are well
known.2 The performance of lactone and lactam ring
closures using this atom transfer methodology has been
the subject of a renewed interest over the last few
years.3,4 To our knowledge most of these works employed
dichloro- and trichloroacetic acid derivatives, none of
which dealt with â-dicarbonylated substrates, with the
exception of the work of Weinreb5 who studied the
cyclization of R,R-dichloro-â-keto esters initiated with
Cu(I) or Ru(II).
We report in this paper the stoichiometric reaction of
R,R-dichlormalonamides and malonates with Cu(I) which
leads to 3-aza- and 3-oxa-2-oxobicyclo[3.1.0]hexanes re-
spectively, in good yields. The fused five-three ring
skeleton is generally built via R-diazo esters or amides,6
although it has recently been reported that the tandem
Michael-SN2 reaction is a safe alternative pathway for
the preparation of bicyclic amides in 50-60% yield.7a An
alternative methodology, developed by Moriarty,7b in-
(1) (a) Bertrand, M. P.; Surzur, J .-M.; Oumar-Mahamat, H.; Mous-
trou, C. J . Org. Chem. 1989, 54, 5684; 1991, 56, 3089. (b) Bertrand,
M. P.; Nouguier, R.; Archavlis, A.; Carrie`re, C. Synlett 1994, 736
(corrigendum, 1995, 216).
(2) (a) Asscher, M.; Vofsi, D. J . Chem. Soc. 1964, 4962. (b) Orochov,
A.; Asscher, M.; Vofsi, D. J . Chem. Soc. B 1969, 255. (c) J ulia, M.;
Saussine, L.; Le Thuillier, G. J . Organomet. Chem. 1979, 359. (d) Mori,
Y.; Tsuji, J . Tetrahedron 1972, 28, 29. (e) Bellus, D. Pure Appl. Chem.
1985, 57, 1827.
(3) For lactone ring closure see: (a) Nagashima, H.; Wakamatsu,
H.; Itoh, K.; Tomo, Y.; Tsuji, J . Tetrahedron Lett. 1983, 24, 2395. (b)
Nagashima, H.; Seki, K.; Ozaki, N.; Wakamatsu, H.; Itoh, K.; Tomo,
Y.; Tsuji, J . J . Org. Chem. 1990, 55, 985. (c) Takano, S.; Nishizawa,
S.; Akiyama, M.; Ogasawara, K. Synthesis 1984, 949. (d) Pirrung, F.
O. H.; Steeman, W. J . M.; Hiemstra, H.; Speckamp, W. N.; Kaptein,
B.; Boesten, W. H. J .; Schoemaker, H. E.; Kamphuis, J . Tetrahedron
Lett. 1992, 33, 5141. (e) Pirrung, F. O. H.; Hiemstra, H.; Kaptein, B.;
Sobrino, M. E. M.; Petra, D. G. I.; Schoemaker, H. E.; Speckamp, W.
N. Synlett 1993, 739. (f) Pirrung, F. O. H.; Hiemstra, H.; Speckamp,
W. N.; Kaptein, B.; Schoemaker, H. E. Tetrahedron 1994, 50, 12415.
(g) Pirrung, F. O. H.; Hiemstra, H.; Speckamp, W. N.; Kaptein, B.;
Schoemaker, H. E. Synthesis 1995, 458.
(4) For lactam ring closure see: (a) Nagashima, H.; Ara, K.;
Wakamatsu, H.; Itoh, K. J . Chem. Soc., Chem. Commun. 1985, 518.
(b) Nagashima, H.; Ozaki, N.; Seki, K.; Ishii, M.; Itoh, K. J . Org. Chem.
1989, 54, 4497. (c) Nagashima, H.; Ozaki, N.; Ishii, M.; Seki, K.;
Washiyama, M.; Itoh, K. J . Org. Chem. 1993, 58, 464. (d) Nagashima,
H.; Wakamatsu, H.; Ozaki, N.; Ishii, T.; Watanabe, M.; Tajima, T.;
Itoh, K. J . Org. Chem. 1992, 57, 1682. (e) Ishibashi, H.; Uemura, N.;
Nakatani, H.; Okazaki, M.; Sato, T.; Nakamura, N.; Ikeda, M. J . Org.
