Nucleophilic displacement reactions of 4-(nosyloxy)-2,3-unsaturated esters and 2-(nosyloxy)-3,4-unsaturated esters

Article abstract of DOI:10.1021/jo960477m

It has been found that 4-(nosyloxy)-2,3-unsaturated esters 2 undergo direct displacement with a wide variety of nucleophiles and yield 4-substituted-2,3-unsaturated products cleanly and in generally good yields. These materials thus have very good synthetic potential for the formation of densely functionalized unsaturated esters. 2-(Nosyloxy)-3,4-unsaturated esters as exemplified by methyl 2-(nosyloxy)-3-butenoate (3d) also undergo direct displacement with a range of good nucleophiles; however, the resulting substitution products are prone to rearrangements and tautomerism, as is the starting material itself, so that the synthetic utility of these compounds is limited.

Full text of DOI:10.1021/jo960477m

J . Org. Chem. 1996, 61, 5567-5573
5567
Nu cleop h ilic Disp la cem en t Rea ction s of 4-(Nosyloxy)-2,3-
u n sa tu r a ted Ester s a n d 2-(Nosyloxy)-3,4-u n sa tu r a ted Ester s
Robert V. Hoffman* and Bryon S. Severns
Department of Chemistry and Biochemistry, New Mexico State University,
Las Cruces, New Mexico 88003-0001
Received March 11, 1996X
It has been found that 4-(nosyloxy)-2,3-unsaturated esters 2 undergo direct displacement with a
wide variety of nucleophiles and yield 4-substituted-2,3-unsaturated products cleanly and in
generally good yields. These materials thus have very good synthetic potential for the formation
of densely functionalized unsaturated esters. 2-(Nosyloxy)-3,4-unsaturated esters as exemplified
by methyl 2-(nosyloxy)-3-butenoate (3d ) also undergo direct displacement with a range of good
nucleophiles; however, the resulting substitution products are prone to rearrangements and
tautomerism, as is the starting material itself, so that the synthetic utility of these compounds is
limited.
In tr od u ction
Sch em e 1
In an earlier report we showed that reaction of 1-[(tri-
methylsilyl)oxy]-1-alkoxy 1,3-dienes 1 with p-nitroben-
zenesulfonyl peroxide [(NsO) ] produces 4-(nosyloxy)-2,3-
2
unsaturated esters 2 and 2-(nosyloxy)-3,4-unsaturated
esters 3.1 By appropriate control, it is possible to achieve
good regioselectivity in the formation of 2 and 3 so that
each can be prepared in good yield as the major isomer.
of amino acid decarboxylase enzymes.5 In addition, vinyl
amino esters are useful synthetic intermediates in the
6
preparation of kainoid-type natural products and statine
derivatives.7 Other nucleophiles could be expected to
yield many other useful products as well.
In looking for literature examples of displacement
reactions in similar systems, it rapidly became clear that
few have been reported. It has been shown that a
4
-bromocrotonate analog of 2 undergoes substitution by
6
a
benzylamine. Yamamoto’s group has prepared a variety
of 4-mesyloxy and 4-tosyloxy analogs of 2 in chiral form
Nosylates 2 and 3 are interesting substrates for
displacement reactions since they could potentially un-
dergo either direct (S 2) or indirect (S 2′) substitution
N N
and showed that the sulfonate group could be replaced
stereospecifically by azide.8 Most work on these sub-
strates, however, is concerned with the S
N
2′ displacement
to provide either R-substituted â,γ-unsaturated esters or
γ-substituted R,â-unsaturated esters (Scheme 1). For
example, use of an ammonia equivalent nucleophile could
produce either a vinylogous amino acid or a vinylglycine
analog. Vinylogous amino acids have been of recent
synthetic interest because of their occurrence in several
drugs,2 protease inhibitors,3 and synthetic vinylogous
of sulfonate by organocuprates to achieve 1,3-chirality
9
10
transfer. Both 2-chloro and 2-bromo-3,4-unsaturated
esters,5b which are halogen analogs of 3, have been
prepared. The chloro analog was used as an S 2′
N
1
0
substrate for organocuprates while the 2-bromo com-
pound undergoes direct S 2 displacement by benzylamine
N
5b
to give a vinyl amino acid product. Another 2-bromo
4
polypeptides of unusual structure. Vinyl amino acids
have long been of interest as mechanism-based inhibitors
analog of 3 was shown to undergo direct substitution by
ammonia in low yield.11
We demonstrated in preliminary studies that several
examples of both 2 and 3 undergo direct substitution by
X
Abstract published in Advance ACS Abstracts, J uly 15, 1996.
(
1) Hoffman, R. V.; Kim, H.-O. J . Org. Chem. 1991, 56, 1014.
(2) (a) Cyclotheonamide B: Fusetani, N.; Matsunaga, S.; Matsumoto,
(5) (a) Pederson, M. L.; Berkowitz, D. B. J . Org. Chem. 1993, 58,
6966 and references therein to the earlier literature. (b) Cardillo, G.;
De Simone, A.; Mingardi, A.; Tomasini, C. Synlett 1995, 1131.
(6) (a) Barco, A.; Benetti, S.; Spalluto, G.; Casolari, A.; Pollini, G.
P.; Zanirato, V.J . Org. Chem. 1992, 57, 6279. (b) Roth, P.; Metternich,
R. Tetrahedron Lett. 1992, 33, 3993.
Y.; Takebayashi, Y. J . Am. Chem. Soc. 1990, 112, 7053. Hagihara, M.;
Schreiber, S. L. J . Am. Chem. Soc. 1992, 114, 6570. Wipf, P.; Kim,
H.-Y. Tetrahedron Lett. 1992, 33, 4275. (b) Keramamide F: Itagaki,
F.; Shigemori, H.; Ishibashi, M.; Nakamura, T.; Sasaki, T.; Kobayashi,
J . J . Org. Chem. 1992, 57, 5540.
(
3) (a) Liu, S.; Hanzlik, R. P. J . Med. Chem. 1992, 35, 1067. (b)
Thompson, S. A.; Andrews, P. R.; Hanzlik, R. P. J . Med. Chem. 1986,
9, 104.
4) Hagihara, M.; Anthony, N. J .; Stout, T. J .; Clardy, J .; Schreiber,
S. L. J . Am. Chem. Soc. 1992, 114, 6568.
(7) Kogen, H. Nishi, T. Chem. Commun. 1987, 311.
(8) Yamamoto, Y.; Asao, N. J . Org. Chem. 1990, 55, 5303.
(9) (a) Ibuka, T.; Yamamoto, Y. Synlett 1992, 769. (b) Yamamoto,
Y.; Chounan, Y.; Tanaka, M.; Ibuka, T. J . Org. Chem. 1992, 57, 1024.
(10) Mathew, J . J . Org. Chem. 1992, 57, 2753.
2
(
S0022-3263(96)00477-X CCC: $12.00 © 1996 American Chemical Society

5
568 J . Org. Chem., Vol. 61, No. 16, 1996
Ta ble 1. Rea ction of 2a -e w ith Nu cleop h iles
Hoffman and Severns
nucleophilea
BnNH2
(% 4)
SCN- SdC(NH2)2
reactant
N3- (% 5) AcO- (% 6) (% 7)
(% 8)
2
2
2
2
2
a
b
c
d
e
72
59
41
60
89
93
62
48
58
59
94
92
77
100b
85
60
1
c
In an extension of earlier work, nosylates 2b-e were
87
75
52
60
c
reacted with benzylamine and 4-benzylamino esters
b-e were obtained in good yields (Table 1). The crude
products were of high purity, but 4b,c could be purified
further by flash chromatography. In contrast, 4d ,e
decomposed significantly upon exposure to silica gel,
although it was possible to obtain samples of analytically
pure 4d ,e by flash chromatography.
