Construction of Azacycles Based on Endo-Mode Cyclization of Allenes

Article abstract of DOI:10.1021/jo035729f

A new procedure for constructing monocyclic five- and six-membered azacycles by the endo-mode ring-closing reaction of allenylazido derivatives under neutral conditions has been developed. The azabicyclo[m.n.0] compounds were prepared by applying this newly developed procedure. The seven-membered azacycle was prepared when the allene possessing an unsubstituted carboxyl amido functionality was submitted to the basic conditions. In addition, indole and quinoline skeletons were synthesized using this procedure.

Full text of DOI:10.1021/jo035729f

Con str u ction of Aza cycles Ba sed on En d o-Mod e Cycliza tion
of Allen es
Chisato Mukai,* Minoru Kobayashi, Shoko Kubota, Yukie Takahashi, and Shinji Kitagaki
Faculty of Pharmaceutical Sciences, Kanazawa University,
Takara-machi 13-1, Kanazawa 920-0934, J apan
cmukai@kenroku.kanazawa-u.ac.jp
Received November 25, 2003
A new procedure for constructing monocyclic five- and six-membered azacycles by the endo-mode
ring-closing reaction of allenylazido derivatives under neutral conditions has been developed. The
azabicyclo[m.n.0] compounds were prepared by applying this newly developed procedure. The seven-
membered azacycle was prepared when the allene possessing an unsubstituted carboxyl amido
functionality was submitted to the basic conditions. In addition, indole and quinoline skeletons
were synthesized using this procedure.
SCHEME 1
In tr od u ction
Nitrogen-containing heterocyclic systems have at-
tracted widespread attention in the field of organic
chemistry as well as in medicinal chemistry. Many
procedures for the construction of five- and six-membered
azacycles1 have been developed. Recent efforts from this
laboratory2 demonstrated that the novel endo-mode ring-
closing reaction of 1-sulfonylallenes 1 (X ) O)2a with a
suitable δ-hydroxyl carbon appendage at the C1-position
underwent an endo-mode-type ring-closing reaction, re-
sulting in the formation of the five- to eight-membered
oxacycles 2 (X ) O) in high yield (Scheme 1). This novel
method was shown to be applicable to the construction
of the carbocycles 2 (X ) active methine),2b if the starting
allenes 1 have a carbon side chain with an active methine
moiety at the C1-position. We were interested in applying
this newly developed endo-mode ring-closing reaction to
the preparation of the nitrogen-containing heterocycles
2 (X ) nitrogen atom). In this paper, we describe the
endo-mode ring-closing reaction of allenes having an
azido functionality at the carbon side chain terminus.
SCHEME 2
resulting primary amino functionality would immediately
attack the sp-hybridized carbon center of the allenic
moiety in an endo-mode manner, leading to the formation
of azacycles in one operation. The required azidoallenes
4a -c for the ring-closing reaction were easily prepared
as follows. The azido alcohols 3a ,4 3b,5 and 3c, derived
from 3-(tert-butyldiphenylsiloxy)-1-propyne by conven-
tional means, were treated with benzenesulfenyl chlo-
ride6 at -78 °C to afford the corresponding sulfinylal-
lenes, which were subsequently exposed to m-chloroper-
benzoic acid (mCPBA) to give the sulfonylallenes 4a -c
(Scheme 2).
Resu lts a n d Discu ssion
We have devoted considerable attention to sulfonyla-
llenes having a δ-azido-carbon tether as the starting
material for this investigation, because the azido func-
tionality of 4, for example, would be easily reduced to
the amino group under neutral conditions,3 and the
With the required allenes 4 for the ring-closure reac-
tion in hand, we first investigated the construction of the
* Corresponding author. Tel: +81-76-234-4411. Fax: +81-76-234-
4410.
(1) For leading references, see: (a) J anosik, T.; Bergman, J . In
Progress in Heterocyclic Chemistry; Gribble, G. W., J oule, J . A., Eds.;
Pergamon: Amsterdam, 2003; Vol. 15, pp 140-166. (b) Coffey, D. S.;
Kolis, S. P.; May, S. A. In Progress in Heterocyclic Chemistry; Gribble,
G. W., J oule, J . A., Eds.; Pergamon: Amsterdam, 2003; Vol. 15, pp
284-305.
(2) (a) Mukai, C.; Yamashita, H.; Hanaoka, M. Org. Lett. 2001, 3,
3385-3387. (b) Mukai, C.; Ukon, R.; Kuroda, N. Tetrahedron Lett.
2003, 44, 1583-1586.
(3) Larock, R. C. Comprehensive Organic Transformations, 2nd ed.;
Wiley-VCH: New York, 1999; pp 815-820.
(4) Hirschmann, R. F.; Nicolaou, K. C.; Pietranico, S.; Reisine, T.
D.; Salvino, J . M.; Sprengeler, P.; Strader, C. D. PCT Int. Appl. WO
95 11686; Chem. Abstr. 1995, 123, 340754.
(5) Pearson, W. H.; Bergmeier, S. C.; Chytra, J . A. Synthesis 1990,
156-159.
(6) Horner, L.; Binder, V. Ann. Chem. 1972, 757, 33-68.
10.1021/jo035729f CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/18/2004
2128
J . Org. Chem. 2004, 69, 2128-2136

Azacycles Based on Endo-Mode Cyclization of Allenes
SCHEME 3 a
SCHEME 4 a
a
Reaction conditions: (a) LDA, R1COR2, THF, -78 °C; (b) NaN3,
DMF, 60 °C; (c) PhSCl, Et3N,THF, -78 °C; (d) mCPBA, CH2Cl2,
rt.
triazabicyclic compound 8 in 90% yield. We next applied
conditions A and B to prepare the seven-membered
azacycle 9. However, it was found that these procedures
were not effective for construction of the larger ring-sized
azacycle. In fact, when 4c was exposed to ring-closing
conditions (conditions A and B), the desired compound 9
(and/or its imine form) could never be detected in the
reaction mixture. The thermal intramolecular cycload-
dition of 4c was effective in refluxing toluene to furnish
the triazabicyclo[5.3.0]ring system 10 in 62% yield,
although the chemical yield was somewhat lower com-
pared to those observed in the cases of 6 and 8.
a
Reaction conditions: (conditions A) Bu3SnH, benzene, rt;
(conditions B) PPh3, H2O, THF, rt; (conditions C) THF, 50 °C.
bCompound 7 was obtained in 72% yield when treated in toluene
c
at 0 °C. Compound 10 was obtained when refluxed in toluene.
five-membered azacycle. Reduction of the azido function-
ality was carried out by treatment of 4a with tributyltin
hydride (Bu3SnH)7 in benzene at room temperature
(conditions A) to furnish directly the desired dihydropyr-
role derivative 58 as the imine in 87% yield. The forma-
tion of 5 could be interpreted to occur via reduction of
the azido functionality to the primary amino group, which
might immediately undergo the endo-mode ring-closing
reaction at the sp-hybridized carbon, accompanied by
double bond isomerization. An alternative procedure
using PPh3/H2O9 in THF at room temperature (conditions
B) also worked well to give 5 in 62% yield. On the other
hand, upon heating at 50 °C in THF (conditions C) in
the absence of reducing reagents, 4a produced the
triazabicyclic derivative 6 in 81% yield (Scheme 3). The
formation of 6 could be rationalized by the thermal
intramolecular [2 + 3]-dipolar cycloaddition3 of the azido
functionality with the distal π-bond of the allenyl moiety,
followed by double-bond migration. The ring-closing
reaction of the one-carbon homologated azido derivative
4b under conditions A provided the desired endo-mode
product 7 in 87% yield as the enamine along with the
triazabicyclic derivative 8 in 7% yield as the byproduct.
The formation of 8 could be suppressed when the reaction
was carried out in toluene at 0 °C to give exclusively 7
in 72% yield. Compound 7 was also formed in 69% yield
under conditions B. The [2 + 3]-dipolar cycloaddition of
the azido derivative 4b produced the corresponding
Our next efforts were directed at confirming the
generality of this endo-mode ring-closing reaction of the
azido derivatives. Preparation of several starting tri- and
tetrasubstituted allenes 15 and 16 is summarized in
Scheme 4. The acetylide, derived from 4-(tosyloxy)but-
1-yne (11), was quenched with a suitable carbonyl
compound to give 13a -c, which were further converted
into the corresponding allenes 15a -c according to the
procedures described in Scheme 4. Similarly, the carbon
homologated 12 was transformed into the allenes 16a -c
via 14a -c.
