Domino "Staudinger/semi-aza-Wittig/fragmentation" reactions of γ-azido-β-hydroxyketones

Article abstract of DOI:10.1021/jo060891e

Treatment of γ-azido-β-hydroxyketones with triphenylphosphine resulted, depending on the structural features of the starting materials, in a domino "Staudinger/semi-aza-Wittig/fragmentation" reaction rather than a normal aza-Wittig reaction. 2-Azido-1-hyd

Full text of DOI:10.1021/jo060891e

Domino “Staudinger/Semi-Aza-Wittig/Fragmentation” Reactions of
γ-Azido-â-hydroxyketones
Ilia Freifeld,†,‡ Heydar Shojaei,‡ Ru¨diger Dede,§ and Peter Langer*,§,|
Institut fu¨r Biochemie, UniVersita¨t Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany, Institut fu¨r
Organische und Biomolekulare 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 April 28, 2006
Treatment of γ-azido-â-hydroxyketones with triphenylphosphine resulted, depending on the structural
features of the starting materials, in a domino “Staudinger/semi-aza-Wittig/fragmentation” reaction rather
than a normal aza-Wittig reaction. 2-Azido-1-hydroxy-1-(2,4-dioxoalkyl)cyclopentanes, readily available
by condensation of 1,3-dicarbonyl dianions with 2-azidocyclopentanone, proved to be optimal starting
materials for these reactions which afforded 1-(1,3-dioxoalkyl)amino-2-(alkylidene)cyclopentanes.
Introduction
1,1-dimethoxyethane with 1,3-bis-silyl enol ethers,7 and of
2-azido-1,1-dimethoxyethane with 1,3-diketones.8 Reactions of
iminophosphoranes with other functional groups have also been
reported. This includes, for example, PPh3 mediated reactions
of organic azides with epoxides,9 alcohols,10 phthalic anhy-
dride,11 and carboxylic acids.12 In the course of our interest in
the development of new cyclization reactions of free and masked
Organic azides represent versatile synthetic building blocks.1
The formation of iminophosphoranes by reaction of tri-
phenylphosphine (PPh3) with azides (Staudinger reaction)2 has
been widely used for the synthesis of primary amines,2,3 imines,
and various nitrogen heterocycles.4 For example, pyrroles have
been prepared by reaction of R-azidoketones with 1,3-dicarbonyl
dianions,5 of R-azidoketals with silyl enol ethers,6 of 2-azido-
(4) (a) Stuckwisch, C. G. Synthesis 1973, 469. (b) Lambert, P. H.;
Vaultier, M.; Carrie´, R. J. Chem. Soc., Chem. Commun. 1982, 1224. (c)
Lambert, P. H.; Vaultier, M.; Carrie´, R. J. Org. Chem. 1985, 50, 5352. (d)
Carboni, B.; Vaultier, M.; Carrie, R. Tetrahedron 1987, 43, 1799. (e)
McClure, K. F.; Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115, 6094.
(5) Langer, P.; Freifeld, I. Chem. Commun. 2002, 2668.
(6) (a) Bertschy, H.; Meunier, A.; Neier, R. Angew. Chem. 1990, 102,
828; Angew. Chem., Int. Ed. Engl. 1990, 29, 777. (b) Montforts, F.-P.;
Schwartz, U. M.; Mai, G. Liebigs Ann. Chem. 1990, 1037.
(7) Bellur, E.; Go¨rls, H.; Langer, P. J. Org. Chem. 2005, 70, 4751.
(8) Bellur, E.; Langer, P. Tetrahedron Lett. 2006, 47, 2151.
(9) Molina, P.; Alajar´ın, M.; Lo´pez-La´zaro, A. Tetrahedron Lett. 1992,
2387.
* To whom correspondence should be addressed. Fax: +381 4986412.
† Universita¨t Greifswald.
‡ Georg-August-Universita¨t.
§ Institut fu¨r Chemie, Universita¨t Rostock.
| Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock.
(1) Bra¨se, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem.,
Int. Ed. 2005, 44, 5188.
(2) Staudinger, H.; Meyer, J. HelV. Chim. Acta 1919, 2, 635.
(3) Reviews of aza-Wittig reactions: (a) Patai, S. The Chemistry of the
Azido Group; Wiley: New York, 1971; pp 333-338. (b) Gololobov, Y.
