Synthesis of 3-aroyl-4-hydroxy-4-arylpiperidine derivatives by DBU-catalyzed reactions of amines with vinyl ketones

Article abstract of DOI:10.1055/s-0031-1291162

In one-pot cascade reaction, a series of functionalized 3-aroyl-4-hydroxy-4-arylpiperidine derivatives were prepared from sulfonamides and vinyl ketones with good to excellent yields and diastereoselectivities. The reaction was catalyzed by the commercially available Lewis base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and could be easily manipulated under mild condition. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1291162

LETTER
▌1691
lSetyternthesis of 3-Aroyl-4-hydroxy-4-arylpiperidine Derivatives by DBU-
Catalyzed Reactions of Amines with Vinyl Ketones
Synthesis of 3-Aroyl-4-hydroxy-4-arylpiperidines
Xiaodong Liu, Qiao Chen, Wenyi Li, Yuan Liang, Rui Wang*
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Science, Institute of Biochemistry and
Molecular Biology School of Life Science, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8912567; E-mail: wangrui@lzu.edu.cn
Received: 14.03.2012; Accepted after revision: 16.04.2012
costly protecting-group manipulations as well as the iso-
lation of reaction intermediates. In addition, molecular
complexities are often achieved quickly in this way, ac-
Abstract: In one-pot cascade reaction, a series of functionalized 3-
aroyl-4-hydroxy-4-arylpiperidine derivatives were prepared from
sulfonamides and vinyl ketones with good to excellent yields and
4
diastereoselectivities. The reaction was catalyzed by the commer- companied by high levels of stereoselectivities. There is,
cially available Lewis base 1,8-diazabicyclo[5.4.0]undec-7-ene however, usually one critical requirement for any cascade
(DBU) and could be easily manipulated under mild condition.
reaction: the conditions for the consecutive reactions are
5
Key words: Michael addition, vinyl ketones, cascade reaction, cy- compatible with the former reaction. Therefore, the ex-
clization, stereoselectivity
ploration of catalyzed cascade reactions by employing a
single catalyst that is capable of promoting each single
step is one of the major topics of current research. Consid-
Piperidine derivatives are key structural components in ering the benefits of tolerance of numerous functional
many biological active compounds and drugs. Such mol- groups and requirement for mild reaction conditions, we
ecules have been investigated as, for instance, cytotoxic consider that the organic bases have been particularly fa-
agents, dopamine transporter (DAT) inhibitors, and po- vorable. Herein, we report a successful Michael–Mi-
1
tential anticonvulsant compounds. These core units can chael–Aldol cascade reaction in which multiple steps are
also be used as intermediates for the synthesis of impor- catalyzed by a Lewis base catalyst and which provides a
tant compounds such as the popular antihistaminic agent series of 3-aroyl-4-hydroxy-4-arylpiperidine derivatives
2
phenindamine tartrate (Thephorin). Therefore, the devel- in cis-form with excellent yields under mild conditions.
opment of highly efficient methodologies for the con-
struction of these heterocyclic compounds is a major
theme in the modern organic chemistry.3
In our reaction design we anticipated that exposure of a
mixture of α,β-unsaturated ketone 2 and p-toluenesulfon-
amide 1 to catalytic amounts of a Lewis base should lead
to the formation of the corresponding 1,4-addition prod-
ucts 4 (Scheme 1). The α,β-unsaturated carbonyl com-
pounds are an important class of reaction partners for
cyclization reactions and a large number of the examples
Cascade reactions have become a flourishing area over the
past few years. These straightforward routes, which allow
two or more reactions to occur in a single operation under
the same reaction conditions, avoid time-consuming,
O
O
O
H
R
R
Lewis base 3
solvent, temp.
