Highly diastereo- and enantioselective silver-catalyzed double [3+2] cyclization of α-imino esters with isocyanoacetate

Article abstract of DOI:10.1002/anie.201402788

Presented herein is a new complexity-generating method in which both functionalities of α-imino esters undergo stereoselective cyclization with isocyanoacetates to produce directly linked oxazole-imidazolines, which can be transformed into highly functionalized α,β-diamino esters and imidazolinium salts in high diastereo- and enantiopurity. Double up: An unprecedented silver-catalyzed title reaction has been developed and provides access to directly linked oxazole-imidazolines. A highly diastereo- and enantioselective variant was also realized using the catalyst Ag/L*. The products can be easily transformed into highly functionalized chiral α,β-diamino esters or imidazolinium salts which are useful motifs in asymmetric synthesis and catalysis.

Full text of DOI:10.1002/anie.201402788

Angewandte
Chemie
DOI: 10.1002/anie.201402788
Asymmetric Catalysis
Highly Diastereo- and Enantioselective Silver-Catalyzed Double [3+2]
Cyclization of a-Imino Esters with Isocyanoacetate**
Pan-Lin Shao, Jia-Yu Liao, Yee Ann Ho, and Yu Zhao*
Dedicated to Professor Amir H. Hoveyda on the occasion of his 55th birthday
Abstract: Presented herein is a new complexity-generating
method in which both functionalities of a-imino esters undergo
stereoselective cyclization with isocyanoacetates to produce
directly linked oxazole-imidazolines, which can be trans-
formed into highly functionalized a,b-diamino esters and
imidazolinium salts in high diastereo- and enantiopurity.
Scheme 1. Double cyclization with both the imine and ester function-
alities in a-imino esters.
The generation of complexity and diversity in molecular
structures in an efficient and economical fashion is an
important goal in organic synthesis and chemical biology,[1]
for which multicomponent reactions (MCRs)[2] and cascade
reactions[3] have proven to be the most useful strategies.
Along these lines, isocyanoacetates (as functionalized iso-
cyanides)[4] have found wide application not only in classical
Passerini- and Ugi-type MCRs, but they have also proven to
be a versatile functionality to react with carbonyls,[5] imines,[6]
a,b-unsaturated carbonyls,[7] activated alkenes/alkynes,[8] etc.
to produce a wide range of heterocyclic compounds. The
combination of these reactions with further functionalization
of the products in a tandem fashion has also been extensively
studied, in particular by the group of Zhu, to produce more
complex structures.[9] We present here a conceptually differ-
ent complexity-generating method, that is, both functional-
ities in a-imino esters (previously recognized as activated
imines only) undergo cyclization with isocyanoacetate to yield
directly linked oxazole-imidazolines catalyzed by a silver salt
(Scheme 1).[10] An asymmetric variant has also been devel-
oped with the Dixon-type catalyst[5e] to produce these
compounds in high diastereo- and enantiopurity, and these
products can be further transformed into other valuable and
highly functionalized entities.
Scheme 2. Oxazole formation from aryl esters. Yields are those of the
isolated products. DMF=N,N’-dimethylformamide, Ts=4-toluenesul-
fonyl. THF=tetrahydrofuran.
known to fail to react even under harsh reaction conditions
because of the low reactivity of the enolate, derived from the
isocyanoacetate, towards an ester.[11] We argued that the use
of aryl esters could be beneficial, as the better leaving group,
aryloxide (compared with simple alkoxide from alkyl esters),
should facilitate the addition of the enolate to the ester. This
indeed led to efficient oxazole formation from different aryl
esters (1) and isocyanoacetates (2; or toluenesulfonylmethyl
isocyanide) by the use of a stoichiometric amount of a strong
base (71–99% yield for 3a–c with the use of NaH). For the
oxalate 4, interestingly, the formation of the bis(oxazole) 5 in
excellent yield was realized by using a much milder silver-
catalyzed procedure, which failed to yield 3a–c at all. Clearly
there is a synergetic effect between the ester functionalities in
4, and thus led us to consider substrates bearing different
functionalities which could mutually activate each other for
the reaction with isocyanoacetate to produce complex
molecules.
Our attention was drawn to this possibility of a double
cyclization during our initial attempts of oxazole formation
from the reaction between isocyanoacetates and esters, as
they should be more functional-group tolerant and easier to
handle than using of strong acylating reagents such as acid
chlorides (Scheme 2).[4a] Such a combination, however, was
[*] Dr. P.-L. Shao, J.-Y. Liao, Y. A. Ho, Prof. Y. Zhao
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
E-mail: zhaoyu@nus.edu.sg
Homepage: zhaoyu.science.nus.edu.sg
[**] We are grateful for the generous financial support from the
Singapore National Research Foundation (NRF Fellowship) and
National University of Singapore.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402788.
