Bromoallenes as allyl dication equivalents in the presence or absence of palladium(0): Direct construction of bicyclic sulfamides containing five- to eight-membered rings by tandem cyclization of bromoallenes

Article abstract of DOI:10.1002/chem.200601373

A highly regioselective synthesis of bicyclic sulfamides is described. Based on our recent discovery that bromoallenes can act as allyl dication equivalents in the presence of a palladium catalyst and alcohol, we investigated tandem cyclization of bromoal

Full text of DOI:10.1002/chem.200601373

DOI: 10.1002/chem.200601373
Bromoallenes as Allyl Dication Equivalents in the Presence or Absence of
Palladium(0): Direct Construction of Bicyclic Sulfamides Containing Five- to
Eight-membered Rings by Tandem Cyclization of Bromoallenes
Hisao Hamaguchi,[a] Shohei Kosaka,[a] Hiroaki Ohno,*[b] Nobutaka Fujii,[b] and
Tetsuaki Tanaka*[a]
Abstract: A highly regioselective syn-
thesis of bicyclic sulfamides is de-
scribed. Based on our recent discovery
that bromoallenes can act as allyl dicat-
ion equivalents in the presence of a
palladium catalyst and alcohol, we in-
vestigated tandem cyclization of bro-
moallenes bearing a sulfamide group.
It is found that some bromoallenes act
as allyl dication equivalents even in the
absence of a palladium(0) catalyst to
afford cyclosulfamides containing five-
or six-membered rings. While the palla-
dium-free cyclization is dependent on
the substrate structure affording the bi-
cyclic sulfamides through the first cycli-
zation onto the proximal or central
carbon atom of the bromoallenes, the
palladium-catalyzed reaction strongly
promotes the first cyclization onto the
central allenic carbon atom to afford
bicyclic sulfamides containing a seven-
or eight-membered ring. Formation of
two types of bicyclic sulfamides from
single bromoallenes by simply changing
the reaction conditions is also de-
scribed.
Keywords: allenes
· cyclization ·
heterocycles · palladium · tandem
reactions
Introduction
view, some cyclic sulfamides have also been used as effective
chiral auxiliaries in asymmetric aldol reactions,[5] condensing
agents between alcohols and carboxylic acids or amides in
Mitsunobu-like reactions,[6] and useful building blocks
within the field of supramolecular chemistry.[7]
In spite of the evident utility of sulfamides, some existing
routes for their synthesis are not an ideal process. For exam-
ple, typical procedures described in previous work for the
synthesis of cyclosulfamides rely upon the reaction of a di-
Cyclic sulfamides are an extremely important class of com-
pounds, the structural motifs of which exist in many pharma-
ceutically useful compounds. It is well documented that
cyclic sulfamides are general templates suitable for the
design of inhibitors such as HIV[1] and serine protease,[2] and
other biologically useful compounds[3] like conformationally
restricted, nonhydrolyzable peptidomimetics.[4] As well as
their evident importance in the pharmaceutical point of
amine with sulfuryl chloride (SO2Cl2) or sulfamide
(H2NSO2NH2).[8,9] However, those approaches can be limit-
ed by the drastic reaction conditions, the formation of poly-
condensation side products, and the preparation of the di-
[a] Dr. H. Hamaguchi, S. Kosaka, Prof. Dr. T. Tanaka
Graduate School of Pharmaceutical Sciences
Osaka University, 1–6 Yamadaoka, Suita
Osaka 565-0871 (Japan)
A
cluding medium-ring ones, by ring-closing metathesis have
Fax : (+81)6-6879-8214
also been reported.[10,11]
E-mail: t-tanaka@phs.osaka-u.ac.jp
Currently, reactions of bromoallenes are attracting much
interest due to their interesting chemical properties associat-
ed with the cumulated double bonds and bromine substitu-
ent.[12] However, except for our recent study on ring-forming
reactions,[13,14] all the reactions of bromoallenes reported to
date are intermolecular reactions.[15,16,17,18] In our previous
work,[14] we found that bromoallenes A can act as allyl dicat-
ion equivalents B in the presence of palladium(0) and alco-
hol, which are extremely useful for the synthesis of medium-
[b] Dr. H. Ohno, Prof. Dr. N. Fujii
Graduate School of Pharmaceutical Sciences
Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan)
Fax : (+81)75-753-4570
E-mail: hohno@pharm.kyoto-u.ac.jp
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author. The Supporting
Information contains the synthetic procedures and characterization
for 7e, 8d–8e, 9b–i, 19a–c, 21b–c, 24–28, 36, 37, 43, 51, 52, 65, 78, 79,
1
and 81; and H NMR spectra for all new compounds.
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FULL PAPER
sized heterocycles (Scheme 1). Thus, reaction of bromoal-
lene 1 with sodium alkoxide in the presence of a palladi-
um(0) catalyst in alcohol affords h3-allylpalladium(II) inter-
Scheme 1. Palladium(0)-catalyzed medium-ring formation from bromoal-
lenes.
Scheme 3. Synthesis of bromoallenes 9 bearing a sulfamide group. Re-
agents: a) MsCl, Et3N; b) CuBr·SMe2, LiBr; c) 1% HCl/EtOH; d)
BocNHSO2NHR, PPh3, DEAD; e) 3n HCl, EtOAc.
mediate 2 by intramolecular nucleophilic attack at the cen-
tral carbon atom of the allenic moiety. A second nucleophil-
ic reaction with alkoxide provides 3 in good to high yields.
In light of this chemistry, we planned a novel synthesis of bi-
cyclic sulfamides 6 by tandem cyclization of bromoallenes 4
through h3-allylpalladium(II) intermediate 5 (Scheme 2).
lation. Condensation of 8a with BocNHSO2NHBn[22] (Boc=
1,1-dimethylethoxycarbonyl) under the Mitsunobu condi-
tions gave the corresponding N-Boc bromoallene, the Boc
group of which was removed with 3n HCl to afford the de-
sired bromoallene 9a with a benzyl group on the terminal
nitrogen atom. Similarly, bromoallene 9b with a methyl
group on the terminal nitrogen atom and 9c with a phenyl
group were prepared from the bromoallenol 8a by the reac-
tion with BocNHSO2NHMe[22] or BocNHSO2NHPh,[22] re-
spectively. According to this procedure, bromoallenes 9d
and (Æ)-9e were similarly prepared from the corresponding
propargyl alcohols 7d[23] and (Æ)-7e,[24] respectively. Other
bromoallenes with a sulfamide group were synthesized in a
straightforward manner by use of a similar protocol (see the
Supporting Information).
Scheme 2. Synthesis of bicyclic sulfamides.
Herein we describe a highly regioselective construction of
bicyclic sulfamides containing five- to eight-membered rings
by using bromoallenes that have a sulfamide moiety as nu-
cleophile. Particularly notable is that highly reactive bro-
moallenes which form five- or six-membered rings in the
first cyclization require no palladium catalyst, affording bi-
cyclic sulfamides in high yields.[19] Formation of two types of
bicyclic sulfamides from single bromoallenes with a four- or
five-atom tether between the sulfamide and bromoallene by
simply changing the reaction conditions is also described.
Formation of cyclic sulfamides containing
a bicyclo-
AHCTREUNG
lization of the bromoallene 9a in the presence of palladi-
um(0). To realize the desired cyclization, selective addition
of the internal sulfamide nitrogen atom onto the central al-
lenic carbon atom followed by advantageous reaction of the
terminal sulfamide nitrogen over that of alkoxide is essen-
tial. As we expected, cyclization of the bromoallene 9a gave
bicyclic sulfamide 11a (72% yield) as the sole isolable prod-
uct (Scheme 4), presumably through the intermediate 10a.
Surprisingly, the same reaction also proceeded in the ab-
sence of palladium(0) to afford 11a in better yield (81%)
along with a small amount of six-membered ring 12a (9%),
although prolonged reaction time was required. These re-
sults demonstrate that bromoallene 9a can act as allyl dicat-
ion equivalent even in the absence of palladium(0). Howev-
er, it should be clearly noted that, in the medium-ring for-
mation,[14] the palladium catalyst is essential for successful
conversion. For example, treatment of bromoallene 13 with
Results and Discussion
Synthesis of bromoallenes bearing a sulfamide group: To in-
vestigate the synthesis of bicyclic sulfamides by tandem cyc-
lization of bromoallenes as depicted in Scheme 2, bromoal-
lenes 9, bearing a sulfamide moiety as nucleophile, were
prepared from propargyl alcohols 7 as shown in Scheme 3.
Propargyl alcohol 7a[20] was easily obtained from the corre-
sponding monoprotected diol by oxidation and alkynylation.
Treatment of 7a with MsCl and Et3N gave the correspond-
ing mesylate, which was then converted to bromoallenol 8a
by the reaction with CuBr·SMe2/LiBr[21] followed by desily-
in situ-generated NaOMe in the presence of [Pd
C
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H. Ohno, T. Tanaka et al.
of 9a with Cs2CO3 in DMF gave six-membered ring 12a as
a major product, along with the bicyclic sulfamide 11a
(34% yield, entry 2). A similar result was obtained using
NaH in DMF, but a small amount of azetidine 17a (20%
yield) was also obtained in this case (entry 3). The reaction
of 9a with K2CO3 in MeOH at 608C gave the bicyclic sulfa-
mide 11a in 84% yield and monocyclic sulfamide 12a in
9% yield (entry 4), which is a comparable result to that ob-
tained with NaH/MeOH (entry 1). On the other hand, the
reaction of 9a with lithium diisopropylamide (LDA; 2.5 or
5.0 equiv) in THF at low temperature gave the azetidine
17a as the sole product in poor yields (2% and 18% yield,
respectively, entries 6 and 7). Furthermore, we investigated
the reaction of 9a using tetrabutyl ammonium fluoride
(TBAF) in THF to obtain the bicyclic sulfamide 16a in high
yield (92%, entry 8).[25] From these observations, it has been
proven that the bromoallene 9a can effectively act as allyl
dication equivalents under appropriate basic conditions such
as base/MeOH or TBAF/THF even in the absence of palla-
dium(0).
We next investigated the palladium-free tandem cycliza-
tion reaction using various bromoallenes under two reaction
conditions (conditions A: NaH in MeOH at 608C; condi-
tions B: TBAF in THF at 608C). The results of the cycliza-
tion are summarized in Table 2. As we expected, treatment
of the bromoallene 9b, which has a methyl group on the ter-
minal nitrogen atom, gave bicyclic sulfamide 11b as the
major product (65% yield) along with a small amount of
monocyclic six-membered ring 12b (10% yield) under the
conditions A (entry 1). On the other hand, under the condi-
tions B, the bromoallene 9b was converted into the isomer-
ized bicyclic sulfamide 16b (41%) and the six-membered
ring 12b (56%) in lower selectivity (entry 2). Exposure of
the bromoallene 9c, which has an aniline moiety as the
second nucleophile, to conditions A afforded six-membered
ring 12c as a major product (50%, entry 3). This is presuma-
bly due to the highly acidic nature of the aniline proton.
When the bromoallene 9d, which has an unsubstituted
carbon tether, was allowed to react under conditions A, bi-
Scheme 4. Cyclization of bromoallenes in the presence or absence of pal-
ladium(0).
result of the first intramolecular nucleophilic attack on the
central carbon atom of the allene moiety followed by the
second nucleophilic reaction by methoxide. However, treat-
ment of the bromoallene 13 with NaH in MeOH in the ab-
sence of [Pd(PPh3)4] gave the six-membered ring 15 in 46%
A
yield by the SN2’-type intramolecular nucleophilic attack on
the proximal carbon atom of the allene moiety. Thus, the re-
action of bromoallenes as an allyl dication in the absence of
a palladium catalyst can be applied to highly reactive bro-
moallenes that easily form the cyclized products such as
five-membered rings.
Next, we investigated the cyclization of bromoallene 9a
under some other reaction conditions (Table 1). Treatment
Table 1. Palladium-free cyclization of bromoallene 9a under various reaction conditions.[a]
Entry
Base
NaH
2CO3
NaH
Solvent
T
[8C]
t
Yield [%][b]
16a 12a
Recov. [%]
10
[h]
11a
17a
1
2Cs
3
4
5
MeOH
DMF
DMF
MeOH
THF
60
RT
RT
60
16
81
34
25
84
68
9
2.5
56
54
9
2
22
6
20
K2CO3
NaH
RT
10
6
LDA
LDA
TBAF
THF
THF
THF
À78 to RT
À78 to RT
60
4
8
1
267
18
7[c]
8
17
92
[a] 2.5 equivalents of base were used. [b] Yields of isolated products. [c] 5.0 equivalents of a base were used.
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Heterocycles
FULL PAPER
Table 2. Synthesis of bicyclic sulfamide in the absence of palladium(0).[a]
in high yields (98% and 93%,
respectively). Treatment of the
bromoallene 9 f, which has a
quaternary carbon center in the
carbon tether, gave a tricyclic
sulfamide 11 f in 89% yield as
the sole isolable product
(entry 8). Similarly, the bro-
moallenes 9g and 9h were con-
verted into a bicyclic sulfamide
11g (91% yield) and 11h (95%
yield) as a single product (en-
tries 10 and 11). Under the con-
ditions B, the bromoallene 9 f,
which contains a protected diol,
was effectively converted into
the isomerized sulfamide 16 f in
92% yield (entry 9). It is worth
noting that the bromoallene 9i,
with a phenyl substituent on
the three-atom tether between
the allenyl and sulfamide
groups, was converted into tri-
cyclic sulfamide 11i[27] in 17%
and 54% yield by exposure to
the conditions A (entry 12) or
B (entry 13), respectively. This
is in striking contrast to the re-
sults obtained with bromoal-
lenes 19a–c, bearing a saturated
three-atom carbon tether (vide
infra), which exclusively form a
five-membered ring on the first
cyclization.[28] Under the condi-
Entry
Substrate
Conditions[a]
t [h]
Product (Yield [%][b]
)
1
A
12
2
9b
B
1
12b (56)
3
4
5
6
A[c]
B
24
1
9c
9d
12c (98)
12d (93)
A
12
1
B
7
A
10
8
9
A
B
6
1
9 f
10
11
A
A
4.5
2
tions
A (entry 12), 15% of
alkyne 18i was also produced
as a side product.[29]
From these observations, the
conditions A (NaH/MeOH) af-
forded the desired bicyclic sul-
famides 11 in moderate to good
selectivities, while the product
distribution under the condi-
tions B (TBAF/THF) is highly
dependent on the structure of
the starting bromoallenes.
12
13
A
19
9i
B[d]
0.25
11i (54)
[a] Conditions A: NaH (2.5 equiv), MeOH, 608C; Conditions B: TBAF (2.5 equiv), THF, 608C, unless other-
wise noted. [b] Yields of isolated products. [c] Heated to reflux. [d] Reaction occurred at RT.
