Synthesis of 2-alkylidenepyrrolidines and pyrroles by condensation of 1,3-dicarbonyl dianions with α-azidoketones and subsequent intramolecular Staudinger-aza-Wittig reaction

Article abstract of DOI:10.1021/jo060593h

The condensation of 1,3-dicarbonyl dianions with α-azidoketones afforded open-chained condensation products that were transformed into pyrroles by Staudinger-aza-Wittig reactions and the subsequent treatment with trifluoroacetic acid.

Full text of DOI:10.1021/jo060593h

Synthesis of 2-Alkylidenepyrrolidines and Pyrroles by Condensation
of 1,3-Dicarbonyl Dianions with r-Azidoketones and Subsequent
Intramolecular Staudinger-Aza-Wittig Reaction
Ilia Freifeld,† Heydar Shojaei,‡ and Peter Langer*,§,|
Institut fu¨r Biochemie, Ernst-Moritz-Arndt UniVersita¨t Greifswald, Soldmannstr. 16,
17487 Greifswald, Germany, Institut fu¨r Organische Chemie, Georg-August-UniVersita¨t Go¨ttingen,
Tammannstr. 2, 37077 Go¨ttingen, Germany, Institut fu¨r Chemie, UniVersita¨t Rostock, Albert-Einstein-Str.
3a, 18059 Rostock, Germany, and Leibniz-Institut fu¨r Katalyse e. V. an der UniVersita¨t Rostock,
Albert-Einstein-Str. 29a, 18059 Rostock, Germany
peter.langer@uni-rostock.de
ReceiVed March 17, 2006
The condensation of 1,3-dicarbonyl dianions with R-azidoketones afforded open-chained condensation
products that were transformed into pyrroles by Staudinger-aza-Wittig reactions and the subsequent
treatment with trifluoroacetic acid.
Introduction
pyrroles. The pyrrole subunit occurs in a number of pharma-
cologically active natural products and synthetic drugs (e.g.,
zomepirac and atorvastatin).4-6 2-Alkylidenepyrrolidines have
been prepared mainly by synthetic modification of suitable
N-heterocycles.7 Synthetic approaches, which rely on the
formation of the N-heterocyclic moiety, are more rare. For
example, 2-alkylidenepyrrolidines have been prepared by the
reaction of 1,3-dicarbonyl dianions with 1-bromo-2-chloroet-
hane, nucleophilic replacement of the chloride by an azido
group, and subsequent Staudinger-aza-Wittig reaction.8 In
addition, 2-alkylidenepyrrolidines have been prepared by the
reaction of 1,3-dicarbonyl dianions with aziridines9 and by ring-
transformation reactions of lactones.10
Recently, we reported the synthesis of functionalized 2-alkyl-
idenepyrrolidines and pyrroles by the reaction of 1,3-bis-silyl
enol ethers with 2-azido-1,1-dimethoxyethane and subsequent
Staudinger-aza-Wittig reaction.11 Pyrroles have been prepared
also by intermolecular Staudinger-aza-Wittig reactions of 1,3-
dicarbonyl compounds with 2-azido-1,1-diethoxyethane and
subsequent acid-mediated cyclization.12 However, the prepara-
tive scope of these methods is limited by the fact that, as a
result of the use of 2-azido-1,1-diethoxyethane, three- and tetra-
2-Alkylidenepyrrolidines represent versatile building blocks
that have shown considerable utility in organic synthesis.1
2-Alkylidenepyrrolidines have been used, for example, during
the synthesis of mitomycin antitumor antibiotics, microsclero-
dermin E, carbapenam-3-carboxylic acid, pyrrolizidines, camp-
tothecin analogues, pyrrolidines, alkaloids (e.g., hygrine, hyg-
roline, or cuskhygrin), and various pharmaceuticals (e.g., the
vasodilator buflomedil).2,3 We have shown earlier that 2-alky-
lidenepyrrolidines represent useful synthetic precursors of
* Corresponding author. Fax: +381 4986412.
