Divergent, Enantioselective Synthesis of Pyrroles, 3H-Pyrroles and Bicyclic Imidazolines by Ag- or P-Catalyzed [3+2] Cycloaddition of Allenoates with Activated Isocyanides

Article abstract of DOI:10.1002/chem.201801768

The divergent, stereoselective formal [3+2] cycloadditions of allenoates with activated isocyanides catalyzed by silver or phosphine-based catalysts were investigated. Silver catalysis is capable of delivering a range of 3H-pyrroles in high stereoselectivities. These enantioenriched heterocycles can either undergo sequential cyclisation with isocyanoacetates to deliver unprecedented bicyclic imidazolines with excellent yields and stereoselectivity or undergo unusual aromatization pathways leading to polysubstituted pyrroles. On the other hand, a simple mix-and-go procedure using an amino acid-derived phosphine as the catalyst produces pyrroles bearing a benzylic stereocenter with good enantioselectivity.

Full text of DOI:10.1002/chem.201801768

A Journal of
Accepted Article
Title: Divergent, Enantioselective Synthesis of Pyrroles, 3H Pyrroles
and Bicyclic Imidazolines by Ag- or P-Catalyzed [3 + 2]
Cycloaddition of Allenoates with Activated Isocyanides
Authors: Yu Zhao, Germaine Pui Yann Kok, Pan-Lin Shao, Jia-Yu Liao,
Siti Nur Fairuz Bte Sheikh Ismail, Weijun Yao, and Yixin Lu
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To be cited as: Chem. Eur. J. 10.1002/chem.201801768
Link to VoR: http://dx.doi.org/10.1002/chem.201801768
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Divergent, Enantioselective Synthesis of Pyrroles, 3H Pyrroles
and Bicyclic Imidazolines by Ag- or P-Catalyzed [3 + 2]
Cycloaddition of Allenoates with Activated Isocyanides
Germaine Pui Yann Kok,+ Pan-Lin Shao,+,§, Jia-Yu Liao, Siti Nur Fairuz Bte Sheikh Ismail, Weijun Yao,
Yixin Lu and Yu Zhao
with chiral cinchona-derived ligand, a highly diastereo- and
enantioselective imidazoline synthesis could be obtained (Eq. 1).
Our group also reported a highly stereoselective, double
cyclisation of isocyanoacetates with cyclic α-imino esters using
the Dixon-type catalyst, in which both functionalities in the
substrate underwent cyclization (Eq. 2).[3j]
Abstract: We report herein our detailed investigation of divergent,
stereoselective formal [3 + 2] cycloadditions of allenoates with
activated isocyanides catalyzed by silver or phosphine-based
catalysts. Silver catalysis is capable of delivering a range of 3H-
pyrroles in high stereoselectivities. These enantioenriched
heterocycles can either undergo sequential cyclisation with
isocyanoacetates to deliver unprecedented bicyclic imidazolines with
excellent yields and stereoselectivity or undergo unusual
aromatization pathways leading to poly-substituted pyrroles. On the
other hand, a simple mix-and-go procedure using an amino acid-
derived phosphine as the catalyst produces pyrroles bearing a
benzylic stereocenter with good enantioselectivity.
Introduction
The efficient and stereoselective synthesis of important
heterocycles is a focal objective in synthetic organic chemistry.
For such processes, activated isocyanides such as
isocyanoacetate hold great potential by nature of its versatile
functionality.[1] It has been reported that they can readily
undergo cycloaddition with various π-systems including
carbonyls,[2] imines,[3] α,β-unsaturated carbonyls[4] and activated
alkenes or alkynes[5] to furnish a wide range of heterocycles
(Scheme 1).
Imidazolines are an important class of N-heterocycles as they
are ubiquitous in natural products and also in biologically active
molecules.[6] For instance, imidazoline receptor I-1 binds to
clonidine and other imidazolines to lower blood pressure through
the inhibition of the sympathetic nervous system.[7] Besides that,
imidazolines are also prevalent scaffolds in N-heterocyclic
carbene (NHC) organocatalysts.[8] Scheme 1a highlights some
examples of imidazoline synthesis. Following Orru’s classical
report on imidazoline synthesis via
a
three-component
condensation using an amine, an aldehyde and a substituted
isocyanoacetate,[3c] stereoselective reactions between imines
and isocyanoacetates have been successfully developed in
recent years. In 2014, Dixon et al.[3h] and Nakamura et al.[3i]
[*]
G. P. Y. Kok, Dr. J.-Y. Liao, S. N. F. Sheikh Ismail, Dr. W. Yao, Prof.
Y. Lu, Prof. Y. Zhao
Department of Chemistry
National University of Singapore
3 Science Drive 3, Singapore 117543
E-mail: zhaoyu@nus.edu.sg; chmlyx@nus.edu.sg
Dr. P.-L. Shao
College of Innovation and Entrepreneurship
Southern University of Science and Technology
Shenzhen 518000, People's Republic of China
Email: shaopl@sustc.edu.cn
Scheme 1. Heterocycle synthesis from activated isocyanides. a) Formation of
imidazoline from reaction with imines. b) Pyrrole synthesis from isocyanide
with various partners. c) This work: divergent reaction of isocyanoacetate with
allenoates using Ag- or P-catalysis.