Next, we investigated the
synthesis of cyclic sulfamide
using bromoallene 19a, which
cyclic sulfamide 11d was isolated (50%) along with six-
membered ring 12d (24%; entry 5). Similarly, under condi-
tions A, bicyclic sulfamide 11e as well as a small amount of
six-membered ring (Æ)-12e and (Æ)-12e’ (entry 7) were ob-
tained by the reaction of the bromoallene (Æ)-9e, which has
a mono-methyl substituent on the carbon atom between the
allenyl and sulfamide groups.[26] In sharp contrast, reaction
of bromoallenes 9c and 9d under the conditions B (entries 4
and 6) afforded six-membered rings 12c and 12d selectively
has a three-atom tether between the sulfamide and bromoal-
lene, under the same reaction conditions. Interestingly, the
first cyclization regioselectively occurred at the allenic
carbon close to the sulfamide group to give 20a (66%) and
21a (18%) (Table 3, entry 1).[30] Treatment of 19a with NaH
in DMF[31c] afforded cyclized products 20–22a in low selec-
tivity (entry 2). Exposure of 19a to tBuOK/THF or pyridine
afforded no cyclized product (entries 3 and 4); however,
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H. Ohno, T. Tanaka et al.
Table 3. Palladium-free cyclization of bromoallene 19a, which has a
three-atom tether between the sulfamide and bromoallene, under various
reaction conditions.[a]
on the terminal nitrogen atom, gave two types of bicyclic
sulfamides (quant.; 20’b/21b=2.5:1).[32,33] It is remarkable
that exposure of the bromoallene 19c, which has an aniline
moiety as the second nucleophile, to the same reaction con-
ditions afforded bicyclic sulfamide 21c as the sole product
in 96% yield, through exclusive 6-endo reaction on the
second cyclization.
Entry
Base
NaH
Solvent
t
Yield [%][b]
The results shown in Table 2and Scheme 6 revealed that
the base-induced cyclization of bromoallenes in the absence
of palladium(0) favors five-membered ring formation on the
[h]
20[c]
20a
21a
22a
1
MeOH
6
66
2
18
9
[d]
2NaH
DMF
2
6
11
first cyclization, except for the phenylallene derivative 9i:
the bromoallenes 9 that have a two-atom tether prefer the
first cyclization onto the central carbon of the allene, while
the bromoallenes 19 with a three-atom tether easily undergo
SN2’-type cyclization on the proximal allenic carbon.
3
4
5
6
tBuOK
pyridine
TBAF
THF
pyridine
THF
THF
2.5
15
3
decomp
decomp
77
18
13
(C4H9)4NOH
2.5
72
[a] Reactions were carried out with a base (2.5 equiv) under reflux.
[b] Yields of isolated products. [c] The reaction was conducted at 608C.
[d] The reaction was conducted at 508C.
Formation of cyclic sulfamides containing
a bicyclo-
AHCTREUNG
quaternary ammonium salts such as TBAF (entry 5)[31b] or
(C4H9)4NOH (entry 6) gave better results affording 20a in
72–77% yields along with 21a (13–18%).
To reveal the intermediate of this tandem cyclization reac-
tion, we investigated stepwise reaction (Scheme 5). Treat-
free cyclization of bromoallenes that have a four-atom
tether between the sulfamide and bromoallene (Table 4).
Treatment of 24, which has a benzyl group on the terminal
nitrogen atom, with NaH in MeOH gave the bicyclic sulfa-
mide 29 with a bicyclo[4.3.0]nonane skeleton in 79% yield
A
(entry 1). This cyclization would proceed through an alkyne
intermediate followed by intramolecular amination of the
triple bond.[34] In the reaction of 25, which has a methyl
group on the terminal nitrogen atom, with NaH and MeOH,
a mixture of double bond regioisomers was obtained in vari-
able ratios. However, we observed exclusive formation of
the isomerized product 30 in 64% yield by washing the di-
luted reaction mixture with 4% HCl (entry 2). Compound
30 was presumably produced by acid-catalyzed isomeriza-
tion of the exomethylene of the cyclized product of the type
29 (entry 1). Bromoallene 26, which has a mono-substituted
carbon tether, afforded 31 in 44% yield (entry 3) along with
Scheme 5. Stepwise reaction of bromoallene 19a.
ment of the bromoallene 19a with NaH in DMF at 08C
gave pyrrolidine 22a in 86% yield. Reaction of 22a under
the reaction conditions shown in entry 1 (Table 3) afforded
the exo-cyclized product 20a (67%) and endo-cyclized prod-
uct 21a (20%) in the essentially same product ratio as the
one-pot reaction. These results strongly suggest that the
alkyne 22 is a plausible intermediate of the tandem cycliza-
tion.[31]
32,[35] which has a bicyclo
[4.4.0]decane skeleton (20% yield),
A
produced by 6-endo cyclization of the alkyne intermediate.
The reaction of 26 with TBAF in THF gave a better com-
bined yield of the bicyclic sulfamides 31 and 32 (90%), but
the exo/endo selectivity on the second cyclization was lower
(entry 4). Similarly, the reaction of 27, which has a tosyla-
mide tether, with TBAF yielded the corresponding bicyclic
sulfamides 33 and 34 with a piperazine skeleton in 41 and
13% yield, respectively.[36] When the bromoallene 28, which
has an unsubstituted carbon tether, was used, bicyclic sulfa-
mide 35 was obtained in 58% yield (entry 6).
Next, we investigated the base-induced tandem cyclization
of bromoallenes 19b and 19c (Scheme 6). As we expected,
the reaction of bromoallene 19b, which has a methyl group
An important limitation of the palladium-free cyclization
is shown in Scheme 7. The reaction of bromoallene 36,
which has a five-atom tether, under the same reaction condi-
tions afforded a complex mixture of unidentified com-
pounds, without isolating the desired cyclosulfamide with a
bicyclo[5.3.0]decane skeleton. However, the palladium-free
T
tandem cyclization of bromoallene 37, which has a phenyl-
ring tether, with TBAF afforded cyclic sulfamides 38 and
39[37] containing a seven-membered ring in 57% yield. From
these results, we found that the palladium-free tandem cycli-
zation of bromoallenes is useful for the synthesis of cyclic
Scheme 6. Base-induced tandem cyclization of bromoallenes 19, with a
three-atom tether between the sulfamide and bromoallene.
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Heterocycles
FULL PAPER
Table 4. Palladium-free tandem cyclization of bromoallenes having a four-atom tether between the sulfamide
and bromoallene.[a]
structure of the starting bro-
moallenes. We then turned our
attention to the palladium-cata-
lyzed reaction, which would fa-
cilitate the cyclization at the
central carbon atom of allenes
forming various cyclic products
including medium-sized rings
Entry
Substrate
Conditions
Product (Yield [%][b]
)
NaH/MeOH
608C, 24 h
1
through
h3-allylpalladium(II)
NaH/MeOH
608C, 20 h
2[c]
intermediate 5, as depicted in
Scheme 2.
First, we investigated the pal-
ladium-catalyzed tandem cycli-
zation reaction of bromoallene
NaH/MeOH
reflux, 30 h
3
4
24, which has
a
four-atom
(Æ)-26
TBAF/THF
reflux, 3 h
31 (49), 32 (41)
tether between the sulfamide
and bromoallene (Scheme 8).
As we expected, treatment of
the bromoallene 24 with NaH
in MeOH in the presence of
palladium(0) gave a bicyclic sul-
TBAF/THF
RT, 8 h
5
6
famide 41, which contains
a
TBAF/THF
608C, 0.5 h
seven-membered ring in 57%
yield, along with 12% of mono-
cyclized product 42 (Scheme 8).
The h3-allylpalladium inter-
mediate 40 is considered as a
[a] All reactions were carried out with NaH/MeOH or TBAF/THF. [b] Yields of isolated products. [c] The re-
action mixture was treated with 4% HCl before purification.
Scheme 8. Reaction of bromoallene 24 that has a four-atom tether be-
tween the sulfamide and bromoallene in the presence of palladium(0).
Scheme 7. Palladium-free tandem cyclization of bromoallenes with a five-
atom tether between the sulfamide and bromoallene.
plausible intermediate, which can be generated by intramo-
lecular amination of the bromoallene moiety at the central
carbon atom. Compared with the palladium-free reaction
(Table 4, entry 1), it was proven that the palladium catalyst
dramatically changes the cyclization mode, and two types of
bicyclic sulfamides 29 and 41 can be selectively obtained
from the single bromoallene 24 by simply changing the reac-
tion conditions.
Then, we investigated the palladium-catalyzed cyclization
of the same bromoallenes shown in Table 4. The results are
summarized in Table 5. As we expected, treatment of bro-
moallene 25 with NaH/MeOH in the presence of [Pd-
sulfamide containing five- to seven-membered rings, al-
though the seven-membered-ring formation requires confor-
mationally favorable bromoallenes such as 37.
Palladium-catalyzed tandem cyclization of bromoallenes:
Although the above-mentioned palladium-free reactions are
extremely useful in that bromoallenes can act as allylic di-
cation equivalents even in the absence of a palladium cata-
lyst, this cyclization is limited to the highly reactive bro-
moallenes, which easily form cyclized products, and the
product distribution and selectivity are dependent on the
AHCTREUNG
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H. Ohno, T. Tanaka et al.
Table 5. Cyclization of bromoallenes in the presence of a palladium cata- Table 6. Cyclization of bromoallenes in the presence of a palladium catalyst.[a]
lyst.[a]
Entry Substrate
t [h] Product (Yield [%][b]
)
Entry Substrate
Conditions
Product
Yield[b]
608C, 4 h
then 4%
HCl
50[c]
1
1.5
1
25
2
(Æ)-26
(Æ)-26
27
558C, 2h
78
2[c]
3
6
3[d]
558C, 2.5 h
45
70
608C, 2h
then 4%
HCl
4
48[e]
3[c]
5
6
608C, 1 h
608C, 1 h
74
4
4
complex mixture
28
28[f]
[a] All reactions were carried out with [Pd(PPh3)4] (10 mol%), NaH (2.5 equiv)
N
in MeOH at 608C. [b] Yields of isolated products. [c] The reaction mixture was
treated with 4% HCl before purification.
[a] Unless otherwise noted, reactions were carried out with [Pd(PPh3)4]
G
(10 mol%), NaH (2.5 equiv) in MeOH. [b] Yields of isolated products.
[c] 18% of 49 was also obtained. [d] The reaction was carried out with
(entry 2).[39] Furthermore, the bromoallene 36 effectively
yielded bicyclic sulfamides 56 and 57, containing an eight-
membered ring, although the acid treatment caused incom-
plete isomerization to 57 in this case (56:57=1:4, entry 3).
In contrast, the reaction of bromoallene 52, lacking a mono-
methyl group, resulted in formation of a complex mixture in
which the desired bicyclic compound was not isolated
(entry 4). This result shows a limitation of the palladium-cat-
alyzed tandem cyclization in eight-membered-ring forma-
tion: an appropriate substituent on the carbon tether be-
tween the bromoallene and the sulfamide group is required
for effective cyclization.[40] However, the palladium catalyst
completely controls the regioselectivity on the first cycliza-
tion onto the central carbon of the bromoallenes, which is in
striking contrast to the base-induced tandem cyclization
without a palladium catalyst favoring a five- or six-mem-
bered ring formation.
[Pd(PPh3)4] (5 mol%) at 558C. [e] 4% of 50 was also obtained. [f] Con-
N
siderable amount of other unidentified products was also obtained.
26–28 and 43 yielded bicyclic sulfamides 45–48 each contain-
ing a seven-membered ring. When the reaction was conduct-
ed with 5 mol% of [Pd
(70%) of the desired bicyclic sulfamide 45 was obtained.[38]
We could not isolate the bicyclo[4.3.0] rings from the reac-
A
AHCTREUNG
tion mixture, which can be formed by the uncatalyzed reac-
tion under the same reaction conditions (Table 4). However,
formation of a small amount of such six-membered rings
cannot be ruled out. These results revealed that the palladi-
um catalyst strongly promotes the first cyclization at the
central carbon atom of the bromoallenes leading to bicyclic
sulfamides having a seven-membered ring.
Next, the palladium-catalyzed cyclization of the bromoal-
lenes that have a five-atom tether between the sulfamide
and bromoallene was investigated. The results are summar-
ized in Table 6. As we expected, the reaction of bromoallene
37, which has a phenyl substituent on the carbon atom be-
tween the bromoallene and the sulfamide group, in the pres-
ence of Pd0 gave tricyclic sulfamides 53 and 54 (53:54=
12:1), containing an eight-membered ring in moderate yield
(57%) (entry 1). Under the same conditions, bromoallene
51, bearing a mono-methyl substituent and a tosylamide on
the five-atom tether between the bromoallene and sulfamide
group, afforded the isomerized product 55 in 58% yield by
washing the diluted reaction mixture with 4% HCl
Mechanism of the cyclization: Possible reaction courses of
the palladium-free cyclization are shown in Scheme 9. In the
reaction of bromoallenes that have a two-atom tether be-
tween the sulfamide and bromoallene (n=1) without a pal-
ladium catalyst, the first intramolecular nucleophilic attack
takes place at the central carbon of bromoallene 59 and is
followed by protonation by MeOH to produce intermediate
60 bearing a bromomethyl group. The second intramolecular
nucleophilic addition affords the bicyclic sulfamide 61. This
reaction pathway through the intermediate 60 is supported
by the experimental results shown in Table 7: NaH-mediated
cyclization of the bromoallene 65, which has a tosylamide
group, in MeOH at lower reaction temperature (entry 1)
yielded dihydropyrrole 66 (8%), which has a bromomethyl
group, with a considerable amount of the starting bromoal-
1698
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1692– 1708

Heterocycles
FULL PAPER
Scheme 10. Possible reaction courses of the palladium-catalyzed tandem
cyclization.
Scheme 9. Possible reaction courses of the palladium-free cyclization.
Table 7. Palladium-free reaction of bromoallene 65.[a]
Entry
T [8C]
t [h]
Product
Yield [%][b]
1
260
RT
7
2
660
67
8[c]
94
[a] Reactions were carried out with NaH (1.5 equiv) in MeOH. [b] Yields
of isolated products. [c] 71% of 65 was recovered.
Scheme 11. Formation of macrocyclic sulfamide 75 through tandem cycli-
zation and subsequent ring-expansion.
lene 65 (71%). In contrast, the same reaction at higher tem-
perature (entry 2) gave the methoxymethyl derivative 67 in
94% yield, which was produced by the nucleophilic substitu-
tion of 66 with methoxide.[41]
In the palladium-free tandem cyclization of bromoallenes
that have a three- or four-atom tether between the sulfa-
mide and bromoallene (n=2or 3), the first S N2’-type intra-
molecular nucleophilic attack of the internal nitrogen at the
proximal carbon of bromoallene 62 affords the alkyne inter-
mediate 63 and is followed by intramolecular amination of
the triple bond to give bicyclic sulfamide 64.[31,34]
This reaction would proceed through acid-catalyzed hydroly-
sis of the relatively unstable tricyclic cyclosulfamide 53
(compare with entry 1, Table 6). This reaction clearly dem-
onstrates the scope of the presented tandem cyclization as a
potential tool for the synthesis of macrocyclic cyclosulfa-
mides.
Conclusion
A possible reaction course for the palladium-catalyzed
cyclization of bromoallenes is shown in Scheme 10. Oxida-
tive addition of bromoallene 68 to Pd0 gives h1-allenylpalla-
dium complex 69, which is in a state of equilibrium with h3-
propargylpalladium complex 70.[42] The first intramolecular
nucleophilic addition occurs to the central carbon atom of
h3-propargylpalladium complex 70 to produce palladacyclo-
butene 71.[43] This is followed by protonation by MeOH to
generate h3-allylpalladium complex 72. In many cases, the
second intramolecular nucleophilic addition by the terminal
nitrogen predominates over that by methoxide to afford the
bicyclic sulfamide 73 as the major product, along with a
small amount of mono-cyclized product 74.
