Desymmetrization of cyclohexadienones viad-camphor-derived triazolium salt catalyzed intramolecular Stetter reaction

Article abstract of DOI:10.1039/c2cc32783j

Enantioselective desymmetrization of cyclohexadienones via a d-camphor-derived triazolium salt catalyzed intramolecular Stetter reaction was realized. With 10 mol% of camphor-derived triazolium salt E and 10 mol% of DIEA, various substituted cyclohexadienones proceeded through an intramolecular Stetter reaction, affording tricyclic products in moderate to good yields and excellent ee.

Full text of DOI:10.1039/c2cc32783j

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COMMUNICATION
Desymmetrization of cyclohexadienones via D-camphor-derived
triazolium salt catalyzed intramolecular Stetter reactionw
Min-Qiang Jia and Shu-Li You*
Received 19th April 2012, Accepted 8th May 2012
DOI: 10.1039/c2cc32783j
Enantioselective desymmetrization of cyclohexadienones via a
D-camphor-derived triazolium salt catalyzed intramolecular
Stetter reaction was realized. With 10 mol% of camphor-derived
triazolium salt E and 10 mol% of DIEA, various substituted
cyclohexadienones proceeded through an intramolecular Stetter
reaction, affording tricyclic products in moderate to good yields
and excellent ee.
N-Heterocyclic carbene (NHC) catalyzed umpolung reactions,
by reversing the reactivity of an aldehyde functionality, have
witnessed rapid development recently.1 The Stetter reaction is
undoubtedly one of the most important reactions in this class
that take advantage of the umpolung reactivity of aldehydes.2
Since the pioneering studies on the enantioselective intra-
molecular Stetter reaction reported by Enders and coworkers
in 1996,3 enormous efforts have been devoted to the develop-
ment of efficient catalysts and protocols for asymmetric Stetter
reactions.4 Particularly elegant studies by Rovis and coworkers
led to the discovery of the aminoindanol-derived triazolium
salts as suitable catalysts and realized the highly enantioselective
intramolecular Stetter reaction for the first time with broad
range of substrates.1h,5 Recently, Glorius and coworkers
further demonstrated that unactivated alkenes are also suitable
acceptors in the Stetter reaction,1j,6 further highly broadening
the reaction scope. On the other hand, dearomatization of
phenols would provide cyclohexadienone derivatives, which
are an excellent type of acceptor for the Stetter reaction. The
dearomatization process together with desymmetrization reaction
will provide a facile construction of optically active cyclic and
polycyclic compounds from readily available starting materials.7
In 2006, Rovis and Liu took advantage of this strategy to realize
the highly enantioselective Stetter type desymmetrization of cyclo-
hexadienones, prepared from the oxidative dearomatization of
phenols.8 Obviously, novel dearomatization reactions providing
new cyclohexadienone derivatives would lead to diverse tricyclic
structures and therefore be highly desirable. In this regard,
Scheme 1 ipso-Iodocyclization/desymmetrization protocols.
recently, Gaunt and coworkers for the first time realized a
secondary amine-catalyzed highly enantioselective desymmetriza-
tion process utilizing cyclohexadienone synthesized via an ipso-
iodocyclization reaction (Scheme 1).9 Intrigued by these elegant
works, we envisaged that this interesting backbone might be
suitable for a desymmetrization process via an NHC-catalyzed
intramolecular Stetter reaction. In this communication, we report
our preliminary results on this subject.
We began our studies with cyclohexadienone aldehyde 1a,
synthesized according to Larock’s ipso-iodocyclization reaction,10
as a model substrate for the NHC catalyzed desymmetrization
reaction. With several readily available chiral NHCs (Fig. 1), the
desymmetrization of cyclohexadienones via an intramolecular
Stetter reaction was examined. The results are summarized
in Table 1. Camphor-derived triazolium salts A–D,11 were
found to be almost ineffective for the intramolecular Stetter
reaction (entries 1–4, Table 1). To our great delight, with
10 mol% of triazolium salt E bearing a C6F5 group and
10 mol% of DIEA in o-xylene, the desired intramolecular Stetter
reaction proceeded smoothly affording desymmetrization
product 2a with excellent results (81% yield, 91% ee, entry 5,
Table 1). Rather surprisingly, the reaction with 10 mol% of the
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, P. R. China.