G.; Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron 1981, 37, 437. (c) Molina,
P.; Viliplana, M. J. Synthesis 1994, 1197. (d) Eguchi, S.; Okano, T.; Okawa,
T. Rec. Res. DeV. Org. Chem. 1997, 337; Chem. Abstr. 1999, 130, 252510.
(e) Fresneda, P. M.; Molina, P. Synlett. 2004, 1.
(10) Ittah, Y.; Sasson, Y.; Shahak, I.; Tsaroom, S.; Bloom, J. J. Org.
Chem. 1978, 43, 4271.
(11) Garcia, J.; Vilarrasa, J. Tetrahedron Lett. 1986, 639.
(12) Garcia, J.; Urp´ı, F.; Vilarrasa, J. Tetrahedron Lett. 1984, 4841.
10.1021/jo060891e CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/08/2006
J. Org. Chem. 2006, 71, 6165-6170
6165

Freifeld et al.
SCHEME 1. Proposed Mechanism of the Formation of 4aa
dianions,13 we recently discovered an unprecedented PPh3
mediated transformation of γ-azido-â-hydroxyketones.14 The
reaction of PPh3 with 2-azido-1-hydroxy-1-(2,4-dioxoalkyl)-
cyclopentanes, readily available by condensation of 1,3-dicar-
bonyl dianions with 2-azidocyclopentanone, afforded 1-(1,3-
dioxoalkyl)amino-2-(alkylidene)cyclopentanes by means of a
domino “Staudinger/semi-aza-Wittig/fragmentation” reaction.
Herein, we wish to report full details of these reactions and
studies related to scope and limitations. The products prepared
represent versatile synthetic building blocks and are of phar-
macological relevance.15
Results and Discussion
Mechanism. The reaction of the dianion16 of ethyl acetoac-
etate (1a) with R-azidocyclopentanone (2a) afforded 2-azido-
1-hydroxy-1-(4-ethoxy-2,4-dioxobutyl)cyclopentane (3a), which
was formed with very good 1,2-diastereoselectivity (ds > 98:
2). The configuration of the product could not be unambiguously
assigned. Detailed NMR studies were carried out on a sample
of derivative 3q (vide infra) containing a small amount of the
minor isomer. NOESY experiments gave ambigious results
(NOE’s between the hydrogen atoms CHN3 and CringCH2(Cd
O) were observed for both isomers). The signal of hydrogen
atom CHN3 is significantly shifted lowfield for the minor
compared to the major diastereomer. This lowfield shift might
be explained by the fact that the hydrogen atom CHN3 of the
cis-diastereomer (minor isomer) is located within the anisotropic
cone of the carbonyl group CringCH2(CdO). In fact, this effect
is not to be expected for the trans-diastereomer (by steric
reasons). Additions of nucleophiles to the carbonyl group of
2-azidocyclopentan-1-ones have, to the best of our knowledge,
not yet been reported. However, a number of reactions of
enolates with 2-substituted cyclopentanones are known. In most
of these reactions, the cis-configured diastereomers were
predominantly formed.17
Treatment of 3a with PPh3 afforded the 1-(1,3-dioxoalkyl)-
amino-2-(methylidene)cyclopentane 4a in up to 58% yield
(Scheme 1). The formation of 4a can be explained by Staudinger
reaction of the azide with PPh3 to give the iminophosphorane
A, attack of the nitrogen atom of A onto the carbonyl group
(intermediate B), shift of the phosphonium moiety (intermediate
C), and fragmentation (intermediate D) with extrusion of
a (i) 2.6 equiv LDA, THF, 0 °C, then 1a (1.1 equiv), 15 min, then 2a
(1.0 equiv), -78 f 20 °C within 12 h, then 3 h at 20 °C; (ii) PPh3, THF,
24 h, 45 °C.
triphenylphosphine oxide. The overall process can be regarded
as a domino18 Staudinger/semi-sza-Wittig/fragmentation reac-
tion. A normal aza-Wittig reaction (leading to 6) was not
observed.
(13) For a review of cyclization reactions of dianions, see (a) Langer,
P.; Freiberg, W. Chem. ReV. 2004, 104, 4125. For a review of 1,3-bis-silyl
enol ethers (masked 1,3-dicarbonyl dianions), see (b) Langer, P. Synthesis
2002, 441.