Chem. 1993, 58, 2360. (f) Seijas, J . A.; Vazquez-Tato, M. P.; Castedo,
L.; Estevez, R. J .; Onega, M. G.; Ruiz, M. Tetrahedron 1992, 48, 1637.
(g) Rachita, M. A.; Slough, G. A. Tetrahedron Lett. 1993, 34, 6821. (h)
Slough, G. A. Tetrahedron Lett. 1993, 34, 6825. (i) Ozaki, S.; Mat-
sushita, H.; Ohmori, H. J . Chem. Soc., Perkin Trans. 1 1993, 2339.
(5) (a) Hayes, T. K.; Villani, R.; Weinreb, S. M. J . Am. Chem. Soc.
1988, 110, 5533. (b) Phelps, J . C.; Bergbreiter, D. E.; Lee, G. M.; Villani,
R.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 3915. (c) Parvez, G. M.
L.; Weinreb, S. M. Tetrahedron 1988, 44, 4671. (d) Lee, G. M.; Weinreb,
S. M. J . Org. Chem. 1990, 55, 1281.
(6) (a) Mustafa, A.; Zayed, S. M. A. D.; Khattab, S. J . Am. Chem.
Soc. 1956, 78, 145. (b) For recent syntheses and a review of previous
work see: Doyle, M. P.; Austin, R. E.; Bailey, A. S.; Dwyer, M. P.;
Dyatkin, A. B.; Kalinin, A. V.; Kwan, M. M. Y.; Liras, S.; Oalmann, C.
J .; Pieters, R. J .; Protopopova, M. N.; Raab, C. E.; Roos, G. H. P.; Zhou,
Q.-L.; Martin, S. F. J . Am. Chem. Soc. 1995, 117, 5763.
(7) (a) Chan, S.; Braish, T. F. Tetrahedron 1994, 50, 9943. (b)
Moriarty, R. M.; Prakash, O.; Vaid, R. K.; Zhao, L. J . Am. Chem. Soc.
1989, 111, 6443.
(8) Snider, B. B.; Mc Carthy, B. A. Tetrahedron 1993, 49, 9447.
(9) (a) Burgess, K.; Lim, D.; Ho, K.-K.; Ke, C.-Y. J . Org. Chem. 1994,
59, 2179. (b) Burgess, K.; Ho, K.-K.; Moye-Sherman, D. Synlett 1994,
575. (c) Koskinen, A. M. P.; Hassila, H. J . Org. Chem. 1993, 58, 4479.
(d) Paulini, K.; Reissig, H.-U. J . Prakt. Chem. 1995, 337, 55.
S0022-3263(95)02099-8 CCC: $12.00 © 1996 American Chemical Society

3206 J . Org. Chem., Vol. 61, No. 9, 1996
Notes
Ta ble 1. Cycliza tion s in th e P r esen ce of 2 equ iv of
Sch em e 1
Cu (bp y)Cl
Sch em e 2
Sch em e 3
the fact that their reductions by Cu(I) proceeded at
different rates. When 1 was allowed to react with 2 equiv
of Cu(I) complex, as reported in Table 1, lactam 3 was
the only product (isolated in 77% yield). Monitoring the
reaction conducted at rt, by HPLC, confirmed the validity
of the above hypotheses. The chlorinated lactams were
formed very rapidly, and though 2a was the major
product in the presence of a catalytic amount of reducing
agent, it was transformed into 3 faster than 2b. Thus,
as the reaction proceeded, the ratio of 2a to 2b decreased
and was progressively reversed (2b became the major
stereoisomer, Figure 1). At rt, due to the slow rate of
the formation of the cyclopropane ring, Cu(I) was par-
tially destroyed before the reaction was ended, and thus,
the monocyclic lactams were not totally transformed into
3.
F igu r e 1. Stoichiometric reduction of 1 (2 equiv of Cu(bpy)-
Cl) at rt.
The high degree of stereocontrol in the cyclization of
amide 6 allowed the stereoselective synthesis of 7 (the
other diastereomer was detected in trace amounts by
NMR).11 The same strategy can be applied to the
synthesis of bicyclic lactones. When allyl ethyl dichlo-
romalonate (8) was treated with 2 equiv of Cu(I) bipyri-
dine complex the reaction led to 9 in 76% yield. It should
be noted that Speckamp12 has achieved the closely related
cyclopropanation of polychloro medium-sized-lactones
through a reaction with a dialkyl cuprate.
