Ring-expanding reaction of cyclopropyl amides with triphenylphosphine and carbon tetrahalide

Article abstract of DOI:10.1021/jo0516988

We succeeded in activating cyclopropyl amides (monoactivated cyclopropane) through the corresponding imidoyl halides prepared in situ in the presence of 2 equiv of PPh₃ and 1 equiv of CX₄, and the ring-expanding products (N-substituted pyrrolidin-2-ones) were obtained in good yields. The reaction mechanism was investigated on the basis of oxygen-18 tracer experiment.

Full text of DOI:10.1021/jo0516988

SCHEME 1
Ring-Expanding Reaction of Cyclopropyl
Amides with Triphenylphosphine and
Carbon Tetrahalide
Yong-Hua Yang and Min Shi*
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Triphenylphosphine with carbon tetrachloride or car-
bon tetrabromide has been found widespread use as a
reagent for the conversion of alcohols, acids, and amide
derivatives into the corresponding halides, nitriles, and
carbo imide derivatives.6 Ziehn and co-workers also
described the preparation of imidoyl halides (chlorides
and bromides) through simultaneous treatment of the
monosubstituted amides with triphenylphosphine and
carbon tetrahalide (CX4, X ) Cl and Br) in acetonitrile.7
On the basis of this result, we suppose that if cyclopropyl
amides 1 can be converted into the corresponding imidoyl
halide derivatives 2, their reactivities would be increased
because there exist two electron-withdrawing groups in
their structures (CdN and C-X) (Scheme 1).
mshi@pub.sioc.ac.cn
Received August 10, 2005
To determine whether this speculation is possible, we
attempted the reaction of cyclopropyl amides 1 with PPh3/
CX4 under similar conditions.
We succeeded in activating cyclopropyl amides (monoacti-
vated cyclopropane) through the corresponding imidoyl
halides prepared in situ in the presence of 2 equiv of PPh3
and 1 equiv of CX4, and the ring-expanding products (N-
substituted pyrrolidin-2-ones) were obtained in good yields.
The reaction mechanism was investigated on the basis of
oxygen-18 tracer experiment.
As an initial examination, we found that the reaction
of N-phenylcyclopropylamide 1a with 2 equiv of Ph3P and
1 equiv of CCl4 produced the N-phenylpyrrolidin-2-one
3a in 62% yield under reflux for 3 days in acetonitrile
(Table SI-1, Supporting Information, entry 1). When we
utilized CBr4 instead of CCl4, this reaction proceeded
smoothly at 60 °C under similar conditions to give 3a in
97% yield after 3 h. After optimization of the reaction
conditions (Table SI-1, Supporting Information), we found
that 2 equiv of Ph3P and 1 equiv of CBr4 are required in
this reaction to give 3a in good yield and acetonitrile is
the best solvent, which is similar to those of other
reaction systems using triphenylphosphine and carbon
tetrahalide as reagents.6,8 It should be emphasized here
that we also attempted to activate cyclopropylamide 1a
with PCl59 and POCl3, respectively,10 typical Vilsmeier-
Haack reaction conditions, but the desired product 3a
was not formed. At the present stage, we only found that
the reagent of PPh3/CBr4 can effectively promote this
ring-expanding reaction.
Cyclopropane derivatives as versatile building blocks
have been more than laboratory curiosities for quite some
time.1 To activate strained three-membered ring, electron-
donating or -accepting substituents are generally in-
volved in their reactions to make polar processes more
favorable. However, cyclopropane-involved synthetically
useful reactions frequently contain two activating groups.2
The ring-opening reactions of monoactivated cyclopro-
pane derivatives are in general sluggish due to their low
reactivities. So far, several examples have been reported
under severe conditions either treated with stronger
nucleophiles such as I- 3 and stronger Lewis acids such
as TiCl44 or assisted by the â-effect of the silicon atom of
trimethylsilyl group.5 Therefore, it is necessary to develop
a method for the ring-opening reaction of simple mono-
activated cyclopropane derivatives under mild conditions.
It is well-known that lactam rings are important
structures in a number of biologically and pharmaceuti-
(1) (a) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151. (b)
Paquette, L. A. Chem. Rev. 1986, 86, 733. (c) Wong, H. N. C.; Hon,
M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989,
89, 165. (d) de Meijere, A.; Wessjohann, L. Synlett 1990, 20. (e)
Kulinkovich, O. G. Russ. Chem. Rev. 1993, 62, 839. (f) Kulinkovich,
O. G. Polish J. Chem. 1997, 849. (g) Wenkert, E. Acc. Chem. Res. 1980,
13, 27. (h) Wenkert, E. Heterocycles 1980, 14, 1703. (i) Seebach, D.
