New approaches to polysubstituted pyrroles and y-lactams based on nucleophilic addition of Ti(IV) enolates derived from α-diazo-β-keto carbonyl compounds to N-tosylimines

Article abstract of DOI:10.1021/jo0605039

The Ti(IV) enolates derived from α-diazo-β-keto esters or ketones efficiently add to TiCl₄-activated N-tosylimines to give δ-N-tosylamino substituted α-diazo-β-keto carbonyl compounds. The diazo decomposition of the addition products occurs und

Full text of DOI:10.1021/jo0605039

New Approaches to Polysubstituted Pyrroles and γ-Lactams Based
on Nucleophilic Addition of Ti(IV) Enolates Derived from
r-Diazo-â-keto Carbonyl Compounds to N-Tosylimines
Changqing Dong, Guisheng Deng, and Jianbo Wang*
Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry
and Molecular Engineering of Ministry of Education, College of Chemistry, Peking UniVersity,
Beijing 100871, China
wangjb@pku.edu.cn
ReceiVed March 7, 2006
The Ti(IV) enolates derived from R-diazo-â-keto esters or ketones efficiently add to TiCl4-activated
N-tosylimines to give δ-N-tosylamino substituted R-diazo-â-keto carbonyl compounds. The diazo
decomposition of the addition products occurs under Rh2(OAc)4-catalyzed or photoinduced conditions to
afford pyrrole or γ-lactam derivatives, both in high yields.
Introduction
drawbacks such as multistep synthesis, limited scope, and
inaccessible starting materials. In recent years, some novel
approaches based on transition metal catalysis have been
developed.1c,7
γ-Lactams are also widespread among natural products and
biologically active molecules and many methodologies have
been developed for their synthesis.8 The most widely applied
ways to synthesize γ-lactams include ring expansion of â-lactam
derivatives,9 formal [3+2] annulations,10 and metal carbene
intramolecular C-H insertions.11
Pyrroles and γ-lactams are two types of important heterocy-
clic compounds. Functionalized pyrroles are found in a range
of natural products and bioactive molecules.1 They have also
found applications in the field of material science.2 Conse-
quently, many synthetic methodologies have been developed
for constructing these heterocycles. The most conventional and
classic ways to prepare pyrroles include the condensation of
R-haloketones with â-keto esters in the presence of amines
(Hantzsch procedure),3,4 the reaction of 1,4-diketones and amines
(Paal-Knorr synthesis),3,5 and the condensation of R-amino
ketones with â-dicarbonyl compounds (Knorr synthesis).3,6
Although these traditional methods have proven powerful in
the synthesis of pyrrole derivatives, they generally suffer from
(4) For recent examples of Hantzsch synthesis of pyrroles, see: (a)
Kameswaran, V.; Jiang, B. Synthesis 1997, 5, 530-532. (b) Trautwein, A.
W.; Sussmuth, R. D.; Jung, G. Bioorg. Med. Chem. Lett. 1998, 8, 2381-
2384. (c) Palacios, F.; Aparicio, D.; de los Santos, J. M.; Vicario, J.
Tetrahedron 2001, 57, 1961-1972. (d) Matiychuk, V. S.; Martyak, R. L.;
Obushak, N. D.; Ostapiuk, Yu. V.; Pidlypnyi, N. I. Chem. Heterocycl.
Compd. (N.Y., NY, U.S.) 2004, 40, 1218-1219.
(1) For recent reviews on the chemistry of pyrroles, see: (a) Compre-
hensiVe Heterocyclic Chemistry; Bird, C. W., Ed.; Pergamon Press: Oxford,
UK, 1996; Vol. 2. (b) Joule, J. A.; Mills, K. In Heterocyclic Chemistry;
Blackwell Science: Oxford, UK, 2000; Chapter 13. (c) Balme, G. Angew.
Chem., Int. Ed. 2004, 43, 6238.
(2) For a review of pyrrole structure in materials, see: Electronic
Materials: The Oligomer Approach; Mu¨llen, K., Wegner, G., Eds.; Wiley-
VCH: Weinheim, Germany, 1998.
