C-1 alkynylation of N-methyltetrahydroisoquinolines through CDC: A direct access to phenethylisoquinoline alkaloids

Article abstract of DOI:10.1055/s-0031-1290532

Direct cross-coupling between N-methyltetrahydroisoquinolines and alkynes using CuI-DEAD is presented. It affords the regioselective C-1-alkynylated products in good yield. This regio-selectivity is in contrast to the results reported earlier in the reaction of N,N-dimethylbenzyl amine where the N-methyl alkynylated product was formed exclusively or predominantly. The C-1-substituted propargylic isoquinolines were easily reduced to phenethylisoquinolines with Pd/C. This reaction sequence provides a short route to synthesize methopholine, homolaudanosine and other phenethylisoquinoline alkaloids. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290532

760
LETTER
C-1 Alkynylation of N-Methyltetrahydroisoquinolines through CDC:
A Direct Access to Phenethylisoquinoline Alkaloids
S
ynthesis of 1-Phe
a
nethylisoqu
m
inoline
s
through CD
a
C
Reactio
l
n
Nain Singh,* Paramjit Singh, Amarjit Kaur, Pushpinder Singh
Department of Chemistry, Panjab University, Chandigarh 160014, India
Fax +91(172)2545074; E-mail: kns@pu.ac.in
Received 16 December 2011
Transition-metal-catalyzed cross-coupling reactions have
been extensively studied6 and CDC (cross dehydrogena-
tive coupling) technique for activation of C–H bond (sp,
sp2, sp3) has evolved as an effective strategy for construc-
Abstract: Direct cross-coupling between N-methyltetrahydroiso-
quinolines and alkynes using CuI–DEAD is presented. It affords the
regioselective C-1-alkynylated products in good yield. This regio-
selectivity is in contrast to the results reported earlier in the reaction
of N,N-dimethylbenzyl amine where the N-methyl alkynylated tion of new C–C bonds.6,7 In these reactions, prefunction-
alization of the substrates is not necessary.7a,c Chao-Jun Li
product was formed exclusively or predominantly. The C-1-substi-
tuted propargylic isoquinolines were easily reduced to phenethyl-
and co-workers explored various aspects of CDC reac-
isoquinolines with Pd/C. This reaction sequence provides a short
tions using diverse substrates8a–e,g and reported that CuBr-
route to synthesize methopholine, homolaudanosine and other
catalyzed alkynylation of N-aryltetrahydroisoquinolines
phenethylisoquinoline alkaloids.
in the presence of tert-butyl hydroperoxide (TBHP) pro-
Key words: cross-coupling, regioselectivity, alkaloids, alkynes,
ceeds efficiently to give the C-1-substituted products.8a,b
amines
Although the authors have cited that methoxy-substituted
aryl group on nitrogen atom can be removed,8b difficulties
have been reported in dearylation, particularly, in case of
In a large number of natural products and pharmaco-
N-phenyltetrahydroisoquinolines.9 A similar CDC reac-
phores, N-methyltetrahydroisoquinoline represents the
tion of N,N-dimethylbenzyl amine exclusively gives the
central framework.1 The C-1-functionalized derivatives of
this moiety, both naturally occurring and synthesized
Table 1 Optimization of Reaction Conditionsa
ones, have been unveiled as highly worthy candidates in
biological study as well as in medicinal developments.2 1-
Alkynyl N-methyltetrahydroisoquinoline derivatives are
potential D3 dopamine receptor ligands in neurological
and neuropsychiatric therapeutics.3 Phenethylisoquino-
line alkaloids (Figure 1),4 a class of homologated 1-ben-
zyl isoquinoline alkaloids, have also evinced considerable
interest.5 A precise and facile method for the synthesis of
these alkaloids is, therefore, highly desirable.