Angew. Chem. 1979, 91, 259; Angew. Chem. Int. Ed. Engl. 1979, 18,
239. (j) Reiser, O. Chem. Rev. 2003, 103, 1603.
(4) (a) Lim, Y.-H.; McGee, K. F., Jr.; Sieburth, S. M. J. Org. Chem.
2002, 67, 6535. (b) Yates, P.; Helferty, P. H.; Mahier, P. Can. J. Chem.
1983, 61, 78. (c) Demuth, M.; Raghavan, P. R. Helv. Chim. Acta 1979,
62, 2338.
(5) Yadav, V. K.; Balamurugan, R. Org. Lett. 2003, 5, 4281.
(6) (a) Rabinowitz, R.; Marcus, R. J. Am. Chem. Soc. 1962, 84, 1312.
(b) Ramirez, F.; Desai, N. B.; Mckelvie, N. J. Am. Chem. Soc. 1962,
84, 1745. (c) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis;
Wiley-Interscience New York, 1972; Vol. 3, p 320. (d) Gadogan, J. I.
G.; Mackie, R. K. Chem. Soc. Rev. 1974, 3, 87.
(7) (a) Appel, R.; Warning, K.; Ziehn, K.-D. Chem. Ber. 1973, 106,
3450. (b) Appel, R.; Angew. Chem., Int. Ed. Engl. 1975, 14, 801. (c)
Zhong, Y.-L.; Lee, J.; Reamer, R. A.; Askin, D. Org. Lett. 2004, 6, 923.
(8) (a) To¨mo¨sko¨zi, I.; Gruber, L.; Radics, L. Tetrahedron Lett. 1975,
16, 2473. (b) Aneja, R.; Davies, A. P.; Knaggs, J. A. Tetrahedron Lett.
1974, 15, 67.
(9) Langer, P.; Helmholz, F.; Schroeder, R. Synlett. 2003, 2389.
(10) Herbert, J. M.; Woodgate, P. D.; Denny, W. A. J. Med. Chem.
1987, 30, 2081.
(2) 2 (a) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66. (b) Avilov,
D. V.; Malusare, M. G.; Arslancan, E.; Dittmer, D. C. Org. Lett. 2004,
6, 2225.
(3) (a) Han, Z.; Uehira, S.; Tsuritani, T.; Shinokubo, H.; Oshima,
K. Tetrahedron 2001, 57, 987. (b) Truce, W. E.; Lindy, L. B. J. Org.
Chem. 1961, 27, 1463. (c) Smith, A. B., III; Scarborough, R. M.
Tetrahedron Lett. 1978, 19, 1649. (d) Ogoshi, H.; Kikuchi, Y.; Yamagu-
chi, T.; Toi, H.; Aoyama, Y. Organometallics 1987, 6, 2175. (e) Hwu,
J. R. Chem. Commun. 1985, 452. (f) Bertozzi, F.; Gustafsson, M.;
Olsson, R. Org. Lett. 2002, 4, 3147. (g) Bertozzi, F.; Gustafsson, M.;
Olsson, R. Org. Lett. 2002, 4, 4333.
10.1021/jo0516988 CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/15/2005
J. Org. Chem. 2005, 70, 8645-8648
8645

TABLE 1. Reaction of Various N-Substituted
(Table 1, entry 7). Moreover, these reactions can be
carried out under ambient atmosphere.
Cyclopropyl Amides with PPh3 and CBr4 in Acetonitrile
Interestingly, when N,N′-bis(cyclopropylcarbonyl)ben-
zidine 4 was utilized as a substrate, the corresponding
ring-expanding product 5 can also be obtained in 86%
yield (Scheme 2). However, when N,N′-bis(cyclopropyl-
carbonyl)[1,1′]binaphthalenyl-2,2′-diamine 6 (racemate)
was employed as a substrate, the ring-opened product 7
was exclusively obtained. We believe that the significant
steric hindrance in this substrate hampered the ring-
expanding reaction. Moreover, this result mechanistically
suggests that the ring-opened product, 4-bromobutyra-
mide, may be a key intermediate in this reaction.