The reaction also proceeds when the substrate carries
a substituted ethylenic linkage. As shown in Table 1, it
can be applied to amide 4 which bears an isoprenyl chain.
(10) A similar conclusion was established by Weinreb for the Cu(I)-
based cyclization of R,R-dichloro-â-keto esters (cf. ref 5a).

Notes
J . Org. Chem., Vol. 61, No. 9, 1996 3207
H2O (2.3 g, 8 mmol, 8 equiv). A CCl4 solution (3 mL) of the
corresponding starting material (400 mg, 1.0 mmol, 1 equiv) was
slowly added dropwise, and the reaction mixture was stirred at
0 °C for 5 h and then at rt for 1 h more. After filtration, the
aqueous layer was extracted three times with cooled (0 °C) CH2-
Cl2. The combined organic layers were washed at 0 °C with
brine and then dried over Na2SO4 and concentrated. The residue
was purified by preparative HPLC (2,2,4-trimethylpentane/
EtOAc 7/3) to isolate 6 (350 mg, 75%).
Sch em e 4
N-Allyl-N-ben zyl-2,2-d ich lor om a lon a m ic Acid Eth yl Es-
ter (1). 1 (2.3 g) was isolated in 60% yield from the correspond-
ing malonamide (3.0 g, 11.5 mmol) after chromatography on
silica gel (pentane/Et2O 8/2). 1H NMR (200 MHz): (7/3 mixture
of rotamers): 1.30 (t, J ) 7.2, 3H); 3.89 (d, J ) 5.1, 0.6H); 4.00
(d, J ) 5.6, 1.4H); 4.32 (2 superimposed q, J ) 6.9, 2H); 4.62 (s,
1.4 H); 4.78 (s, 0.6H); 5.05-5.40 (m, 2H); 5.65-5.90 (m, 1H);
7.15-7.45 (m, 5H). 13C NMR (50 MHz): 13.67 (CH3); 48.50
(NCH2); 49.85 (NCH2); 64.64 (OCH2); 119.76 (dCH2); 127.59
(CHd); 127.91 (CHd); 128.63 (CHd); 131.57 (CHd); 135.70
(Cd);162.09 (CdO); 163.42 (CdO). The other quaternary carbon
did not appear under the registration conditions. Anal. Calcd
for C15H17NO3Cl2: C, 54.70; H, 5.21; N, 4.26. Found: C, 54.69;
H, 5.10; N, 4.22.
N -B e n z y l-N -(3-m e t h y lb u t -2-e n y l)-2,2-d i c h lo r o m a -
lon a m ic Acid Eth yl Ester (4). 4 (1.8 g) was prepared in 73%
yield from the corresponding amide (2.0 g, 6.9 mmol) after
purification by chromatography on silica gel (pentane/Et2O 8/2).
1H NMR (200 MHz): (7/3 mixture of rotamers): 1.33 (t, J ) 7.1,
3H); 1.41 (s, 0.9H); 1.50 (s, 2.1H); 1.70 (s, 0.9H); 1.75 (s, 2.1H);
3.85-4.02 (m, 2H); 4.33 (q, J ) 7.1, 2H); 4.60 (s, 1.4H); 4.72 (s,
0.6H); 5.08-5.22 (m, 1H); 7.15-7.40 (m, 5H). 13C NMR (50
MHz): 13.71 (CH3); 17.96 (CH3); 25.72 (CH3); 44.12 (NCH2);
45.45 (NCH2); 48.56 (NCH2); 50.90 (NCH2); 64.62 (CH2O); 80.15
(CCl2); 90.70 (CCl2); 117.58 (CHd); 118.33 (CHd); 127.19 (CHd);
127.51 (CHd); 127.89 (CHd); 128.58 (CHd); 136.09 (Cd); 137.88
(Cd); 162.08 (CdO); 163.63 (CdO). Anal. Calcd for C17H21NO3-
Cl2: C, 57.13; H, 5.93; N, 3.92. Found: C, 57.13; H, 5.91; N,
3.93.
