Synthesis and mechanistic study of fused 2-pyrrolines via thermolysis of 6-substituted-3,5-hexadienyl azidoformates

Article abstract of DOI:10.1021/jo010218j

Thermolysis of 3,5-hexadienyl azidoformates at 300 °C, 0.05 Torr, led to a fused 2-pyrroline regiospecifically, regardless of the configuration E or Z between the C-3 and C-4 double bond. Thermolysis of 6-substituted-3,5(E)-hexadienyl azidoformates yielded a kinetically controlled 2-pyrroline with cis configuration between H-1 and H-8a whereas 6-substituted-3,5(Z)-hexadienyl azidoformates produced a cis and trans mixture. The mechanism was proposed as the loss of nitrogen to form an acyl nitrene, then addition to a double bond to produce an aziridine. Finally the cleavage of the C-C bond generated a vinylazomethine ylide followed by recyclization to a fused 2-pyrroline.

Full text of DOI:10.1021/jo010218j

J . Org. Chem. 2001, 66, 6585-6594
6585
Syn th esis a n d Mech a n istic Stu d y of F u sed 2-P yr r olin es via
Th er m olysis of 6-Su bstitu ted -3,5-h exa d ien yl Azid ofor m a tes
Pei-Lin Wu,* Ta-Hsien Chung, and Ying Chou
Department of Chemistry, National Cheng Kung University, Tainan, Taiwan 701, Republic of China
wupl@mail.ncku.edu.tw
Received February 28, 2001
Thermolysis of 3,5-hexadienyl azidoformates at 300 °C, 0.05 Torr, led to a fused 2-pyrroline
regiospecifically, regardless of the configuration E or Z between the C-3 and C-4 double bond.
Thermolysis of 6-substituted-3,5(E)-hexadienyl azidoformates yielded a kinetically controlled
2-pyrroline with cis configuration between H-1 and H-8a whereas 6-substituted-3,5(Z)-hexadienyl
azidoformates produced a cis and trans mixture. The mechanism was proposed as the loss of nitrogen
to form an acyl nitrene, then addition to a double bond to produce an aziridine. Finally the cleavage
of the C-C bond generated a vinylazomethine ylide followed by recyclization to a fused 2-pyrroline.
Sch em e 1
In tr od u ction
Hudlicky1 and Pearson2 extensively applied formal [4
+ 1] cycloaddition of azides 1 across a conjugated diene
to form indolizidines and pyrrolizidines (Scheme 1).
Dienyl azide, the nitrene precursor, was found thermally
to undergo intramolecular cycloaddition and loss of
nitrogen to give vinylaziridine before rearrangement to
pyrroline. Aziridine reactions involving C-N bond
cleavage1b,2a,3 occasionally competed with those involving
C-C bond cleavage.4 Therefore, the regiochemistry of the
resulting pyrroline, either 2-pyrroline 2 or 3-pyrroline 3,
was determined mainly by the substitution of the starting
dienes and on the experimental conditions of the reaction.
For example, the absence of substituent on the diene (1,
R ) H) resulted in a complicated reaction mixture. The
presence of a carbethoxyl group on the diene (1, R ) CO2-
Et) gave C-2 functionalized 2-pyrroline 2 due to C-C
bond cleavage.1b However, the presence of a thioether
group on the diene (1, R ) SPh) led to C-3 functionalized
3-pyrroline 3 through C-N bond cleavage as a result of
the ketal-like center at Cx.2a A homodienyl [1,5]-hydrogen
shift behaved as another intensely competing reaction
(path a).
A structural change in the reactant was investigated
to promote the thermal intramolecular cycloaddition of
dienyl azide. We chose N-acyl function that could prevent
the homodienyl hydrogen shift. The developing amide
functionality might stabilize the product, as well as the
reactant. However, the thermolysis of acyl azides caused
Curtius rearrangement, exclusively yielding isocyanates.
Accordingly, dienyl azidoformate 4 was the candidate
molecule for exploring the intramolecular cycloaddition.
Even though Lwowski et al. has shown that no pyrroline
product was observed when carbethoxynitrene reacted
with 1,3 dienes,5 a technique of flash vacuum thermoly-
sis6 (FVT) would still be a means of producing nitrene
and inducing the subsequent thermal cycloaddition. The
intramolecular cycloaddition of the azidoformate is an
interesting and a potentially valuable transformation in
heterocyclic organic chemistry. This is the first time that
the thermal cyclization of the dienyl azidoformate has
been studied.
(1) (a) Hudlicky, T.; Seoane, G.; Price, J . D.; Gadamasetti, K. G.
Synlett 1990, 433. (b) Hudlicky, T.; Frazier, J . O.; Seoane, G.; Tiedje,
M.; Seoane, A.; Kwart, L. D.; Beal, C. J . Am. Chem. Soc. 1986, 108,
3755. (c) Hudlicky, T.; Frazier, J . O.; Kwart, L. D. Tetrahedron Lett.
1985, 26, 3523.
(2) (a) Pearson, W. H.; Bergmeier, S. C.; Degan, S.; Lin, K. C.; Poon,
Y. F.; Schkeryantz, J . M.; Williams, J . P. J . Org. Chem. 1990, 55, 5719.
(b) Pearson, W. H. Tetrahedron Lett. 1985, 26, 3527. (c) Pearson, W.
H.; Celebuski, J . E.; Poon, Y. F.; Dixon, B. R.; Glans, J . H. Tetrahedron
Lett. 1986, 27, 6301. (d) Pearson, W. H.; Poon, Y. F. Tetrahedron Lett.
1989, 30, 6661. (e) Schkeryantz, J . M.; Pearson, W. H. Tetrahedron
Lett. 1996, 52, 3107. (f) Pearson, W. H.; Bergmeier, S. C.; Williams, J .
P. J . Org. Chem. 1992, 57, 3977. (g) Pearson, W. H.; Lin, K. C.; Poon,
Y. F. J . Org. Chem. 1989, 54, 5814.
(3) (a) Lindstrom, U. M.; Somfai, P. J . Am. Chem. Soc. 1997, 119,
8385. (b) Wipf, P.; Fritch, P. C. J . Org. Chem. 1994, 59, 4875. (c)
Stamm, H.; Falkenstein, R. Chem. Ber. 1990, 123, 2227. (d) Stamm,
H.; Sommer, A.; Woderer, A.; Wiesert, W.; Mall, T.; Assithianakis, P.
J . Org. Chem. 1985, 50, 4946. (e) Mente, P. G.; Heine, H. W. J . Org.
Chem. 1971, 36, 3076. (f) Heine, H. W.; Kaplan, M. S. J . Org. Chem.
1967, 32, 3069. (g) Pepito, A. S.; Dittmer, D. C. J . Org. Chem. 1997,
62, 7920. (h) Bergmeier, S. C.; Stanchina, D. M. J . Org. Chem. 1999,
64, 2852.
The dienyl azidoformate 4 should be obtainable from
the corresponding dienyl alcohol by azidoformylation with
trichloromethyl chloroformate (diphosgen, ClCO2CCl3)
(5) Mishra, A.; Rice, S. N.; Lwowski, W. J . Org. Chem. 1968, 33,
481.
(6) (a) Wu, P. L.; Wang, W. S. J . Org. Chem. 1994, 59, 622. (b) Wu,
P. L.; Chen, H. C.; Line, M. L. J . Org. Chem. 1997, 62, 1532. (c) Wu,
P. L.; Chu, M.; Fowler, F. W. J . Org. Chem. 1988, 53, 963. (d) Wu, P.
L.; Fowler, F. W. J . Org. Chem. 1988, 53, 5998.
(4) (a) Anastassiou, A. G.; Hammer, R. B. J . Am. Chem. Soc. 1972,
94, 303. (b) Nozaki, H.; Fujita, S.; Noyori, R. Tetrahedron 1968, 24,
2193.
10.1021/jo010218j CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/01/2001

6586 J . Org. Chem., Vol. 66, No. 20, 2001
Wu et al.
Sch em e 2
Sch em e 4
Sch em e 3
the above analysis, the production of 2-pyrroline 10,
rather than 3-pyrroline, and the formation of isoxazolones
11 and 12 showed that the initial step probably involved
a loss of nitrogen, forming the active nitrene intermediate
8 at such a high temperature.9 Subsequently, nitrene 8
underwent a cyclization to form 2-vinylaziridine 910
followed by the rearrangement through C-C bond cleav-
age to yield pyrroline 10. Thus, a carbonyl substituent
on nitrogen made the cyclization compete more effectively
with insertion and inhibited homodienyl hydrogen shift
reactions. Attempts to influence the ratio of 2-pyrroline
to isoxazolone by varying the FVT temperature caused
little change. At high temperature, the product became
complex.
The addition of nitrene to the double bond and the
rearrangement of vinylaziridine both depended on sub-
stitution. With this initial result, we examined the FVT
of a series of dienyl azidoformates that possessed sub-
stituents on the end of the double bond.
and sodium azide (NaN3) (Scheme 2). The dienyl alcohol
could in turn be produced by the general Wittig reaction.
An oxaindolizidinone ring 5 was produced by the cyclo-
addition of this dienyl azidoformate 4 through FVT.
The methylthio group was first selected for this pur-
pose (Scheme 4). The Wittig reaction between methyl-
thioacetaldehyde and (3-carbethoxyallyl)triphenylphos-
phorane ylide generated a geometric mixture of 6-meth-
ylthio-2,4-dienyl ester 15. Since these isomers produced
the same product in the next step, it was not necessary
to separate them. Kinetic deconjugation of 15 with LDA
and reduction with LiAlH4 yielded the 3(E),5(E)-dienyl
alcohol 16 as the major product. The desired 3(E),5(E)-
dienyl azidoformate 17 was synthesized by chloroformyl-
ation with trichloromethyl chloroformate followed by
azidonation with NaN3. This methylthiodienyl azidofor-
mate 17 was subjected to FVT and gave fused pyrrole
18 as the only product at a 40% yield. Apparently the
elimination of methanethiol to 18 occurred once the
2-pyrroline 19 was formed.2a,11 According to the crude 1H
NMR analysis, the cyclization of azidoformate 17 hap-
Resu lts a n d Discu ssion
Initial model involved the research in unsubstituted
dienyl azidoformate 7 (Scheme 3). Chloroformate 6 could
be synthesized by slowly adding (E)-3,5-hexadien-1-ol into
a suspension of diphosgen along with activated charcoal.
The subsequent reaction between 6 and NaN3 in dry
acetone produced the desired azidoformate 7 in high
yield.7
The azidoformate 7 was quite thermally stable and was
almost quantitatively recovered after evaporation through
a FVT tube at 250 °C and 0.05 Torr. The starting
material was completely consumed at 300 °C and gener-
ated a fused 2-pyrroline 10 at a 33% isolated yield.
2-Pyrroline 10 was verified by the 1H NMR spectrum that
showed a more downfield shifted signal at δ 6.61 and a
more upfield shifted signal at δ 5.17, typical for two
protons in an enamine. In addition, the C-H insertion
product, isoxazolone 11, was purified in a 10% yield, and
the apparent C-C insertion product, isoxazolone 12, was
isolated as a cis and trans isomeric mixture in a 20%
combined yield. The compound 12 might have been
obtained by the Wagner-Meerwein rearrangement of the
betaine 14 that came from the stepwise addition of
nitrene to the double bond.8 Hydrogenation of the mixture
12 resulted in a single isoxazolone 13. On the basis of
(8) (a) Goldsmith, D. J .; Soria, J . Tetrahedron Lett. 1986, 27, 4701.
