Asymmetric Induction in Hydroacylation by Cooperative Iminium Ion-Transition-Metal Catalysis

Article abstract of DOI:10.1021/acs.orglett.6b02825

A new strategy for the rhodium-catalyzed enantioselective hydroacylation is described. This has been achieved through the merger of iminium ion catalysis and transition-metal catalysis such that asymmetric induction derives from a readily accessible, inexpensive chiral nonracemic secondary amine catalyst rather than a chiral nonracemic phosphine as is typical of conventional asymmetric hydroacylation methods.

Full text of DOI:10.1021/acs.orglett.6b02825

Letter
pubs.acs.org/OrgLett
Asymmetric Induction in Hydroacylation by Cooperative Iminium
Ion−Transition-Metal Catalysis
Ettore J. Rastelli, Ngoc T. Truong, and Don M. Coltart*
Department of Chemistry, University of Houston, Houston, Texas 77204-5003, United States
S
* Supporting Information
ABSTRACT: A new strategy for the rhodium-catalyzed enantioselective
hydroacylation is described. This has been achieved through the merger of
iminium ion catalysis and transition-metal catalysis such that asymmetric
induction derives from a readily accessible, inexpensive chiral nonracemic
secondary amine catalyst rather than a chiral nonracemic phosphine as is
typical of conventional asymmetric hydroacylation methods.
he rhodium-catalyzed enantioselective hydroacylation1 of
Talkenes is a highly attractive, atom-economical approach
to the synthesis of chiral nonracemic ketones.2 Such reactions
are thought to proceed via the oxidative insertion of Rh(I) into
the aldehydic C−H bond, followed by migratory insertion of an
alkene into the Rh−H bond, which is followed by reductive
elimination to generate the desired ketone. To achieve
asymmetric induction in such reactions, Rh species having
expensive chiral, nonracemic ligands have been used with
considerable success.3 Unfortunately, in some cases, a
competing side reaction in these transformations is decarbon-
ylation of the acyl−metal hydride intermediate. One means of
circumventing this side reaction is through the incorporation of
chelating functionality in the aldehyde substrate,4 which serves
to stabilize the acyl−metal hydride intermediate, thereby
suppressing or altogether preventing its decarbonylation.
While effective, such methods are, of course, restrictive with
regard to their substrate scope, since only aldehydes capable of
such intramolecular chelation are viable substrates. A clever
means of mitigating unwanted decarbonylation, while not
restricting the substrate scope of the reaction, was put forth by
Suggs5 in 1979 and expanded upon by Jun, starting in 1997.6 In
this approach, an imine is formed from the aldehyde and 2-
amino-3-picoline,7 which enables a stabilizing complexation
with Rh that does not require any additional structural
contribution from the aldehyde.
inexpensive chiral nonracemic secondary amine as the source of
both asymmetric induction and initial C−H activation, thereby
merging asymmetric iminium ion catalysis and transition-metal
catalysis.8 In what follows, we outline our preliminary efforts
along these lines in which the combination of a catalytic
amount of a chiral nonracemic secondary amine and an achiral
Rh species are used to effect asymmetric hydroacylation.
A generalized catalytic cycle consistent with our proposed
idea is shown in Scheme 1. Condensation of an aldehyde with a
Scheme 1. Proposed Catalytic Cycle
It occurred to us that since an imine intermediate is required
of such reactions, it might be possible for an iminium to serve
in its place. Indeed, such a species should be even more
susceptible to oxidative insertion than an imine. If that were the
case, then it might be possible to circumvent the use of a Rh
species having expensive chiral nonracemic phosphine ligands
for asymmetric induction and instead use a readily accessible,
Received: September 20, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02825
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
catalytic amount of a chiral nonracemic secondary amine would
generate an iminium species that would act as a substrate for
oxidative insertion of an achiral rhodium species of some sort.
While such an oxidative insertion has never before been
reported, we felt that it should be even more viable than related
known insertions to imine species.5−7 Diastereoselective olefin
addition followed by reductive elimination would then provide
an iminium ion that would undergo hydrolysis to liberate the
desired cyclic ketone in enantiomerically enriched form, along
with both the Rh catalyst and the chiral secondary amine
catalyst. The success of the proposed method would require
that iminium formation and Rh insertion proceed more rapidly
than the background rhodium-catalyzed hydroacylation of the
aldehyde. The latter would, of course, result in the formation of
the desired product, but in a nonenantioselective manner, and
would potentially lead to decarbonylation as well. Nonetheless,
we felt that it may well be possible to achieve the proposed
catalytic process since iminium formation would be expected to
be rapid under acid-catalyzed conditions and since insertion of
the Rh catalyst into the iminium C−H bond should be faster
than insertion into the corresponding aldehyde bond.
unfortunately, the er was diminished in comparison to the
use of amine 9. Interestingly, the hydroacylation reaction was
almost completely suppressed when amines 11 and 13 were
used. Since amine 9 had given the best er of those tried, we
decided to focus on it and attempt to improve the outcome of
the transformation by modifying other reaction parameters.
