Diastereoselective synthesis of 4-hydroxytetralones via a cascade Stetter-aldol reaction catalyzed by N-heterocyclic carbenes

Article abstract of DOI:10.1021/jo902376t

(Chemical Equation Presented) A cascade Stetter-aldol reaction of phthalaldehyde and Michael acceptors catalyzed by N-heterocyclic carbenes was developed. The corresponding 3-substituted-4-hydroxytetralones were obtained in moderate to good yields with good trans-selectivities. On the contrary, the separated Stetter reaction followed by aldol reaction gave 3-substituted-4- hydroxytetralones with good cis-selectivity. Oxidation or dehydration of the resulted 4-hydroxytetralone gave the corresponding naphthalenediol or naphthol derivative, respectively, in good yield.

Full text of DOI:10.1021/jo902376t

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an enolate, which is a very useful reactive intermediate in
Diastereoselective Synthesis of 4-Hydroxytetralones
via a Cascade Stetter-Aldol Reaction Catalyzed by
N-Heterocyclic Carbenes
organic synthesis, is generated in the Stetter reaction, the
cascade reactions involving this enolate have rarely been
reported.
SCHEME 1. Gravel’s Cascade Stetter-Michael Reaction
Fang-Gang Sun, Xue-Liang Huang, and Song Ye*
Beijing National Laboratory for Molecular Sciences, CAS
Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China
songye@iccas.ac.cn
Received November 6, 2009
During the preparation of this manuscript, Gravel et al.
reported a NHC-catalyzed cascade Stetter-Michael reac-
tion for the synthesis of indanes (Scheme 1).4 In this manu-
script, we wish to report a NHC-catalyzed cascade Stetter-
aldol reaction for the diastereoselective synthesis of 4-hydro-
xytetralones.5
4-Hydroxytetralones and their derivatives are useful inter-
mediates in organic synthesis and present as the key motif in
several natural products and biological active compounds,
such as isocatalponol, isoshinanolone, and plumbagin.6
However, to the best of our knowledge, there are only limited
examples for the synthesis of this motif.7 We envisioned that
the enolate 5, generated from phthalaldehyde 1 and Michael
acceptor 2 via a NHC-catalyzed Stetter reaction, may further
undergo intramolecular aldol reaction to afford 4-hydro-
xytetralones 3 (Figure 1).
Initial experiment revealed that the reaction of phthalal-
dehyde and ethyl(vinyl)ketone 2a catalyzed by NHC 6a0,
generated from thiazolium salt 6a in the presence of the base
Cs2CO3, gave 4-hydroxytetralone 3a in 45% yield with a 1:1
ratio of trans- and cis-isomers (Table 1, entry 1). It should be
noted that only slight epimerization of cis- to trans-isomer or
trans- to cis-isomer was observed in the presence of 20 mol %
Cs2CO3 or DBU.8
A cascade Stetter-aldol reaction of phthalaldehyde and
Michael acceptors catalyzed by N-heterocyclic carbenes
was developed. The corresponding 3-substituted-4-
hydroxytetralones were obtained in moderate to good
yields with good trans-selectivities. On the contrary, the
separated Stetter reaction followed by aldol reaction gave
3-substituted-4-hydroxytetralones with good cis-selecti-
vity. Oxidation or dehydration of the resulted 4-hydro-
xytetralone gave the corresponding naphthalenediol or
naphthol derivative, respectively, in good yield.
After ruling out the in situ isomerization of the trans/
cis-isomers, the optimization of reaction conditions was then
carried out to improve the diastereoselectivity and yield. It
Cascade reactions, which allow two or more reactions to
occur consecutively in one pot, are of great interest in modern
synthesis.1 Generally, two requirements for a cascade reaction
are that (1) a reactive intermediate is formed in the former
reaction that can further react in the latter reaction and (2) the
conditions for the consecutive reactions are compatible. The
Stetter reaction is the addition of aldehydes to Michael accep-
tors catalyzed by N-heterocyclic carbenes (NHCs).2,3 Although
ꢀ
(4) Sanchez-Larios, E.; Gravel, M. J. Org. Chem. 2009, 74, 7536.
(5) For our recent publications on NHC catalysis, see: (a) He, L.; Jian,
T.-Y.; Ye, S. J. Org. Chem. 2007, 72, 7466. (b) Zhang, Y.-R.; He, L.; Wu, X.;
Shao, P.-L.; Ye, S. Org. Lett. 2008, 10, 277. (c) Huang, X.-L.; He, L.; Shao,
P.-L.; Ye, S. Angew. Chem., Int. Ed. 2009, 48, 192.
(6) (a) Inoue, K.; Inouye, H.; Taga, T.; Fujita, R.; Osaki, K.; Kuriyama,
K. Chem. Pharm. Bull. 1980, 28, 1224. (b) Anh, N. H.; Ripperger, H.; Porzel,
A.; Sung, T. V.; Adam, G. Phytochemistry 1997, 44, 549. (c) Tokunaga, T.;
Takada, N.; Ueda, M. Tetrahedron Lett. 2004, 45, 7115. (d) Nyangulu, J. M.;
Nelson, K. M.; rose, P. A.; Gai, Y.; Loewen, M.; Lougheed, B.; Quail, J. W.;
Cutler, A. J.; Abrams, S. R. Org. Biomol. Chem. 2006, 4, 1400.
(1) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115. (b) Enders, D.; Grondal, C.;
€
Huttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570. (c) Tietze, L. F.;
Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis; Wiley-VCH:
Weinheim, Germany, 2006.
(2) (a) Stetter, H.; Schreckenberg, M. Angew. Chem., Int. Ed. Engl. 1973,
12, 81. (b) Stetter, H. Angew. Chem., Int. Ed. 1976, 15, 639.
(3) For recent reviews on NHC-catalyzed reactions, see: (a) Enders, D.;
Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606 and references therein.
(7) (a) Joly, S.; Nair, M. S. Tetrahedron: Asymmetry 2001, 12, 2283. (b)
Gopishetty, S. R.; Heinemann, J.; Deshpande, M.; Rosazza, J. P. N. Enzyme
Microb. Technol. 2007, 40, 1622. (c) Allen, J. G.; Henntemann, M. F.;
Danishefsky, S. J. J. Am. Chem. Soc. 2000, 122, 571. (d) Ferreira, E. M.;
Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725. (e) Dohi, T.; Takenaga, N.;
Goto, A.; Fujioka, H.; Kita, Y. J. Org. Chem. 2008, 73, 7365. (f ) Nakanishi,
M.; Bolm, C. Adv. Synth. Catal. 2007, 349, 861.
ꢀ
(b) Marion, N.; Díez-Gonzalez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46,
2988. (c) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534.
(8) See Supporting Information for details.
DOI: 10.1021/jo902376t
r
Published on Web 12/07/2009
J. Org. Chem. 2010, 75, 273–276 273
2009 American Chemical Society

