Synthesis of 1,3-disubstituted N-amino-1,2,3,4-tetrahydroisoquinolines

Article abstract of DOI:10.1055/s-2007-967948

The synthesis of 1,3-disubstituted N-amino-1,2,3,4-tetrahydroisoquinolines from the corresponding hydrazide intermediate via Pictet-Spengler reaction is described and the effect of the aldehyde on the stereoconfiguration of the products is discussed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-967948

374
LETTER
Synthesis of 1,3-Disubstituted N-Amino-1,2,3,4-tetrahydroisoquinolines
S
ynthesis of 1,3
i
-Disubstitute
Z
d
N
-
Amino-1,2,
h
3,4-tetrahydr
a
oisoquinol
nines g, Xiu-Fang Zheng, Gregory Linn, Kang Zhao*
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P. R. of China
Fax +86(22)27890968; E-mail: kangzhao@tju.edu.cn
Received 17 October 2006
genic processes in the central nervous system6 make
THIQs a new class of noncompetitive AMPAR [2-amino-
3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid re-
ceptor] antagonists7 and have received considerable atten-
tion. Much effort has been devoted to the modification8 of
THIQs in order to afford more potent and selective
ligands.
Abstract: The synthesis of 1,3-disubstituted N-amino-1,2,3,4-tet-
rahydroisoquinolines from the corresponding hydrazide intermedi-
ate via Pictet-Spengler reaction is described and the effect of the
aldehyde on the stereoconfiguration of the products is discussed.
Key words: quinolines, aldehydes, heterocycles, reduction, ring
closure
The N-amino-substituted THIQs 3 (Scheme 1), which ap-
pear to be structurally similar to THIQs 1, can dramatical-
ly change the electronic property of the nitrogen atom in
the molecule, and may present interesting physical and bi-
ological properties. Due to the electronic feature of N–N
bond, the synthesis of N-amino-substituted THIQs 3 can-
not be easily achieved.9a The chemistry for preparation of
N-amino THIQs 39 can start from THIQs 1 (Scheme 1) by
Tetrahydroisoquinolines (THIQs) have become attractive
targets for organic synthesis due to their widespread
occurrence in nature, interesting chemical properties, and
diverse biological activities. This includes functioning as
calcium antagonists,1 cardiovascular,2 antibacterial,3 anti-
tumor antibotics4 and neuromodulation effects.5 Their
neuromodulating effects, in particular, related to patho-
R1
R1
R1
R7
NH
R2
R3
R7
R7
R2
R3
R2
R3
R5X
1. H2SO4 (concd), NaNO2
2. LiAlH4
R5
N
N
NH2
N
H
R4
R6
R4
R4
R6
R6
3a–n
1
2
R1–R4 = H or MeO
R
R
R
5 = PhCO
6 = H, Pr, c-Hex, Ph, 4-NO2C6H4, 4-BrC6H4, 4-MeOC6H4, 2-Furyl, 2-Thienyl, 4-Pyridinyl
7 = H or Me
X = Halogen
Scheme 1
R1
R1
R2
R3
R2
R3
R5NHNH2
R6CHO
R6
N
R5
+
4a–f
N
H
O
N
NaI, TMSCl
MeCN
AcOH
EtOH
r.t., –50 °C
NH
R5
R4
R4
5a–f
4a–f
7a,b
[H] r.t.
R1
R1
R2
R3
R2
R3
R1–R4 = H or MeO
R5 = PhCO
R6CHO
HN
N
R5
NaI, TMSCl
MeCN
r.t.
R6 = H, Pr, c-Hex, Ph,
NH
R5
N
H
4-NO2C6H4, 4-BrC6H4, 4-MeOC6H4,
2-Furyl, 2-Thienyl, 4-Pyridinyl
R4
6a–f
R4
3a–n
R6
Scheme 2
SYNLETT 2007, No. 3, pp 0374–0380
1
5.
0
2.