(b) Dauben, W. G.; Bunce, R. A. J . Org. Chem. 1982, 47, 5042. (c) Wohl.
R. A. Tetrahedron Lett. 1973, 3111.
(9) (a) Lwowski, W.; Mattingly, T. W., J r. J . Am. Chem. Soc. 1965,
87, 1947. (b) Albini, A.; Bettinetti, G.; Minoli, G. J . Am. Chem. Soc.
1997, 119, 9, 7308. (c) Kemnitz, C. R.; Karney, W. L.; Borden, W. T. J .
Am. Chem. Soc. 1998, 120, 3499.
(10) The 2-vinylaziridine was not detected in gas phase thermolysis
even at lower temperature. Actually, using a sealed tube, thermolysis
of a solution of 6-phenyl-3(E),5(E)-hexadienyl azidoformate (34) in
CHCl3 at 150 °C does produce the 2-vinylaziridine which could be
recognized from the 1H NMR spectrum of the crude material. The
purification of vinylaziridine failed.
(7) Wu, P. L.; Su, C. H.; Gu, Y. J . J . Chin. Chem. Soc. 2000, 47,
271.
(11) Kheruze, Y. J .; Galishev, V. A.; Petrov, A. A.; J . Org. Chem.
USSR 1988, 24, 852.

Fused 2-Pyrrolines
J . Org. Chem., Vol. 66, No. 20, 2001 6587
Sch em e 5
F igu r e 1. The NOE correlations of compounds 26 and 27.
Sch em e 6
pened more cleanly than that of unsubstituted azidofor-
mate 8. All attempts to observe the isoxazolone product
by insertion and 3-pyrroline product by 1,4-addition
failed.
The stereochemical features of the annulation were
investigated after the regiochemistry of 2-pyrroline,
instead of 3-pyrroline, was solved by the chemical shifts
of two vinyl protons (δ 5.37 and 6.73 for 24; 5.57 and 6.89
for 25). The stereochemistry of the newly formed chiral
center (C-1) relative to the bridgehead chiral carbon (C-
An azidoformate 23 bearing a methoxyl substituent on
the terminal double bond was synthesized as depicted
in Scheme 5. In contrast to 15, deconjugation of a 2.5:1
mixture of 2(E),4(E)- and 2(E),4(Z)-conjugated ester 20
led to a 1:1 mixture of 3(E),5(E)- and 3(E),5(Z)-dienyl
ester 21.12 The separation of the 3(E),5(Z) and 3(E),5(E)
ester was unsuccessful due to the instability of the enol
ether structure in 21. The hydrolysis of 21 to aldehyde
during prolonged chromatography over silica gel was
seen. Therefore, a low yield of pure 3(E),5(Z)-hexadienyl
ester 21 was obtained for the following reaction. Reduc-
tion of 21 with LiAlH4 yielded alcohol 22 which was
subjected to chloroformylation and azidonation to produce
the 3(E),5(Z)-dienyl azidoformate 23. When pure 23 was
thermolyzed, 2-pyrrolines 24 and 25 with a 2:1 ratio were
isolated in a 44% combined yield. In addition, the fused
pyrrole 18 was obtained in a 11% yield.13 Neither the 1,4-
addition product nor the insertion product was observed.
Owing to the lability of 2-pyrroline during column chro-
matography, only the major 24 was separated for spectral
analysis. The compound 25 was also isolated. However,
we observed that, after 1 day, compound 25 in CDCl3
decomposed to 18 cleanly. Fortunately, two pyrrolidines
26 and 27 from the hydrogenation of the mixture of 24
and 25 were readily separated for spectral and stereo-
chemical examination. Comparing the total FVT yield of
azidoformates 17 and 23 with that of unsubstituted 8,
placing an electron-donating group at terminal double
bond might increase the reactivity of azidoformate toward
cyclization.
1
8a) and the full assignment of H and 13C NMR signals
were obtained from 2D-COSY, HMQC, and NOESY
spectra. For simplicity, we use R and â terminology for
substituents, R substituents being below the ring. In
2-pyrroline 24, the presence of NOE between H-1 (δ 4.69)
and H-8R (δ 1.95) and the absence of NOE between H-1
and H-8a (δ 3.93) suggested a trans relationship between
the protons H-1 and the ring junction methine H-8a,
requiring that the methoxyl substituent orientated to-
ward â direction. Moreover, the separable hydrogenated
products 26 and 27 also offered stereochemical informa-
tion because the hydrogenation did not affect the stereo-
genic center. The absence of NOE between H-8a and H-3â
in 26 and 27 led us to tentatively assign the cis confor-
mation (Figure 1). In 26, the NOEs of H-1 (δ 3.50) with
H-8R and/or H-2R (δ 1.71) as well as OCH3 (δ 3.39) with
H-8a (δ 3.36), H-8â and/or Η-2â (δ 2.28) further con-
firmed the â-methoxyl orientation (Figure 1). In contrast,
the presence of NOEs between H-1 (δ 3.82) and H-8a (δ
3.60), H-2R (δ 2.17), H-2â (δ 1.75) as well as the NOEs
between OCH3 (δ 3.33) and H-2R (δ 2.17) showed an
R-methoxyl orientation in 27.
Subsequently, we prepared an accessible dienyl azido-
formate 30 consisting of an electron-withdrawing group
CO2CH3 at the terminal double bond (Scheme 6). The
Wittig reaction between a protected hydroxyaldehyde 28
and (3-carbomethoxypropenyl)triphenylphosphorane fol-
lowed by deprotection directly yielded the desired alcohol
29 in a 3(E),5(E) and 3(Z),5(E) mixture. Chloroformyla-
tion and azidonation of 29 afforded a mixture of 3(E),5-
(E)- and 3(Z),5(E)-dienyl azidoformate 30. Although we
did not intend to separate mixture 30, a single cyclization
(12) (a) Gutierrez, A. J .; Shea, K. J .; Svoboda, J . J . J . Org. Chem.
1989, 54, 4335. (b) Grieco, P. A.; Yoshida, K.; He, Z. M. Tetrahedron
Lett. 1984, 25, 5715.
(13) We left the compound 25 in CDCl3 for 1 d and then recorded
the 1H NMR spectrum again. Compound 18, instead of 25, was found
cleanly by the loss of methanol.

6588 J . Org. Chem., Vol. 66, No. 20, 2001
Wu et al.
Sch em e 7
Sch em e 9
Sch em e 8
product 31 was obtained stereospecifically at a 71% yield
when it was sent through the FVT tube, implying that
the thermal rearrangement of 30 with 3(E)- and 3(Z)-
geometry proceeded through the same intermediate at a
certain stage. The complete assignments and the R-car-
bomethoxyl stereochemistry of 31 and its hydrogenated
product 32 were clarified by COSY, HMQC, and NOESY
2D-NMR spectra. The structure of 31 was also specified
by a single-crystal X-ray analysis on the pyrrolidine 32.
The crystal structure data confirmed that the car-
bomethoxyl group of 32 occupied an R position. The lone
pair electrons on nitrogen were cis to the bridgehead
proton. Furthermore, the cis-fused oxaindolizidinone
skeleton showed that the six-membered ring was present
as a boatlike conformation and the pyrrolidine ring
adopted an envelop conformation.
A phenyl substituent as part of the conjugation of the
double bond in the azidoformate 34 was synthesized from
phenylacetaldehyde (Scheme 7). Evaporating compound
34 through the FVT tube at 300 °C resulted in a
stereospecific fused 2-pyrroline 35 at a 51% yield. The
NOE between H-1 (δ 4.15) and H-8a (δ 4.39) demon-
strated that the phenyl substituent placed in the R
direction. The NOEs of hydrogenated pyrrolidine 36
between H-1 (δ 3.47) and H-8a (δ 3.92), H-2â (δ 2.33);
H-2′, H-6′ of phenyl (δ 7.02) and H-2R (δ 2.14), H-3R (δ
4.03), H-8R (δ 1.22) further clarified the R phenyl
stereochemistry.
The opposite stereoisomers must be considered to
examine the nature of this stereoselection in detail. We
selected the azidoformate with a phenyl substituent as
an example. Using the same procedure as described
above for the preparation of azidoformate, 6-phenyl-
3(Z),5(E)-hexadien-1-ol yielded 3(Z),5(E)-dienyl azidofor-
mate 37 (Scheme 8). FVT of 37 at 300 °C gave 2-pyrroline
35 at ca. 50% yield. Surprisingly, both 3(E),5(E)-azido-
formate 34 and 3(Z),5(E)-azidoformate 37 afforded the
same cyclized product 35 in the same yield. This phe-
nomenon let us to make a conclusion that an identical
FVT product was obtained regardless of the E or Z
geometry of the C-3 and C-4 double bond in the 3,5-
hexadienyl azidoformates.
Cyclizing the isomers with Z configuration at the C-5
and C-6 double bond would reveal whether the same
product as 35 or an epimer was produced, providing some
insight into the cyclization mechanism. The Wittig reac-
tion between (Z)-3-phenylpropenal and (3-hydroxypro-
pyl)triphenylphosphonium bromide in the presence of two
equivalents of n-BuLi produced a mixture of 3(E),5(Z)-
alcohol 38 and 3(Z),5(Z)-alcohol 39 in a 1:2 ratio (Scheme
9). A pure 39 and a material 38 contaminated with a little
39 was carefully separated by column chromatography.
Azidoformylation of 38 and 39 yielded azidoformates 40
and 41, respectively. FVT of 3(Z),5(Z)-azidoformate 41
yielded 30% of a tricyclic compound 44 and two 2-pyrro-
line products with about a 1:2 ratio in a ca. 39% combined
yield. The two 2-pyrrolines showed a very similar but not
identical NMR spectra. The major 2-pyrroline exhibited
spectral data identical with those of 35 having an R
orientated phenyl group. The minor one was assigned for
the epimer 42 owing to the presence of NOE between
phenyl group (δ 7.30) and H-8a (δ 3.93). The mixture of
35 and 42 was hydrogenated to give the separable
pyrrolidines 36 and 43, respectively. The relative con-
figuration of 43 at junction carbon C-8a and phenyl
substituted carbon C-1 was addressed by the 2D-NMR
experiments. The existence of NOEs of H-1 (δ 2.82) with
H-2R (δ 2.30) and H-8R (δ 1.68); phenyl (δ 7.24) with H-8a
(δ 3.51), H-2â (δ 2.12), and H-8â (δ 2.01) led to a â-phenyl
in 43. FVT of 3(E),5(Z)-azidoformate 40 gave almost
identical product ratio as 41. Therefore, the isomeric ratio
of 35 and 42 would be independent of the geometry of
the C-3 and C-4 double bond again. The production of
two stereoisomeric 2-pyrrolines from 3,5(Z)-azidoformates
40 and 41 was similar to that observed in the case of
FVT of azidoformate 23 involving 5(Z)-6-OCH3 structure.