(5) For recent examples of Paal-Knorr reaction, see: (a) Minetto, G.;
Raveglia, L. F.; Sega, A.; Taddei, M. Eur. J. Org. Chem. 2005, 5277-
5288. (b) Banik, B. K.; Banik, I.; Renteria, M.; Dasgupta, S. K. Tetrahedron
Lett. 2005, 46, 2643-2645. (c) Bharadwaj, A. R.; Scheidt, K. A. Org. Lett.
2004, 6, 2465-2468. (d) Minetto, G.; Raveglia, L. F.; Taddei, M. Org.
Lett. 2004, 6, 389-392. (e) Banik, B. K.; Samajdar, S.; Banik, I. J. Org.
Chem. 2004, 69, 213-216. (f) Wang, B.; Gu, Y.; Luo, C.; Yang, T.; Yang,
L.; Suo, J. Tetrahedron Lett. 2004, 45, 3417-3419.
(3) Li, J. J. Name Reactions: A Collection of Detailed Reaction
Mechanisms; Springer-Verlag: Berlin, Germany, 2002.
(6) For an example of Knorr pyrrole synthesis, see: Alberola, A.; Ortega,
A. G.; Sadaba, M. L.; Sanudo, C. Tetrahedron 1999, 55, 6555-6566.
10.1021/jo0605039 CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/29/2006
5560
J. Org. Chem. 2006, 71, 5560-5564

Polysubstituted Pyrroles and γ-Lactams
SCHEME 1
Although the above methods provide efficient ways to con-
struct pyrrole and γ-lactam structures, it is still necessary to
develop novel and alternative methodologies so that the sub-
stitution patterns of these important hetereocyclic compounds
can be expanded. The application of R-diazocarbonyl com-
pounds to the development of novel synthetic methodologies
has been extensively pursued in our laboratory.12,13 In this paper,
we report a detailed study on the development of a new approach
to both pyrroles and γ-lactams, based on the nucleophilic addi-
tion of Ti(IV) enolates derived from R-diazo-â-keto carbonyl
compounds to N-tosylimines and the subsequent diazo decom-
position under Rh(II)-catalyzed or photoinduced conditions.14
Results and Discussions
The general reaction sequence is outlined in Scheme 1. It is
assumed that the δ-amino-R-diazocarbonyl compound 3 can be
obtained from the addition of an enolate that is derived from
â-keto-R-diazocarbonyl compound 2 to N-tosylimine 1. Rh2-
(OAc)4-catalyzed reaction of 3 gives 3-pyrrolidinone derivative
4 through intramolecular N-H insertion,15 which is further
transformed into pyrrole derivative 6. On the other hand, if the
diazo compound 3 is subjected to photolysis, Wolff rearrange-
ment will occur to generate a ketene intermediate, which may
(7) For recent examples on the pyrrole synthesis based on the transition
metal catalyzed process, see: (a) Takaya, H.; Kojima, S.; Murahashi, S.-I.
Org. Lett. 2001, 3, 421-424. (b) Kel’in, A. V.; Sromek, A. W.; Gevorgyan,
V. J. Am. Chem. Soc. 2001, 123, 2074-2075. (c) Gabriele, B.; Salerno,
G.; Fazio, A. J. Org. Chem. 2003, 68, 7853-7861. (d) Ramanathan, B.;
Keith, A. J.; Armstrong, D.; Odom, A. L. Org. Lett. 2004, 6, 2957-2960.
(e) Shen, H.-C.; Li, C.-W.; Liu, R.-S. Tetrahedron Lett. 2004, 45, 9245-
9247. (f) Wurz, R. P.; Charette, A. B. Org. Lett. 2005, 7, 2313-2316. (g)
Kamijo, S.; Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127,
9260-9266. (h) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc.
2005, 127, 11260-11261. (i) Larionov, O. V.; de Meijere, A. Angew. Chem.,
Int. Ed. 2005, 44, 5664-5667.
(8) For recent reviews on γ-lactam synthesis, see: (a) Huang, P.-Q. In
New Methods for the Asymmetric Synthesis of Nitrogen Heterocycles;
Research Signpost: Trivandrum, India, 2005, pp 197-222. (b) Smith, M.