2
0
0
7
Advanced online publication: 07.02.2007
DOI: 10.1055/s-2007-967948; Art ID: W21306ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 1,3-Disubstituted N-Amino-1,2,3,4-tetrahydroisoquinolines
375
Table 1 Exchange Reaction of Hydrazones with Aldehydes
Entry
1
Substrate
syn/antia
Aldehyde
Product
Yield (%)
25
MeO
CHO
N
HN
O
N
Br
MeO
HN
1:6
OMe
O
OMe
7a
Br
5a
MeO
N
CHO
HN
O
N
MeO
HN
2
1:11
30
Ph
O
Ph
7b
5b
a Ratio was determined by 500 MHz 1H NMR spectroscopy.
using a multi-step procedure (N-nitrosation, LiAlH4 re- Table 2. (b) The R6 group of the aldehydes greatly influ-
duction, and alkylation/acylation). The method is good for ences the steric configuration of products 3. When R6 was
a wide variety of substrates, but the yield is poor due to the aryl or a substituted aryl group, the trans-1,3-disubstituted
generation of byproducts during the nitrating step and N-amino tetrahydroisoquinolines were formed as major
alkylation/acylation steps. Moreover, the synthesis of the products. The trans/cis ratios were as high as 60:1 such
THIQ-skeleton-containing compounds is often achieved that the minor cis isomer could not be detected by the
by using the Pictet–Spengler reaction, and it would be NMR spectroscopy (see Table 2 entries 3 and 4, and
very desirable to study this reaction for the direct prepara- Table 3 entries 1-6). However, when R6 was aliphatic or
tion of N-amino THIQ derivatives, although the scope and a heterocyclic group such as butyl, cyclohexyl, 2-thienyl
usefulness of this kind of Pictet–Spengler reaction have or 2-furyl, these groups did not appear to give product
not been reported before.
with high diastereoselectivity (trans/cis products ratio of
3:1). The absolute configuration of the major isomer of
compound 3b was also confirmed by the X-ray crystal
structure analysis (Figure 1).15,16 (c) The hydrogen atoms
In this letter, we present a simple approach to the synthe-
sis of 1,3-disubstituted N-amino-THIQs starting from
hydrazones 5 (Scheme 2),10,11 through the reduction to hy-
drazides 6,10,12 and finally the Pictet-Spengler reaction4,13
to give a series of a new type of THIQs 3. All reactions
took place at room temperature and all reagents are com-
mercially available or easy to prepare in the laboratory.
The conditions are mild and easy to control. It should
be pointed out that the reduction of C=N (hydrazone) to
C-N (hydrazide) was necessary in order to effect the ring
closure. If this reduction step was not performed, under
the Pictet-Spengler reaction conditions compound 5
underwent an aldehyde-exchange reaction to form com-
pound 7.14 Further, compound 5 is a mixture of two geo-
metric isomers which could be attributed to their anti- and
syn-geometric isomers (Table 1).
1
on C-1 or C-3 gave a broad H NMR signal. This was
probably due to a restricted rotation of the N-hydrazide
bond.17 (d) On the basis of the molecular modeling
study,18 some of these new 1,3-disubstituted N-amino
THIQs (products 3a–g and 3k) fit the preliminary phar-
macophore model18 well, which consists of four features
corresponding to one hydrogen acceptor group (carbonyl
group), one aromatic ring function (benzene ring) and two
hydrophobic group regions (dimethoxy), so theoretically
they could be the lead candidates of a novel series of non-
competitive AMPAR antagonists.
The Pictet–Spengler reaction using hydrazides 6 and alde-
hydes gave product 3 which possessed two chiral centers
(C-1 and C-3; with the exception of formaldehyde) and
therefore could exist as cis or trans diastereoisomers
(Tables 2 and 3). There are four aspects that should be
pointed out: (a) the electron-donating methoxy group is
very important and works only if it is meta-substituted
with respect to the hydrazine moieties (i.e. compound 6c).
The addition of another methoxy group at the para posi-
tion in compound 6d further strengthens this electronic ef-
fect, whereas one more methoxy group at position 5 (i.e.
compound 6e) sterically hindered the electrophilic addi-
tion. These effects can be seen by the results listed in
Figure 1 X-ray of compound 3b (trans)
Synlett 2007, No. 3, 374–380 © Thieme Stuttgart · New York

376
L. Zhang et al.
LETTER
Table 2 Coupling of Compounds 6a–f with Aldehydes via Pictet-Spengler Reaction
Entry
1
Substrate
Aldehyde
Product yielda
trans/cisb
CHO
NH
O
HN
n.r.
–
Ph
Br
6a
OMe
CHO
2
3
n.r.
–
HN
NH2
Br
6b
MeO
MeO
O
O
O
CHO
NH
N
N
N
HN
N
H
Ph
Ph
Ph
Ph
O
60:1
6c
Br
Br
Br
Br
3a (71%)
MeO
MeO
MeO
CHO
Br
NH
O
HN
MeO
N
H
Ph
4
60:1
6d
3b (83%)
MeO
MeO
MeO
CHO
NH
O
HN
MeO
OMe
N
H
OMe
Ph
5
6
1.5:1
6e
Br
3c (78%)
CHO
NH
O
MeO
HN
n.r.
