Synthesis of 2-alkylidenepyrrolidines, pyrroles, and indoles by condensation of silyl enol ethers and 1,3-bis-silyl enol ethers with 1-azido-2,2-dimethoxyethane and subsequent reductive cyclization

Article abstract of DOI:10.1021/jo047856x

The condensation of 1,3-bis-silyl enol ethers with 1-azido-2,2- dimethoxyethane and subsequent reductive cyclization allowed an efficient regio- and diastereoselective synthesis of a variety of 2-alkylidene-4- methoxypyrrolidines. The thermal elimination of methanol resulted in the formation of functionalized pyrroles. Similarly, 2,3,3a,4,5,6-hexahydro-2,3- benzopyrroles were prepared and transformed into 4,5,6,7-tetrahydro-2,3- benzopyrroles. In contrast, treatment of 2-alkylidenepyrrolidines with trifluoroacetic acid resulted in formation of indoles by [4 + 2] cycloaddition and subsequent extrusion of a nitrogen atom.

Full text of DOI:10.1021/jo047856x

Synthesis of 2-Alkylidenepyrrolidines, Pyrroles, and Indoles by
Condensation of Silyl Enol Ethers and 1,3-Bis-Silyl Enol Ethers
with 1-Azido-2,2-dimethoxyethane and Subsequent Reductive
Cyclization
Esen Bellur,†,‡ Helmar Go¨rls,§ and Peter Langer*,†
Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18051 Rostock, Germany, and Institut
fu¨r Chemie und Biochemie, Universita¨t Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany, and
Institut fu¨r Anorganische und Analytische Chemie, Universita¨t Jena, August-Bebel-Str. 2,
07740 Jena, Germany
peter.langer@uni-rostock.de
Received December 3, 2004
The condensation of 1,3-bis-silyl enol ethers with 1-azido-2,2-dimethoxyethane and subsequent
reductive cyclization allowed an efficient regio- and diastereoselective synthesis of a variety of
2-alkylidene-4-methoxypyrrolidines. The thermal elimination of methanol resulted in the formation
of functionalized pyrroles. Similarly, 2,3,3a,4,5,6-hexahydro-2,3-benzopyrroles were prepared and
transformed into 4,5,6,7-tetrahydro-2,3-benzopyrroles. In contrast, treatment of 2-alkylidenepyr-
rolidines with trifluoroacetic acid resulted in formation of indoles by [4 + 2] cycloaddition and
subsequent extrusion of a nitrogen atom.
Functionalized 2-alkylidenepyrrolidines represent ver-
satile intermediates for the synthesis of pyrrolidines and
fused heterocycles.1,2 Numerous applications in the syn-
thesis of natural products have been reported. For
example, an efficient synthesis of mitomycin antitumor
antibiotics relies on the cyclization of 2-alkylidenepyrro-
lidines attached to bromo-substituted quinones.3a,b Other
synthetic applications include, for example, the synthesis
of microsclerodermin E, carbapenam-3-carboxylic acid,
the bridged pyrrolizidine core of asparagamine or camp-
tothecin analogues.3 2-Alkylidenepyrrolidines represent
direct precursors for the stereoselective synthesis of
pyrrolidine substructures4 by reduction3f of the exocyclic
double bond. Pyrrolidines are present in a variety of
alkaloids, such as hygrine, hygroline, or cuskhygrin, and
in non-natural products used in the clinic (e.g., the
vasodilator buflomedil).4
Synthetic approaches to 2-alkylidenepyrrolidines (exo-
cyclic enamino esters) mainly rely on the use of N-
(3) (a) Luly, J. R.; Rapoport, H., J. Am. Chem. Soc. 1983, 105, 2859.
(b) Rebek, J., Jr.; Shaber, S. H.; Shue, Y.-K.; Gehret, J.-C.; Zimmerman,
S., J. Org. Chem. 1984, 49, 5164. (c) Shen, W.; Coburn, C. A.;
Bornmann, W. G.; Danishefsky, S. J., J. Org. Chem. 1993, 58, 611.
Microsclerodermin E: (d) Zhu, J.; Ma, D. Angew. Chem., Int. Ed. 2003,
42, 5348. Bridged pyrrolizidine core of asparagamine: (e) Epperson,
M. T.; Gin, D. Y. Angew. Chem., Int. Ed. 2002, 41, 1778. Carbapenam-
3-carboxylic acid: (f) Stapon, A.; Li, R.; Townsend, C. A. J. Am. Chem.
Soc. 2003, 125, 15746. (g) Danishefsky, S.; Etheredge, S. J. J. Org.
Chem. 1974, 39, 3430. (h) Paulvannan, K.; Stille, J. R. J. Org. Chem.
1994, 59, 1613. (i) Saliou, C.; Fleurant, A.; Celerier, J. P.; Lhommet,
G. Tetrahedron Lett. 1991, 32, 3365.
† Universita¨t Rostock.
‡ Universita¨t Greifswald.
§ Universita¨t Jena.
(1) For reviews, see: (a) Lue, P.; Greenhill, J. V. Enaminones in
Heterocyclic Synthesis. Adv. Heterocycl. Chem. 1997, 67, 209. (b)
Granik, V. G.; Makarov, V. A. Enamines as Synthons in the Synthesis
of Heterocycles. Adv. Heterocycl. Chem. 1999, 72, 283. (c) Sardina, F.
J.; Rapoport, H. Chem. Rev. 1996, 96, 1825 and references therein.
(2) For example, see: (a) Folmer, J. J.; Acero, C.; Thai, D. L.;
Rapoport, H., J. Org. Chem. 1998, 63, 8170. (b) Benovsky, P.;
Stephenson, G. A.; Still, J. R., J. Am. Chem. Soc. 1998, 120, 2493. (c)
Wang, M.-X.; Miao, W. S.; Cheng, Y.; Huang, Z. T., Tetrahedron 1999,
55, 14611.
(4) (a) Ro¨mpp Lexikon Naturstoffe; Steglich, W., Fugmann, B., Lang-
Fugmann, S., Eds.; Thieme: Stuttgart: 1997. (b) Lewis, J. R. Nat. Prod.
Rep. 2001, 18, 95. (c) O’Hagen, D. Nat. Prod. Rep. 2000, 17, 435.
10.1021/jo047856x CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/12/2005
J. Org. Chem. 2005, 70, 4751-4761
4751

Bellur et al.
heterocycles as starting materials. For example, the
Eschenmoser method relies on the condensation of thio-
lactams with bromomethyl ketones or esters, followed by
extrusion of sulfur.5 Other syntheses include, for ex-
ample, the reaction of lactim ethers with active methyl-
ene compounds,6 the reaction of lactams or thiolactams
with organometallic reagents7 or the reaction of methyl
bromoacetate with ω-mesylnitriles.8 Synthetic methods,
which include the formation of the N-heterocyclic moiety,
are more rare. For example, 2-alkylidenepyrrolidines
have been prepared by reaction of 1,3-dicarbonyl dianions
with 1-bromo-2-chloroethane, nucleophilic substitution of
the chloride by sodium azide and subsequent aza-Wittig
reaction of the ω-azido-â-ketoester thus formed.9 2-Alkyl-
idenepyrrolidines are available also by reaction of 1,3-
dicarbonyl dianions with aziridines10 and by ring trans-
formations of lactones.11
and in a number of pharmaceuticals (e.g., the analgetic
zomepirac).19
Results and Discussion
The TiCl4-mediated condensation of simple silyl enol
ethers with R-azidoketals has been reported.16 However,
the TiCl4-mediated reaction of 1-azido-2,2-dimethoxy-
ethane (2)16 with 1,3-bis-silyl enol ether 1a resulted in
formation of a complex mixture, due to oxidative self-
condensation of 1a and decomposition. Based on our
previous studies related to the reaction of 1,3-bis-silyl
enol ethers with 1-chloro-2,2-dimethoxyethane, we turned
to the use of the milder Lewis acid trimethylsilyltrifluo-
romethylsulfonate (Me3SiOTf).20,21 The Me3SiOTf-medi-
ated reaction of 1a with 2 afforded the desired conden-
sation product 3a with good regio- and chemoselectivity
(Scheme 1).
Recently, we have reported12 the synthesis of 2-alkyl-
idenepyrrolidines by condensation of 1,3-dicarbonyl di-
anions with R-azidoketones, cyclization by Staudinger-
aza-Wittig reaction,13 and subsequent acid-mediated
transformation of the products into functionalized pyr-
roles. Unfortunately, the preparative scope of this ap-
proach is limited to the use of R-azidoketones; the reaction
of dianions with R-azidoaldehydes resulted in the forma-
tion of complex mixtures. Herein, we report a solution of
this problem based on what are, to the best of our
knowledge, the first cyclocondensations of 1,3-bis-silyl
enol ethersselectroneutral 1,3-dicarbonyl dianion equiv-
alents14,15swith 1-azido-2,2-dimethoxyethane. These re-
actions allow a convenient synthesis of functionalized
pyrrolidines and pyrroles which are not available from
1,3-dicarbonyl dianions12 and from simple silyl enol
ethers.16 All products are formed with very good regiose-
lectivity. In contrast, the preparative scope of the classic
Knorr or Hantzsch procedures17 is often limited by the
formation of regioisomers. In addition, the preparation
of alkyl-substituted derivatives can be problematic. Pyr-
roles17,18 occur in a variety of natural products, such as
the tetrapyrrol pigments bilirubin and porphobilinogen,
Treatment of a THF solution of 3a with PPh3 resulted
in clean formation of the 2-alkylidenepyrrolidine 4a
(Scheme 1). The formation of 4a proceeds by a domino
Staudinger-aza-Wittig reaction and subsequent migra-
tion of the double bond into the exocyclic position. The
double bond of 4a was formed with good Z-selectivity,
due to the formation of an intramolecular hydrogen bond
N-H‚‚‚O. The transformation of 4a into the pyrrole 5a
was studied next. Treatment of a CH2Cl2 solution of 4a
with trifluoroacetic acid (TFA) resulted in formation of
a complex mixture (Scheme 2, Table 2). The problem
could be solved by reflux of a 1,4-dioxane solution of 4a
for 24 h to give the desired pyrrole 5a. The product was
formed by thermal extrusion of methanol and aromati-
zation by migration of the exocyclic double bond.
To study the preparative scope of the new methodology,
the substituents of the 1,3-bis-silyl enol ethers were
systematically varied (Scheme 1, Table 1). The reaction
of ester-derived dienes 1a-d with 1-azido-2,2-dimethoxy-
ethane (2) gave the open-chained azides 3a-d which
were transformed into the Z-configured 2-alkylidenepyr-
rolidines 4a-d. Reflux of a 1,4-dioxane solution of 4a-d
gave the pyrroles 5a-d in good yields. The reaction of 2
with 1,3-bis-silyl enol ether 1e, prepared from benzoyl-
acetone, gave 3e which was transformed into the Z-
configured 2-alkylidenepyrrolidine 4e. Reflux of a 1,4-
dioxane solution of 4e afforded the pyrrole 5e in good
yield.
(5) Roth, M.; Dubs, P.; Go¨tschi, E.; Eschenmoser, A. Helv. Chim.
Acta 1971, 36, 710;
(6) Celerier, J.-P.; Deloisy, E.; Lhommet, G.; Maitte, P. J. Org. Chem.
1979, 44, 3089.
(7) (a) Lee, H. K.; Kim, J.; Pak, C. S. Tetrahedron Lett. 1999, 40,
2173. (b) Yamaguchi, M.; Hirao, I. J. Org. Chem. 1985, 50, 1975.
(8) Hannick, S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833.
(9) Lambert, P. H.; Vaultier, M.; Carrie, R. J. Org. Chem. 1985, 50,
5352.
The reaction of 2 with 1f-o, containing a substituent
at the terminal carbon atom, gave the corresponding
open-chained products 3f-o. Treatment of 3f-o with
(10) Lygo, B. Synlett 1993, 765.
(11) Wang, M.-X.; Liu, Y.; Gao, H.-Y.; Zhang, Y.; Yu, C.-Y.; Huang,
Z.-T.; Fleet, G. W. J. J. Org. Chem. 2003, 68, 3281.
(12) Langer, P.; Freifeld, I. Chem. Commun. 2002, 2668.
(13) Montforts, F.-P.; Schwartz, U. M.; Mai, G., Liebigs Ann. Chem.
1990, 1037 and references therein.
(14) (a) Chan, T.-H.; Brownbridge, P. J. Chem. Soc., Chem. Commun.
1979, 578. (b) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980,
102, 3534. (c) Molander, G. A.; Cameron, K. O., J. Am. Chem. Soc.
1993, 115, 830. (d) Molander, G. A.; Jeffrey, S. C. Tetrahedron Lett.
2002, 43, 359.
(15) For a review of 1,3-bis-silyl enol ethers, see: Langer, P.
Synthesis 2002, 441.
(16) Bertschy, H.; Meunier, A.; Neier, R., Angew. Chem. 1990, 102,
828; Angew. Chem., Int. Ed. Engl. 1990, 29, 777.
(17) (a) Eicher, T.; Hauptmann, S. Chemie der Heterocyclen; Thieme
Verlag: Stuttgart, 1994; p 94. (b) Sundberg, R. J. In Comprehensive
Heterocyclic Chemistry; Bird, C. W., Cheeseman, G. W. H., Eds.;
Pergamon Press: Oxford, 1984; Vol. 4, p 331. (c) Alberala, A.; Ortega,
A. G.; Sa´daba, M. L.; Snudo, C. Tetrahedron 1999, 55, 6555.
(18) For other syntheses, see, for example: (a) Huisgen, R. Angew.