In conclusion, we have developed a novel cyclization of bro-
moallenes that have a sulfamide moiety as nucleophiles,
leading to bicyclic sulfamides depending on the substrate
structure and reaction conditions. Highly reactive bromoal-
lenes act as allyl dication equivalents even in the absence of
a palladium(0) catalyst to afford cyclosulfamides containing
five- or six-membered rings. On the other hand, the palladi-
um-catalyzed cyclization can be applied to a wide variety of
bromoallenes and proceeds in
a highly regioselective
manner, to give bicyclic sulfamides containing a seven- or
eight-membered ring. These two reactions of bromoallenes
are extremely useful for the synthesis of bicyclic sulfamides
and would extend the pharmacological and chemical poten-
tiality of these compounds.
It is worth noting that eleven-membered cyclosulfamide
75 as well as 54 were obtained in 41% yield when the bro-
moallene 37 was treated with NaH and [Pd
A
MeOH followed by treatment with 4% HCl (Scheme 11).
Chem. Eur. J. 2007, 13, 1692– 1708
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1699

H. Ohno, T. Tanaka et al.
(C=C=C), 1323 cmÀ1 (NHSO2); elemental analysis calcd (%) for
C14H19BrN2O2S: C 46.80, H 5.33, N 7.80; found: C 46.71, H 5.21, N 7.76.
Experimental Section
General procedure for the tandem cyclization of bromoallenes in the ab-
sence of palladium—synthesis of 2-benzyl-5,5-dimethyl-2,3,5,6-tetrahy-
dro-1-thia-2,6a-diaza-pentalene-1,1-dioxide (11a) and (Æ)-2-benzyl-3-
General methods: Melting points are uncorrected. Nominal (LRMS) and
exact mass (HRMS) spectra were recorded on a JEOL JMS-01SG-2or
JMS-HX/HX 110 A mass spectrometer. 1H NMR spectra were recorded
in CDCl3. Chemical shifts are reported in parts per million downfield
from internal Me4Si (s=singlet, d=doublet, dd=double of doublets,
ddd=doublet of doublets of doublets, t=triplet, q=quartet, m=multip-
let). Optical rotations were measured in CHCl3 with a JASCO DIP-360
digital polarimeter. For flash chromatography, silica gel 60 H (silica gel
for thin-layer chromatography, Merck) or silica gel 60 (finer than 230
mesh, Merck) was employed.
ethynyl-4,4-dimethyl-1,2,6-thiadiazinane-1,1-dioxide
(12a)
(Table 1,
entry 1): NaH (60% suspension in mineral oil; 12mg, 0.3 mmol) was
added to MeOH (0.5 mL) at room temperature under nitrogen, and the
mixture was stirred for 10 min at this temperature. A solution of the bro-
moallene 9a (43.1 mg, 0.12mmol) in MeOH (0.7 mL) was added to the
stirred mixture at room temperature, and the resulting mixture was stir-
red for 16 h at 608C. Concentration under reduced pressure gave an oily
residue, which was purified by column chromatography over silica gel
with n-hexane/EtOAc (3:1) to give, in order of elution, 11a (27 mg, 81%
yield) and 12a (3.5 mg, 9% yield).
Compound 11a: Colorless solid; m.p. 488C; 1H NMR (300 MHz,
CDCl3): d=1.21 (s, 6H; 2”CMe), 3.32 (s, 2H; CH2), 3.73 (d, J=1.5 Hz,
2H; CH2), 4.32(s, 2H; C H2Ph), 4.79 (t, J=1.5 Hz, 1H; C=CH), 7.30–
7.37 ppm (m, 5H; Ph); 13C NMR (67.8 MHz, CDCl3): d=27.5 (2C), 46.1,
1-Bromo-5-hydroxy-4,4-dimethylpenta-1,2-diene (8a): Methanesulfonyl
chloride (2.2 mL, 28 mmol) was added to a stirred mixture of the propar-
gylic alcohol 7a (4.85 g, 20 mmol) and Et3N (4.5 mL, 36 mmol) in CH2Cl2
(50 mL) at 08C under nitrogen, and the resulting mixture was stirred for
15 min at this temperature. The mixture was made acidic with 4% HCl,
and the whole was extracted with Et2O. The extract was washed with
water, saturated NaHCO3, water, and brine, and dried over MgSO4.
Usual workup followed by rapid filtration through a short pad of SiO2
with Et2O gave a crude mesylate, which was used without further purifi-
48.4, 51.6, 59.2, 111.6, 128.1, 128.4 (2C), 128.7 (2C), 134.7, 136.3 ppm; IR
À1
À
(KBr): n˜ =1682(C =C N), 1317 cm (NSO2); MS (FAB): m/z (%): 279
(89) [M++H], 91 (100); HRMS (FAB): calcd for C14H19N2O2S [M++H]:
cation.
A mixture of CuBr·DMS (8.2g, 40 mmol) and LiBr (3.5 g,
279.1167; found: 279.1169.
40 mmol) were dissolved in THF (30 mL) at room temperature under ni-
trogen. After stirring for 2min, a solution of the above crude mesylate in
THF (20 mL) was added to this reagent at room temperature. The mix-
ture was stirred for 19 h at this temperature and 3 h at 508C, and
quenched with saturated NH4Cl and 28% NH4OH. The whole was ex-
tracted with Et2O. The extract was washed with water and brine, and
dried over MgSO4. The filtrate was concentrated under reduced pressure
to give an oily residue, which was purified by column chromatography
over silica gel with n-hexane/EtOAc (8:1) to give the protected bromoal-
lene as an oil. This oil was dissolved in a solution of 1% HCl in ethanol
(35 mL), which was prepared from conc. HCl and EtOH, and the result-
ing mixture was stirred for 12h at room temperature. Water was added
to the mixture, and the whole was extracted with EtOAc. The extract
was washed with brine and dried over MgSO4. The filtrate was concen-
trated under reduced pressure to give an oily residue, which was purified
by column chromatography over silica gel with n-hexane/EtOAc (3:1) to
Compound 12a: Colorless crystals; m.p. 1188C (n-hexane/EtOAc);
1H NMR (300 MHz, CDCl3): d=1.05 (s, 3H; CMe), 1.08 (s, 3H; CMe),
2.56 (d, J=2.4 Hz, 1H; C CH), 2.94 (ddd, J=14.4, 5.4, 1.8 Hz, 1H;
CHH), 3.56 (dd, J=2.4, 1.8 Hz, 1H; 3-H), 3.64 (dd, J=14.4, 10.8 Hz, 1H;
CHH), 4.09 (d, J=14.1 Hz, 1H; PhCHH), 4.70–4.76 (m, 1H; NH), 4.78
(d, J=14.1 Hz, 1H; PhCHH), 7.28–7.39 ppm (m, 5H; Ph); 13C NMR
(75 MHz, CDCl3): d=23.16, 23.22, 33.7, 49.4, 52.4, 59.5, 77.0, 77.1, 127.9,
ꢀ
128.6 (2C), 128.9 (2C), 135.2 ppm; IR (KBr): n˜ =3284 (NHSO2), 2114
À1
ꢀ
(C C), 1336 cm (NSO2); elemental analysis calcd (%) for C14H18N2O2S:
C 60.40, H 6.52, N 10.06; found: C 60.19, H 6.52, N 10.00.
2-Ethynyl-4,4-dimethyl-1-(4-methylphenylsulfonyl)piperidine (15): NaH
(60% suspension of mineral oil; 12mg, 0.3 mmol) was added to MeOH
(1 mL) at room temperature under nitrogen, and the mixture was stirred
for 20 min at this temperature.
A solution of the bromoallene 13
(74.5 mg, 0.20 mmol) in MeOH (1 mL) was added to the stirred mixture
at room temperature, and the resulting mixture was stirred for 25 h at
508C. Concentration under reduced pressure gave an oily residue, which
was purified by column chromatography over silica gel with n-hexane/
EtOAc (6:1) to give 15 (26.8 mg, 46% yield) as colorless crystals. Consid-
erable amount of bromoallene 13 (39.0 mg, 52%) was also recovered.
Compound 15: Colorless solid; m.p. 111–1128C; 1H NMR (300 MHz,
CDCl3): d=0.92(s, 3H; CMe), 1.12(s, 3H; CMe), 1.39–1.44 (m, 1H;
CHH), 1.51 (dd, J=12.8, 6.0 Hz, 1H; CHH), 1.63 (dt, J=13.5, 2.0 Hz,
1H; CHH), 1.73 (dd, J=12.8, 6.0 Hz, 1H; CHH), 1.75 (d, J=2.4 Hz, 1H;
1
give 8a (2.6 g, 68% yield) as a colorless oil: H NMR (300 MHz, CDCl3):
d=1.086 (s, 3H; CMe), 1.091 (s, 3H; CMe), 1.58 (brs, 1H; OH), 3.41 (d,
J=10.8 Hz, 1H; 5-CHH), 3.46 (d, J=10.8 Hz, 1H; 5-CHH), 5.37 (d, J=
5.7 Hz, 1H; 3-H), 6.04 ppm (d, J=5.7 Hz, 1H; 1-H); 13C NMR (75 MHz,
CDCl3): d=24.06, 24.11, 38.0, 71.4, 73.8, 107.8, 200.9 ppm; IR (KBr): n˜ =
3344 (OH), 1954 cmÀ1 (C=C=C); MS (FAB): m/z (%): 193 (15) [M++H,
81Br], 191 (10) [M++H, 79Br], 111 (100); HRMS (FAB): calcd for
C7H11BrNaO [M++Na, 79Br]: 212.9891; found: 212.9910.
N-Benzyl-N’-(5-bromo-2,2-dimethylpenta-3,4-dienyl)sulfamide (9a):
A
solution of the bromoallene 8a (382mg, 2.0 mmol) in THF (5 mL) and
diethyl azodicarboxylate (1.57 g, 3.6 mmol; 40% in toluene solution)
were added to a stirred solution of PPh3 (944 mg, 3.6 mmol) and BocNH-
SO2NHBn (1.03 g, 3.6 mmol) in THF (12mL) under nitrogen at 0 8C, and
the resulting mixture was heated under reflux for 1.5 h. Concentration
under reduced pressure gave an oily residue, which was purified by short
column chromatography over silica gel with n-hexane/EtOAc (4:1) to
give the N-Boc derivative as an oil. HCl (3n; 6 mL) was added to a stir-
red solution of this bromoallene in EtOAc (10 mL) at room temperature.
After stirring for 3 h at 608C, the mixture was made basic with 28%
NH4OH. The whole was extracted with EtOAc. The extract was washed
with water and brine, and dried over MgSO4. The filtrate was concentrat-
ed under reduced pressure to give an oily residue, which was purified by
column chromatography over silica gel with n-hexane/EtOAc (3:1) to
give 9a (540 mg, 75% yield) as colorless crystals. M.p. 768C (n-hexane/
Et2O); 1H NMR (300 MHz, CDCl3): d=1.08 (s, 6H; 2”CMe), 2.88 (d,
J=6.9 Hz, 2H; 1-CH2), 4.20 (t, J=6.9 Hz, 1H; NH), 4.23 (d, J=6.0 Hz,
2H; CH2Ph), 4.56 (t, J=6.0 Hz, 1H; NH), 5.20 (d, J=5.7 Hz, 1H; 3-H),
6.04 (d, J=5.7 Hz, 1H; 5-H), 7.31–7.40 ppm (m, 5H; Ph); 13C NMR
(75 MHz, CDCl3): d=25.3, 25.4, 36.1, 47.3, 52.9, 74.4, 107.5, 128.07 (2C),
128.11, 128.9 (2C), 136.6, 200.8 ppm; IR (KBr): n˜ =3300 (NHSO2), 1955
ꢀ
C CH), 2.42 (s, 3H; CMe), 2.99 (dt, J=13.5, 2.0 Hz, 1H; 6-CHH), 3.60–
3.66 (m, 1H; 6-CHH), 4.86–4.90 (m, 1H; 2-H), 7.27 (d, J=8.0 Hz, 2H;
Ph), 7.73 ppm (d, J=8.0 Hz, 2H; Ph); 13C NMR (75 MHz, CDCl3): d=
21.5, 25.4, 29.0, 33.3, 38.3, 38.9, 42.3, 43.7, 74.3, 81.1, 128.0 (2C), 129.1
ꢀ
(2C), 135.7, 143.2 ppm; IR (KBr): n˜ =3267 (NHSO2), 2114 (C C),
1346 cmÀ1 (NHSO2); MS (FAB): m/z (%): 292 (100) [M++H]; HRMS
(FAB): calcd for C16H22NO2S [M++H]: 292.1371; found: 292.1375.
2-Benzyl-5,5-dimethyl-2,4,5,6-tetrahydro-1H-pyrrolo
[1,2-b]-
AHCTREUNG
0.50 mmol; 1.0m solution in THF) was added to a stirred solution of bro-
moallene 9a (71.9 mg, 0.20 mmol) in THF (2 mL) at room temperature,
and the resulting mixture was stirred for 1 h at 608C. Concentration
under reduced pressure gave an oily residue, which was purified by
column chromatography over silica gel with n-hexane/EtOAc (3:1) to
give 16a (51.1 mg, 92% yield) as a colorless oil: 1H NMR (300 MHz,
CDCl3): d=1.19 (S, 6H; CMe2), 2.26 (d, J=1.5 Hz, 2H; CH2), 3.26 (s,
2H; CH2N), 4.46 (s, 2H; CH2Ph), 5.56 (t, J=1.5 Hz, 1H; C=CH), 7.31–
À1
À
7.38 ppm (m, 5H; Ph); IR (KBr): n˜ =1679 (C=C N), 1321 cm (NSO2);
MS (FAB): m/z (%): 279 (47) [M++H], 322 (100); HRMS (FAB): calcd
for C14H19N2O2S [M++H]: 279.1167; found: 279.1168.
1700
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1692– 1708

Heterocycles
FULL PAPER
N-Benzyl-2-ethynyl-3,3-dimethylazetidine-1-sulfonamide (17a) (Table 1,
entry 3): Bromoallene 9a (71.9 mg, 0.200 mmol) was added to a stirred
suspension of NaH (60% suspension of mineral oil; 20.0 mg,
0.500 mmol) in DMF (1.0 mL) at 08C under nitrogen, and the resulting
mixture was stirred for 1 h at room temperature. Concentration under re-
duced pressure gave an oily residue, which was purified by column chro-
matography over silica gel with n-hexane/EtOAc (4:1) to give, in order
of elution, 11a (13.9 mg, 25% yield), 17a (11.2mg, 20% yield), and 12a
(30.1 mg, 54% yield).