–
Ph
Br
6f
a Isolated yield; n.r.: no reaction.
b Ratio of trans/cis was calculated by the 1H NMR spectrum.
Table 3 Coupling of Hydrazide 6d with Aldehydes via Pictet-Spengler Reaction
Entry
Substrate
Aldehyde
Product yielda
trans/cisb
MeO
O
CHO
N
MeO
N
Ph
H
1
6d
20:1
3d (75%)
Synlett 2007, No. 3, 374–380 © Thieme Stuttgart · New York

LETTER
Synthesis of 1,3-Disubstituted N-Amino-1,2,3,4-tetrahydroisoquinolines
377
Table 3 Coupling of Hydrazide 6d with Aldehydes via Pictet-Spengler Reaction (continued)
Entry
Substrate
Aldehyde
Product yielda
trans/cisb
MeO
O
O
O
CHO
N
MeO
N
H
Ph
Ph
Ph
2
6d
6.6:1c
OMe
OMe
3e (87%)
MeO
CHO
Cl
N
MeO
N
H
3
6d
8.2:1c
Cl
3f (p) (90%)
MeO
CHO
N
MeO
N
H
4
5
6d
6d
9.3:1c
Cl
Cl
3f (m) (86%)
MeO
O
CHO
Cl
N
MeO
Cl
N
H
Ph
4.6:1c
3f (o) (80%)
MeO
O
CHO
NO2
N
MeO
N
H
Ph
6
6d
65:1
NO2
3g (91%)
MeO
O
O
N
7
8
6d
6d
HCHO
–
MeO
N
H
Ph
Ph
3h (87%)
MeO
N
MeO
N
H
OHC
3.3:1
3i (84%)
Synlett 2007, No. 3, 374–380 © Thieme Stuttgart · New York

378
L. Zhang et al.
LETTER
Table 3 Coupling of Hydrazide 6d with Aldehydes via Pictet-Spengler Reaction (continued)
Entry
Substrate
Aldehyde
Product yielda
trans/cisb
MeO
O
CHO
N
MeO
N
H
Ph
9
6d
3.3:1
3j (69%)
MeO
O
CHO
N
MeO
N
H
Ph
10
6d
4:1
3k (82%)
MeO
O
N
O
O
MeO
N
H
Ph
11
12
6d
6d
3.3:1
CHO
3l (83%)
MeO
O
N
S
S
MeO
N
H
Ph
3:1
CHO
3m (51%)
MeO
O
CHO
N
N
MeO
N
H
Ph
13
6d
trans
N
3n (30%)
a Isolated yield.
b Ratio of trans/cis was calculated by the 1H NMR spectrum.
c Ratio of trans/cis was calculated by isolated yield.
(5) Vecchietti, V.; Clarke, G. D.; Colle, R.; Giardina, G.;
Petrone, G.; Sbacchi, M. J. Med. Chem. 1991, 34, 2624.
(6) (a) Gremmen, C.; Wanner, M. J.; Koomen, G.-J.
Tetrahedron Lett. 2001, 42, 8885. (b) Kotake, Y.; Tasaki,
Y.; Makino, Y.; Ohta, S.; Hirobe, M. J. Neurochem. 1995,
65, 2633. (c) Grunewald, G. L.; Sall, D. J.; Monn, J. A. J.
Med. Chem. 1998, 31, 824.
(7) (a) Gitto, R.; Barreca, M. L.; De Luca, L.; De Sarro, G.;
Ferreri, G.; Quartarone, S.; Russo, E.; Constanti, A.;
Chimirri, A. J. Med. Chem. 2003, 46, 197. (b) Ferreri, G.;
Chimirri, A.; Russo, E.; Gitto, R.; Gareri, P.; De Sarro, A.;
De Sarro, G. Pharmacol. Biochem. Behav. 2004, 77, 85.
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Acknowledgment
We acknowledge the Tianjin Municipal Science and Technology
Commission (043186011), and the Basic Research Project
(#2003AA223151) of the MOST for financial support.
References and Notes
(1) Dong, H.; Sheng, J. Z.; Wong, T. M. Br. J. Pharmacol. 1993,
109, 109.
(2) Dong, H.; Lee, C. M.; Huang, W. L.; Peng, S. X. Br. J.
Pharmacol. 1992, 107, 262.
(3) Chandrasekhar, S.; Mohanty, P. K.; Harikishan, K.; Sasmal,
P. K. Org. Lett. 1999, 1, 877; and references cited therein.
(4) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669.