Sun et al.
JOCNote
TABLE 2. Synthesis of trans-4-Hydroxytetralones via a Cascade
Stetter-Aldol Reaction Catalyzed by NHC 6b0
FIGURE 1. Proposed cascade Stetter-aldol reaction catalyzed by
NHC.
TABLE 1. Optimization of Reaction Conditions
NHC precursor,
base (mol %)
yield
(%)b
trans:
cisc
entry
solvent
1
2
3
4
5
6
7
6a, Cs2CO3 (10)
6a, Cs2CO3 (10)
6a, Cs2CO3 (10)
6a, Cs2CO3 (10)
6a, Cs2CO3 (10)
6a, Cs2CO3 (10)
6a, Cs2CO3 (10)
THF
45
40
35
62
39
trace
25
1:1
1:1
1:1
8:1
3:1
toluene
CH3CN
DMF
DMSO
MeOH
t-
1:1
BuOH
DMF
DMF
DMF
THF
THF
DMF
THF
DMF
DMF
DMF
DMF
DMF
8d
9
6a, Cs2CO3 (10)
6b, Cs2CO3 (10)
6c, Cs2CO3 (10)
7, DBU (20)
53
65
43
trace
trace
trace
trace
72
33
31
61
54
4:1
9:1
5:1
10
11
12
13
14
15
16
17
18
19
1
aIsolated yield of pure trans-isomers. bDetermined by H NMR
(300 MHz) of the reaction mixture. cThe structure and trans-stereo-
chemistry of 3e and 3j were unambiguous assigned by X-ray analysis of
their crystals.
70 (20)e
8a, Cs2CO3 (10)
8b, DBU (20)
6b, Cs2CO3 (20)
6b, K2CO3 (20)
6b, KOBut (20)
6b, DBU (20)
6b, DIPEA (20)
8:1
>20:1
3:1
temperature gave no benefit (entry 8). Screening of NHCs
showed that NHCs derived from all of the thiazolium salts
6a-c worked well (entries 4, 9, and 10), whereas NHCs
derived from the imidazolium 7 and triazolium salts 8a,b did
not under current reaction conditions (entries 11-14).
Screening of bases revealed that although reaction using
K2CO3 gave the best trans-selectivity, Cs2CO3 is the choice
for balancing the yield and selectivity (entries 15-19). Reac-
tions with 20 mol % catalyst loading resulted in better yield
than with 10 mol % loading (entries 9 and 15).
4:1
3:1
aNHCs 60-80 were generated from the NHC precursors 6-8 (10-20
mol %) in situ in the presence of the noted base (10-20 mol %). bIsolated
yield of the pure trans-3a (entries 4-19), except entries 1-3 (isolated yield
of trans/cis mixture). cDetermined by 1H NMR (300 MHz) of the reaction
mixture. The reaction was carried out at 0 °C. NHC 70 was prepared
from its precursor 7 with t-BuOK as base and used after purification.
d
e
was found that reaction varied a lot in different solvents
(Table 1, entries 1-7), and reaction in DMF gave the best
yield (62%) and selectivity (trans:cis = 8:1). Low reaction
Other Michael acceptors were then tested under the
optimized reaction conditions (Table 2). All of the
274 J. Org. Chem. Vol. 75, No. 1, 2010