We began this work by examining the phosphine ligand.
Shortening the length of the bisphosphine ligand by one
methylene unit through the use of dppe in place of dppp led to
detectable enantiomeric enrichment (85:15) (Table 2, entry 1).
Use of the more structurally rigid bisphosphine ligands BINAP
and Dpe-Phos (Table 2, entries 2 and 3, respectively) caused
the enantioselectivity to decrease appreciably. In the case of the
BINAP ligand, an excellent hydroacylation outcome was
observed (>99% conversion), but unfortunately it seemed
that the rate of the background aldehyde hydroacylation was
relatively very fast in comparison to formation and Rh insertion
into the iminium ion, as the desired product (7a) was obtained
as a racemate. The exchange of PPTS for p-TsOH·H2O
promoted the selective production of byproduct 8 (Table 2,
entry 4). The use of various solvents other than dioxane
diminished the overall reactivity as well as the product ratio
(Table 2, entries 5−7). Notably, despite this, the use of THP
resulted in excellent asymmetric induction (er = 98:2). The use
of the additive AgSbF6, which was expected to generate a
cationic Rh(I) species in situ11 (Table 2, entry 8), apparently
accelerated the background reaction, producing the desired
product with essentially complete conversion but in racemic
form. When the amount of PPTS was increased to 50 mol %
and the temperature was raised to 90 °C (Table 2, entry 10),
the conversion and enantioselectivity were significantly
increased. Using the conditions of entry 10 as a new
benchmark, we next focused our attention on the remaining
two untested reaction parameters, namely the rhodium source
and the reaction concentration.
The proposed transformation was tested using aldehyde 2a
as a model substrate. To do so, 2a was combined with amine 9
(20 mol %), [Rh(cod)Cl]2 (5 mol %), dppp (10 mol %), and
PPTS (20 mol %) in dioxane, and the resulting mixture was
heated to 80 °C for 16 h (Table 1, entry 1).
Table 1. Screening of Chiral, Nonracemic Secondary Amines
This phase of our study was initiated by changing the
rhodium catalyst to Rh(acac)(C2H4)2 while otherwise main-
taining the conditions from entry 10 of Table 2. Under these
conditions (Table 3, entry 1), there was a slight reduction in
conversion and asymmetric induction, but the desired product
and byproduct ratios remained the same. We next tried
increasing the reaction concentration from 0.1 to 0.5 M (Table
3, entry 2), which turned out to have a profound effect on the
reaction outcome; the product ratio increased substantially in
favor of the desired product (5:1) while the enantioselectivity
remained equally high (86:14). We then reduced the Rh
catalyst, phosphine ligand, and PPTS loadings to 2.5, 5, and 20
mol % respectively (Table 3, entry 3). These changes resulted
in the reaction going to completion (100% conversion) and
producing excellent enantioselectivity. However, unfortunately,
the ratio of 7a to 8 decreased to 3:1. Next, we tried increasing
the reaction temperature to 100 °C (entry 4), which led to an
improvement in the product ratio (4:1) in comparison to that
observed for entry 3 in Table 3 while maintaining both high
conversion and asymmetric induction.
Satisfied that we had established suitable reaction conditions
to effect our new asymmetric hydroacylation reaction, we set
out to conduct a preliminary exploration of its scope (Scheme
2). We first investigated varying substituents on the aromatic
ring. In the event, a wide array of both electron-donating and
-withdrawing groups were tolerated with good to excellent er.
Depending on the positioning and electronic nature of the aryl
substituent, the asymmetric induction varied. Interestingly, the
a
entry
amine
conversion (%)
7a/8
er
1
2
3
4
5
9
30
60
<5
50
<5
1:1
80:20
54:46
nd
10
11
12
3.3:1
b
nd
1:0
nd
65:35
nd
13
1
a
b
As judged by H NMR. nd = not determined.
We were pleased to find that the desired cyclized product 7a
was indeed obtained from this transformation, with a promising
er of 80:20.9 Unfortunately, 7a was produced in low yield and
was formed along with an approximately equal amount of
byproduct 8, the latter being the result of an acid-catalyzed
Prins reaction.10 In an effort to improve on the reaction
outcome, we attempted the same reaction but using different
chiral nonracemic secondary amines 10−13. The yield of the
reaction was improved significantly in the case of both amine
10 and amine 12 (entries 2 and 4, respectively), but
B
DOI: 10.1021/acs.orglett.6b02825
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Screening of Reaction Conditions
b
entry
phosphine
additive 1
additive 2
solvent
temp (°C)
conv (%)
7a/8
er
1
2
dppe
PPTS (20 mol %)
PPTS (20 mol %)
PPTS (20 mol %)
none
none
none
none
none
none
none
dioxane
dioxane
dioxane
dioxane
80
80
80
80
80
80
80
80
80
90
49
>99
88
1:3
10:1
1:2.3
0:1
85:15
55:45
55:45
BINAP
Dpe-Phos
dppe
3
c
4
p-TsOH·H2O (20 mol %)
PPTS (20 mol %)
PPTS (20 mol %)
PPTS (20 mol %)
PPTS (20 mol %)
PPTS (50 mol %)
PPTS (50 mol %)
93
nd
d
5
dppe
THP
39
1:2.5
0:1
98:2
nd
e
6
dppe
DCE
24
7
dppe
PhH
14
0:1
nd
8
dppe
AgSbF6 (10 mol %)
none
dioxane
dioxane
100
50
1:0
50:50
96:4
95:5
9
dppe
1:2
10
dppe
none
dioxane
83
1:1.8
a
b
c
d
e
1
All reactions were carried out at 0.1 M concentration. determined by H NMR. nd = not determined. Tetrahydropyran. DCE = 1,2-
dichloroethane.