Therefore, to clarify the mechanism of this reaction,
we treated 4-bromo-N-phenylbutyramide 8 under the
same conditions with PPh3 and CBr4 at 60 °C in aceto-
nitrile and found that the corresponding pyrrolidin-2-one
3a, as expected, was formed in 94% yield after 10 h
(Scheme 3). On the other hand, the control experiments
showed that treatment of 1a with base such as NaOEt,
Brønsted acid such as hydrobromic acid (HBr), or Lewis
acid TiX4 containing halogen ions (X ) Cl or Br) did not
promote this reaction under similar conditions. These
results again indicated that the combination of PPh3 and
CBr4 is the only useful reagents for this reaction.
To further clarify the mechanism of this reaction, we
carried out the reaction of 1a with PPh3/CBr4 in the
presence of 18OH2.15 As a result, we found that 3a-18O
was formed in 88% yield with 59.2% 18O content in the
oxygen atom of carbonyl group, which was determined
by magnetic mass spectroscopic analysis (see Scheme SI-
4, Supporting Information). This result clearly indicates
that the oxygen atom of the carbonyl group in lactam
product 3 comes from H2O in the reaction system and
the original oxygen atom in 1a is taken away by Ph3P as
Ph3PO. After examination of the resulted byproducts, we
confirmed that Ph3PO was indeed formed in this reaction
system.
In view of the above results, a plausible reaction
mechanism is proposed in Scheme 4. At first, triphen-
ylphosphine reacts with carbon tetrahalide to give the
corresponding dihalogentriphenylphosphorane 9 and di-
halogenmethylene ylide 10. Next, the intermediate A is
formed by the reaction of N-substituted cyclopropylamide
1 with dihalogentriphenylphosphorane 9 to release a
dihalogenmethyltriphenylphosphonium salt 11 as white
precipitates, which was dissolved in MeCN after the
solution was heated to 60 °C.8 Thus, the corresponding
N-substituted cyclopropylformimidoyl halogen B, as an
anticipated active iminocyclopropane intermediate hav-
ing two electron-withdrawing groups, is formed along
with the generation of triphenylphosphine oxide. From
intermediate B, two reaction pathways can be considered
for the formation of pyrrolidin-2-one product 3. Formally,
the intermediate C can be first formed via a Cloke-type
rearrangement from intermediate B. The corresponding
pyrrolidin-2-one product 3 is formed through water
substituting X by OH (Scheme 4, path a). However, it
has been reported that typical Cloke rearrangement
normally proceeds from an imine by acid catalysis at
a Isolated yields. b The structure was determined by X-ray
diffraction (see the Supporting Information). c The yield was
determined by 1H NMR spectroscopic data.
cally active compounds as well as some alkaloids such
as cotinine or mannolactam.11 Among these lactam
compounds, pyrrolidinones are often found in a variety
of pharmacologically active compounds, for example,
convultamides,12 enzyme inhibitors,13 and various drugs.14
Therefore, to extend the scope of this interesting ring-
expanding reaction, we next carried out the reactions of
a variety of N-substituted cyclopropylamides 1 in the
presence of PPh3/CBr4 under the optimized reaction
conditions. In all of the cases we examined, the corre-
sponding ring-expanding products (N-substituted pyrro-
lidin-2-ones) 3 were exclusively formed in 58-97% yields.
The results are summarized in Table 1. For both aromatic
cyclopropylamides and aliphatic cyclopropylamides, the
reactions proceeded smoothly to give the desired products
3 in good to high yields. More importantly, for sterically
hindered ortho-substituted cyclopropyl amide 1f, this
reaction also proceeded smoothly to give the correspond-
ing pyrrolidin-2-one product 3f in 86% yield (Table 1,
entry 6). For cyclopropyl amide 1k (R2 ) phenyl group),
the reaction became sluggish and the corresponding ring-
expanding product 3k was only obtained in 26% yield
even if the reaction time was prolonged to 1 day, and in
the meantime, decomposition of starting material was
also observed (Table 1, entry 11). It should be noted that
the ester group is tolerable under the reaction conditions
(11) (a) Milewska, M. J.; Bytner, T.; Połon˜ski, T. Synthesis 1996,
1485. (b) Neurath, G. B. In Nicotine Related Alkaloids; Gorrod, J. W.,
Ed.; Chapman: London, 1993; p 61. (c) Cook, G. R.; Beholz, L. G.; Stille,
J. R. J. Org. Chem. 1994, 59, 3575.
(12) Zhang, M.; Shigemori, H.; Ishibashi, M.; Kosaka, T.; Pettit, G.