Upon treatment with Bu3SnH in benzene (conditions
A), the trisubstituted allenes 15a ,b underwent the ring-
closing reaction in an endo-mode manner to afford the
corresponding dihydropyrrole derivatives 17a ,b in high
yield. The tetrasubstituted allene 15c also produced the
five-membered product 17c in 62% yield. Similar treat-
ment of 16a -c furnished the tetrahydropyridine deriva-
tives 18a -c as shown in Scheme 5. Thus, the newly
developed procedure was found to be applicable not only
to disubstituted allenes but also to tri- and tetra-
substituted allenes, resulting in the formation of five- and
six-membered azacycles possessing a carbon side chain
at the C2-position.
The next phase of this program was the application of
the newly developed ring-closing reaction to the prepara-
tion of bicyclic compounds such as the azabicyclo[3.3.0]-
octane, azabicyclo[4.3.0]nonane, and azabicyclo[4.4.0]-
decane ring systems, because the pyrrolizidine 21 (n )1,
m ) 0), indolizidine 21 (n ) m ) 1), and quinolizidine
21 (n ) 2, m ) 1) skeletons are frequently found to be
(7) Wasserman, H. H.; Brunner, R. K.; Buybak, J . D.; Carter, C. G.;
Oku, T.; Robinson, R. P. J . Am. Chem. Soc. 1985, 107, 519-521.
(8) A trace amount of compound 6 was detected in the reaction
mixture.
(9) Nagarajan, S.; Ganem, B. J . Org. Chem. 1987, 52, 5044-5046.
J . Org. Chem, Vol. 69, No. 6, 2004 2129

Mukai et al.
SCHEME 5 a
SCHEME 7 a
a
Reaction conditions: (a) MsCl, DMAP, Et3N, CH2Cl2, 0 °C; (b)
NaN3, DMF, 60 °C; (c) K2CO3, MeOH, rt, (50%); (d) LDA,
HCtC(CH2)3OTs, THF, -78 °C; (e) PhSCl, Et3N, THF, -78 °C;
(f) mCPBA, CH2Cl2, rt, (91%); (g) Bu3SnH, toluene, rt; (h) TBAF,
THF, rt; (i) CBr4, PPh3, Et3N, CH2Cl2, rt, (64%).
a
a : R1 ) H, R2 ) Me, b: R1 ) H, R2 ) Bu, c: R1 ) R2 ) Me.
SCHEME 6 a
which was protected with the pivaloyl group and selec-
tively desilylated with pyridinium p-toluenesulfonate
(PPTS) to give 22 in 78% overall yield. Compound 22 was
treated with methanesulfonyl chloride (MsCl) and NaN3
to afford the azido derivative, which was consecutively
exposed to desilylation, bromination, and deacylation
conditions to provide the propargyl alcohol derivative 23
in 78% overall yield. Conversion of 23 into the allene 24
(86%) was achieved using the standard conditions. Treat-
ment of 24 with Bu3SnH in toluene (conditions A, toluene
was used instead of benzene)11 at room temperature gave
two tetrahydropyridine derivatives 25 and 26 in 49% and
38% yield, respectively. No azabicyclic derivatives such
as 21 (n ) m ) 1) could be obtained. The debromination
reaction of the starting 24 and/or the intermediate 20 (n
) m ) 1, X ) Br) with Bu3SnH would lead to production
of 25, while the formation of 26 could be rationalized in
terms of intramolecular nucleophilic displacement of
bromide by the carbanion species of 20 (n ) m ) 1). To
avoid reductive debromination and the formation of a
cyclopropyl ring, we performed the ring-closing reaction
of 24 under conditions B (PPh3/H2O). However, the only
isolable product from the reaction mixture was 26 (42%)
and the target azabicyclic derivative 21 (n ) m ) 1) could
never be found in the reaction mixture. Thus, it turned
out that the cyclopropyl-ring formation by the carbanion
species of 20 must be preferred over the formation of the
desired azabicyclic compound 21 (displacement by the
nitrogen nucleophile).
On the basis of the above experiments, we turned our
efforts to the development of the stepwise procedure for
the preparation of the azabicyclic compounds instead of
the direct conversion method. Compound 22 was treated
with MsCl and NaN3 to give the azido derivative, which
was subsequently exposed to K2CO3 in MeOH to afford
the hydroxyl compound 27 in 50% yield. Compound 27
(64%) was prepared in fewer steps and more conveniently
from the aldehyde 28 by treatment with the acetylide of
5-(tosyloxy)pent-1-yne and NaN3. The azido derivative 27
was then converted to the sulfonylallene 29 in 91% yield
by the general procedure described in Scheme 7. Treat-
ment of 29 under conditions A (toluene was used as a
a
Reaction conditions: (a) Dess-Martin Oxid. CH2Cl2, rt; (b)
nBuLi, HCtC(CH2)3OTBS, THF, -30 °C; (c) PivCl, DMAP, Pyr,
CH2Cl2, rt; (d) PPTS, MeOH, (78%); (e) MsCl, DMAP, Et3N,
CH2Cl2, 0 °C; (f) NaN3, DMF, 60 °C; (g) TBAF, AcOH, THF, rt; (h)
CBr4, PPh3, CH2Cl2, 0 °C; (i) K2CO3, MeOH, rt, (78%); (j) PhSCl,
Et3N, THF, -78 °C; (k) mCPBA, CH2Cl2, rt, (86%); (l) Bu3SnH,
toluene, rt, 25 (49%), 26 (38%); (m) PPh3, H2O, THF, rt, 26 (42%).
the major components of many alkaloids. Thus, we hoped
that upon exposure to conditions A and/or B, the azi-
doallene derivatives 19 having a suitably functionalized
carbon appendage at the C3-position would be trans-
formed into the corresponding azacycles 20, which might
immediately undergo a further ring-closing reaction,
leading to the direct formation of the azabicyclic species
21 (Scheme 6). As an initial evaluation of the direct
transformation of 19 into 21, we prepared the azidoallene
derivative 24 having a bromoethyl group at the C3-
position. Oxidation of 3-(tert-butyldiphenylsiloxy)pro-
panol with Dess-Martin periodinane10 was followed by
addition of the acetylide, derived from 5-(tert-butyldi-
methylsiloxy)pent-1-yne, to afford the secondary alcohol,
(11) Changing the solvent from benzene to toluene never affected
the distribution of the products or the chemical yield.
(10) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155-4156.
2130 J . Org. Chem., Vol. 69, No. 6, 2004

Azacycles Based on Endo-Mode Cyclization of Allenes
SCHEME 8 a
SCHEME 9 a
a
Reaction conditions: (a) LDA, HCtC(CH2)nCH2OTs, THF, -78
°C; (b) NaN3, DMF, 60 °C, 33a (75%), 33b (79%), 33c (73%), 33d
(71%), 33e (77%); (c) PhSCl, Et3N, THF, -78 °C; (d) mCPBA,
CH2Cl2, rt, 34a (92%), 34b (92%), 34c (93%), 34d (96%), 34e (93%);
(e) Bu3SnH, toluene, rt; (f) TBAF, THF, rt; (g) CBr4, PPh3, Et3N,
CH2Cl2, rt,35a (31%), 35b (44%), 35c (36%), 35d (77%), 35e (49%).
solvent) furnished the tetrahydropyridine derivative, the
silyl group of which was removed by treatment with
tetrabutylammonium fluoride (TBAF). Exposure of the
resulting primary hydroxyl compound to bromination
conditions (CBr4/PPh3) effected successive bromination
and construction of the azabicyclo[4.3.0]nonene skeleton
to furnish 30 in 64% yield. Thus, the stepwise procedure
provided the desired azabicyclic compound 30 in an
acceptable yield.
a
Reaction conditions: (a) PPh3, H2O, THF; (b) acylating reagent
(Ac2O, PivCl, BzCl), Et3N, rt; (c) p-TsOH, MeOH, rt, 37a (81%),
37b (89%), 37c (91%); (d) PhSCl, Et3N, THF, -78 °C; (e) mCPBA,
CH2Cl2, rt, 38a (39%), 38b (37%), 38c (51%).
lene compounds.12 Thus, by analogy to the preparation
of the aforementioned allenes (in Schemes 2 and 4), the
required carbamoylallene derivatives 38 were prepared
in a straightforward manner as depicted in Scheme 9.