Chem., Int. Ed. Engl. 1967, 2, 565. (b) Huisgen, R.; Gotthard, H.; Bayer,
H. O.; Scha¨fer, F. C. Chem. Ber. 1970, 103, 2611. (c) Chiu, P.-K.; Lui,
K.-H.; Maini, P. N.; Sammes, M. P., J. Chem. Soc., Chem. Commun.
1987, 109. (d) Barton, D. H. R.; Kervagoret, J.; Zard, S. Z. Tetrahedron
1990, 46, 7587.
(19) (a) Falk, H. The Chemistry of Linear Oligopyrroles and Bile
Pigments; Springer-Verlag: Wien, 1989; p 355. (b) Montforts, F.-P.;
Schwartz, U. M. Angew. Chem. 1985, 97, 767; Angew. Chem., Int. Ed.
Engl. 1985, 24, 775. (c) Dutton, C. J.; Fookes, C. J. R.; Battersby, A.
R. J. Chem. Soc., Chem. Commun. 1983, 1237. (d) Stork, G.; Nakahara,
Y.; Nakahara, Y.; Greenlee, W. J., J. Am. Chem. Soc. 1978, 100, 7775.
(e) Stork, G.; Nakamura, E., J. Am. Chem. Soc. 1983, 105, 5510.
(20) Langer, P.; Krummel, T. Chem. Eur. J. 2001, 7, 1720.
(21) For the use of Me3SiOTf in the reaction of simple silyl enol
ethers with monofunctional acetals, see: (a) Murata, S.; Suzuki, M.;
Noyori, R. J. Am. Chem. Soc. 1979, 101, 2738. (b) Murata, S.; Suzuki,
M.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 3248.
4752 J. Org. Chem., Vol. 70, No. 12, 2005

Synthesis of 2-Alkylidenepyrrolidines, Pyrroles, and Indoles
TABLE 1. Derivatives and Yields of Condensation Products 3 and Pyrrolidines 4 by Staudinger-aza-Wittig Reaction
and Pyrroles 5 by Thermal Extrusion of Methanol
3, 4, 5
R1
R2
3a (%)
4a (%)
5a (%)
δb (ppm)
δc (ppm)
trans/cisd
a
b
c
d
e
f
OMe
OEt
H
48
51
47
44
95
76
87
63
81
76
100
100
98
4.55
4.55
4.53
4.61
5.82
4.53
4.53
4.74
4.76
4.56
4.53
4.53
4.53
4.53
4.53
4.53
170.5
170.3
169.9
170.2
188.2
171.1
170.5
170.3
170.3
171.0
170.8
170.8
170.6
170.7
170.8
170.7
H
64
OiPr
H
74
O(CH2)2OMe
Ph
H
74
H
84
82
OMe
Me
Et
OMe
95
100
100
100
100
e
100
100
100
e
93
91
>98:2
<2:98
>98:2
<2:98
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
g
h
OEt
79
OMe
66 (trans)
20 (cis)
94
i
j
k
l
m
n
o
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Allyl
nPr
nBu
nHex
nOct
nNon
nDec
60
82
83
86
82
80
92
86
93
98
86
81
83
a Yields of isolated products. For all compounds 4a-o: Z/E > 98:2 (configuration of the exocyclic double bond). b Chemical shift (1H
NMR, CDCl3) of the hydrogen atom of the exocyclic double bond of 4. c Chemical shift (13C NMR, CDCl3) of the carbonyl group of 4.
d Diastereomeric ratio (trans/cis) of 4f-o. e Experiment (reflux, 1,4-dioxane or CH2Cl2) was not carried out.
SCHEME 1. Synthesis of 4a-o and 5a-oa
TABLE 2. Reaction of Pyrrolidines 4 with TFA:
Derivatives and Yields of Pyrroles 5, Friedel-Crafts
Acylation Products 6, and Indoles 7
5, 6, 7
R1
5 (%)
6 (%)
7 (%)
a
b
c
d
e
OMe
OEt
32b
8b
38a
0
49a
54a
91a
45a
0
0
OiPr
0
19
0
O(CH2)2OMe
Ph
17b
54a
a Yields of isolated products. b Calculated yields based on 1H
NMR integration of a mixture of 5 and 6.
SCHEME 3. Possible Mechanism for the
Formation of 7a-e
a Key: (i) 0.5 equiv of TMSOTf, CH2Cl2, -78 f +20 °C; (ii) PPh3,
6 h, THF, 45 °C; (iii) reflux in 1,4-dioxane or CH2Cl2, 24 h.
SCHEME 2. Synthesis of 5a-e, 6a-e, and 7a-ea
dimethoxy-2-alkylidenepyrrolidines trans-4h and cis-4h
in 66% and 20% yield, respectively. The 2-alkylidenepyr-
rolidines 4f-h,j-l,n,o were transformed into the sub-
stituted pyrroles 5f-h,j-l,n,o in good yields.
The configuration of the exocyclic double bond of
2-alkylidenepyrrolidines 4 was proven by NOESY experi-
ments, X-ray structures and by comparison of the chemi-
cal shifts of the hydrogen atoms of the exocyclic double
bond with those of related compounds (Table 1).9,10,12 As
expected, characteristic chemical shifts in the range of δ
) 4.53-4.76 were observed for all Z-configured ester
derived 2-alkylidenepyrrolidines. In addition, ester-
derived and Z-configured 2-alkylidenepyrrolidines gener-
ally showed a characteristic carbonyl 13C NMR resonance
a Key: (i) TFA, CH2Cl2, 20 °C, 24 h.
PPh3 afforded the Z-configured 2-alkylidenepyrrolidines
4f-o. All alkyl-substituted 2-alkylidenepyrrolidines 4f,g
and 4i-o were formed with good trans-diastereoselec-
tivity. In contrast, the reaction of 1h with 2 afforded 3h
as a mixture of syn/anti diastereomers. The PPh3-
mediated cyclization of 3h and chromatographic separa-
tion of the diastereomers afforded the Z-configured 3,4-
J. Org. Chem, Vol. 70, No. 12, 2005 4753

Bellur et al.
SCHEME 4. Synthesis of 4p and 5pa
in the range of δ ) 169.9-171.1. An independent proof
of the configuration was established by crystal structure
analyses of 4e, 4f, and cis-4h.
The crystal structure of 4f revealed a trans-configura-
tion of the methoxy and the methyl group. In fact,
analysis of the coupling constants (Karplus) indicated
that all alkyl-substituted pyrrolidines 4f-g,i-o possess
a trans-configuration. The excellent 1,2-diastereoselec-
tivity can be explained based on known stereo-electronic
considerations (comparison of acyclic extended transition
states with minimized electrostatic repulsion).20,21 The
transition state leading to the syn-isomer of 3 is sterically
favored over the one leading to the anti-isomer. Interest-
ingly, the configuration of the terminal double bond of
the 1,3-bis-silyl enol ether is irrelevant to the stereo-
selection. Inspection of the crystal lattice showed a
dimeric structure containing two intermolecular hydro-
gen bonds N-H‚‚‚O. The crystal structure of cis-4h
established a cis-configuration of the two methoxy groups
and the presence of a Z-configured exocyclic double bond.
The reaction of 4a-e with trifluoroacetic acid (TFA)
was studied next. Treatment of a CH2Cl2 solution of 4a
with TFA resulted in formation of an inseparable mixture
of the pyrroles 5a and 6a and of the indole 7a which could
be isolated in pure form (49%) (Scheme 2, Table 2). The
formation of pyrrole 6a can be explained by Friedel-
Crafts acylation of 5a with TFA. The formation of large
amounts of indole 7a could be explained by dimerization
of pyrrole 5a to the [4 + 2] cycloadduct A, which
subsequently aromatizes by acid-mediated extrusion of
trifluoroacetamide (Scheme 3). The dimerization of pyr-
role and 2-methylpyrrole, mediated by hydrogen chloride
in ether or by sulfuric acid, was already noted in 1888.22
Despite its synthetic usefulness, this transformation has
not been systematically studied to date. The use of TFA/
CH2Cl2 allows the synthesis of the functionalized (ester-
substituted) indoles 7 which are not available by appli-
cation of the original conditions reported (HCl or sulfuric
acid).
a Key: (i) 0.5 equiv of TMSOTf, CH2Cl2, -78 f +20 °C, 58%;
(ii) PPh3, 3 h, THF, 80 °C, 98%; (iii) reflux in CH2Cl2 or 1,4-dioxane,
24 h, 100%.
ured 5,12-bicyclic pyrrolidine 4p. Heating of 4p in CH2Cl2
gave bicyclic 5p. The structure of 5,12-bicyclic pyrrole 5p
was studied by crystal structure analysis. Inspection of
the crystal lattice revealed, similar to 4f, the presence of
two intermolecular hydrogen bonds N-H‚‚‚O and the
formation of a dimer. The reaction of 2 with 1q, prepared
from ethyl cyclohexan-1-one-2-carboxylate, afforded the
condensation product 3q. Treatment of 3q with PPh3
afforded a separable mixture of the 5,6-bicyclic pyrro-
lidines cis-4q (73%) and trans-4q (15%). Heating trans-
4q in 1,4-dioxane gave bicyclic 5q. The reaction of 2 with
1r, prepared from ethyl cyclooctan-1-one-2-carboxylate,
afforded 3r. The PPh3-mediated cyclization of 3r afforded
the 5,8-bicyclic pyrrolidines cis-4r (14%) and trans-4r
(76%). Heating cis-4r in 1,4-dioxane gave bicyclic 5r. TFA
treatment of trans-4r in CH2Cl2 gave the pyrrole 6f
(58%) by elimination of methanol and subsequent Friedel-
Crafts acylation of the pyrrole moiety. The reaction of 2
with 1s, prepared from ethyl 5-methylcyclohexan-1-one-
2-carboxylate, afforded 3s as a mixture of diastereomers.
The PPh3-mediated cyclization of 3s gave pyrrolidine 4s
as a separable diastereomeric mixture. The relative
configuration of the two diastereomers could not be
unambiguously established. Based on analysis of the
coupling constants and NOESY measurements, on anal-
ogy to the formation of 4q and on the cyclization of
dianions with 1,4-dibromo-2-butene,24 we assume that
diastereomers cis-4s (37%) and trans-4s (34%) possess
the structure assigned. The TFA-mediated transforma-
tion of each diastereomer into 5s failed, due to decom-
position. The reaction of 2 with 1t, prepared from methyl
6-phenylcyclohexan-1-one-2-carboxylate, afforded 3t. Treat-
ment of 3t with PPh3 afforded the 3-methoxyhexahydro-
2,3-benzopyrrole 4t as a separable mixture of two dia-
stereomers. Heating 4t in 1,4-dioxane gave bicyclic 5t as
an inseparable mixture of two diastereomers in good
yield.
The preparative scope of the reaction of 4-methoxy-2-
alkylidenepyrrolidines with TFA was next studied. Treat-
ment of a CH2Cl2 solution of 4b with TFA resulted in
formation of a separable mixture of pyrrole 6b (38%) and
indole 7b (54%). The reaction of 4c with TFA gave the
indole 7c in 91% yield. The reaction of 4d with TFA
afforded mainly the indole 7d (45%) together with an
inseparable mixture of pyrroles 5d and 6d. The reaction
of 4e with TFA gave the pyrrole 6e. The structure of 6e
was independently confirmed by crystal structure analy-
sis. Treatment of alkyl-substituted pyrroles, such as 4f,
with TFA resulted in the formation of an inseparable
complex mixture.
The reaction of cyclic 1,3-bis-silyl enol ethers23 with
1-azido-2,2-dimethoxyethane (2) was studied next (Scheme
4, Table 3). The reaction of 2 with 1p, prepared from ethyl
cyclododecan-1-one-2-carboxylate, afforded the condensa-
tion product 3p with good 1,2-diastereoselectivity. Treat-
ment of the latter with PPh3 afforded the trans-config-
(22) (a) Dennstedt, F. Chem. Ber. 1888, 21, 3439. (b) Dennstedt, F.
Chem. Ber. 1891, 24, 2562.
(23) (a) Molander, G. A.; Bessie`res, B.; Eastwood, P. R.; Noll, B. C.
J. Org. Chem. 1999, 64, 4124; (b) Langer, P.; Eckardt, T.; Stoll, M.;
Karime´, I.; Mu¨ller, P.; Saleh, N. N. R. Eur. J. Org. Chem. 2001, 3657
and references therein.
(24) Langer, P.; Holtz, E.; Saleh, N. N. R. Chem. Eur. J. 2002, 8,
917.
4754 J. Org. Chem., Vol. 70, No. 12, 2005

Synthesis of 2-Alkylidenepyrrolidines, Pyrroles, and Indoles
SCHEME 5. Synthesis of 4u, 5u and 9a
TABLE 3. Bicyclic Derivatives and Yields of
Condensation Products 3 and Pyrrolidines 4 by
Staudinger-aza-Wittig Reaction and Pyrroles 5 by
Thermal Extrusion of Methanol
a Key: (i) 0.3 equiv of TMSOTf, CH2Cl2, -78 f +20 °C; (ii) PPh3,
3 h, THF, 80 °C; (iii) reflux, 1,4-dioxane, 24 h.
tion of 1u with 2, silyl migration and subsequent reaction
with a second molecule of 2. The use of an excess of 2
did not result in an increase of the yield of 8. To the best
of our knowledge, double condensations have been re-
ported earlier for Me3SiOTf-catalyzed reactions of 2-(tri-
methylsilyloxy)propene,25 but not for the 1,3-bis-silyl enol
ether 1u. Treatment of 3u with PPh3 afforded the
Z-configured 2-alkylidenepyrrolidine 4u. Heating 4u in
1,4-dioxane gave 5r. Treatment of 8 with PPh3 resulted
in direct formation of the bis-pyrrole 9.