Sun et al.
JOCNote
SCHEME 2. Dehydration and Oxidation of 4-Hydroxytetra-
lone 3a
aryl(vinyl)ketones 2b-f worked to give the desired products in
moderate to good yields with good trans-selectivities, except
that the vinylketone 2e with an o-ethoxyphenyl group led to
low yield (entries 2-6). Heteroaryl(vinyl)ketone 2g (Ar =
2-furyl) also gave good result (entry 7). Vinylketones (2 h,i)
with an R- or β-substituent did not work. However, the
vinylketone 2j, featuring a “ring-closed” R-substituent, worked
very well to give the spiro-product 3j in 70% with a 9:1 dr
(entry 10). Although methyl acrylate (2k) did not work
(entry 11), the double activated R,β-unsaturated ester 2l
worked well (entry 12).
FIGURE 2. Two possible pathways from adduct 5 to product 3.
SCHEME 3. Synthesis of cis-4-Hydroxytetralone 3a by Sepa-
rated Stetter Reaction Followed by Aldol Reaction
The resulting 4-hydroxytetralone 3a could be transformed
to the corresponding naphthol 9 and naphthalenediol 10 by
dehydration and Oppenauer oxidation, respectively, in good
yield (Scheme 2).
Two possible pathways from the Stetter reaction adduct 5
to final product 3 are depicted in Figure 2. In pathway A, the
NHC motif leaves first to give the simple Stetter reaction
product 11, followed by aldol reaction to give 3. In pathway
B, adduct 5 undergoes the aldol reaction with NHC motif
attached, followed by fragmentation to regenerate free NHC
and afford final product 3.
We envisioned that the reaction may stop before the aldol
reaction if a suitable proton source were provided in the
reaction. It was found that the Stetter reaction product 11a
was obtained in 55% yield when 20 mol % benzoic acid
was used as an additive for the reaction, and no cascade
reaction product 3a was observed (Scheme 3). Interestingly,
aldol reaction of compound 11 gave hydroxytetralone 3a
in 61% yield with cis-3a as the major diastereomer (cis:
trans = 4:1).
developed for the diastereoselective synthesis of trans-
3-substituted-4-hydroxytetralone. The trans-selectivity in
the cascade reaction, which is opposite to cis-selectivity in
separate Stetter reaction followed by aldol reaction, suggests
that the aldol reaction occurs before the leaving of NHC
catalyst (pathway B). Further exploration on cascade
reactions catalyzed by NHCs and their asymmetric versions
are underway in our laboratory.
Experimental Section
The reversed cis/trans selectivities between the cascade
Stetter-aldol reaction (trans-isomer as the major product)
and separate Stetter reaction followed by aldol reaction (cis-
isomer as the major product) suggest pathway B is more
favored for this cascade reaction. This observation is differ-
ent from the reported NHC-catalyzed cascade Stetter-
Michael reaction, in which the pathway with NHC leaving
before Michael addition is suggested.4 Pathway B is more
interesting than pathway A because the NHC motif is still
attached for the aldol reaction in pathway B and thus makes
it possible to control the stereochemistry in both Stetter and
aldol steps by NHC catalysts.
Typical Procedure for the Synthesis of trans-4-hydroxyltetra-
lones via a Cascade Stetter-Aldol Reaction Catalyzed by NHC
6b0. An oven-dried 50 mL Schlenk tube equipped with a stir bar
was charged with thiazolium salt (26.9 mg, 0.1 mmol) and
phthalaldehyde (67 mg, 0.5 mmol). The tube was closed with a
septum, evacuated, and backfilled with argon. To this mixture
was added distilled solvent DMF (2.5 mL) and ethyl(vinyl)-
ketone, and then the mixture was stirred for 10 min at room
temperature. Cs2CO3 (32.6 mg, 0.1 mmol) was added to the tube.
The mixture was further stirred for 3 h, then diluted with ethyl
acetate, and passed through a short silica pad. The solvent was
removed under reduced pressure, and the residue was purified
by chromatography on silica gel (ethyl acetate/petroleum ether)
to give 78.5 mg (72%) of 3a as a white solid, Rf = 0.26
In conclusion, a cascade Stetter-aldol reaction of phtha-
laldehydes and Michael acceptors catalyzed by NHC was
J. Org. Chem. Vol. 75, No. 1, 2010 275