(b) Horiguchi, Y.; Kodama, H.; Nakamura, M.; Yoshimura,
T.; Hanezi, K.; Hamada, H.; Saitoh, T.; Sano, T. Chem.
Pharm. Bull. 2002, 50, 253.
Synlett 2007, No. 3, 374–380 © Thieme Stuttgart · New York

LETTER
Synthesis of 1,3-Disubstituted N-Amino-1,2,3,4-tetrahydroisoquinolines
Selected data of compounds 3:
379
(9) (a) Zalán, Z.; Martinek, T. A.; Lázár, L.; Sillanpää; Fülöp,
F. Tetrahedron 2006, 62, 2883. (b) Biel, J. H. US Patent,
3037984, 1962; Chem. Abstr. 1962, 57, 15082a. (c) Biel, J.
H. US Patent, 2932646, 1960; Chem. Abstr. 1960, 54,
17435h.
3a: mp 227-229 °C. 1H NMR (CDCl3): d = 7.43-7.47 (m, 1
H), 7.39-7.42 (m, 4 H), 7.34 (t, J = 7.5 Hz, 2 H), 7.22 (d,
J = 8.0 Hz, 2 H), 6.96 (br s, 1 H), 6.63 (d, J = 2.5 Hz, 1 H),
6.59 (dd, J = 2.5, 8.5 Hz, 1 H), 6.49 (d, J = 8.5 Hz, 1 H), 5.81
(br s, 1 H), 4.12 (br s, 1 H), 3.76 (s, 3 H), 3.00 (br s, 1 H),
(10) Dutta, A. S.; Morley, J. S. J. Chem. Soc., Perkin Trans. 1
1975, 1712.
2.88 (dd, J = 3.5, 16.0 Hz, 1 H), 1.29 (d, J = 6.5 Hz, 3 H). 13
C
(11) All melting points were determined on a Kofler hot-plate
microscope apparatus and are uncorrected. Mass spectra ESI
were recorded on Q-TOF Micromass spectrometer. 1H NMR
and 13C NMR spectra were recorded on a Varian Inova 500
MHz instrument.
NMR (CDCl3): d = 167.65, 158.03, 142.74, 135.33, 133.78,
131.56, 131.51, 131.19, 129.34, 128.65, 126.64, 121.45,
112.37, 112.25, 66.56, 55.19, 54.11, 39.01, 19.70. MS (ESI):
m/z = 451.2, 453.2 [M + H]+. 3b: mp 216-217 °C. 1H NMR
(CDCl3): d = 7.41-7.47 (m, 5 H), 7.35 (t, J = 7.5 Hz, 2 H),
7.23 (d, J = 7.5 Hz, 2 H), 6.99 (br s, 1 H), 6.59 (s, 1 H), 6.04
(s, 1 H), 5.83 (br s, 1 H), 4.14 (br s, 1 H), 3.85 (s, 3 H), 3.59
(s, 3 H), 2.96 (br s, 1 H), 2.82 (dd, J = 2.5, 15.5 Hz, 1 H), 1.28
(d, J = 6.0 Hz, 3 H). 13C NMR (CDCl3): d = 167.65, 147.78,
147.26, 142.61, 133.75, 131.56, 131.50, 131.21, 129.39,
128.65, 126.65, 126.41, 121.50, 111.08, 110.45, 66.38,
55.90, 55.84, 53.84, 38.38, 19.67. MS (ESI): m/z = 481.0,
483.0 [M + H]+. 3c: mp 171-172 °C. 1H NMR (CDCl3): d =
7.40-7.56 (m, 5 H, 2 isomers), 7.15-7.18 (trans), 7.03-7.05
(m, 4 H, cis), 6.70 (br s, 1 H, 2 isomers), 6.43 (s, 1 H, trans),
6.49 (s, 1 H, cis), 5.69 (br s, 1 H, trans), 5.37 (s, 1 H, cis),
4.00 (br s, 1 H, trans), 3.24–3.26 (m, 1 H, cis), 3.86 (s, 3 H,
trans), 3.87 (s, 3 H, cis), 3.73 (s, 3 H, trans), 3.79 (s, 3 H,