The reaction of mono-silyl enol ethers with 1-azido-2,2-
dimethoxyethane (2) was studied next (Scheme 6, Table
4). The reaction of 2 with silyl enol ethers 10a-l,
prepared from the corresponding 1,3-dicarbonyl com-
pounds, gave the open-chained azides 11a-l. Treatment
of the latter with PPh3 directly afforded the pyrroles
12a-l in good yields. The structure of pyrrole 12b was
studied by crystal structure analysis. Inspection of the
crystal lattice revealed the presence of intermolecular
hydrogen bonds and the formation of a chain-type
structure.
In summary, the cyclization of 1,3-bis-silyl enol ethers
with 1-azido-2,2-dimethoxyethane allowed an efficient
synthesis of a variety of 2-alkylidene-4-methoxypyrro-
lidines. The reactions proceeded with very good chemo-,
regio- and 1,2-diastereoselectivity. Functionalized pyr-
roles were efficiently prepared by thermal elimination
of methanol from 2-alkylidene-4-methoxypyrrolidines. In
a Yields of isolated products. b Reflux, 1,4-dioxane (from
trans-4q, cis-4r and diastereomeric mixture of 4t). c TFA, CH2Cl2
(from trans-4r). d Experiment (reflux) was not carried out; TFA,
CH2Cl2: 0%.
The reaction of 2,4-bis(trimethylsilyloxy)penta-1,3-
diene (1u), prepared from acetylacetone, with 1-azido-
2,2-dimethoxyethane (2) was studied next (Scheme 5).
The reaction of 2 with 1u afforded a separable mixture
of the expected condensation product 3u and of the double
condensation product 8. The latter was formed by reac-
(25) Mikami, K.; Ohmura, H. Chem. Commun. 2002, 2626.
J. Org. Chem, Vol. 70, No. 12, 2005 4755

Bellur et al.
SCHEME 6. Synthesis of 11a-l and 12a-la
CAUTION: The handling of low-molecular weight azides
is dangerous, due to their potentially explosive character.
However, in our hands, neat 2 did not appear to be shock
sensitive, the compound should be handled with great care.
Neat azides must not be heated or distilled and all reactions
should be carried out on a small scale. The use of a safety
shield is highly recommended.
General Procedure for the Reaction of 1,3-Bis-silyl
Enol Ethers (1) or Silyl Enol Ethers (10) with 1-Azido-
2,2-dimethoxyethane (2). To a CH2Cl2 solution (10 mL/
mmol) of 1 or 10 (1 equiv) and 2 (1.3 equiv) was added
Me3SiOTf (0.5 equiv) at -78 °C, and the solution was stirred
for 2 h at -78 °C. The temperature of the reaction mixture
was allowed to rise 20 °C during 14 h and the mixture was
stirred for 3 h at 20 °C. To this solution a saturated aqueous
solution of NaHCO3 was added, the organic layer was sepa-
rated and the aqueous layer was repeatedly extracted with
dichloromethane. The combined organic extracts were dried
over Na2SO4, filtered and the solvent of the filtrate was
removed in vacuo. The residue was purified by column chro-
matography (silica gel, n-hexane/EtOAc) to give 3 or 11.
a Key: (i) 0.5 equiv of TMSOTf, CH2Cl2, -78 f +20 °C; (ii) PPh3,
3 h, THF, reflux.
TABLE 4. Derivatives and Yields of Condensation
Products 11 and Pyrroles 12 by Staudinger-aza-Wittig
Reaction
6-Azido-5-methoxy-3-oxohexanoic Acid Methyl Ester
(3a). Starting with 2 (1.705 g, 13 mmol), 1-methoxy-1,3-bis-
trimethylsilanyloxybuta-1,3-diene (1a) (2.605 g, 10 mmol), and
Me3SiOTf (1.111 g, 5 mmol) in CH2Cl2 (100 mL), 3a was
isolated after chromatography (silica gel, n-Hex/EtOAc ) 100:1
f 1:1) as a yellow oil (1.025 g, 48%). 1H NMR (CDCl3, 300
Hz): δ ) 2.72 (dd, J ) 17.1, 5.7 Hz, 1 H, CH2), 2.89 (dd, J )
17.1, 6.9 Hz, 1 H, CH2), 3.26 (dd, J ) 12.9, 5.1 Hz, 1 H, CH2N3),
3.41 (s, 3 H, OCH3), 3.46 (dd, J ) 12.9, 4.2 Hz, 1 H, CH2N3),
3.50 (s, 2 H, CH2), 3.75 (s, 3 H, OCH3), 3.83-3.88 (m, 1 H,
CH). 13C NMR (CDCl3, 75 MHz): δC ) 44.7, 49.5, 52.1, 52.5,
57.4, 75.7, 167.1, 200.4. IR (neat, cm-1): ν˜ ) 2955 (w), 2938
(w), 2104 (s), 1747 (s), 1276 (s), 1194 (m), 1181 (m), 1151 (m),
1114 (m), 1093 (m), 1042 (w). MS (EI, 70 eV): m/z ) 201 (M+
- Me, 7), 169 (39), 159 (M+ - CH2N3, 65), 153 (5), 127 (95),
115 (14), 101 (97), 85 (100). Anal. Calcd. for C8H13O3N3
(215.209): C, 44.65; H, 6.09; N, 19.53. Found: C 45.46; H, 5.88;
N, 19.53.
6-Azido-5-methoxy-3-oxohexanoic acid 2-Methoxyeth-
yl Ester (3d). Starting with 2 (1.705 g, 13 mmol), 1-(2-
methoxyethoxy)-1,3-bis-trimethylsilanyloxybuta-1,3-diene (1d)
(3.085 g, 10 mmol), and Me3SiOTf (1.111 g, 5 mmol) in CH2-
Cl2 (100 mL), 3d was isolated after chromatography (silica gel,
n-Hex/EtOAc ) 100:1 f 1:1) as a yellow oil (1.145 g, 44%). 1H
NMR (CDCl3, 300 MHz): δ ) 2.72 (dd, J ) 12.9, 5.7 Hz, 1 H,
CH2), 2.90 (dd, J ) 17.4, 6.9 Hz, 1 H, CH), 3.25 (dd, J ) 12.9,
5.1 Hz, 1 H, CH2N3), 3.39 (s, 3 H, OCH3), 3.41 (s, 3 H, OCH3),
3.47 (dd, J ) 12.9, 3.9 Hz, 1 H, CH2N3), 3.53 (s, 2 H, CH2),
3.62 (t, J ) 6.5 Hz, 2 H, OCH2CH2OCH3), 3.87 (quint, J ) 6.6
Hz, 1 H, CH), 4.31 (t, J ) 6.9 Hz, 2 H, OCH2CH2OCH3). 13C
NMR (CDCl3, 75 MHz): δC ) 44.4, 49.7, 52.6, 57.4, 58.7, 64.1,
70.0, 75.7, 166.7, 200.3. IR (neat, cm-1): ν˜ ) 2935 (w), 2103
(s), 1744 (s), 1717 (s), 1453 (w), 1411 (w), 1370 (m), 1316 (m),
1293 (s), 1253 (s), 1200 (m), 1182 (m), 1151 (m), 1129 (s), 1104
(m), 1037 (m). MS (EI, 70 eV): m/z ) 203 (M+ - CH2N3, 100),
184 (3), 145 (21), 127 (55), 112 (37).
6-Azido-5-methoxy-1-phenylhexane-1,3-dione (3e). Start-
ing with 2 (1.705 g, 13 mmol), (1,3-bis-trimethylsilanyloxybuta-
1,3-dienyl)benzene (1e) (3.066 g, 10 mmol), and Me3SiOTf
(1.111 g, 5 mmol) in CH2Cl2 (100 mL), 3e was isolated after
chromatography (silica gel, n-Hex/EtOAc ) 100:1 f 1.1) as a
yellow oil (2.486 g, 95%). 1H NMR (CDCl3, 300 MHz): δ ) 2.60
(dd, J ) 15, 3.0 Hz, 1 H, CH2), 2.74 (dd, J ) 15, 6.9 Hz, 1 H,
CH2), 3.30 (dd, J ) 12.9, 5.4 Hz, 1 H, CH2N3), 3.44 (s, 3 H,
OCH3), 3.46 (dd, J ) 12.9, 3.6 Hz, 1 H, CH2N3), 3.85-3.92 (m,
1 H, CH), 6.22 (s, 1 H, CH from enol form), 7.42 (d, J ) 8.7
Hz, 2 H, 2 × CH from Ph), 7.52 (t, J ) 8.0 Hz, 1 H, CH from
Ph), 7.88 (d, J ) 8.7 Hz, 2 H, 2 × CH from Ph), 16.11 (broad
s, 1 H, OH). 13C NMR (CDCl3, 75 MHz): δC ) 41.6, 53.1, 57.6,
77.2, 97.2, 126.9, 128.5, 132.4, 134.3, 183.1, 193.1. IR (neat,
cm-1): ν˜ ) 2983 (w), 2934 (w), 2831 (w), 2102 (s), 1604 (s),
11, 12
R1
R2
11a (%)
12a (%)
a
b
c
d
e
f
g
h
i
OMe
OEt
H
50
50
85
H
91
O(CH2)2OMe
Me
H
71b
97
H
59
92
OEt
allyl
Et
70b
55b
63b
62b
89
OEt
OEt
nPr
nBu
nHex
nOct
nNon
nDec
OEt
OEt
j
k
l
OEt
65b
68b
67b
OEt
OEt
a Yields of isolated products. b Yields of isolated products over
two steps.
addition, the synthesis of pyrroles by cyclization of
1-azido-2,2-dimethoxyethane with monosilyl enol ethers,
derived from 1,3-dicarbonyl compounds, was reported.
The reaction of 2-alkylidene-4-methoxypyrrolidines with
TFA resulted in the formation of functionalized indoles.
Experimental Section
1-Azido-2,2-dimethoxyethane (2).16 Sodium azide (19.503
g, 300 mmol) and potassium iodide (3.320 g, 20 mmol) were
added to a solution of 1-bromo-2,2-dimethoxyethane (823.64
mL, 200 mmol) in DMSO (140 mL) at room temperature. The
reaction mixture was heated to 90 °C and stirred for 5 days
at 90 °C. After cooling to room temperature, water (200 mL)
and diethyl ether (200 mL) were added, the organic layer was
separated and the aqueous layer was repeatedly extracted with
diethyl ether (4 × 200 mL). The combined organic extracts
were dried over Na2SO4, filtered, and the filtrate was concen-
trated to dryness in vacuo. Product 2 was isolated without
further purification as slightly yellow oil (22.31 g, 85%). For
safety reasons, it is recommended to carry out the reaction on
a small scale (2.0 g sodium azide, no decreasement of the yield
was observed) and to use a safety shield. Although synthetic
applications of 2 have been previously reported,16 a procedure
for its preparation was not provided. 1H NMR (CDCl3, 300
MHz): δ ) 3.27 (d, J ) 5.3 Hz, 2 H, CH2N3), 3.43 (s, 6 H, 2 ×
OCH3), 4.48 (t, J ) 5.3 Hz, 1 H, CH). 13C NMR (CDCl3, 75
MHz): δC ) 51.66 (CH2N3), 54.25 (OCH3), 103.08 (CH). IR
(neat, cm -1): ν˜ ) 2995 (w), 2939 (m), 2837 (w, C-H), 2102 (s,
N3), 1444 (m), 1311 (w), 1275 (s), 1196 (m), 1129 (s), 1089 (s),
1064 (s), 1035 (m), 979 (w), 922 (w). MS (EI, 70 eV): m/z ) 75
+
(M - CH2N3, 100).
4756 J. Org. Chem., Vol. 70, No. 12, 2005

Synthesis of 2-Alkylidenepyrrolidines, Pyrroles, and Indoles
1574 (s), 1492 (m), 1459 (m), 1440 (m), 1363 (w), 1354 (w),
1291 (s), 1182 (w), 1150 (w), 1109 (m), 1083 (m), 766 (m), 698
(w, Ph). MS (EI, 70 eV): m/z ) 205 (M+ - CH2N3, 22), 174
(11), 161 (8), 147 (98), 105 (100).
yellow oil (2.065 g, 58%). 1H NMR (CDCl3, 300 MHz): δ ) 1.28
(t, J ) 7.2 Hz, 3 H, CH3), 1.29-1.35 (m, 12 H, 6 × CH2), 3.05-
3.13 (m, 1 H, CH), 3.21-3.32 (m, 1 H, CH), 3.33, 3.47 (ds, 3H,
OCH3), 3.59 (dt, J ) 13.2, 3.3 Hz, 1 H, CH2N3), 3.64-3.73 (m,
1 H, CH2N3), 3.95-4.03 (m, 1 H, CH), 4.17 (q, J ) 7.2 Hz, 2
H, OCH2). IR (neat, cm-1): ν˜ ) 2933 (s), 2867 (w), 2100 (s),
1743 (s), 1711 (s), 1469 (w), 1443 (w), 1291 (m), 1271 (m), 1250
(m), 1179 (m), 1154 (w), 1114 (m), 1099 (m), 1027 (m). MS (EI,
70 eV): m/z ) 298 (M+ - CH2N3, 100), 266 (5), 252 (95), 224
(9). Anal. Calcd for C18H31O4N3 (353.462): C, 61.17; H, 8.84;
N, 11.89. Found: C, 61.33; H, 8.96; N, 11.64.