(14) Langer, P.; Freifeld, I.; Shojaei, H. Chem. Commun. 2003, 3044.
(15) (a) Miyata, O.; Muroya, K.; Koide, J.; Naito, T. Synlett. 1998, 271.
(b) Miyata, O.; Muroya, K.; Kobayashi, T.; Yamanaka, R.; Kajisa, S.; Koide,
J.; Naito, T. Tetrahedron 2002, 58, 4459.
The reaction time (16 h), stoichiometry and temperature (45
°C) proved to be important parameters during the optimization.
The use of PPh3 (or P(nBu)3 which was equally successful)19
proved to be mandatory. Notably, the hydrogenation of 3a (H2,
cat. Pd/C) afforded the pyrrolidine 6, albeit in low yield, by
reduction of the azide to an amino group and subsequent attack
of the latter onto the carbonyl group (Scheme 2).
(16) (a) Weiler, L. J. Am. Chem. Soc. 1970, 92, 6702. For the reaction
of a 1,3-dicarbonyl dianion with cyclopentanone, see (b) Huckin, S. N.;
Weiler, L. Can. J. Chem. 1974, 52, 2157.
(17) For the reaction of the lithium enolate of 3,3-dimethylbutan-2-one
with 2-methoxy-cyclopentanone, see (a) Das, G.; Thornton, E. R. J. Am.
Chem. Soc. 1993, 115, 1302. For the reaction of the enolate of methyl acetate
with 2-phenylcyclopentanone, see (b) van der Veen, R. H.; Geenevasen, J.
A. J.; Cerfontain, H. Can. J. Chem. 1984, 62, 2202. For the reaction of the
dianion of 2-methylpropionic acid with 2-methyl-cyclopentanone, see (c)
Black, T. H.; Smith, D. C.; Eisenbeis, S. A.; Peterson, K. A.; Harmon, M.
S. Chem. Commun. 2001, 8, 753. For the reaction of the dianion of
phenylacetic acid with 2-chlorocyclopentanone, see (d) Gil, S.; Kneeteman,
M.; Parra, M.; Sotoca, E. Synthesis 2002, 265.; see also (e) Marmsaeter, F.
P.; Murphy, G. K.; West, F. G. J. Am. Chem. Soc. 2003, 125, 14724. (f)
Jones, K.; Toutounji, T. Tetrahedron 2001, 57, 2427. (g) Murphy, G. K.;
West, F. G. Org. Lett. 2005, 9, 1801.
(18) For reviews of domino reactions, see (a) Tietze, L. F.; Beifuss, U.
Angew. Chem. 1993, 105, 137; Angew. Chem., Int. Ed. Engl. 1993, 32,
131. (b) Tietze, L. F. Chem. ReV. 1996, 96, 115. For domino ‘annulation-
retro-aldol’ reactions, see (c) Hamdan, A. J.; Moore, H. W. J. Org. Chem.
1985, 50, 3427. (d) Oda, K.; Ohnuma, T.; Ban, Y. J. Org. Chem. 1984, 49,
953.
(19) For the use of PBu3 in aza-Wittig reactions, see Eguchi, S.;
Yamashita, K.; Matsushita, Y. Synlett. 1992, 295.
6166 J. Org. Chem., Vol. 71, No. 16, 2006

Reactions of γ-Azido-â-hydroxyketones
SCHEME 2. Hydrogenation of 3aa
SCHEME 4. Synthesis of 4qa
a (i) H2, Pd/C.
SCHEME 3. Synthesis of 4a-pa
a (i) (1) 2.6 equiv. LDA, THF, 0 °C, 20 min; (2) 1q (1.1 equiv), 1 h,
then 2a (1.0 equiv), -78 f 20 °C, 21 h; (ii) PPh3, THF, 38 h, 45 °C.
tanes 4b-e. The 2-azido-1-hydroxycyclopentanes 3f-h were
prepared by reaction of 2a with the dianions of methyl
3-oxopentanoate (1f), ethyl 3-oxohexanoate (1g), and methyl
4-methoxyacetoacetate (1h) which all contain an additional
substituent (R1 ) Me, Et, MeO) located at carbon atom C-4 of
the â-ketoester. Treatment of 3f-h with PPh3 furnished the
1-amino-2-(alkylidene)cyclopentanes 4f-h containing the ad-
ditional substituent R1 located at the exocyclic double bond.