Reaction of 2a -e with sodium azide in DMF at 0 °C
produced 4-azido esters 5a -e in good yields (Table 1).
Both DMSO and acetonitrile can be used as the solvent
equally well. The crude products were relatively pure
and could be further purified by bulb to bulb distillation
or radial chromatography. The structures of 5a -e were
85
4
a
b
Isolated yields of purified products Isolated yield of crude
c
product that was >95% pure. Reported previously in ref 1.
benzylamine to produce 4-(benzylamino)-2,3-unsaturated
esters and 2-(benzylamino)-3,4-unsaturated esters, re-
spectively.1 The yields of these displacements were good,
N
and no evidence of indirect (S 2′) substitution was found.
On the basis of these results, the present study was
initiated to determine the range of nucleophiles which
can be incorporated into unsaturated esters by displace-
ment reactions on 2 and 3 and to confirm the generality
-1
indicated by an azide band at 2100 cm , an ester stretch
at 1725 cm indicating R,â-unsaturation, and a trans
coupling constant of 15.6 Hz for the olefinic protons.
Displacement of nosylate by acetate producing acetates
a -d was observed upon treatment of 2a -d with potas-
of the direct nucleophilic displacement pathway (S
N
2)
-1
that was seen for benzylamine. We present results which
show that 2 and 3 react with a variety of nucleophiles
by direct displacement. The chemistry of these two
systems is sufficiently distinct, however, that they will
be discussed separately.
6
sium acetate in DMF at room temperature. No reaction
was observed when acetonitrile was used as the reaction
solvent while the use of DMSO greatly accelerated the
reaction (20-60 min versus 3-4 h in DMF). Presumably
the rate enhancement results from several factors, the
most obvious being the fact that potassium acetate was
completely dissolved in DMSO but only partially soluble
in DMF. Another cause for the increased rate in DMSO
is nucleophilic catalysis in which DMSO displaces the
-nosyloxy group and is subsequently replaced by acetate.
This scenario is supported by the observation that in
DMSO-d
solution the NMR signals for 1d are replaced
after several hours by a new set of resonances that are
assigned to sulfonium salt 9 which results from nosylate
displacement in 1d by DMSO.
Resu lts
A series of silyloxy dienes 1a -e was prepared from the
corresponding unsaturated esters1 and reacted with
2
p-nitrobenzenesulfonyl peroxide/ZnCl in ethyl acetate to
give unsaturated nosyloxy esters (eq 2). Dienes 1a -c
which have an alkyl group at C-4 gave only the 4-nosyl-
oxy product 2. Dienes 1d ,e which have only hydrogen
substituents at C-2 and C-4 gave 2-nosyloxy ester 3 as
the major regioisomer (3:1) The regioisomeric pairs 2d ,
d and 2e, 3e can be separated effectively by radial
chromatography to provide pure samples of 3d ,e.
Thermolysis of the 3:1 mixture of 3e and 2e in refluxing
toluene for 24 h produced the thermodynamically more
stable 2e as the only product (80%).1
4
6
3
1
2
Reaction of 2a -d with potassium thiocyanate in
acetone gave thiocyanates 7a -d in high yields (60-94%).
The crude 4-thiocyanato-2,3-unsaturated esters were
generally obtained in nearly quantitative yields and were
>
90% pure. They were further purified by bulb to bulb
distillation or preparative TLC (7a ). The thiocyanate
Rea ction of 4-(Nosyloxy)-2,3-u n sa tu r a ted Ester s
a -e w ith Nu cleop h iles. With a source of 4-nosyloxy
2
esters 2a -e developed, their reactions with nucleophiles
were examined. 4-Nosyloxy esters 2a -e undergo smooth
displacement by a range of anionic and neutral nucleo-
philes. In most cases the 4-substituted products 4-8
were stable and were isolated and purified without
difficulty (Table 1).
(
11) McDonald, I. A.; Palfreyman, M. G.; J ung, M.; Bey, P. Tetra-
hedron Lett. 1985, 26, 4091.
(12) It was found that purification by radial chromatography gave
consistently higher yields of 2 and 3 than other forms of liquid
chromatography. This is presumably due to the shorter contact time
with the silica gel surface and implies that the unsaturated nosyloxy
esters 2 and 3 begin to decompose on exposure to silica gel.

Nucleophilic Displacement of Nosyloxy Unsaturated Esters
J . Org. Chem., Vol. 61, No. 16, 1996 5569
group of 7a -d gave a characteristic strong, sharp IR
sigmatropic rearrangement to produce the ultimate
product 5d . 3,3-Sigmatropic rearrangements in allylic
azides are well-known, including a similar rearrange-
ment in a 2-azido-3,4-unsaturated ester which was
recently described.14
band at 2150 cm-
1
.
When reacted with thiourea in acetone, nosylate esters
2
a -d afforded 4-isothiouronium-2,3-unsaturated ester
salts 8a -d in high yields (60-80%). Although the
products are salts, the reaction mixtures remained
homogeneous. After removal of the solvent and tritura-
tion with dichloromethane, the residue gave 8a -d as
solids which were recrystallized from acetone.
These results demonstrate that 4-(nosyloxy)-2,3-un-
saturated esters undergo smooth reaction with nucleo-
philes to give a wide range of 4-substituted-2,3-unsatur-
ated esters in generally good yields. In addition to giving
vinylogous amino acid analogs by the incorporation of
amines or azide at C-4, oxygen and sulfur nucleophiles
can also displace the nosylate group effectively. The
results with thiourea can potentially be extended to a
vinylog of the sulfide contraction methodology for the
synthesis of pyrrolidines.13
Confirmation of this scenario was found by carrying
out the substitution reaction at 0 °C and then treating
the reaction mixture with diisopropylamine. This cata-
lyzed double-bond isomerization in 11 and gave vinyl
Rea ction of 2-(Nosyloxy)-3,4-u n sa tu r a ted Ester
3
d w ith Nu cleop h iles. 2-(Nosyloxy)-3,4-unsaturated
esters 3 are isolated from reactions of (NsO) with silyloxy
2
dienes 1 which lack substituents at either C-2 or C-4 and
must be chromatographically separated from their ther-
modynamically more stable 4-nosyloxy regioisomers 2.
Although they are more difficult to obtain in pure form,
they offer the possibility of access to 2-substituted-3,4-
unsaturated esters by direct displacement. Therefore 3d
was used as a model to explore the displacement chem-
istry with a suite of nucleophiles.
Reaction of 3d with benzylamine in dichloromethane
for 4 h led to the formation of benzylamino ester 10 in
high yield by direct displacement of nosylate (eq 3). No
evidence of 4d was seen in the NMR spectrum of the
crude product. The production of 10 from 3d is similar
to displacement of bromide in a 2-bromo-3,4-unsaturated
ester by benzylamine.5b The crude product was >90%
pure, but attempts to further purify 10 were unsuccess-
ful, as decomposition of the material was observed during
chromatography and acid/base extraction.
azide 12, demonstrating that direct S
the initial displacement process (eq 4).
The reaction of 3d with potassium thiocyanate in
acetone (15 min) followed by a rapid workup produced
N
2 displacement is
2
2
-thiocyanato ester 13 in 77% yield. A sharp IR band at
158 cm confirmed the presence of the thiocyanate
-1
group, and addition of diisopropylamine to the reaction
mixture prior to workup gave the vinyl thiocyanate 14,
confirming the direct substitution pathway (eq 5). If the
crude product from the reaction was allowed to stand at
room temperature overnight, complete conversion to
isothiocyanate 15 was seen. Isomerization to the 4-sub-
stituted isomer is clearly indicated by the emergence of
two vinyl proton signals at δ 6.18 and 6.89 which had a
trans coupling constant of J ) 15.5 Hz. The isothiocy-
anate functionality is indicated by a broad,strong IR
-1
absorption at 2066-2200 cm
. In addition the C-4
methylene protons of 15 are shifted downfield to δ 4.38
consistent with an nitrogen atom being bonded to the C-4
carbon atom. Moreover, these spectral data are distinct
from 7d , the 4-thiocyanate analog which has a sharp IR
-
1
band at 2158 cm and methylene protons at δ 3.67. As
in the case of azide 11, formation of 15 presumably occurs
by 3,3-sigmatropic rearrangement of initially formed 13.