[§]
[+]
These authors contributed equally to this work.
Pyrroles represent another important class of N-
heterocycles and likewise, they are found abundantly in
naturally occurring compounds such as porphyrins, chlorophylls,
Supporting information for this article is given via a link at the end of
the document.
showed that with the use of silver or copper salts in combination
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vitamin B12 and lamellarins from marine organisms, which has
promising biological activities.[9] Out of various synthetic
strategies for pyrrole synthesis, the cycloaddition of
isocyanoacetates with activated alkenes, alkynes and β-
enaminones has been achieved (Scheme 1b). In 1990, Barton
and Zard discovered that isocyanoacetates can undergo
cyclisation with nitro-olefins to give substituted pyrroles (Eq.
3).[5a] Cycloaddition of alkynes with isocyanoacetates also
readily occur (Eq. 4) and can be catalyzed by phosphine or
copper (Yamamoto et al.)[5b] or via silver catalysis (Bi et al. and
Lei et al.)[5g-h] More recently, the group of Bi and our group have
independently shown that isocyanoacetates can react with in
situ formed imines from β-enaminones[4d] (Eq. 5) or 3-
formylchromones with amines (Eq. 6).[4e] All these examples of
pyrrole synthesis, to the best of our knowledge, have not been
adopted for asymmetric synthesis.
In 2015, our group reported the first enantioselective
synthesis of 3H pyrroles using Ag2O and Dixon’s ligand 4
(Scheme 2). As shown, the reaction between allenoates 1 and
isocyanoacetates 2a tolerated various substitutions on the
allenoates to deliver a wide range of 3H pyrroles 3 bearing a
quaternary center in good to excellent enantioselectivity. This
represents the first highly enantioselective catalytic synthesis of
3H pyrroles. As originally proposed by the Dixon group,[2g] the
silver Lewis acid presumably binds to this class of ligand in a
bidentate fashion using the phosphine and amide moieties,
which coordinates both isocyanide and the electrophile. The
basic quinuclidine nitrogen is likely involved in the deprotonation
of isocyanoacetate to generate the enolate nucleophile.
Our group has been interested in the application of activated
isocyanides to new modes of heterocycle synthesis. Very
recently, we discovered highly intriguing divergent reactivities
between allenoates with isocyanoacetates to access 3H pyrroles
or aromatic pyrroles by the use of either silver or phosphine
catalysts (synthesis of 3 or 10 in Scheme 1c).[10] We were
intrigued by the possibility of using chiral phosphine to realize an
unprecedented enantioselective pyrrole synthesis. In addition,
we were also interested in exploring the reactivity of the novel
3H pyrroles that were never prepared in an enantioenriched
form before. Herein we report our full studies along these lines.
Not only have we identified intriguing reactivities of the 3H
pyrroles that allowed the preparation of unprecedented bicyclic
imidazolines, we have also come up with a simple mix-and-go
procedure using an amino acid-derived phosphine as the
catalyst that produces pyrroles bearing a benzylic stereocenter
with good enantioselectivity (Scheme 1c).
Results and Discussion
Formation of bicyclic imidazoline and derivatization of 3H
pyrroles
Scheme 3. a) Ag-catalysed one-pot sequential cyclisation of bicyclic
imidazolines. b) Proposed mechanism for the formation of 5.
An intriguing discovery was made during our investigation.
When the amount of 2a (relative to 1) was increased, an
unexpected side product was obtained, which was identified to
be a sequential [3 + 2] cycloaddition product 5 (Scheme 3).
Clearly, the cyclic imine moiety in 3H pyrrole 3 served effectively
as an electrophile to undergo reaction with isocyanoacetate to
deliver an unprecedented bicyclic imidazoline. This sequential
cycloaddition also proceeded with superb level of
diastereoselectivity, although the reaction required slightly
higher temperature to proceed to full conversion. Under the
optimal conditions, when the crude reaction for 3H pyrrole
Scheme 2. Ag-catalysed enantioselective synthesis of 3H pyrrole.
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synthesis was warmed up to room temperature and
1
treatment of 3n or 3o with TFA in CHCl3 under ambient
temperature enabled an effective migration of the benzyl or allyl
group to produce tetra-substituted pyrroles 6 and 7 in excellent
yields respectively (Scheme 4a). When compound 3n was
placed under 1 atm of H2 with Pd/C in ethanol at room
temperature, the benzyl group was removed and rearrangement
occurred to yield the more stable tri-substituted pyrrole 8 again
in nearly quantitative yield (Scheme 4b). Finally, treatment of 3n
with LiOH.H2O in a 1:1 mixture of THF:H2O cleaved the ester
group to give tri-substituted pyrrole 9. It is worth noting that
racemic 3H pyrroles 3 can be accessed by the use of simple
Ag2O and PPh3; this combined with these simple procedures,
resulted in an efficient preparation of poly-substituted pyrroles.
equivalence of 2a was added, a few representative bicyclic
imidazolines 5a-e could be obtained in excellent yields as a
single diastereomer and with retention of stereochemistry from
the first step. The relative configuration of compounds 5a was
assigned by NOESY (see Supporting Information for more
details) and the other compounds were assigned by analogy.