E-mail: slyou@sioc.ac.cn; Fax: (+86) 21-54925087
w Electronic supplementary information (ESI) available: Experimental
procedures and analysis data for new compounds, CIF file of 2a
(CCDC 870941). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2cc32783j
Fig. 1 Several readily available chiral NHC precursors.
Chem. Commun., 2012, 48, 6363–6365 6363
c
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Table 1 Screening of the chiral NHC catalystsa
Table 3 NHC-catalyzed desymmetrization of cyclohexadienones via
intramolecular Stetter reactiona
Entry
Catalyst
Yield (%)
eeb (%)
1
2
3
4
5
6
A
B
C
D
E
F
NR
NR
NR
o5
81
—
—
—
24
91
0
Entry
R
Product Time (h) Yieldb (%) eec (%)
1
Ph
2a
2b
2b
2c
2c
2d
2e
2f
40
50
24
90
72
50
90
48
81
65
55
60
60
52
55
54
61
58
60
85
75
91
58
80
71
71
89
84
86
75
86
85
88
94
2
4-MeC6H4
4-MeC6H4
3-MeC6H4
3-MeC6H4
2-MeC6H4
4-FC6H4
4-ClC6H4
2-Thienyl
Me
3d
4
84
5d
6
a
Reaction conditions: 1a (0.1 mmol), 10 mol% of catalyst, 10 mol% of
b
DIEA in o-xylene (1.0 mL) at room temperature. Determined by HPLC.
7
8d
9
aminoindanol-derived triazolium salt F, under otherwise identical
conditions gave the product in a racemic form, although a good
yield (84%) was obtained (entry 6, Table 1). The high efficiency of
triazolium salts E and F is likely due to acidic protons in the
catalysts because of the electron-withdrawing aryl substituents.
In the presence of 10 mol% of triazolium salt E, different
reaction parameters were further examined. The results are
summarized in Table 2. All tested bases such as DIEA,
KHMDS, DBU, Et3N, and Cs2CO3 were well tolerated,
affording the desired product with good yields and ees
(entries 1–5, Table 2). DIEA gave the best enantioselectivity
(91% ee), while Cs2CO3 resulted in the shortest reaction time.
With DIEA as the base, several other solvents such as toluene,
CH2Cl2, CHCl3, and diethyl ether were tested (entries 6–10,
Table 2). o-Xylene remained to be the optimal solvent.
2g
2h
2i
160
96
60
72
10
11
12
13
n-Pr
Cyclopropyl 2j
t-Bu 2k
120
a
Reaction conditions: 1 (0.2 mmol), 10 mol% of E, 10 mol% of DIEA in
b
o-xylene (2.0 mL) at room temperature, unless noted otherwise. Isolated
c
d
yield. Determined by HPLC. With 10 mol% of Cs2CO3 as base.
due to the fact that the 2-MeC6H4 group could not rotate
freely in its surroundings. When R is an electron-deficient aryl
group such as 4-FC6H4, the corresponding product 2e was
obtained in 55% yield and 84% ee (entry 7, Table 3). The
substrate bearing a 4-ClC6H4 group led to product 2f in 54%
yield and 86% ee with Cs2CO3 as the base (entry 8, Table 3).