The azido derivative 36, derived from 3-(tetrahydropy-
ranyloxy)prop-1-yne by reaction with 1,3-dibromopropane
and NaN3, was subsequently reduced, acylated, and
deprotected to afford 37. Finally, the propargyl alcohol
derivatives 37 were converted into the carbamoylallene
derivatives 38 by the standard method, although the
chemical yields in the conversion of 37 into 38 were
somewhat lower compared to those for the formation of
the azidoallene derivatives 4, 15, and 16. According to
the general procedure described in the previous paper,2a
We next investigated the construction of other ring-
sized azabicyclic systems by taking advantage of the
newly developed stepwise procedure. Reaction of the
aldehydes 28, 31, and 32 with the acetylides provided
33. According to the general procedure, the compounds
33 were subsequently transformed into the azido deriva-
tives 34, which were then submitted to the ring-closing
conditions to provide the corresponding azabicyclic com-
pounds 35. The results are summarized in Scheme 8.
Formation of the tetrahydropyridine-fused azabicyclic
skeletons 30 (Scheme 7), 35d , and 35e (Scheme 8)
occurred in moderate yield ranging from 49% to 77%.
However, the azabicyclic compounds 35a -c containing
the dihydropyrrole moiety were formed in a rather low
yield. In fact, the azabicyclo[5.3.0]decene derivative 35c
was isolated as the sole product from the reaction mixture
in 36% yield. It should be mentioned that the azidoallene
derivatives 34c,e did not cyclize under the standard
conditions at room temperature (Scheme 8). Upon re-
the acetyl derivative 38a was exposed to tBuOK in BuOH
t
at room temperature. However, no ring-closed products
could be detected in the reaction mixture and an intrac-
table mixture was obtained. Changing solvent and/or
base did not afford us a favorable result. Similarly
fruitless reactions were observed when the pivaloyl
derivative 38b was submitted to the ring-closing condi-
tions. On the other hand, the benzoyl derivative 38c
underwent the endo-mode ring-closing reaction and
spontaneous debenzoylation to furnish 7 in 37% yield.
i
fluxing in toluene in the presence of Pr2NEt (instead of
Et3N in CH2Cl2 at room temperature), however, com-
pounds 34c,e afforded the corresponding cyclized prod-
ucts 35c,e in 36% and 49% yield, respectively. Thus, this
endo-mode ring-closing reaction was shown to be ap-
plicable to the construction of several azabicyclic ring
systems, although it is obvious that investigation on the
optimized conditions for the construction of the dihydro-
pyrrole-fused azabicyclic derivative 35a -c is still re-
quired.
t
When THF was used instead of BuOH, debenzoylation
could be suppressed and 39 was obtained as the sole
isolable product in 28% yield. No improvement in the
production of 7 or 39 was found even after screening
several reaction conditions.
The unsubstituted carboxamide derivative 46 was
another substrate investigated to determine whether the
endo-mode ring-closing reaction under basic conditions
would proceed in a reasonable yield. To this end, the
starting compounds 46 and 47 were prepared from 40
and 41, respectively (Scheme 10). The chemical yields in
the conversion of the propargyl alcohol derivatives 43 and
45 to 46 and 47 were again found to be lower than those
In our previous paper,2 the base-catalyzed endo-mode
ring-closing reaction of allenes having a suitable δ-hy-
droxyl carbon appendage at the C1-position was reported
(Scheme 1). We could now develop an efficient procedure
for the formation of five- and six-membered azacycles
from the corresponding azidoallene derivatives under
neutral conditions. However, we were still interested in
the base-catalyzed ring-closing reaction of carbamoylal-
(12) An exo-mode ring-closing reaction of sulfonylallenes having a
carbon side chain at the C3-position has been reported: Gray, M.;
Parsons, P. J .; Neary, A. P. Synlett 1993, 281-282.
J . Org. Chem, Vol. 69, No. 6, 2004 2131

Mukai et al.
SCHEME 10 a
SCHEME 11 a
a
Reaction conditions: (a) Dess-Martin oxidation, CH2Cl2, rt;
(b) NaClO2, NaH2PO4, 2-methyl-2-butene, tBuOH, H2O, rt, 42
(95%), 44 (95%); (c) isobutyl chloroformate, Et3N, THF, 0 °C, then
aq NH3; (d) K2CO3, MeOH, rt, 43 (64%), 45 (84%); (e) PhSCl, Et3N,
THF, -78 °C; (f) mCPBA, CH2Cl2, rt, 46 (39%), 47 (37%).
a
Reaction conditions: (a) propargyl alcohol, Pd(PPh3)2Cl2, CuI,
iPr2NH, THF, rt, (92%); (b) PhSCl, Et3N, THF, -78 °C; (c) mCPBA,
CH2Cl2, rt, 52 (47%), 58 (60%); (d) NaH, THF, rt, (96%); (e)
CF3CO2H, CH2Cl2, rt, 54 (83%); (f) (Boc)2O, THF, reflux; (g) CBr4,
PPh3, CH2Cl2, 0 °C, (69%); (h) In(CtCCH2OTBDMS)3, Pd(dppf)Cl2,
THF, reflux; (i) TBAF, AcOH, THF, rt, (65%); (j) salcomine, O2,
MeOH, rt, (77%).
for the formation of the azidoallene derivatives 4, 15, and
16. After screening several reaction conditions, we found
that NaH in THF at room temperature was effective in
the case of 46 to produce the piperidone derivative 48 in
t
79% yield. When treated with BuOK in THF, 46 also
provided 48 in 64% yield. However, the NaH/THF condi-
tions were no longer useful for the ring-closing reaction
of 47, resulting in the formation of a small amount of 49
(7%), even at reflux. The best yield so far for production
of 49 (44%) was obtained when 47 was exposed to NaH
in a combined solvent of CH2Cl2 and DMF. Thus, it was
shown that the endo-mode ring-closing reaction of the
unsubstituted carboxamide derivatives 46 and 47 under
basic conditions was superior to that of the N-acylated
derivatives 38. It is noteworthy that the seven-membered
lactam azacycle 49 could be obtained from 47 under basic
conditions, whereas the formation of the seven-membered
enamine azacycle, e.g., 9, was never attained in more
than trace amounts in the reaction of the azidoallene
derivative 4c under neutral conditions (Scheme 3).
In the last stage of this study, application of the endo-
mode ring-closing reaction to the preparation of aromatic
five- and six-membered azacycles was investigated
(Scheme 11). The starting aniline derivatives 52 and 58
were easily prepared from the N-protected o-iodoaniline
derivative 50 and o-aminobenzyl alcohol (55) by standard
procedures. The endo-mode ring-closing reaction of 52
proceeded rapidly to afford the indole derivative 53 in
96% yield when treated with sodium hydride at room
temperature. Upon exposure to trifluoroacetic acid (TFA),
52 underwent N-deprotection and spontaneous ring-
closing reaction to produce 54 in 83% yield. On the other
hand, treatment of the sulfonylallene 58 with TFA
provided the unstable dihydroquinoline derivative, which
was subsequently oxidized with salcomine/O213 to give the
quinoline derivative 59 in 77% yield.
from azidoallene derivatives under neutral conditions.
This procedure was shown to be applicable to the
preparation of the azabicyclo[m.n.0] ring system. The
endo-mode ring-closing reaction of allenes having an
unsubstituted carboxamide functionality produced not
only the piperidone skeleton but also the seven-mem-
bered azacycle, which could never be obtained in the
reaction of azidoallene derivatives. In addition, indole and
quinoline skeletons also could be prepared using this
procedure. The application of this endo-mode ring-closing
reaction to the synthesis of alkaloids is now in progress.
Exp er im en ta l Section
Melting points are uncorrected. IR spectra were measured
1
in CHCl3. H NMR spectra were taken in CDCl3. CHCl3 (7.26
ppm) for silyl compounds and tetramethylsilane (0.00 ppm)
for compounds without a silyl group were used as an internal
standard. 13C NMR spectra were recorded in CDCl3 with CHCl3
(77.00 ppm) as an internal standard. All reactions were carried
out under a nitrogen atmosphere unless otherwise stated.
Silica gel (silica gel 60, 230-400 mesh, Merck) was used for
chromatography. Organic extracts were dried over anhydrous
Na2SO4.
7-Azid o-2-h ep tyn -1-ol (3c). To a solution of LDA in THF
(3.0 mL), prepared from the reaction of nBuLi (1.36 M hexane
solution, 2.65 mL, 3.60 mmol) and iPr2NH (0.53 mL, 3.78
mmol), was added a solution of 3-(tert-butyldiphenylsiloxy)-
prop-1-yne (883 mg, 3.00 mmol) in THF (2.0 mL) and N,N′-
dimethylpropyleneurea (DMPU) (1.0 mL) and reaction mixture
was stirred at 0 °C for 20 min. 1,4-Dibromobutane (0.72 mL,
6.03 mmol) was added to the reaction mixture, which was
stirred at room temperature for 8 h. The reaction was
quenched by addition of water and extracted with Et2O. The
extract was washed with water and brine, dried, and concen-
trated. The residue was passed through a short pad of silica
gel with hexane-AcOEt (4:1) to give the crude adduct. To a
In summary, we have developed a new procedure for
constructing monocyclic five- and six-membered azacycles
(13) Inada, A.; Nakamura, Y.; Morita, Y. Chem. Lett. 1980, 1287-
1290.