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Table 2: Catalyst screening for enantioselective double [3+2] cycliza-
The cyclic a-imino ester 6a (for structure see Table 1) was
chosen as the model substrate because of its unique a-imino
aryl ester structure, as well as its easy synthesis.[12] The
proposed double cyclization with both imine and aryl ester
moieties with isocyanoacetate will also be entirely atom
economical as the product incorporates all portions of the
starting materials. It is also noteworthy that the reaction of
isocyanoacetates (or isocyanoacetamides) with imines is
known to follow divergent pathways to produce either
imidazolines[6a,e–g] or oxazoles (initiated by isocyanide addi-
tion to activated imines).[6b–d] These factors, combined with
the reaction at the aryl ester moiety, could in principle lead to
a complex mixture.
tion.[a–d]
Entry
8
Yield [%][b] ee [%][c]
Entry
8
Yield [%][b] ee [%][c]
1
2
3
4
5
6
8a 95
8b 98
8c 67
8d 99
8e 99
8 f 99
<2
<2
<2
81
79
72
7
8
9
10
11[d]
12[e]
8g 99
8h 95
8i 95
8j 99
8d 96
8d 99
58
14
À3
<2
67
As shown in Table 1, various metal salts having different
levels of basicity or Lewis acidity were screened for the
reaction of 6a and 2a at ambient temperature. Gratifyingly,
98
[a,b] See Table 1. [c] Determined by HPLC analysis using a chiral
stationary phase. [d] Ag2CO3 was used instead of Ag2O. [e] The reaction
was carried out at À208C.
Table 1: Metal-salt screening for double [3+2] cyclization of 6a and
2a.[a,b]
Entry Metal salt Yield [%][b]
Entry Metal salt Yield [%][b]
1
2
3
4
5
6
Cu2O
Cu(OAc)2
CuCl2
ZnCl2
AuCl3
72
40
<2
<2
<2
90
7
8
9
10
11
12
Ag2O
Ag2CO3
AgBF4
AgOTf
BF3·OEt2
Sc(OTf)3
99
99
<2
<2
<2
<2
AgOAc
[a] Carried out in air for 24 h. See the Supporting Information for details.
[b] Yield of isolated product. Tf=trifluoromethanesulfonyl.
the desired double [3+2] cyclization product 7a was obtained
cleanly (> 20:1 d.r.) when copper and silver salts, which are
strongly basic, were used with Ag2O and Ag2CO3 as the
optimal choices (99% yield). In contrast, zinc or gold salts,
and even strong Lewis acids such as BF3·OEt2 or Sc(OTf)3,
failed to promote the reaction. This result led us to speculate
that this may be a base-catalyzed process in which the
Mannich reactivity of 2a predominates and yields imidazoline
with concomitant oxazole formation from reaction with the
aryl ester moiety.
With an efficient reaction in hand, we turned our attention
to the development of an asymmetric variant by evaluating
copper or silver complexes supported by various chiral
ligands. After extensive experimentation, Ag2O turned out
to be the most promising choice for the metal salt, and the
screening data for different chiral ligands is summarized in
Table 2. Initially we focused on simple quinine amides, which
we recently disclosed for silicon activation and copper
catalysis,[13] and to our disappointment, they did not lead to
asymmetric induction (entries 1–3). Inspired by the recent
report from the group of Dixon on enantioselective isocya-
noacetate aldol reaction catalyzed by a silver complex with
a new family of cinchona-derived amino phosphine precata-
lysts,[5e,14] we tested the related 8d–g for our reaction. The use
of the quinine-derived phosphine 8d with Ag2O gratifyingly
yielded 7a with a good ee value of 81% (entry 4). Modifica-
tion on the structure of 8d, as reported by the group of Dixon
(reduction to 8e or use of cinchonidine-derived 8 f,g),[5e]
unfortunately led to lower ee values (entries 5–7). The
structurally related imine 8h was also tested, and proved to
be much less selective (entry 8). The simple chiral-phosphine-
containing amide 8i did not result in any enatioselectivity,
thus implying the importance of quinuclidine moiety for the
asymmetric induction in addition to the phosphine amide
moiety (entry 9). Finally, the use of the pyridyl-containing
8j[15] yielded a racemic product. With the optimal ligand
identified, we re-tested the use of Ag2CO3, which again
proved less selective than Ag2O (entry 11 versus entry 4).
Further optimization of the reaction conditions with the use
of the Ag2O/8d system was carried out (see the Supporting
Information for details). While solvent screening showed
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Scheme 4. NMR studies revealed a stepwise reaction profile.
complexity from concomitant imidazoline and oxazole for-
mation.