The products were isolated as unseparable mixtures of E/Z
isomers. The condensation of 2a with ethyl 2-methyl-, ethyl
2-benzyl-, ethyl 2-ethyl-, and ethyl 2-butylacetoaetate (1i-l)s
all containing a substituent located at carbon atom C-2 of the
â-ketoestersgave the 2-azido-1-hydroxycyclopentanes 3i-l.
The reaction of the latter with PPh3 afforded the 1-amino-2-
(methylidene)cyclopentanes 4i-l. The employment of 1,3-
diketones rather than â-ketoesters was next studied. The
condensation of the dianions of pentane-2,4-dione (1m), 5,5-
dimethylhexane-2,4-dione (1n), heptane-3,5-dione (1o), and
benzoylacetone (1p) gave 3m-p. Treatment of 3m-p with PPh3
furnished the 1-(2,4-dioxoalkyl)amino-2-(alkylidene)cyclopen-
tanes 4m-p. Azido alcohols 3a-p were formed with good to
very good trans-1,2-diastereoselectivity (except for 3n). The
pyrrolidines 4e′, 4j′, and 4l′ were isolated in low yield as side
products.
The condensation of R-azidocyclopentanone (2a) with the
dianion of tosylacetone afforded 2-azido-1-hydroxy-1-(3-tosyl-
2-oxopropyl)cyclopentane (3q) with good diastereoselectivity.
Treatment of the latter with PPh3 furnished the 1-amino-2-
(methylidene)cyclopentane 4q (Scheme 4). Despite the low
yield, side-products could not be isolated.
The reaction of the dianion of ethyl acetoacetate with
2-azidoindan-1-one (2b) afforded the 2-azido-1-hydroxyindane
3r with good diastereoselectivity (Scheme 5, Table 2). The
assignment of the relative configuration remains unclear at
present. Treatment of 3r with PPh3 resulted in formation of the
2-amino-1-(methylidene)indane 4r (as an unseparable 4:1
mixture with pyrrolidine 4r′). The reaction of the dianions of
pentane-2,4-dione (1m), 5,5-dimethylhexane-2,4-dione (1n), and
benzoylacetone (1p) gave 3s-u. The latter were transformed
into the 2-amino-1-(methylidene)indanes 4s-u (4t was isolated
as an unseparable 1:1 mixture with pyrrolidine 4t′).
a (i) 2.6 equiv LDA, THF, 0 °C, then 1a-p (1.1 equiv), 15 min, then 2a
(1.0 equiv), -78 f 20 °C within 12 h, then 3 h, 20 °C; (ii) PPh3, THF, 24
h, 45 °C.
TABLE 1. Products and Yields
3, 4
R1
R2
R3
% (3)a
drb
% (4)a
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
H
H
H
H
H
H
H
H
H
H
H
H
Me
CH2Ph
Et
nBu
H
OEt
OMe
57
55
35
64
82
33
65
54
40
32
41
45
48
38
25
15
> 98:2
> 98:2
10:1
10:1
10:1
58
61
52
OCH2Ph
O(CH2)2OMe
OiBu
OMe
OEt
OMe
OEt
OEt
OEt
OEt
Me
tBu
61c
55g
57d
47d
57d
58e
50e,g
49e
51e,g
37c
41
H
Me
Et
OMe
H
H
H
H
H
H
Me
H
> 98:2f
> 98:2f
> 98:2f
> 98:2
> 98:2
> 98:2
> 98:2
10:1
H
H
H
2:1
Et
Ph
> 98:2f
10:1
38
45
a Yields of isolated products. For a number of products 3, impurities
(by partial decomposition) could not be completely removed. b The dia-
stereomeric ratio refers to the relative configuration of alcohol and azido
group. c Triphenylphosphine oxide could not be separated. d Configuration
of the exocyclic double bond: 4g-h: E/Z ) 3:1; 4f,o: E/Z ) 2:1. e dr )
2:1-1:1 (assignment arbitrary). f Two diastereomers (3:1-1:1) with respect
to the relation of the OH and R1 groups. g Besides, 4e′, 4j′, and 4l′ (structures
see below) were isolated.