Compound 12c: Colorless crystals; m.p. 1538C (n-hexane/Et2O);
1H NMR (300 MHz, CDCl3): d=1.19 (s, 3H; CMe), 1.30 (s, 3H; CMe),
ꢀ
2.27 (d, J=2.7 Hz, 1H; C CH), 3.28 (dd, J=15.0, 6.3 Hz, 1H; 5-CHH),
3.46 (dd, J=15.0, 9.9 Hz, 1H; 5-CHH), 4.45 (d, J=2.7 Hz, 1H; 3-H), 4.67
(dd, J=9.9, 6.3 Hz, 1H; NH), 7.32–7.46 ppm (m, 5H; Ph); 13C NMR
(75 MHz, CDCl3): d=19.9, 23.8, 34.8, 54.4, 64.1, 77.0, 77.6, 128.4, 128.90
ꢀ
(2C), 128.94 (2C), 139.3 ppm; IR (KBr): n˜ =3275 (NHSO2), 2123 (C C),
1338 cmÀ1 (NHSO2); elemental analysis calcd (%) for C13H16N2O2S: C
59.07, H 6.10, N 10.60; found: C 58.93, H 6.00, N 10.63.
Compound 17a: Colorless needles; m.p. 81–828C (n-hexane/EtOAc);
1H NMR (300 MHz, CDCl3): d=1.21 (s, 3H; CMe), 1.38 (s, 3H; CMe),
2-Benzyl-2,3,5,6-tetrahydro-1H-pyrrolo
A
G
ide (11d) and 2-benzyl-3-ethynyl-1,2,6-thiadiazinane-1,1-dioxide (12d)
(Table 2, entry 5): By using the procedure described for the preparation
of the bicyclic sulfamide 11a and six-membered ring 12a from bromoal-
lene 9a, the bromoallene 9d (66.2mg, 0.2mmol) was converted into 11d
(25 mg, 50% yield) and 12d (12mg, 24% yield).
ꢀ
2.57 (d, J=2.4 Hz, 1H; C CH), 3.29 (d, J=6.9 Hz, 1H; CHH), 3.64 (d,
J=6.9 Hz, 1H; CHH), 4.29 (d, J=6.0 Hz, 2H; CH2Ph), 4.41 (d, J=
2.4 Hz, 1H; 2-H), 4.53 ppm (t, J=6.0 Hz, 1H; NH); 13C NMR (75 MHz,
CDCl3): d=23.7, 26.1, 34.5, 47.6, 60.2, 60.8, 76.1, 79.2, 128.0, 128.1 (2C),
ꢀ
Compound 11d: Colorless solid; m.p. 87–898C; 1H NMR (300 MHz,
CDCl3): d=2.81–2.90 (m, 2H; CH2), 3.63 (t, J=8.7 Hz, 2H; CH2), 3.73–
3.76 (m, 2H; CH2), 4.33 (s, 2H; CH2Ph), 4.90 (tt, J=2.4, 2.4 Hz, 1H; C=
CH), 7.28–7.41 ppm (m, 5H; Ph); 13C NMR (75 MHz, CDCl3): d=33.3,
128.7 (2C), 136.6 ppm; IR (KBr): n˜ =3286 (NHSO2), 2360 (C C),
1333 cmÀ1 (NHSO2); MS (FAB): m/z (%): 279 (100) [M++H]; HRMS
(FAB): calcd for C14H19N2O2S [M++H]: 279.1167; found: 279.1159.
2,5,5-Trimethyl-2,3,5,6-tetrahydro-1H-pyrrolo
A
N
1,1-dione (11b) and 3-ethynyl-2,4,4-trimethyl-1,2,6-thiadiazinane-1,1-di-
oxide (Table 2, entry 1) (12b): By using the procedure described for the
preparation of the bicyclic sulfamide 11a and six-membered ring 12a
from bromoallene 9a, the bromoallene 9b (53.0 mg, 0.187 mmol) was
converted into 11b (25 mg, 65% yield) and 12b (4.0 mg, 10% yield).
Compound 11b: Colorless oil; 1H NMR (300 MHz, CDCl3): d=1.22 (s,
6H; 2”CMe), 2.84 (s, 3H; NMe), 3.30 (s, 2H; NCH 2), 3.88 (d, J=1.8 Hz,
2H; NCH2), 4.84 ppm (t, J=1.8 Hz, 1H; C=CH); 13C NMR (75 MHz,
45.9, 46.5, 51.6, 100.8, 128.2, 128.5 (2C), 128.8 (2C), 134.8, 138.9 ppm; IR
À1
À
(KBr): n˜ =1684 (C=C N), 1308 cm (NSO2); MS (FAB): m/z (%): 251
(51) [M++H], 136 (100); HRMS (FAB): calcd for C12H15N2O2 [M++H]:
251.0854; found: 251.0826.
1
Compound 12d: Colorless oil; H NMR (300 MHz, CDCl3): d=1.83–2.01
ꢀ
(m, 2H; 4-CH2), 2.52 (d, J=2.4 Hz, 1H; C CH), 3.39–3.49 (m, 1H; 5-
CHH), 3.79–3.92(m 1H; 5-CH H), 4.11 (d, J=14.1 Hz, 1H; PhCHH),
4.15–4.19 (m, 1H; 3-H), 4.52(dd, J=9.9, 5.1 Hz, 1H; NH), 4.74 (d, J=
14.1 Hz, 1H; PhCHH), 7.28–7.42 ppm (m, 5H; Ph); 13C NMR (75 MHz,
CDCl3): d=27.5 (2C), 34.5, 48.3, 48.9, 59.2, 111.5, 136.4 ppm; IR (KBr):
À1
À
n˜ =1680 (C=C N), 1319 cm (NHSO2); MS (FAB): m/z (%): 203 (100)
CDCl3): d=30.6, 42.2, 49.5, 49.6, 75.3, 78.8, 128.0, 128.6 (2C), 129.0 (2C),
[M++H]; HRMS (FAB): calcd for C8H15N2O2S [M++H]: 203.0854;
ꢀ
À1
135.2ppm; IR (KBr): n˜ =3278 (NHSO2), 2114 (C C), 1321 cm (NSO2);
MS (FAB): m/z (%): 251 (100) [M++H]; HRMS (FAB): calcd for
C12H15N2O2S [M++H]: 251.0854; found: 251.0859.
found: 203.0856.
Compound 12b: Colorless solid; m.p. 144–1458C (n-hexane/EtOAc);
1H NMR (300 MHz, CDCl3): d=1.10 (s, 3H; CMe), 1.20 (s, 3H; CMe),
(Æ)-2-Benzyl-5-methyl-2,3,5,6-tetrahydro-1H-pyrrolo
N
ꢀ
2.52 (d, J=2.4 Hz, 1H; C CH), 2.89 (s, 3H; NMe), 3.14 (dd, J=14.4,
A
6.0 Hz, 1H; CHH), 3.31 (dd. J=14.4, 6.0 Hz, 1H; CHH), 3.83 (d, J=
2.4 Hz, 1H; 3-H), 4.43 ppm (t, J=6.0 Hz, 1H; NH); 13C NMR (75 MHz,
4-methyl-1,2,6-thiadiazinane-1,1-dioxide (12e) and its (Æ)-(3R*,4S*)-
isomer (12e’) (Table 2, entry 7): By using the procedure described for the
preparation of the bicyclic sulfamide 11a and six-membered ring 12a
from bromoallene 9a, the bromoallene 9e (69 mg, 0.2mmol) was con-
verted into 11e (30 mg, 57% yield), 12e (5 mg, 9% yield) and 12e’
(2.5 mg, 5% yield).
CDCl3): d=20.0, 24.0, 34.1, 34.4, 54.2, 63.4, 76.6, 77.0 ppm; IR (KBr): n˜ =
À1
2119 (C C), 1332cm (NSO2); MS (FAB): m/z (%): 203 (35) [M++H],
ꢀ
154 (100); HRMS (FAB): calcd for C8H15N2O2S [M++H]: 203.0854;
found: 203.0861; elemental analysis calcd (%) for C8H14N2O2S: C 47.50,
H 6.98, N 13.85; found: C 47.27, H 6.79, N 13.55.
Compound 11e: Colorless oil; 1H NMR (500 MHz, CDCl3): d=1.17 (d,
J=6.5 Hz, 3H; CMe), 3.18 (dd, J=9.5, 8.0 Hz, 1H; CHH), 3.28–3.36 (m,
1H; 5-H), 3.70–3.78 (m, 3H; CHH and CH2), 4.29 (d, J=14.0 Hz, 1H;
PhCHH), 4.36 (d, J=14.0 Hz, 1H; PhCHH), 4.85–4.86 (m, 1H; 4-H),
7.30–7.40 ppm (m, 5H; Ph); 13C NMR (75 MHz, CDCl3): d=19.6, 41.6,
2,5,5-Trimethyl-2,4,5,6-tetrahydro-1H-pyrrolo
N
N
1,1-dione (16b) (Table 2, entry 2): By using the procedure described for
the preparation of the bicyclic sulfamide 16a from 9a, the bromoallene
9b (42mg, 0.15 mmol) was converted into 16b (12.5 mg, 41% yield) and
12b (16.9 mg, 56% yield).
Compound 16b: Colorless oil; 1H NMR (300 MHz, CDCl3): d=1.20 (s,
6H; CMe2), 2.31 (d, J=1.5 Hz, 2H; CH2), 3.00 (s, 3H; NMe), 3.23 (s,
46.0, 51.6, 53.5, 106.9, 128.2, 128.5 (2C), 128.8 (2C), 134.8, 137.9 ppm; IR
À1
À
(KBr): n˜ =1682(C =C N), 1315 cm (NSO2); MS (FAB): m/z (%): 287
(100) [M++Na]; HRMS (FAB): calcd for C13H16N2NaO2S [M++Na]:
287.0830; found: 287.0836.
Compound 12e: Colorless oil; 1H NMR (300 MHz, CDCl3): d=1.05 (d,
J=6.6 Hz, 3H; CMe), 1.92–2.04 (m, 1H; 4-H), 2.52 (d, J=2.4 Hz, 1H;
2H; CH2N), 5.63 ppm (t, J=1.5 Hz, 1H; C=CH); IR (KBr): n˜ =1651 (C=
À1
C N), 1321 cm (NHSO2); MS (FAB): m/z (%): 203 (35) [M++H], 69
À
(100); HRMS (FAB): calcd for C8H15N2O2S [M++H]: 203.0854; found:
203.0856.
ꢀ
C CH), 3.20 (ddd, J=14.4, 7.2, 7.2 Hz, 1H; 5-CHH), 3.69 (ddd, J=14.4,
8.1, 3.9 Hz, 1H; 5-CHH), 4.01 (dd, J=6.9, 2.4 Hz, 1H; 3-H), 4.27 (d, J=
14.4 Hz, 1H; PhCHH), 4.59 (dd, J=8.1, 7.2Hz, 1H; NH), 4.66 (d, J=
14.4 Hz, 1H; PhCHH), 7.27–7.44 ppm (m, 5H; Ph); 13C NMR (75 MHz,
5,5-Dimethyl-2-phenyl-2,3,5,6-tetrahydro-1H-pyrrolo
A
ACHTREUNG
1,2,6-thiadiazinane-1,1-dioxide (12c) (Table 2, entry 3): By using the pro-
cedure described for the preparation of the bicyclic sulfamide 11a and
six-membered ring 12a from bromoallene 9a, the bromoallene 9c
(51.8 mg, 0.15 mmol) was converted into 11c (10 mg, 27% yield) and 12c
(18.5 mg, 50% yield).
CDCl3): d=15.0, 33.2, 48.6, 49.8, 56.7, 75.9, 79.1, 127.8, 128.4 (2C), 128.8
À1
ꢀ
(2C), 136.2 ppm; IR (KBr): n˜ =3269 (NHSO2), 2123 (C C), 1331 cm
(NSO2); MS (FAB): m/z (%): 265 (100) [M++H]; HRMS (FAB): calcd
for C13H17N2O2S [M++H]: 265.1011; found: 265.1011.
Compound 12e’: Colorless oil; 1H NMR (300 MHz, CDCl3): d=0.97 (d,
J=7.2 Hz, 3H; CMe), 2.05–2.15 (m, 1H; 4-H), 2.57 (d, J=2.4 Hz, 1H;
Compound 11c: Colorless oil; 1H NMR (300 MHz, CDCl3): d=1.27 (s,
6H; 2”CMe), 3.42 (s, 2H; 6-CH 2), 4.40 (d, J=1.8 Hz, 2H; 3-CH2), 4.99
(t, J=1.8 Hz, 1H; 4-H), 7.15–7.18 (m, 1H; Ph), 7.20–7.29 (m, 2H; Ph),
7.38–7.42ppm (m, 2H; Ph); 13C NMR (67.8 MHz, CDCl3): d=27.5 (2C),
ꢀ
C CH), 3.18 (dddd, J=14.4, 3.6, 3.6, 2.1 Hz, 1H; 5-CHH), 3.66 (ddd, J=
14.4, 11.7, 11.7 Hz, 1H; 5-CHH), 3.83 (ddd, J=4.5, 2.4, 2.1 Hz, 1H; 3-H),
4.03 (d, J=13.5 Hz, 1H; PhCHH), 4.47 (dd, J=11.7, 3.6 Hz, 1H; NH),
4.82(d, J=13.5 Hz, 1H; PhCHH), 7.30–7.40 ppm (m, 5H; Ph); 13C NMR
(75 MHz, CDCl3): d=14.6, 34.6, 47.5, 49.4, 54.5, 76.1, 77.1, 128.1, 128.7
45.8, 48.0, 59.4, 112.3, 119.1 (2C), 124.9, 129.6 (2C), 134.7, 137.6 ppm; IR
À1
À
(KBr): n˜ =1685 (C=C N), 1325 cm (NSO2); MS (FAB): m/z (%): 265
(21) [M++H], 136 (100); HRMS (FAB): calcd for C13H17N2O2S [M++H]:
ꢀ
265.1011; found: 265.1011.
(2C), 129.2 (2C), 134.7 ppm; IR (KBr): n˜ =3269 (NHSO2), 2112 (C C),
Chem. Eur. J. 2007, 13, 1692– 1708
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1701

H. Ohno, T. Tanaka et al.
1325 cmÀ1 (NSO2); MS (FAB): m/z (%): 265 (100) [M++H]; HRMS
(FAB): calcd for C13H17N2O2S [M++H]: 265.1011; found: 265.1018.
m/z (%): 335 (28) [M++Na], 312(100); HRMS (FAB): calcd for
C17H16N2NaO2Si [M++Na]: 335.0830; found: 335.0814.
Compound 18i: Colorless oil; 1H NMR (300 MHz, CDCl3): d=3.41 (s,
3H; Me), 4.30 (s, 2H; CH2), 4.08 (d, J=6.0 Hz, 2H; CH2), 4.31 (s, 2H;
CH2), 4.36 (d, J=6.0 Hz, 2H; CH2), 4.60 (t, J=6.0 Hz, 1H; NH), 4.86 (t,
J=6.0 Hz, 1H; NH), 7.17–7.39 (m, 8H; Ph), 7.34–7.40 ppm (m, 1H; Ph);
13C NMR (75 MHz, CDCl3): d=46.1, 47.3, 58.0, 60.4, 83.8, 90.5, 121.9,
2-Benzyl-5,5-bis(hydroxymethyl)-O,O-isopropylidene-2,3,5,6-tetrahydro-
1H-pyrrolo
N
N
using the procedure described for the preparation of the bicyclic sulfa-
mide 11a and six-membered ring 12a from bromoallene 9a, the bromoal-
lene 9 f (75.3 mg, 0.170 mmol) was converted into 11 f (54.6 mg, 89%
1
127.9, 128.0 (3C), 128.7 (2C), 128.8, 129.0, 132.7, 136.5, 138.7 ppm; IR
yield) as colorless needles. M.p. 149–1518C; H NMR (500 MHz, CDCl3):
À1
ꢀ
(KBr): n˜ =3292 (NHSO2), 2231 (C C), 1327 cm (NHSO2); MS (FAB):
d=1.41 (s, 3H; CMe), 1.43 (s, 3H; CMe), 3.67 (s, 2H; NCH2), 3.71–3.86
(m, 6H; NCH2 and 2”OCH2), 4.33 (s, 2H; CH2Ph), 4.75 (s, 1H; C=CH),
7.31–7.37 ppm (m, 5H; Ph); 13C NMR (75 MHz, CDCl3): d=20.8, 26.5,
m/z (%): 345 (45) [M++H], 91 (100); HRMS (FAB): calcd for
C18H21N2O3S [M++H]: 345.1273; found: 345.1272.