Cu(I), DEAD
+
Ph
H
solvent, r.t., 6 h
N
N
Me
Me
6a
7a
Ph
8a
Entry
Solvent
THF
Catalyst
–
mol%
Yield (%)b
1
2
3
4
5
6
7
8
9
0
CH2Cl2
MeCN
toluene
Et2O
CuI
5
5
78
R1
R2
CuI
75
N
Me
CuI
5
76c
73
CuI
5
THF
CuI
5
82
R3
THF
CuBr
CuBr
CuCl
5
80d
82e
70f
R1 = OMe, R2 = OMe, R3 = 4-Cl; methopholine (1)
THF
10
5
R
R
R
1 = OMe, R2 = OMe, R3 = 3,4-(OMe)2; homolaudanosine (2)
1 = OH, R2 = OMe, R3 = 4-OMe; colchiethine (3)
1 = OMe, R2 = OMe, R3 = 4-OH; colchicine precursor
THF
a Reaction conditions: N-methyltetrahydroisoquinoline (1 equiv),
DEAD (1.1 equiv), phenylacetylene (1.5 equiv), r.t., 6 h.
b Isolated yield.
Figure 1 Phenethylisoquinoline alkaloids and derivatives
c Reaction time: 24 h.
SYNLETT 2012, 23, 760–764
x
x.
x
x.
2
0
1
2
d Reaction time: 15 h.
Advanced online publication: 24.02.2012
DOI: 10.1055/s-0031-1290532; Art ID: B77811ST
© Georg Thieme Verlag Stuttgart · New York
e Reaction time: 7 h.
f Reaction time: 20 h.

LETTER
Synthesis of 1-Phenethylisoquinolines through CDC Reaction
761
(DEAD).11a These reactions furnish the methyl alkynylat-
ed products in excellent yield.11a They further observed
that in the reaction of N,N-dimethylbenzyl amine, under
these conditions, the ratio for the alkynylation of methyl
and methylene is ca. 63:37 (4:5) in 82% overall yield
(Scheme 1).11a This reaction has been postulated to pro-
ceed through the intermediacy of iminium ion.11 The se-
lective oxidation of the methyl group of N,N-
dimethylbenzyl amine has been exploited by others also.12
We envisaged that in case of N-methyltetrahydroisoquin-
oline, which has a rigid structure, it is probable that the
proton loss to form the iminium ion may occur preferen-
tially from the C-1 position instead of the methyl group.
Herein we wish to report our findings of Cu-catalyzed re-
actions of N-methyltetrahydroisoquinoline with alkynes
using DEAD which have so far not been investigated.13
Me
N
Me
N
Me
N
Me
Ph
,
Me
Cu[O]
CuI, DEAD
N
Ph
Ph
Me
4
5
6a
this
work
N
Me
Ph
C-1 alkynylation
We initiated our study with oxidative coupling between
6a and phenylacetylene (Scheme 1). The reaction was
performed by taking the amine–alkyne–DEAD–CuI mix-
ture in the ratio 1:1.5:1.1:0.05 in THF as solvent and the
reaction mixture was stirred at room temperature for six
hours. Workup and purification by column chromatogra-
phy afforded the C-1 alkynylated amine 8a as the only
product in 82% yield (Table 1, entry 6). Although three
different kinds of hydrogens a to the nitrogen atom are
Scheme 1 CDC of N,N-dimethylbenzyl amine and N-methyltetra-
hydroisoquinoline
methyl alkynylated product 4 (Scheme 1).8a This result
has been interpreted as similar to the anodic methoxyla-
tion of this amine.10 Xiaonian Li and Xiaoliong Xu report-
ed CDC reactions of unactivated aliphatic tertiary amines
and terminal alkynes using CuI–diethyl azodicarboxylate
Table 2 Oxidative Coupling of N-Methyltetrahydroisoquinoline and Alkynes Using CuI–DEADa
R1
R1
CuI/DEAD
H
+
N
N
THF, r.t., 6 h
R3
R2
Me
R2
Me
6a–b
7a–d
6a R1 = H, R2 = H;
7a R3 = H;
6b R1 = OMe, R2 = OMe;
6c R1 = Oi-Pr, R2 = OMe;
7b R3 = 4-Cl;
7c R3 = 4-OMe;
7d R3 = 3,4-(OMe)2;
R3
8a–j
Entry
6
7
8b
Yield (%)c
1
2
6a
7a
7b
7c
7d
7a
7b
7c
7d
7c
8a
8b
8c
8d
8e
8f
82
70
80
82
81
68
78
80
76
82
6a
6a
6a
6b
6b
6b
6b
6c
6a
3
4
5
6
7
8g
8h
8i
8
9
10
7e (C8H14)d
8j
a Reaction conditions: N-methyltetrahydroisoquinoline (1 equiv), DEAD (1.1 equiv), alkyne (1.5 equiv), CuI (5 mol%), THF (0.5 M), 6 h.
b Products were characterized by 1H NMR and 13C NMR.
c Isolated yields are based on N-methyltetrahydroisoquinolines.
d Aliphatic alkyne (oct-1-yne).