S
+
S
N
H
O
O
OH
R
O
NH2
1
2
6
aldol
cyclization
Michael
addition
H+
H+
O
R
Michael
addition
H+
O
S
O
O
S
N
O
O
NH
H+
N
S
O
O
R
R
R
R
δ–
R
δ–
4
O
5
a
O
O
5b
O
Scheme 1 Lewis base catalyzed multiple reaction cascade
SYNLETT 2012, 23, 1691–1695
Advanced online publication: 11.06.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1291162; Art ID: ST-W0234-L
Georg Thieme Verlag Stuttgart · New York
©

1692
X. Liu et al.
LETTER
Table 1 Initial Attempts for the Base-Mediated Cascade Reactiona
O
R2
OH
R2
R2
Lewis base 3
(20 mmol%)
H
R1
R1 NH2
N
+
H
O
solvent, r.t.
R1 = Ts, 1a
R1 = benzoyl, 1b
2
2
R
= Ph, 2a
= 2-MeOC H , 2b
R
6
4
6
Yield (%) (cis/trans)c
b
Entry
1, 2
Lewis base
Solvent
Time (h)
1
2
3
4
5
6
7
8
9
1a, 2a
1a, 2a
1a, 2a
1a, 2a
1a, 2a
1a, 2a
1a, 2a
1a, 2a
1b, 2a
1a, 2b
Et N
Toluene
Toluene
Toluene
Toluene
24
24
24
8
6a, trace
3
K CO
6a, trace
2
3
DABCO
DBU
DBU
DBU
DBU
DBU
DBU
DBU
6a, trace
6a, 74 (cis)
6a, 60 (cis)
6a, 51 (cis)
6a, 73 (cis)
6a, 51 (cis)
trace
Et O
8
2
MeCN
THF
8
8
CH Cl
8
2
2
Toluene
Toluene
24
8
1
0
6b, 91 (cis)
a
b
c
Reaction conditions: 1 (1.0 equiv), 2 (2.5 equiv), DBU, r.t.
Isolated yield.
1
Determined by H NMR spectroscopic analysis.
have been described for carbon–carbon bond formation toluene at room temperature. However, only starting ma-
6
with these substrates. Subsequent action of the Lewis terial and none of the desired adduct 6a was observed (Ta-
base catalyzed another Michael addition to afford adduct ble 1, entry 1). The same result was found when 1,4-
5a. The following Lewis base catalyzed deprotonation diazobicyclo[2.2.2]octane ((DABCO) was used. These
should effect the generation of 5b, which was activated to results may due to the weakly basic conditions provided
give the desired product 6 through an intramolecular Al- by Et N and DABCO. Use of the stronger inorganic base
3
dol cyclization. The last cyclization step was expected to K CO was also ineffective in this reaction. In view of
2
3
be the key to stereochemical control of adduct formation. these results, we tried to use a stronger organic base 1,8-
Compared with the hydroxyl group, both aryl moieties de- diazabicyclo[5.4.0]undec-7-ene (DBU). To our delight,
rived from α,β-unsaturated ketone were bulkier groups. this base delivered an excellent performance in the reac-
The steric hindrance in the reaction would force these tion, and adduct 6a was obtained in an all cis-form with
groups to remain on the different sides of the ring. In ad- yields up to 74% yield. The effects of solvents were then
dition, hydrogen bonding between the hydroxyl and car- investigated in the presence of DBU (Table 1, entries 5–
bonyl groups would lead these groups to remain on the 8), and toluene proved to be optimal. Subsequently,
same side, thus adding to the stability of adduct.
changes to the protecting groups on the amines was tested.
Unfortunately, when benzamide was used to react with
phenyl vinyl ketone, only traces of the desired product
was found after 24 hours reaction. The employment of p-
At the beginning of the reaction optimization, we used p-
toluenesulfonamide (1a) and 2.5 equiv of phenyl vinyl ke-
tone (2a) as the starting materials and Et N as the base in
3
Cl
Cl
O
H
Ph DBU (20 mmol%)
+
toluene, r.t.
N
H
Ph
Ph
H2N
H
O
1
c
2a
7
5
O
O
H
Ph
DBU (20 mmol%)
toluene, r.t.
