Formation of dihydronaphthalenes via organocatalytic enatioselective michael-aldol cascade reactions with arylalkanes

Article abstract of DOI:10.1021/ol402489e

An organocatalytic highly enantioselective Michael-aldol cascade access to valuable chiral dihydronaphthalenes has been realized. Notably, the strategy via activation of nucleophilic alkyl chains by introducing nitro, chloro, or CF₃ group(s) at the ortho- and/or para-position(s) on an aromatic ring renders them readily deprotonated to produce highly reactive nulecophilic species in the cascade process under mild conditions.

Full text of DOI:10.1021/ol402489e

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5634–5637
Formation of Dihydronaphthalenes
via Organocatalytic Enatioselective
MichaelꢀAldol Cascade Reactions
with Arylalkanes
Xiangmin Li,† Sinan Wang,† Tengfei Li,† Jian Li,† Hao Li,*,† and Wei Wang*,†,‡
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, and State Key
Laboratory of Bioengineering Reactor, East China University of Science and
Technology, 130 Mei-long Road, Shanghai 200237, China, and Department of
Chemistry and Chemical Biology, University of New Mexico, Albuquerque,
New Mexico 87131-0001, United States
hli77@ecust.edu.cn; wwang@unm.edu
Received August 29, 2013
ABSTRACT
An organocatalytic highly enantioselective Michaelꢀaldol cascade access to valuable chiral dihydronaphthalenes has been realized. Notably, the
strategy via activation of nucleophilic alkyl chains by introducing nitro, chloro, or CF3 group(s) at the ortho- and/or para-position(s) on an aromatic
ring renders them readily deprotonated to produce highly reactive nulecophilic species in the cascade process under mild conditions.
The dihydronaphthalene framework is featured in a
number of natural products with a broad spectrum of
interesting biological activities,1 such as lipoxygenase en-
zyme inhibition1a and anti-HIV2 and -cancer properties.3
They also serve as versatile building blocks in the construc-
tion of biologically important compounds.4 Given their
significance in medicinal and organic chemistry, several
synthetic methods have been developed. Organometallic
nucleophilic addition to electrophilic double bonds is a
valuable approach to the scaffold.5 Photoinitiated cycliza-
tions to form dihydronaphthalene have been significantly
expanded by Nicolaou and colleagues in the synthesis
of biologically relevant tetralins.6,7 Suzuki8 presented a
Pd(II)-catalyzed cross-coupling reaction via benzylic boro-
nates, and Yamamoto9 reported the Cu(OTf)2-catalyzed
[4 þ 2] cycloaddition reaction of alkynylbenzenes with
alkenes. However, the asymmetric versions for the synthesis
† East China University of Science and Technology.
‡ University of New Mexico.
(1) (a) Rehman, A.; Malik, A.; Riaz, N.; Ahmad, H.; Nawaz, S.;
Iqbal, M. Chem. Pharm. Bull. 2005, 53, 263. (b) Yang, J.-H.; Li, L.;
Wang, Y.-S.; Zhao, J.-F.; Zhang, H.-B.; Luo, S.-D. Helv. Chim. Acta
2005, 88, 2523. (c) Li, Y.; Wu, L.; Ouyang, D.; Yu, P.; Xia, J.; Pan, Y.;
Yang, X.; Zeng, H.; Cheng, X.; Jin, H.; Zhang, W. Chem. Biodivers.
2011, 8, 2299.
(2) Meragelman, K. M.; McKee, T. C.; Boyd, M. R. J. Nat. Prod.
2001, 64, 546.
(3) Andrews, R. C.; Teague, S. J.; Meyers, A. I. J. Am. Chem. Soc.
1988, 110, 7854.
(6) Reviews: (a) Segura, J. L.; Martin, N. Chem. Rev. 1999, 99, 3199.
(b) Quinkert, G.; Stark, H. Angew. Chem., Int. Ed. 1983, 22, 637.
(7) Examples: (a) Yang, N. C.; Rivas, C. J. Am. Chem. Soc. 1961, 83,
2213. (b) Arnold, B. J.; Mellows, S. M.; Sammes, P. G. J. Chem. Soc.,
PerkinTrans. 1 1973, 1266. (c) Macdonald, D. I.; Durst, T. J. Org. Chem.
