Tandem reduction + cyclization of ortho-substituted cinnamic esters

Article abstract of DOI:10.1016/j.tetlet.2011.08.039

Conjugate reduction of ortho-substituted cinnamic esters by Stryker's reagent to form copper enolates, followed by intramolecular aldol-type cyclization, successfully generated indane and tetralin rings in one pot efficiently. This tandem reaction is generally diastereoselective and provides good yields.

Full text of DOI:10.1016/j.tetlet.2011.08.039

Tetrahedron Letters 52 (2011) 5371–5374
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Tandem reduction + cyclization of ortho-substituted cinnamic esters
Daiane Cristina Sass, Emílio Carlos de Lucca Jr., Jader da Silva Barbosa, Kleber Thiago de Oliveira,
⇑
Mauricio Gomes Constantino
Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Avenida dos Bandeirantes, 3900, 14040-901 Ribeirão Preto, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Conjugate reduction of ortho-substituted cinnamic esters by Stryker’s reagent to form copper enolates,
followed by intramolecular aldol-type cyclization, successfully generated indane and tetralin rings in
one pot efficiently. This tandem reaction is generally diastereoselective and provides good yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 26 July 2011
Revised 5 August 2011
Accepted 7 August 2011
Available online 16 August 2011
Keywords:
Tandem reduction + cyclization
Aldol-type cyclization
Stryker’s reagent
Indanes
Tetralins
In the course of our investigation on the use of Stryker’s re-
agent in organic synthesis1 we came across the possibility of pre-
paring indanes and tetralins from simple cinnamic acid
derivatives.
The indane ring is present in a number of natural products and
drugs with biological activity, such as IndinavirÒ—an HIV-protease
inhibitor,2 AriceptÒ—used in the treatment of Alzheimer’s disease,3
the mutisiantol4 and (+)-indacrinone—drug against hypertension.5
The tetralin ketones are very valuable as starting material for the
preparation of steroids, tinctures, compounds with biological activ-
ity similar to prostaglandins and tyrosines. Moreover, its structure
is present in a large number of natural products with cytotoxic
properties as juncusol6 (Fig. 1). Indanes and tetralins derivatives
have been attractive targets for several syntheses described in
the literature.7–9
Although there are methods already described to synthesize
indanes and tetralins,10 alternate novel methods are desirable
due to the considerable importance of these compounds.
Ph
OH
N
N
OH
O
H
N
O
N
MeO
NH
t-Bu
O
N
H
MeO
Aricept®
Indinavir®
OH
HO
Cl
O
Cl
Ph
Me
HO
HO2C
O
(+) Indacrinone
Figure 1. Examples of compounds containing the indane and tetralin systems.
( )-Mutisiantol
Juncusol
⇑
Corresponding author. Tel.: +55 16 3602 3747; fax: +55 16 3602 4838.
E-mail address: mgconsta@usp.br (M.G. Constantino).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.039