NH2
+
Ph
N
H
O
Ph
1
d
2a
c
Scheme 2 The reactions of p-chloroaniline and benzylamine with phenyl vinyl ketone (2a)
Synlett 2012, 23, 1691–1695
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3-Aroyl-4-hydroxy-4-arylpiperidines
1693
8
chloroaniline (1c) afforded the Michael addition product perature (Figure 1). In general, a range of benzene sulfon-
after 12 hours reaction, and the double Michael addition amides could be applied successfully to this multiple-
adduct 5c was gained by the use of benzylamine (Scheme cascade reaction, providing a diverse set of 3-aroyl-4-hy-
7
2
). When the vinylketone with an o-methoxyphenyl droxy-4-arylpiperidine derivatives 6b–h with different ar-
group was used to react with p-toluenesulfonamide, the omatic and aliphatic substituents in cis-form with good
cascade adduct 6b was afforded with an excellent yield of yields. Especially, up to 99% yield was obtained when p-
9
1%.
chlorobenzene sulfonamide (1h) and 2,5-dimethoxyphe-
nyl vinylketone (2c) were used. The propylamine also
proved to be a suitable substrate, affording the corre-
sponding adduct 6i in high yield.
With the optimized conditions established, we explored
the reactions of a variety of substituted amides with o-me-
thoxyphenyl vinylketone (2b) and 2,5-dimethoxyphenyl
vinylketone (2c) by using 20 mmol% DBU at room tem- Furthermore, consistently good to excellent yields and
high stereoselectivities (all cis-form) were observed for p-
MeO
methylbenzene sulfonamide with a range of aryl vinyl ke-
tones (Figure 2). Phenyl vinyl ketone tolerated substitu-
O
9
O
S
tions at any position of the aromatic ring, and both
electron-donating and electron-withdrawing functional-
ities were compatible. The additions of more sterically
hindered phenyl vinyl ketone with a 2-naphthyl group
proceeded equally well, with a high yield of the cis-form,
and the vinyl ketone derived from cinnamic aldehyde also
performed efficiently. Except for somewhat longer reac-
tion time, the additions of aryl vinyl ketones with alkyl
N
O
OH
6b
MeO
MeO
9
1% yield,a cis b
O
O
S
N
Cl
O
OH
OMe
OMe
MeO
O
6f
MeO
O
MeO
O
O
S
Ts
N
96% yield, cis
O
OH
Ts
N
OH
N
OH
OMe
OMe
6c
MeO
6a
MeO
6m
O
MeO
O
8
3% yield, cis
4% yield,a cis b
7
S
95% yield, cis
N
O
OH
OMe
OMe
O
Br
MeO
Ts
O
O
6g
N
O
OH
Ts
Br
MeO
S
N
OH
N
97% yield, cis
O
OH
6
j
Br
6n
6d
MeO
73% yield, cis
8
1% yield, cis
9
5% yield, cis
Cl
Me
O
MeO
O
O
O
Ts
S
9
N
Ts
N
OH
O
OH
OMe
OMe
N
OH
6o
6h
6k
MeO
Me
MeO
MeO
9% yield, cis
76% yield, cis
9
2% yield, cis
O
O
S
O
CF3
O
N
O
OH
O
Ts
Ts
N
OH
N
OH
6e
N
OH
MeO
6
p
6
l
67% yield, cis
70% yield,c cis
6i
CF3
5
2% yield, cis
78% yield, cis
Figure 2 Scope of the vinyl ketones in the cascade reaction. Reagents
and conditions: 1, 2 (2.5 equiv), DBU(20 mmol%), r.t., toluene, 4–8
Figure 1 The cascade reactions with different substituted benzene
sulfonamides. Reagents and conditions: 1, 2 (2.5 equiv), DBU(20
a
b
h. Yields were determined after column chromatography. Deter-
a
c
mmol%), r.t., toluene, 4–8 h. Yields were determined after column
mined by NMR spectroscopic analysis. The reaction was performed
chromatography. b Determined by NMR spectroscopic analysis.
for 48 h with 100 mmol% DBU.
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1691–1695

1694
X. Liu et al.
LETTER
groups proceeded smoothly to furnish the corresponding References and Notes
products.
(
1) (a) Gul, H. I.; Calis, U.; Vepsalainen, J. Arzneim.-Forsch.
2002, 12, 863. (b) Wang, S.; Sakamuri, S.; Enyedy, I. J.;
Kozikowski, A. P.; Zaman, W. A.; Johnson, K. M. Bioorg.