R.; Konano, Y.; Kobayashi, J. Tetrahedron 1994, 50, 10201.
(13) Baures, P. W.; Eggleston, D. S.; Erhard, K. F.; Cieslinski, L.
B.; Torphy, T. J.; Christensen, S. B. J. Med. Chem. 1993, 36, 3274.
(14) Marson, C. M.; Grabowska, U.; Walsgrove, T.; Eggleston, D.
S.; Baures, P. W. J. Org. Chem. 1994, 59, 284.
(15) H2O (1.0 equiv) must be added slowly to the reaction mixture
of 1a with PPh3/CBr4 in MeCN at 60 °C; otherwise, the yield of 3a
would be decreased.
8646 J. Org. Chem., Vol. 70, No. 21, 2005

SCHEME 2. Ring-Expanding Reaction of 4 and Ring-Opening Reaction of 6 with PPh3/CBr4
I- could promote Cloke-type rearrangement through a
ring-opening process under milder reaction conditions
(85-90 °C).17 Therefore, on the basis of above results, we
believe that ring-opening reaction of intermediate B,
having two electron-withdrawing groups, takes place by
the nucleophilic attack of X- in dihalogen methyltri-
phenylphosphonium salt 11 to give another cyclopropyl-
formimidoyl halogen intermediate D which is labile
toward ambient H2O in any sense.18 In the presence of
ambient moisture (H2O), 4-halobutyrimidic acid inter-
mediate E is formed through water substituting X by OH
which is in an equilibrium with 4-halobutyramide F
(Scheme 4, path b). The intramolecular nucleophilic
attack produces the corresponding ring-closure product
3 by release of a HX (path b). If the ring-closure process
is difficult to take place because of the steric hindrance,
the corresponding 4-halobutyramide F will be obtained.
The control experiment has showed that 4-halobutyra-
mide F, which has been isolated from a steric hindered
cyclopropyl amide in Scheme 2, can be transformed to
product 3 under the reaction conditions (Scheme 3).
In conclusion, treatment of cyclopropyl amides with 2
equiv of PPh3 and 1 equiv of CX4 (X ) Cl, Br) produce
the corresponding N-substituted pyrrolidin-2-one 3 in
good to high yields via imidoyl halides intermediate. On
the basis of oxygen-18 labeled experimenst, we clarified
that the oxygen atom of the obtained lactam arises from
participation of adventitious H2O in the reaction system
and a plausible reaction mechanism was proposed.
Continuing efforts are in progress to disclose the mecha-
nistic details of this reaction and to determine its scope
and limitations.
SCHEME 3. Ring-Closure Reaction of
4-Bromo-N-phenylbutyramide 8 with PPh3 and
CBr4
SCHEME 4. Plausible Reaction Mechanism of the
Ring-Expanding Reaction of Cyclopropyl Amide in
the Presence of PPh3 and CX4
Experimental Section
1
General Methods. Melting points are uncorrected. H and
13C NMR spectra were recorded at 300 and 75 MHz, respectively.
Mass and HRMS spectra were recorded by EI methods. Organic
solvents used were dried by standard methods when necessary.
Commercially obtained reagents were used without further
purification. All reactions were monitored by TLC with silica
gel coated plates. Flash column chromatography was carried out
using silica gel at increased pressure.
elevated temperatures, typically by heating the substrate
as a melt, or in xylene with ammonium chloride at >130
°C.16 Moreover, Giller and co-workers also reported that
General Procedure for the Reactions of Cyclopropan-
ecarbonyl Amide with PPh3 and CBr4. A mixture of cyclo-
propanecarbonyl amide (0.3 mmol), PPh3 (197 mg, 0.75 mmol),
and CBr4 (100 mg, 0.3 mmol) was dissolved in acetonitrile (3
(16) Cloke, J. B. J. Am. Chem. Soc. 1929, 51, 1174. (b) Stevene, R.
V.; Ellis, M. C.; Wentland, M. P. J. Am. Chem. Soc. 1968, 90, 5576. (c)
Stevene, R. V.; Wentland, M. P. J. Am. Chem. Soc. 1968, 90, 5580. (d)
Stevene, R. V.; Luh, Y.; Sheu, J.-T. Tetrahedron Lett. 1976, 3799.