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D. C. Sass et al. / Tetrahedron Letters 52 (2011) 5371–5374
Stryker’s reagent [Ph3PCuH]611,12 is very efficient to make conju-
gate reductions of various
,b-unsaturated carbonyl derivatives.13
In the presence of additional suitably positioned electrophilic cen-
ters, this reagent can also promote, after the 1,4-reduction, a second
reaction consisting of an intramolecular addition.14–17
We have thus decided to investigate the possibility of synthe-
sizing indanes and tetralins from ortho-substituted cinnamic esters
as outlined in Scheme 1.
All products were obtained in good yields, although for starting
a
materials 2 and 3 two stereoisomers were formed in each case,
thus lowering the yield for each stereoisomer. We decided to verify
if the stereoselectivity could be improved by lowering the temper-
ature of reaction to 0 °C. The results shown in Table 2, however, are
disappointing: the time for completing the reaction was clearly in-
creased, but no significant difference in the isomers ratio could be
observed.
Starting materials 1–4 (Table 1) were prepared by procedures
described in the literature, with minor modifications and adapta-
tions.18–28 Due to differences in the methods, most products are
trans-cinnamic esters, but 3 is a cis-product. This is not relevant
for our investigation because the stereochemistry of the cinnamic
ester is lost in the first step.
Each one of compounds 1–4 was treated with Stryker’s reagent
(0.5 mol of the reagent for each mol of the substrate) in toluene
solution at room temperature until disappearance of the starting
material and intermediate ester29 by TLC. The results are summa-
rized on Table 1.
These results, considered together with the control experiment
mentioned on note 29, suggest that the reduction of the conjugate
double bond is a faster process. The second step, intramolecular
addition, is slower and determines the time required for a com-
plete reaction. The global velocity of the reaction, thus, strongly de-
pends on the nature of the electrophilic group. Compound 4,
however, cannot be directly compared to the others because a
six-membered ring is formed only in this case.
The structure of all products could be determined by usual NMR
techniques such as 1H NMR, 13C NMR, gCOSY, gHMQC, gHMBC and
J-resolved.
The relative stereochemistry of isomers 7a and 7b was deter-
mined by comparing the experimental 1H NMR spectroscopic data
with literature data.30 However, for isomers 6a and 6b, we did not
find reliable data in the literature. First, we compared the experi-
mental vicinal coupling values between H1 and H2 with the corre-
sponding calculated values (GAUSSIAN program31). The result, shown
on Table 3, is acceptable but not unequivocal.
As NOESY experiments with these stereoisomers gave inconclu-
sive results, we prepared the corresponding methoxymethyl ethers
(9a and 9b) from a mixture of 6a and 6b (Scheme 2); the products
were separated and submitted to NOESY experiments.
Only stereoisomer 9b showed the NOE correlations depicted in
Figure 2, which confirm the trans stereochemistry of the substitu-
ents in C1 and C2.
Each isomer (9a and 9b) was hydrolyzed to the corresponding
alcohol (6a and 6b, respectively), thus completing the unequivocal
O
O
O
H
[(Ph3P)CuH]6
OMe
OMe
OMe
E
n
E
n
E
(Stryker)
( )
( )
( )
n
E: electrophilic center
n = 0 or 1
n = 0: Indane
n = 1: Tetralin
Scheme 1. Outline of the investigated reactions.
Table 1
Tandem reactions of 1–4 at 25 °C
SM
Time (h)
20
Products and yields
CO2Me
CO2Me
CO2Me
O
5
1
85%
CO2Me
2
2
CO2Me
CO2Me
CO2Me
+
1
1
CHO
1
OH
6a
OH
6b
2
32%
48%
CO2Me
CO2Me
OH
7a
+
COCH3
OH
0.5
3
7b
16%
74%
CO2Me
CN
CO2Me
NH2
0.25
4
8
95%