Med. Chem. 2001, 9, 1753. (c) Wang, S.; Sakamuri, S.;
Enyedy, I. J.; Kozikowski, A. P.; Deschaux, O.;
The constitution and configuration of the new products
were proven by X-ray crystal structure analysis of 3-aro-
yl-4-hydroxy-4-arylpiperidine derivative 6a (Figure 3).
1
0
Bandyopadhyay, B. C.; Tella, S. R.; Zaman, W. Z.; Johnson,
K. M. J. Med. Chem. 2000, 43, 351. (d) Dimmock, J. R.;
Vashishta, S. C.; Quail, J. W.; Pugazhenthi, U.; Zimpel, Z.;
Sudom, A. M.; Allen, T. M.; Kao, G. Y.; Balzarini, J. E.; De
Clercq, E. J. Med. Chem. 1998, 41, 4012.
(
2) (a) Lansdell, M. I.; Hepworth, D.; Calabrese, A.; Brown, A.
D.; Blagg, J.; Burring, D. J.; Wilson, P.; Fradet, D.; Brown,
T. B.; Quinton, F.; Mistry, N.; Tang, K.; Mount, N.; Stacey,
P.; Edmunds, N.; Adams, C.; Gaboardi, S.; Neal-Morgan, S.;
Wayman, C.; Cole, S.; Phipps, J.; Lewis, M.; Verrier, H.;
Gillon, V.; Feeder, N.; Heatherington, A.; Sultana, S.;
Haughie, S.; Martin, S. W.; Sudworth, M.; Tweedy, S.
J. Med. Chem. 2010, 53, 3183. (b) Cwik, A.; Fuchs, A.; Hell,
Z.; Clacens, J. M. J. Mol. Catal. A: Chem. 2004, 219, 377.
Figure 3 Molecular structure of 3-aroyl-4-hydroxy-4-arylpiperidine
derivative 6a
(c) Vashishtha, S. C.; Zello, G. A.; Nienaber, K. H.;
Balzarini, J.; Clercq, E. D.; Stables, J. P.; Dimmock, J. R.
Eur. J. Med. Chem. 2004, 39, 27. (d) Upton, C.; Osborne, R.
H.; Jaffar, M. Bioorg. Med. Chem. Lett. 2000, 10, 1277.
3) (a) Joensuu, P. M.; Murray, G. J.; Fordyce, E. A. F.;
Luebbers, T.; Lam, H. W. J. Am. Chem. Soc. 2008, 130,
In addition, we attempted the conversion of compound 6b
into other functionalized compounds (Scheme 3). It was
found that compound 8 could be easily obtained by hydro-
(
genation reduction with NaBH4.
7
328. (b) Lam, H. W.; Joensuu, P. M.; Murray, G. J.;
Fordyce, E. A. F. Prieto O.; Luebbers, T. Org. Lett. 2006, 8,
729. (c) For selected examples with heterocycle reactions
MeO
MeO
O
HO
3
NaBH4, THF
reflux
Ts
Ts
in our group, see: Sun, W. S.; Zhu, G. M.; Hong, L.; Wang,
R. Chem. Eur. J. 2011, 17, 13958. (d) See also: Liu, X. D.;
Deng, L. J.; Song, H. J.; Jia, H. Z.; Wang, R. Org. Lett. 2011,
N
N
OH
OH
1
3, 1494. (e) See also: Jiang, X. X.; Cao, Y. M.; Wang, Y.
Q.; Liu, L. P.; Shen, F. F.; Wang, R. J. Am. Chem. Soc. 2010,
32, 15328. (f) See also: Liu, X. D.; Deng, L. J.; Jiang, X. X.;
MeO
MeO
1
7
0% yield, cis
6
b
8
Yan, W. J.; Liu, C. L.; Wang, R. Org. Lett. 2010, 12, 876.
4) For selected reviews of domino reactions, see: (a) Grondal,
C.; Jeanty, M.; Enders, D. Nature Chem. 2010, 2, 167.