B. In Science of Synthesis; Weinreb, S., Ed; Georg Thieme Verlag: Stuttgart,
Germany, 2005; Vol. 21, pp 647-711.
(9) Recent examples of the synthesis of γ-lactams by ring expansions,
see: (a) Banfi, L.; Guanti, G.; Rasparini, M. Eur. J. Org. Chem. 2003,
1319-1336. (b) Alcaide, B.; Almendros, P.; Alonso, J. M. J. Org. Chem.
2004, 69, 993-996. (c) Park, J.-H.; Ha, J.-R.; Oh, S.-J.,; Kim, J.-A.; Shin,
D.-S.; Won, T.-J.; Lam, Y.-F.; Ahn, C. Tetrahedron Lett. 2005, 46, 1755-
1757. (d) Alcaide, B.; Almendros, P.; Cabrero, G.; Ruiz, M. P. Org. Lett.
2005, 7, 3981-3984.
(10) For examples of [3+2] annulations in γ-lactam synthesis, see: (a)
Roberson, C. W.; Woerpel, K. A. J. Org. Chem. 1999, 64, 1434-1435. (b)
Sun, P.-P.; Chang, M.-Y.; Chiang, M. Y.; Chang, N.-C. Org. Lett. 2003, 5,
1761-1763.
be attacked by the internal nucleophile to afford γ-lactam
derivative 7.16
The aldol condensation of R-diazo-â-ketoesters with alde-
hydes was reported by Calter and co-workers by using TiCl4/
Et3N.17,18 However, these conditions have not been applied to
Mannich-type reaction with imines. Very recently, Doyle and
co-workers reported their work on nucleophilic attack of silyl
enol ethers derived from R-diazo-â-ketoesters to aldehydes and
imines employing the Mukaiyama strategy.19 We have adopted
the TiCl4/Et3N system and expanded it to Mannich-type
reactions with N-tosylimines.
The initial investigation of the reaction of N-tosylimine with
the Ti(IV) enolate 8, derived from R-diazo-â-ketoester by
treating the diazo ester with TiCl4/Et3N at -78 °C in CH2Cl2,
failed to afford the expected product. This is presumably due
to the fact that N-tosylimines are not as reactive as aldehydes
toward the Ti(IV) enolate. To further increase the electrophilicity
of the CdN bond, N-tosylimine was activated by a second
equivalent of TiCl4 before reacting with the Ti(IV) enolate. With
use of this protocol, the expected condensation product 3 was
obtained in moderate yield (Scheme 2 and Table 1, entry 1).
During the optimization of the reaction condition, it was
observed that the starting materials 1 and 2 were not completely
(11) For the recent examples of γ-lactam synthesis by metal carbene
intramolecular C-H insertions, see: (a) Yoon, C. H.; Zaworotko, M. J.;
Moulton, B.; Jung, K. W. Org. Lett. 2001, 3, 3539-3542. (b) Wee, A. G.
H.; Duncan, S. C. Tetrahedron Lett. 2002, 43, 6173-6179. (c) Yoon, C.
H.; Nagle, A.; Chen, C.; Gandhi, D.; Jung, K. W. Org. Lett. 2003, 5, 2259-
2262. (d) Choi, M. K.-W.; Yu, W.-Y.; Che, C.-M. Org. Lett. 2005, 7, 1081-
1084. (e) Wee, A. G. H.; Duncan, S. C.; Fan, G.-j. Tetrahedron: Asymmetry
2006, 17, 297-307.
(12) For comprehensive reviews on the chemistry of R-diazocarbonyl
compounds, see: (a) Ye, T.; McKervey, M. A. Chem. ReV. 1994, 94, 1091-
1160. (b) Doyle, M. P.; McKervey, M. A.; Ye, T. In Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; Wiley-Inter-
science: New York, 1998.
(13) For an account, see: Zhao, Y.; Wang, J. Synlett 2005, 2886-2892.
(14) Part of this investigation has been reported in a communication,
see: Deng, G.; Jiang, N.; Ma, Z.; Wang, J. Synlett 2002, 1913-1915.