1986, 51, 4749. (d) Charlton, J. L.; Koh, K. J. Org. Chem. 1992, 57, 1514.
(e) Sano, H.; Asanuma, D.; Kosugi, M. Chem. Commun. 1999, 1559.
(f) Nicolaou, K. C.; Gray, D. Angew. Chem., Int. Ed. 2001, 40, 761.
(g) Nicolaou, K. C.; Gray, D. Angew. Chem., Int. Ed. 2001, 40, 3675.
(h) Nicolaou, K. C.; Gray, D. Angew. Chem., Int. Ed. 2001, 40, 3679.
(i) Nicolaou, K. C.; David, L. F.; Gray, D.; Tae, J. J. Am. Chem. Soc.
2004, 126, 613.
€
(4) Pape, A. R.; Kaliappan, K. P.; Kundig, E. P. Chem. Rev. 2000,
100, 2917.
(8) Kanai, G.; Miyaura, N.; Suzuki, A. Chem. Lett. 1993, 845.
(9) Asao, N.; Kasahara, T.; Yamamoto, Y. Angew. Chem., Int. Ed.
2003, 42, 3504.
(5) (a) Meyers, A. I.; Brown, J. D. Tetrahedron Lett. 1987, 28, 5279.
(b) Ahmed, A.; Clayden, J.; Rowley, M. Chem. Commun. 1998, 297. (c)
Tomioka, K.; Shindo, M.; Koga, K. J. Am. Chem. Soc. 1989, 111, 8266.
r
10.1021/ol402489e
Published on Web 10/25/2013
2013 American Chemical Society

of enantioselective dihydronaphthalenes are very scarce.
Tomioka disclosed a C2-symmetric chiral diether catalyzed
enantioselective conjugate addition of an organolithium to
an R,β-unsaturated aldimine process to assemble the chiral
molecular architecture.5c An elegant photochemical enan-
tioselective process between o-alkyl-substituted benzalde-
hyde and dienophiles in the presence of a chiral complexing
agent has been realized by Bach.10 Enders and co-workers
reported a nice organocatalytic enantioselective Michaelꢀ
aldol approach to the chiral framework.11 Nevertheless, in
this study, one of the substrates is limited to 2-(nitromethyl)-
benzaldehydes. To overcome the limitation, herein we dis-
close a new strategy without relying on the highly active pre-
enolized or readily enolizable nucleophilic “C” species for
the synthesis of the chiral dihydronaphthalenes (Scheme 1).
Activation of the alkyl moiety by introducing electron-
withdrawing groups on an aromatic ring enables the methyl
and ethyl groups to serve as effective nucleophiles for the
Michaelꢀaldol cascade reaction.12 Notably, for the first
time, aryl methyl/ethyl nucleophiles are explored under mild
reaction conditions in a cascade manner with excellent
enantioselectivity while these activating groups can be con-
veniently transformed into new functionalities (Scheme 2).
electrophilic group such as an aldehyde at the ortho-
position may create a new Michaelꢀaldol cascade process
for facile assembly of chiral dihydronaphthalenes.
To test the feasibility of the proposed Michaelꢀaldol
process, wecarried outa model reaction between2-methyl-
3,5-dinitrobenzaldehyde (1a) with trans-cinnamaldehyde
(2a, 1.0 equiv) in the presence of organocatalyst I in
CH2Cl2 at rt for 48 h (Table 1).15 Despite the low yield
(36%) for the formed product 3a, excellent enantioselec-
tivity (95%) was obtained (entry 1). Encouraged by the
outcome, we attempted to optimize reaction conditions to
improve reaction yields. Under the same reaction condi-
tions, solvent screening showed that the use of Cl(CH2)2Cl
as a solvent provided the highest yield (48%, entry 2), and
THF gave a similar result (entry 3), while toluene and
CH3CN were not the choice (entries 4ꢀ5). No reaction
took place with polar DMF and DMSO (entries 6ꢀ7).