(
Scheme 3 The transforms of adduct 6b
(
b) Davies, H. M. L.; Sorensen, E. J. Chem. Soc. Rev. 2009,
38, 2981. (c) Kim, J.; Movassaghi, M. Chem. Soc. Rev.
009, 38, 3035. (d) Nicolaou, K. C.; Chen, J. S. Chem. Soc.
Rev. 2009, 38, 2993. (e) Young, I. S.; Baran, P. S. Nature
Chem. 2009, 1, 193. (f) Burns, N. Z.; Baran, P. S.;
Hoffmann, R. W. Angew. Chem. Int. Ed. 2009, 48, 2854.
In conclusion, a highly efficient and easily manipulated
one-pot cascade reaction of sulfonamides and aryl vinyl
ketones was developed. Catalyzed by DBU, functional 3-
aroyl-4-hydroxy-4-arylpiperidine derivatives were ob-
tained under mild reaction conditions in good to excellent
yields as well as the highest levels of diastereoselectivi-
ties. An asymmetric version and application of this ap-
proach to natural product total synthesis are under
investigation.
2
(
g) Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem.
Soc. Rev. 2009, 38, 3010. (h) Wender, P. A.; Verma, V. A.;
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008, 25, 254. (j) Yua, X.-H.; Wang, W. Org. Biomol.
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Acknowledgment
(
3
(
m) Guo, H.-C.; Ma, J.-A. Angew. Chem. Int. Ed. 2006, 45,
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We are grateful for the grants from the NSFC of China (20932003),
the Key National S & T Major Project and Major New Drugs Deve-
lopment of China (2012ZX09504-001-003) and Young Scholar of
Distinction for Doctoral Candidate of Lanzhou University.
in Organic Synthesis; Wiley-VCH: Weinheim, 2006.
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L.-S.; Li, H.; Xie, H.-X.; Wang, J.; Jiang, W.; Tang, Y.;
Wang, W. Angew. Chem. Int. Ed. 2007, 46, 3732.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
n
ungIifoop
r
t
(
2
e) Rueping, M.; Antonchick, A. P. Angew. Chem. Int. Ed.
007, 46, 4562. (f) Wang, W.; Li, H.; Wang, J.; Zu, L.-S.
Primary Data for this article are available online at
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Antonchick, A. P.; Theissmann, T. Angew. Chem. Int. Ed.
cited using the following DOI: PmriDyramPatrDi yar
1
at 0.4125/pd0030th. mPirayrDaZtahenl1
0
1Chemyrt
Synlett 2012, 23, 1691–1695
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3-Aroyl-4-hydroxy-4-arylpiperidines
1695
2
006, 45, 3683. (h) Rueping, M.; Azap, C. Angew. Chem.
7.41 (dd, J = 10.5, 4.7 Hz, 2 H), 7.27–7.21 (m, 2 H), 7.13
(ddd, J = 7.3, 3.8, 1.2 Hz, 1 H), 5.16 (d, J = 2.7 Hz, 1 H),
4.40 (d, J = 8.0 Hz, 1 H), 3.04–2.83 (m, 2 H), 2.69 (t,
J = 11.4 Hz, 2 H), 2.44 (dd, J = 8.6, 7.2 Hz, 2 H), 2.07 (t,
J = 12.8 Hz, 1 H), 1.82 (dt, J = 13.9, 2.6 Hz, 1 H), 1.64–1.46
Int. Ed. 2006, 45, 7832.
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6) (a) Bunce, R. A.; Nago, T. J. Heterocycl. Chem. 2009, 46,
623. (b) Herath, A.; Thompson, B. B.; Montgomery, J.
J. Am. Chem. Soc. 2007, 129, 8712. (c) Herath, A.;
Montgomery, J. J. Am. Chem. Soc. 2006, 128, 14030.
1
3
(m, 2 H), 0.92 (t, J = 7.4 Hz, 3 H). C NMR (75 MHz,
(d) Maezaki, N.; Sawamoto, H.; Ishihara, H.; Tanaka, T.
CDCl ): δ = 204.46, 147.21, 137.03, 135.90, 133.93, 133.05,
3
Chem. Commun. 2005, 3992. (e) Montgomery, J.; Oblinger,
E.; Savchenko, A. V. J. Am. Chem. Soc. 1997, 119, 4911.