(15) For intramolecular N-H bond insertion in the synthesis of 3-pyr-
rolidinone derivatives, see: (a) Moyer, M. P.; Feldman, P. L.; Rapoport,
H. J. Org. Chem. 1985, 50, 5223-5230. (b) Wang, J.; Hou, Y.; Wu, P. J.
Chem. Soc., Perkin Trans. 1 1999, 2277-2280. (c) Davis, F. A.; Fang, T.;
Goswami, R. Org. Lett. 2002, 4, 1599-1602.
(16) (a) Wang, J.; Hou, Y. J. Chem. Soc., Perkin Trans. 1 1998, 1919-
1924. (b) Wang, J.; Hou, Y.; Wu, P.; Qu, Z.; Chan, A. S. C. Tetrahedron:
Asymmetry 1999, 10, 4553-4561. (c) Lee, D. J.; Kim, K.; Park, Y. J. Org.
Lett. 2002, 4, 873-876. (d) For a recent review on Wolff rearrangement,
see: (e) Kirmse, W. Eur. J. Org. Chem. 2002, 2193-2256.
(17) (a) Calter, M. A.; Sugathapala, P. M.; Zhu, C. Tetrahedron Lett.
1997, 38, 3837-3840. (b) Calter, M. A.; Sugathapala, P. M. Tetrahedron
Lett. 1998, 39, 8813-8816. (c) Calter, M. A.; Zhu, C. J. Org. Chem. 1999,
64, 1415-1419.
(18) We have extended the reaction of Ti(IV) enolate 8 with ketones,
see: Deng, G.; Tian, X.; Wang, J. Tetrahedron Lett. 2003, 44, 587-590.
(19) Doyle, M. P.; Kundu, K.; Russell, A. E. Org. Lett. 2005, 7, 3131-
3134.
J. Org. Chem, Vol. 71, No. 15, 2006 5561

Dong et al.
TABLE 1. TiCl4-Promoted Condensation of Diazo Compounds
2a-c with Aromatic N-Tosylimine 1
TABLE 2. TiCl4-Promoted Condensation of 2a, 2d, and 2e with
Aromatic or Aliphatic N-Tosylimine 1
diazo
substrate 2
product
yield
(%)a
entry
imine 1
a, C6H5
a, C6H5
b, o-MeC6H4
c, p-FC6H4
d, p-ClC6H4
e, m-CNC6H4
f, p-MeOC6H4
g, p-Me2NC6H4
h, (E)-CHdCHC6H4
i, 2-furyl
a, C6H5
i, 2-furyl
h, (E)-CHdCHC6H4
a, C6H5
f, p-MeOC6H4
j, m-BrC6H4
3
1
2
3
4
5
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2c
2c
2c
a
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
62b
93c
84
79
86
87
94
0
85
96
97
76
79
72
85
80
6
7
8
9
diazo
substrate 2
product
yielda
(%)
entry
imine 1
a, C6H5
f, p-MeOC6H4
a, C6H5
b, o-MeOC6H4
d, p-ClC6H4
k, i-Bu
3
drb
10
11
12
13
14
15
16
1
2
3
4
5
6
7
2d
2d
2e
2e
2e
2a
2a
p
q
r
s
t
u
v
90
97
94
92
94
55
56
88:12
89:11
53:47
64:36
76:24
l, n-hexyl
a Isolated yield after silica gel chromatography. b The reaction was not
carried out under optimized reaction conditions. c The reaction was carried
out under optimized conditions.
a Refer to the combined isolated yield for the diastereomeric isomers.
The diastereoisomers could be separated by flash column chromatography
in the cases of entries 3, 4, and 5. b Diastereomeric ratios were determined
1
by H NMR.
SCHEME 2
SCHEME 3
CH2Cl2 at room temperature in the presence of 1 mol % of Rh2-
(OAc)4. However, when it was refluxed in benzene with Rh2-
(OAc)4, the diazo compound disappeared within 10 min, leading
to clean formation of a new compound. Spectroscopic data of
the isolated product confirmed its structure as pyrrole 6a
(Scheme 3). The pyrrolidine derivative 4, which was expected
to form through intramolecular N-H insertion of the Rh(II)-
carbene intermediate, was not observed in this reaction. Other
diazo compounds all gave similar results to afford the corre-
sponding pyrrole derivatives in moderate to good yields when
reacted with catalytic Rh2(OAc)4 under the same conditions.