Table 3. Screening of Reaction Conditions with
Rh(acac)(C2H4)2 as Catalyst
Scheme 2. Preliminary Test of Substrate Scope
a
concn
(M)
temp
(°C)
conv
(%)
entry
X
Y
Z
7a/8
er
1
2
3
4
10
10
2.5
2.5
20
20
5
50
50
20
20
0.1
0.5
0.5
0.5
90
90
73
93
1:1.7
5:1
87:13
86:14
94:6
90
100
100
3:1
5
100
4:1
94:6
a
1
As judged by H NMR.
hydroacylation product 7e, containing a strongly electron-
withdrawing group in the 4-position, produced much lower er
compared to the other compounds with electron-donating or
weakly withdrawing substituents at the 4-position (7b−d).
Electronically neutral substituents in the 5-position (7f and 7h)
were formed with very good enantioselectivity; however, when
either electron-donating or -withdrawing groups were incorpo-
rated at the 5-position, the er was diminished. We next explored
the scope of the hydroacylation reaction with respect to the
vinyl group substituent. Addition of a phenyl group to the vinyl
moiety (7j) provided a moderate er but vastly improved the
yield. Alkyl groups of varying length were also examined.
Interestingly, incorporation of an n-butyl group (7k) provided
excellent er, but when an n-hexyl group was used (7l) the er
was somewhat diminished. Lastly, acetates 7m and 7n were
furnished with a very good er.
A crystal structure of compound 7b was obtained which
indicated the configuration of the newly formed stereogenic
center is S (Figure 1).
In conclusion, we have demonstrated a new approach to
effecting asymmetric induction in the venerable hydroacylation
reaction. Our approach is based on the merger of asymmetric
immium ion catalysis and transition-metal catalysis. Asymmetric
induction is achieved through the use of a readily accessible,
inexpensive chiral nonracemic secondary amine catalyst rather
a
Reaction conducted at 80 °C.
than through the use of a chiral nonracemic phosphine, as is
typical of asymmetric hydroacylation methods. A key feature of
C
DOI: 10.1021/acs.orglett.6b02825
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Organic Letters
Letter
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Figure 1. X-ray crystal structure of 7b.
(8) For selected examples of cooperative catalysis, see: (a) Ibrahem,
our method appears to be a novel oxidative insertion of Rh into
an iminium C−H bond. Studies are underway to investigate the
mechanism of the transformation and to expand its scope.
Furthermore, the utility of iminium C−H insertion in the
context of other transformations is being explored and will be
reported in due course.
I.; Cor
́
dova, A. Angew. Chem., Int. Ed. 2006, 45, 1952−1956.
(b) Ibrahem, I.; Ma, G.; Afewerki, S.; Cor
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38, 2745−2755. (d) Mo, F.; Dong, G. Science 2014, 345, 68−72.
(9) Determined by GC analysis using a chiral, nonracemic stationary
phase. See the Supporting Information for details.
(10) It was found that byproduct 8 is formed as a racemate.
(11) Phan, D. H. T.; Kim, B.; Dong, V. Y. J. Am. Chem. Soc. 2009,
131, 15608−15609.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02825.
Experimental procedures and analytical data for all new
compounds (PDF)
X-ray crystallographic data for 7b (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: dcoltart@uh.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Dr. Daniel Lim (Yeshiva University) for
conducting preliminary experiments related to this work and
Dr. James Korp (University of Houston) for X-ray crystal
structure determination. We thank the NSF (NSF 1300652),
the Welch Foundation (E-1806), and the University of
Houston for financial support.
REFERENCES
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■
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W.; Chen, Z.; Dong, V. M. J. Am. Chem. Soc. 2016, 138, 3310−3313.
(4) For selected examples of O-chelation, see: (a) Kokubo, K.;
Matsumasa, K.; Miura, M.; Nomura, M. J. Org. Chem. 1997, 62, 4564−
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D
DOI: 10.1021/acs.orglett.6b02825
Org. Lett. XXXX, XXX, XXX−XXX