7) CCDC 857042 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
128.81, 128.60, 128.34, 128.28, 128.08, 126.76, 124.57,
73.16, 60.46, 52.83, 50.51, 49.17, 39.86, 20.15, 12.03. IR
(
(CDCl ): 3458, 2959, 2929, 2818, 1663, 1448, 1377, 1205,
3
–
1
1070, 701 cm . HRMS (ESI): m/z calcd for C H NO +H:
2
1
25
2
324.1958; found: 324.1959.
(9) The analytical data of some typical compounds: Compound
1
(
8) General Procedure for the Cascade Reaction: To a
mixture of amines 1 (0.2 mmol) and vinyl ketones 2 (0.45
mmol) in toluene (1.0 mL) was added DBU (0.04 mmol) at
room temperature. After 6–8 h the reaction was complete (as
determined by TLC). The reaction mixture was concentrated
and the residue was purified by flash chromatography
6k: White solid; m.p. 197–198 °C. H NMR (300 MHz,
CDCl ): δ = 7.73–7.56 (m, 4 H), 7.43–7.29 (m, 4 H), 7.23 (s,
3
1 H), 7.18–7.02 (m, 2 H), 6.93 (d, J = 7.1 Hz, 1 H), 4.95 (d,
J = 2.6 Hz, 1 H), 4.38 (dd, J = 11.5, 3.8 Hz, 1 H), 3.94 (dd,
J = 11.6, 2.3 Hz, 1 H), 3.85–3.66 (m, 1 H), 3.04–2.79 (m,
2 H), 2.44 (s, 3 H), 2.38 (s, 3 H), 2.25 (s, 3 H), 2.18–2.06 (m,
13
(petroleum ether/ethyl acetate, 5:1) to afford the product 6.
1 H), 1.82 (d, J = 14.0 Hz, 1 H). C NMR (75 MHz,
The analytical data of some typical compounds:
Compound 6b: White solid; m.p.179–180 °C. H NMR
CDCl ): δ = 203.4, 145.8, 143.9, 138.9, 138.0, 135.6, 135.3,
133.4, 129.9, 128.9, 128.9, 128.3, 127.9, 127.6, 125.7,
125.3, 121.4, 72.7, 49.5, 45.3, 42.5, 39.1, 21.6, 21.4. IR
3
1
(
300 MHz, CDCl ): δ = 7.69 (d, J = 8.1 Hz, 2 H), 7.57 (dd,
3
J = 7.7, 1.1 Hz, 1 H), 7.36 (dd, J = 13.7, 5.1 Hz, 3 H), 7.09
t, J = 7.1 Hz, 1 H), 6.98–6.81 (m, 2 H), 6.78–6.63 (m, 2 H),
(CDCl ): 3443, 2925, 1654, 1584, 1387, 1341, 1280, 1163,
3
–1
(
924, 545 cm . HRMS (ESI): m/z calcd for
+
6.50 (d, J = 8.1 Hz, 1 H), 5.08 (dd, J = 11.4, 3.7 Hz, 1 H),
4.47 (d, J = 2.4 Hz, 1 H), 4.14 (dd, J = 10.6, 2.3 Hz, 1 H),
4.02 (s, 3 H), 3.76–3.67 (m, 1 H), 3.42 (s, 3 H), 2.92 (ddd,
C H NO S+Na : 486.1710; found: 486.1689.