Resubjection of pyrrolines 35 or 42 through a hot tube
under the same FVT condition resulted in recovery of
starting material quantitatively. At higher FVT temper-
ature, the starting material recovered was contaminated

Fused 2-Pyrrolines
J . Org. Chem., Vol. 66, No. 20, 2001 6589
Sch em e 10
nylaziridines 49 and 50, or 54 and 55 happened during
the FVT process. Because cis- and trans-vinylaziridines
49 and 50, or 54 and 55 produced the same intramolecu-
lar cycloadducts 53 or 58, the azomethine ylides 51, 52,
56, and 57, a fully conjugated 1,3-dienyl anion, was
proposed as the intermediate in this process.18 In fact,
cleavage of the allylic C-N bond was preferred when the
substituent on nitrogen was an anion-stabilizing group,
for example, a carbethoxyl group. The energetic cost of
making the cleavage of C-C bond was partially compen-
sated by the resonance of the vinylazomethine ylide.
In the case of 5(E)-azidoformates, the formation of
azomethine ylides 51 and 52 from aziridines 49 and 50
(∆Gq ca. 122 kJ /mol) was usually controlled by the
4-electron conrotatory ring opening. A rotation about one
of the ylide C-N bonds (∆Gq ca. 92 kJ /mol) led to the
loss of original stereochemistry.19 The conformation given
in 52 was required for successful closure to form the
2-pyrroline 53. An equilibrium should present between
51 and 52. In addition to possess the same intermediate
52, the reclosure of the vinylazomethine ylide underwent
a 6-electron electrocyclic reaction with disrotatory pro-
cess, producing the thermodynamically less stable prod-
uct 53.18e,f,20 Complete control of the stereochemistry of
C-1 was thus observed.
with some unknown compounds, none of which were its
epimer or 44. No equilibrium was established between
35 and 42.
Mech a n istic Stu d y. Since the reaction temperature
of 300 °C was above that normally required for the
formation of nitrene from azides, the cyclization reaction
of 3,5-hexadienyl azidoformate unambiguously proceeded
by the loss of nitrogen followed by double bond addition
to form vinylaziridine. We postulated that the initial
aziridine formation might have been nonstereospecific
from the fact that 3(E),5(E)-phenylazidoformates 34 and
3(Z),5(E)-phenylazidoformate 37 or the mixture of 3(Z),5-
(E)- and 3(E),5(E)-carbomethoxyazidoformates 30 always
cyclized to give 2-pyrroline derivatives 35 or 31 as the
exclusive product. It was reported that alkenes isomer-
ized considerably more slowly than the rate of cycliza-
tion.14 To prove it, 1-phenyl-1(Z),3(Z)-heptadiene which
lacked an azidoformate group was synthesized and did
not isomerize into any of the E isomer under the same
FVT conditions. Hence, the formation of vinylaziridine
from its corresponding nitrene should be not stereospe-
cific. The suggestion was confirmed by the FVT of (E)-
and (Z)-4-phenyl-3-butenyl azidoformates 45 and 46
under identical conditions. Both 45 and 46 generated a
mixture of aziridines 47 and 48 in 6:1 and 2.5:1 ratios,
respectively, without retaining the configuration (Scheme
10).15 The identity of 47 and 48 was determined by the
1H NMR spectral characteristics of two methine protons
on an aziridine ring. The trans methine protons in 47
appeared at δ 2.83 (ddd, J ) 8.7, 6.2, 3.0 Hz, H-6â) and
3.30 (d, J ) 3.0 Hz, H-7R) with an expected smaller
coupling constant (3.0 Hz), whereas the cis methine
protons in 48 at δ 3.14 (ddd J ) 11.3, 6.3, 5.0 Hz, H-6â)
and 3.91 (d, J ) 5.0 Hz, H-7â) with a larger coupling
constant (5.0 Hz).16 Accordingly, at such a high temper-
ature and a short reaction time, the formation of the
adducts 47 and 48 was readily interpreted by assuming
that 45 and 46 initially lose nitrogen to leave active
triplet nitrenes which subsequently cyclized with a
neighboring double bond to form nonstereospecifically the
primary cycloadducts.17
Similarly, 5(Z)-azidoformates lost nitrogen and cyclized
nonstereospecifically to vinylaziridines 54 and 55. The
three-membered ring was opened to form azomethine
ylides 56 and 57. The vinylazomethine ylide 57 proceeded
through a disrotatory recyclization and gave the expected
2-pyrroline 58 with â-orientated substituent. The termi-
nal substituent in 57 which was cis to the diene chain
was forced to assume a more crowded position than in
52. Furthermore, the double bond character was reduced
by resonance among the dienyl anion system and rotation
from 57 to 52 was made possible.21 Therefore, the
cyclization of 57 to 58 obtained from 5(Z)-azidoformates
was slow enough to allow competition from isomerization
via rotation about the C-C double bond to form 52 which
then cyclized to 53. Comparing the FVT product ratio for
the phenyl substituent (â-Ph-42:R-Ph-35 ) 1:2) to that
for methoxyl substituent (â-OCH3-24:R-OCH3-25 ) 2:1),
the larger phenyl group was seriously hindered in the
azomethine ylide stage and gave more R-phenyl product
35 (R ) Ph).
The isolation of 44 provided a sufficient evidence for
the formation of vinylazomethine ylide 57. Electrocyclic
reaction of 57 (R ) Ph) through 8-electron conrotatory
(18) (a) Tsuge, O.; Kanemasa, S. In Advances in Heterocyclic
Chemistry; Katritzky, A. R., Ed.; Academic: San Diego, 1989; Vol. 45,
p 231. (b) Lown, J . W. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley-Interscience: New York, 1984; Vol. 1, Chapter 6, pp
653-732. (c) Farina, F.; Martin-Ramos, M. V.; Romanach, M. Hetero-
cycles 1995, 40, 379. (d) Ramaiah, D.; Cyr, D. R.; Barik, R.; Gopidas,
K. R.; Das, D. K.; George, M. V. J . Phys. Chem. 1992, 96, 1271. (e)
Pommelet, J . C.; Chuche, J . Can. J . Chem. 1976, 54, 1571. (f) Borel,
D.; Gelas-Mialhe, Y.; Vessiere, R. Can. J . Chem. 1976, 54, 1590. (g)
Gaebert, C.; Siegner, C.; Mattay, J .; Toubartz, M.; Steenken, S. J .
Chem. Soc., Perkin Trans. 2 1998, 2735.
(19) (a) Huisgen, R.; Mader, H. J . Am. Chem. Soc. 1971, 93, 1777.
(b) Hermann, H.; Huisgen, R.; Mader, H. J . Am. Chem. Soc. 1971, 93,
1779.
(20) (a) Medimagh, M. S.; Chuche, J . Tetrahedron Lett. 1977, 793.
(b) Padwa, A.; Carlsen, P. H. J . J . Am. Chem. Soc. 1975, 97, 3862. (c)
Fleming, I. Frontier Orbitals and Organic Chemical Reactions; Wiley:
New York, 1976.
The above facts could be accommodated by Scheme 11.
The double bond isomerization did not occur and non-
stereospecific cyclization from dienyl acylnitrene to vi-
(14) Chou, S. S. P.; Liou, S. Y.; Tsai, C. Y.; Wang, A. J . J . Org. Chem.
1987, 52, 4468.
(15) Lwowski, W.; McConaghy, J . S., J r. J . Am. Chem. Soc. 1967,
89, 4450.
(16) Ibuka, T.; Mimura, N.; Aoyama, H.; Akaji, M.; Ohno, H.; Miwa,
Y.; Taga, T.; Nakai, K.; Tamamura, H.; Fujii, N J . Org. Chem. 1997,
62, 999.
(17) (a) Lwowski, W., Ed. Nitrenes; J ohn Wiley & Sons: New York,
1970; Chapter 6, pp 185-224. (b) Autrey, T.; Schuster, G. B. J . Am.
Chem. Soc. 1987, 109, 5814. (c) Sigman, M. E.; Autrey, T.; Schuster,
G. B. J . Am. Chem. Soc. 1988, 110, 4297. (d) Marcinek, A.; Leyva, E.;
Whitt, D.; Platz, M. S. J . Am. Chem. Soc. 1993, 115, 8609.
(21) Marvell, E. N.; Caple, G.; Delphey, C.; Platt, J .; Polston, N.;
Tashiro, J . Tetrahedron 1973, 29, 3797.

6590 J . Org. Chem., Vol. 66, No. 20, 2001
Wu et al.
Sch em e 11
Sch em e 12
by recyclization to give 2-pyrroline through a 6-electron
disrotatory mode. Regardless of E or Z configuration
between the C-3 and C-4 double bond, the 3,5-hexadienyl
azidoformates gave the same products. The E configu-
ration on the C-5 and C-6 double bond yielded a kineti-
cally controlled product with the substituent in the
R-position, whereas the Z configuration produced a
mixture of the substituent toward R- and â-direction. The
reactivity of the cycloaddition of azidoformates increased
by the presence of substituents at the terminal double
bond, such as methoxycarbonyl, methylthio, methoxyl,
and phenyl.
process followed by a 1,5-hydrogen shift to form 44
(Scheme 12) competed with the direct cyclization to form
53 and 58.
The actual yield of 2-pyrrolines reflected the reactivity
of azidoformates. The electron-withdrawing substituent
CO2CH3 (71% yield) and the conjugating group Ph (50%
yield) attached to the terminal double bond of the diene
could stabilize the vinylazomethine ylides and accelerate
the disrotatory rotation to 2-pyrrolines. The electron-
donating substituent OCH3 retarded the cyclization.22
However, the combined yield of two isomeric 2-pyrrolines
24 and 25, and one demethanol product 18 was 55%. This
value was attributed to the fact that an oxygen-contain-
ing substituent could still stabilize the positive charge
on nitrogen by inductive effect. Furthermore, an electron-
donating group could facilitate the primary cycloaddition
for the electron-deficient nitrene to the electron-rich
double bond, enhancing the reaction.23
In summary, the FVT of 3,5-hexadienyl azidoformates
gave a regiospecific and stereospecific fused 2-pyrroline.
This azide-diene annulation occurred by nitrogen extru-
sion to form a triplet acylnitrene then intramolecular
cycloaddition to yield a mixture of aziridines. The cleav-
age of C-C bond produced vinylazomethine ylide followed
Exp er im en ta l Section
Gen er a l. Melting points were taken on
a Buchi 535
melting-point apparatus and were not corrected. Infrared
spectra were measured on a Nicolet Magna FT-IR spectrom-
eter as either thin films or solid dispersions in KBr. Nuclear
magnetic resonance spectra were recorded on Bruker AC-200
and AMX-400 FT-NMR spectrometers; all chemical shifts are
reported in ppm from tetramethylsilane as an internal stan-
dard. Low- and high-resolution mass spectra were obtained
on a VG 70-250S spectrometer. Elemental analyses were
performed on a Heraeus CHN-RAPID elemental analyzer.
Column chromatography was carried out using 70-230 mesh
silica gel (E. Merck). The alkenyl azidoformates, for example
6-phenyl-3,5-hexadienyl azidoformate (34), could decompose
at ∼150 °C from DTA (differential thermal analysis) data.9a,24
(E)-3,5-Hexa d ien yl Azid ofor m a te (7). A suspension of
trichloromethyl chloroformate (0.59 g, 3 mmol) in THF (25 mL)
along with catalytic amount of activated charcoal (5 mg, 0.4
mmol) was stirred at room temperature for 10 min. A solution
of (E)-3,5-hexadien-1-ol25 (0.39 g, 4 mmol) in THF (10 mL) was
added dropwise for 2 h. The reaction mixture was stirred for
an additional hour at room temperature. The resulting mixture
(22) Carpenter, B. K. Tetrahedron 1978, 34, 1877.
