Synthesis of fused and linked bicyclic nitrogen heterocycles by palladiumcatalyzed domino cyclization of propargyl bromides

Article abstract of DOI:10.1002/chem.201000653

The palladium(0)-catalyzed direct construction of bicyclic heterocycles is described. Treatment of propargyl bromides that have nucleophilic functional groups connected by two or three carbon atoms with catalytic [Pd(PPh ₃)₄] affords

Full text of DOI:10.1002/chem.201000653

DOI: 10.1002/chem.201000653
Synthesis of Fused and Linked Bicyclic Nitrogen Heterocycles by Palladium-
Catalyzed Domino Cyclization of Propargyl Bromides
Akinori Okano,[a] Koji Tsukamoto,[b] Shohei Kosaka,[c] Hatsuo Maeda,[b] Shinya Oishi,[a]
Tetsuaki Tanaka,*[c] Nobutaka Fujii,*[a] and Hiroaki Ohno*[a]
Abstract: The palladium(0)-catalyzed
direct construction of bicyclic heterocy-
cles is described. Treatment of proparg-
yl bromides that have nucleophilic
functional groups connected by two or
three carbon atoms with catalytic [Pd-
heterocycles can be obtained selective-
ly when using substrates with appropri-
ate nucleophilic groups. We also de-
scribe the reaction of a 2-alkynylazeti-
dine derivative with a catalytic amount
of [PdACTHUNRTGNEUNG(PPh3)4] under base-free condi-
tions, which affords the same fused het-
erocycles as the corresponding prop-
argyl bromides.
Keywords: cyclization · domino re-
actions · heterocycles · palladium ·
propargylic compounds
ACHTUNGTRENNUNG(PPh3)4] affords bis-cyclization prod-
ucts in good yields. The desired bicyclic
Introduction
Development of useful druglike templates is an important
subject in drug discovery. Although polycyclic structures
fused by a 1,2-diamine motif are found in many biologically
active alkaloids,[1] this type of structure has not been widely
used as a scaffold for biologically active compounds. Poten-
tial scaffolds that have seen little use include the bicyclic
Scheme 1. Bicyclic heterocycles with 1,2-diamine fusion motif.
structures of the pyrroloACTHNUGRTENUNG[3,2-b]pyridines A and 1,5-naphthyr-
idines B (Scheme 1).[2] In contrast, the b-carboline deriva-
tives C have been more widely applied.[3] The minimal use
of these bicyclic structures is partly due to the absence of re-
liable methods for their construction. In our previous work,
we found that bromoallenes D could act as allyl dication
equivalents E in the presence of a palladium(0) catalyst and
alcohol. These were extremely useful for the synthesis of
medium-sized heterocycles 3[4] and bicyclic sulfamides 6[5]
(Scheme 2).
Based on this dual reactivity of bromoallenes, we planned
a direct construction of bicyclic structures A and B by
domino cyclization of the allenyl/propargyl bromides 7/8
containing nucleophilic functional groups on each terminal
carbon (Scheme 3). This cyclization would proceed through
formation of h3-propargylpalladium 9 by palladation of the
bromides 7/8. Subsequent nucleophilic attack on the central
carbon of 9 would lead to the h3-allylpalladium intermedi-
ates 10 and/or 11. A second nucleophilic cyclization at the
distal or proximal carbon atom of the intermediates 10 and
11 would provide the corresponding four fused or linked bi-
cyclic compounds 12–15. Apparently, regioselectivity in the
first and second cyclizations (path A vs. B, C vs. D, and E vs.
F) is key to success with this strategy.