46.1, 51.7, 52.1, 53.5, 66.7 (2C), 98.0, 102.2, 128.3, 128.5 (2C), 128.9 (2C),
1,3-Diaza-3-benzyl-7,7-dimethyl-4-methylene-2-thiabicyclo
2,2-dione (20a) and 1,3-Diaza-3-benzyl-8,8-dimethyl-2-thiabicyclo-
[4.3.0]non-4-ene-2,2-dione (21a) (Table 3, entry 1): NaH (60% suspen-
[3.3.0]octane-
À1
À
134.5, 140.1 ppm; IR (KBr): n˜ =2999 (C=C), 1672(C =C N), 1317 cm
(NSO2); elemental analysis calcd (%) for C17H22N2O4S: C 58.27, H 6.33,
N 7.99; found: C 58.30, H 6.28, N 7.85.
AHCTREUNG
sion in mineral oil; 15 mg, 0.375 mmol) was added to MeOH (1 mL) at
room temperature under nitrogen, and the mixture was stirred for 10 min
at this temperature. A solution of bromoallene 19a (56 mg, 0.15 mmol)
in MeOH (1 mL) was added to the stirred mixture at room temperature,
and the resulting mixture was stirred for 20 h at 608C. Concentration
under reduced pressure gave an oily residue, which was purified by
column chromatography over silica gel with n-hexane/EtOAc (6:1) to
give, in order of elution, 20a (29 mg, 66% yield) and 21a (8 mg, 18%
yield).
Compound 20a: Colorless oil; 1H NMR (300 MHz, CDCl3): d=1.15 (s,
3H; CMe), 1.17 (s, 3H; CMe), 1.76 (dd, J=12.6, 7.5 Hz, 1H; 6-CHH),
2.14 (dd, J=12.6, 8.1 Hz, 1H; 6-CHH), 3.19 (d, J=9.9 Hz, 1H; 8-CHH),
3.35 (d, J=9.9 Hz, 1H; 8-CHH), 3.929 (s, 1H; C=CHH), 3.933 (s, 1H;
C=CHH), 4.30 (d, J=16.2Hz, 1H; C HHPh), 4.65 (dd, J=8.1, 7.5 Hz,
1H; 5-H), 4.72(d, J=16.2Hz, 1H; CH HPh), 7.28–7.36 ppm (m, 5H;
Ph); 13C NMR (75 MHz, CDCl3): d=26.0, 26.4, 40.3, 46.92, 46.94, 62.8,
2-Benzyl-5,5-bis(hydroxymethyl)-O,O-isopropylidene-2,4,5,6-tetrahydro-
1H-pyrrolo
N
N
using the procedure described for the preparation of the bicyclic sulfa-
mide 16a from bromoallene 9a, the bromoallene 9 f (10 mg, 0.023 mmol)
was converted into 16 f (7.5 mg, 92% yield) as a colorless oil; 1H NMR
(300 MHz, CDCl3): d=1.43 (s, 6H; CMe2), 2.40 (d, J=1.2Hz, 2H; CH 2),
3.48 (s, 2H; CH2N), 3.71–3.83 (m, 4H; 2”CH2O), 4.46 (s, 2H; CH2Ph),
5.59 (t, J=1.2Hz, 1H; C =CH), 7.32–7.36 ppm (m, 5H; Ph); IR (KBr):
À1
À
n˜ =3273 (NSO2), 1614 (C=C N), 1321 cm (NSO2); MS (FAB): m/z
(%): 351 (29) [M++H], 154 (100); HRMS (FAB): calcd for C17H23N2O4S
[M++H]: 351.1379; found: 351.1378.
2-Benzyl-5,5-bis[(tert-butyldimethylsiloxy)methyl]-2,3,5,6-tetrahydro-1H-
pyrrolo
N
N
using the procedure described for the preparation of the bicyclic sulfa-
mide 11a and six-membered ring 12a from bromoallene 9a, the bromoal-
lene 9g (60.1 mg, 0.097 mmol) was converted into 11g (47.3 mg, 91%
63.2, 83.1, 127.3 (2C), 127.7, 128.6 (2C), 135.0, 145.1 ppm; IR (KBr): n˜ =
À1
1664 (C=C N), 1333 cm (NSO2); MS (FAB): m/z (%): 293 (100) [M+
À
1
yield) as colorless solids. M.p. 86–878C; H NMR (300 MHz, CDCl3): d=
+H]; HRMS (FAB): calcd for C15H21N2O2S [M++H]: 293.1324; found:
0.027 (s, 12H; SiMe2), 0.88 (s, 18H; 2”CMe3), 3.39 (s, 2H; NCH2), 3.57–
3.63 (m, 4H; 2”CH2OTBS), 3.74 (d, J=1.5 Hz, 2H; CH2NBn), 4.32(s,
2H; CH2Ph), 4.80 (t, J=1.5 Hz, 1H; C=CH), 7.31–7.37 ppm (m, 5H;
Ph); 13C NMR (75 MHz, CDCl3): d=À5.55 (2C), À5.52 (2C), 18.2 (2C),
25.8 (6C), 46.1, 50.7, 51.6, 60.3, 63.9 (2C), 104.5, 128.2, 128.5 (2C), 128.8
293.1307.
Compound 21a: Colorless solid; m.p. 728C (n-hexane/Et2O); 1H NMR
(300 MHz, CDCl3): d=1.10 (s, 3H; CMe), 1.16 (s, 3H; CMe), 1.58 (dd,
J=13.2, 3.9 Hz, 1H; 7-CHH), 2.12 (dd, J=13.2, 9.3 Hz, 1H; 7-CHH),
2.83 (d, J=9.3 Hz, 1H; 9-CHH), 3.11 (d, J=9.3 Hz, 1H; 9-CHH), 4.35
(d, J=15.0 Hz, 1H; CHHPh), 4.65–4.71 (m, 2H; 5-H and 6-H), 4.70 (d,
J=15.0 Hz, 1H; CHHPh), 5.79 (dd, J=8.7, 2.1 Hz, 1H; 6-H), 7.28–
7.37 ppm (m, 5H; Ph); 13C NMR (75 MHz, CDCl3): d=28.0, 29.0, 37.9,
À
(2C), 134.7, 139.2 ppm; IR (KBr): n˜ =2929 (C=C), 1680 (C=C N),
1327 cmÀ1 (NSO2); MS (FAB): m/z (%): 539 (57) [M++H], 73 (100);
HRMS (FAB): calcd for C26H47N2O4SSi2 [M++H]: 539.2795; found:
539.2793.
46.4, 51.3, 61.3, 61.5, 107.4, 127.1, 128.0, 128.5 (2C), 128.7 (2C),
5,5-Bis[(tert-butyldimethylsiloxy)methyl]-2-methyl-2,3,5,6-tetrahydro-1H-
À1
À
136.1 ppm; IR (KBr): n˜ =1645 (C=C N), 1354 cm (NSO2); MS (FAB):
pyrrolo
N
N
m/z (%): 293 (100) [M++H], HRMS (FAB): calcd for C15H21N2O2S [M+
+H]: 293.1324; found: 293.1335.
using the procedure described for the preparation of the bicyclic sulfa-
mide 11a and six-membered ring 12a from bromoallene 9a, the bromoal-
lene 9h (48.2mg, 0.0887 mmol) was converted into 11h (39.0 mg, 95%
yield) as colorless oil. 1H NMR (300 MHz, CDCl3): d=0.04 (s, 12H; 2”
SiMe2), 0.88 (s, 18H; 2”CMe3), 2.84 (s, 2H; CH2), 3.36 (s, 2H; CH2),
3.603–3.609 (m, 4H; 2”CH2), 3.89 (d, J=1.5 Hz, 2H; CH2), 4.86 ppm (s,
1H; 4-H); 13C NMR (75 MHz, CDCl3): d=À5.56 (2C), À5.53 (2C), 18.2
N-Benzyl-2-ethynyl-4,4-dimethylpyrrolidine-1-sulfonamide (22a): A solu-
tion of bromoallene 19a (149 mg, 0.4 mmol) in DMF (2mL) was added
to a stirred suspension of NaH (60% suspension of mineral oil; 40 mg,
1.0 mmol) in DMF (2mL) at 0 8C under nitrogen at 08C. After the mix-
ture was stirred for 3.5 h at this temperature, the mixture was poured
into ice-water saturated with NH4Cl. The mixture was extracted with
Et2O. The extract was washed with water and brine, and dried over
MgSO4. The filtrate was concentrated under reduced pressure to give an
oily residue, which was purified by column chromatography over silica
gel with n-hexane/EtOAc (5:1) to give 22a (101 mg, 86% yield) as color-
less crystals. M.p. 92–938C (n-hexane/Et2O); 1H NMR (300 MHz,
CDCl3): d=1.09 (s, 3H; CMe), 1.22 (s, 3H; CMe), 1.92 (dd, J=12.3,
6.3 Hz, 1H; 3-CHH), 2.11 (dd, J=12.3, 7.8 Hz, 1H; 3-CHH), 2.40 (d, J=
(2C), 25.8 (6C), 34.6, 49.0, 50.7, 60.3, 63.9 (2C), 104.3, 139.1 ppm; IR
À1
À
(KBr): n˜ =2929 (C=C), 1682(C =C N), 1329 cm (NHSO2); MS (FAB):
m/z (%): 463 (46) [M++H], 73 (100); HRMS (FAB): calcd for
C20H43N2O4SSi2 [M++H]: 463.2482; found: 463.2471.
2-Benzyl-3,9-dihydro
A
G
N
(11i) and N-benzyl-N’-{[2-(3-methoxyprop-1-ynyl)phenyl]methyl}sulfa-
mide (18i) (Table 2, entry 12): By using the procedure described for the
preparation of the bicyclic sulfamide 11a and six-membered ring 12a
from bromoallene 9a, the bromoallene 9i (177 mg, 0.45 mmol) was con-
verted into 11i (24.3 mg, 17%) and 18i (23.4 mg, 15%).
ꢀ
1.8 Hz, 1H; C CH), 3.14 (d, J=9.9 Hz, 1H; 5-CHH), 3.27 (d, J=9.9 Hz,
1H; 5-CHH), 4.26 (dd, J=13.5, 5.4 Hz, 1H; CHHPh), 4.33 (dd, J=13.5,
6.9 Hz, 1H; CHHPh), 4.51 (ddd, J=7.8, 6.3, 1.8 Hz, 1H; 2-H), 4.59 (dd,
J=6.9, 5.4 Hz, 1H; NH), 7.28–7.38 ppm (m, 5H; Ph); 13C NMR
(67.5 MHz, CDCl3): d=26.2, 26.4, 38.5, 47.2, 47.4, 49.5, 60.9, 72.1, 83.8,
127.6, 127.9 (2C), 128.5 (2C), 136.7 ppm; IR (KBr): n˜ =3278 (NHSO2),
Compound 11i: Colorless crystals; m.p. 156–1578C (n-hexane/EtOAc);
1H NMR (300 MHz, CDCl3): d=3.93 (d, J=1.8 Hz, 2H; 3-CH2), 4.30 (s,
2H; CH2), 4.68 (s, 2H; CH2), 5.52(t, J=1.8 Hz, 1H; C=CH), 6.93 (dd,
J=6.9, 1.8 Hz, 1H; Ph), 7.08–7.21 (m, 3H; Ph), 7.34–7.40 ppm (m, 5H;
Ph); 13C NMR (75 MHz, CDCl3): d=44.7, 48.8, 51.6, 100.0, 124.7, 126.15,
126.24, 126.9, 128.3, 128.4, 128.6 (2C), 128.9 (2C), 130.8, 133.0,
134.3 ppm; IR (KBr): n˜ =1668 (C=CN), 1322 cmÀ1 (NHSO2); MS (FAB):
2116 (C C), 1336 cmÀ1 (NHSO2); elemental analysis calcd (%) for
ꢀ
C15H20N2O2S: C 61.61, H 6.89, N 9.58; found: C 61.53, H 6.81, N 9.52.
2,6,6-Trimethyl-4a,5,6,7-tetrahydro-2H-pyrrolo
G
G
1,1-dione (21b) and 2-acetyl-N,4,4-trimethylpyrrolidine-1-sulfonamide
1702
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1692– 1708

Heterocycles
FULL PAPER
(23b): TBAF (0.635 mL, 0.635 mmol; 1.0m solution in THF) was added
to a stirred solution of the bromoallene 19b (75.5 mg, 0.254 mmol) in
THF (2.5 mL) under nitrogen at room temperature, and the mixture was
stirred for 2.5 h under reflux. HCl (3n; 0.5 mL) was added to the stirred
mixture, and the resulting mixture was stirred for 0.5 h at room tempera-
ture. The whole was extracted with EtOAc. The extract was washed with
water, saturated NaHCO3 and brine, and dried over MgSO4. The filtrate
was concentrated under reduced pressure to give an oily residue, which
was purified by column chromatography over silica gel with n-hexane/
EtOAc (2:1) to give, in order of elution, 21b (6.9 mg, 13% yield) and
23b (41.5 mg, 70% yield).
Compound 21b: Colorless oil; 1H NMR (300 MHz, CDCl3): d=1.15 (s,
3H; CMe), 1.17 (s, 3H; CMe), 1.63 (dd, J=12.3, 3.6 Hz, 1H; CHH), 2.13
(dd, J=12.3, 9.0 Hz, 1H; CHH), 2.95 (d, J=9.0 Hz, 1H; CHHN), 3.05 (s,
3H; NMe), 3.14 (d, J=9.0 Hz, 1H; CHHN), 4.65–4.68 (m, 1H; CH), 4.70
(dd, J=8.7, 1.8 Hz, 1H; 5-H), 5.75 ppm (dd, J=8.7, 2.1 Hz, 1H; 6-H);
13C NMR (67.5 MHz, CDCl3): d=27.9, 28.8, 35.4, 37.8, 46.6, 61.4, 61.5,
for the preparation of the bicyclic sulfamide 29 from bromoallene 24, the
bromoallene 25 (46.7 mg, 0.150 mmol) was converted into 30 (22.2 mg,
64% yield) as colorless solids. M.p. 71–738C (n-hexane/Et2O); 1H NMR
(300 MHz, CDCl3): d=0.98 (s, 6H; 2”CMe), 1.64 (t, J=5.4 Hz, 2H;
CH2), 1.81 (s, 3H; CMe), 2.06 (s, 2H; CH2), 2.97 (s, 3H; NMe), 3.31 ppm
(t, J=5.4 Hz, 2H; CH2); 13C NMR (75 MHz, CDCl3): d=9.32, 27.2 (2C),
À
29.0, 29.3, 35.8, 36.3, 40.6, 116.4, 117.5 ppm; IR (KBr): n˜ =1698 (C=C
N), 1309 cmÀ1 (NSO2); MS (FAB): m/z (%): 231 (100) [M++H]; HRMS
(FAB): calcd for C10H19N2O2S [M++H]: 231.1167; found: 231.1176.