Reaction of 3d with sodium azide in acetonitrile at
room temperature gave methyl 4-azido-2-butenoate (5d )
as the only product in nearly quantitative yield. The
crude product was >90% pure. There was no indication
of the formation of the expected 2-azido product. Azide
5
d was obtained in 71% after radial chromatography.
While at first sight this result appears to be a case of
2′ displacement, monitoring of the reaction in aceto-
nitrile-d at 0 °C showed a new set of peaks corresponding
S
N
3
to methyl 2-azido-3-butenoate (11) as the first-formed
product (eq 4). Besides a methoxy singlet (δ 3.75), the
R-proton was a one proton doublet at δ 4.59 (J ) 6.6 Hz)
and there were vinyl signals at δ 5.44δ (2H) and δ 5.95
Reaction of 3d with thiourea in acetone at 0 °C led to
the consumption of the starting material in 4 h. Removal
of the solvent gave a mixture of isothiouronium displace-
ment product 16 and vinyl isothiouronium salt 17 (eq 6).
(1H) for the terminal vinyl group. Upon warming to room
temperature, 11 was slowly converted to 5d . Attempts
to isolate 11, however, gave only 5d . These results
suggest that direct substitution to 11 is followed by a 3,3-
(14) (a) Panek, J . S.; Yang, M.; Muler, I. J . Org. Chem. 1992, 57,
4
063 and references therein to allylic azide rearrangements. (b) See
also: Murahashi, S.-I.; Taniguchi, Y.; Imada, Y.; Tanigawa, Y. J . Org.
Chem. 1989, 54, 3292. (c) Naidorf-Meier, S.; Hassner, A. J . Org. Chem.
1992, 57, 5102.
(
13) Hernandez, A. S.; Thaler, A.; Castells, J .; Rapoport, H. J . Org.
Chem. 1996, 61, 314 and references therein.

5
570 J . Org. Chem., Vol. 61, No. 16, 1996
Hoffman and Severns
Storage of the products in the freezer for 1 month
resulted in complete conversion to 17. Alternatively
stirring the reaction mixture at room temperature for 5
d gave a quantitative yield of 17. Salts 16 and 17 were
easily distinguished by the vinyl signals in the NMR.
Tautomerized salt 17 had a one-proton vinyl quartet at
δ 7.91 whereas 16 had three vinyl protons as part of an
ABMX system which came at δ 5.49 (2 H) and 5.91 (1
H). From the 1H NMR spectrum of pure 17, it was
possible to extract the NMR spectrum of 16 from the
mixture of 16 and 17. It was not possible to obtain a
pure sample of 16 uncontaminated with 17. The isothio-
uronium group apparently acidifies the R-proton so that
tautomerism takes place under even very mild conditions.
Sch em e 2
direct displacement with a range of good nucleophiles;
however, the resulting substitution products are prone
to rearrangements and tautomerism, as is 3d itself, so
that the synthetic utility of these compounds is limited.
Exp er im en ta l Section
Melting points are uncorrected. Infrared spectra of liquids
were acquired using neat samples, and KBr pellets were used
for solids. NMR spectra were acquired in chloroform-d solu-
tion (unless otherwise noted) at either 400 or 200 MHz, and
shifts are reported in ppm relative to tetramethylsilane (TMS).
Carbon-13 NMR spectra were obtained at 100 MHz. Thin
layer chromatography (TLC) was carried out on 2 × 5 cm glass-
supported silica gel 60 F254 plates from EM Reagents. Visu-
alization of TLC spots was accomplished with UV irradiation
for nosylate compounds, but most other compounds required
iodine exposure or oxidation by a spray of aqueous potassium
permanganate. Preparative TLC was performed on glass-
supported 20 × 20 cm × 250 mm silica gel 60 F254 plates.
Radial chromatography was performed on 2 mm layers of silica
gel 60 F254. Flash chromatography was carried out using a
20 mm × 25 cm column of silica gel 60 (230-400 mesh).
Combustion analyses were performed by M-W-H Laboratories,
Phoenix, AZ.
The use of nucleophiles that were either more basic or
less nucleophilic than those described above were gener-
ally ineffective in displacement reactions of 3d . Instead,
two base-promoted processes of 3d were observed. The
first is tautomerism of 3d to vinyl nosylate 18, and the
second is ipso-substitution to give p-nitrophenyl alcohol
1
9 (eq 7).15 More hindered amines such as piperidine and
diisopropylamine or charged bases such as methoxide,
acetate, or sulfite in alcohol solvents gave predominately
tautomerized 18. Conversely, anionic bases such as
methoxide, acetate, cyanide, and fluoride in aprotic
solvents such as DMF or acetonitrile gave mostly ipso-
product 19.
Most reagents including methyl and ethyl crotonate, trans-
2
-hexenoic acid, trans-2-pentenoic acid, hydrocinnamaldehyde,
and triethyl phosponoacetate were purchased from Aldrich.
Technical grade p-nitrobenzenesulfonyl chloride was pur-
chased from Fluka Chemical Co. and was recrystallized from
chloroform and hexane. Most solvents used were HPLC grade.
Tetrahydrofuran (THF) was distilled under nitrogen from
sodium benzophenone ketyl. The literature method was used
1
6
for the preparation of p-nitrobenzenesulfonyl peroxide. Si-
lyloxy dienes 1b-e and the unsaturated nosyloxy esters 2b-e
and 3d ,e were prepared by literature methods.1
,17
Eth yl 5-p h en yl-2-p en ten oa te, the starting material for
silyloxy diene 1a is a known compound; however no data were
reported for it. It was prepared in 60% yield using the
literature method of carboxyvinylation developed by Wad-
sworth and Emmons.18 H NMR: δ 1.28 (t, J ) 7 Hz, 3H),
2.53 (ddt, J ) 1, 7, 8.3 Hz, 2H), 2.78 (dt, J ) 7, 8.3 Hz, 2H),
1
These results suggest that while good nucleophiles
displace the nosylate group in 3d , the nosylate group also
acidifies the R-proton of 3d significantly and proton
removal by the nucleophile/base can compete with dis-
placement if the basicity is high and/or the nucleophilicity
is reduced. Under protic conditions the resulting enolate
is rapidly reprotonated to give the conjugated vinyl
nosylate 18. In aprotic conditions, either trapping is
slower or the enolate is more reactive, and ipso-substitu-
tion is the primary process of the enolate (Scheme 2).
Both processes are detrimental to displacement reactions.
In summary, these results demonstrate that 4-(nosy-
loxy)-2,3-unsaturated esters 2 undergo direct displace-
ment with a wide variety of nucleophiles and yield
4
.18 (q, J ) 7 Hz, 2H), 5.85 (dt, J ) 1, 15.7 Hz, 1H), 7.01 (dt,
13
J ) 7, 15.7 Hz, 1H), 7.30 (m, 5H). C NMR: 14.2, 33.9, 34.4,
6
0.2, 121.9, 126.2, 128.3, 128.5, 140.8, 148.0, 166.5. IR
-
1
(neat): 3062, 1720, 1656, 1604.0 cm
.
Anal. Calcd for
C
13 16 2
H O : C, 76.44; H, 7.90. Found: C, 76.60; H, 7.69. This
1
material was converted to 1a in the usual way.