2
7
29
4
1
Compound 6n: White solid; m.p. 192–193 °C. H NMR
(300 MHz, CDCl ): δ = 8.50 (s, 1 H), 7.96 (d, J = 6.6 Hz,
3
J = 11.0, 7.4, 3.2 Hz, 2 H), 2.74–2.52 (m, 1 H), 2.44 (s, 3 H),
2 H), 7.83–7.63 (m, 8 H), 7.55 (p, J = 6.7 Hz, 3 H), 7.40–
7.27 (m, 4 H), 5.27 (d, J = 2.3 Hz, 1 H), 4.74 (dd, J = 11.4,
3.6 Hz, 1 H), 4.18–4.03 (m, 1 H), 3.88 (d, J = 11.2 Hz, 1 H),
3.08 (ddd, J = 16.1, 8.0, 4.0 Hz, 2 H), 2.41 (s, 3 H), 2.35–
1
3
1
2
1
1
.57 (d, J = 13.6 Hz, 1 H). C NMR (75 MHz, CDCl ): δ =
3
07.6, 158.6, 155.6, 143.5, 133.9, 133.5, 132.4, 129.8,
29.2, 129.0, 128.7, 127.6, 127.5, 120.7, 120.5, 111.0,
10.7, 72.5, 55.8, 54.5, 51.9, 44.0, 42.3, 34.7, 21.6. IR
13
2.21 (m, 1 H), 1.92 (d, J = 14.0 Hz, 1 H). C NMR (75
(
7
CDCl ): 3459, 2926, 1648, 1592, 1456, 1319, 1160, 913,
MHz, CDCl ): δ = 203.0, 143.9, 143.3, 136.1, 133.4, 133.1,
3
3
–1
29, 573 cm . HRMS (ESI): m/z calcd for
132.7, 132.4, 132.4, 131.0, 130.0, 129.9, 129.4, 129.0,
128.4, 128.2, 127.8, 127.7, 127.4, 127.2, 126.2, 126.0,
123.7, 123.4, 122.6, 73.1, 49.4, 45.6, 42.6, 39.2, 21.6. IR
+
C H NO S+Na : 518.1608; found: 518.1587.
27
29
6
1
Compound 6d: White solid; m.p. 162–163 °C. H NMR
300 MHz, CDCl ): δ = 7.96 (t, J = 1.6 Hz, 1 H), 7.74 (d,
(
(CDCl ): 3443, 3058, 2924, 1655, 1345, 1163, 922, 730,
3
3
–
1
+
J = 7.9 Hz, 2 H), 7.58 (dd, J = 7.8, 1.6 Hz, 1 H), 7.51–7.31
m, 2 H), 7.15–7.04 (m, 1 H), 6.91 (t, J = 8.4 Hz, 2 H), 6.80–
549 cm . HRMS (ESI): m/z calcd for C H NO S+Na :
33 29 4
(
6
3
558.1710; found: 558.1716.
Compound 6o: White solid; m.p. 159–160 °C. H NMR
1
.62 (m, 2 H), 6.51 (d, J = 8.1 Hz, 1 H), 5.08 (dd, J = 11.4,
.8 Hz, 1 H), 4.50 (d, J = 2.7 Hz, 1 H), 4.15 (dd, J = 11.0, 2.4
(300 MHz, CDCl ): δ = 7.66 (dd, J = 12.1, 3.9 Hz, 3 H),
3
Hz, 1 H), 4.04 (s, 3 H), 3.82–3.66 (m, 1 H), 3.42 (s, 3 H),
.00 (td, J = 11.1, 4.8 Hz, 2 H), 2.70–2.51 (m, 1 H), 1.60 (d,
7.60–7.52 (m, 2 H), 7.46–7.36 (m, 3 H), 7.24 (m, 7 H), 6.69
(dd, J = 30.5, 16.0 Hz, 2 H), 6.15 (d, J = 15.9 Hz, 1 H), 4.54
(d, J = 2.4 Hz, 1 H), 3.86 (dd, J = 11.5, 2.6 Hz, 1 H), 3.73
(dd, J = 9.4, 2.0 Hz, 1 H), 3.48 (dd, J = 11.6, 3.9 Hz, 1 H),
2.88–2.71 (m, 2 H), 2.44 (s, 3 H), 2.00–1.84 (m, 1 H), 1.75
3
1
3
J = 13.6 Hz, 1 H). C NMR (75 MHz, CDCl ): δ = 207.4,
3
158.6, 155.5, 138.7, 135.8, 133.9, 132.2, 130.7, 130.3,
129.2, 128.9, 128.7, 127.5, 126.0, 123.3, 120.7, 120.5,
111.0, 110.7, 72.5, 55.8, 54.6, 51.8, 43.9, 42.3, 34.6. IR
1
3
(d, J = 15.2 Hz, 1 H). C NMR (75 MHz, CDCl ): δ = 202.3,
3
(
7
CDCl ): 3432, 2934, 1655, 1597, 1462, 1245, 1166, 1022,
146.1, 143.9, 136.3, 133.8, 133.6, 133.0, 131.6, 129.9,
129.5, 129.1, 128.9, 128.5, 127.7, 127.6, 126.6, 125.4, 71.0,
3
–1
57, 580 cm . HRMS (ESI): m/z calcd for
+
C H BrNO S+H : 560.0737; found: 560.0738.