(23) (a) Loreto, M. A.; Pellacani, L.; Tardella, P. A. Tetrahedron Lett.
1989, 30, 5025. (b) J ones, D. W.; Thornton-Pett, M. J . Chem. Soc.,
Perkin Trans. 1 1995, 809. (c) Dyall, L. K.; Labbe, G.; Dehaen, W. J .
Chem. Soc., Perkin Trans. 2 1997, 971.
(24) Fioravanti, S.; Loreto, A.; Pellacani, L.; Sabbatini, F.; Tardella,
P. A. Tetrahedron: Asymmetry 1994, 5, 473.
(25) Martin, S. F.; Tu, C. Y.; Chou, T. S. J . Am. Chem. Soc. 1980,
102, 5274.

Fused 2-Pyrrolines
J . Org. Chem., Vol. 66, No. 20, 2001 6591
was filtered and concentrated under reduced pressure to
produce chloroformates 6 quantitatively. This chloroformate
could be used in the following reaction without further
purification. Therefore the chloroformate 6 added immediately
into a suspension of NaN3 (0.52 g, 8 mmol) in dry acetone (20
mL) and stirred for 3 h at room temperature.7 The reaction
mixture was filtered, concentrated in vacuo, and chromato-
graphed over silica gel eluting with hexane-EtOAc (30:1) to
yield azidoformate 7 (0.55 g, 83% yield) as colorless oil: IR
(film) νmax 2184, 2136, 1728, 1238 cm-1; 1H NMR (CDCl3, 200
MHz) δ 2.47 (2H, q, J ) 6.8 Hz), 4.24 (2H, t, J ) 6.8 Hz), 5.04
(1H, dd, J ) 10.3, 1.9 Hz), 5.14 (1H, dd, J ) 16.7, 1.9 Hz),
5.62 (1H, dt J ) 14.8, 6.8 Hz), 6.13 (1H, dd, J ) 14.8, 10.3
Hz), 6.30 (1H, dt, J ) 16.7, 10.3 Hz); 13C NMR (CDCl3, 50 MHz)
δ 31.6, 67.5, 116.5, 128.3, 134.0, 136.5, 157.4; MS m/z (rel int)
167 (2, M+), 80 (100), 67 (26), 55 (15), 53 (14); HRMS m/z
167.0659 (Calcd for C7H9N3O2 167.0695).
Gen er a l Meth od for F VT. A modified FVT technique was
applied. A hollow tube (10 mm i.d. × 200 mm length) wraped
with a heating tape was attached by two flasks. One long flask
as a receiver had a sidearm for appling vacuum. The reactant
(10∼300 mg) was frozen in the other small flask under liquid
nitrogen bath, and a vacuum was applied. Once the vacuum
(0.1-0.01 Torr) had been established, the heater was turned
on. The temperature of the hot tube was regulated by a
temperature controller. When the set temperature was reached,
the receiver was placed in a liquid nitrogen bath and the
reactant was heated to thaw and evaporate through the hot
tube. The product was condensed in the receiver and washed
out with acetone. After removal of the solvent, the crude
product was purified by column chromatography over silica
gel eluting with hexane-EtOAc (1:1).
NaOH (5 mL) was added dropwise. The fresh prepared
methylthioacetaldehyde28 (0.54 g, 6 mmol) was added. The
resulting solution was stirred at 0 °C for 3 h and concentrated
in vacuo. The aqueous solution was extracted with EtOAc (25
mL × 3). The combined organic extract was dried with
anhydrous MgSO4, filtered, and concentrated in vacuo. The
crude product was chromatographed over silica gel eluting
with hexane-EtOAc (80:1) to give an inseparable geometric
mixture of ethyl 6-methylthio-2,4-hexadienoate (15) (0.71 g,
64%) as colorless oil.
6-Meth ylth io-3(E),5(E)-h exa d ien -1-ol (16). Deconjuga-
tion of the mixture 15 was proceeded with LDA. A solution of
LDA in THF was prepared by the slow addition of n-BuLi (2.5
M in hexane, 2.4 mL, 6 mmol) to a solution of diisopropylamine
(0.61 g, 6 mmol) in anhydrous THF (15 mL) under N2 at -78
°C.29 Dry hexamethylphosphoramide (1.08 g, 6 mmol) was
added dropwise and the mixture allowed to stir 30 min. Ester
15 (0.93 g, 5 mmol) was added to the cold solution dropwise.
Stirring was continued an additional hour at -78 °C, then the
dark-red mixture was poured into a rapidly stirred solution
of acetic acid (0.90 g, 15 mmol) in H2O (30 mL). The resulting
solution was extracted with EtOAc (20 mL × 3), and the
combined extract was dried with anhydrous MgSO4, filtered,
and concentrated in vacuo. The crude product was chromato-
graphed over silica gel eluting with hexane-EtOAc (80:1) to
give pure ethyl 6-methylthio-3(E),5(E)-hexadienoate (0.66 g,
71% yield) as colorless oil: IR (film) νmax 1728 (CdO) cm-1; 1H
NMR (CDCl3, 200 MHz) δ 1.26 (3H, t, J ) 7.2 Hz), 2.27 (3H,
s), 3.09 (2H, d, J ) 7.2 Hz), 4.14 (2H, q, J ) 7.2 Hz), 5.62 (1H,
dt, J ) 14.4, 7.2 Hz), 6.00 (1H, dd, J ) 14.4, 9.9 Hz), 6.15 (1H,
dd, J ) 14.4, 9.9 Hz), 6.24 (1H, d, J ) 14.4 Hz); 13C NMR
(CDCl3, 50 MHz) δ 14.1, 14.6, 38.0, 60.0, 121.5, 124.6, 128.4,
132.7, 171.6; MS m/z (rel int) 186 (23, M+), 155 (27), 115 (51),
103 (51), 97 (100), 87 (60), 81 (59), 61 (63), 55 (49); HRMS m/z
186.0713 (Calcd for C9H14O2S 186.0715).
By the general method for FVT, azidoformate 7 (167 mg, 1
mmol) gave 10 (46 mg, 33% yield), 11 (14 mg, 10% yield), and
a cis and trans mixture of 12 (28 mg, 20% yield).
Subsequently, the 6-methylthio-3(E),5(E)-hexadienoate (0.93
g, 5 mmol) in anhydrous Et2O (5 mL) was added dropwise to
a suspension of LiAlH4 (0.29 g, 7.5 mmol) in anhydrous Et2O
(15 mL). After the addition had completed, the reaction
mixture was stirred at room temperature for 2 h. With cooling
in an ice bath, a solution of 5% NaOH was added carefully to
destroy the excess hydride until the hydrogen evolution ceased.
The resulting solution was extract with Et2O (20 mL × 3). The
combined extract was dried with anhydrous MgSO4, filtered,
and concentrated in vacuo. The crude product was chromato-
graphed over silica gel eluting with hexane-EtOAc (1:3) to
give 16 (0.66 g, 91% yield) as colorless oil: IR (film) νmax 3370
6-Oxa -1,7,8,8a -tetr a h yd r oin d olizin -5-on e (10). White
powder (EtOAc-hexane), mp 50-51 °C; IR (KBr) νmax 1694
1
(CdO) cm-1; H NMR (CDCl3, 200 MHz) δ 2.00 (1H, m), 2.23
(1H, m), 2.49 (1H, m), 2.72 (1H, m), 4.13 (2H, m), 4.37 (1H,
m), 5.17 (1H, m), 6.61 (1H, m); 13C NMR (CDCl3, 50 MHz) δ
28.1, 36.7, 56.7, 66.8, 109.7, 129.8, 150.0; MS m/z (rel int) 139
(64, M+), 94 (77), 80 (56), 67 (100), 53 (28). Anal. Calcd for
C7H9NO2: C, 60.42; H, 6.52; N, 10.07. Found: C, 60.38; H,
6.65; N, 10.08.
4-(1,3-Bu ta d ien yl)-2-oxa zolid in on e (11). Colorless oil; IR
(film) νmax 3268 (br, NH), 1737 (CdO) cm-1; 1H NMR (CDCl3,
200 MHz) δ 4.04 (1H, dd, J ) 7.8, 6.5 Hz), 4.48 (2H, m), 5.18
(1H, d, J ) 9.3 Hz), 5.27 (1H, d, J ) 16.4 Hz), 5.62 (1H, dd, J
) 14.5, 7.4 Hz), 6.2 (1H, br s, NH), 6.25 (2H, m); 13C NMR
(CDCl3, 50 MHz) δ 54.8, 70.2, 118.8, 132.9, 133.8, 136.8, 159.7;
MS m/z (rel int) 139 (40, M+), 94 (20), 80 (100), 68 (27), 53
(26); HRMS m/z 139.0636 (Calcd for C7H9NO2 139.0633).
N-Bu tyl-2-oxa zolid in on e (13). The inseparable geometric
mixture 12 was subjected to hydrogenation using 5% Pd/C as
catalyst in EtOAc at room temperature for 12 h. The reaction
mixture was filtered, concentrated in vacuo, and chromato-
graphed over silica gel eluting with hexane-EtOAc (1:1) to
yield 13 quantitatively as colorless oil: IR (film) νmax 1743 (Cd
1
(br, OH) cm-1; H NMR (CDCl3, 200 MHz) δ 2.12 (1H, br s,
OH), 2.27 (3H, s), 2.33 (2H, dt, J ) 7.1, 6.4 Hz), 3.65 (2H, t, J
) 6.4 Hz), 5.52 (1H, dt, J ) 15.0, 7.1 Hz), 5.99 (1H, dd, J )
14.7, 10.1 Hz), 6.15 (1H, dd, J ) 15.0, 10.1 Hz), 6.20 (1H, d, J
) 14.7 Hz); 13C NMR (CDCl3, 50 MHz) δ 14.7, 35.9, 62.0, 125.3,
126.4, 127.5, 132.3; MS m/z (rel int) 144 (64, M+), 113 (74),
111 (70), 97 (47), 67 (100), 65 (96), 57 (55), 55 (40); HRMS m/z
144.0610 (Calcd for C7H12OS 144.0609).
6-Meth ylth io-3(E),5(E)-h exa d ien yl Azid ofor m a te (17).