2132 J . Org. Chem., Vol. 69, No. 6, 2004

Azacycles Based on Endo-Mode Cyclization of Allenes
solution of the crude adduct in MeOH (15 mL) was added 10%
HCl (1.5 mL) at room temperature. The reaction mixture was
allowed to stand for 10 h, quenched by addition of saturated
aqueous NaHCO3, and extracted with Et2O. The extract was
washed with water and brine, dried, and concentrated to
dryness. The residue was passed through a short pad of silica
gel with hexane-AcOEt (3:1) to give the crude alcohol. A
solution of the crude alcohol, NaN3 (215 mg, 3.31 mmol), and
NaI (450 mg, 3.00 mmol) in DMF (7.5 mL) was heated at 60
°C for 3 h, quenched by addition of water, and extracted with
Et2O. The extract was washed with water and brine, dried,
and concentrated to dryness. Chromatography of the residue
with hexane-AcOEt (3:1) gave 3c (320 mg, 70%) as a colorless
6-Azid o-3-h exyn -2-ol (13a ). To a solution of 11 (224 mg,
1.00 mmol) in THF (10 mL) was added LDA (1.00 M THF
solution, 1.00 mL, 1.00 mmol) at -78 °C. The reaction mixture
was stirred at the same temperature for 1 h, to which
acetaldehyde (0.11 mL, 1.96 mmol) was added. The reaction
mixture was stirred at -78 °C for 1.5 h, quenched by addition
of water, and extracted with Et2O. The extract was washed
with water and brine, dried, and concentrated to dryness.
NaN3 (97.5 mg, 1.50 mmol) was added to a solution of the crude
alcohol in DMF (5.0 mL), and the mixture was heated at 60
°C for 6 h, diluted with water, and extracted with Et2O. The
extract was washed with water and brine, dried, and concen-
trated to dryness. Chromatography of the residue with hex-
ane-AcOEt (4:1) gave 13a (74.6 mg, 54%) as a colorless oil:
1
oil: IR 3609, 3435, 2224, 2100 cm-1; H NMR δ 4.24 (2H, dt,
1
IR 3603, 3433, 2245, 2110 cm-1; H NMR δ 4.52 (1H, tq, J )
J ) 5.9, 2.4 Hz), 3.30 (2H, t, J ) 6.8 Hz), 2.27 (2H, tt, J ) 2.4,
7.3 Hz), 1.74-1.69 (2H, m), 1.63-1.57 (3H, m); 13C NMR δ
2.0, 6.4 Hz), 3.37 (2H, t, J ) 6.8 Hz) 2.51 (2H, dt, J ) 2.0, 6.8
Hz), 1.79 (1H, brs), 1.44 (3H, d, J ) 6.4 Hz); 13C NMR δ 84.4,
80.4, 58.5, 49.8, 24.4, 19.9; FABMS m/z 162 (M+ + Na, 5.0);
FABHRMS calcd for C6H16N3O 140.0824, found 140.0823.
85.5, 79.0, 51.3, 51.0, 27.9, 25.6, 18.3; FABMS m/z 154 (M+
1, 100). Anal. Calcd for C7H11N3O: C, 54.89; H, 7.24; N, 27.43.
Found: C, 54.50; H, 7.45; N, 27.62.
+
5-Azid o-3-p h en ylsu lfon ylp en ta -1,2-d ien e (4a ). To a so-
lution of 3a (275 mg, 2.20 mmol) and Et3N (1.84 mL, 13.2
mmol) in THF (9.0 mL) was added PhSCl (954 mg, 6.60 mmol)
at -78 °C. The reaction mixture was stirred for 2 h, quenched
by addition of water, and extracted with Et2O. The extract was
washed with water and brine, dried, and concentrated to
dryness. The residue was passed through a short pad of silica
gel with hexane-AcOEt (2:1) to give the crude sulfoxide. To a
solution of the crude sulfoxide in CH2Cl2 (11 mL) was added
mCPBA (569 mg, 3.30 mmol) at room temperature. The
reaction mixture was stirred for 1 h at room temperature,
quenched by addition of aqueous Na2S2O3, and extracted with
Et2O. The extract was washed with water and brine, dried,
and concentrated to dryness. Chromatography of the residue
with hexane-AcOEt (4:1) gave 4a (417 mg, 76%) as a colorless
1-(ter t-Bu tyld ip h en ylsiloxy)-3-(p iva loyloxy)-4-octyn -8-
ol (22). To a solution of 3-(tert-butyldiphenylsiloxy)propan-1-
ol (1.40 g, 4.45 mmol) in CH2Cl2 (11 mL) was added Dess-
Martin periodinane (2.45 g, 5.78 mmol) at 0 °C, and the
reaction mixture was allowed to stand for 30 min. The reaction
was quenched by addition of aqueous Na2S2O3 and extracted
with Et2O. The extract was washed with water and brine,
dried, and concentrated. To a solution of 5-(tert-butyldimeth-
ylsiloxy)pent-1-yne (1.06 g, 5.34 mmol) in THF (15 mL) was
added n-BuLi (1.40 M hexane solution, 3.81 mL, 5.33 mmol)
at -30 °C, and the reaction mixture was stirred for 30 min. A
solution of the crude aldehyde in THF (8.0 mL) was added to
a solution of the acetylide in THF and the reaction mixture
was stirred at -30 °C for 2 h. The reaction was quenched by
addition of water and extracted with Et2O, which was washed
with water and brine, dried, and concentrated to dryness. The
residue was passed through a short pad of silica gel with
hexane-AcOEt (20:1) to give the crude adduct. To a solution
of the crude adduct in CH2Cl2 (8.0 mL) and pyridine (1.0 mL)
was added DMAP (48.5 mg, 0.40 mmol) and PivCl (0.73 mL,
5.93 mmol) at 0 °C. The reaction mixture was stirred for 12 h
at room temperature, quenched by addition of water, and
extracted with Et2O. The extract was washed with water and
brine, dried, and concentrated to dryness. The residue was
passed through a short pad of silica gel with hexane-AcOEt
(10:1) to give the crude pivaloyloxy derivative. PPTS (49.9 mg,
0.20 mmol) was added to a solution of the crude ester in MeOH
(16 mL) at room temperature and the reaction mixture was
stirred for 24 h. MeOH was evaporated off and the residue
was chromatographed with hexane-AcOEt (4:1) to give 22
1
oil: IR 2104, 1969, 1936 cm-1; H NMR δ 7.91-7.54 (5H, m),
5.44 (2H, t, J ) 2.9 Hz), 3.41 (2H, t, J ) 6.8 Hz), 2.54 (2H, tt,
J ) 2.9, 6.8 Hz); 13C NMR δ 208.0, 139.8, 133.7, 129.2, 128.1,
110.0, 84.8, 49.0, 27.3; MS m/z 249 (M+, 5.0). Anal. Calcd for
C
11H11N3O2S: C, 53.00; H, 4.45; N, 16.86. Found: C, 52.82;
H, 4.44; N, 16.78.
Rin g-Closin g Rea ction of 4a . Con d ition s A. To a solu-
tion of 4a (25.4 mg, 0.10 mmol) in benzene (1.0 mL) was added
Bu3SnH (0.14 mL 0.52 mmol) at room temperature and the
reaction mixture was stirred for 24 h. Benzene was evaporated
off and chromatography of the residue with AcOEt gave
5-methyl-4-phenylsulfonyl-3,4-dihydro-2H-pyrrole (5) (19.8 mg,
87%) along with a trace amount of 6. Compound 5 was a
colorless needle: mp 74-75.5 °C (from Et2O); IR 1645 cm-1
;
1H NMR δ 7.90-7.44 (5H, m), 4.28-4.24 (1H, m), 3.78-3.73
(1H, m), 3.40-3.33 (1H, m), 2.34-2.26 (4H, m), 2.20-2.11 (1H,
m); 13C NMR δ 165.8, 137.4, 134.1, 129.3, 128.6, 75.1, 59.1,
27.1, 20.0; MS m/z 223 (M+, 8.4). Anal. Calcd for C11H13NO2S:
C, 59.17; H, 5.87; N, 6.27. Found: C, 58.92; H, 5.81; N, 6.22.