52.0, 44.4, 41.9, 36.6, 21.6. IR (CDCl ): 3451, 3029, 2926,
26
26
6
3
1
–1
Compound 6e: White solid; m.p. 177–178 °C. H NMR
300 MHz, CDCl ): δ = 7.80–7.69 (m, 2 H), 7.57 (dd,
2253, 1598, 1339, 1160, 1091, 919, 733 cm . HRMS (ESI):
+
(
m/z calcd for C H NO S+Na : 510.1735; found: 510.1713.
3
29 29
4
1
J = 7.8, 1.7 Hz, 1 H), 7.41–7.31 (m, 1 H), 7.09 (td, J = 8.1,
.7 Hz, 1 H), 7.05–6.98 (m, 2 H), 6.94–6.83 (m, 2 H), 6.72
qd, J = 7.6, 1.4 Hz, 2 H), 6.55–6.41 (m, 1 H), 5.08 (dd,
J = 11.4, 3.8 Hz, 1 H), 4.47 (d, J = 2.7 Hz, 1 H), 4.17–4.11
m, 1 H), 4.02 (s, 3 H), 3.88 (s, 3 H), 3.75–3.65 (m, 1 H),
.42 (s, 3 H), 3.01–2.81 (m, 2 H), 2.63 (tdd, J = 13.1, 4.8, 2.8
Compound 6p: White solid; m.p. 83–85 °C. H NMR (300
1
(
MHz, CDCl ): δ = 7.62 (d, J = 8.2 Hz, 2 H), 7.32 (d, J = 8.1
3
Hz, 2 H), 3.75–3.50 (m, 3 H), 2.97 (dd, J = 11.6, 3.8 Hz,
1 H), 2.80–2.47 (m, 4 H), 2.43 (s, 3 H), 1.68 (dd, J = 11.2,
2.5 Hz, 1 H), 1.60–1.51 (m, 1 H), 1.41 (dtd, J = 28.6, 14.2,
(
3
7.2 Hz, 2 H), 1.05 (t, J = 7.2 Hz, 3 H), 0.86 (t, J = 7.5 Hz,
1
3
13
Hz, 1 H), 1.57 (dd, J = 11.2, 2.3 Hz, 1 H). C NMR (75
3 H). C NMR (75 MHz, CDCl ): δ = 215.9, 143.8, 132.9,
3
MHz, CDCl ): δ = 207.6, 162.9, 158.6, 155.5, 133.9, 132.4,
129.8, 127.6, 70.5, 53.6, 44.2, 41.9, 38.3, 33.7, 33.3, 21.5,
3
1
1
3
1
29.6, 129.2, 129.0, 128.7, 128.0, 127.4, 120.6, 120.5,
14.3, 111.0, 110.7, 72.5, 55.8, 55.6, 54.5, 51.8, 44.0, 42.3,
7.6, 7.1. IR (CDCl ): 3488, 2971, 2930, 1696, 1343, 1161,
3
1
–
921, 744, 548 cm . HRMS (ESI): m/z calcd for
+
4.7. IR (CDCl ): 3454, 2936, 1656, 1597, 1254, 1159,
C H NO S+H : 340.1577; found: 340.1587.
3
17 25
4
–
1
023, 756, 559 cm . HRMS (ESI): m/z calcd for
(10) CCDC 857043 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
+
C H NO S+Na : 534.1557; found: 534.1568.
Compound 6i: White solid; m.p. 95–96 °C. H NMR (300
MHz, CDCl ): δ = 7.99–7.81 (m, 2 H), 7.59–7.46 (m, 3 H),
27
29
7
1
3
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1691–1695

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