N-Ben zyl-N-[1-[(4-m eth oxyph en oxy)m eth yl]pr op-2-en yl]-
2,2-d ich lor om a lon a m ic Acid Eth yl Ester (6). 1H NMR (200
MHz): (mixture of rotamers): 1.20-1.40 (m, 3H); 3.75 (s, 3H);
3.80-4.60 (m, 5H); 4.60-5.50 (m, 4H); 5.80-6.20 (m, 1H); 6.65-
6.90 (m, 4H); 7.15-7.40 (m, 5H). 13C NMR (25 MHz): 13.75
(CH3); 40.10 (CH2); 55.75 (CH3); 63.08 (CH); 64.80 (CH2); 68.66
(CH2); 114.68 (CHd); 115.80 (CHd); 119.19 (CH2d); 126.89
(CHd); 128.11 (CHd); 128.59 (CHd); 132.55 (CHd); 135.14 (Cd);
152.43 (Cd); 154.29 (Cd); 163.52 (CdO). The other quaternary
carbons did not appear under the registration conditions.
Correct elemental analysis could not be obtained due to thermal
decomposition.
Allyl Eth yl Dich lor om a lon a te (8). 8 (3.13 g) was prepared
in 65% yield from allyl ethyl malonate (3.44 g, 20 mmol) after
purification by chromatography on silicagel (pentane/Et2O 9/1).
1H NMR (200 MHz): 1.34 (t, J ) 7.1, 3H); 4.38 (q, J ) 7.1, 2H);
4.79 (d, J ) 5.8, 2H); 5.30-5.46 (m, 2H); 5.93 (ddt, J ) 17.2,
10.4, 5.8, 1H). 13C NMR (50 MHz): 13.81 (CH3); 64.79 (OCH2);
68.70 (OCH2);120.06 (CH2d); 130.22 (CHd); 162.59 (CdO);
162.74 (CdO). The signal of the quaternary carbon bearing the
chlorine atoms is not visible, under the conditions of registration.
Anal. Calcd for C8H10Cl2O4: C, 39.86; H, 4.18; Cl, 29.41.
Found: C, 39.82; H, 4.16; Cl, 29.30.
N-Allyl-N-(p-ch lor oben zyl)-r,r-d ich lor oa ceta m id e (10).
A solution containing p-chlorobenzylamine (1.46 g, 8.1 mmol, 1
equiv) and triethylamine (1.01 g, 10 mmol, 1.2 equiv) in
dichloromethane (15 mL) was added at 0 °C to a solution of
dichloroacetyl chloride (1.30 g, 10 mmol, 1 equiv) in dichlo-
romethane (30 mL). After the addition was ended the reaction
mixture was allowed to warm to rt and was stirred for 4 h more.
The solution was washed with water and then with brine and
dried over anhydrous sodium sulfate. After concentration, the
oily residue was chromatographed on silica gel (Et2O/pentane
5/95), leading to 10 (1.56 g, 66%) as a mixture of rotamers. 1H
NMR (200 MHz): 3.92-4.04 (m, 2H); 4.58 (s, 1.4H); 4.69 (s,
0.6H); 5.06-5.38 (m, 2H); 5.60-5.91 (m, 1H); 6.20 (s, 0.3H); 6.24
(s, 0.7 H); 7.10-7.41 (m, 4H). 13C NMR (50 MHz): 48.73 (CH2);
49.45 (CH2); 49.82 (CH2); 64.87 (CH); 65.10 (CH); 118.37 (CH2d);
118.55 (CH2d); 128.02 (CHd); 128.89 (CHd); 129.17 (CHd);
129.41 (CHd); 130.96 (CHd); 131.74 (CHd); 133.62 (Cd); 133.68
(Cd); 133.91 (Cd); 134.49 (Cd); 164.23 (CdO). Anal. Calcd for
In addition, we investigated if the presence of two
carbonyl functions was absolutely necessary for obtaining
bicyclo[3.1.0]hexanes. Neither 10 nor 12 (Scheme 4) gave
bicyclic products when submitted to 2 equiv of reducing
complex.