6-Azido-5-methoxy-4-methyl-3-oxohexanoic Acid Meth-
yl Ester (3f). Starting with 2 (1.705 g, 13 mmol), 1-methoxy-
1,3-bis-trimethylsilanyloxypenta-1,3-diene (1f) (2.745 g, 10
mmol), and Me3SiOTf (1.111 g, 5 mmol) in CH2Cl2 (100 mL),
3f was isolated after chromatography (silica gel, n-Hex/EtOAc
) 100:1f 1:1) as a yellow oil (2.177 g, 95%). 1H NMR (CDCl3,
300 MHz): δ ) 1.12 (dd, J ) 40.2, 6.9 Hz, 3 H, CH3), 2.97-
3.11 (m, 1 H, CH), 3.15-3.65 (m, 1 H, CH2N3), 3.39 (s, 3 H,
OCH3), 3.49 (s, 2 H, CH2), 3.50-3.65 (m, 1 H from CH2N3, and
1 H from CH), 3.77 (s, 3 H, OCH3). IR (neat, cm-1): ν˜ ) 2983
(w), 2952 (m), 2940 (m), 2102 (s), 1748 (s), 1715 (s), 1653 (w),
1632 (w), 1454 (m), 1439 (m), 1406 (w), 1379 (w), 1346 (w),
1285 (m), 1261 (s), 1196 (m), 1180 (m), 1151 (m), 1098 (s), 1053
(m), 1017 (m). MS (EI, 70 eV): m/z ) 173 (M+ - CH2N3, 43),
99 (100). Anal. Calcd for C9H15O4N3 (229.236): C, 47.16; H,
6.60; N, 18.33. Found C, 46.55; H, 6.67; N, 18.09.
6-Azido-4-ethyl-5-methoxy-3-oxohexanoic Acid Ethyl
Ester (3g). Starting with 2 (1.705 g, 13 mmol), 1-ethoxy-1,3-
bis-trimethylsilanyloxyhexa-1,3-diene (1g) (3.026 g, 10 mmol),
and Me3SiOTf (1.111 g, 5 mmol) in CH2Cl2 (100 mL), 3g was
isolated after chromatography (silica gel, n-Hex/EtOAc ) 100:1
f 1:1) as a yellow oil (2.512 g, 98%). 1H NMR (CDCl3, 300
MHz): δ ) 9.3 (t, J ) 7.4 Hz, 3 H, CH3), 1.28 (t, J ) 7.2 Hz,
3 H, OCH2CH3), 1.62 (quint, J ) 7.4 Hz, 2 H, CH2), 2.52 (t, J
) 7.5 Hz, 1 H, CH), 2.91-3.06 (m, 1 H, CH2N3), 3.15-3.20
(m, 1 H, CH2N3), 3.40 (ds, J ) 19.8 Hz, 3 H, OCH3), 3.38-
3.49 (m, 1 H, CH), 3.51 (ds, J ) 17.1 Hz, 2 H, CH2), 4.20 (q, J
) 7.2 Hz, 2 H, OCH2).
4-(2-Azido-1-methoxyethyl)-3-oxohept-6-enoic Acid Eth-
yl Ester (3i). Starting with 2 (1.967 g, 15 mmol), 1-ethoxy-
1,3-bis-trimethylsilanyloxyhepta-1,3,6-triene (1i) (3.146 g, 10
mmol), and Me3SiOTf (1.111 g, 5 mmol) in CH2Cl2 (100 mL),
3i was isolated after chromatography (silica gel, n-Hex/EtOAc
) 100:1 f 1:1) as a brownish oil (1.614 g, 60%). 1H NMR
(CDCl3, 300 MHz): δ ) 1.28 (t, J ) 7.2 Hz, 3 H, CH3), 2.28-
2.39 (m, 2 H, CH2), 2.63-2.68 (m, 1 H, CH), 3.09-3.22 (m, 1
H, CH2N3), 3.37 (s, 3 H, OCH3), 3.38-3.46 (m, 1 H, CH2N3),
3.48 (s, 2 H, CH2), 3.49-3.57 (m, 1 H, CH), 4.10-4.24 (m, 1
H, OCH2), 4.98-5.12 (m, 2 H, CH2dCH), 5.63-5.84 (m, 1 H,
CH)CH2). IR (neat, cm-1): ν˜ ) 2982 (w), 2936 (w), 2102 (s),
1742 (s), 1717 (s), 1643 (w), 1444 (w), 1370 (w), 1306 (m), 1249
(s) 1180 (s), 1156 (s), 1100 (m), 1031 (m), 853 (w). MS (EI, 70
eV): m/z ) 224 (M+ - OEt, 3), 213 (M+ - CH2N3, 100), 194
(4), 170 (16), 168 (3), 141 (13), 125 (85).
4-(2-Azido-1-methoxyethyl)-3-oxoheptanoic Acid Ethyl
Ester (3j). Starting with 2 (1.967 g, 15 mmol), 1-ethoxy-1,3-
bis-trimethylsilanyloxyhepta-1,3-diene (1j) (3.166 g, 10 mmol),
and Me3SiOTf (1.111 g, 5 mmol), in CH2Cl2 (100 mL), 3j was
isolated after chromatography (silica gel, n-Hex/EtOAc ) 100:1
f 1:1) as a yellow oil (2.227 g, 82%). 1H NMR (CDCl3, 300
MHz): δ ) 0.88 (t, J ) 6.9 Hz, 3 H, CH3), 1.28 (t, J ) 7.2 Hz,
3 H, OCHCH3), 1.22-1.35 (m, 2 H, CH2), 1.56-1.62 (m, 2 H,
CH2), 3.01 (dt, J ) 3.0, 8.4 Hz, 1 H, CH), 3.19 (dd, J ) 13.5,
4.5 Hz, 1 H, CH2N3), 3.36 (s, 3 H, OCH3), 3.43-3.50 (m, 1 H,
CH2N3), 3.54 (s, 2 H, CH2), 3.57 (dd, J ) 13.5, 3.0 Hz, 1 H,
CH), 4.20 (q, J ) 7.2 Hz, 2 H, OCH2). 13C NMR (CDCl3, 75
MHz): δC ) 13.9, 14.0, 20.2, 30.2, 50.3, 51.6, 53.2, 58.0, 61.0,
82.0, 166.6, 205.3. IR (neat, cm-1): ν˜ ) 2962 (s), 2936 (s), 2874
(w), 2101 (s), 1745 (s), 1715 (s), 1647 (m), 1463 (m), 1411 (w),
1369 (m), 1301 (s), 1275 (s), 1238 (s), 1179 (m), 1156 (m), 1100
(s), 1034 (m). MS (EI, 70 eV): m/z ) 226 (M+ - OEt, 4), 215
(M+ - CH2N3, 55), 184 (4), 142 (3), 127 (100).
7-Azido-6-methoxyheptane-2,4-dione (3u). Starting with
2 (1.705 g, 13 mmol), 2,4-bis-trimethylsilanyloxypenta-1,3-
diene (1u) (2.445 g, 10 mmol), and Me3SiOTf (1.111 g, 5 mmol)
in CH2Cl2 (100 mL), 3u and 8 were isolated after chromatog-
raphy (silica gel, n-Hex/EtOAc ) 100:1 f 1:1) as brownish oils
(0.536 g, 27%; 0.582 g, 24%). 1H NMR (CDCl3, 300 MHz): δ)
2.07 (s, 3 H, CH3), 2.46 (dd, J ) 14.7, 6.0 Hz, 1 H, CH2), 2.59
(dd, J ) 14.7, 6.6 Hz, 1 H, CH2), 3.28 (dd, J ) 12.9, 5.4 Hz, 1
H, CH2), 3.42 (s, 3 H, OCH3), 3.43 (dd, J ) 12.9, 3.9 Hz, 1 H,
CH2N3), 3.78-3.86 (m, 1 H, CH), 5.55 (s, 1 H, CHdC), 15.39
(broad s, 1 H, OH). 13C NMR (CDCl3, 75 MHz): δc) 24.5, 40.6,
53.0, 57.5, 77.0, 101.0, 190.6, 191.0. IR (neat, cm-1): ν˜ ) 2935
(m), 2102 (s), 1724 (w), 1708 (m), 1685 (w), 1618 (s), 1613 (s),
1562 (w), 1536 (w), 1458 (m), 1439 (m), 1426 (m), 1361 (m),
1293 (s), 1254 (m), 1195 (w), 1181 (w), 1152 (w), 1109 (m), 1036
(w). MS (EI, 70 eV): m/z ) 184 (M+ - Me, 98), 143 (M+
CH2N3, 80), 128 (92), 99 (100).
-
1,9-Diazido-2,8-dimethoxynonane-4,6-dione (8). 1H NMR
(CDCl3, 300 MHz): δ ) 2.49 (ddd, J ) 15, 6, 0.9 Hz, 2 H, CH2),
2.61 (dd, J ) 15, 6 Hz, 2 H, CH2), 3.28 (dd, J ) 12.9, 5.7 Hz,
2 H, CH2-N3), 3.43 (s, 6 H, 2 × OCH3), 3.41-3.50 (m, 2 H, 2 ×
CH), 5.60 (s, 1 H, CH), 15.29 (broad s, 1 H, OH). 13C NMR
(CDCl3, 75 MHz): δ ) 40.7, 53.0, 57.6, 77.0, 101.8, 190.5. IR
(neat, cm-1): ν˜ ) 3333 (br), 2935 (s), 2832 (w), 2101 (s), 1711
(s), 1668 (s), 1613 (s), 1442 (s), 1355 (s), 1291 (s), 1254 (s), 1195
(m), 1153 (m), 1039 (m), 931 (w), 844 (m). MS (EI, 70 eV): m/z
) 298 (M+, 100), 256 (10), 214 (22), 198 (80), 183 (26).
2-Acetyl-4-azido-3-methoxybutyric Acid Methyl Ester
(11a). Starting with 2 (1.967 g, 15 mmol), 3-trimethylsilanyl-
oxybut-2-enoic acid methyl ester (10a) (1.883 g, 10 mmol), and
Me3SiOTf (1.111 g, 5 mmol) in CH2Cl2 (100 mL), 11a was
isolated after chromatography (silica gel, n-Hex/EtOAc ) 100:1
f 1:1) as a yellow oil (1.081 g, 50%). 1H NMR (CDCl3, 300
MHz): δ ) 2.27, 2.33 (ds, 3 H, CH3), 3.23-3.40 (m, 1 H, CH2-
N3), 3.44, 3.47 (ds, 3 H, OCH3), 3.63 (dt, J ) 13.2, 3.0 Hz, 1 H,
CH2-N3), 3.73, 3.78 (ds, 3 H, OCH3), 3.92 (dd, J ) 9.6, 3.0
Hz, 1 H, CH), 3.99-4.03 (m, 1 H, CH). 13C NMR (CDCl3, 150
MHz): δC ) 3.6, 31.7, 51.1, 51.1, 52.8, 52.9, 58.5, 58.6, 60.2,
61.7, 78.5, 79.1, 167.6, 167.9, 201.0, 201.5. IR (neat, cm-1): ν˜
) 2998 (w), 2956 (w), 2938 (w), 2105 (s), 1746 (s), 1720 (s),
1648 (w), 1438 (m), 1360 (m), 1260 (s), 1212 (m), 1197 (m),
1173 (m), 1150 (m), 1117 (m), 1096 (s), 1050 (w), 994 (w). MS
(EI, 70 eV): m/z ) 139 (M+ - OMe, 14), 159 (M+ - CH2N3, 3),
155 (1), 146 (3), 117 (79), 101 (6), 85 (85), 55 (9), 43 (100).
2-Acetyl-4-azido-3-methoxybutyric Acid Ethyl Ester
(11b). Starting with 2 (1.967 g, 15 mmol), 3-trimethylsilanyl-
oxybut-2-enoic acid ethyl ester (10b) (2.023 g, 10 mmol), and
Me3SiOTf (1.111 g, 5 mmol) in CH2Cl2 (100 mL), 11b was
isolated after chromatography (silica gel, n-Hex/EtOAc ) 100:1
f 1:1) as a yellow oil (1.144 g, 50%). 1H NMR (CDCl3, 300
MHz): δ ) 1.29 (m, 3 H, CH3), 2.27, 2.33 (ds, 3 H, CH3), 3.25-
3.37 (m, 1 H, CH2-N3), 3.41, 3.44 (ds, 3 H, OCH3), 3.63 (m, 1
H, CH2-N3), 3.89 (dd, J ) 8.7, 2.4 Hz, 1 H, CH), 3.99-4.04
(m, 1 H, CH), 4.17-4.26 (m, 2 H, OCH2). 13C NMR (CDCl3,
150 MHz): δC ) 13.9, 14.0, 30.1, 31.2, 50.0, 50.9, 58.2, 58.3,
60.3, 61.7, 61.6, 61.7, 78.8, 166.8, 167.1, 200.8, 201.2. IR (neat,
cm-1): ν˜ ) 2986 (w), 2939 (w), 2104 (s), 1742 (s), 1718 (s), 1642
(w), 1447 (w), 1366 (m), 1295 (s), 1256 (s), 1212 (m), 1179 (s),
1151 (m), 1115 (m), 1097 (s), 1044 (w), 1025 (w). MS (EI, 70
3-(2-Azido-1-methoxyethyl)-2-oxocyclododecanecar-
boxylic Acid Ethyl Ester (3p). Starting with 2 (1.967 g, 15
mmol), 12-(ethoxytrimethylsilanyloxymethylene)-1-trimethyl-
silanyloxycyclododecene (1p) (3.967 g, 10 mmol), and Me3SiOTf
(1.111 g, 5 mmol) in CH2Cl2 (100 mL), 3p was isolated after
chromatography (silica gel, n-Hex/EtOAc ) 100:1 f 1:1) as a
J. Org. Chem, Vol. 70, No. 12, 2005 4757

Bellur et al.
eV): m/z ) 198 (M+ - OMe, 1), 173 (M+ - CH2N3, 2), 141 (1),
131 (84), 128 (3), 113 (2), 103 (26), 99 (3), 85 (100), 82 (2), 55
(6), 43 (68).
