Synthesis of (1R,2R)-DPEN-derived triazolium salts and their application in asymmetric intramolecular Stetter reactions

Article abstract of DOI:10.1039/c1ob00025j

A series of novel chiral triazolium salts has been synthesized from readily available (1R,2R)-DPEN and found to be efficient for the enantioselective intramolecular Stetter reaction. With 10 mol% of the catalyst, the intramolecular Stetter reaction was re

Full text of DOI:10.1039/c1ob00025j

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Synthesis of (1R,2R)-DPEN-derived triazolium salts and their application in
asymmetric intramolecular Stetter reactions†
Min-Qiang Jia, Yi Li, Zi-Qiang Rong and Shu-Li You*
Received 6th January 2011, Accepted 2nd February 2011
DOI: 10.1039/c1ob00025j
A series of novel chiral triazolium salts has been synthesized
from readily available (1R,2R)-DPEN and found to be effi-
cient for the enantioselective intramolecular Stetter reaction.
With 10 mol% of the catalyst, the intramolecular Stetter
reaction was realized in excellent yields with up to 97% ee.
triazolium salts 5 derived from the (1S,2R)-(+)-2-amino-1,2-
diphenyl ethanol backbone and found they were highly efficient in
desymmetrization of 1,3-diketones (up to 96% ee)8 and addition of
homoenolates to nitrones (up to 94% ee).9 We therefore envisaged
that (1R,2R)-DPEN might be an efficient chiral scaffold for
triazolium salts, precursors for NHC catalysts. Compared with
the bicyclic triazolium salts 5 derived from (1S,2R)-(+)-2-amino-
1, 2-diphenyl ethanol backbone, bicyclic triazolium salts 6 based
on (1R,2R)-DPEN scaffold show the advantage of having fine-
tunable R group (Scheme 2).
N-Heterocyclic carbenes (NHCs) as organocatalysts have received
considerable attention in the last two decades.1–2 Various kinds of
chiral NHCs have been developed to catalyze asymmetric reac-
tions, in which the bicyclic triazolium salts 1–3 are one of the highly
efficient classes (Scheme 1). Their bicyclic molecular scaffolds can
restrict unfavorable internal rotation around the N–C (substituent)
axis, which may enhance the chiral induction. Moreover, the
aryl groups on the nitrogen atom may affect both reactivity and
selectivity. Because of their structural advantages, these triazolium
salts have achieved great success in many asymmetric reactions.3–5
Scheme 2 Several related N-heterocyclic carbene precursors.
As part of our ongoing endeavors to develop new N-heterocyclic
carbene catalysts and their applications to novel organocatalytic
reactions,10 in this paper, we report our preliminary results
on the synthesis of novel chiral bicyclic triazolium salts from
(1R,2R)-DPEN and their application to the asymmetric catalytic
intramolecular Stetter reaction.
A series of triazolium salts were easily prepared from the
commercially available (1R,2R)-DPEN11 (Scheme 3). With these
catalyst precursors in hand, we then examine their catalytic ability
in the intramolecular Stetter reaction.
Scheme 1 Chiral bicyclic triazolium salts.
However, there exist only a limited number of backbone
scaffolds for chiral NHCs, and most of them suffer from high
cost of the enantiopure starting materials and tedious synthetic
procedures. The development of a novel NHC catalyst that can
be synthesized from a readily available chiral source and is fine-
tunable with steric and electronic properties is highly desirable.
(1R,2R)-DPEN ((1R,2R)-(+)-diphenyl ethylenediamine) has
been used widely as an excellent chiral source for chiral auxiliary
and organic synthesis.6 Tomioka et al. reported the synthesis of
dihydroimidazolium salt 4 in 2006, and applied it as organocat-
alyst in the intramolecular asymmetric Stetter reaction with up
to 80% ee.7 In 2007, Scheidt and co-workers devised bicyclic
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
† Electronic supplementary information (ESI) available: Experimen-
tal procedures and analysis data for all new compounds. See DOI:
10.1039/c1ob00025j
Scheme 3 Synthesis of triazolium salts from (1R,2R)-DPEN.