The analogous procedure for the preparation of azidoformate
8 was used. Alcohol 16 (0.58 g, 4 mmol) gave 17 (0.68 g, 80%
yield) as colorless oil: IR (film) νmax 2186 and 2134 (N3), 1725
O) cm-1 1H NMR (CDCl3, 200 MHz) δ 0.92 (3H, t, J ) 7.4
;
1
(CdO) cm-1; H NMR (CDCl3, 200 MHz) δ 2.28 (3H, s), 2.45
Hz), 1.33 (2H, sextet, J ) 7.4 Hz), 1.52 (2H, quintet, J ) 7.4
Hz), 3.24 (2H, t, J ) 7.4 Hz), 3.53 (2H, t, J ) 8.0 Hz), 4.30
(2H, t, J ) 8.0 Hz); 13C NMR (CDCl3, 50 MHz) δ 13.6, 19.8,
29.4, 43.9, 44.5, 61.6, 158.5; MS m/z (rel int) 143 (3, M+), 128
(2H, dt, J ) 7.2, 6.7 Hz), 4.23 (2H, t, J ) 6.7 Hz), 5.46 (1H, dt,
J ) 14.5, 7.2 Hz), 5.97 (1H, dd, J ) 14.5, 9.7 Hz), 6.14 (1H,
ddt, J ) 14.5, 9.7, 1.1 Hz), 6.21 (1H, d, J ) 14.5 Hz); 13C NMR
(CDCl3, 50 MHz) δ 14.7, 31.7, 67.7, 124.2, 124.9, 128.1, 132.5,
157.4; MS m/z (rel int) 213 (22, M+), 126 (61), 97 (48), 79 (100),
65 (56). Anal. Calcd for C8H11N3O2S: C, 45.06; H, 5.20; N,
19.70. Found: C, 45.07; H, 5.36; N, 19.68.
(24), 100 (60), 56 (100); HRMS m/z 143.0947(Calcd for C7H13
-
NO2 143.0946).
Eth yl 6-Meth ylth io-2,4-h exa d ien oa te (15). The Wittig
reaction used by Mallory et al. was slightly modified to reduce
the decomposition of phosphorane.26 A solution of (3-carb-
ethoxyallyl)phosphoniun bromide27 (3.19 g, 7 mmol) in CH2-
Cl2 (30 mL) was stirred at 0 °C while a solution of 6% aqueous
6-Oxa -7,8-d ih yd r oin d olizin -5-on e (18). By the general
method for FVT, azidoformate 17 (213 mg, 1 mmol) gave 18
(55 mg, 40% yield) as colorless oil: IR (film) νmax 1746 (CdO)
1
cm-1; H NMR (acetone-d6, 200 MHz) δ 3.08 (2H, td, J ) 6.0,
(26) Mallory, F. B.; Butler, K. E.; Evans, A. C.; Brondyke, E. J .;
Mallory, C. W.; Yang, C.; Ellenstein, A. J . Am. Chem. Soc. 1997, 119,
2119.
(28) Mikolajczyk, M.; Balczewski, P. Synthesis 1987, 659.
(29) Stevens, R. V.; Cherpeck, R. E.; Harrison, B. L.; Lai, J .;
Lapalme, R. J . Am. Chem. Soc. 1976, 98, 6371.
(27) Howe, R. K. J . Am. Chem. Soc. 1971, 93, 3457.

6592 J . Org. Chem., Vol. 66, No. 20, 2001
Wu et al.
1.2 Hz), 4.57 (2H, t, J ) 6.0 Hz), 6.04 (1H, m), 6.23 (1H, t, J
) 3.2, 2.0 Hz), 7.20 (1H, dd, J ) 3.2, 1.5 Hz); 13C NMR
(acetone-d6, 50 MHz) δ 22.6, 69.0, 108.7, 113.0, 119.2, 130.1,
148.3; MS m/z (rel int) 137 (100, M+), 92 (77), 66 (60), 52 (24);
HRMS m/z 137.0479 (Calcd for C7H7NO2 137.0477).
column chromatography eluting with EtOAc-hexane (1:1)
yielded pure 26 (45 mg) and 27 (22 mg).
1â-Meth oxy-6-oxa -8a â-in d olizid in -5-on e (26). Colorless
oil; IR (film) νmax 1686 (CdO) cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.71 (2H, m, H-2R and H-8R), 2.28 (2H, m, H-2â and H-8â),
3.36 (1H, m, H-8a), 3.39 (3H, s, OCH3), 3.50 (1H, m, H-1), 3.54
(1H, m, H-3R), 3.62 (1H, dt, J ) 10.0, 2.0 Hz, H-3â), 4.14 (1H,
td, J ) 11.2, 2.4 Hz, H-7â), 4.36 (1H, ddd, J ) 11.2, 4.4, 1.6
Hz, H-7R); 13C NMR (CDCl3, 100 MHz) δ 26.9 (C-8), 28.3 (C-
2), 44.1 (C-3), 57.6 (OCH3), 60.0 (C-8a), 66.2 (C-7), 84.6 (C-1),
152.6 (C-5); MS m/z (rel int) 171 (79, M+), 149 (30), 139 (22),
113 (33), 100 (61), 72 (74), 71 (50), 68 (100), 56 (36). Anal. Calcd
for C8H13NO3: C, 56.14; H, 7.60; N, 8.19. Found: C, 56.08; H,
7.63; N, 8.26.
1r-Meth oxy-6-oxa -8a â-in d olizid in -5-on e (27). Colorless
oil; IR (film) νmax 1683 (CdO) cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.75 (1H, m, H-2â), 1.99 (1H, m, H-8R), 2.11 (1H, m, H-8â),
2.17 (1H, m, H-2R), 3.33 (3H, s, OCH3), 3.49 (1H, td, J ) 10.8,
1.1 Hz, H-3â), 3.60 (1H, m, H-8a), 3.63 (1H, m, H-3R), 3.82
(1H, t, J ) 3.2 Hz, H-1), 4.16 (1H, ddd, J ) 13.1, 10.9, 2.2 Hz,
H-7â), 4.38 (1H, ddd, J ) 10.9, 4.3, 1.8 Hz, H-7R); 13C NMR
(CDCl3, 100 MHz) δ 21.8 (C-8), 27.2 (C-2), 44.8 (C-3), 56.6
(OCH3), 60.6 (C-8a), 66.1 (C-7), 80.3 (C-1), 153.4 (C-5); MS m/z
(rel int) 171 (55, M+), 149 (59), 139 (18), 113 (25), 100 (46), 72
(59), 71 (52), 68 (100), 56 (39); HRMS m/z 171.0893 (Calcd for
C8H13NO3 171.0895).
Meth yl 7-Hyd r oxy-2(E),4(E)-h ep ta d ien oa te a n d Meth -
yl 7-Hyd r oxy-2(E),4(Z)-h ep ta d ien oa te (29). The Wittig
reaction procedure for the preparation of 15 was used. 3-(tert-
Butyldimethylsiloxy)propanal31 (1.13 g, 6 mmol) gave a 1:1
mixture of a protected hydroxyl ester (0.75 g, 46% yield). A
solution of tetrabutylammonium fluoride in THF (1.0 M, 4 mL)
was added to a stirred solution of the above ester (1.08 g, 4
mmol) in THF (20 mL).32 The mixture was stirred for 2 h at
room temperature. The resulting solution was extracted with
EtOAc (20 mL × 3). The combined extract was dried with
anhydrous MgSO4, filtered, and concentrated in vacuo. The
crude product was chromatographed over silica gel eluting
with hexane-EtOAc (10:1) to give a 1:1 mixture of 29 (0.51 g,
82% yield). The mixture was not necessary to separate and
use directly in the next step.
6-Meth oxy-3(E),5(Z)-h exa d ien -1-ol (22). The analogous
procedure for the preparation of ester 15 and alcohol 16 was
used. The methoxyacetaldehyde30 (0.44 g, 6 mmol) gave a
geometric mixture of conjugated ester 20 (0.71 g, 70% yield).
Deconjugation of ester 20 (0.85 g, 5 mmol) gave a 1:1 mixture
of 3(E),5(E)- and 3(E),5(Z)-hexadienoates (0.64 g, 75% yield).
By careful separation of the mixture, we got 200 mg of pure
ethyl 6-methoxy-3(E),5(Z)-hexadienoate (21) as colorless oil:
IR (film) νmax 1731 (CdO) cm-1; 1H NMR (CDCl3, 200 MHz) δ
1.23 (3H, t, J ) 7.0 Hz), 3.07 (2H, dd, J ) 7.2, 1.2 Hz), 3.62
(3H, s), 4.11 (2H, q, J ) 7.0 Hz), 5.04 (1H, dd J ) 10.9, 6.3
Hz), 5.60 (1H, dt, J ) 15.7, 7.2 Hz), 5.85 (1H, d, J ) 6.3 Hz),
6.43 (1H, ddq, J ) 15.7, 10.9, 1.2 Hz); 13C NMR (CDCl3, 50
MHz) δ 14.1, 38.3, 59.9, 60.5, 106.0, 121.3, 126.2, 147.0, 171.8;
MS m/z (rel int) 170 (34, M+), 155 (22), 141 (28), 125 (27), 113
(66), 97 (100), 87 (45), 83 (68), 55 (80); HRMS m/z 170.0945
(Calcd for C9H14O3 170.0943).
Reduction of 21 (0.85 g, 5 mmol) gave 22 (0.60 g, 94% yield)
as colorless oil: IR (film) νmax 3382 (br, OH) cm-1 1H NMR
;
(CDCl3, 200 MHz) δ 1.84 (1H, br s, OH), 2.33 (2H, qd, J ) 6.3,
1.1 Hz), 3 0.63 (3H, s), 3.64 (2H, t, J ) 6.3 Hz), 5.04 (1H, dd
J ) 10.8, 6.2 Hz), 5.51 (1H, dt, J ) 15.6, 6.3 Hz), 5.83 (1H, d,
J ) 6.2 Hz), 6.44 (1H, ddq, J ) 15.6, 10.8, 1.1 Hz); 13C NMR
(CDCl3, 50 MHz) δ 36.2, 60.0, 62.1, 106.4, 125.7, 126.2, 146.4;
MS m/z (rel int) 128 (66, M+), 111 (35), 97 (100), 81 (45), 68
(46), 55 (45); HRMS m/z 128.0837 (Calcd for C7H12O2 128.0837).
6-Meth oxy-3(E),5(Z)-h exadien yl Azidofor m ate (23). The
analogous procedure for the preparation of azidoformate 8 was
used. Alcohol 22 (0.51 g, 4 mmol) gave 23 (0.41 g, 70% yield)
as colorless oil: IR (film) νmax 2186 and 2134 (N3), 1728 (Cd
1
O) cm-1; H NMR (CDCl3, 200 MHz) δ 2.45 (2H, qd, J ) 7.0,
1.2 Hz), 3.65 (3H, s), 4.22 (2H, t, J ) 7.0 Hz), 5.03 (1H, dd, J
) 10.9, 6.3 Hz), 5.46 (1H, dt, J ) 15.6, 7.0 Hz), 5.85 (1H, d, J
) 6.3 Hz), 6.44 (1H, ddq, J ) 15.6, 10.9, 1.2 Hz); 13C NMR
(CDCl3, 50 MHz) δ 32.0, 60.0, 67.9, 106.1, 124.0, 125.9, 146.8,
157.4; MS m/z (rel int) 197 (1, M+), 110 (100), 97 (39), 79 (22),
67 (34), 53 (17). Anal. Calcd for C8H11N3O3: C, 48.73; H, 5.59;
N, 21.32. Found: C, 48.73; H, 5.58; N, 21.27.