(dd, J ) 1.1, 5.4 Hz, 1 H, CH2NH), 4.06 (quint, J ) 3.0 Hz, 1
H, CH), 4.20 (t, J ) 4.5 Hz, 2 H, OCH2), 4.61 (s, 1 H, CHdC),
7.80 (broad s, 1 H, NH). 13C (CDCl3, 75 MHz): δC ) 38.4, 52.3,
56.6, 59.0, 61.7, 71.1, 77.2, 77.7, 164.2, 170.2. IR (KBr, cm-1):
ν˜ ) 3384 (m), 2983 (w), 2970 (w), 2939 (w), 2921 (w), 2895
(m), 2846 (w), 2818 (w), 1658 (s), 1611 (s), 1491 (m), 1454 (w),
1371 (w), 1342 (w), 1295 (m), 1251 (s), 1235 (s), 1221 (s), 1201
(w), 1188 (w), 1164 (m), 1145 (m), 1129 (s), 1096 (s), 1078 (m),
1057 (s), 1044 (m), 774 (m), 709 (w), 655 (w). MS (EI, 70 eV):
m/z ) 215 (M+, 29), 184 (21), 168 (4), 153 (20), 140 (100), 126
(6), 112 (60). The exact molecular mass m/z ) 215.1158 ( 2
ppm [M+] for C10H17O4N was confirmed by HRMS (EI, 70 eV).
3-(2-Azido-1-methoxyethyl)pentane-2,4-dione (11d).
Starting with 2 (0.786 g, 6.0 mmol), 4-trimethylsilanyloxypent-
3-en-2-one (10d) (0.862 g, 5 mmol), and Me3SiOTf (0.556 g,
2.5 mmol) in CH2Cl2 (100 mL), 11d was isolated after chro-
matography (silica gel, n-Hex/EtOAc ) 50:1 f 1:1) as a yellow
1
oil (0.540 g, 59%). H NMR (CDCl3, 300 MHz): δ ) 2.21 (s, 3
H, CH3), 2.29 (s, 3 H, CH3), 3.17 (dd, J ) 13.2, 3.6 Hz, 1 H,
CH2-N3), 3.39 (s, 3 H, OCH3), 3.63 (dd, J ) 13.2, 3.0 Hz, 1 H,
CH2-N3), 4.06 (dt, J ) 9.3, 3.6 Hz, 1 H, CH), 4.15 (d, J ) 9.3
Hz, 1 H, CH). 13C NMR (CDCl3, 75 MHz): δC ) 30.6, 30.7,
50.4, 57.8, 69.2, 79.0, 201.2, 201.7. IR (neat, cm-1): ν˜ ) 2993
(w), 2938 (m), 2833 (w), 2104 (s), 1725 (s), 1703 (s), 1558 (m),
1423 (m), 1360 (s), 1276 (s), 1187 (m), 1153 (m), 1110 (s), 1197
(s), 1048 (w), 1024 (w), 956 (w), 930 (w), 579 (w). MS (EI, 70
eV): m/z ) 199 (M+, 2), 157 (2), 143 (9), 130 (1), 125 (3), 101
(58), 83 (15), 70 (5), 43 (100). Anal. Calcd for C8H13O3N3
(199.210): C, 48.24; H, 6.58; N, 21.09. Found: C, 48.70; H,
6.17; N, 21.30.
2-(4-Methoxypyrrolidin-2-ylidene)-1-phenyletha-
none (4e). Starting with 3e (2.000 g, 7.66 mmol) and PPh3
(2.409 g, 9.19 mmol) in THF (70 mL), 4e was isolated after
chromatography (silica gel, n-Hex/EtOAc) 100:1 f 1:1) as a
1
yellow solid (1.392 g, 84%). H NMR (CDCl3, 300 MHz): δ )
2.80 (dd, J ) 17.3, 28 Hz, 1 H, CH2), 2.92 (dd, J ) 17.5, 6.3
Hz, 1 H, CH2), 3.35 (s, 3 H, OCH3), 3.69 (dd, J ) 11.8, 2.2 Hz,
1 H, CH2NH), 3.79 (dd, J ) 11.9, 5.3 Hz, 1 H, CH2NH), 4.13
(quint, J ) 2.8 Hz, 1 H, CH), 5.82 (s, 1 H, CHdC), 7.36-7.43
(m, 3 H, 3 × CH from Ph), 7.85-7.88 (m, 2 H, 2 × CH from
Ph), 10.17 (broad s, 1 H, NH). 13C NMR (CDCl3, 75 MHz): δC
) 39.0, 52.8, 56.4, 76.5, 87.0, 126.9, 128.0, 130.4, 140.1, 166.5,
188.2. IR (KBr, cm-1): ν˜ ) 3270 (w), 2994 (w), 2937 (m), 2880
(w), 2832 (w), 1609 (s), 1580 (s), 1523 (s), 1485 (s), 1457 (m),
1442 (w), 1410 (m), 1362 (m), 1342 (m), 1305 (s), 1288 (m),
1265 (s), 1240 (m), 1199 (w), 1178 (m), 1162 (m), 1092 (s), 1063
(w), 1039 (m), 1026 (w), 995 (w), 943 (w), 851 (m), 749 (s), 716
(s), 679 (m), 548 (w, Ph). MS (EI, 70 eV): m/z ) 217 (M+, 100),
202 (1), 186 (68), 140 (25), 112 (1), 80 (37), 77 (59). Anal. Calcd
for C13H15O2N (217.267): C, 71.87; H, 6.96; N, 6.45. Found:
C, 72.01; H, 7.41; N, 6.44.
2-(2-Azido-1-methoxyethyl)-3-oxodecanoic Acid Ethyl
Ester (11i). Starting with 2 (0.984 g, 7.5 mmol), 3-trimeth-
ylsilanyloxydec-2-enoic acid ethyl ester (10i) (1.432 g, 5.0
mmol), and Me3SiOTf (0.556 g, 2.5 mmol) in CH2Cl2 (100 mL),
11i was isolated after chromatography (silica gel, n-Hex/EtOAc
) 100:1 f 5:1) as a yellow oil (2.058 g, 92%). 1H NMR (CDCl3,
300 MHz): δ ) 0.88 (t, J ) 6.9 Hz, 3 H, CH3), 1.23-1.33 (m,
11 H, 4 × CH2, OCH2CH3), 154-1.62 (m, 2 H, CH2), 2.53 (t, J
) 7.2 Hz, 2 H, CH2), 3.15-3.37 (m, 1 H, CH2-N3), 3.38, 3.43
(ds, 3 H, OCH3), 3.46-3.70 (m, 2 H, CH, CH2-N3), 4.20 (q, J )
7.2 Hz, 2 H, OCH2), 4.15-4.23 (m, 1 H, CH). IR (neat, cm-1):
ν˜ ) 2957 (s), 2930 (s), 2858 (s), 2120 (s), 1745 (s), 1717 (s),
1647 (w), 1463 (m), 1410 (w), 1371 (m), 1300 (s), 1234 (s), 1178
(s), 1158 (s), 1158 (m), 1126 (m), 1100 (s), 1033 (m). MS (EI,
70 eV): m/z ) 257 (M+ - N3, 7), 196 (4), 185 (2), 169 (12), 143
(22), 130 (90), 127 (57), 114 (18), 102 (11), 85 (30), 70 (16), 57
(100), 43 (74). HRMS (ESI): calcd for C15H27O4N3Na ([M +
Na]+) ) 336.18993; found ) 336.18912.
(4-Methoxy-3-methylpyrrolidin-2-ylidene)acetic Acid
Methyl Ester (4f). Starting with 3f (2.000 g, 8.73 mmol) and
PPh3 (3.433 g, 13.1 mmol) in THF (70 mL), 4f was isolated
after chromatography (silica gel, n-Hex/EtOAc ) 100:1 f 1:1)
1
as a brownish oil (1.532 g, 95%). H NMR (CDCl3, 300 MHz):
δ ) 1.19 (d, J ) 7.5 Hz, 3 H, CH3), 2.72-2.81 (m, 1 H, CH),
3.36 (s, 3 H, OCH3), 3.43 (dd, J ) 7.5, 3.6 Hz, 1 H, CH), 3.64
(s, 3 H,OCH3), 3.66-3.76 (m, 2 H, CH2NH), 4.53 (s, 1 H, CHd
General Procedure for the Preparation of 2-Alkyl-
idene-4-methoxypyrrolidines (4). To a THF-solution (10
mL/mmol) of 3 (1 equiv) was added triphenylphosphine (1.2
equiv) at room temperature. The reaction mixture was heated
and stirred for 4 h at 80 °C. After cooling to 20 °C, the solvent
was removed in vacuo and the residue was purified by
chromatography (silica gel, n-hexane/EtOAc) to give 4.
C), 7.72 (broad s, 1 H, NH). 13C NMR (CDCl3, 75 MHz): δC
)
16.6, 44.5, 50.1, 50.2, 57.1, 76.8, 84.3, 168.6, 171.1. IR (neat,
cm-1): ν˜ ) 3373 (m), 2969 (w), 2954 (m), 2936 (m), 2903 (w),
2876 (w), 1737 (m), 1664 (s), 1604 (s), 1491 (w), 1458 (m), 1432
(m), 1314 (w), 1296 (w), 1257 (m), 1230 (s), 1203 (m), 1152 (s),
1106 (m), 1043 (m), 1018 (w), 784 (w). MS (EI, 70 eV): m/z )
185 (M+, 100), 170 (1), 154 (92), 138 (12), 127 (17), 122(55).
Anal. Calcd for C9H15O3N (185.223): C, 58.36; H, 8.16; N, 7.56.
Found: C, 58.87; H, 7.56; N, 7.80.
(4-Methoxypyrrolidin-2-ylidene)acetic Acid Methyl
Ester (4a). Starting with 3a (0.400 g, 1.86 mmol) and PPh3
(0.585 g, 2.23 mmol) in THF (10 mL), 4a was isolated after
chromatography (silica gel, n-Hex/EtOAc ) 100:1 f 1:1) as a
1
(3-Ethyl-4-methoxypyrrolidin-2-ylidene)acetic Acid
Ethyl Ester (4g). Starting with 3g (1.000 g, 3.9 mmol) and
PPh3 (1.223 g, 4.7 mmol) in THF (50 mL), 4g was isolated after
chromatography (silica gel, n-Hex/EtOAc ) 100:1 f 1:1) as a
yellow solid (0.257 g, 81%). Mp ) 42.6 °C. H NMR (CDCl3,
300 MHz): δ ) 2.64 (dd, J ) 17.1, 2.7 Hz, 1 H, CH2), 2.77 (dd,
J ) 17.1, 6.3 Hz, 1 H, CH2), 3.32 (s, 3 H, OCH3), 3.56 (d, J )
10.5 Hz, 1 H, CH2NH), 3.62 (s, 3 H, OCH3), 3.60-3.68 (m, 1
H, CH2NH), 4.05 (quint, J ) 1.8 Hz, 1 H, CH), 4.55 (s, 1 H,
CHdC), 7.82 (broad s, 1 H, NH). 13C NMR (CDCl3, 75 MHz):
δC ) 38.2, 49.9, 52.1, 56.3, 76.9, 77.1, 163.8, 170.5. IR (KBr,
cm-1): ν˜ ) 3367 (m), 2982 (w), 2940 (m), 2881 (w), 1663 (s),
1603 (s), 1489 (m), 1458 (w), 1433 (w), 1340 (m), 1293 (m),
1225 (s), 1188 (m), 1152 (s), 1097 (s), 1045 (s), 904 (w), 782
(m). MS (EI, 70 eV): m/z ) 171 (M+, 87), 156 (4), 141 (15),
140 (100), 124 (17), 112 (28), 109 (22), 80 (41). Anal. Calcd for
C8H13O3N (171.196): C, 56.13; H, 7.65; N, 8.18. Found: C,
55.76; H, 7.30; N, 8.01.
1
brownish oil (0.660 g, 79%). H NMR (CDCl3, 300 MHz): δ )
0.99 (t, J ) 4.2 Hz, 3 H, CH3), 1.25 (t, J ) 7.2 Hz, 3 H, OCH2-
CH3), 1.39-1.53 (m, 1 H, CH2), 1.58-1.66 (m, 1 H, CH2), 2.63-
2.66 (m, 1 H, CH), 3.33 (s, 3 H, OCH3), 3.49 (dt, J ) 10.8, 1.5
Hz, 1 H, CH), 3.67 (dd, J ) 10.8, 5.4 Hz, 1 H, CH2NH), 3.72-
3.75 (m, 1 H, CH2NH), 4.10 (dq, J ) 1.5, 7.2 Hz, 2 H, OCH2),
4.53 (s, 1 H, CHdC), 7.79 (broad s, 1 H, NH). 13C NMR (CDCl3,
75 MHz): δC ) 11.0, 14.4, 24.3, 50.8, 51.2, 56.1, 58.1, 77.4,
81.9, 167.4, 170.5. IR (neat, cm-1): ν˜ ) 3368 (m), 2971 (s), 2934
(s), 2901 (m), 2877 (m), 2827 (w), 1729 (w), 1659 (s), 1604 (s),
1491 (m), 1462 (m), 1368 (m), 1345 (w), 1311 (m), 1225 (s),
1246 (s), 1199 (s), 1149 (s), 1094 (s), 1050 (s), 783 (s). UV-vis
(CH2Cl2, nm): λmax (log ꢀ) ) 280 (4.16). MS (EI, 70 eV): m/z )
213 (M+, 25), 185 (18), 182 (4), 154 (100), 136 (15), 107 (31).