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Table 3 Screening of solvents
Our studies began with testing different chiral NHCs in the
intramolecular Stetter reaction of 9a. As summarized in Table 1,
when triazolium salts 6a–6d (20 mol%) were used together with
KHDMS (20 mol%), generally appreciable enantioselectivities in
the cyclization were afforded (entries 1–4, Table 1). NHC derived
from triazolium salt 6c led to the Stetter reaction product 10a in
excellent yield and promising asymmetric induction (95% yield
and 85% ee, entry 3, Table 1). With 6c, the catalyst loading
could be decreased to 10 mol% without significantly affecting
the reactivity and only slight erosion of the ee value was observed
(entry 5, Table 1). Several conventional bases were found tolerable
(entries 1–5, Table 2) and Et3N was optimal in terms of both yield
and ee of the product (entry 6, Table 2). Various solvents such
as xylene, CH2Cl2, THF, Et2O, and toluene were tested in this
reaction (entries 1–5, Table 3). Finally, reaction in xylene led to an
optimal combination of 95% yield and 93% ee.
entrya
solvent
time (h)
yield (%)b
ee (%)c
1
2
3
4
5
xylene
CH2Cl2
Et2O
toluene
THF
16
65
52
22
42
95
82
79
95
93
93
74
80
88
87
a Reaction conditions: 0.1 M solution, addition of 9a to the prior generated
catalyst. b Isolated yields. c Determined by chiral HPLC (Daicel Chirapak
AD-H).
Under these optimized conditions (that is, 6c, Et3N, 0.1 M of
substrate in xylene at room temperature), various salicylaldehyde-
derived substrates were tested and the results are summarized
in Table 4. Substrates 9b–d bearing electron-donating groups (5-
Me, 5-MeO, 4-MeO, entries 2–4, Table 4) on the salicylaldehyde-
structure were well tolerated and led to their corresponding
chromanone derivatives in good to excellent yields (87–98%) and
generally high ees (88–97%). It should be noted that the reaction
did not occur when substrate 9e was used under the standard
Table 4 Substrate scope for enantioselective intramolecular Stetter
reactions
entrya
9
time (h) yield (%)b ee (%)c
1
2
3
9a X = O, n = 1, R = H
16
21
31
26
67
8
34
9
12
48
15
66
95
98
95
87
56
98
98
98
93
70
90
59
93
95
88
97
95
80
81
78
78
89
0
9b X = O, n = 1, R = 5-CH3
9c X = O, n = 1, R = 5-OCH3
9d X = O, n = 1, R = 4-OCH3
9e X = O, n = 1, R = 4-NEt2
9f X = O, n = 1, R = 3-CH3
9g X = O, n = 1, R = 3-OCH3
9h X = O, n = 1, R = 5-Cl
9i X = O, n = 1, R = 5-Br
9j X = S, n = 1, R = H
Table 1 Screening of different catalysts
4
5d
6
7
8
9
10
11
12
entrya
catalyst
time (h)
yield (%)b
ee (%)c
9k X = O, n = 1, R = 5-NO2
9l X = O, n = 0, R = H
0
1
2
3
6a
6b
6c
6d
6c
36
36
0.6
36
0.6
60
43
95
17
95
51
68
85
10
82
a Reaction conditions: 0.1 M solution, addition of 9 to the prior generated
catalyst. b Isolated yields. c Determined by chiral HPLC. d KHMDS was
used instead of Et3N.
4
5d
a Reaction conditions: 0.1 M solution, addition of 9a to the prior generated
catalyst. b Isolated yields. c Determined by chiral HPLC (Daicel Chirapak
AD-H). d 10 mol% triazolium salt and 10 mol% KHMDS were used.
conditions. When KHMDS was used instead of Et3N under the
standard conditions, substrate 9e underwent the intramolecular
Stetter reaction affording the desired product in 56% yield with
95% ee (entry 5, Table 4). When substrates 9f–g containing
substituents adjacent to the linker were used, the reactions ran
smoothly with high yield but moderate to good enantioselectivities
(entries 6–7, Table 4). The reaction of substrates 9h–i bearing weak
electron-drawing groups (5-Cl or 5-Br, entries 8–9, Table 4) led to
their desired products in excellent yields but with relatively low ees
(78%). The sulfur-tethered substrate 9j gave a moderate yield (70%)
with excellent ee (89%) (entry 10, Table 4). When substrate 9k
bearing 5-NO2 group was used, the desired product was obtained
in 90% yield but with no enantioselectivity (entry 11, Table 4).