© Thieme Stuttgart · New York
Synlett 2012, 23, 760–764

762
K. N. Singh et al.
LETTER
present in 6a, alkynylation occurred exclusively at the A tentative mechanism, as depicted in Scheme 2, is pro-
benzylic (C-1) position. In the absence of copper catalyst posed in accordance with literature.8,11 N-Methyltetrahy-
no reaction was observed (Table 1, entry 1). The reaction droisoquinoline and DEAD undergo a nucleophilic
conditions were optimized by screening different solvents addition to form a 1:1 adduct which cleaves to form imin-
and copper catalysts. CuBr and CuCl also gave the C-1 ium ion intermediate A. A further addition of the generat-
alkynylated product in good yield after prolonging the re- ed copper alkynylide leads to the desired product 8. The
action time (Table 1, entries 7–9). A slight decrease in the selective formation of intermediate A in this case is in
yield was observed with solvents like dichloromethane, contrast to the preferential formation of intermediate D in
acetonitrile, toluene and diethyl ether (Table 1, entries 2– the similar reaction of N,N-dimethylbenzyl amine11a
5). Thus, the best result was obtained with CuI (5 mol%) (Scheme 2). It is possible that in the iminium ion interme-
using THF as solvent (Table 1, entry 6).14
diate C, an unfavorable steric interaction between one of
the ortho-phenyl hydrogens and the syn-substituents at ni-
trogen develops.12 This non-bonded steric interaction
could be removed by rotation of the phenyl ring, but this
stereochemical change reduces the conjugation and leads
to instability of the system. Due to this, the kinetically fa-
vored intermediate D is formed. However, in a rigid struc-
ture like N-methyltetrahydroisoquinoline, where free
rotation of phenyl ring is prohibited, the thermodynami-
cally more stable intermediate A gets formed. This results
Under the optimized conditions, differently substituted
phenylacetylenes were successfully coupled with 6a and
the corresponding C-1-alkynylated products were ob-
tained in good yields (Table 2, entries 1–4).14 Reactions of
substituted
N-methyltetrahydroisoquinolines
with
alkynes also gave satisfactory results (Table 2, entries 5–
9). Even an aliphatic alkyne reacted smoothly (Table 2,
entry 10). In none of the reactions was the N-methyl alky-
nylated product detected.
COOEt
N
+
Me
N
N
N
N
COOEt
Me
H
H
COOEt
6
N
COOEt
Me
N
N
COOEt
CH2
N
N
H
COOEt
HN
2H⋅DEAD
HN
COOEt
COOEt
H
Ph
COOEt
N
HN
COOEt
N
Cu
Ph
CuI
CH2
N
Me
B
A
N
Me
8
Ph
H
Me
Me
N
Me
CuI, DEAD
N
N
Me
CH2
Me
C
D
Scheme 2 Proposed mechanism
Synlett 2012, 23, 760–764
© Thieme Stuttgart · New York

LETTER
Synthesis of 1-Phenethylisoquinolines through CDC Reaction
763
Acknowledgment
Table 3 Reduction of Propargylic Amines to Phenethylisoquino-
lines
We acknowledge financial support vide scheme no. 01(2138)/07/
EMR-II from CSIR, New Delhi, India. One of the authors, Pushpin-
der Singh, is thankful to CSIR, New Delhi for providing CSIR-JRF
fellowship.
R1
R2
R1
R2
H2, Pd/C
N
N
EtOH, r.t., 1 atm
Me
Me
References and Notes
(1) (a) Ozturk, T. The Alkaloids, Vol. 53; Cordell, G. A., Ed.;
Academic Press: New York, 2000, 120. (b)Wu, W.; Beal, J.
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Chem. 2001, 66, 243; and references therein.
(3) Byrator, E.; Sasse, B. C.; Stark, H.; Schneider, G.
ChemBioChem 2005, 6, 997.