Eth yl 5-p h en yl-4-[[(p-n itr op h en yl)su lfon yl]oxy]-2-p en -
ten oa te, 2a , was prepared from 1a . Three identical reactions
were carried out, and the products were combined during the
workup to give the final crude product. In an oven-dried flask
pNBSP (1.21 g, 3 mmol) was dissolved in a room temperature
2
mixture of ethyl acetate (90 mL) and ZnCl (800 mg, 6 mmol)
and stirred for 30 min until the solution became homogeneous.
A dropping funnel was attached, and the apparatus was
purged with nitrogen. Silyloxy diene 2a (1.11 g, 4 mmol) in
ethyl acetate (20 mL) was placed into the dropping funnel and
added dropwise to the reaction mixture which was cooled to
-78 °C. The reaction was stirred for 3 h. Three such reaction
solutions were combined, washed with brine (3 × 100 mL),
4
-substituted-2,3-unsaturated products cleanly and in
generally good yields. In addition to the peroxide route
to these materials utilized here, these materials can be
made by more conventional routes8,9 and thus have very
good synthetic potential for the formation of densely
functionalized unsaturated esters. 2-(Nosyloxy)-3,4-
unsaturated esters as exemplified by 3d also undergo
4
dried (MgSO ), passed through a short pad of silica gel, and
(16) Dannley, R. L.; Gagen, J . E.; Stewart, O. J . J . Org. Chem. 1970,
3
5, 3076.
(15) Analogous ipso-substitution has been observed previously in
(17) Kim, H.-O. Ph. D. Thesis, New Mexico State University, 1990.
R-nosyloxy ketones and esters. Hoffman, R. V.; J ankowski, B. C.; Carr,
C. S.; Duesler, E. N. J . Org. Chem. 1986, 51, 130.
(18) Wadsworth, W. S., J r.; Emmons, W. D. J . Am. Chem. Soc. 1961,
83, 1733.

Nucleophilic Displacement of Nosyloxy Unsaturated Esters
J . Org. Chem., Vol. 61, No. 16, 1996 5571
concentrated under reduced pressure to give a brown oil (3.86
Meth yl 4-a zid o-2-h exen oa te, 5b, was prepared from 2b
(200 mg, 0.61 mmol) and sodium azide (80 mg, 1.2 mmol) using
a 4 h reaction time at 0 °C (yellow oil, 100 mg). Purification
by Kugelrohr distillation with a bath temperature of 35-40
g). Flash chromatography (hexane-ethyl acetate, 95:5 to 9:1)
1
gave 2a as a white solid (1.25 g, 34%): mp 92-4 °C; H NMR
1
5
6
.29 (t, J ) 7 Hz, 3H), 2.98 (ABm, 2H), 4.20 (q, J ) 7 Hz, 2H),
.29 (dd, J ) 1.3, 5.8 Hz, 1H), 6.07 (dd, J ) 1.3, 15.8 Hz, 1H),
.87 (dd, J ) 5.8, 15.8 Hz, 1H), 7.10 (m, 5H), 7.74 and 8.16
1
°C/0.5 mmHg gave 5b as a colorless oil (60 mg, 59%): H NMR
0.99 (t, J ) 7 Hz, 3H), 1.67 (pent, J ) 7 Hz, 2H), 3.77 (s, 3H),
3.96 (dt, J ) 6.4, 7 Hz, 1H), 6.04 (d, J ) 15.6 Hz, 1H), 6.80
(dd, J ) 6.4, 15.6 Hz, 1H); 13C NMR 10.1, 27.2, 51.8, 64.0,
1
3
(
1
1
ABq, J ) 8.6 Hz, 4H); C NMR 14.6, 41.0, 61.0, 82.9, 124.1,
24.2, 127.3, 128.7, 128.8, 129.4, 134.7, 141.9, 142.0, 150.4,
-1
-1
65.2; IR (KBr) 1716, 1664, 1608 cm . Anal. Calcd for C19
: C, 56.29; H, 4.72; N, 3.46. Found: C, 56.15; H, 4.78;
N, 3.48.
H
19
-
122.8, 144.65, 166.2; IR (neat) 1731, 1666 cm . Anal. Calcd
NSO
7
7 11 3 2
for C H N O : C, 49.7; H, 6.55; N, 24.84. Found: C, 49.58;
H, 6.67; N, 24.68.
Meth yl 4-(N-ben zyla m in o)-2-bu ten oa te, 4d , was pre-
pared by the following general method. Nosylate 2d (280 mg,
Meth yl 4-a zid o-2-p en ten oa te, 5c, was prepared from 2c
(200 mg, 0.63 mmol) and sodium azide (80 mg, 1.2 mmol) using
a 3.5 h reaction time at 0 °C (yellow oil, 50 mg). Purification
by Kugelrohr distillation with a bath temperature of 35-40
0
.93) and benzylamine (360 mg, 3.4 mmol) in dichloromethane
(20 mL) were stirred at room temperature for 24 h. The cloudy
1
white solution was concentrated, and ethyl acetate (100 mL)
°C/0.5 mmHg gave 5c as a colorless oil (40 mg, 41%): H NMR
was added. The solution was washed with brine (2 × 100 mL)
1.38 (d, J ) 7 Hz, 3H), 3.77 (s, 3H), 4.17 (m, 1H), 6.03 (dd, J
1
3
and dried (MgSO
4
), and the cloudy white solution was passed
) 1, 15.6 Hz, 1H), 6.84 (dd, J ) 6, 15.6 Hz, 1H); C NMR
1
-
through a short pad of silica gel to give crude 4d as a yellow
oil (100 mg) which was greater than 95% pure by 1H NMR
analysis. Separation by preparative TLC (hexane-ethyl
acetate, 100:0 to 90:10) gave analytically pure 9d as a yellow
19.2, 51.8, 57.5, 121.9, 145.8, 166.3; IR (neat) 1730, 1662 cm .
Anal. Calcd for C
H, 6.00.
6 9 3 2
H N O : C, 46.45; H, 5.85. Found: C, 46.26;
Meth yl 4-a zid o-2-bu ten oa te, 5d , was prepared from 2d
(300 mg, 1.0) and sodium azide (130 mg, 2.0 mmol) in DMF
(10 mL) at 0 °C for 3 h as a colorless oil (110 mg, 60%) after
separation by radial chromatography (hexane-ethyl acetate,
95:5 to 90:10): 1H NMR 3.77 (s, 3H), 4.01 (dd, J ) 1.6, 5.3 Hz,
2H), 6.10 (dt, J ) 1.6, 15.6 Hz, 1H), 6.91 (dt, J ) 5.3, 15.6 Hz,
1H); 13C NMR 51.2, 51.8, 123.3, 140.7, 166.1; IR (neat) 1725,
1
oil (50 mg, 26%): H NMR 1.75 (s, 1H, 3.43 (dd, J ) 1.8, 5.4
Hz, 2H), 3.74 (s, 3H), 3.81 (s, 2H), 6.04 (dt, J ) 1, 8, 15.8 Hz,
1
4
H), 7.03 (dt, J ) 5.4, 15.8 Hz, 1H), 7.32 (m, 5H); 13C NMR
9.5, 51.5, 53.3, 121.2, 127.2, 128.1, 128.5, 139.7, 146.9, 166.9;
-
1
2
IR (neat) 1726, 1661, 1606 cm . Anal. Calcd for C12H15NO :
C, 70.22; H, 7.37; N, 6.82. Found: C, 70.40; H, 7.21; N, 6.97.