D. C. Sass et al. / Tetrahedron Letters 52 (2011) 5371–5374
5373
Table 2
Supplementary data
Tandem reactions of 2–3 at 0 °C
SM
Time (h)
5
Products and yields
+
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.039.
2
6a
6b
26%
7a
12%
48%
7b
63%
3
2.5
+
References and notes
1. (a) Sass, D. C.; Heleno, V. C. G.; Lopes, J. L. C.; Constantino, M. G. Tetrahedron Lett.
2008, 49, 3877; (b) Sass, D. C.; Heleno, V. C. G.; Morais, G. O.; Lopes, J. L. C.;
Lopes, N. P.; Constantino, M. G. Org. Biomol. Chem. 2011. doi:10.1039/
c1ob05734k.
2. Ghosh, A. K.; Bilcer, G.; Schiltz, G. Synthesis 2001, 2203.
3. Sugimoto, H. Pure Appl. Chem. 1999, 71, 2031.
Table 3
Experimental and calculated J values (Hz) between H1 and H2 in isomers 6a and 6b
4. Ho, T. L.; Lee, K. Y.; Chen, C. K. J. Org. Chem. 1997, 62, 3365.
5. Jain, A. K.; Michael, R.; Ryan, J. R.; McMahon, F. G. Pharmacotherapy 1984, 4,
278.
6. Boger, D. L.; Mitscher, L. A.; Mullican, M. D.; Drake, S. D.; Kitos, P. J. Med. Chem.
1985, 28, 1543.
J
Calculated J1,2 (Hz)
Experimental J1,2 (Hz)
Isomer 6a
Isomer 6b
4.9 (cis)
7.3 (trans)
4.6
6.7
7. Giorgi, G.; Arroyo, F. J.; López-Alvarado, P.; Menéndez, J. C. Synlett 2010, 2465.
8. Aubertin, Anne-Marie; Vierling, Pierre Org. Biomol. Chem. 2004, 4, 345.
9. Kesavan, S.; Panek, J. S.; Porco, J. A., Jr. Org. Lett. 2007, 9, 5203.
10. As examples of related procedures see, for instance: (a) Harb, H. Y.; Collins, K.
D.; Altur, J. V. G.; Bowker, S.; Campbell, L.; Procter, D. J. Org. Lett. 2010, 12, 5446;
(b) Samanta, S.; Yasmin, N.; Kundu, D.; Ray, J. K. Tetrahedron Lett. 2010, 51,
4132; (c) Mukherjee, H.; McDougal, N. T.; Virgil, S. C.; Stoltz, B. M. Org. Lett.
2011, 13, 825.
11. Chiu, P.; Li, Z.; Fung, K. C. M. Tetrahedron Lett. 2003, 44, 455.
12. Lee, D.; Yun, J. Tetrahedron Lett. 2005, 46, 2037.
13. Koenig, T. M.; Daeuble, J. F.; Brestensky, D. M.; Stryker, J. M. Tetrahedron Lett.
1990, 31, 3237.
6a
6b
+
CO2Me
CO2Me
+
95 %
OCH2OCH3
OCH2OCH3
9a
9b
Scheme 2. Preparation of methoxymethyl ethers (ClMOM and DIPEA in CH2Cl2).
14. Lipshutz, B. H.; Chrisman, W.; Noson, K.; Papa, P.; Scalfani, J. A.; Vivian, R. W.;
Keith, J. M. Tetrahedron 2000, 56, 2779.
15. Chiu, P.; Szeto, C.-P.; Geng, Z.; Cheng, K.-F. Org. Lett. 2001, 3, 1901.
16. Kamenecka, T. M.; Overman, L. E.; Lysakata, S. K. Org. Lett. 2002, 4, 79.
17. Chung, W. K.; Chiu, P. Synlett 2005, 55.
18. Starting material 1 was prepared from 2-naphthol by oxidative ring opening19
followed by esterification. An isomerization of the double bond has occurred,
possibly by the influence of Na2MoO4, since our product 1 has 1H NMR
consistent with the trans-isomer described in the literature.20
CO2H
H2O2 / AcOH
MeOH
Na2MoO4
47 %
H2SO4
94 %
OH
CO2H
10
2-Naphthol
The other starting material (3) also prepared by oxidative ring opening, however,
conserved the cis-stereochemistry of the double bond. Wolff–Kishner reduction of
1121 produced 12 which was ozonized22 and reduced with Ph3P to give 3.
N2H4
.
H2O
1. O3, CH2Cl2
KOH / DEG
80 %
2. Ph3P
38 %
OMe
OMe
CHO
CH3
12
11
Compound 3: 1H NMR (CDCl3, 300 MHz), d (ppm): 2.60 (s, 3H); 3.58 (s, 3H); 6.01 (d,
1H, J = 12.1 Hz); 7.34 (d, 1H, J = 7.5 Hz); 7.41–7.53 (m, 3H); 7.86 (dd, 1H, J = 7.5 Hz,
J = 1.1 Hz). 13C NMR (CDCl3, 75 MHz), d (ppm): 199.7 (C@O); 166.3 (C@O); 146.6
(CH); 136.8 (C); 135.7 (C); 131.6 (CH); 130.4 (CH); 129.5 (CH); 128.2 (CH); 118.4
(CH); 51.1 (CH3); 28.3 (CH3). IR (KBr, cmÀ1): 2952; 1724; 760.
Figure 2. Key NOE correlations found in isomer 9b.
determination of the relative stereochemistry of these
stereoisomers.
Starting materials 2 and 4 were both prepared from the bromo-ester 13: simple sub-
stitution with KCN23 gave 4 (spectroscopic data consistent with the literature,24
)
In conclusion we can say that the treatment of ortho-substi-
tuted cinnamic esters with Stryker’s reagent is a simple and effi-
cient method for preparing indanes and tetralins appropriately
substituted for using as building blocks in the synthesis of several
natural products.
while treatment with formic acid and Et3N gave a formic ester which was hydro-
26
lyzed to 14.25 The benzylic alcohol was then oxidized with MnO2 to produce 2
(spectroscopic data consistent with the literature27).
CO2Me
MnO2
HCl
HCOOH
CO2Me
MeOH
90 %
CH2Cl2
85 %
Acknowledgments
Et3N
OH
14
KCN
DMF
15 %
The authors thank the Fundação de Amparo à Pesquisa do Esta-
do de São Paulo (FAPESP), the Conselho Nacional de Desenvolvi-
Br
4
13
mento Científico
e Tecnológico (CNPq), the Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and the
Financiadora de Estudos e Projetos (FINEP) for financial support.
The bromo-ester 13 was prepared from o-tolualdehyde by condensation with malon-
ic acid28, esterification and benzylic bromination with NBS.