† Ernst-Moritz-Arndt Universita¨t Greifswald.
‡ Georg-August-Universita¨t Go¨ttingen.
§ Institut fu¨r Chemie, Universita¨t Rostock.
| Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock.
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10.1021/jo060593h CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/23/2006
J. Org. Chem. 2006, 71, 4965-4968
4965

Freifeld et al.
SCHEME 1. Synthesis of 5a-5ada
substituted pyrroles are not available. Some years ago, Montforts
and co-workers reported13 the synthesis of highly substituted
pyrroles based on reactions of simple silyl enol ethers with
azidoketals and a subsequent aza-Wittig reaction.14 However,
the application of this method to the use of 1,3-bis-silyl enol
ethers failed (due to the formation of complex mixtures in their
reaction with azidoketals). To overcome these limitations, we
developed a new synthesis of highly substituted pyrroles based
on the reaction of R-azidoketones with 1,3-dicarbonyl dianions.
Herein, we report full details of this work. With regard to our
preliminary communication in this field,15 we significantly
extended the preparative scope of our methodology and report,
(5) For pyrrole natural products, see: (a) Falk, H. The Chemistry of Linear
Oligopyrroles and Bile Pigments; Springer-Verlag: Wien, Germany, 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. (f) Lindel, T.; Breckle, G.; Hochgu¨rtel, M.; Volk, C.; Grube,
A.; Ko¨ck, M. Tetrahedron Lett. 2004, 45, 8149.
(6) (a) Huisgen, R.; Gotthard, H.; Bayer, H. O.; Scha¨fer, F. C. Chem.
Ber. 1970, 103, 2611. (b) Chiu, P.-K.; Lui, K.-H.; Maini, P. N.; Sammes,
M. P. J. Chem. Soc., Chem. Commun. 1987, 109. (c) Barton, D. H. R.;
Kervagoret, J.; Zard, S. Z. Tetrahedron 1990, 46, 7587. (d) Roskamp, E.
J.; Dragovich, P. S.; Hartung, J. B.; Pederson, S. F. J. Org. Chem. 1989,
54, 4736. (e) Tang, J.; Verkade, J. G. J. Org. Chem. 1994, 59, 7793. (f) De
Kimpe, N.; Tehrani, K. A.; Stevens, C.; De Cooman, P. Tetrahedron 1997,
53, 3693. (g) Alberala, A.; Ortega, A. G.; Sa´daba, M. L.; Snudo, C.
Tetrahedron 1999, 55, 6555. (h) Grigg, R.; Savic, V. Chem. Commun. 2000,
873. (i) Trofimov, B. A.; Tarasova, O. A.; Mikhaleva, A. I.; Kalinina, N.
A.; Sinegovskaya, L. M.; Henkelmann, J. Synthesis 2000, 11, 1585. (j) Nair,
V.; Vinod, A. U.; Rajesh, C. J. Org. Chem. 2001, 66, 4427. (k) Ranu, B.
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F.; Zard, S. Z. Chem. Commun. 2002, 2214. (n) Demir, A. S.; Akhmedov,
I. M.; Sesenoglu, O¨ . Tetrahedron 2002, 58, 9793. (o) Yoshida, M.; Kitamura,
M.; Narasaka, K. Bull. Chem. Soc. Jpn. 2003, 76, 2003. (p) Knight, D. W.;
Sharland, C. M. Synlett 2003, 2258. (i) Yu, M.; Pagenkopf, B. L. Org.
Lett. 2003, 5, 5099. (q) Dhawan, R.; Arndtsen, B. A. J. Am. Chem. Soc.