Eth yl 4-(N-ben zyla m in o)-2-bu ten oa te, 4e, was prepared
from 2e (240 mg, 0.77 mmol) and benzylamine (290 mg, 2.7
mmol) by the same procedure. The crude product was a yellow
oil (180 mg) which showed four spots by TLC. Ethyl acetate
-
1
5 7 3 2
1666 cm . Anal. Calcd for C H N O : C, 42.55; H, 5.00; N,
29.77. Found: C, 42.67; H, 5.15; N, 29.56.
Eth yl 4-a zid o-2-bu ten oa te, 5e, was prepared from 2e (420
mg, 1.4 mmol) and sodium azide (182 mg, 2.8 mmol) in DMF
(10 mL) at 0 °C for 3 h as a colorless oil (120 mg, 55%) after
purification by radial chromatography (hexane-ethyl acetate,
95:5): 1H NMR 1.31 (t, J ) 7.1 Hz, 3H), 4.01 (dd, J ) 1.7, 5.2
Hz, 2H), 4.23 (q, J ) 7.1 Hz, 2H), 6.09 (dt, J ) 1.7, 15.6 Hz,
1H), 6.90 (dt, J ) 5.2, 15.6 Hz, 1H); 13C NMR 14.2, 51.2, 60.7,
(30 mL) was added, and the solution was extracted with 1 N
HCl (30 mL and then 20 mL) and water (100 mL) to obtain a
colorless aqueous phase (the organic phase was yellow). The
aqueous phase was washed with ethyl acetate (2 × 100 mL)
and then made basic by the addition of 10% NaOH (40 mL).
The basic aqueous solution was extracted with ethyl acetate
-
1
123.7, 140.35, 165.6; IR (neat) 1722, 1662 cm . Anal. Calcd
for C : C, 46.40; H, 5.84; N, 27.05. Found: C, 46.19;
(
2 × 100 mL), and the resulting organic phase was washed
with brine (2 × 100 mL), dried (MgSO
), and concentrated to
give 4e as a colorless oil (100 mg, 60%) which was greater than
6 9 3 2
H N O
4
H, 5.63; N, 26.94.
Eth yl 4-a cetoxy-5-p h en yl-2-p en ten oa te, 6a , was pre-
pared by the following general procedure. Nosylate 2a (250
mg, 0.62 mmol) and potassium acetate (120 mg, 1.2 mmol)
were stirred in DMF (10 mL) at room temperature for 4 h.
Ethyl acetate (100 mL) was added, and the solution was
1
9
5% pure by H NMR. An analytical sample was obtained by
preparative TLC (hexane-ethyl acetate, 95:5) as a colorless
1
oil: H NMR 1.29 (t, J ) 7.1 Hz, 3H), 1.54 (broad s, 1H), 3.43
(
dd, J ) 1.8, 3.7 Hz, 2H), 3.81 (s, 2H), 4.20 (q, J ) 7.1 Hz,
2
1
1
H), 6.03 (dt, J ) 1.8, 15.8 Hz, 1H), 7.02 (dt, J ) 3.7, 15.8 Hz,
washed with brine (2 × 100 mL), dried (MgSO
4
), passed
1
3
H), 7.33 (m, 5H); C NMR 14.3, 49.5, 53.3, 60.3, 121.7, 127.1,
28.1, 128.5, 139.8, 146.6, 166.4; IR (neat) 1718, 1658 cm-1
: C, 71.21; H, 7.81. Found: C,
through a short pad of silica gel, and concentrated under
.
reduced pressure to give crude 6a as a yellow oil (150 mg)
1
Anal. Calcd for C13
1.20; H, 7.55.
Meth yl 4-(N-ben zyla m in o)-2-p en ten oa te, 4c, was pre-
pared from 2c (150 mg, 0.45 mmol) and benzylamine (190 mg,
.7 mmol) in dichloromethane (20 mL) with stirring at room
H
17NO
2
which was approximately 95% pure by H NMR. Purification
7
of 70 mg of the crude product by preparative TLC gave 6a as
a colorless oil (30 mg, 39%): 1H NMR 1.27 (t, J ) 7.1 Hz, 3H),
2.03 (s, 3H), 2.96 (AB of ABX, J ) 6, 7 Hz, 2H), 4.18 (q, J )
7.1 Hz, 2H), 5.60 (m, 1H), 5.91 (dd, J ) 1.5, 15.6 Hz, 1H), 6.88
(dd, J ) 5.5, 15.6 Hz, 1H), 7.25 (m, 5H); 13C NMR 14.2, 20.9,
40.4, 60.6, 73.0, 122.0, 126.9, 128.5, 129.4, 136.0, 144.4, 165.9,
1
temperature for 6 days. Amine 9c was isolated as a yellow
1
oil (70 mg) which was about 90% pure by H NMR. The
-
1
observed spectrum matched the spectrum of an authentic
169.8; IR (neat) 1743, 1720, 1662, 1627, 1601 cm
.
Anal.
1
sample.
Calcd for C15
6.87.
18 4
H O : C, 68.69; H, 6.92. Found: C, 68.87; H,
Eth yl 4-a zid o-5-p h en yl-2-p en ten oa te, 5a , was prepared
by the following general method. Nosylate 2a (170 mg, 0.42
mmol) and sodium azide (60 mg, 0.9 mmol) were stirred in
acetonitrile (10 mL) at room temperature for 4 h. The reaction
was quenched with a solution of saturated ammonium chloride
Meth yl 4-a cetoxy-2-h exen oa te, 6b, was prepared from 2b
(200 mg, 0.61 mmol) and potassium acetate (120 mg, 1.2 mmol)
in DMSO (10 mL) at room temperature for 1 h as a colorless
oil (110 mg). Purification by Kugelrohr distillation with a bath
temperature of 35-40 °C/0.5 mmHg gave 6b as a colorless oil
(70 mg, 62%): 1H NMR 0.93 (t, J ) 7.6 Hz, 3H), 1.71 (m, 2H),
2.10 (s, 3H), 3.75 (s, 3H), 5.35 (m, 1H), 5.95 (dd, J ) 1.6, 15.6
Hz, 1H), 6.85 (dd, J ) 5.6, 15.6 Hz, 1H); 13C NMR 9.2, 21.0,
(6 mL) and aqueous ammonium hydroxide (2 mL). The
solution was extracted with ethyl acetate (100 mL). The
organic phase was washed with brine (2 × 100 mL), dried
4
(MgSO ), passed through a short pad of silica gel, and
concentrated under reduced pressure to give 5a as a yellow
oil (74 mg) which was greater than 95% pure by 1H NMR.
Purification by flash chromatography (hexane-ethyl acetate,
26.9, 51.7, 73.5, 121.3, 145.5, 166.4, 170.1; IR (neat) 1746, 1726,
-1
1664 cm
9 14 4
. Anal. Calcd for C H O : C, 58.05; H, 7.58.
Found: C, 58.02; H, 7.62.
1
00:0 to 95:5 to 90:10) gave 5a as a colorless oil (50 mg, 33%):
Meth yl 4-a cetoxy-2-p en ten oa te, 6c, was prepared from
2c (150 mg, 0.48 mmol) and potassium acetate (94 mg, 0.96
mmol) in DMSO (10 mL) at room temperature for 1 h as a
pale yellow oil (60 mg) which was homogeneous by TLC.
Purification by Kugelrohr distillation with a bath temperature
of 35-40 °C/0.5 mmHg gave 6c as a colorless oil (40 mg,
48%): 1H NMR 1.37 (d, J ) 6.4 Hz, 3H), 2.09 (s, 3H), 3.75 (s,
1
H NMR 1.29 (t, J ) 7.2 Hz, 3H), 2.89 (d, J ) 7 Hz, 2H), 4.21
(
q + m, J ) 7.2 Hz, 3H), 6.01 (d, J ) 16 Hz, 1H), 6.85 (dd, J
1
3
)
7, 16 Hz, 1H), 7.30 (m, 5H); C NMR 14.2, 40.6, 60.7, 63.82
1
1
6
23.4, 127.1, 128.7, 129.4, 136.2, 143.7, 165.6; IR (neat) 1720,
-
1
658, 1604 cm . Anal. Calcd for C13
15 3 2
H N O : C, 63.66; H,
.16; N, 17.13. Found: C, 63.70; H, 6.03; N, 17.06.