Scope and Limitations. The reactions of R-azidocyclopen-
tanone (2a) with various 1,3-dicarbonyl dianions were next
studied (Scheme 3, Table 1). The condensation of 2a with the
dianions of methyl, benzyl, methoxyethyl, and iso-butyl ac-
etoacetate (1b-e) gave the 2-azido-1-hydroxy-1-(2,4-dioxoal-
kyl)cyclopentanes 3b-e. Treatment of 3b-e with PPh3 afforded
the 1-(4-alkoxy-2,4-dioxobutyl)amino-2-(methylidene)cyclopen-
The reaction of 1,3-dicarbonyl dianions with open-chained
azides was next studied. The condensation of the dianion of
acetylacetone with R-azidoacetone (2c) afforded 3v which was
successfully transformed into 4v (Scheme 6, Table 3). The azido
alcohol 3w was prepared by reaction of 2-azidobutan-3-one (2d)
J. Org. Chem, Vol. 71, No. 16, 2006 6167

Freifeld et al.
SCHEME 5. Synthesis of 4r-ua
SCHEME 7. Reaction of PPh3 with
2-Azido-1-hydroxycyclohexane 3x (ref 5)a
a (i) 2.6 equiv LDA, THF, 0 °C, then 1a,m,n,p (1.1 equiv), 15 min,
then 2b (1.0 equiv), -78 f 20 °C within 12 h, then 3 h, 20 °C; (ii) PPh3,
THF, 24 h, 45 °C.
TABLE 2. Products and Yields
3,4
R
% (3)a
drb
% (4)a
r
s
t
OEt
Me
tBu
Ph
63
54
61
55
10:1
2:1
5:1
5:1
35c
52
a (i) (1) 2.4 equiv. LDA, THF, 0 °C; (2) -78 f 20 °C; (ii) PPh3, CH2Cl2,
24 h, THF, 45 °C; (iii) TFA, CH2Cl2, 1 h, 20 °C.
50d
46
u
a Yields of isolated products. For a number of products 3, impurities
(by partial decomposition) could not be completely removed. b Diastereo-
meric ratio (assignment arbitrary). c Unseparable mixture 4r/4r′ ) 4:1.
d Unseparable mixture 4t/4t′ ) 1:1.
azido alcohols derived from â-ketoesters.5 The reason for this
different behavior remains unclear at present. Notably, we have
reported earlier7 that the reaction of PPh3 with N3CH2CH(OMe)-
CH2(CO)CH2(CO)CH3, containing a capped (albeit secondary
rather than tertiary) hydroxy group, resulted in the formation
of a 2-alkylidenepyrrolidine rather than rearrangement. This
result supports the assumption (vide supra) that the presence of
a free hydroxy group is necessary for the rearrangement to occur.
We have reported earlier that the condensation of the dianion
of ethyl acetoacetate with 2-azidocyclohexanone (2e) afforded
the 2-azido-1-hydroxycyclohexane 3x (Scheme 7).5,20 The
reaction of 3x with PPh3 furnished the bicyclic 2-alkylidenepyr-
rolidine 7 (which was subsequently transformed into the
tetrahydroindole 8).5,20 The formation of 1-amino-2-(alkylidene)-
cyclohexane 4x was not observed. The formation of pyrrolidines
rather than 1-amino-2-(alkylidene)cycloalkanes was observed
also for 7-, 8- and 12-membered rings.5,20 The normal aza-Wittig
reaction of six-membered ring 3x proceeds by initial formation
of a bicyclic imine which undergoes a 1,3-H shift to give 7.
The normal aza-Wittig reaction of 3a would result in the
formation of the more strained 5,5-bicyclic product 6 (see
Scheme 2) which seems to be less stable than the corresponding
5,6-bicyclic product 7. Notably, the ring-size of the starting
material influences the competition between the normal aza-
Wittig and the domino Staudinger/semi-aza-Wittig/fragmentation
reaction.
SCHEME 6. Synthesis of 4v,wa
a (i) 2.6 equiv LDA, THF, 0 °C, then 1m,p (1.1 equiv), 15 min, then
2c,d (1.0 equiv), -78 f 20 °C within 12 h, then 3 h, 20 °C; (ii) PPh3,
THF, 24 h, 45 °C.