6-Ca r bom eth oxy-3(E),5(E)-h exa d ien yl Azid ofor m a te
a n d 6-Ca r bom eth oxy-3(Z),5(E)-h exa d ien yl Azid ofor m a te
(30). The analogous procedure for the preparation of azido-
formate 8 was used. Alcohol 29 (0.62 g, 4 mmol) gave a 4:5
mixture of 3(E),5(E) and 3(Z), 5(E) azidoformates 30 (0.81 g,
90% yield) by 1H NMR spectrum. The mixture was rechro-
matographed with 1% EtOAc/hexane to give a little of pure
3(Z),5(E) isomer as colorless oil and material enriched in
3(E),5(E) isomer for spectral analysis: IR (film) νmax 2184 and
By the general method for FVT, azidoformate 23 (197 mg,
1 mmol) gave a 2:1 mixture of 1â-methoxyindolizinone 24 and
1R-methoxyindolizinone 25 (74 mg, 44% yield), accompanied
with 18 (15 mg, 11% yield). Due to the instability of 2-pyrro-
line, only the major 24 was separated by column chromatog-
raphy for spectral analysis. The compound 25 was isolated but
tended to decompose spontaneously.
2136 (N3), 1724 (CdO) cm-1 1H NMR for 3(E),5(E) isomer
;
1â-Me t h oxy-6-oxa -1,7,8,8a â-t e t r a h yd r oin d olizin -5-
(CDCl3, 200 MHz) δ 2.56 (2H, q, J ) 6.6 Hz), 3.74 (3H, s), 4.29
(2H, t, J ) 6.6 Hz), 5.85 (1H, d, J ) 15.5 Hz), 6.04 (1H, dt, J
) 15.0, 6.6 Hz), 6.27 (1H, dd, J ) 15.0, 10.6 Hz), 7.25 (1H, dd,
J ) 15.5, 10.6 Hz); for 3(Z),5(E) isomer δ 2.71 (2H, dtd, J )
7.5, 6.7, 1.0 Hz), 3.76 (3H, s), 4.28 (2H, t, J ) 6.7 Hz), 5.81
(1H, dt, J ) 10.6, 7.6 Hz), 5.93 (1H, d, J ) 15.2 Hz), 6.27 (1H,
br t, J ) 11.2 Hz), 7.54 (1H, ddt, J ) 15.2, 11.6, 1.0 Hz); 13C
NMR for 3(E),5(E) isomer (CDCl3, 50 MHz) δ 32.0, 51.5, 66.8,
120.5, 131.2, 137.3, 144.1, 157.4, 167.3; for 3(Z),5(E) isomer δ
27.5, 51.6, 67.0, 122.5, 129.4, 134.2, 138.4, 157.4, 167.3; MS
m/z (rel int) 225 (2, M+), 138 (21), 107 (30), 79 (100), 59
(34).Anal. Calcd for C9H11N3O4: C, 48.00; H, 4.93; N, 18.56.
Found: C, 48.02; H, 4.94; N, 18.55.
on e (24). Colorless oil; IR (film) νmax 1689 (CdO) cm-1 1H
;
NMR (acetone-d6, 400 MHz) δ 1.95 (1H, m, H-8R), 2.30 (1H,
m, H-8â), 3.34 (3H, s, OCH3), 3.93 (1H, ddd, J ) 12.0, 6.6, 3.8
Hz, H-8a), 4.30 (1H, td, J ) 11.2, 2.9 Hz, H-7â), 4.37 (1H, ddd,
J ) 11.2, 5.2, 1.6 Hz, H-7R), 4.69 (1H, ddd, J ) 6.6, 2.1, 1.1
Hz, H-1), 5.37 (1H, dd, J ) 4.4, 2.1 Hz, H-2), 6.73 (1H, dd, J
) 4.4, 1.1 Hz, H-3); 13C NMR (acetone-d6, 100 MHz) δ 27.7
(C-8), 56.3 (OCH3), 62.9 (C-8a), 67.9 (C-7), 89.3 (C-1), 110.2
(C-2), 132.9 (C-3), 149.7 (C-5); MS m/z (rel int) 169 (5, M+),
129 (21), 101 (100), 87 (54), 75 (24), 56 (78). Anal. Calcd for
C8H11NO3: C, 56.80; H, 6.51; N, 8.28. Found: C, 56.77; H, 6.58;
N, 8.20.
1r-Ca r bom eth oxy-6-oxa -1,7,8,8a â-tetr a h yd r oin d olizin -
5-on e (31). By the general method for FVT, azidoformate
mixture 30 (113 mg, 0.5 mmol) gave 31 (70 mg, 71% yield) as
single product: White crystal (EtOAc-hexane), mp 140-141
1r-Me t h oxy-6-oxa -1,7,8,8a â-t e t r a h yd r oin d olizin -5-
1
on e (25). The partial H NMR data for 25: (acetone-d6, 400
MHz) δ 3.29 (3H, s, OCH3), 5.57 (1H, dd J ) 4.2, 2.6 Hz, H-2),
6.89 (1H, d, J ) 4.2 Hz, H-3); the 13C NMR data: (acetone-d6,
100 MHz) δ 22.1, 56.2, 60.7, 67.7, 82.0, 110.4, 134.4, 150.5.
Hydrogenation of the 2:1 mixture of 24 and 25 (68 mg, 0.4
mmol) with Pd/C in EtOAc also gave a 2:1 mixture of 1â and
1R-methoxyindolizidinones quantitatively. After separation by
°C; IR (film) νmax 1728 (CdO), 1695 (CdO) cm-1 1H NMR
;
(acetone-d6, 400 MHz) δ 1.90 (1H, qd, J ) 13.4, 4.4 Hz, H-8R),
2.24 (1H, m, H-8â), 3.66 (3H, s, OCH3), 3.80 (1H, ddd, J )
(31) Pirrung, M. C.; Webster, N. J . G. J . Org. Chem. 1987, 52, 3603.
(32) Ihara, M.; Katsumata, A.; Setsu, F.; Tokunaga, Y.; Fukumoto,
K. J . Org. Chem. 1996, 61, 677.
(30) Hatch, L. F.; Nesbitt, S. S. J . Am. Chem. Soc. 1945, 67, 39.

Fused 2-Pyrrolines
J . Org. Chem., Vol. 66, No. 20, 2001 6593
10.0, 2.9, 1.2 Hz, H-1), 4.27 (1H, ddd, J ) 13.4, 10.8, 2.0 Hz,
H-7â), 4.38 (1H, ddd, J ) 10.8, 4.4, 2.0 Hz, H-7R), 4.42 (1H,
ddd, J ) 13.4, 10.0, 4.0 Hz, H-8a), 5.23 (1H, dd, J ) 4.0, 2.9
Hz, H-2), 6.78 (1H, dd, J ) 4.0, 1.2 Hz, H-3); 13C NMR (acetone-
d6, 100 MHz) δ 25.4 (C-8), 51.8 (C-1), 52.0 (OCH3), 58.8 (C-
8a), 67.4 (C-7), 108.6 (C-2), 133.3 (C-3), 149.9 (C-5), 171.4 (OCd
O); MS m/z (rel int) 197 (31, M+), 167 (15), 138 (100), 94 (88),
67 (34), 59 (18), 57 (47). Anal. Calcd for C9H11NO4: C, 54.82;
H, 5.63; N, 7.10. Found: C, 54.83; H, 5.65; N, 7.15.
(C-5); MS m/z (rel int) 215 (77, M+), 170 (84), 143 (90), 128
(67), 115 (100), 91 (28), 77 (20). Anal. Calcd for C13H13NO2:
C, 72.56; H, 6.05; N, 6.51. Found: C, 72.47; H, 6.10; N, 6.50.
1r-P h en yl-6-oxa -8a â-in d olizid in -5-on e (36). Hydrogena-
tion of 35 (65 mg, 0.3 mmol) with Pd/C in EtOAc also gave
pure 36 quantitatively: White crystal (EtOAc-hexane), mp
141-142 °C; IR (film) νmax 1673 (CdO) cm-1; 1H NMR (CDCl3,
400 MHz) δ 1.22 (1H, qd, J ) 11.7, 5.1 Hz, H-8R), 1.70 (1H,
m, H-8â), 2.14 (1H, m, H-2R), 2.33 (1H, m, H-2â), 3.47 (1H, t,
J ) 6.0 Hz, H-1), 3.61 (1H, td, J ) 11.7, 2.9 Hz, H-3â), 3.92
(1H, dt, J ) 11.7, 6.0 Hz, H-8a), 4.03 (1H, dt, J ) 11.7, 8.8
Hz, H-3R), 4.18 (2H, m, H-7), 7.02 (2H, d, J ) 7.2 Hz, H-2′
and -6′ of Ph), 7.26 (1H, t, J ) 7.2 Hz, H-4′ of Ph), 7.32 (2H,
t, J ) 7.2 Hz, H-3′ and -5′ of Ph); 13C NMR (CDCl3, 100 MHz)
δ 24.9 (C-8), 29.7 (C-2), 46.2 (C-3), 47.9 (C-1), 59.6 (C-8a), 66.0
(C-7), 127.1 (C-4′), 127.9 (C-2′ and -6′), 128.8 (C-3′ and -5′),
140.4 (C-1′), 153.0 (C-5); MS m/z (rel int) 217 (100, M+), 118
1r-Ca r bom eth oxy-6-oxa -8aâ-in d olizid in -5-on e (32). Hy-
drogenation of 31 (59 mg, 0.3 mmol) with Pd/C in EtOAc also
gave pure 32 quantitatively: White crystal (EtOAc-hexane),
mp 79-80 °C; IR (film) νmax 1730 (CdO), 1690 (CdO) cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.61 (1H, qd, J ) 12.8, 4.3 Hz,
H-8R), 1.99 (1H, m, H-2â), 2.09 (1H, dq, J ) 12.8, 1.8 Hz, H-8â),
2.20 (1H, m, H-2â), 3.15 (1H, t, J ) 6.6 Hz, H-1), 3.48 (1H, td,
J ) 11.0, 2.0 Hz, H-3â), 3.69 (3H, s, OCH3), 3.84 (1H, m, H-8a),
3.88 (1H, m, H-3R), 4.15 (1H, td, J ) 12.8, 1.8 Hz, H-7â), 4.35
(1H, ddd, J ) 12.8, 4.3, 1.8 Hz, H-7R); 13C NMR (CDCl3, 100
MHz) δ 25.0 (C-8), 26.0 (C-2), 46.1 (C-3), 47.2 (C-1), 51.9
(OCH3), 57.9 (C-8a), 65.9 (C-7), 152.5 (C-5), 172.0 (OCdO); MS
m/z (rel int) 199 (35, M+), 168 (20), 140 (51), 68 (100), 59 (23)
55 (29). Anal. Calcd for C9H13NO4: C, 54.27; H, 6.58; N, 7.03.
Found: C, 53.94; H, 6.72; N, 7.10.
(60), 113 (81), 91 (17), 77 (7), 68 (63). Anal. Calcd for C13H15
-
NO2: C, 71.89; H, 6.91; N, 6.45. Found: C, 71.86; H, 7.02; N,
6.43.
6-P h en yl-3(Z),5(E)-h exa d ien yl Azid ofor m a te (37). The
analogous procedure for the preparation of azidoformate 8 was
used. 6-Phenyl-3(Z),5(E)-hexadien-1-ol21 (0.70 g, 4 mmol) gave
37 (0.86 g, 88% yield) as colorless oil: IR (film) νmax 2186 and
2137 (N3), 1729 (CdO) cm-1; 1H NMR (CDCl3, 200 MHz) δ 2.69
(2H, dt, J ) 7.7, 6.9 Hz), 4.28 (2H, t, J ) 6.9 Hz), 5.46 (1H, dt,
J ) 10.8, 7.7 Hz), 6.30 (1H, td, J ) 10.8 Hz), 6.58 (1H, d, J )
15.5 Hz), 7.01 (1H, dd, J ) 15.5, 10.8 Hz), 7.30 (5H, m); 13C
NMR (CDCl3, 50 MHz) δ 27.3, 67.5, 123.3, 125.5, 126.4, 127.7,
128.6, 131.9, 133.8, 137.1, 157.4; MS m/z (rel int) 243 (11, M+),
156 (100), 141 (24), 128 (21), 115 (45), 91 (56), 77 (8); HRMS
m/z 243.1010 (Calcd for C13H13N3O2 243.1008).