(1.66 g, 78%) as a colorless oil: IR 3628, 3443, 2245, 1724 cm-1
;
1H NMR δ 7.68-7.63 (4H, m), 7.44-7.35 (6H, m), 5.57-5.53
(1H, m), 3.80-3.71 (2H, m), 3.69 (2H, t, J ) 6.4 Hz), 2.29 (2H,
dt, J ) 2.0, 6.4 Hz), 2.09-1.95 (2H, m), 1.71 (2H, quint, J )
6.4 Hz), 1.44 (1H, brs), 1.16 (9H, s), 1.05 (9H, s); 13C NMR δ
177.2, 135.6, 135.5, 133.7, 133.6, 129.6, 127.6, 85.0, 78.4, 61.6,
61.4, 59.8, 38.7, 37.9, 31.1, 27.0, 26.8, 19.2, 15.3; FABMS m/z
481 (M+ + 1, 0.5). Anal. Calcd for C29H40O4Si: C, 72.46; H,
8.39. Found: C, 72.16; H, 8.55.
Con d ition s B. To a solution of 4a (25.2 mg, 0.10 mmol) in
THF (1.0 mL) and H2O (0.1 mL) was added PPh3 (79.5 mg,
0.30 mmol) at room temperature, and the reaction mixture was
stirred for 24 h. THF was evaporated off and the residue was
purified by chromatography with AcOEt to afford 5 (14.0 mg,
62%).
[2 + 3]-Cycloa d d ition Rea ction of Com p ou n d 4a . Con -
d ition s C. A solution of 4a (25.2 mg, 0.10 mmol) in THF (1.0
mL) was heated at 50 °C for 3 days. THF was evaporated off
and the residue was chromatographed with AcOEt to give
6-phenylsulfonyl-1,2,3-triazabicyclo[3.3.0]octa-2,4-diene (6) (20.5
mg, 81%) as a colorless needle: mp 129-130 °C (from AcOEt-
hexane); 1H NMR δ 7.77-7.57 (5H, m), 7.23 (1H, s), 4.68 (1H,
dd, J ) 2.4, 8.8 Hz), 4.36 (1H, ddd, J ) 2.4, 9.3, 11.7 Hz), 4.17
(1H, dt, J ) 11.7, 8.3 Hz), 3.36 (1H, ddt, J ) 8.3, 14.7, 2.4
Hz), 3.24 (1H, ddt, J ) 9.3, 14.7, 8.3 Hz); 13C NMR δ 135.7,
135.6, 134.8, 129.5, 129.2, 129.0, 59.2, 45.3, 30.8; MS m/z 249
(M+, 3.1). Anal. Calcd for C11H11N3O2S: C, 53.00; H, 4.45; N,
16.86. Found: C, 52.97; H, 4.42; N, 16.86.
8-Azid o-1-br om o-4-octyn -3-ol (23). To a solution of 22
(929 mg, 1.93 mmol), Et3N (0.81 mL, 5.81 mmol), and DMAP
(23.6 mg, 0.19 mmol) in CH2Cl2 (10 mL) was added MsCl (0.22
mL, 2.84 mmol) at 0 °C. The reaction mixture was stirred for
20 min, quenched by addition of water, and extracted with
Et2O. The extract was washed with water and brine, dried,
and concentrated. NaN3 (188 mg, 2.89 mmol) was added to a
solution of the crude mesylate in DMF (10 mL). The reaction
mixture was heated at 60 °C for 5 h, diluted by addition of
water, and extracted with Et2O, which was washed with water
and brine, dried, and concentrated to dryness. The residue was
passed through a short pad of silica gel with hexane-AcOEt
(20:1) to give the crude azide derivative. To a solution of the
crude azide derivative in THF (6.8 mL) was successively added
J . Org. Chem, Vol. 69, No. 6, 2004 2133

Mukai et al.
AcOH (0.33 mL, 5.76 mmol) and TBAF (1.0 M THF solution,
2.90 mL, 2.90 mmol) at room temperature. The reaction
mixture was stirred for 12 h. THF was evaporated off and the
residue was passed through a short pad of silica gel with
hexane-AcOEt (4:1) to give crude alcohol. CBr4 (768 mg, 2.32
mmol) and Ph3P (607 mg, 2.31 mmol) were added to a solution
of the crude alcohol in CH2Cl2 (10 mL) at 0 °C. The reaction
mixture was stirred for 1 h and CH2Cl2 was evaporated off.
The residue was passed through a short pad of silica gel with
hexane-AcOEt (4:1) to give the crude primary bromide. To a
solution of the crude bromide, thus obtained, in MeOH (10 mL)
was added K2CO3 (293 mg, 2.12 mmol) at room temperature.
The reaction mixture was allowed to stand for 24 h, diluted
by addition of water, and extracted with AcOEt, which was
washed with water and brine, dried, and concentrated to
dryness. Chromatography of the residue with hexane-AcOEt
(4:1) gave 23 (370 mg, 78%) as a colorless oil: IR 3607, 3420,
2224, 2100 cm-1; 1H NMR δ 4.61-4.56 (1H, m), 3.59-3.48 (2H,
m), 3.40 (2H, t, J ) 6.8 Hz), 2.35 (2H, dt, J ) 2.0, 6.8 Hz)
2.27-2.14 (2H, m), 1.93 (1H, d, J ) 4.9 Hz), 1.78 (2H, quint,
J ) 6.8 Hz); 13C NMR δ 84.6, 81.1, 60.8, 50.2, 40.5, 28.9, 27.7,
16.0; FABMS m/z 246(M+ + 1, 9.3), 248 (M+ + 1, 9.1). Anal.
Calcd for C8H12BrN4O: C, 39.04; H, 4.91; N, 17.07. Found: C,
38.81; H, 4.97; 17.01.
Rin g-Closin g Rea ction of 24. According to conditions A,
24 (15.3 mg, 0.04 mmol) was treated with Bu3SnH (0.05 mL
0.19 mmol) in toluene (0.8 mL) at room temperature for 36 h
to give 1,2,3,4-tetrahydro-5-phenylsulfonyl-6-propylpyridine
(25) (5.4 mg, 49%) and 6-cyclopropyl-1,2,3,4-tetrahydro-5-
phenylsulfonylpyridine (26) (4.1 mg, 38%). Compound 25 was
a colorless oil: IR 3452, 3383 cm-1; 1H NMR δ 7.85-7.43 (5H,
m), 4.19-4.13 (1H, m), 3.21-3.14 (2H, m), 2.64-2.58 (2H, m),
2.40 (2H, t, J ) 5.9 Hz), 1.76 (2H, quint, J ) 5.9 Hz), 1.61-
1.50 (2H, m), 0.94 (3H, t, J ) 7.3 Hz); 13C NMR δ 154.4, 144.6,
131.5, 128.6, 126.1, 97.4, 41.3, 34.4, 23.5, 22.6, 21.3, 13.9; MS
m/z 265 (M+, 27); HRMS calcd for C14H19NO2S 265.1137, found
265.1140. Compound 26 was a colorless needle: mp 118-119
°C (from AcOEt-hexane); IR 3460 cm-1; 1H NMR δ 7.87-7.84
(2H, m), 7.50-7.43 (3H, m), 4.00 (1H, brs), 3.13-3.09 (2H, m),
2.79-2.73 (1H, m), 2.46 (2H, t, J ) 5.9 Hz), 1.74 (2H, quint, J
) 5.9 Hz), 0.80-0.75 (2H, m), 0.56-0.52 (2H, m); 13C NMR δ
153.2, 144.8, 131.5, 128.6, 126.1, 99.6, 41.2, 24.0, 21.4, 12.7,
6.2; MS m/z 263 (M+, 26). Anal.Calcd for C14H17NO2S: C, 63.85;
H, 6.51; N, 5.32. Found: C, 63.69; H, 6.56; N, 5.25.
δ 7.85-7.83 (2H, m), 7.66-7.63 (4H, m), 7.58-7.54 (1H, m),
7.48-7.36 (8H, m), 5.84 (1H, sept, J ) 2.9 Hz), 3.64 (2H, t, J
) 6.4 Hz), 3.21 (2H, t, J ) 6.4 Hz), 2.35-2.30 (4H, m), 1.74-
1.62 (2H, m), 1.05 (9H, s); 13C NMR δ 203.6, 140.0, 135.50,
135.48, 133.46, 133.45, 133.4, 129.77, 129.75, 129.0, 128.1,
127.74, 127.71, 112.5, 98.6, 62.7, 50.3, 31.6, 27.1, 26.8, 24.2,
19.2; FABMS m/z 546 (M+ + 1, 1.7). Anal. Calcd for C30H35N3O3-
SSi: C, 66.02; H, 6.46; N, 7.70. Found: C, 65.88; H, 6.70; N,
7.72.