cis), 3.14 (s, 3 H, trans), 3.46 (s, 3 H, cis), 2.95 (br s, 1 H, 2
isomers), 2.74-2.83 (m, 1 H, 2 isomers), 1.23 (d, J = 6.0 Hz,
3 H, trans), 1.17 (d, J = 6.0 Hz, 3 H, cis). 13C NMR (CDCl3):
d (trans/cis) = 166.35/167.48, 152.56/153.22, 150.70/
151.06, 140.57/144.76, 140.46/139.35, 133.75/134.04,
131.61/131.45, 131.17/130.87, 130.81/130.77, 128.67/
129.32, 126.76/127.04, 121.61/123.79, 120.43/119.81,
106.14/106.56, 64.05/60.71, 60.50/60.38, 59.12/60.16,
55.87/55.93, 48.52/53.08, 39.53/32.95, 19.63/18.86. MS
(ESI): m/z = 511.1, 513.1 [M + H]+. 3d: mp 215-218 °C. 1H
NMR (CDCl3): d = 7.42 (t, J = 7.5 Hz, 1 H), 7.34-7.36 (m,
4 H), 7.27-7.33 (m, 5 H), 6.95 (br s, 1 H), 6.59 (s, 1 H), 6.09
(s, 1 H), 5.79 (br s, 1 H), 4.13 (br s, 1 H), 3.85 (s, 3 H), 3.56
(s, 3 H), 2.97 (br s, 1 H), 2.83 (dd, J = 3.5, 15.5 Hz, 1 H), 1.30
(d, J = 6.0 Hz, 3 H). 13C NMR (CDCl3): d = 167.75, 147.63,
147.14, 143.33, 134.07, 131.36, 130.08, 129.52, 128.53,
128.38, 127.65, 126.68, 126.38, 113.31, 110.38, 68.07,
55.83, 54.06, 38.46, 19.73. MS (ESI): m/z = 403.3 [M + H]+.
3e (trans): mp 210-211 °C. 1H NMR (CDCl3): d = 7.42-
7.45 (m, 3 H), 7.33 (t, J = 7.5 Hz, 2 H), 7.25 (d, J = 8.5 Hz,
2 H), 6.91 (br s, 1 H), 6.82 (d, J = 8.5 Hz, 2 H), 6.58 (s, 1 H),
6.10 (s, 1 H), 5.73 (br s, 1 H), 4.10 (br s, 1 H), 3.85 (s, 3 H),
3.78 (s, 3 H), 3.58 (s, 3 H), 2.96 (br s, 1 H), 2.82 (dd, J = 3.5,
15.5 Hz, 1 H), 1.29 (d, J = 6.0 Hz, 3 H). 13C NMR (CDCl3):
d = 167.79, 158.98, 147.60, 147.12, 135.37, 134.12, 131.36,
130.59, 130.29, 128.55, 126.70, 126.37, 113.69, 111.34,
110.33, 55.86, 55.21, 38.39, 19.78. MS (ESI): 433.1 [M +
H]+. 3e (cis): mp 210-211 °C. 1H NMR (CDCl3): d = 7.66
(d, J = 7.5 Hz, 2 H), 7.48 (t, J = 7.5 Hz, 1 H), 7.40 (t, J = 7.5
Hz, 2 H), 7.19 (d, J = 8.5 Hz, 2 H), 6.85 (d, J = 9.0 Hz, 2 H),
6.75 (s, 1 H), 6.66 (s, 1 H), 6.39 (s, 1 H), 5.18 (s, 1 H), 3.90
(s, 3 H), 3.79 (s, 3 H), 3.72 (s, 3 H), 3.36 (sept, J = 6.0 Hz, 1
H), 2.90 (dd, J = 5.0, 17.0 Hz, 1 H), 2.82 (dd, J = 10.0, 17.0
Hz, 1 H), 1.17 (d, J = 6.5 Hz, 3 H). 13C NMR (CDCl3): d =
166.18, 159.10, 148.23, 147.70, 134.18, 132.46, 131.50,
131.21, 128.60, 127.02, 126.20, 125.72, 113.54, 111.46,
110.84, 67.83, 55.87, 55.27, 49.04, 33.05, 18.26. MS (ESI):
m/z = 433.1 [M + H]+. 3f (p, cis): mp 202-204 °C. MS (ESI):
m/z = 437.1, 439.1 [M + H]+. 3f (m, trans): mp 182-183 °C.