5
572 J . Org. Chem., Vol. 61, No. 16, 1996
Hoffman and Severns
3
H), 5.49 (ddq, J ) 1.2, 5, 6.4 Hz, 1H), 5.97 (dd, J ) 1.2, 16
CH
2
Cl
2
(10 mL) was added, and the solution was cooled in a
1
3
Hz, 1H), 6.88 (dd, J ) 5, 16 Hz, 1H); C NMR 19.6, 21.1, 51.7,
6
cm . Anal. Calcd for C
C, 55.61; H, 7.25.
freezer overnight to give 8b as white crystals (78 mg), mp 119-
122 °C, which were essentially pure by H NMR. Recrystal-
lization from hot acetone gave pure 8b (20 mg, 22%): mp 151-
152 °C; H NMR (DMSO-d
1
8.8, 120.6, 146.6, 166.5, 169.9; IR (neat) 1751, 1730, 1664
-
1
8
H
12
O
4
: C, 55.81; H, 7.03. Found:
1
6
) 0.94 (t, J ) 8 Hz, 3H), 1.77 (dq,
Meth yl 4-a cetoxy-2-bu ten oa te, 6d , was prepared from 2d
J ) 7, 8 Hz, 2H), 4.45 (dt, J ) 7, 9 Hz, 1H), 6.09 (d, J ) 15.6
Hz, 1H), 6.74 (dd, J ) 9, 15.6 Hz, 1H), 7.84 and 8.21 (ABq, J
(100 mg, 0.33 mmol) and sodium acetate trihydrate (92 mg,
1
3
0
.68 mmol) in DMF (10 mL) at room temperature for 1.5 h as
) 8 Hz, 4H), 9.06 and 9.17 (two broad s, 4H); C NMR (DMSO-
1
a pale yellow oil (30 mg) which was 95% pure by H NMR.
d
6
) 11.1, 25.4, 47.5, 51.61, 122.6, 123.2, 126.8, 144.8, 147.2,
Purification by preparative TLC gave 6d as a colorless oil (20
mg, 15%): H NMR 2.13 (s, 3H), 3.76 (s, 3H), 4.75 (dd, J ) 2,
154.2, 165.3, 167.3; IR (KBr) 1949, 1724, 1678, 1656, 1604
1
-1
cm
19 3 2 7
. Anal. Calcd for C14H N S O : C, 41.47; H, 4.72.
4
1
1
.6 Hz, 2H), 6.04 (dt, J ) 2, 15.8 Hz, 1H), 6.96 (dt, J ) 4.6,
Found: C, 41.36; H, 4.86.
13
5.8 Hz, 1H); C NMR 20.7, 51.8, 62.6, 121.8, 141.5, 166.3,
Eth yl 4-isoth iou r on iu m -5-p h en yl-2-p en ten oa te p-n i-
tr oben zen esu lfon a te, 8a , was prepared from 2a (100 mg,
0.25 mmol) and thiourea (18.8 mg, 0.247 mmol) in refluxing
acetone (20 mL) for 2 days (TLC monitoring) as a yellow oil
-
1
7 10 4
70.3; IR (neat) 1726, 1666 cm . Anal. Calcd for C H O :
C, 53.16; H, 6.37. Found: C, 52.96; H, 6.45.
Eth yl 4-th iocya n a to-5-p h en yl-2-p en ten oa te, 7a , was
prepared by the following general procedure. Nosylate 2a (180
mg, 0.44 mmol) and potassium thiocyanate (86 mg, 0.88 mmol)
were stirred in acetone (10 mL) at room temperature for 3 h.
The solution was concentrated under reduced pressure, ethyl
acetate (100 mL) was added, and the cloudy white solution
was passed through a short pad of silica gel. Some additional
white solid formed after filtration. The solvent was removed
by rotary evaporation, chloroform (50 mL) was added, and the
solid was removed by filtration. The solution was evaporated
under reduced pressure to give a crude product, 7a , as a yellow
oil (120 mg). Purification of 60 mg of the crude product by
1
(120 mg, 100%) which was soluble in acetone: H NMR
(acetone-d ) 1.21 (t, J ) 7.1 Hz, 3H), 3.17 (dd, J ) 7.4, 7.6 Hz,
6
2H), 4.13 (q, J ) 7.1 Hz, 2H), 5.01 (m, 1H), 6.12 (d, J ) 15.6
Hz, 1H), 6.88 (dd, J ) 6.5, 15.6 Hz, 1H), 7.30 (m, 5H), 7.69
and 8.27 (ABq, J ) 8.9 Hz, 4H), 8.72 and 9.56 (two broad s,
4H). This material was not characterized further.
Met h yl 4-isot h iou r on iu m -2-p en t en oa t e p -n it r ob en -
zen esu lfon a te, 8c, was prepared from 2c (80.0 mg, 0.25
mmol) and thiourea (19.3 mg, 0.25 mmol) in refluxing acetone
(10 mL) for 15 h as a crude white solid (99.3 mg). Recrystal-
lization from hot acetone gave 8c (60 mg, 60%) as a white
1
preparative TLC (hexane-ethyl acetate, 95:5 to 90:10) gave
solid: mp 161-4 °C; H NMR (DMSO-d
6
) 1.44 (d, J ) 6.9 Hz,
1
7
3
a as colorless oil (34 mg, 59%): H NMR 1.22 (t, J ) 7.1 Hz,
H), 3.04 and 3.06 (two ABq’s, J ) 9.6, 14.2 Hz, 2H), 4.04 (dt,
3H), 3.69 (s, 3H), 4.63 (m, 1H), 6.01 (d, J ) 15.6 Hz, 1H), 6.82
(dd, J ) 8.3, 15.6 Hz, 1H), 7.86 and 8.23 (ABq, J ) 8.9 Hz,
J ) 8.6, 9.6 Hz, 1H), 4.11 (7.1, 2H), 5.91 (d, J ) 15.6 Hz, 1H),
4H), 9.11 and 9.21 (two broad s, 4H); 13C NMR (DMSO-d
6
) 20.7,
1
3
6
3
1
.85 (dd, J ) 8.6, 15.6 Hz, 1H), 7.28 (m, 5H); C NMR 14.2,
9.9, 51.9, 61.0, 110.2, 124.9, 127.7, 128. 9, 129.1, 135.5,
42.46, 165.1; IR (neat) 2154, 1718, 1652, 1606 cm-1. Anal.
43.4, 54.1, 124.1, 125.7, 129.27, 148.3, 149.7, 156.5, 167.9,
-
1
169.7; IR (KBr) 1930, 1728, 1674, 1668.0, 1602 cm . Anal.
Calcd for C13
H, 4.24.
17 3 2 7
H N S O : C, 39.89; H, 4.38. Found: C, 40.00;
Calcd for C14
4.38; H, 5.71; N, 5.19.