2004, 126, 468. (r) Flo¨gel, O.; Reissig, H.-U. Synlett 2004, 895. (s) Song,
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Vasil’tsov, A. M.; Mikhaleva, A. I.; Ushakov, I. A.; Vashchenko, A. V.;
Zorina, N. V. Tetrahedron Lett. 2004, 45, 3789. (w) Agarwal, S.; Kno¨lker,
H.-J. Org. Biomol. Chem. 2004, 2, 3060. (x) Dieltiens, N.; Stevens, C. V.;
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(7) For the condensation of thiolactams with bromomethyl ketones or
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(d) Yamaguchi, M.; Hirao, I. J. Org. Chem. 1985, 50, 1975. For the reaction
of methyl bromoacetate with ω-mesylnitriles, see: (e) Hannick, S. M.; Kishi,
Y. J. Org. Chem. 1983, 48, 3833.
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(12) Bellur, E.; Langer, P. Tetrahedron Lett. 2006, 47, 2151.
a (i) 2.4 equiv of LDA, THF, 0 °C; (ii) -78 °C f 20 °C; (iii) PPh3,
CH2Cl2, 24 h, THF, 45 °C; (iV) TFA, CH2Cl2, 1 h, 20 °C.
for example, the synthesis of bicyclic pyrroles and 4,5,6,7-
tetrahydroindoles. All reactions proceed with excellent regiose-
lectivity. In contrast, the preparative scope of the classic Knorr
or Hantzsch procedures4 is often limited by the formation of
regioisomers. Notably, the substitution pattern of the pyrroles
prepared by our methodology is not readily accessible by other
methods.
Results and Discussion
The reaction of the dianions of 1,3-dicarbonyl compounds
1a-o with R-azidoketones 2a-f afforded the 6-azido-5-
hydroxy-3-oxoalkanoates 3a-ad. The intramolecular Staudinger-
aza-Wittig reaction of the latter gave the 2-alkylidenepyrrolidines
4a-ad, which were transformed into the pyrroles 5a-ad by
treatment with trifluoroacetic acid (TFA; Scheme 1, Table 1).
The reaction of dilithiated ethyl and tert-butyl acetoacetate
(1a,b) with 3-azidobutan-2-one (2a) and 1-azidopropan-2-one
(2b) afforded the open-chained products 3a-d, which were
transformed into the 2-alkylidenepyrrolidines 4a-d. The reac-
tion of the ethyl esters 4a,b with TFA gave the desired pyrroles
5a,b. Treatment of the tert-butyl esters 4c,d with TFA resulted
in decomposition. The reaction of dilithiated methyl 4-meth-
oxyacetoacetate (1c) with 2a and 2b and subsequent cyclization
afforded the 2-alkylidenepyrrolidines 4e,f. Treatment of the latter
with TFA resulted in decomposition. The reaction of dilithiated
methyl 3-oxopentanoate (1d) with 2a and subsequent cyclization
afforded the 2-alkylidenepyrrolidine 4g, which was transformed
into the 3,4,5-trimethylpyrrole 5g. Likewise, 3-ethyl-4-meth-
ylpyrrole 5h was prepared from ethyl 6-oxohexanoate (1e) and
2b. The cyclocondensation of dilithiated ethyl 2-methylacetoac-
etate (1f) with 2b gave 4i, which was transformed into the
pyrrole 5i by treatment with TFA. The pyrroles 5j and 5l were
prepared based on reactions of dilithiated ethyl 2-benzylac-
etoacetate (1g) and 2-acetyl-γ-butyrolactone (1h) with 2b.
The cyclocondensation of the dianions of ethyl cycloalkanone-
2-carboxylates 1i-k with 2a,b afforded 4m-p, which were
(13) (a) Montforts, F.-P.; Schwartz, U. M.; Mai, G. Liebigs Ann. Chem.
1990, 1037. (b) Eguchi, S.; Matsushita, Y.; Yamashita, K. Org. Prep.
Proced. Int. 1992, 24, 211. (c) Eguchi, S.; Okano, T. J. Synth. Org. Chem.,
Jpn. 1993, 51, 203. (d) Wamhoff, H.; Richard, G.; Stoelben, S. AdV.
Heterocycl. Chem. 1995, 64, 159.