2-P h en ylsu lfon yl-6-a za bicyclo[4.3.0]n on -1-en e (30). To
a solution of 29 (109 mg, 0.20 mmol) in toluene (2.0 mL) was
added Bu3SnH (0.27 mL 1.00 mmol) at room temperature, and
the reaction mixture was stirred for 37 h. Toluene was
evaporated off and the residue was passed through a short
pad of silica gel with hexane-AcOEt (3:1) to give the crude
enamine derivative. TBAF (1.0 M THF solution, 0.40 mL, 0.40
mmol) was added to a solution of the crude enamine derivative
in THF (0.6 mL) at room temperature. The reaction mixture
was stirred for 1.5 h, quenched by addition of water, and
extracted with AcOEt. The extract was washed with water and
brine, dried, and concentrated to dryness. To a solution of
crude alcohol in CH2Cl2 (2.0 mL) were added Et3N (0.11 mL,
0.79 mmol), CBr4 (133 mg, 0.40 mmol), and Ph3P (105 mg, 0.40
mmol) at 0 °C. The reaction mixture was stirred at room
temperature for 1 h and concentrated. Chromatography of the
residue was with hexane-AcOEt (2:1) gave 30 (33.8 mg, 64%)
a colorless solid: mp 90.5-91.5 °C (from AcOEt-hexane); IR
1597 cm-1; 1H NMR δ 7.82-7.79 (2H, m), 7.49-7.42 (3H, m),
3.28 (2H, t, J ) 7.3 Hz), 3.14-3.10 (4H, m), 2.34 (2H, t, J )
6.4 Hz), 1.92 (2H, quint, J ) 7.3 Hz), 1.82 (2H, quint, J ) 6.4
Hz);13C NMR δ 156.0, 144.7, 131.2, 128.6, 126.1, 92.2, 52.8,
44.6, 31.3, 22.1, 21.2, 20.1; MS m/z 263 (M+, 31). Anal. Calcd
for C14H17NO2S: C, 63.85; H, 6.51; N, 5.32. Found: C, 63.80;
H, 6.49; N, 5.26.
6-Azid o-1-(tetr a h yd r op yr a n yloxy)h ex-2-yn e (36). To a
solution of 3-(tetrahydropyranyloxy)prop-1-yne (9.27 g, 66.1
mmol) in THF (60 mL) was added n-BuLi (1.40 M hexane
solution, 52.0 mL, 72.8 mmol) at -30 °C and the reaction
mixture was stirred for 1 h at the same temperature. A
solution of 1,3-dibromopropane (13.4 mL, 132 mmol) in DMPU
(6.0 mL) was then added to a solution of the acetylide, thus
formed, in THF solution. The reaction mixture was stirred at
room temperature for 2 h, quenched by addition of water, and
extracted with Et2O. The extract was washed with water and
brine, dried, and concentrated. The residue was passed
through a short pad of silica gel with hexane-AcOEt (20:1) to
give the crude monobromo de4rivative. NaN3 (6.45 g, 99.2
mmol) and NaI (991 mg, 6.61 mmol) were added to a solution
of the crude bromo derivative in DMF (66 mL), which was
heated at 60 °C for 10 h. The reaction was quenched by
addition of water and extracted with Et2O. The extract was
washed with water and brine, dried, and concentrated to
dryness. Chromatography of the residue with hexane-AcOEt
(20:1 to 4:1) gave 36 (4.50 g, 30%) as a colorless oil: IR 2222,
2100 cm-1; 1H NMR δ 4.78 (2H, t, J ) 3.0 Hz), 4.26 (1H, dt, J
) 15.5, 2.0 Hz), 4.17 (1H, dt, J ) 15.5, 2.0 Hz), 3.87-3.78 (1H,
m), 3.55-3.47 (1H, m), 3.39 (2H, t, J ) 6.9 Hz), 2.33 (2H, tt,
J ) 2.0, 6.9 Hz), 1.88-1.46 (8H, m); 13C NMR δ 96.7, 84.5,
77.0, 62.0, 54.5, 50.2, 30.2, 27.7, 25.3, 19.1, 16.1; FABMS m/z
224 (M+ + 1, 3.3). Anal. Calcd for C11H17N3O2: C, 59.17; H,
7.67; N, 18.82. Found: C, 58.96; H, 7.76; N, 18.75.
8-Azid o-1-(ter t-bu tyld ip h en ylsiloxy)-4-octyn -3-ol (27).
To a solution of 5-(tosyloxy)pent-1-yne (68.6 mg, 0.29 mmol)
in THF (1.8 mL) was added LDA (0.50 M THF solution, 0.58
mL, 0.29 mmol) at -78 °C, to which a solution of 3-(tert-
butyldiphenylsiloxy)propanal 28 (76.5 mg, 0.24 mmol) in THF
(0.6 mL) was added. The reaction mixture was stirred at the
same temperature for 2 h, quenched by addition of water, and
extracted with Et2O. The extract was washed with water and
brine, dried, and concentrated to dryness. NaN3 (23.4 mg, 0.36
mmol) was added to a solution of the crude tosylate in DMF
(2.4 mL). The reaction mixture was heated at 60 °C for 6 h,
diluted by addition of water, and extracted with Et2O. The
extract was washed with water and brine, dried, and concen-
trated to dryness. Chromatography of the residue with hex-
ane-AcOEt (4:1) gave 27 (66.3 mg, 64%) as a colorless oil: IR
1
3599, 3470, 2232, 2102 cm-1; H NMR δ 7.71-7.67 (4H, m),
7.46-7.38 (6H, m), 4.71-4.60 (1H, m), 4.05-3.99 (1H, m),
3.86-3.81 (1H, m), 3.38 (2H, t, J ) 6.8 Hz), 3.16 (1H, d, J )
6.8 Hz), 2.34 (2H, dt, J ) 1.5, 6.8 Hz), 2.03-1.87 (2H, m), 1.77
(2H, quint, J ) 6.8 Hz), 1.06 (9H, s); 13C NMR δ 135.6, 135.5,
133.0, 129.8, 127.8, 83.5, 81.9, 61.9, 61.8, 50.2, 39.2, 27.8, 26.8,
19.1, 16.1; FABMS m/z 422 (M+ + 1, 1.8). Anal. Calcd for
6-Aceta m id o-2-h exyn -1-ol (37a ). To a solution of 36 (986
mg, 5.00 mmol) in THF (10 mL) was added Ph3P (1.57 g, 5.99
mmol) and H2O (0.14 mL, 7.77 mmol) at room temperature.
The reaction mixture was heated under reflux for 2 h and
cooled to 0 °C. Et3N (3.48 mL, 25.0 mmol) and Ac2O (1.42 mL,
15.0 mmol) were added to the crude amine derivative in THF.
After being stirred for 20 min at same temperature, the
reaction mixture was diluted by addition of saturated aqueous
NaHCO3 and extracted with Et2O. The extract was washed
with water and brine, dried, and concentrated to dryness. The
residue was passed through a short pad of silica gel with
C
24H31N3O2Si: C, 68.37; H, 7.41; N, 9.97 Found: C, 68.10; H,
7.52; N, 10.12.
8-Azid o-1-(ter t-bu tyld ip h en ylsiloxy)-5-p h en ylsu lfon yl-
octa -3,4-d ien e (29). According to the procedure described for
the preparation of 4a , 29 (559 mg, 91%) was obtained 27 (476
mg, 1.13 mmol) as a colorless oil: IR 2100, 1962 cm-1; 1H NMR
2134 J . Org. Chem., Vol. 69, No. 6, 2004

Azacycles Based on Endo-Mode Cyclization of Allenes
AcOEt to give the crude amide. pTsOH‚H2O (86.1 mg, 0.50
mmol) was added to a solution of the crude amide in MeOH
(10 mL) at room temperature and the reaction mixture was
allowed to stand for 10 h. MeOH was evaporated off and the
residue was chromatographed with AcOEt to afford 37a (556
extract was washed with water and brine, dried, and concen-
trated. To a solution of the crude aldehyde and 2-methyl-
2butene (8.0 mL) in BuOH (20 mL) were added NaClO2 (2.21
t
g, 19.5 mmol) and NaH2PO4 (2.44 g, 15.6 mmol) in H2O (8.0
mL) at room temperature. The reaction mixture was stirred
for 4 h, quenched by addition of 10% HCl, and extracted with
AcOEt. The extract was washed with water and brine, dried,
and concentrated to dryness. Chromatography of the residue
with hexane-AcOEt (2:1) gave 42 (786 mg, 95%) as a colorless
oil: IR 3141, 2239, 1724 cm-1; 1H NMR δ 4.62 (2H, t, J ) 2.0
Hz), 2.63-2.49 (4H, m), 1.20 (9H, s); 13C NMR δ 177.9, 177.6,
84.6, 75.3, 52.5, 38.7, 33.0, 27.0, 14.4; FABMS m/z 213 (M+,
52); FABHRMS calcd for C11H17O4 213.1127, found 213.1126.