[a] Dr. A. Okano, Dr. S. Oishi, Prof. Dr. N. Fujii, Prof. Dr. H. Ohno
Graduate School of Pharmaceutical Sciences
Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan)
Fax : (+81)75-753-4570
E-mail: nfujii@pharm.kyoto-u.ac.jp
hohno@pharm.kyoto-u.ac.jp
[b] Dr. K. Tsukamoto, Prof. Dr. H. Maeda
School of Pharmacy, Hyogo University of Health Sciences
1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo 650-8530 (Japan)
[c] Dr. S. Kosaka, Prof. Dr. T. Tanaka
Graduate School of Pharmaceutical Sciences
Osaka University, 1–6 Yamadaoka
Suita, Osaka 565-071 (Japan)
Fax : (+81)6-6879-8214
E-mail: t-tanaka@phs.osaka-u.ac.jp
Tsuji and co-workers originally developed palladium-cata-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000653.
lyzed domino reactions of propargylic compounds.[6,7] It is
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FULL PAPER
Results and Discussion
Synthesis of propargyl bromides that have nucleophilic func-
tional groups: Because efficient chemoselective synthesis of
1,3-disubstituted bromoallenes of type 7 with conventional
methods has proven to be difficult,[11] we focused on the
domino reaction of propargyl bromides 8. The representa-
tive propargyl bromides 18 and 19 that have nitrogen and
oxygen nucleophiles for the domino cyclization were readily
prepared as described below (Scheme 4). Oxidation of N-
Scheme 2. Palladium(0)-catalyzed construction of medium-ring heterocy-
cles and bicyclic sulfamides by using bromoallenes as allyl dication equiv-
alents.
Scheme 4. Synthesis of propargyl bromides 18 and 19 that have nitrogen
or oxygen nucleophiles. Reagents: a) PCC, molecular sieves (MS; 4 ꢁ),
ꢀ
CH2Cl2, 08C; b) HC C
U
protected 3-aminopropan-1-ols 16 to the aldehydes with
PCC (PCC=pyridinium chlorochromate) followed by addi-
tion of acetylide derived from protected but-3-yn-1-ol af-
forded propargyl alcohols 17. Bromination with CBr4 and
PPh3 in the presence of imidazole and subsequent removal
of the silyl group with 1% HCl/EtOH provided the proparg-
yl bromides 18. Introduction of a sulfonamide group by a
Mitsunobu reaction with N-Boc sulfonamide followed by
cleavage of the Boc group with 3n HBr/EtOAc afforded the
desired propargyl bromides 19a–e. Other propargyl bro-
mides that have nitrogen or oxygen nucleophiles on each
terminal carbon were prepared in a straightforward manner
by a similar protocol (see the Supporting Information).
The malonate derivatives 23 were synthesized from prop-
argyl alcohols 17a and 20 as shown in Scheme 5. The iodides
21 were produced after silylation of a secondary hydroxy
group, desilylation of the primary hydroxy group with dilute
HCl, and iodination with I2 and PPh3 in the presence of im-
idazole. Treatment of 21 with sodium dimethyl malonate
and cleavage of the silyl ether with TBAF provided proparg-
yl alcohols 22. Finally, bromination of 22 with CBr4 and
PPh3 gave the desired propargyl bromides 23.
Scheme 3. Reaction courses of palladium(0)-catalyzed domino cyclization
of allenyl/propargyl bromides 7 and 8.
widely documented that these reactions provide a powerful
approach for construction of heterocyclic frameworks by
combination of inter- and intramolecular nucleophilic at-
tacks.[6,8,9] In contrast, there is no precedent for the direct
construction of bicyclic heterocycles through intramolecular
domino cyclizations of propargylic compounds. In the pres-
ent study, we report full details of our investigation into
direct construction of pyrroloACTHNUGRTNEUNG[3,2-b]pyridines A and 1,5-
naphthyridines B by palladium-catalyzed domino cyclization
of propargyl bromides that have two nucleophilic moiet-
ies.[10] We also investigated the treatment of a 2-alkynylazeti-
dine derivative with a catalytic amount of palladium(0), and
found that under base-free conditions it affords the same
fused heterocycle as the corresponding propargyl bromide.
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H. Ohno, T. Tanaka, N. Fujii et al.