The results are summarized in Table 3.
As shown in Table 3, all of the diazo substrates investigated
could be decomposed efficiently to produce the corresponding
pyrrole derivatives in moderate to good yields. When diazo
substrate 3v (R1 ) hexyl) was reacted under the same reaction
condition, intramolecular 1,5 C-H insertion product could be
detected together with the corresponding pyrrole derivative 6j
(Table 3, entry 14).
Although the chemistry of R-diazocarbonyl compounds has
been extensively investigated, the formation of pyrrole deriva-
tives from Rh2(OAc)4-mediated reaction is unprecedented. A
mechanistic rationale for this reaction is given in Scheme 4.
Rh(II) carbene is generated upon the treatment of 3a with
catalytic Rh2(OAc)4.21 Intramolecular N-H insertion occurs
from Rh(II) carbene to give 9, from which p-toluenesulfinic
acid is eliminated to give intermediate 10. A 1,5-H shift in 10
then affords 6a. Under the reaction conditions, the p-toluene-
sulfinic acids eliminated from 9 condense with each other by
consumed, even though TiCl4 was used in excess. On the basis
of a recent report by Mikami and co-workers,20 we speculated
that the Ti(IV) enolate might not be formed efficiently at -78
°C. Thus, at 0 °C, TiCl4 (1.1 equiv) and the diazocarbonyl
compound were mixed in CH2Cl2 to promote more efficient
complexation. The mixture was then cooled to -78 °C and Et3N
was added, followed by the addition of a solution of N-
tosylimine/TiCl4 in CH2Cl2. Under these modified conditions,
product 3a was obtained in excellent yield (Table 1, entry 2).
As shown in Table 1, the substituent group on the phenyl
ring had little influence on the reaction. Electron-donating and
electron-withdrawing groups gave similar results. Most of the
N-tosylimines gave good yields except for 1g derived from
4-(N,N-dimethyl)aminobenzaldehyde, which gave none of the
desired product. This likely results from complexation of the
dimethylamino substituent with TiCl4.
As shown in Table 2, the same condensation reaction occurred
with the diazo compounds 2d and 2e as substrates. However,
the diastereomeric ratios were only moderate (Table 2, entries
1-5). When aliphatic aldimines were employed, the yields
decreased considerably, presumably due to the instability of the
imines under the reaction conditions (Table 2, entries 6 and 7).
Nevertheless, the yields were still acceptable and could be
applied to prepare nitrogen-containing heterocyclic compounds
(vide infra).
With the δ-(N-tosyl)amino-â-oxo-R-diazo ester or ketones
3a-v in hand, we proceeded to study their catalytic decomposi-
tion reaction under Rh2(OAc)4. The reactivity of 3a was first
investigated. The decomposition of 3a occurred very slowly in
(21) For a mechanistic investigation on Rh(II) complex mediated diazo
decomposition, see: Qu, Z.; Shi, W.; Wang, J. J. Org. Chem. 2001, 66,
8139-8144 and references therein.
(20) Itoh, Y.; Yamanaka, M.; Mikami, K. J. Am. Chem. Soc. 2004, 126,
13174-13175.