(4) (a) Shamma, M. The Isoquinoline Alkaloids, Vol. 25;
Blomquist, A. T.; Wasserman, H., Eds.; Academic Press:
New York, 1972, Chap. 24, 458. (b) Battersby, A. R.;
Bradbury, R. B.; Herbert, R. B.; Munro, M. H. G.; Ramage,
R. J. Chem. Soc., Perkin Trans. 1 1974, 1394.
R3
R3
8
1–3, 9–13
Entry
8
Producta
Yield
(%)b
1
2
3
4
5
6
7
8
8a 9 (R1 = H, R2 = H, R3 = H)
8c
10 (R1 = H, R2 = H, R3 = OMe)
8d 11 [R1 = H, R2 = H, R3 = 3,4-(OMe)2]
75
73
74
74
76
75
78
67c
8e
8f
12 (R1 = OMe, R2 = OMe, R3 = H)
1 (R1 = OMe, R2 = OMe, R3 = Cl)
8g 13 (R1 = OMe, R2 = OMe, R3 = OMe)
(c) Kametani, T.; Koizumi, M. The Alkaloids, Vol. 14;
Manske, R., Ed.; Academic Press: London, 1979, Chap. 7,
265.
8h 2 [R1 = OMe, R2 = OMe, R3 = 3,4-(OMe)2]
8i
3 (R1 = OH, R2 = OMe, R3 = OMe)
(5) (a) Cass, L. J.; Frederik, W. S. Am. J. Med. Sci. 1963, 246,
550. (b) Meyers, A. I.; Dickman, D. A.; Boes, M.
a Products were characterized by 1H NMR and 13C NMR.
b Isolated yield.
Tetrahedron 1987, 43, 5095. (c) Zbigniew, C.; MacLean, D.
B.; Szarek, W. A. J. Chem. Soc., Chem. Commun. 1987, 7,
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2003, 349, 1647. (g) Tojo, E.; Önür, M. A.; Freyer, A. J.;
Shamma, M. J. Nat. Prod. 1990, 53, 634.
c Product was isolated after deprotection of i-Pr group with overall
yield.
in a complete change in the regioselectivity of the reac-
tion.
However, theoretical calculations may be needed to firm-
ly establish the mechanistic details of the regioselectivity.
(6) For representative papers, see: (a) Miyaura, N.; Suzuki, A.
Chem. Rev. 1995, 95, 2457. (b) Kotha, S.; Lahiri, K.;
Kashinath, D. Tetrahedron 2002, 58, 9633. (c)Nicolaou, K.
C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44,
4442. (d) Dyker, G. Handbook of C-H Transformation;
Wiley-VCH: Weinheim, 2005. (e) Zapf, A.; Beller, M.
Chem. Commun. 2005, 431. (f) Herreries, C.; Yao, X.; Li,
Z.; Li, C.-J. Chem. Rev. 2007, 107, 2546. (g) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
(h) Miyaura, N. Bull. Chem. Soc. Jpn. 2008, 81, 1535.
(i) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41,
1461. (j) Chen, X.; Engle, K.-M.; Wang, D.-H.; Yu, J.-Q.
Angew. Chem. Int. Ed. 2009, 48, 5094. (k) Bellina, F.;
Rossi, R. Chem. Rev. 2010, 110, 1082. (l) Liu, C.; Zhang,
H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780.
The C-1-alkynylated tetrahydroisoquinolines were easily
reduced, using Pd/C in ethanol at room temperature and
atmospheric pressure,15 to afford the corresponding phen-
ethylisoquinolines in good yield (Table 3, entries 1–8).16
Thus, methopholine (1),4a,5a homolaudanosine (2)5b–d and
phenethylisoquinoline 1217 were obtained in 76%, 78%
and 74% yield, respectively (Table 3, entries 5, 7, and 4).
Colchiethine (3)5g was isolated after deprotection of iso-
propyl group, using anhydrous AlCl3 in dichloromethane,
in 67% overall yield (Table 3, entry 8).
In summary, reactions of N-methyltetrahydroisoquino-
lines and alkynes using CuI–DEAD exclusively afford C-
1-substituted propargylic amines and these were reduced
to phenethylisoquinoline alkaloids. Further investigations
of these unique CDC reactions using substrates other than
alkynes are in progress.
(7) (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335.
(b) Scheuermann, C.-J. Chem. Asian J. 2010, 5, 436.
(c) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.
(8) (a) Li, Z.-P.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810.