(17) Giller, K.; Baird, M. S.; de Meijere, A. Synlett 1992, 524.
(18) The hydroscopic tendency of imidoyl halides has been mentioned
in many papers: (a) Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe,
H.; Uneyama, K. J. Org. Chem. 1993, 58, 32. (b) Ghosez, L.; Haveaux,
B.; Viehe, H. G. Angew. Chem., Int. Ed. Engl. 1969, 8, 454. (c) Sidani,
A.; Marchand-Brynaert, J.; Ghosez, L. Angew. Chem., Int. Ed. Engl.
1974, 13, 267. (d) Marchand-Brynaert, J.; Ghosez, L. J. Am. Chem.
Soc. 1972, 94, 2870. (e) Ghosez, L. Angew. Chem., Int. Ed. Engl. 1972,
12, 852. (f) Harvill, E. K.; Herbst, R. M.; Screiner, E. C.; Boberts, C.
W. J. Org. Chem. 1950, 58, 662. (g) Uneyama, K.; Kobayashi, M.
Tetrahedron Lett. 1991, 32, 5981.
J. Org. Chem, Vol. 70, No. 21, 2005 8647

mL). A short time later, a white precipitate was formed from
the reaction solution. Then, the reaction system was heated to
60 °C, and the precipitate was dissolved again in the reaction
solution. The solvent was evaporated after all starting amides
were consumed. The residue was dissolved in CH2Cl2 (50 mL)
and washed with H2O (50 mL × 2). After the residue was dried
over anhydrous MgSO4, the solvent was removed under reduced
pressure and the residue was purified by a silica gel column
chromatography to give pyrrolidin-2-one product.
2H, Ar), 7.57-7.61 (m, 2H, Ar). 13C NMR (75 MHz, CDCl3,
TMS): δ 18.0, 32.7, 48.8, 119.9, 124.5, 128.8, 139.4, 174.2. MS
(EI) m/z: 161 (M+, 42), 132 (3), 119 (3), 106 (100), 104 (11), 91
(5), 79 (6), 77 (28), 51 (15). HRMS (MALDI) calcd for (C10H12NO
+ H)+ 162.0913, found 162.0913.
Acknowledgment. We thank Dr. Hao-Yang Wang
and Guo-Qing Dong for mass spectrometry assistance.
We also thank the State Key Project of Basic Research
(Project 973) (No. G2000048007), Shanghai Municipal
Committee of Science and Technology, and the National
Natural Science Foundation of China for financial
support (20025206, 203900502, and 20272069).
1-Phenylpyrrolidin-2-one 3a. This compound was obtained
as a white solid. Yield: 47 mg, 97%. Mp: 64-65 °C. IR (CH2-
Cl2): ν 1120, 1226, 1301, 1396, 1459, 1500, 1597, 1684, 2930,
2986 cm-1 1H NMR (300 MHz, CDCl3, TMS): δ 2.12 (tt, J )
.
8.1 Hz, J ) 7.2 Hz, 2H, CH2), 2.58 (t, J ) 8.1 Hz, 2H, CH2), 3.82
(t, J ) 7.2 Hz, 2H, CH2), 7.10-7.15 (m, 1H, Ar), 7.32-7.38 (m,
(19) The crystal data of 3c have been deposited at the CCDC, no.
264862: empirical formula, C12H15NO3; formula weight, 221.25; crystal
size, 0.508 × 0.249 × 0.214; crystal color, habit, colorless, prismatic;
crystal system, triclinic; lattice type, primitive; lattice parameters, a
) 8.4864(11) Å, b ) 8.5841(11) Å, c ) 8.6437(12) Å, R ) 98.452(2)°, â
) 101.450(2)°, γ ) 114.134(2)°, V ) 544.40(12) Å3; space group, P-1; Z
) 8; Dcalc ) 1.350 g/cm3; F000 ) 236; R1 ) 0.0579, wR2 ) 0.1479.
Diffractometer: Rigaku AFC7R.
Supporting Information Available: The spectroscopic
data, the detailed description of experimental procedures, the
mass spectroscopy of 18O-labeled N-phenylpyrrolidin-2-one 3a,
and the X-ray crystal data of 3c.19 This material is available
free of charge via the Internet at http://pubs.acs.org.
JO0516988
8648 J. Org. Chem., Vol. 70, No. 21, 2005