5562 J. Org. Chem., Vol. 71, No. 15, 2006

Polysubstituted Pyrroles and γ-Lactams
TABLE 3. Rh2(OAc)4-Mediated Reaction of 3
TABLE 4. Irradiation of Diazo Compounds 3 in Benzene
product 6
substrate
yield
(%)a
entry
3
R1
R2
R3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
a
b
e
h
i
k
l
n
p
q
s
a, C6H5
H
H
H
H
H
H
H
H
Me
Me
Ph
Ph
H
OEt
OEt
OEt
OEt
OEt
Ph
75
73
64
75
91
88
94
90
87
85
74b
78b
73
51c
b, o-MeC6H4
c, m-CNC6H4
d, (E)-CHdCHC6H4
e, 2-furyl
product 7
f, 2-furyl
substrate
yield
(%)a
g, (E)-CHdCHC6H4
h, p-MeOC6H4
i, C6H5
j, p-MeOC6H4
k, o-MeC6H4
l, p-ClC6H4
Ph
Me
entry
3
R1
R2
R3
drb
OEt
OEt
OEt
OEt
OEt
OEt
1
2
3
4
5
6
7
8
9
10
11
12
13
a
b
d
e
i
a, C6H5
H
H
H
H
H
H
H
OEt
OEt
OEt
OEt
OEt
Ph
83
89
71
74
75
c
63:37
84:16
68:32
61:39
92:8
b, o-MeC6H4
c, p-ClC6H4
d, m-CNC6H4
e, 2-Furyl
f, (E)-CHdCHC6H4
g, p-MeOC6H4
h, C6H5
i, p-MeOC6H4
j, o-MeC6H4
k, p-ClC6H4
l, i-Bu
t
u
v
m, i-Bu
n, n-hexyl
H
l
n
p
q
s
t
u
v
Me
a Isolated yield after silica gel chromatography. b The reaction was carried
out in refluxing toluene. c The 1,5 intramolecular C-H insertion product
was isolated in 30% yield.
Me OEt
Me OEt
Ph OEt
Ph OEt
H
H
75
75
73
74
62
71
68:19:13d
68:19:13
53:36:11
63:22:15
66:34
OEt
OEt
SCHEME 4
m, n-hexyl
67:33
a Isolated yield after silica gel separation. b The product ratio was
determined by crude 1H NMR. c The reaction afforded a complex mixture.
d Only three diastereoisomers could be detected by 1H NMR. It was noted
that one of the minor diastereoisomers could form from the major
diastereoisomer during silica gel chromatography.
that pyrrole 15 was not formed directly from N-Boc substrate
12 by carrying out the reaction with only trifluoroacetic acid.
This experiment indicates that TolSO2H is easily eliminated
from 9 or 14, thus supporting the proposed mechanism.
Next, the diazo compounds 3a-v were irradiated, with the
expectation that Wolff rearrangement would occur. On the basis
of the previous investigation,16a-c the ketene intermediate should
be formed and followed by an intramolecular nucleophilic attack
to provide a γ-lactam.
SCHEME 5
Diazo compound 3a was first irradiated in benzene with a
high-pressure Hg lamp (λ > 300 nm). Diazo decomposition
occurs smoothly within 30 min to afford the expected γ-lactam
derivative 7a in 83% isolated yield with a diastereomeric ratio
of 63:37 (Table 4, entry 1). It was noted that silica gel
chromatography promoted equilibration of the diastereomeric
mixture.
The scope of this Wolff rearrangement/annulation process is
summarized in Table 4. The irradiation gave moderate to good
yields with diazo ester substrates. However, when diazo ketone
substrates 3l and 3n were subjected to irradiation, the reactions
gave complex mixtures. Obviously, this is due to the existence
of competitive migration of the two substituents that are
connected to the two carbonyl carbons in those cases. For diazo
substrates 3p-t, the diastereomeric mixture was irradiated.
The stereochemistry of 7j was investigated by NOE experi-
ments (Scheme 6). The major isomer of 7j was determined as
trans,trans-7j, while one of the minor products is trans,cis-7j.
For trans,trans-7j, irradiation of the signal for Ha led to en-
hancements of 4.0%, 1.0%, and 1.1% for Hd, Hb, and Hc, respec-
tively. Irradiation of the signal for Hc led to enhancement of
5.1%, and 1.0% for Hd and Ha. Similarly, for trans,cis -7j, ir-
radiation of the signal for Ha, a 5.5% enhancement was observed
for Hb, and no enhancement was observed for Hc. Irradiation
of signal for Hc gave signal enhancement of 7.7% and 0% for
Hd and Ha. With these data, it could be concluded that in the
removal of H2O, forming thiosulfonic ester 11 that is isolated
and characterized.22
To gain insights into the reaction mechanism, independent
preparation of 14 from 1215c was attempted by the reaction
shown in Scheme 5. Compound 14 was not obtained, however,
and the N-tosyl pyrrole derivative 13 was isolated as the main
product. The formation of 13 most likely occurred through the
tosylation of 15, which is formed by base-promoted elimination
of TolSO2H from the intermediate 14. We confirmed that 6a
could be readily tosylated with TsCl/Et3N to give the corre-
sponding tosylated pyrrole derivative. We have also confirmed
(22) (a) Noguchi, Y.; Kurogi, K.; Sekioka, M.; Furukawa, M. Bull. Chem.