We initially investigated the domino cyclization with prop-
argyl bromide 30 that has two hydroxy groups (Table 1,
entry 1). Contrary to our expectations, furan derivative 31
Table 1. Reaction of propargyl bromides that have oxygen and/or nitro-
gen nucleophiles.[a]
Entry
Substrate
t [h]
Product (Yield [%])[b]
1
4.5
30
31 (62)
2
3
18a: NuA =NTs, NuB =O
18c: NuA =O, NuB =NTs
3.5
4.5
32 (64 from 18a)
32 (52 from 18c)
Scheme 5. Synthesis of propargyl bromides 23 that have carbon and ni-
trogen nucleophiles. Reagents: a) TBDPSCl, imidazole, THF, RT; b) 1%
HCl/EtOH, RT; c) I2, PPh3, imidazole, THF, RT; d) NaH, CH2ACTHNUTRGNEUNG(CO2Me)2,
19a
Pd source
33a
DMF, RT; e) TBAF, THF, RT; and f) CBr4, PPh3, imidazole, THF, RT.
Abbreviations: TBDPS=tert-butyldiphenylsilyl; TBAF=tetrabutylam-
monium fluoride.
4
[Pd
[Pd2A(dba)3·CHCl3]
2A(dba)3·CHCl3], DPPF
[Pd(OAc)2]
(PPh3)4]
0.5
16
12
3
89
0
0
5[c]
6[c,d]
7
G
CHTUNGTRENNUNG
E
G
N
trace
Reaction of propargyl bromides that have nucleophilic
groups tethered by two carbon atoms: We first investigated
the domino cyclization of propargyl bromides of type 24
with the nucleophiles connected by two carbon atoms
(Scheme 6). In this reaction, highly symmetrical h3-propar-
[a] All reactions were carried out with [Pd
(2.5 equiv) in MeOH at 608C. [b] Yields of isolated products. [c] [Pd2-
(dba)3·CHCl3] (2.5 mol%) was used. [d] DPPF (5 mol%) was used.
ACHTUNGTREN(NUNG PPh3)4] (5 mol%) and NaH
AHCTUNGTRENNUNG
was obtained in 62% yield under standard conditions for
the formation of bicyclic sulfamides from bromoallenes
([PdACHTNUGRTNEUNG
(PPh3)4], NaH, MeOH, 608C).[5] Likewise, the reaction
of propargyl bromides 18a and 18c that have hydroxy and
tosylamide nucleophilic groups afforded the furan 32 in
moderate yields (64 and 52%; Table 1, entries 2 and 3, re-
spectively). These results demonstrate that the hydroxy
group of 18 and 30 is more reactive than the tosylamide
group in the first cyclization, and that a more reactive nucle-
ophilic group promotes the first cyclization irrespective of
its location. These results are consistent with our hypothesis.
In other words, both NuA and NuB with appropriate carbon
tethers in the palladium complex 25 (Scheme 6) can react
with the central carbon of the propargylic moiety. Encourag-
ingly, when the bis-tosylamide 19a was employed, the de-
sired domino cyclization proceeded to provide the fused bis-
cyclization product 33a in 89% yield (Table 1, entry 4).[13]
Other palladium sources and ligands have proven to be inef-
fective for the desired reaction (Table 1, entries 5–7).
Proposed reaction mechanisms for the formation of furan
31 and bis-cyclization product 33a are shown in Scheme 7.
Oxidative addition of propargyl bromides 19a or 30 to palla-
dium(0) would result in h3-propargylpalladium complexes.