(b) Li, Z.-P.; Li, C.-J. Org. Lett. 2004, 6, 4997. (c)Li,Z.-P.;
Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672. (d) Li, Z.-P.;
Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968. (e) Zhang, Y.;
Li, C.-J. J. Am. Chem. Soc. 2006, 128, 4242. (f) Murahashi,
S.-I.; Nakae, T.; Terai, H.; Komiya, N. J. Am. Chem. Soc.
2008, 130, 11005. (g) Li, Z.; Li, C.-J. Angew. Chem. Int. Ed.
2008, 47, 7075. (h) Sud, D.; Sureshkumar, D.; Klussmann,
M. Chem. Commun. 2009, 3169. (i) Shen, Y.-M.; Li, M.;
Wang, S.-Z.; Zhan, T.-G.; Tan, Z.; Guo, C.-C. Chem.
Commun. 2009, 953. (j) Condie, A.-G.; Gonzalez-Gomez,
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
© Thieme Stuttgart · New York
Synlett 2012, 23, 760–764

764
K. N. Singh et al.
LETTER
J.-C.; Stephenson, C.-R.-J. J. Am. Chem. Soc. 2010, 132,
1464. (k) Liu, P.; Zhou, C.-Y.; Xiang, S.; Che, C.-M. Chem.
Commun. 2010, 2739.
55.96, 55.80, 48.53, 43.58, 28.33. MS (ESI): m/z = 342.1
[M + H]+.
6,7-Dimethoxy-1-(3,4-dimethoxyphenylethynyl)-2-
methyl-1,2,3,4-tetrahydroisoquinoline (8h): yellow
viscous liquid. 1H NMR (300 MHz, CDCl3): d = 6.90 (dd,
J = 8.1, 1.8 Hz, 1 H), 6.80 (d, J = 1.8 Hz, 1 H), 6.72 (s, 1 H),
6.65 (d, J = 8.4 Hz, 1 H), 6.49 (s, 1 H), 4.50 (s, 1 H), 3.78 (s,
6 H), 3.77 (s, 6 H), 2.73–2.94 (m, 3 H), 2.58–2.62 (m, 1 H),
2.52 (s, 3 H). 13C NMR (75 MHz, CDCl3): d = 149.39,
148.59, 148.21, 147.45, 127.18, 125.43, 125.00, 115.38,
114.61, 111.27, 110.93, 110.48, 86.14, 85.90, 56.57, 56.52,
55.92, 55.89, 55.74, 48.66, 43.66, 28.39. MS (ESI): m/z =
368.1 [M + H]+.
(9) (a) Ghobrial, M.; Harhammer, K.; Mihovilovic, M. D.;
Schnurch, M. Chem. Commun. 2010, 46, 8836. (b) Tsang,
S.-K.; Todd, M. H. Tetrahedron Lett. 2009, 50, 1199.
(10) Weinberg, N. L.; Brown, E. A. J. Org. Chem. 1966, 31,
4058.
(11) (a) Xu, X.; Li, X. Org. Lett. 2009, 11, 1027. (b) Xu, X.; Li,
X.; Ma, L.; Ye, N. J. Am. Chem. Soc. 2008, 130, 14048.
(12) (a) Lewis, F. D.; Ho, T.-I.; Simpson, J. T. J. Am. Chem. Soc.
1982, 104, 1924. (b) Dumbrowski, G. W.; Dinnocenzo, J.
P.; Farid, S.; Goodman, J. L.; Gould, I. R. J. Org. Chem.
1999, 64, 427. (c) Barry, J. E.; Finkelstein, M.; Mayeda,
E. A.; Ross, S. D. J. Org. Chem. 1974, 39, 2695.
(13) DDQ-promoted cyanation and VO(acac)2–MCPBA-
promoted coupling of nucleophiles like nitroalkanes,
ketones and heteroaromatics such as indole and pyrrole with
N-alkyltetrahydroisoquinolines have been reported earlier:
(a) Sundberg, R. J.; Theret, M.-H.; Wright, L. Org. Prep.
Proced. Int. 1994, 26, 386. (b) Jones, K. M.; Karier, P.;
Klussmann, M. ChemCatChem 2012, 4, 51.
(14) General Procedure: To a solution of appropriate N-
methyltetrahydroisoquinoline (1 mmol) in THF (2 mL),
taken in 10-mL two-necked round bottom flask, was added
DEAD (1.1 mmol) dropwise in 1–2 min at 0–5 °C and the
reaction mixture was allowed to reach r.t. and stirred for 1 h.