Anal. Calcd for C11H16NO4‚1/4H2O: C, 60.96; H, 7.67. Found:
C, 61.19; H, 7.66.
mg, 81%) as a colorless oil: IR 3449, 3331, 2235, 1663 cm-1
;
1H NMR δ 6.09 (1H, brs), 4.22 (2H, t, J ) 2.0 Hz), 3.34 (2H, q,
J ) 6.8 Hz), 3.2-2.7 (1H, brs), 2.26 (2H, tt, J ) 2.0, 6.8 Hz),
1.97 (3H, s), 1.70 (2H, quint, J ) 6.8 Hz); 13C NMR δ 170.6,
84.7, 79.7, 50.9, 38.7, 28.0, 23.2, 16.3; MS m/z 155 (M+, 7.5);
HRMS calcd for C8H13NO2 155.0946, found 155.0948. Anal.
Calcd for C8H13NO2‚1/2H2O: C, 58.52; H, 8.59; N, 8.53.
Found: C, 58.70; H, 8.43; N, 8.59.
6-Aceta m id o-3-p h en ylsu lfon ylh exa -1,2-d ien e (38a ). Ac-
cording to the procedure described for the preparation of 4a ,
38a (31.2 mg, 39%) was obtained from 37a (44.9 mg, 0.29
6-Hyd r oxy-4-h exyn a m id e (43). To a solution of 42 (1.08
g, 5.09 mmol) and Et3N (0.85 mL, 6.10 mmol) in THF (17 mL)
was added isobutyl chloroformate (0.80 mL, 6.09 mmol) at 0
°C, and the reaction mixture was stirred for 30 min. Aqueous
NH3 (28%, 0.62 mL) was added to the mixed anhydride in THF
solution and the reaction mixture was stirred for 2 h. The
resulting solids were filtered off, and the filtrate was concen-
trated. To a solution of the crude amide in MeOH (13 mL) was
added K2CO3 (1.06 g, 7.67 mmol) at room temperature. After
being stirred for 12 h at room temperature, the reaction
mixture was diluted with AcOEt, and the resulting solids were
filtered off. The filtrate was evaporated off and the residue
was chromatographed with AcOEt-EtOH (1:0 to 10:1) to give
43 (481 mg, 74%) as a colorless needle: mp 77-79 °C (from
mmol) as a colorless oil: IR 3449, 3402, 1971, 1936, 1666 cm-1
;
1H NMR δ 7.89-7.50 (5H, m), 5.89 (1H, brs), 5.35 (2H, t, J )
3.3 Hz), 3.20 (2H, q, J ) 6.6 Hz), 2.25 (2H, tt, J ) 3.3, 7.6 Hz),
1.92 (3H, s), 1.66 (2H, quint, J ) 7.6 Hz); 13C NMR δ 207.5,
170.2, 139.7, 133.6, 129.1, 128.0, 112.4, 84.8, 38.3, 27.3, 24.0,
23.2; MS m/z 279 (M+, 5.6); FABHRMS calcd for C14H18NO3S
280.1007, found 280.1008. Anal. Calcd for
C
14H18NO3S‚1/
4H2O: C, 59.24; H, 6.21; N, 4.93. Found: C, 59.04; H, 6.28; N,
4.91.
1-Ben zoyl-1,2,3,4-t et r a h yd r o-6-m et h yl-5-p h en ylsu lfo-
n ylp yr id in e (39). To a solution of 38c (6.8 mg, 0.02 mmol)
in THF (0.4 mL) was added tBuOK (3.4 mg, 0.03 mmol) at room
temperature. The reaction mixture was stirred for 20 min,
quenched by addition of water, and extracted with AcOEt. The
extract was washed with water and brine, dried, and concen-
trated to dryness. Chromatography of the residue with AcOEt
gave 39 (1.9 mg, 28%) as a colorless plate: mp 117-118 °C
(from Et2O-hexane); IR 1659 cm-1; 1H NMR δ 7.92-7.35 (10H,
m), 3.63 (2H, t, J ) 5.9 Hz), 2.63-2.55 (2H, m), 2.20 (3H, t, J
) 2.0 Hz), 1.93-1.83 (2H, m); 13C NMR δ 171.4, 148.4, 141.8,
135.7, 133.0, 131.7, 129.1, 128.6, 128.4, 127.0, 125.0, 46.3, 24.9,
23.5, 20.9; MS m/z 342 (M+, 6.6). Anal. Calcd for C19H19NO3S:
C, 66.84; H, 5.61; N, 4.10. Found: C, 66.72; H, 5.70; N, 4.02.
AcOEt); IR (KBr) 3369, 3200, 22245, 1670 cm-1 1H NMR δ
;
4.25 (2H, t, J ) 2.0 Hz), 2.58 (2H, tt, J ) 2.0, 7.3 Hz), 2.45
(2H, t, J ) 7.3 Hz); 13C NMR (CD3OD) δ 177.3, 84.7, 80.7, 51.2,
35.9, 16.1; FABMS m/z 128 (M+ + 1, 69). Anal. Calcd for C6H9-
NO2: C, 56.68; H, 7.13; N, 11.02. Found: C, 56.36; H, 7.21; N,
10.73.
1,2,3,4-Tetr a h yd r o-6-m eth yl-5-p h en ylsu lfon ylp yr id -2-
on e (48). To a solution of 46 (12.6 mg, 0.05 mmol) in THF
(0.5 mL) was added NaH (60% in oil, 3.0 mg, 0.08 mmol) at
room temperature, and the reaction mixture was stirred for
2.5 h. The reaction was quenched by addition of water and
extracted with AcOEt, which was washed with water and
brine, dried, and concentrated to dryness. Chromatography of
the residue with hexane-AcOEt (1:1) gave 48 (9.9 mg, 79%)
as a colorless needle: IR 3400, 3227, 1707, 1643 cm-1; 1H NMR
δ 7.86-7.52 (5H, m), 7.64 (1H, brs), 2.67 (2H, dt, J ) 1.5, 8.3
Hz), 2.49 (2H, dd, J ) 7.8, 8.3 Hz) 2.36 (3H, s); 13C NMR δ
170.5, 144.1, 142.0, 133.1, 129.3, 126.8, 112.9, 30.0, 22.0, 17.7;
MS m/z 251 (M+, 15). Anal. Calcd for C12H13NO2S: C, 57.35;
H, 5.21; N, 5.57. Found: C, 57.25; H, 5.32; N, 5.49.
t
When this reaction was carried out in BuOH instead of THF,
compound 7 was obtained in 37% yield.