MS (ESI): m/z = 437.1, 439.1 [M + H]+. 3f (o): mp 99-
101 °C. MS (ESI): m/z = 437.1, 439.1 [M + H]+. 3g: mp
203-206 °C. 1H NMR (DMSO-d6): d = 9.43 (br s, 1 H), 8.12
Selected data of compounds 5:
5a: mp 109-110 °C. 1H NMR (CDCl3): d = 7.76 (br s, 1 H,
anti), 7.85 (br s, 1 H, syn), 6.79-6.83 (m, 2 H, 2 isomers),
6.75-6.77 (m, 2 H, anti), 6.66–6.68 (m, 2 H, syn), 6.74 (s, 1
H, anti), 6.62 (br s, 1 H, syn), 3.85-3.87 (m, 9 H, 2 isomers),
3.57 (d, J = 4.0 Hz, 2 H, anti), 3.52 (br s, 2 H, syn), 1.71 (d,
J = 1.0 Hz, 3 H, anti), 2.06 (d, J = 6.5 Hz, 3 H, syn). MS
(ESI): m/z = 267.0 [M + H]+. 5b: mp 144-146 °C. 1H NMR
(CDCl3): d = 8.75 (br s, 1 H, anti), 8.99 (br s, 1 H, syn), 7.83
(br s, 2 H, anti), 7.60 (d, J = 16.0 Hz, 2 H, syn), 7.52–7.54
(m, 1 H, anti), 7.49–7.52 (m, 2 H + 1 H¢), 7.36 (t, J = 7.5 Hz,
2 H, syn), 6.81 (s, 3 H, anti), 6.71 (s, 3 H, syn), 3.86 (s, 3 H,
anti), 3.88 (s, 3 H, syn), 3.85–3.86 (m, 3 H, 2 isomers), 3.63–
3.69 (m, 2 H, 2 isomers), 1.86 (s, 3 H, anti), 2.15 (s, 3 H,
syn). MS (ESI): m/z = 313.0 [M + H]+.
(12) Selected data of compounds 6:
6a: mp 114-116 °C. 1H NMR (CDCl3): d = 7.60 (d, J = 7.0
Hz, 2 H), 7.49 (t, J = 2.0 Hz, 1 H), 7.40 (t, J = 2.5 Hz, 2 H),
7.30-7.32 (m, 2 H), 7.20–7.26 (m, 3 H), 4.49 (br s, 1 H),
3.40 (sext, J = 6.5 Hz, 1 H), 2.83 (q, J = 6.5 Hz, 1 H), 2.67
(q, J = 7.0 Hz, 1 H), 1.13 (d, J = 6.0 Hz, 3 H). MS (ESI):
m/z = 255.2 [M + H]+. 6b: 1H NMR (CDCl3): d = 7.16 (td,
J = 8.0, 9.5 Hz, 1 H), 7.16 (dd, J = 1.5, 7.5 Hz, 1 H), 6.86 (td,
J = 7.5, 8.5 Hz, 1 H), 6.80 (d, J = 8.5 Hz, 1 H), 4.01 (sext,
J = 6.0 Hz, 1 H), 3.73 (s, 3 H), 2.71–2.76 (m, 2 H), 1.16 (s,
3 H). MS (ESI): m/z = 181.4 [M + H]+. 6f: mp 82-84 °C. 1H
NMR (CDCl3): d = 7.61-7.63 (m, 2 H), 7.48-7.52 (m, 1 H),
7.39-7.42 (m, 2 H), 7.68-7.87 (m, 2 H), 7.14-7.17 (m, 2
H), 3.79 (s, 3 H), 3.37 (sext, J = 6.5 Hz, 1 H), 2.78 (q, J = 7.0
Hz, 1 H), 2.64 (q, J = 6.5 Hz, 1 H), 1.14 (d, J = 6.5 Hz, 3 H).
MS (ESI): m/z = 285.4 [M + H]+.
(13) (a) Bates, H. A. J. Org. Chem. 1983, 48, 1932. (b) Cox, E.
D.; Cook, J. M. Chem. Rev. 1995, 95, 1797. (c) Nakamura,
S.; Tanaka, M.; Taniguchi, T.; Uchiyama, M.; Ohwada, T.
Org. Lett. 2003, 5, 2087. (d) Magnus, P.; Matthews, K. S.;
Lynch, V. Org. Lett. 2003, 5, 2181. (e) Munchhof, M. J.;
Meyers, A. I. J. Org. Chem. 1996, 61, 4607.
(14) Compound 7a: 1H NMR (300 MHz, DMSO-d6): d = 11.21
(br s, 1 H), 7.99 (s, 1 H), 7.57-7.63 (m, 4 H) 3.69 (s, 3 H).
7b: 1H NMR (300 MHz, DMSO-d6): d = 11.87 (br s, 1 H),
8.47 (s, 1 H), 7.92 (d, J = 7.5 Hz, 2 H), 7.74 (d, J = 5.4 Hz,
2 H), 7.46-7.61 (m, 6 H).
(15) 3b: Crystallized in triclinic, space group P–1 with cell
parameters: a = 5.2532(11) Å, b = 10.676(2) Å, c =
20.717(4) Å, a = 101.19°, b = 93.87°, g = 102.61°, V =
1104.9(4) Å3, Dc = 1.447 g/cm3, Z = 2.