The dichloroacetamide 10 led to the diastereomeric
lactams 11a b, in a similar ratio, not depending on the
amount of reducing metallic complex (as 2a and 2b,
neither 11a nor 11b were isomerized on further treat-
ment with 0.1 equiv of Cu(bpy)Cl). These results support
the conclusion that the C-Cl bond cannot be cleaved
again by Cu(I). 12 was reported to give 13 in 98% yield
in the presence of 0.3 equiv of Cu(bpy)Cl.4c Therefore,
the low yield of lactam 13 from 12 in the presence of 2
equiv of Cu(I) suggested that 13 can further be degraded
via radical 14. But the absence of the cyclopropane ring
closure seemed to indicate that no further reduction of
14 had occurred.
In summary, the treatment of dichloromalonic deriva-
tives with 2 equiv of Cu(I) provides an easy access to
fused five-three ring skeletons. Further studies in the
field of Cu(I)-mediated cyclopropanations are currently
under investigation.
Exp er im en ta l Section
NMR spectra were recorded in CDCl3 solutions on a Bruker
AC 200 or AC 100 spectrometer. J values are given in Hz.
Column chromatography was performed on silica gel 60 (Merck
7734). HPLC analyses were conducted on a Waters Nova-Pack
Silica (4 µm) column (3.9 i.d. × 15 cm) coupled to a refractometer.
The amides and the ester, precursors of the substrates, were
prepared by classical procedures involving the substitution of
ethyl chlorocarbonyl ethanoate with the corresponding amines
or alcohol.
Gen er a l P r oced u r e for th e P r ep a r a tion of Dich lor i-
n a ted Su bstr a tes. In a typical experiment, in a 50 mL flask,
cooled at 0 °C with an ice bath, were introduced sodium
hypochlorite (1.8 M, 2.2 mL, 4.0 mmol, 4 equiv) and Na2CO3, 10
(11) For other examples of total 4,5-stereocontrol in 5-hexenyl
radical cyclizations see ref 8 and: (a) Rajanbabu, T. V. Acc. Chem.
Res. 1991, 24, 139. (b) Curran, D. P.; Geib, S. J .; Lin, C.-H. Tetrahe-
dron: Asymmetry 1994, 5, 199. (c) Wilcox, C. S.; Thomasco, L. M. J .
Org. Chem. 1985, 50, 546. (d) Matsumoto, K.; Miura, K.; Oshima, K.;
Utimoto, K. Tetrahedron Lett. 1992, 33, 7031. (e) Stork, G.; Mook, J r.,
R.; Biller, S. A.; Rychnovsky, S. D. J . Am. Chem. Soc. 1983, 105, 3741.
(f) Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.; Okawara, M. Ibid.
1982, 104, 5564.
(12) Speckamp, W. N. Private communication.

3208 J . Org. Chem., Vol. 61, No. 9, 1996
Notes
C12H12NOCl3: C, 49.26; H, 4.13; N, 4.79, Cl, 36.35. Found: C,
49.20; H, 4.15, N, 4.76, Cl, 36.3.
h, by Cu(bpy)Cl (2 equiv). After treatment, a purification by
semipreparative HPLC (2,2,4-trimethylpentane/EtOAc 65/35)
afforded 7 (180 mg, 70%).
N-Allyl-N-ben zyltr ich lor oa ceta m id e (12).4c According to
the same protocol, N-benzylallylamine was allowed to react with
trichloroacetyl chloride; 12 was obtained in 60% yield. 1H NMR
(200 MHz): 3.67 (broad s, 0.6H); 4.00 (broad s, 1.4H); 4.37 (broad
s, 1.4H); 4.67 (broad s, 0.6H); 4.83-5.15 (m, 2H); 5.37-5.70 (m,
1H); 6.88-7.15 (m, 5H). 13C NMR (50 MHz): 49.86 (CH2); 51.08
(CH2); 52.26.(CH2); 93.03 (C); 118.27 (CHd); 119.60 (CHd);
127.05 (CHd); 127.66 (CHd); 128.35 (CHd); 128.67 (CHd);
130.66 (CHd); 131.78 (CHd); 135.68 (Cd); 160.67 (CdO). Anal.
Calcd for C12H12NOCl3: C, 49.26; H, 4.13; N, 4.49. Found: C,
49.20; H, 4.12; N, 4.77.