Substrate 9l which led to a five-membered ring was also examined
and the desired product 10l was obtained also in racemic (entry
12, Table 4). In both cases, they were also known to be challenging
substrates in the literature probably due to the ready racemization
of the products.4a Notably, in some cases, running the reaction for
a prolonged time will cause a certain degree of racemization of the
product.
Table 2 Screening of bases
entrya
base
time (h)
yield (%)b
ee (%)c
1
2
3
4
5
6
KHMDS
NaHMDS
LiHMDS
DBU
DIEA
Et3N
0.6
1.3
48
4
85
16
95
97
56
90
90
95
82
85
90
87
93
93
a Reaction conditions: 0.1 M solution, addition of 9a to the prior generated
catalyst. b Isolated yields. c Determined by chiral HPLC (Daicel Chirapak
AD-H).
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In conclusion, we have developed a series of novel bicyclic
triazolium salts from readily available (1R,2R)-DPEN. The NHC
catalyst derived from the chiral triazolium salt 6c and Et3N
is found to be efficient for the enantioselective intramolecu-
lar Stetter reaction. In general, excellent yields with up to
97% ee could be obtained for the intramolecular Stetter re-
action. Further application of these (1R,2R)-DPEN derived
triazolium salts in other asymmetric reactions are currently under
way.
3 Selected examples of benzoin reactions: (a) D. Enders and U. Kallfass,
Angew. Chem., Int. Ed., 2002, 41, 1743; (b) D. Enders, O. Niemeier and
T. Balensiefer, Angew. Chem., Int. Ed., 2006, 45, 1463; (c) H. Takikawa,
H. Hachisu, J. W. Bode and K. Suzuki, Angew. Chem., Int. Ed., 2006,
45, 3492.
4 Selected examples of Stetter reactions: (a) M. S. Kerr, J. Read de Alaniz
and T. Rovis, J. Am. Chem. Soc., 2002, 124, 10298; (b) M. S. Kerr and
T. Rovis, J. Am. Chem. Soc., 2004, 126, 8876; (c) J. Read de Alaniz and
T. Rovis, J. Am. Chem. Soc., 2005, 127, 6284; (d) Q. Liu and T. Rovis,
J. Am. Chem. Soc., 2006, 128, 2552; (e) S. C. Cullen and T. Rovis, Org.
Lett., 2008, 10, 3141; (f) Q. Liu, S. Perreault and T. Rovis, J. Am.
Chem. Soc., 2008, 130, 14066; (g) D. A. DiRocco, K. M. Oberg, D.
M. Dalton and T. Rovis, J. Am. Chem. Soc., 2009, 131, 10872; (h) C.
M. Filloux, S. P. Lathrop and T. Rovis, Proc. Natl. Acad. Sci. U. S.
A., 2010, 107, 20666; (i) T. Jousseaume, N. E. Wurz and F. Glorius,
Angew. Chem., Int. Ed., 2011, 50, 1410; For recent elegant examples of
NHC catalyzed Stetter-type reactions of non-active olefins and alkynes,
see: (j) K. Hirano, A. T. Biju, I. Piel and F. Glorius, J. Am. Chem. Soc.,
2009, 131, 14190; (k) A. T. Biju, N. E. Wurz and F. Glorius, J. Am.
Chem. Soc., 2010, 132, 5970.
Acknowledgements
We thank the National Natural Science Foundation of China
(20732006, 20821002, 20972177, 21025209) and National Basic
Research Program of China (973 Program 2009CB825300) for
generous financial support.
5 Selected examples of Diels–Alder reactions: (a) M. He, J. R. Struble
and J. W. Bode, J. Am. Chem. Soc., 2006, 128, 8418; (b) M. He, J. Uc
Gerson and J. W. Bode, J. Am. Chem. Soc., 2006, 128, 15088; (c) J.
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6 Selected examples: (a) P. Mangeney, A. Alexakis and J. F. Normant,
Tetrahedron Lett., 1988, 29, 2677; (b) D. Cuvinot, P. Mangeney and
A. Alexakis, J. Org. Chem., 1989, 54, 2420; (c) E. J. Corey, C. M. Yu
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Kozawa, A. F. England, T. Ikariya and R. Noyori, Angew. Chem., Int.
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