The LDA mediated reaction of acetone with 2a failed. In
contrast, the TiCl4 mediated reaction of 2-(trimethylsilyloxy)-
prop-2-ene with 2a (Mukaiyama aldol reaction) afforded 3y in
good yield (Scheme 8). Treatment of 3y with PPh3 afforded
the known21 5,5-bicyclic pyrrole 9 rather than the expected
1-amino-2-(methylidene)cyclopentane 4y. This experiment shows
that the presence of a 1,3-dicarbonyl or related subunit (see 4q)
represents an important structural feature of the starting material
for a domino reaction to be observed.
TABLE 3. Products and Yields
3, 4
R1
R2
% (3)a
% (4)a
% (5)a
% (6)a
v
w
Me
Ph
H
Me
60
52
30
63
0
0
0
15
a Yields of isolated products. All azido alcohols 3 were obtained as
diastereomeric mixtures (dr ) 3:1-1:1, assignment arbitrary).
with the dianion of benzoylacetone. Treatment of 3w with PPh3
afforded 4w. A successful domino reaction of open-chained 1,2-
azido alcohols required the use of 1,3-diketones. In contrast,
the formation of pyrroles was observed for open-chained 1,2-
(20) Freifeld, I.; Shojaei, H.; Langer, P. J. Org. Chem. 2006, 71, 4965-
4968.
(21) Wollweber, H.-J.; Wentrup, G. J. Org. Chem. 1985, 50, 2041.
6168 J. Org. Chem., Vol. 71, No. 16, 2006

Reactions of γ-Azido-â-hydroxyketones
a
SCHEME 8. Reaction of 3y with PPh3
After stirring for further 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 alcohol 3. Because of its instability, the product should be
used for further transformations within 24 h. In some cases, small
amounts of decomposition products could not be removed. The
following products reside in their enolic form: 3n-u,w-y.
Ethyl 4-(2-Azido-1-hydroxycyclopentyl)-3-oxobutyrate (3a).
The starting materials diisopropylamine (0.63 g, 6.30 mmol), nBuLi
(4.1 mL, 6.30 mmol, 15% solution in hexane), ethyl acetoacetate
(1a) (0.34 g, 2.64 mmol), and 2-azidocyclopentanone (2a) (0.30 g,
2.40 mmol) yielded 3a as a yellow oil (0.51 g, 57%, dr > 98:2).
a (i) (1) TiCl4, CH2Cl2, 0 °C; (2) -78 f 20 °C; (ii) PPh3, 24 h, THF, 45
°C.
3
1H NMR (300 MHz, CDCl3, major isomer): δ ) 1.25 (t, J ) 7
Hz, 3 H), 1.55-2.04 (m, 6 H), 2.63 (d, 2J ) 16 Hz, 1 H), 2.98 (d,
2J ) 16 Hz, 1 H), 3.32 (t, 3J ) 6 Hz, 1 H), 3.45 (s, 2 H), 4.18 (q,
3J ) 7 Hz, 2 H). 13C NMR (50.3 MHz, CDCl3, major isomer): δ
) 14.0, 19.2, 26.9, 36.0, 49.8, 50.4, 61.5, 67.7, 79.8, 166.9, 203.3.
IR (neat): V˜) 3503 (br, w), 2978 (w), 2106 (d), 1740 (s), 1711
(s), 1446 (w), 1407 (w), 1369 (w), 1318 (m), 1258 (m), 1181 (m),
1096 (w), 1028 (m) cm-1. MS (DCI, NH3): m/z (%) ) 528 ([2M
+ NH4]+, 84), 483 (80), 438 (22), 273 ([M + NH4]+, 100), 228
(36), 210 (18). Anal. Calcd for C11H17N3O4 (255.27): C, 51.70;
H, 6.66. Found: C, 51.59; H, 6.43.
Conclusions. The competition between the domino Staudinger/
semi-aza-Wittig/fragmentation reaction and the normal aza-
Wittig reaction is influenced by a number of parameters. The
presence of a γ-azido-â-hydroxyketone moiety is the minimal
structural requirement for a domino reaction to be observed. It
was shown that the domino process is most likely to be observed
when a cyclopentane derivative, that is, a 2-azido-1-hydroxy-
1-(2,4-dioxoalkyl)cyclopentane, is employed. The use of an
acceptor-substituted ketone, for example, a 1,3-diketone, a
â-ketoester, or a â-ketosulfone is required. For open-chained
γ-azido-â-hydroxyketones, the domino process is only observed
for 1,3-diketones.