(14) Reviews of aza-Wittig reactions: (a) Molina, P.; Viliplana, M. J.
Synthesis 1994, 1197. (b) Eguchi, S.; Okano, T.; Okawa, T. Recent Res.
DeV. Org. Chem. 1997, 337; Chem. Abstr. 1999, 130, 252510. (c) Fresneda,
P. M.; Molina, P. Synlett 2004, 1. (d) Eguchi, S. ArkiVoc 2005, ii, 98.
(15) Langer, P.; Freifeld, I. Chem. Commun. 2002, 2668.
4966 J. Org. Chem., Vol. 71, No. 13, 2006

Synthesis of 2-Alkylidenepyrrolidines and Pyrroles
TABLE 1. Products and Yields
mixtures (ds ) 5:1-1.5:1, assignment arbitrary). Due to the
formation of an intramolecular hydrogen bond N-H‚‚‚O, all
pyrrolidines contain a Z-configured exocyclic double bond.
However, the configuration of the exocyclic double bond and
the formation of diastereomeric mixtures is irrelevant for the
synthesis of pyrroles 5.
4a
5a
1
2
3,4,5 R1
R2
R3
OEt
OEt
R4
R5 3a (%) (%) (%)
a
a
b
a
b
a
b
a
b
b
b
a
b
a
b
b
b
b
c
a
H
H
H
H
H
H
H
H
H
Me Me 59
41b
Me
61c 41b
O(t-Bu) Me Me
50
57
69
59
49
53
52
56
70
51
48
61
73
71
32
28
55
54
51
81
72
32
32
21
50
97
41
34
63
36
a
b
b
c
c
d
e
f
g
g
h
i
b
c
H
H
H
66
55
66
71
0
0
0
0
d
e
f
g
h
i
H
O(t-Bu)
OMe
OMe
OMe
OEt
H
Me
Me Me
Me
Me Me
The first step of the synthesis, the condensation of the dianion
with the azidoketone, was generally accomplished with moderate
to very good yields (except for the reactions of the dianion of
acetylacetone). The intramolecular Staudinger-aza-Wittig reac-
tion was successful for most of the substrates; the formation of
2-alkylidenepyrrolidines from 3j-l, 3y, and 3aa-ad proved to
be unsuccessful. Either pyrroles were directly formed, albeit in
low yield, or decomposition was observed. The TFA-mediated
aromatization proved to be unsuccessful for substrates 4c-f,
as a result of decomposition. Unexpectedly, pyrrole 5v could
not be isolated. Tetrahydropyrrole 5z was obtained from 4z in
good yield. The bicyclic products 4aa-ad, required for the
synthesis of the corresponding tetrahydropyrroles, could not be
prepared. The desired tetrahydropyrroles were isolated in low
yields during the intramolecular Staudinger-aza-Wittig reaction
of 3aa-ad. Notably, some pyrrolidines 4 and pyrroles 5 tend
to be unstable, and decomposition products could not be
completely removed. For some products, a small amount of
triphenylphosphane oxide could not be removed, despite much
synthetic efforts. Notably, the handling of azides is dangerous,
due to their potentially explosive character. In fact, all reactions
should be carried out on a small scale, and the use of a safety
shield is highly recommended.