(16) Synthesis of compound 3: To the mixture of compound 6a
(200 mg, 0.64 mmol) and 4-bromobenzaldehyde (118 mg,
0.64 mmol) in MeCN (8 mL), anhyd NaI (334 mg, 2.23
mmol) was added under stirring at r.t., followed by TMSCl
(0.28 mL, 2.23 mmol). After 40 min, the reaction was
concentrated and the products were purified by column
chromatography (10–30% EtOAc–PE). Unless otherwise
indicated, each product was separated as an enantiomeric
mixture and characterized by NMR spectroscopy.
Synlett 2007, No. 3, 374–380 © Thieme Stuttgart · New York

380
L. Zhang et al.
LETTER
13C NMR (CDCl3): d = 167.14, 147.41, 147.20, 139.87,
(d, J = 8.5 Hz, 2 H), 7.63 (br s, 2 H) 7.49 (d, J = 7.5 Hz, 2 H)
7.45 (t, J = 7.5 Hz, 1 H), 7.36 (t, J = 7.5 Hz, 2 H), 6.74 (s, 1
H), 6.02 (s, 1 H), 5.24 (br s, 1 H), 3.71 (s, 3 H), 3.42 (s, 3 H),
3.23 (br s, 1 H), 2.91 (br s, 1 H), 2.83 (dd, J = 3.0, 16.0 Hz,
1 H), 1.17 (d, J = 6.0 Hz, 3 H). 13C NMR (125 Hz, CDCl3):
d = 167.40, 151.23, 148.08, 147.46, 147.41, 133.33, 131.70,
130.25, 128.63, 126.56, 126.49, 123.53, 110.83, 110.73,
67.78, 55.88, 55.83, 54.47, 38.29, 19.48. MS (ESI): m/z =
448.2 [M + H]+. 3h: mp 158-160 °C. 1H NMR (CDCl3): d =
7.72 (d, J = 7.0 Hz, 2 H), 7.50 (t, J = 7.5 Hz, 1 H), 7.42 (t,
J = 7.5 Hz, 2 H), 7.08 (br s, 1 H), 6.60 (s, 1 H), 6.52 (s, 1 H),
4.36 (d, J = 10.0 Hz, 1 H), 4.12 (d, J = 15.0 Hz, 1 H), 3.86
(s, 3 H), 3.84 (s, 3 H), 3.45 (br s, 1 H), 2.73-2.84 (m, 2 H),
1.30 (d, J = 6.5 Hz, 3 H). 13C NMR (CDCl3): d = 166.65,
147.85, 147.63, 133.81, 131.49, 128.49, 126.97, 125.04,
123.97, 111.13, 109.32, 56.94, 55.80, 55.45, 33.13, 18.69.
MS (ESI): m/z = 327.1 [M + H]+. 3i (trans): mp 184-186 °C.
1H NMR (CDCl3): d = 7.71 (d, J = 7.5 Hz, 2 H), 7.51 (t, J =
7.5 Hz, 1 H), 7.43 (t, J = 7.5 Hz, 2 H), 6.82 (br s, 1 H), 6.68
(s, 1 H), 6.57 (s, 1 H), 4.31 (br s, 1 H), 3.87 (s, 3 H), 3.86 (s,
3 H), 3.46 (br s, 1 H), 2.77-2.82 (m, 1 H), 2.67 (dd, J = 3.5,
16.5 Hz, 1 H), 1.93-2.00 (m, 1 H), 1.73-1.80 (m, 1 H),
1.56-1.63 (m, 1 H), 1.40 (m, 1 H), 1.27 (d, J = 6.5 Hz, 3 H),
0.90 (t, J = 6.0 Hz, 3 H). 13C NMR (CDCl3): d = 167.18,
147.67, 147.60, 134.21, 131.53, 128.68, 128.43, 126.92,
110.92, 109.34, 64.22, 56.06, 55.85, 35.84, 35.19, 19.82,
18.31, 14.57. MS (ESI): m/z = 369.3 [M + H]+. 3i (cis): mp
183–184 °C. MS (ESI): m/z = 369.3 [M + H]+. 3k (trans): mp
170-172 °C. 1H NMR (CDCl3): d = 7.59 (d, J = 7.0 Hz, 2 H),
7.48-7.51 (m, 1 H), 7.39-7.42 (m, 2 H), 7.23-7.26 (m, 4
H), 7.14-7.17 (m, 1 H), 7.01 (br s, 1 H), 6.53 (s, 1 H), 6.46
(s, 1 H), 4.73 (br s, 1 H, Ha), 3.84 (s, 3 H), 3.63 (s, 3 H),
3.54-3.56 (m, 1 H, He), 3.28 (dd, Jee = 5.0 Hz, Jea = 14.0 Hz,
1 H, He), 3.09 (dd, Jaa = 6.5 Hz, Jae = 14.0 Hz, 1 H, Ha), 2.65
(dd, Jaa = 11.0 Hz, Jae = 16.0 Hz, 1 H, Ha), 2.59 (dd, Jea = 3.5
Hz, Jea = 16.0 Hz, 1 H, He), 1.23 (d, J = 6.0 Hz, 3 H).