Subsequent nucleophilic attack onto the central carbon
atoms of these complexes would produce h3-allylpalladiums
syn-34 and anti-34, which are in equilibrium.[14] For the
second cyclization to proceed and afford a fused ring, it is
necessary to form anti-34, which has the nucleophilic group
Scheme 6. Reaction courses of propargyl bromides 24 with nucleophiles
connected by two carbon atoms.
gylpalladium complex 25 will be formed as the intermedi-
ate.[12] Therefore, use of the substrates in which two nucleo-
philes are the same (NuA =NuB) would avoid the regioselec-
tivity issue during the first cyclization (path A vs. B). Fur-
thermore, the regioselectivity of the first cyclization is ex-
pected to be controlled by the relative reactivity of the two
nucleophiles (NuA and NuB). Otherwise, we can estimate
the reactivity difference of a nucleophilic group depending
on its location. The second cyclization on the distal carbon
of the h3-allylpalladium complex 26 or 27 would afford the
fused bicyclic products 28 or 29, respectively.
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Direct Construction of Bicyclic Heterocycles
FULL PAPER
Table 2. Palladium-catalyzed formation of fused bicyclic heterocycles.[a]
Entry
Substrate
t [min]
Product (Yield [%])[b]
1
5
19b
19c
36
33b (79)
33b (87)
2
3
4
5
6
5
45
5
33c (68)
33d (91)
19d
19e
45
30
Scheme 7. Plausible reaction mechanisms for the formation of furan 31
and bicyclic product 33a.
33e (51)
33 f (16)
located in proximity to the distal carbon of the h3-allylpalla-
dium moiety. Although syn-34 would usually be more stable
than anti-34,[15] it is an inappropriate isomer for the second
cyclization at the distal position. Accordingly, the reaction
of propargyl bromide 30 that has two hydroxy groups under-
goes b-hydride elimination from syn-34 (Nu=O) followed
by aromatization of diene 35 to produce furan 31. Formation
of furan 32 from 18 can be explained in a similar manner. In
sharp contrast, the propargyl bromide 19a that has two
23a
37 (78)
[a] All reactions were carried out with [PdAHCUTNTGERG(NNUN PPh3)4] (5 mol%) and NaH
(2.5 equiv) in MeOH at 608C. [b] Yields of isolated products.
33c (68%) and 33d (91%), respectively (Table 2, entries 3
and 4). When propargyl bromide 19e that has tosyl- and me-
sylamide groups was utilized, the first cyclization by the me-
sylamide group preferentially proceeded to afford 33e as a
major product (33e: 51%; 33 f: 16%; Table 2, entry 5).[16]
When using the malonate derivative 23a, the first cyclization
by the tosylamide group and the second cyclization by the
malonate moiety selectively proceeded to afford 37 in 78%
yield (Table 2, entry 6).
The bis-cyclization products can be easily converted into
the pyrrole derivatives. For example, the desired fused pyr-
roles 39a–f were obtained in moderate yields (51–70%)
through isomerization of 33 in CDCl3 followed by DDQ-
mediated (DDQ=2,3-dichloro-5,6-dicyano-p-benzoquinone)
oxidation except for 33d (Scheme 8).[17,18]
tosylACHTUNGTRENNUNG
amide groups will form h3-allylpalladium complexes
syn- and anti-34 with a sterically congested Nu group (Nu=
NTs), which would destabilize syn-34. Thus, formation of
the desired product 33a from the bis-tosylamide derivative
19a can be rationalized by the assistance of the tosylamide
group in the five-membered ring.
Next, we investigated the reactivity of several nucleophilic
groups in the domino cyclization. The results are summar-
ized in Table 2. The propargyl bromide 19b that has nosyl-
and tosylamide groups afforded bicyclic product 33b in
79% yield, in which the tosylamide group was incorporated
into the five-membered ring (Table 2, entry 1). Similarly, the
same bicyclic product 33b was formed in 87% yield from
the regioisomeric propargyl bromide 19c (Table 2, entry 2).
These results show that the tosylamide group participates in
the first cyclization to form a five-membered ring, which is
followed by the second cyclization by the nosylamide, irre-
spective of their location. Propargyl bromides 36 and 19d
that have bis-mesyl or bis-nosylamide groups were also effi-
ciently converted into the corresponding bicyclic products
Next, the domino reaction of the 2-alkynylazetidine deriv-
ative 40 was examined (Scheme 9). As we expected, the de-
sired domino reaction through ring-expansion of 40 was fa-
cilitated with catalytic [PdACHTNUGRTNEUNG(PPh3)4] in MeOH to produce bi-
cyclic product 33a in 81% yield. Because aza-anionic inter-
mediate 41 will be directly formed from 40, the reaction
proceeded under base-free conditions.