OMe
OMe
Me
Et
H
75c 87
H
H
H
Me
Me
Me
78
75
H
Me
OEt
68b 81
j
H
PhCH2 OEt
PhCH2 OEt
-(CH2)2O-
0
0
0
32
0
k
l
H
H
Me Me
Me
Me Me
H
33d
91
88
m
n
o
p
q
r
-(CH2)3-
-(CH2)3-
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OEt
OEt
OMe
OEt
Me
62
71
i
j
H
H
H
H
H
H
H
Me
Me
Me
Me
Ph
-(CH2)4-
-(CH2)5-
-(CH2)2-
H
43c,e 83c
k
l
a
d
i
a
d
f
m
n
a
f
28
0
93c
43
94
77
73
77
0
66
33
15b
69
0
H
73
93
57
93
75
58
0
0
27
0
c
c
s
Me
H
Ph
Ph
t
u
v
w
x
-(CH2)3-
d
d
d
c
b
e
e
f
f
e
H
H
H
Me Ph
Me Ph
Me Ph
H
H
-(CH2)4-
-(CH2)4-
-(CH2)3-
-(CH2)3-
-(CH2)4-
Me
H
H
Me
H
Ph
Me
y
z
aa
ab
ac
ad
-(CH3)3-
Ph
H
H
H
H
H
H
OEt
OEt
N(Et)2
Me
H
-(CH2)2O-
o
h
o
0
0
0
15
23
76b
H
N(Et)2
a Isolated yields. All pyrrolidines 4 (except for 4b,d,s,z) were obtained
as diastereomeric mixtures (ds ) 5:1-1.5:1, assignment arbitrary). b Un-
stable compound; a small amount of the decomposition products could not
be separated. c A small amount of triphenylphosphane oxide could not be
separated. d Unseparable mixture with isomer 5l′. e Together with 5o.
Experimental Section
General. All solvents were dried by standard methods, and all
1
reactions were carried out under an inert atmosphere. For H and
13C NMR spectra, the deuterated solvents indicated were used. Mass
spectrometric (MS) data were obtained by electron ionization (EI,
70 eV), chemical ionization (CI, H2O), or electrospray ionization
(ESI). For preparative scale chromatography, silica gel (60-200
mesh) was used. Melting points are uncorrected. The R-azidoketones
2a-f were prepared according to literature procedure. 3-Azidobu-
tan-2-one (2a) was prepared by reaction of 3-chlorobutan-2-one
with NaN3.16 1-Azidopropan-2-one (2b) was prepared from 3-chlo-
robutan-2-one and NaN3.17 R-Azidoacetophenone (2c) was prepared
from R-chloroacetophenone.18 R-Azidopropiophenone (2d) was
prepared from R-chloropropiophenone.19 2-Azidocyclohexanone
(2e)19 and 2-azidocyclopentanone (2f)20 were prepared from 2-chlo-
rocyclohexanone and 2-chlorocyclopentanone, respectively.
CAUTION: The handling of azides is dangerous due to their
potentially explosive character. Although, in our hands, azides 2
did not appear to be shock sensitive, the compounds 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.
transformed into the 5,6-, 5,7-, and 5,8-bicyclic pyrroles 5m-
p. The condensation of ethyl cyclopentanone-2-carboxylate (1l)
with 2b gave 4q. The Staudinger-aza-Wittig reaction of the
latter directly furnished the 5,5-bicyclic pyrrole 5q. The
condensation of the dianions of 1a, 1d, and 1i with R-azido-
acetophenone (2c) gave the condensation products 3r-t, which
were transformed into the pyrroles 5r-t via 4r-t. The reaction
of dilithiated 1a, 1d, and 1f afforded 3u-w, which were
transformed into the corresponding 2-alkylidenepyrrolidines
4u-w. Treatment of 4u and 4w with TFA afforded the pyrroles
5u and 5w. The addition of TFA to 4v resulted in decomposi-
tion. The condensation of dilithiated acetylacetone with 2c
afforded 3x in low yield. The Staudinger-aza-Wittig reaction
of the latter directly furnished the 5x. The 5,6-bicyclic pyrrole
5y was prepared, albeit in low yield, from 2-benzoylcyclohex-
anone (1n) and 2b. The reaction of dilithiated 1a with
2-azidocyclohexanone (2e) and the subsequent aza-Wittig
reaction afforded 4z. Treatment of the latter with TFA furnished
the 5,6-bicyclic pyrrole 5z. The reaction of the dianion of N,N-
diethyl-acetylacetamide (1o) with 2e gave 3ad, which was
directly transformed into 5ad by the aza-Wittig reaction. The
condensation of dilithiated 1o and 1h with 2-azidocyclopen-
tanone afforded 3ab and 3ac, which were directly transformed,
albeit in low yield, into the corresponding 5,5-bicyclic pyrroles
3ab and 3ac. Pyrrolidines 4 were isolated as diastereomeric
General Procedure for the Reaction of 1,3-Dicarbonyl Com-
pounds 1a-o with r-Azidoketones 2a-f. To a solution of
diisopropylamine (2.6 equiv) in anhydrous THF (35 mL) was added
n-BuLi (2.6 equiv, 23 or 15% solution in hexane) at 0 °C. After
stirring for 15 min, the dicarbonyl compound 1 (1.1 equiv) was
added, and the solution was stirred for 1 h at 0 °C. A THF solution
(5 mL) of azidoketone 2 (1.0 equiv) was added at -78 °C, and the
(16) Forster, M. O.; Fierz, M. E. J. Chem. Soc. 1908, 93, 675.