133.79, 131.61, 129.61, 129.03, 128.59, 128.30, 126.87,
126.81, 126.04, 110.63, 109.99, 66.23, 55.82, 55.69, 55.06,
43.72, 36.26, 20.04. MS (ESI): m/z = 417.3 [M + H]+. 3m:
mp 195-196 °C. 1H NMR (CDCl3): d = 7.44-7.51 (m,
3 H + 1 H¢), 7.71 (d, J = 7.5 Hz, 2 H, cis), 7.34-7.37 (m,
2 H, trans), 7.41 (t, J = 7.5 Hz, 2 H, cis), 7.26 (d, J = 4.0 Hz,
1 H, trans), 7.31 (d, J = 4.0 Hz, 1 H, cis), 7.19 (br s, 1 H, 2
isomers), 7.11 (d, J = 3.0 Hz, 1 H, trans), 6.84 (d, J = 3.0 Hz,
1 H, cis), 6.91 (dd, J = 3.5, 5.5 Hz, 1 H, trans), 6.98 (dd, J =
3.5, 5.5 Hz, 1 H, cis), 6.58 (s, 1 H, trans), 6.63 (s, 1 H, cis),
6.32 (s, 1 H, trans), 6.48 (s, 1 H, cis), 6.17 (br s, 1 H, trans),
5.50 (s, 1 H, cis), 4.11 (br s, 1 H, trans), 3.42-3.49 (m, 1 H,
cis), 3.86 (s, 1 H, trans), 3.88 (s, 1 H, cis), 3.64 (s, 1 H,
trans), 3.75 (s, 1 H, cis), 2.84-2.96 (m, 1 H, 2 isomers), 2.80
(dd, J = 3.5, 15.5 Hz, 1 H, 2 isomers), 1.30 (d, J = 6.5 Hz, 3
H, trans), 1.24 (d, J = 6.5 Hz, 3 H, cis). 13C NMR (CDCl3):
d (trans/cis)= 167.85/166.05, 147.87/148.48, 147.24/
147.60, 133.88/133.92, 131.49/131.58, 128.58/128.61,
127.47/127.00, 126.75/126.55, 125.96/125.92, 125.85/
125.36, 110.96/111.11, 110.37/110.58, 63.68/62.86, 55.80/
55.85, 49.77/54.66, 38.11/34.52, 19.74/18.78. MS (ESI):
m/z = 409.4 [M + H]+. 3n (trans): mp 192-194 °C. 1H NMR
(CDCl3): d = 8.44 (d, J = 5.5 Hz, 2 H), 7.61 (br s, 1 H), 7.43-
7.55 (m, 3 H), 7.30–7.34 (m, 2 H), 7.27-7.28 (m, 2 H), 6.61
(s, 1 H), 6.02 (s, 1 H), 5.86 (br s, 1 H), 4.00 (br s, 1 H), 3.85
(s, 3 H), 3.58 (s, 3 H), 2.95 (br s, 1 H), 2.82 (dd, J = 3.5, 15.5
Hz, 1 H), 1.27 (d, J = 6.0 Hz, 3 H). MS (ESI): m/z = 404.4
[M + H]+.
(17) Davis, F. A.; Mohanty, P. K.; Burns, D. M.; Andemichael,
Y. W. Org. Lett. 2000, 2, 3901.
(18) (a) Rezessy, B.; Sólyom, S. Lett. Drug Des. Discov. 2004, 1,
217. (b) Barreca, M. L.; Gitto, R.; Quartarone, S.; De Luca,
L.; De Sarro, G.; Chimirri, A. J. Chem. Inf. Comput. Sci.
2003, 43, 651.
Synlett 2007, No. 3, 374–380 © Thieme Stuttgart · New York