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H. Ohno, T. Tanaka, N. Fujii et al.
ed the corresponding bicyclic products (43b: 57%; 44b:
10%; Table 3, entry 2). Interestingly, the reaction of anti-
42a afforded the bicyclic products 43a and 44a (43a: 42%;
44a: 22%; Table 3, entry 3), which are the same products as
from syn-42a. These results clearly demonstrate that the ste-
reochemistry of the substrates was not reflected in that of
the product. Remarkably, when the propargyl bromide anti-
42b was employed, the first cyclization by a more congested
nitrogen atom preferentially proceeded to afford the bicyclic
product 44b as a major isomer (43b: 21%; 44b: 49%;
Table 3, entry 4). The unambiguous structure assignments
for 33d, 43b, and 44b were confirmed by X-ray analysis
(Figure 1).[19,20] Interestingly, the bulkier isopropyl group of
Scheme 8. Synthesis of fused pyrrole derivatives 39a–f.
Scheme 9. Ring-expansion and domino cyclization of 2-alkynylazetidine
40.
We then investigated the stereochemical courses of the
domino cyclization by using propargyl bromides syn- and
anti-42 that have an alkyl group (Me or iPr) on the carbon
substituted by a tosylamide group (Table 3). When the reac-
tion of propargyl bromide syn-42a was conducted under
standard conditions, the first nucleophilic attack by the less-
hindered nitrogen atom proceeded in moderate selectivity
to afford bis-cyclization product 43a as a major product
(43a: 52%; 44a: 13%; Table 3, entry 1). Similarly, propargyl
bromide syn-42b that has a bulkier alkyl group (iPr) afford-
Table 3. Domino cyclization of propargyl bromides syn- and anti-42.[a]
Entry
Substrate
t [min]
Product (Yield [%])[b]
1
2
3
4
syn-42a: R1 =Me
syn-42b: R1 =iPr
anti-42a: R1 =Me
anti-42b: R1 =iPr
30
45
30
30
43a (52)
43b (57)
43a (42)
43b (21)
44a (13)
44b (10)
44a (22)
44b (49)
[a] All reactions were carried out with [Pd
G
Figure 1. The crystal structures of a) 33d, b) 43b, and c) 44b. Ellipsoids
(2.5 equiv). [b] Yields were determined by using NMR spectroscopy.
are shown at the 30% probability level.
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Direct Construction of Bicyclic Heterocycles
FULL PAPER
43b and 44b was located in the pseudoaxial position, pre-
sumably due to steric repulsion between oxygen atoms of
the sulfonyl group and the isopropyl group.
Based on these results, plausible stereochemical courses
of the domino cyclization of propargyl bromides syn- and
anti-42 are shown in Scheme 10. Stereoselective anti-SN2ꢂ
attack of palladium(0) onto syn-42 would provide the alle-
nylpalladium complex 45,[21] which will be followed by trans-
formation into h3-propargylpalladium complex 46. The first
cyclization by the less-hindered nitrogen atom would pro-
cates that inversion of the configuration occurs during these
steps. One possible explanation is that unfavorable steric re-
pulsions around the alkyl group in h3-allylpalladium com-
plexes 53 and 54, which will be produced from anti-42
through path C and path D in a similar manner to the reac-
tion of syn-42, might interfere the anti-nucleophilic attack of
the nitrogen nucleophile. Therefore, inversion of the config-
uration of 53 and 54 would be promoted to afford the inter-
mediates 49 and 52, respectively, the same complexes as de-
rived from syn-42.