Moreover, the 2-thienyl bearing substrate was also well tolerated
under the optimized conditions, providing the desired tricyclic
product with 75% ee (entry 9, Table 3). Various alkyl
substituents were then evaluated as suitable substrates
(entries 10–13, Table 3). The methyl, n-propyl, cyclopropyl
and tert-butyl derived products were obtained in 58–85% yield
and 85–94% ee. The absolute configuration of the product was
determined by X-ray crystallographic analysis of the single
crystal of enantiopure 2a as (6aS,10aR).12
Under the optimized conditions (10 mol% of E, 10 mol% of
DIEA, o-xylene, rt), various substrates were tested to investigate the
generality of the reaction. The results are summarized in Table 3.
When a tolyl group was introduced, the position of the methyl
substituent had significant influence on the enantioselectivity
(58% ee for 4-MeC6H4, 71% ee for 3-MeC6H4, 89% ee for
2-MeC6H4, entries 2, 4 and 6, Table 3). When Cs2CO3 was used
as base, product 2b (with 4-MeC6H4 substituent) could
be obtained with 80% ee, while the ee value of 3-MeC6H4
product 2c remained unchanged (entries 3, 5, Table 3). It is
worth mentioning that product 2d bearing a 2-MeC6H4 group
seems to have two interconvertible atropisomers from NMR
and HPLC analysis (two sets of peaks were observed), probably
The dimethyl substituted cyclohexadienone substrate 1l was
also synthesized and tested in the intramolecular Stetter reaction.
The desired product 2l was obtained with excellent enantio-
selectivity (99% ee) but low yield (9%). The relative stereo-
chemistry of the methyl substituent was determined by NOE
experimentw (Scheme 2).
The highly functionalized tricyclic products generated here
could be subjected to versatile chemoselective transformations.
As shown in Scheme 3, enantiopure 2a, obtained after one single
recrystallization of 2a (91% ee), was treated under Pd-catalyzed
Table 2 Optimization of the reaction conditionsa
Entry
Base
Solvent
Time (h)
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
DIEA
KHMDS
DBU
o-Xylene
o-Xylene
o-Xylene
o-Xylene
o-Xylene
Toluene
THF
CH2Cl2
CHCl3
Et2O
40
40
40
40
10
40
40
40
40
40
81
84
74
67
84
50
30
64
60
30
91
83
90
80
87
88
72
50
28
81
Et3N
Cs2CO3
DIEA
DIEA
DIEA
DIEA
DIEA
a
Reaction conditions: 1a (0.1 mmol), 10 mol% of E, 10 mol% of base
b
in solvent (1.0 mL) at room temperature. Determined by HPLC.
Scheme 2 Reaction of the dimethyl substituted cyclohexadienone 1l.
c
6364 Chem. Commun., 2012, 48, 6363–6365
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¨
¨
Sonogashira and Suzuki cross-coupling reaction conditions
respectively, their corresponding coupling products 2aa and
2ab were obtained in good to excellent yields without notable
loss of enantiomeric purity. On treatment of 2a with Pd/C
under 1 atm H2 at room temperature, deiodination product
2ac was obtained in 64% yield and 99% ee.
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In summary, desymmetrization of cyclohexadienones, derived
from Larock’s ipso-iodocyclization reaction, via an intramolecular
Stetter reaction was realized. D-Camphor-derived triazolium
salt was found to be the most efficient catalyst to furnish the
intramolecular Stetter reaction in moderate to good yields
and excellent ees. Highly functionalized tricyclic structures
containing a quaternary stereogenic center and two contiguous
stereocenters could be formed efficiently under mild reaction
conditions, and the products were compatible for various
chemical transformations.
We thank the National Basic Research Program of China
(973 Program 2009CB825300) and NSFC (20972177, 21025209,
21121062) for generous financial support.
R. Frohlich, S. Grimme and F. Glorius, Angew. Chem., Int. Ed., 2011,
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50, 4983; (f) F. Liu, X. Bugaut, M. Schedler, R. Frohlich and F. Glorius,
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for (6aS,10aR)-2aw.
c
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Chem. Commun., 2012, 48, 6363–6365 6365