(17) Forster, M. O.; Fierz, M. E. J. Chem. Soc. 1908, 93, 81.
(18) Boyer, J. M.; Straw, D. J. Am. Chem. Soc. 1953, 75, 1642.
(19) Batanero, B.; Escudero, J.; Barba, F. Synthesis 1999, 10, 1809.
(20) Effenberger, F.; Beisswenger, T.; Az, R. Chem. Ber. 1985, 118,
4869.
J. Org. Chem, Vol. 71, No. 13, 2006 4967

Freifeld et al.
reaction mixture was warmed to ambient temperature over a period
of 12 h. After stirring for an additional 3 h at 20 °C, a saturated
aqueous solution of NH4Cl (50 mL) was added, the organic layer
was separated, and the aqueous layer was extracted with Et2O (2
× 70 mL) and with CH2Cl2 (2 × 50 mL). The combined organic
layers were extracted with brine, dried (Na2SO4), and filtered, and
the solvent of the filtrate was removed in vacuo. The residue was
purified by chromatography (silica gel, ether/petroleum ether ) 1:4
f 1:3) to give the azido alcohol 3 as a diastereomeric mixture.
Due to its instability, the product should be used for further
transformations within 24 h.
4a as a yellow oil (0.09 g, 59%, a small amount of the E-isomers
was present). 1H NMR (250 MHz, CDCl3): δ 1.04-1.38 (m, 9H,
3
3 × CH3), 2.64 (m, 2H, dCCH2), 3.60, 3.70 (2 × q, J ) 6 Hz,
1H, CHCH3), 4.13 (q, 3J ) 7 Hz, 2H, CH2CH3), 4.52, 4.54 (2 × s,
1H, CHdC, Z-isomer), 4.83, 4.92 (2 × s, 1H, CHdC, E-isomer),
7.74, 7.81 (2 × br, 1H, NH). 13C NMR (50.3 MHz, CDCl3): δ
13.2, 14.6, 17.3, 21.8, 23.2, 46.0, 47.4, 58.5, 58.6, 62.7, 64.4, 78.2,
78.4, 110.4, 162.4, 170.4. MS (EI, 70 eV): m/z (%) 199 (M+, 100),
184 (26), 156 (84), 154 (64), 110 (47). The exact molecular mass
m/z ) 199.1208 ( 2 ppm [M+] for C10H17NO3 was confirmed by
HRMS (EI, 70 eV).
Ethyl 6-Azido-5-hydroxy-5-methyl-3-oxoheptanoate (3a). The
starting materials diisopropylamine (0.92 g, 9.2 mmol), n-BuLi (3.9
mL, 9.2 mmol, 23% solution in hexane), ethyl acetoacetate (1a;
0.51 g, 3.9 mmol), and 3-azidobutan-2-one (2a; 0.40 g, 3.54 mmol)
General Procedure for the Synthesis of the Pyrroles 5a-ad.