3-(2-Azido-1-hydroxycyclopentyl)-1-tosylpropan-2-one (3q).
To a THF solution (100 mL) of diisopropylamine (3.68 g, 36.4
mmol) was added a 1.6 M solution of nBuLi in hexane (22.8 mL,
36.5 mmol) at 0 °C. After the mixture was stirred for 20 min,
1-tosylpropan-2-one (2.89 g, 13.6 mmol) was added, and the
solution was stirred for 1 h at 0 °C. 2-Azidocyclopentanone (1.70
g, 13.6 mmol) was added at -78 °C, and the reaction mixture was
warmed to ambient temperature within 21 h. A saturated solution
of NH4Cl (100 mL) was added, and the organic layer was separated.
The organic layer was extracted with Et2O (2 × 50 mL) and CH2-
Cl2 (3 × 50 mL). The combined organic layers were washed with
brine, dried (Na2SO4), and filtered, and the solvent of the filtrate
was removed in vacuo. The residue was purified by chromatography
(silica gel, hexane/ethyl acetate ) 3/1) to give 3q as a brownish
oil (1.06 g, 23%, dr ) 10:1). An analytical sample of the pure
cis-diastereomer could be separated. 1H NMR (CDCl3, 300 MHz):
δ ) 1.50-1.75 (m, 2 H), 1.75-2.10 (m, 4 H), 2.46 (s, 3 H), 2.83
Experimental Section
General. All solvents were dried by standard methods and all
reactions were carried out under an inert atmosphere. For H and
1
13C NMR spectra the deuterated solvents indicated were used. Mass
spectrometric data (MS) 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 procedures. 2-Azidocy-
clopentanone (2f) was prepared from 2-chlorocyclopentanone.22
2-Azidoindan-1-one (2b) was prepared in three steps by a literature
procedure.23 1-Azidopropan-2-one (2c) was prepared from 3-chlo-
robutan-2-one and NaN3.24 3-Azidobutan-2-one (2d) was prepared
by the reaction of 3-chlorobutan-2-one with NaN3.25 2-Azidocy-
clohexanone (2e) was prepared from 2-chlorocyclohexanone.26
CAUTION: The handling of azides is dangerous, because of
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.
2
2
3
(d, J ) 16.4 Hz, 1 H), 3.14 (d, J ) 16.4 Hz, 1 H), 3.37 (dd, J1
3
2
2
) J2 ) 8.4 Hz, 1 H), 4.17 (d, J ) 13.1 Hz, 1 H), 4.31 (d, J )
13.1 Hz, 1 H), 7.38 (d, 3J ) 8.2 Hz, 2 H), 7.76 (d, 3J ) 8.2 Hz, 2
H). 13C NMR (CDCl3, 75 MHz): δ ) 19.2, 21.6, 27.0, 35.9, 51.4,
67.7, 68.0, 79.8, 128.2, 130.0, 135.5, 145.6, 198.5.
General Procedure for the Synthesis of 1-Amino-2-(al-
kylidene)cyclopentanes 4a-w. To a anhydrous THF solution (15
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 (80 mL) was added. The organic
and the aqueous layer were separated, and the latter was extracted
with CH2Cl2 (4 × 50 mL). The combined organic layers were
extracted with brine (1 × 80 mL), 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
) 1:2 or ether/petroleum ether ) 1:40 f 1:3) to give compounds
4.
General Procedure for the Synthesis of 2-Azido-1-hydroxy-
1-(2,4-dioxoalkyl)cyclopentanes 3a-w. To a solution of diiso-
propylamine (2.6 equiv) in anhydrous THF (35 mL) was added
nBuLi (2.6 equiv, 23% or 15% solution in hexanes) 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
reaction mixture was warmed to ambient temperature during 12 h.
N-(2-Methylenecyclopentyl)malonamic Acid Ethyl Ester (4a).
Treatment of 3a (0.39 g, 1.55 mmol) with PPh3 yielded, after
purification by chromatography (silica gel, ether/petroleum ether
) 1:40 f 1:3), 4a as a yellow solid (0.19 g, 58%). 1H NMR (300
(22) Effenberger, F.; Beisswenger, T.; Az, R. Chem. Ber. 1985, 118,
4869.