Anal. Calcd for C11H19O3N (213.276): C, 61.95; H, 8.98; N, 6.57.
Found: C, 62.30; H, 8.32; N, 5.98.
(4-Methoxypyrrolidin-2-ylidene)acetic Acid 2-Meth-
oxyethyl Ester (4d). Starting with 3d (0.300 g, 1.16 mmol)
and PPh3 (0.364 g, 1.39 mmol) in THF (30 mL), 4d was isolated
after chromatography (silica gel, n-Hex/EtOAc ) 100:1 f 1:1)
1
as a yellow solid (0.184 g, 74%). H NMR (CDCl3, 300 MHz):
δ ) 2.64 (dd, J ) 16.8, 2.7 Hz, 1 H, CH2), 2.77 (dd, J ) 17.1,
6.0 Hz, 1 H, CH2), 3.32 (s, 3 H, OCH3), 3.38 (s, 3 H, OCH3),
3.53-3.60 (m, 2 H from OCH2 and 1 H from CH2NH), 3.66
(3-Allyl-4-methoxypyrrolidin-2-ylidene)acetic Acid Eth-
yl Ester (4i). Starting with 3i (0.300 g, 1.11 g) and PPh3 (0.351
4758 J. Org. Chem., Vol. 70, No. 12, 2005

Synthesis of 2-Alkylidenepyrrolidines, Pyrroles, and Indoles
g, 1.34 mmol) in THF (15 mL), 4i was isolated after chroma-
tography (silica gel, n-hex/EtOAc ) 100:1 f 1:1) as a brownish
mass m/z ) 155.0946 ( 2 ppm [M+] for C8H13O2N was
confirmed by HRMS (EI, 70 eV).
1
oil (0.236 g, 94%). H NMR (CDCl3, 300 MHz): δ ) 1.26 (t, J
General Procedure for the Synthesis of Pyrroles (5).
A solution of 4 in CH2Cl2 (10 mL/mmol) or in 1,4-dioxane (5
mL/mmol) was stirred at reflux for 24 h. After the solution
was cooled to 20 °C, the solvent was removed in vacuo and
the residue was purified by chromatography (silica gel, n-Hex/
EtOAc) to give 5.
(1H-Pyrrol-2-yl)acetic Acid Methyl Ester (5a). Starting
with 4a (0.100 g, 0.32 mmol) in 1,4-dioxane (10 mL), 5a was
isolated after chromatography (silica gel, n-Hex/EtOAc ) 100:1
f 10:1) as a black oil (0.068 g, 76%). 1H NMR (CDCl3, 600
MHz): δ ) 3.69 (s, 2 H, CH2), 3.72 (s, 3 H, OCH3), 6.01 (m, 1
H, CH), 6.15 (m, 1 H, CH), 6.75 (m, 1 H, CH), 8.70 (broad s, 1
H, NH). 13C NMR (CDCl3, 75 MHz): δc ) 33.0, 52.2, 107.4,
108.3, 115.0, 117.8, 171.6. IR (neat, cm-1): ν˜ ) 3382 (s), 2955
(m), 2926 (m), 1734 (s), 1646 (m), 1599 (w), 1574 (w), 1436 (s),
1343 (w), 1330 (w), 1260 (s), 1201 (m), 1150 (m), 1128 (m),
1095 (m), 1045 (w), 1024 (m), 796 (w), 723 (m). MS (EI, 70
eV): m/z ) 139 (M+, 33), 124 (2), 107 (5), 80 (100). The exact
molecular mass m/z ) 139.0633 ( 2 ppm [M+] for C7H9O2N
was confirmed by HRMS (EI, 70 eV).
(1H-Pyrrol-2-yl)acetic Acid 2-Methoxyethyl Ester (5d).
Starting with 4d (0.030 g, 0.14 mmol) in 1,4-dioxane (3 mL),
5d was isolated after chromatography (silica gel, n-Hex/EtOAc
) 100:1 f 10:1) as a black oil (0.025 g, 98%). 1H NMR (CDCl3,
300 MHz): δ ) 3.39 (s, 3 H, OCH3), 3.60-3.63 (m, 2 H, OCH2),
3.72 (s, 2 H, CH2), 4.27-4.32 (m, 2 H, OCH2), 6.02 (m, 1 H,
CH), 6.14 (q, J ) 3.0 Hz, 1 H, CH), 6.75 (m, 1 H, CH), 8.82
(broad s, 1 H, NH). 13C NMR (CDCl3, 75 MHz): δC ) 33.1,
58.8, 64.1, 70.1, 107.2, 108.1, 117.6, 122.9, 170.9. IR (neat,
cm-1): ν˜ ) 3359 (m), 2932 (m), 2895 (m), 2825 (w), 1741 (s),
1643 (m), 1577 (w), 1452 (m), 1409 (m), 1369 (m), 1320 (s),
1264 (s), 1197 (s), 1178 (s), 1152 (s), 1227 (s), 1097 (s), 1037
(s), 861 (w), 790 (w), 728 (m). MS (EI, 70 eV): m/z ) 183 (M+,
25), 125 (11), 107 (46), 80 (100). The exact molecular mass m/z
) 183.0895 ( 2 ppm [M+] for C9H13O3N was confirmed by
HRMS (EI, 70 eV).
1-Phenyl-2-(1H-pyrrol-2-yl)ethanone (5e). Starting with
4e (0.026 g, 0.12 mmol) in 1,4-dioxane (5 mL), 5e was isolated
after chromatography (silica gel, n-Hex/EtOAc ) 100:1 f 1:1)
as a brownish solid (0.018 g, 82%). 1H NMR (CDCl3, 300
MHz): δ ) 4.32 (s, 2 H, CH2), 6.07 (m, 1 H, CH),), 6.15 (dd, J
) 6.0, 1.8 Hz, 1 H, CH), 6.76 (m, 1 H, CH), 7.44-7.50 (m, 2 H,
2 × CH of Ph), 7.55-7.60 (m, 1 H, CH of Ph), 7.99-8.03 (m, 2
H, 2 × CH from Ph), 8.85 (broad s, 1 H, NH). 13C NMR (CDCl3,
75 MHz): δC ) 36.9, 107.4, 108.2, 117.8, 123.9, 128.4, 128.7,
133.4, 136.3, 197.7. IR (KBr, cm-1): ν˜ ) 3351 (s), 2902 (w),
1676 (s), 1587 (w), 1341 (m), 1285 (w), 1239 (m), 1215 (m),
999 (m), 796 (m), 742 (s), 731 (s), 690 (m), 600 (w). MS (EI, 70
eV): m/z ) 185 (M+, 33), 105 (79), 80 (100). The exact
molecular mass m/z ) 185.0841 ( 2 ppm [M+] for C12H11ON
was confirmed by HRMS (EI, 70 eV).
) 7.2 Hz, 3 H, CH3), 2.18-2.42 (m, 1 H, CH), 3.63-3.76 (m, 2
H, CH2NH), 4.11 (dq, J ) 1.5, 7.2 Hz, 2 H, OCH2), 4.56 (s, 1
H, CHdC), 5.09-5.15 (m, 2 H, CH2dCH), 5.76-5.88 (m, 1 H,
CH)CH2), 7.80 (broad s, 1 H, NH). 13C NMR (CDCl3, 150
MHz): δC ) 14.8, 35.9, 49.6, 51.0, 56.8, 58.7, 77.9, 81.7, 117.7,
134.9, 170.0, 171.0. IR (neat, cm-1): ν˜ ) 3367 (m), 2980 (s),
2934 (m), 2905 (m), 2829 (w), 1732 (s), 1661 (s), 1603 (s), 1488
(m), 1463 (m), 1444 (m), 1418 (w), 1369 (m), 1299 (s), 1245 (s),
1221 (s), 1183 (s), 1151 (s), 1099 (s), 1051 (s), 998 (w), 974 (w),
918 (m), 854 (m), 785 (w). MS (EI, 70 eV): m/z ) 225 (M+,
22), 194 (71), 180 (17), 151 (32), 120 (100). The exact molecular
mass m/z ) 225.1365 ( 2 ppm [M+] for C12H19O3N was
confirmed by HRMS (EI, 70 eV).
(4-Methoxy-3-propylpyrrolidin-2-ylidene)acetic Acid
Ethyl Ester (4j). Starting with 3j (0.350 g, 1.29 mmol) and
PPh3 (0.406 g, 1.55 mmol) in THF (15 mL), 4j was isolated
after chromatography (silica gel, n-Hex/EtOAc ) 100:1 f 1:1)
1
as a brownish oil (0.252 g, 86%). H NMR (CDCl3, 300 MHz):
δ ) 0.98 (t, J ) 6.6 Hz, 3 H, CH3), 1.25 (t, J ) 7.1 Hz, 3 H,
OCH2CH3), 1.39-1.49 (m, 4 H, 2 × CH2), 2.68-2.72 (m, 1 H,
CH), 3.32 (s, 3 H, OCH3), 3.49 (dt, J ) 10.5, 1.5 Hz, 1 H, CH),
3.64-3.72 (m, 2 H, CH2NH), 4.10 (dq, J ) 1.5, 7.2 Hz, 2 H,
OCH2), 4.53 (s, 1 H, CHdC), 7.78 (broad s, 1 H, NH). 13C NMR
(CDCl3, 150 MHz): δC ) 14.1, 14.7, 20.3, 34.0, 49.9, 51.0, 56.5,
58.5, 77.7, 82.7, 168.0, 170.8. IR (neat, cm-1): ν˜ ) 3367 (w),
2960 (m), 2934 (m), 2873 (w), 1661 (s), 1605 (s), 1489 (w), 1462
(w), 1369 (w), 1313 (w), 1286 (w), 1241 (s), 1220 (s), 1192 (m),
1149 (s), 1097 (m), 1050 (m), 783 (w). UV-vis (CH2Cl2, nm):
λmax (log ꢀ) ) 280 (4.18). MS (EI, 70 eV): m/z ) 227 (M+, 12),
196 (4), 182 (17), 167 (7), 154 (100). HRMS (ESI): calcd for
C12H22O3N ([M + 1]+) ) 228.15997; found ) 228.15923.
3-Methoxy-2,3,3a,4,5,6,7,8,9,10,11,12-dodecahydro-1H-
cyclododeca[b]pyrrole-13-carboxylic Acid Ethyl Ester
(4p). Starting with 3p (1.900 g, 5.38 mmol) and PPh3 (1.692
g, 6.45 mmol) in THF (10 mL), 4p was isolated after chroma-
tography (silica gel, n-Hex/EtOAc ) 100:1 f 1:1) as a brownish
1
oil (1.624 g, 98%). H NMR (CDCl3, 600 MHz): δ ) 1.23 (t, J
) 7.2 Hz, 3 H, CH3), 1.25-1.45 (m, 12 H, 6 × CH2), 1.52-1.65
(m, 2 H, CH2), 1.71-1.76 (m, 1 H, CH2), 1.82-1.87 (m, 1 H,
CH2), 2.11-2.19 (m, 2 H, CH2), 3.00 (dd, J ) 9.2 Hz, 1 H, CH),
3.28 (s, 3 H, OCH3), 3.53 (dd, J ) 9.2 Hz, 1 H, CH), 3.58 (d, J
) 4.6 Hz, 1 H, CH2NH), 3.65 (dd, J ) 18.4, 4.6 Hz, 1 H, CH2-
NH), 4.04-4.14 (m, 2 H, OCH2), 8.04 (broad s, 1 H, NH). 13C
NMR (CDCl3, 50 MHz): δc ) 14.1, 21.1, 23.1, 24.1, 24.9, 25.6,
26.7, 27.9, 28.3, 37.3, 50.4, 50.7, 56.0, 58.6, 82.4, 90.3, 166.1,
175.3. IR (neat, cm-1): ν˜ ) 3355 (m), 2929 (s), 2860 (s), 1727
(s), 1656 (s), 1583 (s), 1468 (m), 1445 (m), 1367 (w), 1315 (w),
1296 (w), 1337 (s), 1226 (s), 1178 (s), 1146 (m), 1095 (s), 1049
(s). MS (EI, 70 eV): m/z ) 309 (M+, 29), 278 (100), 264 (9),
236 (4), 204 (51). The exact molecular mass m/z ) 309.2304 (
2 ppm [M+] for C18H31O3N was confirmed by HRMS (EI, 70
eV).
(3-Methyl-1H-pyrrol-2-yl)acetic Acid Methyl Ester (5f).
Starting with 4f (0.300 g, 1.62 mmol) in CH2Cl2 (30 mL), 5f
was isolated after chromatography (silica gel, n-Hex/EtOAc )
1
1-(4-Methoxypyrrolidin-2-ylidene)propan-2-one (4u).