duce
a
fused palladacyclobutene intermediate 47
(path A).[22] Protonation of 47 leads to the h3-allylpalladium
complex 48, which is in equilibrium with 49. The second
anti-cyclization by the more hindered nitrogen atom of 49
Reaction of propargyl bromides that have a nucleophilic
group connected by three carbon atoms: Finally, we investi-
gated the domino cyclization of the propargyl bromides 55
having a longer carbon tether between the NuBH group and
propargyl moiety (Scheme 11). In this case, h3-propargylpal-
ladium complex 56 would be formed. Thus, two types of h3-
allylpalladium complexes 57 and/or 58 can be produced in
the first cyclization (path A vs. path B). The second cycliza-
tion of the resulting h3-allylpalladium complex 57 will pro-
would give the major isomer 43 in
a stereoselective
manner.[23] The first cyclization by the more hindered nitro-
gen atom will form the minor isomer 44 in a similar pathway
via palladacycle (50) formation (path B), protonation to give
51, and the anti-type second cyclization of 52. The fact that
anti-42 affords the same isomeric products 43 and 44 indi-
Scheme 10. Stereochemical courses of the domino reaction of propargyl bromides syn- and anti-42.
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H. Ohno, T. Tanaka, N. Fujii et al.
Table 4. Palladium(0)-catalyzed formation of fused and linked bicyclic
heterocycles.[a]
Entry
Substrate
t [min]
Product (Yield [%])[b]
1
35
61a
61b
61c
61d
61e
62
63a (70)
64a (13)
64b (5)
2
3
4
5
6
7
45
40
35
20
90
30
Scheme 11. Reaction courses of propargyl bromides 55.
63b (74)
vide the linked bicyclic product 59, whereas the intermedi-
ate 58 will form a 6,6-fused bicyclic product 60.
First, the domino cyclization of the propargyl bromides
having various nucleophilic groups was examined. The re-
sults are summarized in Table 4. Reaction of propargyl bro-
mides 61a and 61b that have bis-tosyl or bis-nosylamide
group favored six-membered ring formation in the first cyc-
lization to afford the corresponding fused bicyclic product
63a (70%) and 63b (74%), respectively, in good yields
(Table 4, entries 1 and 2).[24] Interestingly, when the proparg-
yl bromide 61c that has nosyl- and tosylamide groups on
each terminus was employed, fused bicyclic heterocycle 63c
was obtained as the sole isomer in 73% yield (Table 4,
entry 3). This product may result from the predominant six-
membered ring formation by the nosylamide group over
five-membered ring formation by the tosylamide group. The
regioisomeric propargyl bromide 61d, which has a nosyl-
63c (73)
63d (67)
63e (39)
64d (15)
64e (21)
65 (72)
66 (60)
ACHTUNGTRENNUNGamide group on the carbon close to the bromine atom, also
resulted in formation of the same type of 6,6-fused bicyclic
product 63d with somewhat decreased selectively (63d:
67%; 64d: 15%; Table 4, entry 4). The reaction of propargyl
bromide 61e that has mesyl- and tosylamide groups afforded
the fused bicyclic product 63e (39%) and the linked bicyclic
heterocycle 64e (21%), which shows relatively lower reac-
tivity of the mesylamide group in the first cyclization
(Table 4, entry 5). From these observations, the first cycliza-
tion of the diamine derivatives generally favors six-mem-
bered ring formation, in which the selectivity depends on
the relative reactivity of the nitrogen functionality. In sharp
contrast, amino alcohol derivative 62 selectively afforded
linked bis-cyclization product 65 in 72% yield (Table 4,
entry 6). In a similar manner, malonate derivative 23b ex-
clusively produced linked bicyclic product 66 in 60% yield
(Table 4, entry 7). Therefore, the regioselectivity of the first
cyclization is controlled by a subtle balance of the nucleo-
philicity of the functional group and ring size of the cycliza-
tion.