6-P h en yl-3(E),5(E)-h exa d ien -1-ol (33). The analogous
procedure for the preparation of ester 15 and alcohol 16 was
used. The phenylacetaldehyde (0.72 g, 6 mmol) gave the
conjugated ethyl 6-phenyl-2,4-hexadienoate (0.86 g, 66% yield).
Deconjugation of the ester (1.08 g, 5 mmol) gave ethyl
6-phenyl-3(E),5(E)-hexadienoate (0.81 g, 75% yield) as colorless
oil: IR (film) νmax 1731 (CdO) cm-1; 1H NMR (CDCl3, 200 MHz)
δ 1.27 (3H, t, J ) 7.2 Hz), 3.15 (2H, dd, J ) 7.2, 0.9 Hz), 4.14
(2H, q, J ) 7.2 Hz), 5.88 (1H, dt, J ) 15.2, 7.2 Hz), 6.27 (1H,
ddd, J ) 15.2, 10.2, 0.9 Hz), 6.48 (1H, d, J ) 15.7 Hz), 6.77
(1H, dd, J ) 15.7, 10.2 Hz), 7.30 (5H, m); 13C NMR (CDCl3, 50
MHz) δ 14.2, 38.2, 60.7, 125.7, 126.3, 127.5, 128.3, 128.6, 132.0,
133.9, 137.2, 171.4; MS m/z (rel int) 216 (24, M+), 143 (46),
128 (100), 115 (17), 91 (12), 77 (9); HRMS m/z 216.1150 (Calcd
for C14H16O2 216.1150).
Reduction of this ester (1.08 g, 5 mmol) gave 33 (0.81 g, 93%
yield): White plates νmax 3281 (br, OH) cm-1; 1H NMR (CDCl3,
200 MHz) δ 1.68 (1H, br s, OH), 2.43 (2H, br q, J ) 6.3 Hz),
3.72 (2H, t, J ) 6.3 Hz), 5.80 (1H, dt, J ) 15.1, 7.2 Hz), 6.32
(1H, dd, J ) 15.1, 10.2 Hz), 6.49 (1H, d, J ) 15.6 Hz), 6.77
(1H, dd, J ) 15.6, 10.2 Hz), 7.30 (5H, m); 13C NMR (CDCl3, 50
MHz) δ 36.1, 61.9, 126.2, 127.3, 128.5, 128.7, 130.7, 131.1,
133.2, 137.3; MS m/z (rel int) 174 (47, M+), 143 (100), 128 (91),
115 (30), 91 (28), 77 (7). Anal. Calcd for C12H14O: C, 82.72; H,
8.10. Found: C, 82.73; H, 8.12.
6-P h en yl-3(E),5(E)-h exa d ien yl Azid ofor m a te (34). The
analogous procedure for the preparation of azidoformate 8 was
used. Alcohol 33 (0.70 g, 4 mmol) gave 34 (0.83 g, 85% yield)
as colorless oil: IR (film) νmax 2186 and 2138 (N3), 1733 (Cd
O) cm-1; 1H NMR (CDCl3, 200 MHz) δ 2.53 (2H, br q, J ) 6.8
Hz), 4.27 (2H, t, J ) 6.8 Hz), 5.73 (1H, dt, J ) 15.1, 6.8 Hz),
6.29 (1H, dd, J ) 15.1, 10.2 Hz), 6.48 (1H, d, J ) 15.6 Hz),
6.74 (1H, dd, J ) 15.6, 10.2 Hz), 7.30 (5H, m); 13C NMR (CDCl3,
50 MHz) δ 31.9, 67.6, 126.2, 127.4, 128.4, 128.5, 131.7 (two
carbons), 133.6, 137.1, 157.5; MS m/z (rel int) 243 (11, M+),
156 (100), 128 (51), 115 (39), 91 (47), 77 (7). Anal. Calcd for
6-P h en yl-3(E),5(Z)-h exa d ien -1-ol (38) a n d 6-P h en yl-
3(Z),5(Z)-h exa d ien -1-ol (39). The solution of n-BuLi (2.5 M
in hexane, 5.6 mL, 14 mmol) was added dropwise to a
suspension of (3-hydroxypropyl)triphenylphosphonium bro-
mide33 (2.81 g, 7 mmol) in THF (30 mL) at -78 °C. The
resulting mixture was stirred for 1 h at room temperature and
cooled to -35 °C. A fresh distilled chlorotrimethylsilane (0.76
g, 7 mmol) was added and stirred for 30 min. Then, (Z)-3-
phenylpropenal34 (0.79 g, 6 mmol) was added and stirred for
2.5 h. The mixture was warmed to room temperature and
stirred for another 3 h. The resulting solution was quenched
with 5% aqueous HCl and extracted with EtOAc (20 mL × 3).
The combined extract was dried with anhydrous MgSO4,
filtered, and concentrated in vacuo. The crude product was
chromatographed over silica gel eluting with hexane-EtOAc
(10:1) to give a 1:4 mixture of 6-phenyl-3(E),5(Z)-hexadien-1-
ol and 6-phenyl-3(Z),5(Z)-hexadien-1-ol (0.84 g, 80% yield). The
mixture was rechromatographed with 10% EtOAc/hexane to
give pure 39 (0.65 g, 62% yield) as colorless oil: IR (film) νmax
1
3384 (br, OH), 1671 (CdO) cm-1; H NMR (CDCl3, 200 MHz)
δ 2.58 (2H, dtd, J ) 7.6, 6.6, 1.4 Hz), 3.73 (2H, t, J ) 6.6 Hz),
5.62 (1H, dt, J ) 10.6, 7.6 Hz), 6.65 (3H, m), 7.30 (5H, m); 13
C
NMR (CDCl3, 50 MHz) δ 31.1, 61.9, 124.8, 126.9, 127.2, 128.1,
129.0, 129.8, 130.4, 137.2; MS m/z (rel int) 174 (37, M+), 143
(90), 128 (100), 115 (42), 91 (30), 77 (21), 65 (12); HRMS m/z
174. (Calcd for C13H13N3O2 174.). In addition, a material
enriched in 38 isomer was also isolated for spectral analysis:
1H NMR (CDCl3, 200 MHz) δ 2.38 (2H, dt, J ) 7.2, 6.4 Hz),
3.70 (2H, t, J ) 6.4 Hz), 5.85 (1H, dt, J ) 15.0, 7.2 Hz), 6.23
(1H, dd, J ) 11.5, 10.7 Hz), 6.38 (1H, d, J ) 11.5 Hz), 6.71
(1H, dd, J ) 15.0, 10.7 Hz), 7.30 (5H, m).
C
13H13N3O2: C, 64.19; H, 5.39; N, 17.27. Found: C, 64.01; H,
5.46; N, 17.14.
1r-P h en yl-6-oxa -1,7,8,8a â-t et r a h yd r oin d olizin -5-on e
(35). By the general method for FVT, azidoformate 34 (121
mg, 0.5 mmol) gave 35 (55 mg, 51% yield): White crystal
(EtOAc-hexane), mp 130-131 °C; IR (film) νmax 1692 (CdO)
6-P h en yl-3(E),5(Z)-h exa d ien yl Azid ofor m a te (40) a n d
6-P h en yl-3(Z),5(Z)-h exa d ien yl Azid ofor m a te (41). The
analogous procedure for the preparation of azidoformate 8 was
used. Alcohol 39 (0.70 g, 4 mmol) gave 41 (0.86 g, 88% yield)
as colorless oil: IR (film) νmax 2184 and 2137 (N3), 1729 (Cd
1
cm-1; H NMR (acetone-d6, 400 MHz) δ 1.04 (1H, m, H-8R),
1.80 (1H, m, H-8â), 4.15 (1H, dd, J ) 9.3, 3.6 Hz, H-1), 4.22
(2H, m, H-7), 4.39 (1H, ddd, J ) 13.5, 9.3, 4.1 Hz, H-8a), 5.37
(1H, dd, J ) 4.1, 3.6 Hz, H-2), 6.91 (1H, d, J ) 4.1 Hz, H-3),
7.09 (2H, d, J ) 7.3 Hz, H-2′ and -6′ of Ph), 7.27 (1H, t, J )
7.3 Hz, H-4′ of Ph), 7.34 (2H, t, J ) 7.3 Hz, H-3′ and -5′ of
Ph); 13C NMR (acetone-d6, 100 MHz) δ 25.0 (C-8), 52.1 (C-1),
60.9 (C-8a), 67.3 (C-7), 113.7 (C-2), 128.1 (C-4′), 129.3 (C-2′
and -6′), 129.4 (C-3′ and -5′), 131.8 (C-3), 139.3 (C-1′), 150.7
1
O) cm-1; H NMR (CDCl3, 200 MHz) δ 2.71 (2H, qd, J ) 7.0,
(33) Couturier, M.; Dory, Y. L.; Rouillard, F.; Deslongchamps, P.
Tetrahedron 1998, 54, 1529.
(34) (a) Delmas, M.; Bigot, Y. L.; Gaset, A.; Gorrichon, J . P. Synth.
Commun. 1981, 125. (b) Gamboni, G.; Theus, V.; Schinz, H. Helv. Chim.
Acta 1955, 38, 255.

6594 J . Org. Chem., Vol. 66, No. 20, 2001
Wu et al.
1.5 Hz), 4.30 (2H, t, J ) 7.0 Hz), 5.55 (1H, dt, J ) 10.7, 7.0
Hz), 6.52 (1H, t, J ) 10.7 Hz), 6.56 (1H, d, J ) 10.7 Hz), 6.66
(1H, tt, J ) 10.7, 1.5 Hz), 7.32 (5H, m); 13C NMR (CDCl3, 50
MHz) δ 27.0, 67.5, 124.3, 127.1, 127.3, 127.9, 128.2, 129.1,
131.3, 137.1, 157.4; MS m/z (rel int) 243 (15, M+), 156 (100),
141 (42), 128 (82), 115 (66), 91 (85), 77 (17), 65 (17); HRMS
m/z 217.0853 (Calcd for C11H11N3O2 217.0851). In addition, a
material enriched in 40 was also isolated for spectral analy-
sis: 1H NMR (CDCl3, 200 MHz) δ 2.51 (2H, dt, J ) 7.2, 6.6
Hz), 4.26 (2H, t, J ) 6.6 Hz), 5.79 (1H, dt, J ) 15.1, 7.2 Hz),
6.21 (1H, t, J ) 11.2 Hz), 6.32 (1H, d, J ) 11.2 Hz), 6.68 (1H,
dd, J ) 15.1, 11.2 Hz), 7.33 (5H, m).
cedure for the preparation of azidoformate 40 and 41 was used.