2-Benzyl-3-methyl-5-phenyl-4,5,6,7-tetrahydro-2H-[1,2,5]thiadiazolo
a]pyridine 1,1-dioxide (31) and (Æ)-(4aR*,6R*)-2-benzyl-6-phenyl-
2,4a,5,6,7,8-hexahydropyrido[1,2-b][1,2,6]thiadiazine 1,1-dioxide (32)
(Table 4, entry 3): TBAF (0.375 mL, 0.375 mmol; 1.0m solution in THF)
was added to stirred solution of the bromoallene 26 (65.3 mg,
A
A
ACHTREUNG
a
0.15 mmol) in THF (1.5 mL) under nitrogen at room temperature, and
the resulting mixture was stirred for 3 h under reflux. Concentration
under reduced pressure gave an oily residue, which was purified by
column chromatography over silica gel with n-hexane/EtOAc (5:1) to
give, in the order of elution, 31 (21.8 mg, 41% yield) and 32 (26.2 mg,
49% yield; ca. 90% purity).
À
107.1, 129.6 ppm; IR (KBr): n˜ =3315 (NHSO2), 1645 (C=C N),
1351 cmÀ1 (NHSO2); MS (FAB): m/z (%): 217 (100) [M++H], HRMS
(FAB): calcd for C9H17N2O2S [M++H]: 217.1011; found: 217.1016.
Compound 23b: Colorless oil; 1H NMR (300 MHz, CDCl3): d=1.11 (s,
3H; CMe), 1.14 (s, 3H; CMe), 1.64 (dd, J=12.3, 9.0 Hz, 1H; CHH), 2.10
(ddd, J=12.3, 9.0, 1.0 Hz, 1H; CHH), 2.20 (s, 3H; CMe), 2.81 (s, 3H;
NMe), 3.14 (d, J=9.6 Hz, 1H; CHHN), 3.35 (dd, J=9.6, 1.0 Hz, 1H;
CHHN), 4.48–4.53 (brs, 1H; NH), 4.50 ppm (t, J=9.0 Hz, 1H; CH);
13C NMR (67.5 MHz, CDCl3): d=25.76, 25.82, 26.4, 29.5, 38.9, 43.5, 61.0,
67.6, 207.9 ppm; IR (KBr): n˜ =3300 (NSO2), 1711 (C=O), 1315 cmÀ1
(NHSO2); MS (FAB): m/z (%): 235 (100) [M++H], HRMS (FAB): calcd
for C9H19N2O3S [M++H]: 235.1116; found: 235.1119.
Compound 31: Colorless crystals; m.p. 117–1198C (ca. 90% purity, n-
hexane/EtOAc); 1H NMR (500 MHz, CDCl3): d=1.70 (s, 3H; CMe),
2.02–2.15 (m, 2H; CH2), 2.34–2.39 (m, 1H; CHH), 2.63–2.71 (m, 2H;
CHH and 5-H), 3.19 (ddd, J=11.5, 11.5, 4.0 Hz, 1H; 7-CHH), 3.68 (ddd,
J=11.5, 4.5, 4.5 Hz, 1H; 8-CHH), 4.61 (s, 2H; CH2Ph), 7.18–7.45 ppm
(m, 10H; Ph); 13C NMR (75 MHz, CDCl3): d=10.0, 29.9, 31.0, 40.4, 44.4,
46.5, 116.6, 116.8, 126.6 (2C), 126.9, 127.4 (2C), 127.7, 128.6 (2C), 128.7
À1
À
(2C), 136.6, 144.0 ppm; IR (KBr): n˜ =1695 (C=C N), 1306 cm (NSO2);
MS (EI) m/z (%): 354 (60) [M+], 289 (100); HRMS (EI) calcd for
C20H22N2O2S [M+]: 354.1402; found: 354.1414.
6,6-Dimethyl-2-phenyl-4a,5,6,7-tetrahydro-1H-pyrrolo
[1,2-b]-
Compound 32: Colorless needles; m.p. 116–1198C (n-hexane/EtOAc);
1H NMR (500 MHz, CDCl3): d=1.75–1.84 (m, 1H; 7-CHH), 1.87–1.91
(m, 1H; 7-CHH), 1.96–2.08 (m, 2H; 5-CH2), 2.66–2.71 (m, 2H; 6-H and
8-CHH), 3.51 (ddd, J=11.0, 4.0, 4.0 Hz, 1H; 8-CHH), 4.51 (d, J=
15.0 Hz, 1H; CHHPh), 4.66 (dd, J=8.5, 1.5 Hz, 1H; 4-H), 4.71 (d, J=
15.0 Hz, 1H; CHHPh), 4.90–4.91 (m, 1H; 4a-H), 5.99 (dd, J=8.5, 1.5 Hz,
1H; 3-H), 7.18–7.38 ppm (m, 10H; Ph); 13C NMR (75 MHz, CDCl3): d=
31.3, 36.3, 36.8, 43.8, 51.4, 56.2, 102.5, 126.7 (3C), 128.1, 128.4 (2C), 128.6
G
ACHTREUNG
1.0m solution in THF) was added to a stirred solution of the bromoallene
19c (50.0 mg, 0.145 mmol) in THF (1.4 mL) under nitrogen at room tem-
perature, and the resulting mixture was stirred for 30 h under reflux.
Concentration under reduced pressure gave an oily residue, which was
purified by column chromatography over silica gel with n-hexane/EtOAc
(2:1) to give 21c (37.0 mg, 96% yield) as a colorless oil: 1H NMR
(300 MHz, CDCl3): d=1.20 (s, 3H; CMe), 1.21 (s, 3H; CMe), 1.72 (dd,
J=12.8, 3.8 Hz, 1H; CHH), 2.21 (dd, J=12.8, 8.8 Hz, 1H; CHH), 3.07
(d, J=9.0 Hz, 1H; NCHH), 3.20 (d, J=9.0 Hz, 1H; NCHH), 4.78–4.82
(m, 1H; 4a-H), 4.88 (dd, J=8.6, 1.8 Hz, 1H; 4-H), 6.14 (dd, J=8.6,
1.5 Hz, 1H; 3-H), 7.29–7.48 ppm (m, 5H; Ph); 13C NMR (75 MHz,
CDCl3): d=28.1, 29.0, 38.0, 46.5, 61.41, 61.48, 107.8, 125.8 (2C), 127.1,
À
(2C), 128.8 (2C), 129.7, 136.1, 144.6 ppm; IR (KBr): n˜ =1635 (C=C N),
1356 cmÀ1 (NSO2); elemental analysis calcd (%) for C20H22BrN2O2S: C
67.77, H 6.26, N 7.90; found: C 67.78, H 6.25, N 7.89.
3,6,8-Triaza-8-benzyl-9-methylene-3-(4-methylphenylsulfonyl)-7-
thiabicyclo
ACHTREUNG
À
128.6, 129.3 ppm (2C); IR (KBr): n˜ =1643 (C=C N), 1363 (NSO2),
sulfonyl)-2,4a,5,6,7,8-hexahydro-1H-pyrazino
A
ACHTREUNG
1170 cmÀ1 (NSO2); MS (FAB): m/z (%): 279 (100) [M++H]; HRMS
(FAB): calcd for C14H19N2O2S [M++H]: 279.1167; found: 279.1169.
1,1-dione (34) (Table 4, entry 5): By using the procedure described for
the preparation of the bicyclic sulfamides 31 and 32 from bromoallene
26, the bromoallene 27 (51.4 mg, 0.100 mmol) was converted into 33
(17.9 mg, 41% yield) and 34 (5.7 mg, 13% yield).
6,8-Diaza-8-benzyl-3,3-dimethyl-9-methylene-7-thiabicyclo[4.3.0]nonane-
U
7,7-dione (29) (Table 4, entry 1): NaH (60% suspension in mineral oil;
10 mg, 0.25 mmol) was added to MeOH (0.5 mL) at room temperature
under nitrogen, and the mixture was stirred for 10 min at this tempera-
ture. A solution of bromoallene 24 (38.7 mg, 0.10 mmol) in MeOH
(0.5 mL) was added to the stirred mixture at room temperature, and the
resulting mixture was stirred for 24 h at 608C. Concentration under re-
duced pressure gave an oily residue, which was purified by column chro-
matography over silica gel with n-hexane/EtOAc (5:1) to give 29
(24.3 mg, 79% yield) as colorless crystals. M.p. 85–878C (n-hexane/
Et2O); 1H NMR (300 MHz, CDCl3): d=1.03 (s, 6H; 2”CMe), 1.44–1.70
(m, 4H; 2-CH2 and 4-CH2), 3.01 (ddd, J=12.6, 12.6, 3.0 Hz, 1H; 5-
CHH), 3.52(ddd, J=12.6, 5.1, 2.1 Hz, 1H; 5-CHH), 3.87 (dd, J=2.4,
2.4 Hz, 1H; C=CHH), 3.91 (dd, J=2.4, 2.4 Hz, 1H; C=CHH), 3.93–3.99
(m, 1H; 1-H), 4.52(d, J=16.8 Hz, 1H; PhCHH), 4.69 (d, J=16.8 Hz,
1H; PhCHH), 7.27–7.39 ppm (m, 5H; Ph); 13C NMR (75 MHz, CDCl3):
Compound 33: Colorless solid; m.p. 172–1738C (n-hexane/CHCl3);
1H NMR (300 MHz, CDCl3): d=2.45 (s, 3H; PhMe), 2.54–2.58 (m, 2H;
CH2), 2.70 (dt, J=11.7, 3.0 Hz, 1H; CHH), 3.25 (dt, J=11.7, 3.0 Hz, 1H;
CHH), 3.65–3.75 (m, 2H; CH2), 3.88 (dd, J=10.5, 2.7 Hz, 1H; C=CHH),
4.01–4.06 (m, 2H; C=CHH and NCH), 4.56 (d, J=3.0 Hz, 2H; CH2Ph),
7.28–7.36 (m, 7H; Ph), 7.63 ppm (d, J=8.1 Hz, 2H; Ph); 13C NMR
(67.8 MHz, CDCl3): d=21.7, 41.6, 43.7, 46.3, 47.9, 56.5, 84.2, 127.0 (2C),
127.4 (2C), 127.8, 128.7 (2C), 130.0 (2C), 132.4, 134.2, 138.0, 144.3 ppm;
À1
À
IR (KBr): n˜ =1597 (C=C N), 1356 cm (NSO2); MS (FAB): m/z (%):
234 (30) [M++H], 154 (100); HRMS (FAB): calcd for C20H24N3O4S2 [M+
+H]: 434.1208; found: 434.1225.
Compound 34: Colorless oil; 1H NMR (300 MHz, CDCl3): d=2.45 (s,
3H; PhMe), 2.51 (dt, J=11.7, 3.0 Hz, 1H; CHH), 2.70 (dd, J=11.7,
3.6 Hz, 1H; CHH), 2.85 (dt, J=11.7, 3.0 Hz, 1H; CHH), 3.25 (dt, J=
11.7, 3.6 Hz, 1H; CHH), 3.60–3.68 (m, 2H; CH2), 4.50 (d, J=15.3 Hz,
1H; PhCHH), 4.52–4.62 (m, 1H; NCH), 4.64 (d, J=15.3 Hz, 1H;
PhCHH), 4.77 (dd, J=8.1, 1.5 Hz, 1H; CH=CH), 5.99 (dd, J=8.1,
2.7 Hz, 1H; CH=CH), 7.32–7.39 (m, 7H; Ph), 7.62 ppm (d, J=8.4 Hz,
2H; Ph); 13C NMR (67.8 MHz, CDCl3): d=21.6, 42.7, 44.5, 48.4, 51.8,
55.6, 101.6, 127.6 (2C), 128.3, 128.4 (2C), 128.9 (2C), 130.0 (2C), 130.1,
d=23.5, 29.5, 32.3, 36.1, 38.8, 40.9, 46.1, 54.6, 81.3, 127.0 (2C), 127.6,
128.6 (2C), 135.1, 142.6 ppm; IR (KBr): n˜ =1670 (C=C N), 1315 cm
(NSO2); elemental analysis calcd (%) for C16H22N2O2S: C 62.71, H 7.24,
N 9.14; found: C 62.52, H 7.13, N 9.03.
À1
À
2,3,5,5-Tetramethyl-4,5,6,7-tetrahydro
1,1(2H)-dione (30) (Table 4, entry 2): By using the procedure described
[1,2,5]thiadiazolo
N
ACHTREUNG
Chem. Eur. J. 2007, 13, 1692– 1708
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1703

H. Ohno, T. Tanaka et al.
À1
À
132.3, 135.5, 144.3 ppm; IR (KBr): n˜ =1639 (C=C N), 1352cm (NSO2);
MS (FAB): m/z (%): 434 (36) [M++H], 154 (100); HRMS (FAB): calcd
for C20H24N3O4S2 [M++H]: 434.1208; found: 434.1223.
cedure described for the preparation of the compound 41 and 42 from
bromoallene 24, the bromoallene 25 (62mg, 0.20 mmol) was converted
into 44 (23 mg, 50% yield) and 49 (9.4 mg, 18% yield). This reaction
mixture was treated with 4% HCl before purification.
2-Benzyl-3-methyl-4,5,6,7-tetrahydro-1H-[1,2,5]thiadiazolo
[2,3-a]pyri-
dine-1,1(2H)-dione (35) (Table 4, entry 6): By using the procedure de-
A
Compound 44: Colorless crystals; m.p. 66–678C (n-hexane/EtOAc);
1H NMR (300 MHz, CDCl3): d=0.99 (s, 6H; 2”CMe), 1.47–1.51 (m, 2H;
CH2), 1.58–1.62(m, 2H; CH 2), 2.29–2.33 (m, 2H; CH2), 2.97 (s, 3H;
NMe), 3.49–3.53 (m, 2H; CH2), 5.52ppm (t, J=1.2Hz, 1H; C =CH);
scribed for the preparation of the bicyclic sulfamides 31 and 32 from bro-
moallene 26, the bromoallene 28 (50.0 mg, 0.139 mmol) was converted
into 35 (22.4 mg, 58% yield) as a colorless oil. 1H NMR (300 MHz,
CDCl3): d=1.59 (tt, J=5.7, 5.7 Hz, CH2), 1.68 (s, 3H; Me), 1.85 (tt, J=
5.7, 5.7 Hz, CH2), 2.30 (t, J=5.7 Hz, 2H; CH2), 3.28 (t, J=5.7 Hz, 2H;
CH2), 4.57 (s, 2H; CH2Ph), 7.25–7.42 ppm (m, 5H; Ph); 13C NMR
(75 MHz, CDCl3): d=9.99, 22.1, 22.3, 23.7, 44.5, 46.4, 116.0, 116.9, 127.4
(2C), 127.6, 128.6 (2C), 136.7 ppm; IR (KBr): n˜ =1604 (N-C=C), 1313
(NSO2), 1166 cmÀ1 (NSO2); MS (FAB): m/z (%): 301 (23) [M++Na], 91
(100); HRMS (FAB): calcd for C14H18N2NaO2S [M++Na]: 301.0987;
found: 301.0975.