To an anhydrous CH2Cl2 solution (10 mL) of the pyrrolidine 4 was
slowly added TFA (0.5 mL), and the solution was stirred at 20 °C
for 1 h. The solvent and the acid were removed in vacuo, and the
residue was purified by chromatography (silica gel, ether/petroleum
ether ) 1:10) to give the pyrrole 5.
Methyl (3,4,5-Trimethylpyrrol-2-yl)acetate (5g). Starting with
4g (0.95 g, 4.77 mmol), pyrrole 5g was isolated as a brownish oil
(0.75 g, 87%). 1H NMR (250 MHz, CDCl3): δ 1.92 (s, 3H, CH3),
1.94 (s, 3H, CH3), 2.16 (s, 3H, CH3), 3.56 (s, 2H, CH2), 3.71 (s,
3H, OCH3), 7.94 (br, 1H, NH). 13C NMR (50.3 MHz, CDCl3): δ
9.0, 9.0, 11.0, 31.2, 52.0, 113.8, 115.6, 116.4, 122.6, 171.9. IR (neat)
ν˜: 3394 (m), 2951 (m), 2921 (m), 2860 (w), 1731 (s), 1715 (s),
1600 (m), 1436 (m), 1383 (w), 1345 (w), 1316 (w), 1238 (s), 1208
(s), 1193 (s), 1166 (s), 1119 (w), 1019 (w) cm-1. MS (EI, 70 eV):
m/z (%) 181 (M+, 25), 122 (100), 107 (6), 77 (4), 53 (2). The exact
molecular mass m/z ) 181.1103 ( 2 ppm [M+] for C10H15NO2
was confirmed by HRMS (EI, 70 eV).
1
yielded 3a as a yellow oil (0.43 g, 50%). H NMR (250 MHz,
CDCl3, major isomer): δ 1.14-1.32 (m, 9H, 3 × CH3), 2.78 (m,
2H, 4-H), 3.39-3.65 (m, 1H, 6-H), 3.54 (s, 2H, 2-H), 4.20 (q, J )
7 Hz, 2H, CH2CH3). 13C NMR (50.3 MHz, CDCl3, major isomer):
δ 13.3, 14.0, 23.7, 49.3, 50.7, 61.5, 64.2, 74.3, 166.8, 203.9. IR
(neat) ν˜: 3587 (br, w), 2984 (w), 2112 (s), 2008 (s), 1730 (s), 1728
(s), 1709 (s), 1655 (w), 1648 (w), 1449 (w), 1384 (m), 1371 (m),
1319 (m), 1259 (m), 1208 (w), 1180 (m), 1113 (w), 1095 (w), 1056
(w), 1030 (w) cm-1. MS (DCI, 70 eV): m/z (%) 261 ([M + NH4]+,
40), 216 (24), 200 (40), 190 (100), 147 (40).
General Procedure for the Synthesis of 2-Alkylidenepyrro-
lidines 4a-ad. To a THF solution (10 mL) of 3 was added PPh3
(1.2 equiv) at 20 °C, and the reaction mixture was stirred for 24 h
at 45 °C. The solution was cooled to ambient temperature, and water
(50 mL) was added. The organic and the aqueous layers were
separated, and the latter was extracted with CH2Cl2 (3 × 50 mL).
The combined organic layers were extracted with brine, dried (Na2-
SO4), and filtered, and the solvent of the filtrate was removed in
vacuo. The residue was purified by chromatography (silica gel,
ether/petroleum ether ) 1:2 or ether/petroleum ether ) 1:5 f 1:2)
to give pyrrolidine 4.
Acknowledgment. We are grateful to Dr. H. Feist for his
help during the preparation of this manuscript. Financial support
from the DFG is gratefully acknowledged.
Supporting Information Available: Experimental procedures
and spectroscopic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
Ethyl (Z)-(4-Hydroxy-4,5-dimethylpyrrolidin-2-ylidene)ac-
etate (4a). Treatment of 3a (0.20 g, 0.82 mmol) with PPh3 yielded
JO060593H
4968 J. Org. Chem., Vol. 71, No. 13, 2006