When an excess amount of 2-methyl-3,5-dinitrobenzalde-
hyde (1.2 equiv) was used, the reaction yield was raised to
54% (entry 8). Further increase of the ratio of 1a/2a to
1.5 led tobetter yield (61%, entry 9). Interestingly, decreas-
ing of the catalyst loading gave rise to higher efficiency
(entries 10 and 11). Moreover, the reaction yield was
increased to 79% when the reaction concentration was
diluted to half with 5 mol % catalyst loading (entry 12).
The optimal reaction was established with 2.0 equiv of 1a
and 1.0 equiv of 2a in Cl(CH2)2Cl catalyzed by 5 mol % of
catalyst I (83% yield and 99% ee, entry 13).
Scheme 1. Organocatalytic Enantioselective MichaelꢀAldol
Cascade Reactions
With the optimal reaction conditions in hand, we next
probed the scope of the tandem carbon-initiated Michaelꢀ
aldol process by using 2-methyl-3,5-dinitrobenzaldehyde
1a and in variation with R,β-unsaturated aldehydes 2.
As shown in Table 2, the reactions proceeded smoothly
in high yields (70ꢀ96%) and excellent levels of enantio-
selectivities (91ꢀ99% ee) (Table 2). The electronic nature
of the R,β-unsaturated aldehydes 2 has an influence on the
reaction yields. Generally, R,β-unsaturated aldehydes 2
bearing electron-donating groups afforded higher yields
(80ꢀ96%, entries 2ꢀ5) than those with electron-with-
drawing moieties (70ꢀ81%, entries 6ꢀ10). Furthermore,
a combination of withdrawing and donating groups on
R,β-unsaturated aldehydes (entry 11) and heteroaromatic
(entry 12) groups alsocouldefficiently participate toafford
chiral dihydronaphthalenes (entries 11 and 12). Finally, it
appears that the steric effect of the R,β-unsaturated alde-
hydes is trivial (entries 2ꢀ7). Interestingly, more hindered
substrates gave even higher yields (entries 2, 4, and 6).
The limitation of this process is also recognized that
enals bearing aliphatic chains could not work under these
reaction conditions. The absolute configuration of the
products is determined by single-crystal X-ray diffraction
analysis based on compound 3g (Figure S1, Supporting
Information).16
The very weak nucelophilicity of the benzene-tethered
methyl group renders it impossible to perform a conjugate
addition under mild conditions, where an organocatalyzed
reaction is generally conducted. Recently, we have devel-
oped a novel masking strategy to activate the methyl group
by introducing nitro group(s) at the ortho- and/or para-
position(s) on an aromatic ring, thereby rendering the
methyl group hydrogen acidic, and thus, it is readily
deprotonated to produce highly reactive nulecophilic
species.13,14 Driven by the broad synthetic utility of this
chemistry in the facile construction of ubiquitous chiral
benzylicandrelated structures, we envision thatincorpora-
tion of the functionality into a substrate bearing an
(10) Grosch, B.; Orlebar, C. N.; Herdtweck, E.; Massa, W.; Bach, T.
Angew. Chem., Int. Ed. 2003, 42, 3693.
(11) Enders, D.; Wang, C.; Bats, J. W. Synlett 2009, 11, 1777.
(12) For reviews on organocatalytic domino reactions, see: (a) Guo,
H.; Ma, J. Angew. Chem., Int. Ed. 2006, 45, 354. (b) Pellissier, H.
€
Tetrahedron 2006, 62, 1619. (c) Enders, D.; Grondal, C.; Huttl,
M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570. (d) Yu, X.; Wang,
W. Org. Biomol. Chem. 2008, 6, 2037. (e) Jensen, K. L.; Dickmeiss, G.;
Jiang, H.; Albrecht, Q.; Jørgensen, K. A. Acc. Chem. Res. 2012, 45, 248.
(f) Arceo, E.; Melchiorre, P. Angew. Chem., Int. Ed. 2012, 51, 5290.
(g) Li, J.-L.; Liu, T.-Y.; Chen, Y.-C. Acc. Chem. Res. 2012, 45, 1491. (h)
Jiang, H.; Albrechtab, Q.; Jørgensen, K. A. Chem. Sci. 2013, 4, 2287.