In an effort to better understand the mechanism of the
system, the kinetics of the reaction between 6a and 2a were
monitored by NMR spectroscopy (Scheme 4). With a lower
catalyst loading and, in turn, decreased reaction rate, the two
cyclization reactions were identified to be stepwise. Strikingly,
an essentially full conversion of 6a into the monocyclization
product 9a was observed within 60 minutes at 218C before
the formation of 7a began. As expected, the enantioselectiv-
ity was determined in the first step; 9a and 7a were obtained
with the same 79% ee.
Scheme 3. Scope for enantioselective double [3+2] cyclization of 6 and
2. Yields are those of the isolated products. With a few exceptions, the
reactions were carried out at À208C for 24 h. See the Supporting
Information for details.
THF was still the optimal solvent, lowering the reaction
temperature led to a dramatic increase in the enantioselec-
tivity. When the reaction was carried out at À208C, 7a was
obtained in excellent yield (99%) with 98% ee (entry 12).[16]
The substrate scope of this system was studied next
(Scheme 3). It is noteworthy that in almost all cases perfect
diastereoselectivity was obtained for the product 7 with an
anti-diamine moiety. Isocyanoacetates bearing different ester
groups were all suitable substrates, thus producing the
products 7a–e in uniformly high yields with excellent
ee values (91–99%). Different substitution patterns on the
aryl ring (para, meta, and ortho) were well tolerated and
formed highly functionalized imidazolines with different
phenol units in excellent enantioselectivity (7 f–l). Ketimines
turned out to be difficult substrates for the double cyclization.
A mixture of the mono-[3+2] cycloaddition product (with
imine) and the desired product 7m was obtained for the
methyl-substituted ketimine. Surprisingly a different syn dias-
tereomer was formed, with a lower ee value of 37%.
While the nature of this stepwise reaction profile neces-
sitates further investigation, it provided more possibilities for
our methodology to produce structurally different com-
pounds. As shown in Scheme 5a, the mono-[3+2] cyclization
products 9a–g could be isolated in high yield with good to
excellent ee values when the reaction was carried out at
À208C with 2 as the limiting reagent (see the Supporting
Information for details). Alternatively, a three-component
reaction of two different isocyanoacetates with 6a was also
realized (Scheme 5b). The compounds 2e and 2a were added
sequentially to yield 7n in 67% yield with 97% ee. In
addition, the use of substituted isocyanoacetates such as 2 f
led to a smooth [3+2] cycloaddition with 6a, and subsequent
cyclization of 2a with the ester unit in the intermediate, to
yield 7o in 73% yield and a slightly lower ee value of 71%.
X-ray analysis of 7o[19] further confirmed the directly linked
oxazole-imidazoline structure of the products.
The products of this reaction can be easily converted into
useful entities in asymmetric catalysis. The imidazoline
moiety could be readily hydrolyzed under acidic conditions
to yield highly functionalized a,b-diamino esters, such as 10,
in high yield (Scheme 6a), the X-ray analysis of which[19]
confirmed the relative and absolute configuration of the
products 7. The formamide 10 has been identified to be
a highly efficient Lewis base catalyst for the addition of
allyltrichlorosilane to aliphatic aldehydes, a process which
It is worth noting that the current reaction is simple to
perform with catalysts which can be easily prepared from
inexpensive starting materials. The reactions are set up open
to air with no need for exclusion of air or moisture. The level
of diastereo- and enantioselectivity compares favorably with
previously reported Mannich reaction of isocyanoacetate
with imines,[6e–g] with the additional advantage of generating
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Alternatively, 7a was transformed into the imidazolinium
salt 11 in high yield upon treatment with an alkylating reagent
such as methyl iodide (Scheme 6b). The application of related
compounds as bidentate N-heterocyclic carbine/phenoxide
ligand in enantioselective catalysis has been beautifully
demonstrated by the group of Hoveyda.[18] The unique
structure of our products, bearing multiple functionalities,
may provide new opportunities in asymmetric catalysis.
Experimental Section
Anhydrous THF (1 mL) was added to a 10 mL vial charged with 8d
(12 mg, 0.020 mmol) and Ag2O (2.3 mg, 0.010 mmol). The mixture
was stirred at ambient temperature for 5 min and then cooled to
À208C. The cyclic a-imino ester 6a (0.10 mmol) was added, followed
by isocyanoacetate 2a (0.20 mmol) using a micropipette. The reaction
mixture was stirred at À208C for 24 h, and then concentrated and
purified by flash chromatography (hexanes/ethyl acetate) to afford
the product 7a (99%).
Received: February 25, 2014
Revised: March 22, 2014
Published online: April 22, 2014
Keywords: asymmetric catalysis · cyclization ·
.
enantioselectivity · heterocycles · multicomponent reaction
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b) imidazolinium salt.
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data is also included in the Supporting Information.
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