Meth yl 4-th iocya n a to-2-h exen oa te, 7b, was prepared
2
H15NSO : C, 64.34; H, 5.79; N, 5.36. Found: C,
6
Meth yl 4-isoth iou r on iu m -2-bu ten oa te p-n itr oben zen e-
su lfon a te, 8d , was prepared from 2d (50.0 mg, 0.166 mmol)
and thiourea (13.0 mg, 0.17 mmol) in acetone (10 mL) at room
temperature for 2 h as a white solid (53.5 mg, 85%) after
from 2b (170 mg, 0.52 mmol) and KSCN (100 mg, 1.0 mmol)
in acetone (10 mL) at room temperature for 3 h as a colorless
oil (90 mg) which showed a single component by TLC and was
1
recrystallization from hot acetone: mp 169-171 °C; H NMR
1
approximately 95% pure by H NMR. Kugelrohr distillation
6
(DMSO-d ) 3.69 (s, 3H), 4.04 (dd, J ) 1, 7 Hz, 2H), 6.13 (dt, J
with a bath temperature of 45-50 °C/0.5 mmHg gave 7b as a
) 1, 15.6 Hz, 1H), 6.83 (dt, J ) 7, 15.6 Hz, 1H), 7.84 and 8.21
1
13
colorless oil (50.6 mg, 53%): H NMR 1.08 (t, J ) 7.2 Hz, 3H),
(ABq, J ) 8.9 Hz, 4H), 9.1 (broad s, 4H); C NMR (DMSO-d
6
)
1
1
5
.90 (dq, J ) 7.2, 8 Hz, 2H), 3.78 (s, 3H), 6.04 (d, J ) 15.6 Hz,
H), 6.86 (dd, J ) 8, 15.6 Hz, 1H); 13C NMR 11.6, 27., 51.8,
2.0, 110.2, 124.2, 143.2, 165.7; IR (neat) 2154, 1728, 1656
30.6, 51.6, 123.3, 123.6, 126.8, 141.2, 147.3, 153.9, 165.3, 168.3;
-1
IR (KBr) 1722, 1682, 1670, 1602.0 cm
. Anal. Calcd for
12 15 3 2 7
C H N S O
: C, 38.19; H, 4.01; N, 11.13; S, 16.99. Found:
-
1
cm . Anal. Calcd for C
C, 51.80; H, 5.90.
8
H
11NSO
2
: C, 51.87; H, 5.99. Found:
C, 38.39; H, 4.25; N, 10.93; S, 16.79.
Meth yl 2-(N-ben zyla m in o)-3-bu ten oa te, 10, was pre-
pared from 3d (50 mg, 0.17 mmol) and benzylamine (70 mg,
0.67) in dichloromethane (20 mL) by stirring at room temper-
ature for 24 h. Amine 10 was obtained as a yellow oil (30 mg)
Meth yl 4-th iocya n a to-2-p en ten oa te, 7c, was prepared
from 2c (140 mg, 0.44 mmol) and KSCN (86 mg, 0.88 mmol)
in acetone (10 mL) at room temperature for 3 h as a yellow oil
1
1
(
70 mg) which was >90% pure by H NMR. Purification by
which contained several impurities by H NMR. The observed
Kugelrohr distillation with a bath temperature of 50-55 °C/
spectra of the major component (>90%) was in agreement with
.5 mmHg gave 7c as a colorless oil (43.4 mg, 57%): 1H NMR
.63 (d, J ) 6.9 Hz, 3H), 3.78 (s, 3H), 4.04 (dq, J ) 1.1, 6.9
1,17
0
1
the reported spectra of 14.
None of the 4-amino isomer 4d
was detected in the products. The sample decomposed during
an attempted separation by preparative TLC on silica gel.
Rea ction s of 3d w ith Sod iu m Azid e. Reaction of 3d (300
mg, 1.0 mmol) and sodium azide (130 mg, 2.0 mmol) in
acetonitrile (10 mL) at room temperature for 1.5 h gave 5d as
a colorless oil (100 mg, 71%) after purification by radial
chromatography. When a mixture of 3d (50 mg, 0.166 mmol)
Hz, 1H), 6.01 (dd, J ) 1.1, 15.6 Hz, 1H), 6.93 (dd, J ) 6.9,
1
3
1
1
5.6 Hz, 1H); C NMR 19.8, 44.7, 52.0, 110.2, 123.4, 144.2,
-
1
65.7; IR (neat) 2154, 1726, 1656 cm . Anal. Calcd for C
: C, 49.11; H, 5.30; N, 8.18. Found: C, 48.90; H, 5.53;
N, 7.98.
7 9
H -
NSO
2
Meth yl 4-th iocya n a to-2-bu ten oa te, 7d , was prepared
from 2d (100 mg, 0.33 mmol) and KSCN (60 mg, 0.62 mmol)
in acetonitrile (10 mL) at 0 °C for 2 h as a yellow oil (40 mg)
which appeared to be a single component by TLC. Purification
by preparative TLC (hexane-ethyl acetate, 100:0 to 90:10)
and sodium azide (11 mg, 0.17 mmol) was stirred in acetoni-
1
trile-d
3
(5 g) at 0 °C for 2 h, examination of an aliquot by H
NMR showed that it was a mixture of methyl 2-azido-3-
butenoate, 11, and 5d along with a small amount of starting
1
1
gave 7d as a colorless oil (20 mg, 38%): H NMR 3.67 (dd, J
material 3d (70:25:5). From this sample was obtained the H
NMR spectrum of 11: 1H NMR 3.75 (s, 3H), 4.59 (d, J ) 6.6
Hz, 1H), 5.44 (dd, J ) 6, 13 Hz, 2H), 5.95 (m, 1H). Reaction
of 3d (140.0 mg, 0.465 mmol) and sodium azide (30.2 mg, 0.465
mmol) in acetonitrile (15 mL) at 0 °C for 4 h followed by
addition of diisopropylamine (six drops) caused isomerization
of 11 to 12. After workup the crude product was a yellow oil
(40 mg) which contained methyl 2-azido-2-butenoate (12) as
)
1.0, 7.5 Hz, 2H), 3.79 (s, 3H), 6.11 (dt, J ) 1.0, 15.4 Hz,
13
1
1
H), 6.96 (dt, J ) 7.5, 15.4 Hz, 1H); C NMR 34.4, 52.0, 110.8,
26.1, 138.6, 165.5; IR (neat) 2156, 1724, 1658 cm-1. Anal.
Calcd for C H NSO : C, 45.85; H, 4.49; N, 8.91; S, 20.40.
6 7 2
Found: C, 46.03; H, 4.62; N, 8.72; S, 20.16.
Meth yl 4-isoth iou r on iu m -2-h exen oa te p-n itr oben zen e-
su lfon a te, 8b, was prepared by the following general proce-
dure. Nosylate 2b (74.4 mg, 0.226 mmol) and thiourea (27
mg, 0.36 mmol) were dissolved in acetone (10 mL) and stirred
at 50 °C for 8 h. The clear reaction solution was concentrated,
1
the major component (ca. 25% yield by NMR). The H NMR
1
for 12 obtained in this mixture confirms its structure: H NMR
1.80 (d, J ) 7 Hz, 3H), 3.83 (s, 3H), 6.26 (q, J ) 7 Hz, 1H).

Nucleophilic Displacement of Nosyloxy Unsaturated Esters
J . Org. Chem., Vol. 61, No. 16, 1996 5573
Particularly revealing is the vinyl quartet at δ 6.26 coupled
to the allylic methyl doublet at δ 1.8.
Rea ction s of 3d w ith P ota ssiu m Th iocya n a te. A mix-
ture of 3d (50.0 mg, 0.166 mmol) and KSCN (17 mg, 0.17
) 7 Hz, 1H), 8.01 and 8.24 (ABq, J ) 8 Hz, 4H), 8.6 (s, 2H)
9.2 (s, 2H); 13C NMR (DMSO-d
) 18.1, 53.5, 119.0, 124.0, 127.4,
6
147.2, 154.5, 159.7, 163.8, 168.5; IR (KBr) 1702, 1670, 1606
-
1
cm
15 3 2 7
. Anal. Calcd for C12H N S O : C, 38.19; H, 4.01.