(13) Li, T.; Zhu, J.; Wu, D.; Li, X.; Wang, S.; Li, H.; Li, J.; Wang, W.
Chem.;Eur. J. 2013, 19, 9147.
(15) For reviews of prolinol ether catalysis, see: (a) Mielgo, A.;
Palomo, C. Chem. Asian J. 2008, 3, 922. (b) Jensen, K. L.; Dickmeiss,
G.; Jiang, H.; Albrecht, Ł.; Jørgensen, K. A. Acc. Chem. Res. 2012, 45,
248. See leading references: (c) Marigo, M.; Wabnitz, T. C.; Fielenbach,
D.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 794. (d) Hayashi,
Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44,
4212. (e) Chi, Y.; Gellman, S. H. Org. Lett. 2005, 7, 4253.
ꢀ
€
(14) Dell’Amico, L.; Companyo, X.; Naicker, T.; Brauer, T. M.;
Jørgensen, K. A. Eur. J. Org. Chem. 2013, 5262.
Org. Lett., Vol. 15, No. 22, 2013
5635

electron-withdrawing capacity of these groups, high cata-
lyst loadings are necessary to ensure efficient transforma-
tions. For example, switch of the 3-nitro group to CF3
functionality gave the desired product 3m in high yield
(84%) and with excellent ee value (98%, entry 2) when
20 mol % of catalyst I was used. It seems that the effect by
the replacement of the proton by the groups, such as Br
and methyl moieties at the 4-position of 2-methyl-3,5-
dinitrobenzaldehyde, is limited (entries 3 and 4). In both
cases, impressive results are achieved. The use of 2,6-
dichloro-4-methylnicotinaldehyde without assistance from
nitro group(s) can also make the cascade process possible
(entry 5). The corresponding chiral dihydroisoquinoline 3p
was obtained with high yield and excellent enantioselec-
tivity. Finally, we also probed the more sterically hindered
2-ethyl-3,5-dinitrobenzaldehyde in the cascade reaction
(entry 6). To our delight, the process proceeded in good
reaction yield and with high enantioselectivity. It is note-
worthy that two stereogenic centers are created highly
diastereoselectively (10:1 dr).
Table 1. Optimization of Reaction Conditionsa
cat. loading
entry
solvent
CH2Cl2
ratio 1a/2a
(mol %)
yieldb (%) eec (%)
1
1
20
20
20
20
20
20
20
20
20
10
5
36
48
45
12
23
0
95
99
99
99
99
2
ClCH2CH2Cl
THF
1
3
1
4
toluene
1
5
CH3CN
1
d
6
DMF
1
d
7
DMSO
1
0
8
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
1.2
1.5
1.5
1.5
1.5
2.0
54
61
68
72
79
83
99
9
99
99
99
99
99
10
11
12e ClCH2CH2Cl
13e ClCH2CH2Cl
5
5
Table 3. Organocatalytic Enantioselective MichaelꢀAldol
Cascade Reaction of 1 with trans-Cinnamaldehyde (2)a
a Unless specified, a solution of 1a (0.1 mmol) and 2a with the
catalyst (0.02 mmol) in a solvent (0.5 mL) was stirred at rt for 48 h.
b Isolated yield. c The ee was determined by chiral HPLC analysis. d Not
determined. e The reaction was run in 1.0 mL of solvent.
Table 2. Scope of Organocatalytic Enantioselective Mi-
chaelꢀAldol Cascade Reaction of 2-Methyl-3,5-dinitrobenzal-
dehyde (1a) with Enals (2)a
entry
Ar
yieldb (%)
eec (%)
1
C6H5 (3a)
83
96
93
86
80
81
78
70
77
72
72
73
99
97
97
99
97
98
99
91
97
92
96
92
2
2-MeOC6H4 (3b)
4-MeOC6H4 (3c)
2-MeC6H4 (3d)
4-MeC6H4 (3e)
2-ClC6H4 (3f)
3
4
5
6
7
4-ClC6H4 (3g)
8
3-FC6H4 (3h)
9
3-CF3C6H4 (3i)
3-BrC6H4 (3j)
10
11
12d
3-MeO-4-AcOC6H3 (3k)
2-furanyl (3l)
a Unless specified, for reactions conditions see footnote a in Table 1
and the Supporting Information. b Isolated yield. c The ee was deter-
mined by chiral column. d DMSO was used as solvent in the reaction.