Eth yl 3-Ben zyl-4-[(4-m eth oxyp h en oxy)m eth yl]-2-oxo-3-
a za bicyclo [3.1.0]h exa n e-1-ca r boxyla te (7). 1H NMR (200
MHz): 0.98 (pseudo t, J ) 5.0, 1H); 1.33 (t, J ) 7.1, 3H); 1.90
(dd, J ) 8.0, 4.7, 1H); 2.29 (dd, J ) 8.0, 5.2, 1H); 3.60 (t, J )
4.9, 1H); 3.75 (s, 3H); 3.95 (ABX pattern, J AB ) 9.7, 2H); 4.02
(d, J ) 14.8, 1H); 4.28 (q, J ) 7.1, 2H); 4.93 (d, J ) 14.8, 1H);
6.80 (AA′BB′ pattern, 4H); 7.15-7.25 (m, 2H); 7.25-7.40 (m, 3H).
13C NMR (50 MHz): 14.25 (CH3); 19.26 (CH2); 25.52 (CH); 31.12
(C); 45.04 (CH2); 55.76 (CH3); 56.19 (CH); 61.56 (CH2); 69.33
(CH2); 114.79 (CHd); 115.46 (CHd); 127.80 (CHd); 128.32
(CHd); 128.84 (CHd); 136.76 (Cd); 152.38 (Cd); 154.40 (Cd);
168.51 (CdO) 169.74 (CdO). Correct elemental analysis could
not be obtained due to thermal instability. HRMS: calcd for
Gen er a l P r oced u r e for Ra d ica l Cycliza tion . CuCl was
prepared according to a known procedure,13 dried under vacuum,
and stored under nitrogen in the dark. In a typical experiment,
into a three-necked flask fitted with a lateral bent glass tube
filled with freshly prepared CuCl (18 mg, 0.18 mmol, 0.1 equiv)
were introduced 1 (0.6 g, 1.8 mmol, 1 equiv), 2,2′-bipyridine (27
mg, 0.18. mmol, 0.1 equiv), and isobutyronitrile (10 mL). The
solution was degassed several times under vacuum and then
brought back to atmospheric pressure under argon. The reaction
mixture was stirred at reflux, and CuCl was added all at once.
After the reaction was ended, metallic salts were filtered on a
short pad of silica and the solvent was evaporated under reduced
pressure. Purification of the residue by preparative HPLC
(2,2,4-pentane/EtOAc 8/2) afforded by order of elution 1 (150 mg,
25%), 2a (140 mg, 23%), and 2b (210 mg, 35%).
C
23H25NO5 395.1733, found 395.1737.
Cycliza tion of 8. After 8 (0.51 g, 2.1 mmol, 1 equiv) was
treated with Cu(bpy)Cl (2 equiv) at reflux of butyronitrile (16
mL) during 22 h, chromatography on silica gel of the residue
(pentane/Et2O 10/0-5/5) afforded lactone 9 (270 mg, 76%).
Eth yl 3-Oxa-2-oxobicyclo[3.1.0]h exan e-1-car boxylate (9).
1H NMR (200 MHz): 1.32 (t, J ) 7.1, 3H); 1.35 (t, J ) 4.7, 1H);
2.08 (dd, J ) 8.1, 4.7, 1H); 2.73 (dtd, J ) 8.1, 4.7, 1.3, 1H); 4.12
(broad d, J ) 9.6, 1H); 4.27 (q, J ) 7.1, 2H); 4.37 (dd, J ) 9.6,
4.7, 1H). 13C NMR (50 MHz): 14.14 (CH3); 20.80 (CH2); 28.02
(CH); 29.40 (C); 62.04 (OCH2); 67.12 (CH2) (C5); 166.77 (CdO);
170.73 (CdO). Anal. Calcd for C8H10O4: C, 56.47, H, 5.92.
Found: C, 56.41; H, 6.01.
Cycliza tion of 10.4c After 10 (0.25 g, 0.8 mmol, 1 equiv) was
treated with CuCl (0.17 g, 1.7 mmol, 2 equiv) at reflux of
isobutyronitrile (16 mL) during 24 h, filtration on a short pad
of silica, and concentration, 250 mg of an oily residue was
isolated. Preparative HPLC on silica gel (pentane/Et2O 10/0-
5/5) afforded lactone 11a (149 mg, 60%) and 11b (49 mg, 20%).