13C NMR (75 MHz, CDCl3): d=22.4, 28.5 (2C), 31.6, 33.1, 38.2, 41.4,
À1
À
42.1, 107.4, 127.4 ppm; IR (KBr): n˜ =1658 (C=C N), 1303 cm (NSO2);
MS (FAB): m/z (%): 231 (81) [M++H], 154 (100); HRMS (FAB): calcd
for C10H19N2O2S [M++H]: 231.1167; found: 231.1167.
Compound 49: Colorless oil; 1H NMR (300 MHz, CDCl3): d=0.95 (s,
6H; 2”CMe), 1.67–1.70 (m, 2H; CH 2), 2.13 (d, J=7.2Hz, 2H; CH 2),
2.77 (d, J=5.4 Hz, 3H; NMe), 3.35 (s, 3H; OMe), 3.39–3.43 (m, 2H;
CH2), 4.10 (s, 2H; OCH2), 4.58 (q, J=5.4 Hz, 1H; NH), 5.62ppm (t, J=
7.2Hz, 1H; C =CH); 13C NMR (75 MHz, CDCl3): d=28.2, 29.2, 29.8, 39.2
2-Benzyl-1-methyl-2,4,9,10-tetrahydro-3-thia-2,3a-diazabenzo[f]azulene
3,3-dioxide (38) and 3-benzyl-5,10,11,11a-tetrahydro-3H-4-thia-3,4a-
(2C), 43.7, 46.3, 57.7, 74.0, 126.8, 140.0 ppm; IR (KBr): n˜ =3298
À1
À
diazadibenzo
A
(NHSO2), 1666 (C=C N), 1331 cm (NSO2); MS (FAB): m/z (%): 263
0.375 mmol; 1.0m solution in THF) was added to a stirred solution of
bromoallene 37 (65.3 mg, 0.15 mmol) in THF (1.5 mL) under nitrogen at
room temperature, and the resulting mixture was stirred for 3 h under
reflux. Concentration under reduced pressure gave an oily residue, which
was purified by flash column chromatography over silica gel with n-
hexane/EtOAc (4:1) to give 38 and 39 (29 mg, 57% yield; 38:39=95:5).
Compound 38: Colorless oil; 1H NMR (300 MHz, CDCl3): d=1.76 (s,
3H; CMe), 2.56–2.60 (m, 2H; CH2), 2.90–2.94 (m, 2H; CH2), 4.36 (s, 2H;
CH2Ph), 4.53 (s, 2H; CH2Ph), 7.14–7.37 ppm (m, 9H; Ph); 13C NMR
(75 MHz, CDCl3): d=10.6, 25.2, 32.5, 48.0, 51.6, 119.2, 122.3, 126.8, 127.6
(64) [M++H], 231 (100); HRMS (FAB): calcd for C11H23N2O3S [M++H]:
263.1429; found: 263.1431.
2-Benzyl-6-phenyl-2,4,5,6,7,8-hexahydro
N
N
1,1-dioxide (45) (Table 5, entry 2): By using the procedure described for
the preparation of the compound 41 and 42 from bromoallene 24, the
bromoallene 26 (65.3 mg, 0.15 mmol) was converted into 45 (41.7 mg,
78% yield) as colorless crystals. M.p. 88–908C (decomp, n-hexane/
EtOAc); 1H NMR (300 MHz, CDCl3): d=1.57–1.70 (m, 1H; CHH),
1.88–2.13 (m, 3H; CHH and CH2), 2.32–2.52 (m, 2H; CH2), 2.62–2.70
(m, 1H; 6-H), 2.70–3.46 (m, 1H; 8-CHH), 3.94–4.01 (m, 1H; 8-CHH),
4.45 (d, J=15.0 Hz, 1H; CHHPh), 4.51 (d, J=15.0 Hz, 1H; CHHPh),
5.54 (s, 1H; 3-H), 7.15–7.40 ppm (m, 10H; Ph); 13C NMR (75 MHz,
CDCl3): d=26.6, 36.6, 37.2, 42.0, 48.8, 48.9, 105.2, 126.4, 126.6 (2C),
127.0, 128.2, 128.5 (2C), 128.6 (2C), 128.7 (2C), 135.0, 146.4 ppm; IR
(2C), 127.7, 128.45, 128.53 (2C), 129.1, 129.4, 134.8, 136.2, 141.0 ppm; IR
À1
À
(KBr): n˜ =1674 (C=C N), 1327 cm (NSO2); MS (FAB): m/z (%): 341
(60) [M++H], 91 (100); HRMS (FAB): calcd for C19H21N2O2S [M++H]:
341.1324; found: 341.1338.
À1
À
(KBr): n˜ =1662(C =C N), 1302cm
(NSO2); MS (EI) m/z (%): 355
General procedure for the palladium-catalyzed tandem cyclization of
bromoallenes—synthesis of 2-benzyl-6,6-dimethyl-2,3,5,6,7,8-hexahydro-
(1.8) [M+], 213 (100); HRMS (EI) calcd for C20H22N2O2S [M+]:
1H-1l6-[1,2,5]thiadiazolo
[2,3-a]azepine-1,1-dione (41) and N-benzyl-7-
G
354.1402; found: 355.1419.
(methoxymethyl)-4,4-dimethyl-2,3,4,5-tetrahydro-1H-azepine-1-sulfona-
mide (42): MeOH (1.0 mL) was added to NaH (60% suspension in min-
eral oil; 20 mg, 0.25 mmol) at 08C under nitrogen, and the mixture was
2-Benzyl-6-(4-methylphenylsulfonyl)-2,4,5,6,7,8-hexahydro-1H-
[1,2,5]thiadiazolo
N
N
(methoxymethyl)-4-(4-methylphenylsulfonyl)-2,3,4,5-tetrahydro-1H-1,4-
diazepine-1-sulfamide (50) (Table 5, entry 4): By using the procedure de-
scribed for the preparation of the compound 41 and 42 from bromoallene
24, the bromoallene 27 (77.2mg, 0.150 mmol) was converted into 46
(31.4 mg, 48% yield) and 50 (2.5 mg, 4% yield). This reaction mixture
was treated with 4% HCl before purification.
stirred for 10 min at room temperature. [Pd(PPh3)4] (11.6 mg,
A
0.010 mmol) and a solution of bromoallene 24 (77.0 mg, 0.20 mmol) in
MeOH (1.0 mL) were added to the stirred mixture at room temperature,
and the resulting mixture was stirred for 6 h at 608C. Concentration
under reduced pressure gave an oily residue, which was purified by
column chromatography over silica gel with n-hexane/EtOAc (3:1) to
give, in order of elution, 41 (50.0 mg, 74% yield) and 42 (8.0 mg, 12%).
Compound 41: Colorless oil; 1H NMR (300 MHz, CDCl3): d=0.97 (s,
6H; 2”CMe), 1.73–1.77 (m, 2H; CH 2), 2.00 (d, J=6.0 Hz, 2H; CH2),
3.42–3.46 (m, 2H; NCH2), 3.66 (dd, J=3.3, 1.5 Hz, 2H; NCH2), 4.18 (s,
2H; PhCH2), 4.60 (tdd, J=6.3, 1.5, 1.5 Hz, 1H; C=CH), 7.32–7.39 ppm
(m, 5H; Ph); 13C NMR (75 MHz, CDCl3): d=28.7 (2C), 32.6, 39.5, 41.4,
Compound 46: Colorless solid; m.p. 105–1068C (n-hexane/Et2O);
1H NMR (300 MHz, CDCl3): d=2.43 (s, 3H; PhMe), 2.56–2.59 (m, 2H;
CH2), 3.28–3.31 (m, 2H; CH2), 3.41–3.44 (m, 2H; CH2), 3.76–3.79 (m,
2H; CH2), 4.41 (s, 2H; CH2Ph), 5.51 (s, 1H; C=CH), 7.30–7.37 (m, 7H;
Ph), 7.62ppm (d, J=8.4 Hz, 2H; Ph); 13C NMR (75 MHz, CDCl3): d=
21.5, 28.8, 44.2, 48.7, 49.2, 50.0, 106.9, 124.5, 127.0 (2C), 128.3, 128.4 (2C),
128.8 (2C), 130.0 (2C), 134.5, 135.0, 143.9 ppm; IR (KBr): n˜ =1596 (C=
À1
C N), 1309 cm (NSO2); MS (FAB): m/z (%): 434 (11) [M++H], 154
À
42.7, 50.4, 51.3, 102.6, 128.1, 128.7 (2C), 128.7 (2C), 133.6, 134.6 ppm; IR
À1
(KBr): n˜ =2956 (C=C), 1691 (C=C N), 1321 cm (NSO2); MS (FAB):
(100); HRMS (FAB): calcd for C20H24N3O4S2 [M++H]: 434.1208; found:
À
m/z (%): 307 (100) [M++H]; HRMS (FAB): calcd for C16H23N2O2S [M+
+H]: 307.1480; found: 307.1461.
434.1219.
Compound 50: Colorless oil; 1H NMR (300 MHz, CDCl3): d=2.43 (s,
3H; PhMe), 3.25 (s, 3H; OMe), 3.45–3.48 (m, 2H; CH2), 3.54–3.57 (m,
2H; CH2), 3.79 (d, J=6.9 Hz, 2H; CH2), 4.12(s, 2H; OC H2), 4.29 (d, J=
6.3 Hz, 2H; CH2Ph), 5.13 (t, J=6.3 Hz, 1H; NH), 5.79 (t, J=6.9 Hz, 1H;
C=CH), 7.22–7.36 (m, 7H; Ph), 7.65 ppm (d, J=8.7 Hz, 2H; Ph);
13C NMR (75 MHz, CDCl3): d=21.5, 45.1, 47.3, 50.4, 50.9, 57.9, 73.2,
Compound 42: Colorless oil; 1H NMR (300 MHz, CDCl3): d=0.96 (s,
6H; 2”CMe), 1.68–1.72 (m, 2H; CH 2), 2.14 (d, J=6.9 Hz, 2H; CH2),
3.30 (s, 3H; OMe), 3.42–3.46 (m, 2H; CH2N), 4.12(s, 2H; C H2OMe),
4.27 (d, J=6.3 Hz, 2H; CH2Ph), 4.95 (t, J=6.3 Hz, 1H; NH), 5.61 (t, J=
6.9 Hz, 1H; C=CH), 7.28–7.36 ppm (m, 5H; Ph); 13C NMR (75 MHz,
CDCl3): d=28.4, 29.8 (2C), 39.2, 43.7, 46.3, 47.1, 57.7, 74.0, 126.4, 127.8,
122.0, 127.2 (2C), 127.3, 128.0 (2C), 128.8 (2C), 129.9 (2C), 35.3, 36.7,
À1
À
128.0 (2C), 128.7 (2C), 137.1, 140.1 ppm; IR (KBr): n˜ =3298 (NH), 2954
43.5, 43.8 ppm; IR (KBr): n˜ =1597 (C=C N), 1333 cm (NSO2); MS
À1
(C=C), 1666 (C=C N), 1346 cm (NSO2); MS (FAB): m/z (%): 339 (70)
(FAB): m/z (%): 466 (28) [M++H], 154 (100); HRMS (FAB): calcd for
C21H28N3O5S2 [M++H]: 466.1470; found: 466.1483.
À
[M++H], 91 (100); HRMS (FAB): calcd for C17H27N2O3S [M++H]:
339.1742; found: 339.1743.
AHCTREUNG
2-Methyl-6,6-dimethyl-2,3,5,6,7,8-hexahydro
A
[2,3-a]aze-
A
ACHTREUNG
pine-1,1-dione (44) and 7-(methoxymethyl)-4,4,N’-trimethyl-2,3,4,5-tetra-
hydro-1H-azepine-1-sulfamide (49) (Table 5, entry 1): By using the pro-
entry 5): By using the procedure described for the preparation of the
compound 41 and 42 from bromoallene 24, the bromoallene 43 (80.0 mg,
1704
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1692– 1708

Heterocycles
FULL PAPER
0.105 mmol) was converted into 47 (50.0 mg, 74% yield) as colorless
crystals. M.p. 96–978C (n-hexane/EtOAc); [a]2D4 =+17.0 (c=1.00 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=0.88 (d, J=6.9 Hz, 3H; CMe),
2.29 (dd, J=15.3, 4.8 Hz, 1H; CHH), 2.43 (s, 3H; PhMe), 2.75–2.80 (m,
1H; CHH), 3.18 (dd, J=15.3, 4.8 Hz, 1H; CHH), 3.52(dd, J=15.3,
4.8 Hz, 1H; CHH), 3.88 (dd, J=15.3, 4.8 Hz, 1H; CHH), 4.07 (dd, J=
15.3, 4.8 Hz, 1H; CHH), 4.37–4.42(m, 1H; 5-H), 4.45 (d, J=3.0 Hz, 2H;
PhCH2), 5.51 (d, J=1.5 Hz, 1H; C=CH), 7.28–7.35 (m, 7H; Ph),
7.66 ppm (d, J=8.1 Hz, 2H; Ph); 13C NMR (75 MHz, CDCl3): d=14.3,
21.5, 34.7, 43.2, 44.7, 48.9, 49.8, 108.7, 121.7, 126.8 (2C), 128.3, 128.4 (2C),
give 55 (42.5 g, 58% yield) as colorless crystals. M.p. 127–1288C (n-
hexane/EtOAc); [a]2D6 =+75.0 (c=1.00 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=0.75 (d, J=6.9 Hz, 3H; CMe), 1.92–2.00 (m, 1H; CHH),
2.07–2.21 (m, 1H; CHH), 2.15 (dd, J=15.6, 4.2Hz, 1H; C HH), 2.42 (s,
3H; PhMe), 2.74 (dd, J=15.6, 4.2Hz, 1H; CH H), 2.92 (ddd, J=19.2,
12.3, 3.6 Hz, 1H; CHH), 3.45 (dd, J=15.6, 4.2Hz, 1H; C HH), 3.72(ddd,
J=19.2, 12.3, 3.6, 1H; CHH), 3.82(dd, J=15.6, 4.2Hz, 1H; CH H), 4.09–
4.23 (m, 1H; 6-H), 4.45 (s, 2H; PhCH2), 5.45 (s, 1H; C=CH), 7.24–7.40
(m, 7H; Ph), 7.70 ppm (d, J=8.1 Hz, 2H; Ph); 13C NMR (75 MHz,
CDCl3): d=14.8. 21.5, 30.5, 33.7, 37.9, 39.1, 48.7, 50.9, 108.2, 120.1, 127.0
128.8 (2C), 129.9 (2C), 134.6, 137.7, 143.6 ppm; n˜ =IR (KBr): 1597 (C=
(2C), 128.3, 128.4 (2C), 128.7 (2C), 129.8 (2C), 134.7, 136.9, 143.5 ppm;
À1
À1
C N), 1323 cm (NSO2); MS (FAB): m/z (%): 448 (51) [M++H], 154
IR (KBr): n˜ =1597 (C=C N), 1331 cm (NSO2); MS (FAB): m/z (%):
À
À
(100); HRMS (FAB): calcd for C21H26N3O4S2 [M++H]: 448.1365; found:
462(34) [ M++H], 154 (100); HRMS (FAB): calcd for C22H28N3O4S2 [M+
+H]: 462.1521; found: 462.1512.