6-(P iva loyloxy)-4-h exyn -1-ol (40). To a solution of 5-(tert-
butyldimethylsiloxy)pent-1-yne (2.51 g, 12.7 mmol) in THF (25
mL) was added nBuLi (1.41 M hexane solution, 10.8 mL, 15.2
mmol) at 0 °C for 30 min. Paraformaldehyde (763 mg, 25.4
mmol) was added to the reaction mixture, which was stirred
at room temperature for 2 h. The reaction was quenched by
addition of water and extracted with AcOEt. The extract was
washed with water and brine, dried, and concentrated. To a
solution of the crude adduct in CH2Cl2 (25 mL) and pyridine
(2.5 mL) were added DMAP (155 mg, 1.27 mmol) and PivCl
(2.35 mL, 19.1 mmol) at 0 °C. The reaction mixture was stirred
for 10 h at room temperature, quenched by addition of water,
and extracted with Et2O. The extract was washed with water
and brine, dried, and concentrated to dryness. The residue was
passed through a short pad of silica gel with hexane-AcOEt
(10:1) to give the crude pivaloyloxy derivative. pTsOH (219
mg, 1.27 mmol) was added to a solution of the crude ester in
MeOH (25 mL) at room temperature and the reaction mixture
was stirred for 1 h. MeOH was evaporated off and the residue
was chromatographed with hexane-AcOEt (4:1) to give 40
N -(t er t -Bu t oxyca r b on yl)-2-(3-h yd r oxyp r op yn -1-yl)-
a n ilin e (51). To a solution of 50 (957 mg, 3.00 mmol), PdCl2-
(Ph3P)2 (21.1 mg, 0.03 mmol), and CuI (11.4 mg, 0.06 mmol)
i
in THF (15 mL) were added Pr2NH (2.0 mL) and propargyl
alcohol (0.26 mL, 4.50 mmol) at room temperature. The
reaction mixture was stirred for 2.5 h, and the resulting solids
were filtered off. The filtrate was concentrated to leave the
residue, which was chromatographed with hexane-AcOEt (4:
1) to give 51 (679 mg, 92%) as a colorless oil: IR 3603, 3408,
1
2230, 1726 cm-1; H NMR δ 8.10 (1H, d, J ) 8.6 Hz), 7.37-
7.29 (2H, m), 7.22 (1H, brs), 6.93(1H, dt, J ) 1.0, 7.6 Hz), 4.56
(2H, d, J ) 4.3 Hz), 2.50 (1H, brs), 1.54 (9H, s);13C NMR δ
152.5, 139.6, 132.1, 129.8, 122.1, 117.7, 110.5, 94.1, 81.04,
80.95, 51.5, 28.3; MS m/z 247 (M+, 22); HRMS calcd for
(2.15 g, 86%) as a colorless oil: IR 3622, 3456, 2235, 1726 cm-1
;
1H NMR δ 4.61 (2H, t, J ) 2.4 Hz), 3.71 (2H, t, J ) 6.4 Hz),
2.32 (2H, tt, J ) 2.4, 6.4 Hz), 1.74 (2H, quint, J ) 6.4 Hz),
1.19 (9H, s); 13C NMR δ 177.9, 86.3, 74.8, 61.4, 52.7, 38.7, 31.0,
27.0, 15.3; MS m/z 198 (M+, 4.4); HRMS calcd for C11H18O3
198.1256, found 198.1255.
C
14H17NO3 247.1208, found 247.1204.
N-(ter t-Bu toxyca r bon yl)-2-(1-p h en ylsu lfon ylp r op -1,2-
d ien -1-yl)a n ilin e (52). According to the procedure described
for the preparation of 4a , 52 (35.1 mg, 47%) was obtained from
51 (49.5 mg, 0.20 mmol). Compound 52 was a colorless
needle: mp 100-101 °C (from Et2O); IR 3425, 1965, 1925, 1724
cm-1; 1H NMR δ 7.95 (1H, d, J ) 8.3 Hz), 7.71-7.68 (2H, m),
7.61 (1H, tt, J ) 1.3, 7.6 Hz), 7.59-7.42 (2H, m), 7.34-7.27
(1H, m), 7.22 (1H, brs), 6.87 (1H, dt, J ) 1.0, 7.6 Hz), 6.71
6-(P iva loyloxy)-4-h exyn oic Acid (42). To a solution of 40
(776 mg, 3.91 mmol) in CH2Cl2 (20 mL) was added Dess-
Martin periodinane (2.16 g, 5.09 mmol) at room temperature.
The reaction mixture was stirred for 20 min, quenched by
addition of aqueous Na2S2O3, and extracted with AcOEt. The
J . Org. Chem, Vol. 69, No. 6, 2004 2135

Mukai et al.
(1H, dd, J ) 1.3, 7.6 Hz), 5.53 (2H, s), 1.51 (9H, s); 13C NMR
δ 208.3, 152.8, 138.5, 137.6, 133.9, 131.5, 130.5, 128.9, 128.4,
122.9, 121.5, 118.7, 111.2, 83.1, 80.5, 28.3; MS m/z 371 (M+,
11). Anal. Calcd for C20H21NO4S: C, 64.67; H, 5.70; N, 3.77.
Found: C, 64.67; H, 5.74; N, 3.64.
1-(ter t-Bu toxyca r bon yl)-2-m eth yl-3-p h en ylsu lfon ylin -
d ole (53). To a solution of 52 (37.1 mg, 0.10 mmol) in THF
(1.0 mL) was added NaH (60% NaH in oil, 6.00 mg, 0.15 mmol)
at room temperature. The reaction mixture was stirred for 4
min, quenched by addition of water, and extracted with AcOEt.
The extract was washed with water and brine, dried, and
concentrated to dryness. Chromatography of the residue with
hexane-AcOEt (10:1) afforded 53 (35.5 mg, 96%) as a colorless
cube: mp 132-133 °C (from hexane-AcOEt); IR 1742 cm-1;1H
NMR δ 8.20-8.16 (1H, m), 8.06-7.96 (3H, m), 7.55-7.27 (5H,
m), 2.98 (3H, s), 1.68 (9H, s); 13C NMR δ 149.5, 143.4, 143.3,
135.1, 132.8, 129.1, 126.3, 125.3, 124.9, 124.2, 120.0, 118.3,
115.2, 85.9, 28.1, 14.3; MS m/z 371 (M+, 15). Anal. Calcd for
2-Meth yl-3-p h en ylsu lfon ylqu in olin e (59). To a solution
of 58 (56.3 mg, 0.15 mmol) in CH2Cl2 (0.6 mL) was added TFA
(0.15 mL) at room temperature. The reaction mixture was
stirred for 30 min, quenched by addition of saturated aqueous
NaHCO3, and extracted with CH2Cl2. The extract was washed
with water and brine, dried, and concentrated. To a solution
of the crude product in MeOH (0.7 mL) was added salcomine
(4.70 mg, 0.01 mmol) at room temperature under an oxygen
atmosphere. The reaction mixture was stirred for 24 h at same
temperature, and MeOH was evaporated off to leave the
residue, which was chromatographed with hexane-AcOEt (4:
1) to give 59 (31.8 mg, 77%) as a colorless needle: mp 145.5-
146.5 °C (from hexane-AcOEt); 1H NMR δ 9.07 (1H, s), 8.07-
7.82 (5H, m), 7.67-7.50 (4H, m), 2.79 (3H, s); 13C NMR δ 155.2,
149.2, 140.3, 139.3, 133.6, 133.5, 132.7, 129.3, 129.0, 128.6,
128.0, 127.4, 125.6, 24.2; MS m/z 283 (M+, 63). Anal. Calcd
for C16H13NO2S: C, 67.82; H, 4.62; N, 4.94. Found: C, 67.66;
H, 4.71; N, 4.77.
C
20H21NO4S: C, 64.67; H, 5.70; N, 3.77. Found: C, 64.34; H,
5.79; N, 3.72.
Ack n ow led gm en t. This work was supported in part
by a Grant-in Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science and
Technology, J apan, to which the authors’ thanks are
due.
2-Meth yl-3-p h en ylsu lfon ylin d ole (54). To a solution of
52 (77.5 mg, 0.21 mmol) in CH2Cl2 (2.0 mL) was added TFA
(0.20 mL) at room temperature. The reaction mixture was
stirred for 30 min, quenched by addition of saturated aqueous
NaHCO3, and extracted with CH2Cl2. The extract was washed
with water and brine, dried, and concentrated to dryness.
Chromatography of the residue with hexane-AcOEt (4:1)
afforded 54 (47.5 mg, 83%) as a colorless needle: mp 174.5-
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 13a ,b, 16a -c, 17a ,b, 25, 34c, 35a , 35b,
35e, 37c, 40, 41, 44, 45 and 51 and characterization data for
compounds 4b, 4c, 7, 8, 10, 13b, 13c, 14a -c, 15a -c, 16a -c,
17a -c, 18a -c, 24, 33a -e, 34a -e, 35a -e, 37b, 37c, 38b, 38c,
41, 44, 45, 46, 47, 49, 56, 57, and 58. This material is available
free of charge via the Internet at http://pubs.acs.org.
176°C (from hexane-AcOEt); IR 3450 cm-1; H NMR δ 8.60
1
(1H, brs), 8.04-7.97 (3H, m), 7.50-7.42 (3H, m), 7.29-7.19
(3H, m), 2.74 (3H, s);13C NMR δ 144.1, 141.1, 134.2, 132.4,
129.0, 126.1, 125.5, 123.2, 122.3, 119.6, 111.8, 110.9, 13.1; MS
m/z 271 (M+, 100). Anal. Calcd for C15H13NO2S‚1/4H2O: C,
65.31; H, 4.93; N, 5.08. Found: C, 65.03; H, 4.81; N, 4.94.
J O035729F
2136 J . Org. Chem., Vol. 69, No. 6, 2004