Benzaldehyde (0.64 g, 6 mmol) gave a 1:3 mixture of (E)- and
(Z)-4-phenyl-3-buten-1-ol (0.75 g, 46% yield). The mixture was
rechromatographed with 10% EtOAc/hexane to give pure (E)-
and (Z)-4-phenyl-3-buten-1-ol as colorless oil. For (E)-4-phenyl-
3-buten-1-ol: 1H NMR (CDCl3, 200 MHz) δ 2.45 (2H, qd, J )
6.8, 1.0 Hz), 3.72 (2H, t, J ) 6.8 Hz), 6.18 (1H, dt, J ) 15.9,
6.8 Hz), 6.47 (1H, dt, J ) 15.9, 1.0 Hz), 7.25 (5H, m); For (Z)-
4-phenyl-3-buten-1-ol: 1H NMR (CDCl3, 200 MHz) δ 2.58 (2H,
qd, J ) 7.0, 1.7 Hz), 3.69 (2H, t, J ) 7.0 Hz), 5.67 (1H, dt, J )
11.7, 7.0 Hz), 6.56 (1H, dt, J ) 11.7, 1.7 Hz), 7.25 (5H, m).
The analogous procedure for the preparation of azidoformate
8 was used. The pure (E)-4-phenyl-3-buten-1-ol (0.59 g, 4
mmol) gave 45 (0.76 g, 87% yield) as colorless oil: IR (film)
λmax 2184 and 2139 (N3), 1731 (CdO) cm-1; 1H NMR (CDCl3,
200 MHz) δ 2.61 (2H, qd, J ) 6.8, 1.3 Hz), 4.33 (2H, t, J ) 6.8
Hz), 6.14 (1H, dt, J ) 15.9, 6.8 Hz), 6.49 (1H, dt, J ) 15.9, 1.3
Hz), 7.30 (5H, m); 13C NMR (CDCl3, 50 MHz) δ 32.2, 67.7,
124.3, 126.1, 127.4, 128.3, 133.1, 137.0, 157.5; MS m/z (rel int)
217 (4, M+), 130 (100), 117 (82), 115 (94), 91 (82), 77 (21);
HRMS m/z 217.0853 (Calcd for C11H11N3O2 217.0851). the pure
(Z)-4-Phenyl-3-buten-1-ol (0.59 g, 4 mmol) gave 46 (0.72 g, 83%
yield) as colorless oil: IR (film) νmax 2185 and 2138 (N3), 1731
By the general method for FVT, azidoformate 40 or 41 (121
mg, 0.5 mmol) gave 35 (28 mg, 26% yield), 42 (14 mg,
13%yield), and 44 (32 mg, 30% yield).
1â-P h en yl-6-oxa -1,7,8,8a â-t et r a h yd r oin d olizin -5-on e
(42). White powder; IR (film) νmax 1695 (CdO) cm-1; 1H NMR
(acetone-d6, 400 MHz) δ 2.10 (1H, m, H-8R), 2.25 (1H, m, H-8â),
3.93 (1H, td, J ) 11.0, 4.0 Hz, H-8a), 4.16 (1H, m, H-1), 4.20
(1H, m, H-7â), 4.35 (1H, ddd, J ) 11.1, 4.5, 1.6 Hz), H-7R)
5.27 (1H, dd, J ) 4.3, 1.9 Hz, H-2), 6.77 (1H, dd, J ) 4.3, 2.2
Hz, H-3), 7.30 (5H, m, C6H5); 13C NMR (acetone-d6, 100 MHz)
δ 28.0 (C-8), 56.8 (C-1), 66.4 (C-8a), 67.6 (C-7), 113.8 (C-2),
128.0 (C-4′), 128.5 (C-2′ and -6′), 129.6 (C-3′ and -5′), 131.6
(C-3), 142.7 (C-1′), 149.8 (C-5); MS m/z (rel int) 215 (100, M+),
187 (28), 170 (84), 156 (18), 143 (58), 128 (32), 115 (78), 77
(11); HRMS m/z 215.0949 (Calcd for C13H13NO2 215.0946).
5,6-Ben zo-1-a za -10-oxa b icyclo[5.4.0]u n d eca -3,5-d ien -
11-on e (44). White powder (EtOAc-hexane), mp 156-158 °C;
IR (film) νmax 1684 (CdO) cm-1; 1H NMR (acetone-d6, 400 MHz)
δ 2.38 (1H, dddd, J ) 14.7, 9.5, 5.5, 4.5 Hz, H-8â), 2.70 (1H,
dtd, J ) 14.7, 5.5, 3.6 Hz, H-8R), 4.10 (1H, ddd, J ) 17.2, 5.0,
1.3 Hz, H-2R), 4.25 (1H, ddd, J ) 17.2, 5.0, 1.5 Hz, H-2â), 4.35
(1H, ddd, J ) 12.6, 5.5, 4.5 Hz, H-9â), 4.47 (1H, ddd, J ) 12.6,
9.5, 3.6 Hz, H-9R),4.74 (1H, t, J ) 5.5 Hz, H-7), 6.06 (1H, dt,
J ) 11.5, 5.0 Hz, H-3), 6.65 (1H, d, J ) 11.5 Hz, H-4), 7.29
(3H, m, H-1′, 2′, 3′), 7.46 (1H, d, J ) 7.7 Hz, H-4′); 13C NMR
(acetone-d6, 100 MHz) δ 26.1 (C-8), 48.4 (C-2), 56.5 (C-7), 65.4
(C-9), 126.2 (C-4′), 128.2 (C-3′), 128.5 (C-2′), 129.4 (C-3), 131.9
(C-1′), 132.0 (C-4), 138.0 (C-5), 139.0 (C-6), 152.8 (C-11); MS
m/z (rel int) 215 (100, M+), 187 (22), 170 (24), 154 (70), 143
(90), 128 (60), 115 (92), 89 (17), 77 (17), 63 (14); HRMS m/z
215.0947 (Calcd for C13H13NO2 215.0946). Anal. Calcd for
1
(CdO) cm-1; H NMR (CDCl3, 200 MHz) δ 2.72 (2H, qd, J )
7.0, 1.7 Hz), 4.29 (2H, t, J ) 7.0 Hz), 5.63 (1H, dt, J ) 11.6,
7.0 Hz), 6.59 (1H, dt, J ) 11.6, 1.7 Hz), 7.30 (5H, m); 13C NMR
(CDCl3, 50 MHz) δ 27.8, 67.7, 126.0, 126.9, 128.2, 128.5, 132.0,
136.7, 157.4; MS m/z (rel int) 217 (2, M+), 130 (100), 117 (59),
115 (67), 91 (59), 77 (15); HRMS m/z 217.0852 (Calcd for
C
11H11N3O2 217.0.0851).
tr a n s-1-Aza -3-oxa -2-oxo-7â-p h en yl-6â-b icyclo[4.1.0]-
h ep t a n e (47) a n d cis-1-Aza -3-oxa -2-oxo-7â-p h en yl-6â-
bicyclo[4.1.0]h ep ta n e (48). By the general method for FVT,
azidoformate 45 (108 mg, 0.5 mmol) gave 47 and 48 as 6:1
mixture quantitatively whereas azidoformate 46 (108 mg, 0.5
mmol) gave 47 and 48 as 2.5:1 mixture determined by crude
1H NMR spectrum. The mixture of 47 and 48 obtained from
FVT was not further separated due to the instability of
aziridine ring skeleton. For the major isomer 47: IR (film) νmax
1717 (CdO) cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.58 (1H, dddd,
J ) 14.6, 12.3, 8.7, 4.4 Hz, H-5R), 2.46 (1H, ddt, J ) 14.6, 6.2,
1.9 Hz, H-5â), 2.83 (1H, ddd, J ) 8.7, 6.2, 3.0 Hz, H-6â), 3.30
(1H, d, J ) 3.0 Hz, H-7R), 4.37 (1H, ddd, J ) 10.8, 4.6, 1.9 Hz,
H-4R), 4.53 (1H, ddd, J ) 12.3, 10.8, 2.0 Hz, H-4â), 7.25 (5H,
m, C6H5); 13C NMR (CDCl3, 50 MHz) δ 25.0, 43.8, 48.9, 68.1,
126.1, 128.3, 128.5, 135.7, 159.9; MS m/z (rel int) 189 (79, M+),
144 (39), 130 (81), 117 (100), 91 (75), 77 (32), 56 (38); HRMS
C
13H13NO2: C, 72.56; H, 6.05; N, 6.51. Found: C, 72.47; H,
6.09; N, 6.39.
1â-P h en yl-6-oxa -8a â-in d olizid in -5-on e (43). Hydrogena-
tion of 42 (30 mg, 0.14 mmol) with Pd/C in EtOAc also gave
pure 43 quantitatively: White powder (EtOAc-hexane), mp
102-103 °C; IR (film) νmax 1690 (CdO) cm-1; 1H NMR (CDCl3,
400 MHz) δ 1.68 (1H, m, H-8R), 2.01 (1H, m, H-8â), 2.12 (1H,
qd, J ) 10.7, 2.3 Hz, H-2â), 2.30 (1H, m, H-2R), 2.82 (1H, td,
J ) 10.7, 6.4 Hz, H-1), 3.51 (1H, td, J ) 10.7, 4.0 Hz, H-8a),
3.70 (2H, m, H-3), 4.12 (1H, td, J ) 11.2, 2.0 Hz, H-7â), 4.36
(1H, ddd, J ) 11.2, 4.4, 1.5 Hz, H-7R), 7.24 (2H, dd, J ) 7.4,
3.5 Hz, H-2′ and -6′ of Ph), 7.29 (1H, t, J ) 7.4 Hz, H-4′ of
Ph), 7.36 (2H, t, J ) 7.4 Hz, H-3′ and -5′ of Ph); 13C NMR
(CDCl3, 100 MHz) δ 27.0 (C-8), 30.8 (C-2), 46.2 (C-3), 52.2 (C-
1), 62.7 (C-8a), 66.4 (C-7), 127.3 (C-2′ and -6′), 127.5 (C-4′),
128.9 (C-3′ and -5′), 138.4 (C-1′), 152.9 (C-5); MS m/z (rel int)
217 (100, M+), 118 (50), 113 (74), 100 (41), 91 (40), 77 (12), 68
(50). Anal. Calcd for C13H15NO2: C, 71.89; H, 6.91; N, 6.45.
Found: C, 71.65; H, 6.91; N, 6.33.
1
m/z 189.0789 (Calcd for C11H11NO2 189.0790). The partial H
NMR spectrum for the minor isomer 48: δ 3.14 (1H, ddd J )
11.3, 6.3, 5.0 Hz, H-6â), 3.91 (1H, d, J ) 5.0 Hz, H-7â).
Ack n ow led gm en t. The authors would like to thank
the National Science Council of the Republic of China
for financially supporting this research under Contract
No: NSC 89-2113-M-006-003. We also thank Mr. Y. H.
Liu for X-ray single crystal structural analysis.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of 7, 10, 11, 13, 16-18, 22-24, 26, 27, 29-37,
and 41-44; X-ray data for 32. This material is avaliable free
charge via the Internet at http://pubs.acs.org
(E)-4-P h en yl-3-bu ten yl Azid ofor m a te (45) a n d (Z)-4-
P h en yl-3-bu ten yl Azid ofor m a te (46). The analogous pro-
J O010218J