448.1363.
2-Benzyl-2,4,5,6,7,8-hexahydro-1H-[1,2,5]thiadiazolo
A
2-Benzyl-5-methyl-7-(4-methylphenylsulfonyl)-4,5,6,7,8,9-hexahydro-
dione (48) (Table 5, entry 6): By using the procedure described for the
preparation of the compound 41 and 42 from bromoallene 24, the bro-
moallene 28 (50 mg, 0.14 mmol) was converted into 48 (11 mg, 28%
C
G
N
G
(57)
(Table 6,
1
yield) as colorless oil: H NMR (300 MHz, CDCl3): d=1.61–1.73 (m, 4H;
2”CH2), 1.79–1.83 (m, 2H; CH2), 2.28 (m, 2H; CH2), 3.58 (t, J=5.1 Hz,
2H; CH2), 4.45 (s, 2H; CH2Ph), 5.47 (s, 1H; C=CH), 7.29–7.40 ppm (m,
5H; Ph); 13C NMR (75 MHz, CDCl3): d=27.7, 28.8, 29.9, 30.5, 43.3, 48.9,
105.0, 127.4, 128.0, 128.4 (2C), 128.6 (2C), 134.9 ppm; IR (KBr): n˜ =1660
(N-C=C), 1303 (NSO2), 1172cm À1 (NSO2); MS (FAB): m/z (%): 301 (49)
[M++Na], 278 (100); HRMS (FAB): calcd for C14H18N2NaO2S [M+
+Na]: 301.0987; found: 301.0963.
2-Benzyl-3,5,6,11-tetrahydro
G
G
ACHTREUNG
20 mg, 0.625 mmol) was added to MeOH (1 mL) at room temperature
under nitrogen, and the mixture was stirred for 10 min at this tempera-
ture. [Pd
A
lene 37 (84.3 mg, 0.2mmol) in MeOH (1 mL) were added to the stirred
mixture at room temperature, and the resulting mixture was stirred for
1.5 h at 608C. After the mixture was quenched with saturated NH4Cl, the
whole was extracted with EtOAc. The extract was washed with water, sa-
turated NaHCO3 and brine, and dried over MgSO4. The filtrate was con-
centrated under reduced pressure to give an oily residue, which was puri-
fied by column chromatography over silica gel with n-hexane/EtOAc
(4:1) to give 53 (containing a small amount of 54; 53:54=12:1; 39 mg,
57% yield). Full characterization of the compound 53 was hampered by
its instability (the compound 53 is easily isomerized into the double bond
isomer 54).
Compound 53: Colorless oil; 1H NMR (300 MHz, CDCl3): d=2.57 (dt,
J=7.5, 7.5 Hz, 2H; CH2), 3.12(t, J=7.5 Hz, 2H; CH2), 3.49 (d, J=
1.5 Hz, 2H; CH2), 4.08 (s, 2H; CH2), 4.51 (tt, J=7.5, 1.5 Hz, 1H; C=
CH), 4.81 (s, 2H; CH2), 7.09–7.13 (m, 1H; Ph), 7.23–7.36 (m, 7H; Ph),
7.43–7.47 ppm (m, 1H; Ph).
Compound 54: Colorless oil; 1H NMR (300 MHz, CDCl3): d=1.75–1.83
(m, 2H; 5-CH2), 2.33 (t, J=6.0 Hz, 2H; 4-CH2), 2.80–2.84 (m, 2H; 6-
CH2), 4.10 (s, 2H; PhCH2), 4.60 (s, 2H; PhCH2), 5.37 (s, 1H; 3-H), 7.12–
7.54 ppm (m, 9H; Ph); 13C NMR (75 MHz, CDCl3): d=27.2, 31.8, 33.8,
47.3, 50.9, 111.2, 126.7, 127.5, 127.9, 128.4 (2C), 128.5 (2C), 128.9, 129.9,
À1
À
131.2, 133.2, 134.5, 141.4 ppm; IR (KBr): n˜ =1653 (C=C N), 1317 cm
(NSO2); MS (FAB): m/z (%): 340 (40) [M++Na], 91 (100); HRMS
(FAB): calcd for C19H20N2NaO2S [M++Na]: 363.1143; found: 363.1132.
5-Methoxymethyl-3,3-dimethyl-1-(4-methylphenylsulfonyl)-2,3-dihydro-
1H-pyrrole (67) (Table 7, entry 2): NaH (60% suspension of mineral oil;
9 mg, 0.225 mmol) was dissolved in MeOH (0.7 mL) at room temperature
under nitrogen, and the mixture was stirred for 10 min at this tempera-
ture. A solution of the bromoallene 65 (51.6 mg, 0.15 mmol) in MeOH
(0.8 mL) was added to the stirred mixture at room temperature, and the
resulting mixture was stirred for 7 h at 608C. Concentration under re-
duced pressure gave an oily residue, which was purified by column chro-
matography over silica gel with n-hexane/EtOAc (5:1) to give 67
(41.6 mg, 94% yield) as colorless crystals. M.p. 69–718C (n-hexane/
Et2O); 1H NMR (300 MHz, CDCl3): d=0.85 (s, 6H; 2”CMe), 2.42 (s,
3H; PhMe), 3.42(s, 3H; OMe), 3.46 (s, 2H; 2-CH 2), 4.30 (d, J=1.5 Hz,
2H; 1’-CH2), 5.08 (t, J=1.5 Hz, 1H; 4-H), 7.31–7.33 (m, 2H; Ph), 7.70–
7.73 ppm (m, 2H; Ph); 13C NMR (75 MHz, CDCl3): d=21.5, 28.1 (2C),
ACHTREUNG
A
G
U
G
(55)
(Table 6, entry 2): MeOH (0.7 mL) was added to NaH (60% suspension
of mineral oil; 15 mg, 0.38 mmol) at 08C under nitrogen, and the mixture
was stirred for 10 min at room temperature. [Pd(PPh3)4] (17.3 mg,
E
0.015 mmol) and a solution of the bromoallene 51 (86.2mg, 0.159 mmol)
in MeOH (1.0 mL) were added to the stirred mixture at room tempera-
ture, and the resulting mixture was stirred for 6 h at 608C. 4% HCl
(0.5 mL) was added to the mixture at room temperature. The whole was
extracted with EtOAc. The extract was washed with water, saturated
NaHCO3, and brine, and dried over MgSO4. The filtrate was concentrat-
ed under reduced pressure to give an oily residue, which was purified by
column chromatography over silica gel with n-hexane/EtOAc (4:1) to
Chem. Eur. J. 2007, 13, 1692– 1708
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1705

H. Ohno, T. Tanaka et al.
40.5, 58.6, 63.1, 68.4, 122.4, 127.6 (2C), 129.6 (2C), 134.3, 138.0,
[3] a) J. L. Castro, V. G. Matassa, Tetrahedron Lett. 1993, 34, 4705–
4708; b) J. L. Castro, R. Baker, A. R. Guiblin, S. C. Hobbs, M. R.
Jenkins, M. G. N. Russell, M. S. Beer, J. A. Stanton, K. Scholey, R. J.
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2004, 6, 556–563.
À1
À
143.6 ppm; IR (KBr): n˜ =1655 (C=C N), 1348 cm (NSO2); MS (FAB):
m/z (%): 318 (100) [M++Na]; HRMS (FAB): calcd for C15H22NO3S [M+
+Na]: 296.1320; found: 296.1340.
8-Benzyl-7,7-dioxo-5,6,7,8,9,11,12,13-octahydro-7-thia-6,8-diazabenzocy-
cloundecen-10-one (75) and 2-benzyl-4,5,6,11-tetrahydro-2H-1-thia-
2,11a-diazabenzo[a]cyclopenta[d]cyclooctene 1,1-dioxide (54): NaH
(60% suspension of mineral oil; 15 mg, 0.375 mmol) was dissolved in
MeOH (0.5 mL) at room temperature under nitrogen, and the mixture
was stirred for 10 min at this temperature. [Pd
A
[4] a) S. Boudjabi, G. Dewynter, N. Voyer, L. Toupet, J.-L. Montero,
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0.015 mmol) and a solution of the bromoallene 37 (63.2mg, 0.15 mmol)
in MeOH (1 mL) were added to the stirred mixture at room temperature,
and the resulting mixture was stirred for 1.5 h at 608C. The mixture was
made acidic with 4% HCl, and the whole was extracted with Et2O. The
extract was washed with water and brine, and dried over MgSO4. The fil-
trate was concentrated under reduced pressure to give an oily residue,
which was purified by column chromatography over silica gel with n-
hexane/EtOAc (4:1) to give 75 (22 mg, 41% yield) and 54 (11.4 mg, 22%
yield).
Compound 75: Colorless crystals; m.p. 148–1498C (n-hexane/EtOAc);
1H NMR (300 MHz, CDCl3): d=2.10 (tt, J=6.3, 6.3 Hz, 2H; 12-CH 2),
2.42 (t, J=6.3 Hz, 2H; 11-CH2), 2.65 (t, J=6.3 Hz, 2H; 13-CH2), 3.61 (s,
2H; 9-CH2), 4.15 (d, J=5.4 Hz, 2H; 5-CH2), 4.44 (t, J=5.4 Hz, 1H;
NH), 4.70 (s, 2H; CH2Ph), 7.20–7.37 ppm (m, 9H; Ph); 13C NMR
(75 MHz, CDCl3): d=25.0, 29.7, 40.5, 45.3, 51.1, 53.1, 126.7, 128.0, 128.7
(2C), 128.9 (3C), 130.1, 130.8, 134.0, 135.5, 140.7, 208.6 ppm; IR (KBr):
n˜ =3298 (NHSO2), 1716 (C=O), 1321 cmÀ1 (NHSO2); elemental analysis
calcd (%) for C19H22N2O3S: C 63.66, H 6.19, N 7.82; found: C 63.58, H
6.21, N 7.78.
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Acknowledgements
This work was supported by a Grant-in-Aid for Encouragement of
Young Scientists from the Ministry of Education, Culture, Sports, Science
and Technology of Japan and Meiji Seika, which are gratefully acknowl-
edged. H.H. is grateful to Research Fellowships of the Japan Society for
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1692– 1708

Heterocycles
FULL PAPER
1257–1259; c) R. W. Saalfrank, M. Haubner, C. Deutscher, W.
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G
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[23] W. H. Pearson, M. J. Postich, J. Org. Chem. 1994, 59, 5662–5671.
[24] For synthesis of the propargyl alcohol (Æ)-7e, see the Supporting
Information.
Hauck, J. Org. Chem. 1996, 61, 5013–5023; c) M. M. Cid, D. Domꢃ-
nguez, L. Castedo, E. M. Vꢇzquez-Lꢈpez, Tetrahedron 1999, 55,
5599–5610.
[25] We observed by 1H NMR spectra that the isomer 16a is gradually
converted into the isomer 11a in CD3OD. Therefore, it is apparent
that the isomer 11a is thermodynamically more stable than the
isomer 16a. At the present stage of our understanding, preferential
formation of the relatively unstable isomer 16a by the reaction with
TBAF/THF over the isomer 11a is unclear.
[32] Isolation of 20’b was extremely difficult due to the hydrolysis during
purification, yielding a ring-opening product 23b. Accordingly, 23b
was isolated in 70% yield after acidic workup and fully character-
ized.
[26] Structure of trans-12e and cis-12e’ were determined by comparison
of J values of the ring protons, as shown below.
[33] The ratio of 20’b/21b was determined as follows: concentration of
the reaction mixture and rapid filtration with short pad of SiO2 gave
a crude mixture, 1NMR analysis of which showed formation of 20’b
and 21b (2.5:1) quantitatively, without detecting 23b.
[34] To reveal the intermediate of this tandem cyclization reaction, we
investigated stepwise reaction of the bromoallene 24. Treatment of
the bromoallene 24 with NaH in DMF gave piperidine 78 in 79%
yield. Reaction of 78 under the same reaction conditions as the one-
pot reaction afforded the exo-cyclized product 29 (93%) as a single
isomer.
[27] The structure of 11i was determined by NOE analysis.
[28] The phenyl group of 9i promotes the regioselective cyclization onto
the central allenic carbon, presumably through a highly conjugated
anionic transition state A and/or intermediate B.
[35] Structure of (Æ)-32 was confirmed by NOE analysis as shown
below.
[29] Formation of the alkyne 18i can be rationalized by addition-elimina-
tion mechanism. One plausible pathway is shown below.
[30] A similar result was obtained by the cyclization in the presence of
palladium(0), although the yield was lower, as shown below.
[31] Related five-membered ring formations by intramolecular amination
of carbon–carbon triple bond have been already reported, see: a) Y.
Tamaru, M. Kimura, S. Tanaka, S. Kure, Z. Yoshida, Bull. Chem.
Soc. Jpn. 1994, 67, 2838–2849; b) P. A. Jacobi, H. L. Brielmann, S. I.
[36] The reaction of 27 with NaH in MeOH afforded an inseparable mix-
ture of (E)- and (Z)-enynes, produced by elimination of HBr under
the basic reaction conditions.
[37] A trace amount of 39 was also detected by 1H NMR spectroscopy.
[38] The reaction with 2mol% [Pd (PPh3)4] was ineffective: only 15% of
A
the cyclosulfamide 49 and a trace amount of 32, produced by the un-
catalyzed reaction (Table 5), were obtained.
Chem. Eur. J. 2007, 13, 1692– 1708
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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H. Ohno, T. Tanaka et al.
[39] Without treatment with HCl, the ratio of regioisomers (products of
the type 53 and 54) is variable.
[40] The palladium-catalyzed cyclization of bromoallene 79 having a six-
atom tether between the sulfamide and allenyl group gave a trace of
the desired tricyclic sulfamide 80 containing a nine-membered ring
(<5% yield).
[42] a) S. Ogoshi, K. Tsutsumi, S. Nishiguchi, H. Kurosawa, J. Organo-
met. Chem. 1995, 493, C19–C21; b) K. Tsutsumi, S. Ogoshi, S. Nishi-
guchi, H. Kurosawa, J. Am. Chem. Soc. 1998, 120, 1938–1939; c) K.
Tsutsumi, T. Kawase, K. Kakiuchi, S. Ogoshi, Y. Okada, H. Kurosa-
wa, Bull. Chem. Soc. Jpn. 1999, 72, 2687–2692; d) S. Ogoshi, H. Kur-
osawa, J. Synth. Org. Chem. Jpn. 2003, 61, 14–23.
[43] In the reaction of propargylic carbonates, it is proposed that the first
nucleophilic addition onto the h3-propargylpalladium produces a
metallacyclobutene, protonation of which generates the h3-allylpalla-
dium complex: C. P. Casey, J. R. Nash, C. S. Yi, A. D. Selmeczy, S.
Chung, D. R. Powell, R. K. Hayashi, J. Am. Chem. Soc. 1998, 120,
722–733.
[41] Treatment of bromoallene 65 with NaOMe in DMF gave azetidine
81 as a major product and a small amount of dihydropyrrole 67
having a methoxymethyl group. We have already reported the for-
mation of azetidines by NaH-mediated intramolecular amination of
bromoallenes: see, reference [13b].
Received: September 25, 2006
Published online: January 2, 2007
1708
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1692– 1708