Soc. Jpn. 1983, 56, 349-350. (b) Sas, W. J. Chem. Res. Synop. 1993, 160-
161.
J. Org. Chem, Vol. 71, No. 15, 2006 5563

Dong et al.
SCHEME 6
Experimental Section
Caution: Diazo compounds are generally toxic and potentially
explosive. They should be handled with care in a well-ventilated
fume hood.
General Procedure for the TiCl4-Promoted Condensation of
R-Diazo-â-keto Ketone or Ester 2 with N-Tosylimine 1. To a
solution of 2 (3 mmol) in dichloromethane (15 mL) was added
titanium tetrachloride (360 µL, 3.3 mmol) at 0 °C and the system
was stirred for 10 min under nitrogen atmosphere. Then the mixture
was cooled to -78 °C and triethylamine (460 µL, 3.3 mmol) was
added. The solution was stirred for 15 min and then a solution of
N-tosylimine 1 (1.23 mmol) and another portion of titanium
tetrachloride (360 µL, 3.3 mmol) in CH2Cl2 (5 mL) were added.
After stirring for 2-5 h at -78 °C, the reaction was quenched with
saturated aqueous NH4Cl and then allowed to warm to room
temperature. The organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (2 × 15 mL). Then the organic layers
were combined, washed with saturated aqueous NaHCO3, and dried
over Na2SO4. The crude product was purified by flash silica gel
column chromatography to yield the addition products 3a-v.
General Procedure for Catalytic Decomposition of Diazo
Compound 3 with Rh2(OAc)4. A solution of 3 (1 mmol) in
benzene (20 mL) was heated to reflux and Rh2(OAc)4 (0.01 mmol)
was added. The solution was refluxed for 10 min and was then
concentrated under reduced pressure to afford a crude product,
which was purified by flash column chromatography with silica
gel to yield pyrrole 6.
General Procedure for the Irradiation of the Diazo Com-
pound 3. A solution of 3 (1 mmol) in benzene (25 mL) in a Pyrex
tube was irradiated with a 300-W Hg lamp for 30 min. The reaction
temperature was between room temperature and the boiling point
of the solvent. The solution was cooled to room temperature and
concentrated under reduced pressure to give the crude product,
which was purified by flash silica gel column chromatography to
yield the diastereomeric mixture of the corresponding γ-lactam
derivative 7. The diastereomeric mixture could not be purified by
column chromatography because of the isomerization of the mixture
on silica gel.
major product of 7j the phenyl group at the 4-position is trans
to the o-methylphenyl at the 5-position and the carboethoxyl
group at the 3-position. In one of the minor products of 7j, the
phenyl group at the 4-position is cis to the o-methylphenyl at
the 5-position and trans to the carboethoxyl group at the
3-position. From the stereochemistry of the major product of
7j, we can deduce the major isomer of 3s has anti configuration.
Conclusion
In summary, the nucleophilic addition of Ti(IV) enolate of
R-diazo-â-ketoester or R-diazo-â-ketoketone to aromatic and
aliphatic N-tosylaldimines has been successfully achieved to give
δ-N-tosylamino-substituted â-keto diazocarbonyl compounds in
good yields. The diazo decompositions of the addition products
by Rh2(OAc)4 or under irradiation were investigated. Pyrrole
and γ-lactam derivatives were obtained in good to excellent
yields, respectively. The two-step methods provide a new and
convenient way to prepare these two classes of important
heterocyclic compounds.
Acknowledgment. The project is generously supported by
Natural Science Foundation of China (Grant Nos. 20572002,
20521202, 20225205, and 20390050) and the Ministry of
Education of China (Cheung Kong Scholars Program).
Supporting Information Available: Characterization data and
1H and 13C NMR for 7i, 7k, and 7m. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO0605039
5564 J. Org. Chem., Vol. 71, No. 15, 2006