Starting with 3u (0.130 g, 0.653 mmol) and PPh3 (0.188 g,
0.718 mmol) in THF (5 mL), 4u was isolated after chroma-
tography (silica gel, n-Hex/EtOAc ) 50:1 f 1:1) as a yellow
solid (1:1 mixture of product and PPh3, calculated yield of
product: 0.082 g, 81%). 1H NMR (CDCl3, 300 MHz): δ ) 2.03
(s, 3 H, CH3), 2.64 (dd, J ) 17.1, 1.8 Hz, 1 H, CH2), 2.78 (ddd,
J ) 17.1, 6.3, 0.6 Hz, 1 H, CH2), 3.32 (s, 3 H, OCH3), 3.60 (dd,
J ) 11.7, 2.4 Hz, 1 H, CH2NH), 3.69 (dd, J ) 11.7, 5.1 Hz, 1
H, CH2NH), 4.06 (sept, J ) 3.0 Hz, 1 H, CH), 5.12 (s, 1 H,
CHdC), 9.68 (broad s, 1 H, NH). 13C NMR (CDCl3, 75 MHz):
δc ) 28.7, 38.6, 52.7, 56.5, 76.7, 90.5, 164.9, 195.4. IR (neat,
cm-1): ν˜ ) 3297 (w), 2929 (m), 1624 (s), 1550 (s), 1504 (m),
1463 (w), 1438 (m), 1417 (w), 1361 (m), 1294 (m), 1252 (m),
1188 (s), 1097 (s), 21038 (w). MS (EI, 70 eV): m/z ) 155 (M+,
82), 140 (100), 124 (48), 80 (26), 68 (9). The exact molecular
100:1 f 10:1) as a brownish solid (0.248 g, 100%). H NMR
(CDCl3, 300 MHz): δ ) 2.04 (s, 3 H, CH3), 3.60 (s, 2 H, CH2),
3.71 (s, 3 H, OCH3), 6.00 (t, J ) 1.8 Hz, 1 H, CH), 6.67 (t, J )
1.8 Hz, 1 H, CH), 8.49 (broad s, 1 H, NH). 13C NMR (CDCl3,
75 MHz): δC ) 10.6, 30.9, 51.9, 109.7, 115.7, 116.4, 119.2,
171.7. IR (KBr, cm-1): ν˜ ) 3353 (s), 2953 (w), 2922 (w), 1717
(s), 1448 (w), 1436 (m), 1401 (m), 1344 (m), 1290 (w), 1256
(m), 1224 (s), 1178 (m), 1099 (m), 986 (m), 848 (w), 787 (w),
721 (s), 592 (m), 568 (w). UV-vis (CH2Cl2, nm): λmax (log ꢀ) )
227 (3.65), 460 (2.39). MS (EI, 70 eV): m/z ) 153 (M+, 49),
138 (1), 94 (100), 80 (2). Anal. Calcd for C8H11O2N (153.181):
C, 62.73; H, 7.24; N, 9.14. Found: C, 63.04; H, 7.82; N, 8.73.
(3-Ethyl-1H-pyrrol-2-yl)acetic Acid Ethyl Ester (5g).
Starting with 4g (0.120 g, 0.56 mmol) in CH2Cl2 (12 mL), 5g
was isolated after chromatography (silica gel, n-Hex/EtOAc )
100:1 f 1:1) as a brownish oil (0.102 g, 100%). 1H NMR (CDCl3,
J. Org. Chem, Vol. 70, No. 12, 2005 4759

Bellur et al.
300 MHz): δ ) 1.16 (t, J ) 7.5 Hz, 3 H, CH3), 1.27 (t, J ) 7.2
Hz, 3 H, OCH2CH3), 2.43 (q, J ) 7.5 Hz, 2 H, CH2), 3.59 (s, 2
H, CH2), 4.17 (q, J ) 7.2 Hz, 2 H, OCH2), 6.05 (t, J ) 1.8 Hz,
1 H, CH), 6.68 (t, J ) 1.8 Hz, 1 H, CH), 8.53 (broad s, 1 H,
NH). 13C NMR (CDCl3, 75 MHz): δc ) 13.9, 15.4, 18.6, 31.1,
60.8, 107.8, 116.4, 118.5, 122.6, 171.2. IR (neat, cm-1): ν˜ )
3392 (m), 2965 (m), 2933 (w), 2873 (w), 1730 (s), 1478 (w), 1460
(m), 1425 (w), 1401 (w), 1370 (m), 1331 (w), 1297 (m), 1251
(m), 1182 (m), 1139 (m), 1096 (w), 1030 (m), 724 (m). MS (EI,
70 eV): m/z ) 181 (M+, 37), 166 (5), 120 (3), 107 (100), 93 (23).
The exact molecular mass m/z ) 181.1103 ( 2 ppm [M+] for
C10H15O2N was confirmed by HRMS (EI, 70 eV).
(3-Propyl-1H-pyrrol-2-yl)acetic Acid Ethyl Ester (5j).
Starting with 4j (0.200 g, 0.88 mmol) in CH2Cl2 (20 mL), 5j
was isolated without further purification as a brownish oil
(0.172 g, 100%). 1H NMR (CDCl3, 300 MHz): δ ) 0.93 (t, J )
7.2 Hz, 3 H, CH3), 1.27 (t, J ) 7.2 Hz, 3 H, OCH2CH3), 1.55
(sextet, J ) 7.5 Hz, 2 H, CH2), 2.37 (t, J ) 7.2 Hz, 2 H, CH2),
3.59 (s, 2 H, CH2), 4.17 (q, J ) 7.2 Hz, 2 H, OCH2), 6.03 (t, J
) 2.7 Hz, 1 H, CH), 6.68 (t, J ) 2.7 Hz, 1 H, CH), 8.56 (broad
s, 1 H, NH). 13C NMR (CDCl3, 150 MHz): δC ) 14.15, 14.20,
24.5, 27.9, 31.4, 61.0, 108.7, 116.6, 119.2, 121.2, 171.5. IR (neat,
cm-1): ν˜ ) 3393 (s), 2960 (s), 2931 (s), 2871 (m), 1731 (s), 1639
(w), 1461 (m), 1399 (w), 1371 (m), 1327 (m), 1303 (m), 1248
(s), 1231 (s), 1181 (s), 1140 (s), 1098 (m), 1067 (w), 1031 (s),
721 (m). MS (EI, 70 eV): m/z ) 195 (M+, 48), 180 (1), 166 (49),
122 (100). The exact molecular mass m/z ) 195.1259 ( 2 ppm
[M+] for C11H17O2N was confirmed by HRMS (EI, 70 eV).
brownish oil (0.047 g {0.039 g, 32%; 0.008 g, 4%}; 0.056 g, 49%
) 85%). [Inseparable mixture of 5a/6a ) 4.5:1].
5a, 6a. [*Signals of 6a] 1H NMR (CDCl3, 300 MHz): δ )
3.69 (s, 2 H, CH2), 3.72 (s, 3 H, OCH3), *3.77 (s, 2 H, CH2),
*3.78 (s, 3 H, OCH3), 6.01 (m, 1 H, CH), 6.13-6.16 (m, 1 H,
CH), *6.23 (m, 1 H, CH), 6.76 (m, 1 H, CH), 7.13 (m, 1 H, CH),
8.71 (broad s, 1 H, NH), *9.98 (broad s, 1 H, NH).13C NMR
(CDCl3, 75 MHz): δC ) *32.9, 33.0, 52.1, *52.6, 107.4, 108.3,
*112.3, 115.1, 117.8, *118.9, *122.0, *123.1, *125.8, *135.6,
*169.7, 171.7. IR (KBr, cm-1): ν˜ ) 3413 (w), 3298 (m), 2925
(w), 1746 (s), 1650 (s), 1437 (m), 1353 (m), 1261 (m), 1201 (s),
1145 (s), 1103 (w), 1062 (m), 1027 (w), 886 (w), 804 (m), 766
(m). MS (EI, 70 eV): m/z ) *235 (M+, 60), *176 (100), *166
(47), 139 (M+, 1), 124 (1), 106 (52), 79 (36). The exact molecular
mass m/z ) 139.0633 ( 2 ppm [M+] for C7H9O2N was
confirmed by HRMS (EI, 70 eV).
1
7a. H NMR (CDCl3, 300 MHz): δ ) 3.67 (s, 3 H, OCH3),
3.74 (s, 3 H, OCH3), 3.84 (s, 2 H, CH2), 3.86 (s, 2 H, CH2), 6.40
(m, 1 H, CH), 6.98 (d, J ) 7.2 Hz, 1 H, CH), 7.11 (t, J ) 7.2
Hz, 1 H, CH), 7.26 (d, J ) 7.2 Hz, 1 H, CH), 8.76 (broad s, 1
H, NH).13C NMR (CDCl3, 75 MHz): δC ) 33.7, 39.2, 51.9, 52.3,
100.3, 110.1, 120.7, 121.9, 125.4, 127.8, 130.5, 136.3, 171.0,
172.2. IR (neat, cm-1): ν˜ ) 3374 (w), 2954 (w), 1735 (s), 1641
(m), 1551 (w), 1437 (m), 1340 (w), 1262 (m), 1203 (m), 1161
(s), 1103 (w), 1045 (w), 1015 (w), 769 (w). MS (EI, 70 eV): m/z
) 261 (M+, 74), 215 (1), 202 (100), 166 (8), 143 (32), 115 (10).
HRMS (ESI): calcd for C14H16O4N ([M + 1]+) ) 262.10793,
found ) 262.10718.
4,5,6,7,8,9,10,11,12,13-Decahydro-1H-cyclododeca[b]-
pyrrole-13-carboxylic Acid Ethyl Ester (5p). Starting with
4p (0.800 g, 2.59 mmol) in CH2Cl2 (40 mL), 5p was isolated
without further purification as a black solid (0.719 g, 100%).
1H NMR (CDCl3, 300 MHz): δ ) 1.25 (t, J ) 7.11 Hz, 3 H,
CH3), 1.18-1.43 (m, 12 H, 6×CH2), 1.54-1.68 (m, 2 H, CH2),
1.88-1.95 (m, 2 H, CH2), 2.40-2.51 (m, 2 H, OCH2), 3.84 (t, J
) 7.5 Hz, 1 H, CH), 4.06-4.20 (m, 2 H, OCH2), 6.00 (t, J ) 2.7
Hz, 1 H, CH), 6.71 (t, J ) 2.7 Hz, 1 H, CH), 8.39 (broad s, 1 H,
NH). 13C NMR (CDCl3, 50 MHz): δc ) 14.2, 22.1, 22.3, 22.5,
24.1, 24.16, 24.2, 24.7, 29.0, 32.7, 39.3, 60.8, 108.0, 117.2, 121.2,
124.6, 174.9. IR (KBr, cm-1): ν˜ ) 3345 (s), 2928 (s), 2860 (m),
1721 (s), 1458 (w), 1232 (m), 1201 (m), 1153 (m). MS (EI, 70
eV): m/z ) 277 (M+, 100), 248 (1), 204 (100). UV-Vis (CH2-
Cl2, nm): λmax (log ꢀ) ) 231 (3.71). The exact molecular mass
m/z ) 277.2042 ( 2 ppm [M+] for C17H27O2N was confirmed
by HRMS (EI, 70 eV). The structure was confirmed by X-ray
crystallography.
1-(1H-Pyrrol-2-yl)propan-2-one (5u). Starting with 4u
(0.050 g, 0.32 mmol) in 1,4-dioxane (5 mL), 5u was isolated
after chromatography (silica gel, n-Hex/EtOAc ) 10:1 f 1:1)
as a brownish solid (0.034 g, 87%). 1H NMR (CDCl3, 300
MHz): δ ) 2.20 (s, 3 H, CH3), 3.74 (s, 2 H, CH2), 6.00 (m, 1 H,
CH), 6.15 (dd, J ) 6.0, 3.0 Hz, 1 H, CH), 6.75 (m, 1 H, CH),
8.62 (broad s, 1 H, NH). 13C NMR (CDCl3, 75 MHz): δC ) 29.5,
42.1, 107.4, 108.3, 117.8, 123.8, 206.8. IR (KBr, cm-1): ν˜ )
3328 (s), 2912 (w), 1706 (s), 1427 (w), 1390 (w), 1358 (w), 1331
(w), 1286 (w), 1234 (w), 1168 (w), 1127 (w), 1029 (w), 799 (m),
758 (m), 728 (m), 607 (w), 561 (w). MS (EI, 70 eV): m/z ) 123
(M+, 22), 82 (100). The exact molecular mass m/z ) 123.0684
( 2 ppm [M+] for C7H9ON was confirmed by HRMS (EI, 70
eV).
5d-[5-(2,2,2-Trifluoroacetyl)-1H-pyrrol-2-yl]acetic Acid
2-Methoxyethyl Ester (6d) and [7-(2-Methoxyethoxycar-
bonylmethyl)-1H-indol-2-yl]acetic Acid 2-Methoxyethyl
Ester (7d). Starting with 4d (0.050 g, 0.23 mmol) and TFA
(0.23 mL, 3.02 mmol) in CH2Cl2 (5 mL), 5, 6d and 7d were
isolated after chromatography (silica gel, n-Hex/EtOAc ) 100:1
f 1:1) as black and brownish oils (0.019 g {0.008 g, 19%; 0.011
g, 17%}; 0.018, 45% ) 81%). [Inseparable mixture of 5d/6d )
1:1.4].
1
5d, 6d. [*Signals of 6d] H NMR (CDCl3, 300 MHz): δ )
3.40 (s, 3 H, OCH3), 3.42 (s, 3 H, OCH3), 3.60-3.67 (m, 4 H, 2
× OCH2), *3.72 (s, 2 H, CH2), 3.80 (s, 2 H, CH2), 4.27-4.30
(m, 2 H, OCH2), 4.32-4.36 (m, 2 H, OCH2), 6.02 (m, 1 H, CH),
6.12-6.15 (m, 1 H, CH), *6.23 (m, 1 H, CH), 6.75 (m, 1 H,
CH), *7.13 (m, 1 H, CH), 8.78 (broad s, 1 H, NH), *10.18 (broad
s, 1 H, NH). IR (neat, cm-1): ν˜ ) 3375 (w), 3300 (m), 2978
(w), 2954 (w), 2926 (w), 2893 (w), 2856 (w), 1741 (m), 1653
(m), 1503 (w), 1452 (w), 1435 (w), 1407 (w), 1373 (w), 1342
(w), 1259 (m), 1192 (s), 1145 (s), 1102 (m), 1059 (m), 1034 (m),
883 (w), 804 (w), 765 (m), 731 (w). MS (EI, 70 eV): m/z ) *279
(M+, 1), *203 (11), 183 (M+, 18), *176 (6), 107 (34), 80 (100).