6
mmol) in acetone-d (5 mL) was stirred at room temperature
Found: C, 38.45; H, 4.35.
for 15 min. The white solid was filtered off, and the resulting
Salt 17 could also be prepared from 3d (50.0 mg, 0.166
mmol) and thiourea (13.0 mg, 0.17 mmol) in acetone (10 mL)
by stirring at room temperature for 5 days. No solid formed
during the reaction. The solvent was removed to give the
crude 17 as a colorless oil (63 mg) which did not contain any
solution contained only methyl 2-thiocyanato-3-butenoate (13)
1
by H NMR. The solution was immediately concentrated
under reduced pressure to give the crude product, 13, as a
yellow oil (20 mg). This compound was not stable enough for
1
3
1
1
C NMR or combustion analysis, but its H NMR and IR
16 by H NMR.
1
spectra confirmed its structure as 13. H NMR 3.84 (s, 3H),
Meth yl 2-[[(p-n itr op h en yl)su lfon yl]oxy]-2-bu ten oa te,
18, was produced as a major product in the reaction of 3d with
bases under protic conditions. For example, a mixture of 3d
(50.0 mg, 0.166 mmol) and diisopropylamine (70 mg, 0.69
mmol) in dichloromethane (30 mL) was stirred at room
temperature overnight. TLC showed that the reaction was
about 40% complete in half an hour. The solvent was removed,
ethyl acetate (50 mL) was added, and the solution was washed
with 5% HCl (50 mL) and brine (2 x 100 mL), dried (MgSO4),
and concentrated under reduced pressure to give the crude
product 18 as a yellow oil (50 mg) which was about 95% pure
4
.85 (d, J ) 8.9 Hz, 1H), 5.52 and 5.56 (two d, J ) 5.4 and 9.9
Hz, 2H,), 6.01 (m, 1H); IR (neat) 2158.0 (sharp), 1742.0, 1634.0
cm
-
1
.
Reaction of 3d (63.1 mg, 0.209 mmol) and KSCN (20.4 mg,
0
.21 mmol) in acetone (5 mL) at 0 °C for 3 h followed by
addition of diisopropylamine (three drops) and stirring at 0
C for 10 min gave 14 was a yellow oil (29.3 mg). Purification
by bulb to bulb distillation with a bath temperature of 50-55
C/0.5 mmHg gave 14 as a colorless oil (9.7 mg, 30%). Trace
°
°
impurities were observed by NMR so no combustion analysis
1
1
was performed. 14: H NMR 2.20 (d, J ) 7.1 Hz, 3H), 3.89
by H NMR. Purification by preparative TLC (hexane-ethyl
1
3
1
(
1
s, 3H), 7.65 (q, J ) 7.1 Hz, 1H); C NMR 17.4, 53.4, 109.2,
acetate, 80:20) gave 18 as a colorless oil (20, 40%): H NMR
19.5, 152.6, 163.0; IR (neat) 2162, 1727, 1622 cm-1
Reaction of 3d (300 mg, 1 mmol) and KSCN (196 mg, 2
.
1.93 (d, J ) 7 Hz, 3H), 3.69 (s, 3H), 6.89 (q, J ) 7 Hz, 1H),
8.24 and 8.43 (ABq, J ) 9 Hz, 4H); 13C NMR 12.7, 52.6, 124.1,
129.8, 132.9, 137.9, 142.4, 150.9, 161.6; IR (neat) 1735, 1663,
mmol) in acetonitrile (10 mL) at 0 °C for 1.5 h gave a yellow
oil (110 mg) which was a mixture of 13 and 15 (40:60). After
neat overnight stirring, the mixture contained only isothiocy-
anate 15. Purification by preparative TLC (hexane-ethyl
acetate, 95:5) gave methyl 4-isothiocyano-2-butenoate (15) as
-
1
7
1608 cm . Anal. Calcd for C11H11NSO : C, 43.86; H, 3.68;
N, 4.65; S, 10.64. Found: C, 43.61; H, 3.76; N, 4.50; S, 10.81.
Met h yl 2-(p-n it r op h en yl)-2-h yd r oxy-3-b u t en oa t e, 19,
was produced as the major product from the reaction of 3d
with anionic bases in aprotic conditions. For example, a
mixture of 3d (270 mg, 0.90 mmol) and sodium cyanide (90
mg, 1.8 mmol) in acetonitrile (9 mL) was stirred at room
temperature for 21 h. The solution was concentrated, ethyl
acetate (50 mL) was added, and the organic phase was washed
1
a colorless oil (20 mg, 13%). H NMR 3.78 (s, 3H), 4.38 (dd, J
)
2, 4 Hz, 2H), 6.18 (dt, J ) 2, 15.5 Hz, 1H), 6.89 (dt, J ) 4,
-1
1
5.5 Hz, 1H); IR (neat) 2060 (br), 1728, 1666 cm . Insufficient
material was available for purification to analytical purity.
Rea ction s of 3d w ith Th iou r ea . Methyl 2-isothiouro-
nium-3-butenoate p-nitrobenzenesulfonate, 16, was prepared
from 3d (50.0 mg, 0.166 mmol) and by stirring with thiourea
with water (3 × 50 mL), dried (MgSO
4
), and concentrated
under reduced pressure. The crude product, 19, was a yellow
1
(13 mg, 0.17) in acetone (10 mL) at room temperature for 3 h.
oil (190 mg, 80%) which was about 95% pure by H NMR. An
The solvent was removed by under reduced pressure, dichlo-
analytical sample of 19 was obtained by preparative TLC
(hexane-ethyl acetate, 90:10 to 80:20): 1H NMR 3.85 (s, 3H),
4.00 (s, 1H), 5.40 (dd, J ) 1, 10.5 Hz, 1H), 5.64 (dd, J ) 1, 17
Hz, 1H), 6.38 (dd, J ) 10.5, 17 Hz, 1H), 7.77 and 8.22 (ABq, J
) 9 Hz, 4H); 13C NMR 54.0, 78.2, 116.9, 123.5, 127.3, 137.0,
romethane (10 mL) was added, and a white solid mp 72-5 °C
(
(
47.7 mg), crystallized out of solution upon addition of hexane
ca. 3 mL) and storing in the freezer overnight. The solid
product was a mixture of 16 and tautomer 17 (90:10) and was
soluble in chloroform. The spectrum of 16 could be obtained
from the spectrum of the mixture, and the spectra of an
-
1
147.6, 147.8, 173.4; IR (neat) 1737 cm
. Anal. Calcd for
11 5
C H11NO
: C, 55.70; H, 4.67; N, 5.90. Found: C, 55.72; H,
1
authentic sample of 17. 16: H NMR 3.79 (s, 3H), 5.07 (d, J
4.71; N, 5.76.
)
7.9 Hz, 1H), 5.42 (d, J ) 10.3 Hz, 1H), 5.51 (d, J ) 17 Hz,
H), 5.88 (m, 1H), 8.01 and 8.02 (ABq, J ) 8.6 Hz, 4H), 8.6 (s,
H), 9.6 (s, 2H); IR (neat) 1742, 1682, 1601 cm-1
An authentic sample of methyl 2-isothiouronium-2-butenoate
p-nitrobenzenesulfonate, 17, was prepared from 3d (50.0 mg,
.166 mmol) and thiourea (13.0 mg, 0.17 mmol) in acetone (10
1
2
Ack n ow led gm en t. This work was made possible
through a grant from the National Science Foundation
CHE 9004980).
.
(
0
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
mL) by stirring at 0 °C for 4 h followed by storing in the freezer
for 1 month. No solid formed during the reaction. The solvent
was removed, and dichloromethane (10 mL) and hexane (ca.
13
8
a , 11, 13, 15, and 16 and the C NMR spectrum of 14 (6
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
3
mL) were added to give crystallization of 17 as a white solid
(
41 mg), mp 74-8 °C. An analytical sample was obtained by
recrystallization from acetone/hexane: mp 215-216 °C (white
solid); H NMR 2.15 (d, J ) 7 Hz, 3H), 3.79 (s, 3H), 7.91 (q, J
1
J O960477M