Eth yl 1-Ben zyl-3-ch lor o-4-(ch lor om eth yl)-2-oxop yr r oli-
d in e-3-ca r boxyla te (2a ). 1H NMR (200 MHz): 1.23 (t, J )
7.2, 3H); 3.03-3.15 (m, 1H); 3.20 (pseudo t, J ) 8.9, 1H); 3.38
(pseudo t, J ) 10.5, 1H); 3.50 (dd, J ) 8.9, 7.1, 1H); 3.80 (dd, J
) 10.8, 4.4, 1H); 4.26 (q, J ) 7.2, 2H); 4.55 (AB quartet, J AB
)
14.6, ∆ν ) 79.2 Hz, 2H); 7.23-7.43 (m, 5H). 13C NMR (50
MHz): 13.98 (CH3); 41.00 (CH2); 47.90 (CH2); 48.31 (CH2); 49.75
(CH); 63.64 (CH2); 71.84 (C); 128.12 (CHd); 128.38 (CHd);
128.84 (CHd); 134.79 (Cd); 165.00 (Cd0); 166.96 (Cd0). 2b.
1H NMR (200 MHz): 1.35 (t, J ) 7.1, 3H); 3.05 (m, 1H); 3.40-
3.49 (m, 2H); 3.50-3.63 (m, 1H); 3.65-3.78 (m, 1H); 4.37 (q, J
) 7.1, 2H); 4.50 (AB quartet, J AB ) 14.9 Hz, ∆ν ) 39.5 Hz, 2H);
7.20-7.40 (m, 5H). 13C NMR (50 MHz): 13.98 (CH3); 41.3 (CH2);
44.87 (CH); 47.24 (CH2); 47.39 (CH2); 63.73 (CH2); 71.90 (C);
128.04 (CHd); 128.12 (CHd); 128.96 (CHd); 134.91 (Cd); 166.12
(CdO); 167.33 (CdO). Anal. Calcd for C15H17NO3Cl2 (2a +
2b): C, 54.70; H, 5.21; N, 4.26; Cl, 21.25. Found: C, 54.62; H,
5.17; N, 4.21; Cl, 21.20.
3-(p -Ch lor ob en zyl)-5-ch lor o-2-(ch lor om et h yl)-3-a za cy-
clop en ta n -2-on e (11a ). 1H NMR (200 MHz): 2.84 (m, 1H); 3.19
(dd, J )10.0, 7.1, 1H); 3.40 (dd, J ) 10.0, 8.1, 1H); 3.62-3.78
(AB part of an ABX spectrum, J AB ) 11.7, 2H); 4.40 (d, J ) 7.8,
1H); 4.48 (AB quartet, J AB ) 14.9, ∆ν ) 28.2 Hz, 2H); 7.21-
7.65 (AA′XX′ pattern, 4H). 13C NMR (50 MHz): 43.43 (CH2);
44.75 (CH); 46.72 (CH2); 46.95 (CH2); 56.56 (CH); 129.04 (CHd);
129.13 (CHd); 129.62 (CHd); 133.72 (Cd); 134.01 (Cd); 168.66
(CdO).
3-(p -Ch lor ob en zyl)-5-ch lor o-2-(ch lor om et h yl)-3-a za cy-
clop en ta n -2-on e (11b). 1H NMR (200 MHz): 2.90 (pseudo-
quint, J ) 7.3, 1H); 3.15 (dd, J ) 10.0, 8.0, 1H); 3.35 (dd, J )
10.0, 7.3, 1H); 3.57 (dd, J ) 11.2, 7.8, 1H); 3.78 (dd, J ) 11.0,
6.8, 1H); 4.45 (AB quartet, J AB ) 14.6, ∆ν ) 38.1 Hz, 2H); 4.50
(d, J ) 6.3, 1H); 7.10-7.35 (AA′XX′ pattern, 4H). 13C NMR (50
MHz): 40.49 (CH); 41.73 (CH2); 46.09 (CH2); 47.74 (CH2); 57.32
(CH); 128.91 (CHd); 129.25 (CHd); 133.61 (Cd); 133.73 (Cd);
169.13 (CdO). Anal. Calcd for C12H12NOCl3 (11a + 11b): C,
49.26; H, 4.13; N, 4.79; Cl, 36.35. Found: C, 49.30; H, 4.26; N,
4.79; Cl, 36.2.