The exact molecular mass m/z ) 183.0895 ( 2 ppm [M+] for
C9H13O3N was confirmed by HRMS (EI, 70 eV).
1
7d. H NMR (CDCl3, 300 MHz): δ ) 3.35 (s, 3 H, OCH3),
3.42 (s, 3 H, CH3), 3.56-3.67 (m, 4 H, 2 × OCH2), 3.88 (s, 2 H,
CH2), 3.89 (s, 2 H, CH2), 4.23-4.26 (m, 2 H, OCH2), 4.29-
4.34 (m, 2 H, OCH2), 6.42 (m, 1 H, CH), 6.99 (d, J ) 7.2 Hz, 1
H, CH), 7.11 (t, J ) 7.2 Hz, 1 H, CH), 7.26 (d, J ) 7.2 Hz, 1 H,
CH), 8.89 (broad s, 1 H, NH). IR (neat, cm-1): ν˜ ) 3364 (w),
2928 (w), 1736 (s), 1643 (m), 1552 (w), 1441 (m), 1407 (m),
1376 (w), 1325 (w), 1254 (m), 1159 (s), 1129 (s), 1037 (m), 769
(w). MS (EI, 70 eV): m/z ) 349 (M+, 23), 199 (14), 167 (27),
143 (30), 141 (100), 114 (12), 104 (58). HRMS (ESI): calcd for
C18H24O6N ([M + 1]+) ) 350.16036; found ) 350.15946.
General Procedure for the TFA Reactions of Pyrro-
lidines (4). To a CH2Cl2 solution (20 mL/mmol) of 4 (1 equiv)
was added TFA (13 equiv), and the solution was stirred for 24
h at 20 °C. The solvent was removed in vacuo and the residue
was purified by chromatography (silica gel, n-hexane/EtOAc)
to give 5, 6, and 7.
5a-[5-(2,2,2-Trifluoroacetyl)-1H-pyrrol-2-yl]acetic Acid
Methyl Ester (6a) and (7-Methoxycarbonylmethyl-1H-
indol-2-yl)acetic Acid Methyl Ester (7a). Starting with 4a
(0.150 g, 0.88 mmol) and TFA (0.88 mL, 11.4 mmol) in CH2-
Cl2 (15 mL), 5, 6a and 7a were isolated after chromatography
(silica gel, n-Hex/EtOAc ) 100:1 f 1:1) as black solid and
2,2,2-Trifluoro-1-[5-(2-oxo-2-phenylethyl)-1H-pyrrol-2-
yl]ethanone (6e). Starting with 4e (0.200 g, 0.92 mmol) and
TFA (0.9 mL, 12.0 mmol) in CH2Cl2 (20 mL), 6e was isolated
after chromatography (silica gel, n-Hex/EtOAc ) 100:1 f 1:1)
as a black solid (0.139 g, 54%). Mp ) 121.7 °C. 1H NMR (CDCl3,
300 MHz): δ ) 4.44 (s, 2 H, CH2), 6.28 (dd, J ) 3.9, 2.7 Hz, 1
H, CH), 7.16 (m, J ) 2.0 Hz, 1 H, CH), 7.54 (m, 2 H, 2 × CH
from Ph), 7.61-7.66 (m, 1 H, CH from Ph), 8.00-8.07 (m, 2
H, 2 × CH from Ph), 10.34 (broad s, 1 H, NH). 13C NMR
(CDCl3, 75 MHz): δc ) 36.5, 112.6, 115.2, 119.0, 122.0, 125.9,
4760 J. Org. Chem., Vol. 70, No. 12, 2005

Synthesis of 2-Alkylidenepyrrolidines, Pyrroles, and Indoles
128.4, 129.0, 134.1, 135.9, 136.7, 195.2. IR (neat, cm-1): ν˜ )
3295 (m), 2962 (w), 2925 (w), 1692 (m), 1641 (s), 1559 (w), 1497
(w), 1448 (w), 1430 (w), 1406 (w), 1355 (w), 1332 (w), 1261
(m), 1187 (m), 1142 (s), 1098 (m), 1063 (m), 1024 (m), 883 (w),
794 (m), 758 (m), 687 (w). MS (EI, 70 eV): m/z ) 281 (M+, 4),
212 (5), 176 (4), 105 (100), 77 (45). HRMS (ESI): calcd for
C14H11O2NF3 ([M + 1]+) ) 282.07419; found ) 282.07346.
General Procedure for the Preparation of Pyrroles 9
and 12. To a THF solution (10 mL/mmol) of 11 (1 equiv) was
added triphenylphosphine (1.2 equiv) at room temperature.
The reaction mixture was heated and stirred for 4 h at 80 °C.
After the mixture was cooled to 20 °C, the solvent was removed
in vacuo and the residue was purified by chromatography
(silica gel, n-hexane/EtOAc) to give 12.
1697 (s), 1675 (s), 1578 (m), 1499 (m), 1447 (m), 1411 (m), 1369
(m), 1325 (s), 1267 (s), 1227 (w), 1201 (s), 1127 (s), 1095 (s),
1053 (s), 901 (m), 781 (m), 754 (m), 722 (m). MS (EI, 70 eV):
m/z ) 153 (M+, 95), 124 (61), 108 (100). The exact molecular
mass m/z ) 153.0790 ( 2 ppm [M+] for C8H11O2N was
confirmed by HRMS (EI, 70 eV).
1-(2-Methyl-1H-pyrrol-3-yl)ethanone (12d). Starting with
11d (0.100 g, 0.55 mmol) and PPh3 (0.172 g, 0.66 mmol) in
THF (10 mL), 12d was isolated after chromatography (silica
gel, n-Hex/EtOAc ) 30:1 f 2:1) as a brownish solid (0.066 g,
97%). Mp ) 75 °C. 1H NMR (CDCl3, 300 MHz): δ ) 2.43 (s, 3
H, CH3), 2.55 (s, 3 H, CH3), 6.52-6.54 (m, 1 H, CH), 6.57-
6.59 (m, 1 H, CH), 8.52 (broad s, 1 H, NH). 13C NMR (CDCl3,
75 MHz): δC ) 13.8, 28.3, 110.5, 115.9, 120.5, 135.4, 195.8.
IR (KBr, cm-1): ν˜ ) 3211 (s), 3110 (s), 3021 (m), 2981 (w),
2962 (m), 2926 (m), 2843 (w), 1636 (s), 1569 (s), 1491 (s), 1465
(s), 1402 (s), 1364 (s), 1333 (w), 1279 (m), 944 (m), 892 (m),
858 (w), 799 (w), 775 (w), 733 (m), 677 (w), 636 (w). MS (EI,
70 eV): m/z ) 123 (M+, 44), 107 (100) 94 (3), 80 (25), 66 (2),
43 (11). Anal. Calcd for C7H9ON (123.155): C, 68.27; H, 7.37;
N, 11.37. Found: C, 68.12; H, 7.15; N, 11.53.
2-1H-Pyrrole-2-ylmethyl-1H-pyrrole (9). Starting with
8 (0.100 g, 0.34 mmol) and PPh3 (0.198 g, 0.75 mmol) in THF
(10 mL), 9 was isolated after chromatography (silica gel, n-Hex/
1
EtOAc ) 75:1 f 10:1) as a brownish solid (0.041 g, 83%). H
NMR (CDCl3, 300 MHz): δ ) 3.97 (s, 2 H, CH2), 6.02-6.042
(m, 2 H, 2 × CH), 6.14 (dd, J ) 5.7, 2.7 Hz, 2 H, 2 × CH), 6.64
(dd, J ) 4.2, 2.7 Hz, 2 H, 2 × CH), 6.64 (dd, J ) 4.2, 2.7 Hz,
2 H, 2 × CH), 7.83 (broad s, 2 H, 2 × NH). 13C NMR (CDCl3,
75 MHz): δC ) 26.4, 106.4, 108.4, 117.2, 129.0. IR (KBr, cm-1):
ν˜ ) 3333 (s), 2923 (w), 1631 (w), 1564 (w), 1468 (w), 1439
(w), 1425 (w), 1332 (w), 1261 (w), 1250 (w), 1183 (w), 1114
(m), 1094 (m), 1026 (m), 804 (m), 729 (s), 682 (w), 689 (w), 625
(w), 586 (m), 549 (w). MS (EI, 70 eV): m/z ) 146 (M+, 100), 80
(39), 67 (26). The exact molecular mass m/z ) 146.0844 ( 2
ppm [M+] for C9H10N2 was confirmed by HRMS (EI, 70 eV).
2-Methyl-1H-pyrrole-3-carboxylic Acid Methyl Ester
(12a). Starting with 11a (0.030 g, 0.14 mmol) and PPh3 (0.044
g, 0.17 mmol) in THF (5 mL), 12a was isolated after chroma-
tography (silica gel, n-Hex/EtOAc ) 100:1 f 5:1) as a brownish
solid (0.017 g, 85%). 1H NMR (CDCl3, 300 MHz): δ ) 2.53 (s,
3 H, CH3), 3.80 (s, 3 H, OCH3), 6.55 (d, J ) 2.7 Hz, 1 H, CH),
6.56 (d, J ) 2.7 Hz, 1 H, CH), 8.23 (broad s, 1 H, NH). 13C
NMR (CDCl3, 75 MHz): δC ) 13.2, 50.8, 110.4, 110.5, 115.8,
135.3, 166.1. IR (neat, cm-1): ν˜ ) 3312 (m), 2978 (s), 2952 (w),
2933 (w), 2867 (m), 1707 (s), 1680 (s), 1607 (w), 1580 (m), 1493
(w), 1452 (s), 1408 (w), 1381 (m), 1348 (w), 1329 (m), 1268 (m),
1226 (w), 1202 (m), 1177 (w), 1125 (s), 1076 (w), 1053 (w), 1026
(w), 900 (w), 844 (w), 790 (w), 726 (w). MS (EI, 70 eV): m/z )
139 (M+, 46), 124 (19), 107 (100), 80 (33). The exact molecular
mass m/z ) 139.0633 ( 2 ppm [M+] for C7H9O2N was
confirmed by HRMS (EI, 70 eV).
2-Heptyl-1H-pyrrole-3-carboxylic Acid Ethyl Ester
(12i). Starting with 11i (0.100 g, 0.33 mmol) and PPh3 (0.105
g, 0.40 mmol) in THF (10 mL), 12i was isolated after chro-
matography (silica gel, n-Hex/EtOAc ) 100:1 f 5:1) as a
1
brownish solid (0.069 g, 89%). H NMR (CDCl3, 300 MHz): δ
) 0.86 (t, J ) 6.9 Hz, 3 H, CH3), 1.15-1.40 (m, 11 H, 4 × CH2,
CH3), 1.50-1.64 (m, 2 H, CH2), 2.92 (t, J ) 7.5 Hz, 2 H, CH2),
4.27 (q, J ) 7.2 Hz, 2 H, OCH2), 6.56 (d, J ) 3.0 Hz, 1 H, CH),
6.58 (d, J ) 3.3 Hz, 1 H, CH), 8.21 (broad s, 1 H, NH). 13C
NMR (CDCl3, 75 MHz): δC ) 13.9, 14.3, 22.5, 27.3, 29.0, 29.3,
29.5, 31.7, 59.2, 110.9, 110.9, 115.8, 140.1, 165.8. IR (neat,
cm-1): ν˜ ) 3324 (s), 2956 (s), 2928 (s), 2871 (m), 2857 (m),
1726 (m), 1702 (s), 1673 (s), 1574 (m), 1496 (m), 1466 (s), 1394
(m), 1370 (m), 1331 (m), 1297 (m), 1264 (m), 1197 (m), 1181
(m), 1128 (s), 1096 (w), 1077 (w), 1049 (m), 1028 (w), 902 (w),
790 (w), 724 (m). MS (EI, 70 eV): m/z ) 237 (M+, 40), 208
(18), 192 (12), 164 (39), 151 (38), 138 (6), 124 (100). Anal. Calcd
for C14H23O2N (237.342): C, 70.85; H, 9.77; N, 5.90. Found:
C, 70.47; H, 10.10; N, 5.91.
Acknowledgment. We thank Dr. Ilia Freifeld for
an experimental contribution. Financial support from
the DAAD (scholarship for E.B.) from the Landesfors-
chungsschwer punkt “Neue Wirkstoffe und Screen-
ingverfahren”, and from the Deutsche Forschungsge-
meinschaft is gratefully acknowledged.
2-Methyl-1H-pyrrole-3-carboxylic Acid Ethyl Ester
(12b). Starting with 11b (0.100 g, 0.44 mmol) and PPh3 (0.137
g, 0.52 mmol) in THF (10 mL), 12b was isolated after
chromatography (silica gel, n-Hex/EtOAc ) 100:1 f 5:1) as a
1
brownish solid (0.061 g, 91%). Mp ) 64 °C. H NMR (CDCl3,
Supporting Information Available: Details of the crys-
tal structure determinations and copies of NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
300 MHz): δ ) 1.34 (t, J ) 7.2 Hz, 3 H, OCH2CH3), 2.52 (s, 3
H, CH3), 4.27 (q, J ) 7.2 Hz, 2 H, OCH2), 6.56 (d, J ) 2.4 Hz,
2 H, 2 × CH), 8.51 (broad s, 1 H, NH). 13C NMR (CDCl3, 75
MHz): δC ) 13.2, 14.5, 59.4, 110.4, 111.7, 15.7, 135.2, 165.8.
IR (KBr, cm-1): ν˜ ) 3294 (s), 2985 (m), 2938 (w), 2906 (w),
JO047856X
J. Org. Chem, Vol. 70, No. 12, 2005 4761