e 10:1 dr; the diastereomeric ratio (dr) was calculated on the basis of
crude 1H NMR.
a Unless specified, for reactions conditions see footnote a in Table 1
and the Supporting Information. b Isolated yield. c The ee was deter-
mined by chiral HPLC analysis. d 10 mol % of catalyst of TES instead of
TMS of catalyst I was used.
Next, we examined the structural alternation of the
substrates 1 (Table 3). It was found that significant varia-
tion of the electron-withdrawing groups on the aryl sub-
strates could be tolerated. Moreover, as a result of weaker
(16) The structure of compound 3g was determined by X-ray crystal
analysis. CCDC-953104 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via www.
ccdc.cam.ac.uk and see the Supporting Information.
5636
Org. Lett., Vol. 15, No. 22, 2013

Scheme 2. Transformations of the Nitro Group of 3m to New
Functionalities
Scheme 3. Proposed Mechanism for the MichaelꢀAldol
Cascade Reaction
Michaelꢀaldol cascade reaction for “one-pot” construc-
tion of valuable chiral dihydronaphthalenes. Notably,
for the first time, aryl methyl nucleophiles are explored
under mild reaction conditions in a cascade manner. As
demonstrated, activation of the alkyl group by the strong
electron-withdrawing groups in aryl aldehydes enables
the cascade process while they can be conveniently trans-
formed into new functionalities. Further exploration of the
strategyin new cascade reactionsand the application of the
methodology in the synthesis of biologically relevant
molecules are being pursued in our laboratory.
We have demonstrated that introducing electron-with-
drawing groups such as nitro group(s) at the ortho- and/or
para-position(s) on an aromatic ring enables the methyl
and ethyl groups to serve as effective nucleophiles for the
Michaelꢀaldol cascade reaction. Although they are neces-
sary to activate the methyl and ethyl groups, it is desired
that they can be transformed into other functionalities.
Accordingly, we have carried out the studies using dihy-
dronaphthalene 3m as example (Scheme 2). It is found that
the conversion of the aldehyde to hydrazone is necessary
to achieve higher efficiency in these transformations.
Hydrogenation of the nitro group gives rise to amine 4 in
quantitative yield. The amine can be conveniently trans-
ferred to iodide 6 directly or via dimer 5 with higher yield
in two steps. Furthermore, the amine 4 also can be trans-
ferredtoazide product 7 in85% yield. It isnoteworthythat
in these reactions no ee erosion is observed.
The proposed mechanism is described in Scheme 3.
Activation of R,β-unsaturated aldehyde 2by a chiral organo-
catalyst I produces iminium ion A. Then conjugate addition
of a nucleophilic anion derived from 1 to A affords enamine
B, followed by a subsequent intramolecular aldol process
to give adduct C. Finally, the catalyst is recycled and mean-
while the formed intermediate D undergoes a spontaneous
dehydration to give the product 3.
Acknowledgment. Financial support of this research
from the Program for Professor of Special Appointment
(Eastern Scholar) at Shanghai Institutions of Higher
Learning (No. 201226, H.L.), Shanghai Pujiang Scholar-
ship Program (No. 11PJ1411900, H.L.), the National
Science Foundation of China (No. 21372073, W.W.), the
Fundamental Research Funds for the Central Universities
and East China University of Science and Technology
(start-up fund, H.L. and W.W.), and the National
Science Foundation (CHE-1057569, W.W.) is gratefully
acknowledged.
Supporting Information Available. Experimental pro-
cedures and 1H and 13C NMR and HRMS data for
experimental procedures and characterization of the
products 3 and 4ꢀ7 and X-ray information 3g (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have developed a new organocataly-
tic highly enantioselective nucleophilic carbon initiated
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
5637