Treating 1 (0.5 g, 1.5 mmol) with 2 equiv of Cu(bpy)Cl afforded
3 (300 mg, 77%) after 2 h of reflux and a purification by
chromatography on silica gel (Et2O).
E t h yl 3-Ben zyl-2-oxo-3-a za b icyclo[3.1.0]h exa n e-1-ca r -
boxyla te (3). 1H NMR (200 MHz): 0.93 (pseudo t, J ) 4.9, 1H);
1.20 (t, J ) 7.2, 3H); 1.80 (dd, J ) 8.1, 4.6, 1H); 2.20 (pseudo dt,
J ) 8.4, 5.6, 1H); 2.99 (d, J ) 10.5, 1H); 3.32 (dd, J ) 10.5, 5.6,
1H); 4.13 (q, J ) 7.2, 2H); 4.26 (AB quartet, J AB ) 14.9, ∆ν )
47.7 Hz, 2H); 7.00-7.27 (m, 5H). 13C NMR (50 MHz): 14.09
(CH3); 20.59 (CH2); 22.61 (CH); 31.50 (C); 46.26 (CH2); 46.35
(CH2); 61.33 (CH2); 127.57 (CHd); 128.06 (CHd); 128.61 (CHd);
136.21 (Cd); 168.58 (CdO); 169.13 (CdO). Anal. Calcd for:
Cycliza tion of 12. 12 (0.3 g, 1.0 mmol) was treated with 2
equiv of Cu(bpy)Cl in isobutyronitrile (10 mL) over 36 h, at
reflux. After purification by preparative HPLC (2,2,4-trimeth-
ylpentane/EtOAc 8/2) 13 was isolated (100 mg, 33%).
C
15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.44; H, 6.59;
N, 5.39.
Cycliza tion of 4. According to the above protocol, 4 (0.5 g,
1.4 mmol) was treated for 16 h by Cu(bpy)Cl (2 equiv). After
treatment, a purification by semipreparative HPLC (2,2,4-
trimethylpentane/EtOAc: 65/35) afforded 5 (280 mg, 70%).
E t h yl 3-Ben zyl-6,6-d im et h yl-2-oxo-3-a za b icyclo[3.1.0]-
h exa n e-1-ca r boxyla te (5). 1H NMR (200 MHz): 0.99 (s, 3H);
1.21 (s, 3H); 1.33(t, J ) 7.1, 3H); 2.10 (d, J ) 6.6, 1H); 2.95 (d,
J ) 11.0, 1H); 3.44 (dd, J ) 11.0, 6.6, 1H); 4.27 (q, J ) 7.1, 2H);
4.35 (AB quartet, J AB ) 14.4 Hz, ∆ν ) 36.9 Hz, 2H); 7.15-7.36
(m, 5H). 13C NMR (50 MHz): 14.29 (CH3); 14.90 (CH3); 21.74
(CH3); 29.37 (CH); 43.50 (C); 43.86 (CH2); 46.63 (CH2); 61.42
(CH2); 127.72 (CHd); 128.58 (CHd); 128.70 (CHd); 135.83 (Cd);
167.60 (CdO); 168.00 (CdO). Anal. Calcd for C17H21NO3: C,
71.06; H, 7.37; N, 4.87. Found: C, 71.05; H, 7.32; N, 4.83.
Cycliza tion of 6. According to the above protocol, 6 (300
mg, 0.64 mmol) was treated at reflux of isobutyronitrile, for 6
3-Ben zyl-2-(ch lor om et h yl)-5,5-d ich lor o-3-a za cyclop en -
ta n -2-on e (13).4c 1H NMR (200 MHz): 3.00-3.15 (m, 2H);
3.35-3.53 (m, 1H); 3.57-3.73 (m, 1H); 3.95 (dd, J ) 11.5, 4.1,
1H); 4.53 (AB quartet, J AB ) 14.9Hz, ∆ν ) 37.3 Hz, 2H); 7.17-
7.40 (m, 5H).
Ack n ow led gm en t. The authors wish to thank Pro-
fessor Philippe Renaud for fruitful suggestions.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 6 and 7 and COSY HH and COSY CH
of compound 7 (7 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
(13) Vogel, A. I. A Text-Book of Practical Organic Chemistry, 3rd
ed.; Longmans: London, 1956; p 190.
J O952099B