Sun et al.
JOCNote
(petroleum ether/ethyl acetate = 3:1), mp 143-144 °C. 1H
NMR (300 MHz, CDCl3) δ 8.00 (d, J = 7.8 Hz, 1H),
7.76 (d, J = 7.8 Hz, 1H), 7.66-7.61 (m, 1H), 7.44-7.39
(m, 1H), 5.28 (dd, J = 4.5 Hz, 9.5 Hz, 1H), 3.35-3.26
(m, 2H), 2.96 (dd, J = 3.9 Hz, 17.0 Hz, 1H), 2.71-2.51
(m, 3H), 1.11 (t, J = 8.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 211.7, 194.6, 144.3, 134.5, 130.5, 128.0, 126.9, 126.2, 68.8, 55.2,
38.9, 35.6, 7.4; IR (KBr) v 1716, 1691, 1601, 1297, 767; EIMS m/z
218 (4.0), 161 (100); HRMS-(EI) (m/z) Mþ calcd for C13H14O3
218.0943, found 218.0946.
Acknowledgment. Financial support from National
Science Foundation of China (20602036, 20932008), the
Ministry of Science and Technology of China (2009ZX-
09501-018), and the Chinese Academy of Sciences is grate-
fully acknowledged.
Supporting Information Available: Experimental proce-
dures, compound characterizations, and crystal structure data
of tetralone 3e and 3j in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
276 J. Org. Chem. Vol. 75, No. 1, 2010