23b
[a] All reactions were carried out with [PdACHTNURTGNEUNG(PPh3)4] (5 mol%) and NaH
(2.5 equiv) in MeOH at 608C. [b] Yields of isolated products.
cleophilic functionalities on each terminal carbon. In many
cases, when using substrates with appropriate nucleophiles
and carbon tethers, this reaction selectively provides the de-
sired bicyclic heterocycles. The 2-alkynylazetidine derivative
also provides the same bicyclic compound through a ring-ex-
pansion reaction under base-free conditions. This strategy
could provide a convenient approach to the development of
druglike templates such as pyrrolo
naphthyridines.
ACHTUNGERTN[NUNG 3,2-b]pyridines and 1,5-
Experimental Section
General procedure for domino cyclization of propargylic bromides: To
form compound 33a (Table 1, entry 4), MeOH (0.5 mL) was added to
NaH (60% suspension of mineral oil; 9.4 mg, 0.234 mmol) at 08C under
nitrogen, and the mixture was stirred at room temperature for 15 min.
Conclusion
In conclusion, we have developed a palladium(0)-catalyzed
novel domino cyclization of propargyl bromides that has nu-
[Pd
ACHTUNGTREN(NUNG PPh3)4] (5.4 mg, 0.00468 mmol) and a solution of the propargyl bro-
mide 19a (48.0 mg, 0.0937 mmol) in MeOH (0.5 mL) were successively
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Direct Construction of Bicyclic Heterocycles
FULL PAPER
added to the stirred mixture at room temperature, and the resulting mix-
ture was stirred at 608C for 30 min and filtered through a short pad of
silica gel with n-hexane/EtOAc (1:1). The filtrate was concentrated and
purified by flash chromatography over silica gel with n-hexane/EtOAc
(3:2) to give 33a (36.0 mg, 89% yield) as colorless crystals. M.p. 145–
1468C (n-hexane/CHCl3); 1H NMR (500 MHz, CDCl3): d=1.89 (dddd,
J=12.0, 12.0, 12.0, 9.0 Hz, 1H), 2.03 (dddd, J=17.5, 9.0, 7.0, 5.0 Hz, 1H),
2.31–2.38 (m, 1H), 2.42 (s, 3H), 2.44 (s, 3H), 2.48 (dd, J=12.0, 6.0 Hz,
1H), 2.64 (ddd, J=12.0, 9.0, 5.0 Hz, 1H), 3.00–3.05 (m, 1H), 3.27 (ddd,
J=12.0, 10.5, 6.0 Hz, 1H), 3.59 (ddd, J=12.0, 5.0, 5.0 Hz, 1H), 3.75 (dd,
J=10.5, 9.0 Hz, 1H), 5.78 (dd, J=7.0, 5.0 Hz, 1H), 7.26 (d, J=8.0 Hz,
2H), 7.30 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.65 ppm (d, J=
8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3): d=21.5 (2C), 23.8, 30.2, 44.3,
47.1, 56.0, 105.0, 127.2 (2C), 127.5 (2C), 129.6 (2C), 129.8 (2C), 133.5,
134.3, 135.9, 143.9, 144.1 ppm; IR (KBr): n˜ = 1597 (C=C), 1357 (NSO2),
1152 cmÀ1 (NSO2); MS (FAB): m/z (%): 433 (93) [M+H], 277 (100);
HRMS (FAB): calcd for C21H25N2O4S2 [M+H]: 433.1256; found:
433.1249.
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Acknowledgements
This work was supported in part by Grants-in-Aid for Encouragement of
Young Scientists (A) (H.O.) and for Scientific Research (B) (T.T.) from
the Ministry of Education, Culture, Sports, Science and Technology of
Japan, and Targeted Proteins Research Program. A.O. is grateful for Re-
search Fellowships from the Japan Society for the Promotion of Science
(JSPS) for Young Scientists. Appreciation is expressed to Fundamental
Studies in Health Sciences of the National Institute of Biomedical Inno-
vation (NIBIO).
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Chem. Eur. J. 2010, 16, 8410 – 8418
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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Received: March 15, 2010
Published online: June 14, 2010
8418
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