(23) Patonay, T.; Hoffman, R. V. J. Org. Chem. 1994, 59, 2902.
(24) Forster, M. O.; Fierz, M. E. J. Chem. Soc. 1908, 93, 81.
(25) Forster, M. O.; Fierz, M. E. J. Chem. Soc. 1908, 93, 675.
(26) Batanero, B.; Escudero, J.; Barba, F. Synthesis 1999, 10, 1809.
3
MHz, CDCl3): δ ) 1.25 (t, J ) 7 Hz, 3 H), 1.38 (m, 1 H), 1.62
(m, 1 H), 1.73 (m, 1 H), 2.16 (m, 1 H), 2.37 (m, 2 H), 3.31 (s, 2
H), 4.17 (q, 3J ) 7 Hz, 2 H), 4.62 (dd, 3J ) 7 Hz, 3J ) 3 Hz, 1 H),
4.98 (m, 2 H), 7.05 (br, 1 H). 13C NMR (50.3 MHz, CDCl3): δ )
J. Org. Chem, Vol. 71, No. 16, 2006 6169

Freifeld et al.
14.0, 22.3, 30.9, 33.8, 41.2, 53.7, 61.5, 106.8, 152.0, 164.7, 169.57.
(d, br, 3J ) 7.3 Hz, 1 H), 7.37 (d, 3J ) 8.2 Hz, 2 H), 7.79 (d, 3J )
8.2 Hz, 2 H). 13C NMR (CDCl3, 75 MHz): δ ) 21.7, 22.4, 30.9,
33.6, 54.1, 62.0, 107.5, 128.1, 130.0, 135.2, 145.6, 151.3, 160.3.
IR (KBr, cm-1): ν˜ ) 3331 (s), 2993 (m), 2964 (m), 2917 (m),
1650 (s), 1521 (s), 1324 (s), 1299 (m), 1159 (s), 1087 (m), 814
(m), 522 (m). MS (EI, 70 eV): m/z (%) ) 294.0 ([M + 1]+, 2),
293.0 (M+, 20), 214.0 (4), 155.1 (6), 138.1 (100), 96.1 (30), 91.0
(36), 32.1 (23), 28.1 (90). HRMS (EI, 70 eV): calcd for C15H19-
NO3S (M+), 293.10802; found, 293.10758.
IR (neat) V˜ ) 3286 (br, m), 2960 (s), 1750 (s), 1650 (s), 1547 (s),
1465 (w), 1417 (w), 1369 (m), 1182 (s), 1033 (m), 885 (w) cm-1
.
MS (EI, 70 eV): m/z (%) ) 211 (M+, 65), 123 (18), 97 (56), 96
(100), 81 (28), 69 (29). The exact molecular mass m/z ) 211.1208
( 2 ppm [M+] for C11H17NO3 was confirmed by HRMS (EI, 70
eV).
N-(2-Methylidenecyclopentyl)-2-tosylacetamide (4q). Com-
pound 3q (260 mg, 0.77 mmol) was dissolved in dry THF (10 mL),
and triphenylphosphine (244 mg, 0.93 mmol) was added. The
reaction mixture was stirred at 45 °C for 38 h. Water (50 mL) and
CH2Cl2 (50 mL) were added, and the aqueous layer was extracted
with CH2Cl2 (3 × 50 mL). The combined organic layers were
washed with brine, dried (Na2SO4), and filtered, and the solvent of
the filtrate was removed in vacuo. The residue was purified by
chromatography (silica gel, petroleum ether/ethyl acetate ) 3/1)
to give 4q as a yellow solid (46 mg, 20%). 1H NMR (CDCl3, 300
MHz): δ ) 1.37-1.52 (m, 1 H), 1.52-1.71 (m, 1 H), 1.71-1.85
(m, 1 H), 2.07-2.20 (m, 1 H), 2.36-2.44 (m, 2 H), 2.45 (s, 3 H),
Acknowledgment. We are grateful to Dr. H. Feist for his
help during the preparation of this manuscript and to Dr. D.
Michalik for NMR studies. 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.
2
4.02 (d, J ) 1.1 Hz, 2 H), 4.58 (m, br, 1 H), 5.03 (m, 2 H), 6.67
JO060891E
6170 J. Org. Chem., Vol. 71, No. 16, 2006