After re-cooling the reaction mixture to 0–5 °C, CuI (0.05
mmol) was added followed by dropwise addition of the
alkyne (1.5 mmol). The resulting mixture was stirred for 5–
6 h at r.t. and then the solvent was evaporated under reduced
pressure. The residue was purified by column chromatog-
raphy over silica gel using hexane–EtOAc mixture (9:1–6:4)
as the eluent to give the pure products 8a–j.
(15) (a) Hershberg, E. B.; Oliveto, E. P.; Gerold, C.; Johnson, L.
J. Am. Chem. Soc. 1951, 73, 5073. (b) Taylor, A. M.;
Schreiber, S. L. Org. Lett. 2006, 8, 143.
(16) Spectral data of selected phenethylisoquinolines:
1-(4-Methoxyphenethyl)-2-methyl-1,2,3,4-tetrahydro-
isoquinoline (10): light yellow oil. 1H NMR (300 MHz,
CDCl3): d = 7.07–7.14 (m, 6 H), 6.79–6.82 (m, 2 H), 3.77 (s,
3 H), 3.46 (t, J = 5.4 Hz, 1 H), 3.12–3.18 (m, 1 H), 2.64–2.84
(m, 4 H), 2.42–2.47 (m, 1 H), 2.44 (s, 3 H), 2.00–2.09 (m, 2
H). 13C NMR (75 MHz, CDCl3): d = 157.60, 138.18, 134.94,
129.29, 128.71, 127.06, 125.80, 125.74, 113.70, 63.03,
55.22, 48.31, 42.82, 36.93, 30.59, 26.14. Anal. Calcd for
C19H23NO: C, 81.10; H, 8.24; N, 4.98. Found: C, 81.19; H,
8.33; N, 4.89.
6,7-Dimethoxy-2-methyl-1-phenethyl-1,2,3,4-tetra-
hydroisoquinoline (12):17 yellow pasty mass. 1H NMR (300
MHz, CDCl3): d = 7.16–7.21 (m, 2 H), 7.09–7.12 (m, 3 H),
6.50 (s, 1 H), 6.44 (s, 1 H), 3.77 (s, 3 H), 3.74 (s, 3 H), 3.44
(t, J = 4.8 Hz, 1 H), 3.11–3.19 (m, 1 H), 2.66–2.87 (m, 4 H),
2.50–2.59 (m, 1 H), 2.44 (s, 3 H), 1.94–2.10 (m, 2 H). 13
C
NMR (75 MHz, CDCl3): d = 147.46, 147.33, 142.43, 128.74,
128.39, 128.29, 125.85, 125.65, 111.26, 110.06, 62.59,
55.93, 55.76, 47.41, 42.03, 36.64, 31.76, 24.82. MS (ESI):
m/z = 308.1 [M + H]+.
Spectral data of selected compounds:
1-(4-Chlorophenylethynyl)-6,7-dimethoxy-2-methyl-
1,2,3,4-tetrahydroisoquinoline (8f): yellow viscous liquid.
1H NMR (300 MHz, CDCl3): d = 7.23–7.27 (m, 2 H), 7.15–
7.18 (m, 2 H), 6.97 (s, 1 H), 6.49 (s, 1 H), 4.53 (s, 1 H), 3.78
(s, 3 H), 3.77 (s, 3 H), 2.86–2.96 (m, 2 H), 2.78–2.83 (m, 1
H), 2.70–2.73 (m, 1 H), 2.51 (s, 3 H). 13C NMR (75 MHz,
CDCl3–CCl4): d = 148.35, 147.54, 134.15, 132.96, 128.54,
126.73, 125.48, 121.62, 111.35, 110.37, 88.59, 85.21, 56.42,
(17) (a) Brossi, A.; Besendrof, H.; Pellmont, B.; Walter, M.;
Schinder, O. Helv. Chim. Acta 1960, 43, 1459. (b) Brossi,
A.; Besendrof, H.; Pirk, L. A.; Rheiner, A. Med. Chem.
1965, 5, 281. (c) Ito, K.; Furukawa, H.; Tanaka, H.; Kato, S.
J. Pharm. Soc. Jpn. 1970, 90, 1169.
Synlett 2012, 23, 760–764
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