5374
D. C. Sass et al. / Tetrahedron Letters 52 (2011) 5371–5374
21. Gabbutt, C. D.; Heron, B. M.; Instone, A. C.; Thomas, D. A.; Partington, S. M.;
1. MeOH / H2SO4
92 %
CHO
CO2H
Hursthouse, M. B.; Gelbrich, T. Eur. J. Org. Chem. 2003, 1220.
22. Bernatek, E.; Frengen, C. Acta Chem. Scand. 1962, 16, 2421.
23. Hirakawa, K.; Ogiue, E.; Motoyoshiya, J.; Kakurai, T. J. Org. Chem. 1986, 51, 1083.
24. Miura, T.; Harumashi, T.; Murakami, M. Org. Lett. 2007, 9, 741.
25. Alexander, J.; Renyer, M. L.; Veerapanane, H. Synth. Commun. 1995, 25, 3875.
26. Fatiadi, A. J. Synthesis 1976, 65.
HO2C
CO2H
Pyr, Piperidine
82 %
2. NBS
35 %
o-Tolualdehyde
15
27. Meegalla, S. K.; Rodrigo, R. J. Org. Chem. 1991, 56, 1882.
28. Liu, J.-M.; Young, J.-J.; Li, Y.-J.; Sha, C.-K. J. Org. Chem. 1986, 51, 1120.
29. In a control experiment we treated the diester 1 with Stryker’s reagent, under
the same reaction conditions, but for a period of only 30 min. Isolation and
analysis of the product showed that half of the diester had been reduced, but
only a small amount had been cyclized.
30. Clark, G. R.; Metzler, M. R.; Whitaker, G.; Woodgate, P. D. J. Organomet. Chem.
1996, 513, 109.
31. Frisch, M. J. et al., GAUSSIAN 98, Revision A.7, Gaussian Inc., Pittsburgh, PA, 1998.
19. Raacke, I. D.; Wang, C. H.; Robins, R. K.; Christensen, B. E. J. Org. Chem. 1950, 15,
627.
20. Bernini, R.; Cacchi, S.; Fabrizi, G.; Forte, G.; Niembro, S.; Petrucci, F.; Pleixats, R.;
Prastaro, A.; Sebastián, R. M.; Soler, R.; Tristany, M.; Vallribera, A. Org. Lett.
2008, 10, 561.