Based on the proposed mechanism by Dixon et al.,[3i] it is
postulated that Dixon ligand 4 creates a chiral pocket by binding
with silver, which in turn coordinates with allenoate 1 and the
enolate form of isocyanoacetate 2a to form intermediate II via [3
+ 2] cyclisation. This exocyclic olefin subsequently undergoes a
1,3-H shift to form 3H pyrrole 3. Then, another equivalent of
isocyanoacetate 2a undergoes another [3 + 2] cyclisation with 3
to form bicyclic imidazoline 5. The configuration of the second
cyclisation is believed to be dictated by the chirality created in
the first step.
Formation of enantioenriched 1H pyrroles
Scheme 4. Derivatization of 3H pyrroles 3 to give various polysubstituted 1H
pyrroles.
It is noteworthy that the presence of the quaternary
stereocenter in 3H pyrroles 3 is essential for the stabilities of
these non-aromatic heterocycles. Without the fully substituted
carbon center, the related 3H pyrroles are known to undergo
highly facile tautomerization through H-transfer to yield the
corresponding aromatic 1H pyrroles. In attempts to further
explore the utility of our 3H pyrrole products, a series of
derivatization was carried out on 3 (Scheme 4). Intriguingly,
Scheme 5. a) Selected examples of 1H pyrrole synthesis by PPh3 catalysis. b)
Proposed mechanism for the formation of 10.
In contrast to the reaction of 1 and 2 under silver catalysis,
simple PPh3 works as an effective catalyst for the formation of
polysubstitutted 1H pyrroles from the reaction of 1 and 2 using a
simple mix-and-go procedure (Scheme 5a). Di- or tri-substituted
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attempted first (e.g., entries 1-2). However, to our
disappointment, the yields were low and only moderate
enantioselectivity was obtained. In hopes of improving the
enantioselectivity, we then turned our attention to amino acid-
derived bifunctional phosphines that were developed by us
before.[13] To our delight, by using threonine-derived phosphine
11c (entry 3), higher yield of 10 was obtained, albeit with low
enantioselectivity. We continued to screen a range of amino-acid
derived phosphines (entries 4-6) and found that catalyst 11f
gave the best enantioselectivity, although this was achieved at
the cost of lower yields. From our previous work, we found that
chloroform acts as a proton source in facilitating the formation of
10. When the solvent was changed from p-xylene to chloroform,
pyrroles bearing a benzylic stereogenic center can be accessed
in good efficiency. Both isocyanoacetate and the analogous p-
toluenesulfonylmethyl isocyanide could be used for the 1H
pyrrole synthesis.
With this method in hand, we were particularly attracted to
the development of an asymmetric variant of this process to
deliver, for the first time, enantioenriched pyrroles. A close
examination of the mechanistic pathway for the pyrrole synthesis,
however, points out a few key challenges to overcome.
As illustrated in Scheme 5b, a key intermediate I is formed
upon nucleophilic addition of the phosphine catalyst to 1, which
then deprotonates 2 to generate the nucleophile in situ. The
formation of ylide II would actually serve as the key enantio-
determining step when a chiral phosphine catalyst is used.
Cyclisation to form intermediate III is then followed by solvent-
assisted proton transfer and release of catalyst to yield 2H
pyrrole V. At this stage, we propose two sequential 1,5- and 1,3-
H shift will take place to convert V to VI and then the desired
product 10.[11] Based on the proposed mechanism, it is important
to note that not only the chiral catalyst has to be capable of
inducing high enantioselectivity for the formation of
intermediates II to V, the formation of final product 10 from V
also has to proceed with high degree of retention of
indeed,
a
drastic increase in both the yields and
enantioselectivity was obtained (entry 7). We also found that
increasing the amount of p-toluenesulfonylmethyl isocyanide 2b
in the reaction also led to
enantioselectivity (entry 8).
a
slight enhancement in
With the optimal condition in hand, the scope of this catalytic
procedure proved to broad. Different substituents on the benzyl
ring of the allenoate as well as different ester groups on the
activated isocyanides can be well-tolerated to produce pyrroles
10 in good to high enantioselectivity (Scheme 6). Increasing the
bulk of the ester from methyl to a tert-butyl group experienced
enhanced enantioselectivity, albeit at the cost of diminishing
yields (10q-10t). Electron-donating groups at the para position of
the benzyl ring of the allenoate (10u-x) was also well tolerated,
with moderate yields and good enantioselectivity. Electron
donating groups at the ortho position (10y) gave moderate yields
and good enantioselectivity, whereas election withdrawing
groups at the ortho position (10z) or 2,6-position (10aa) suffered
low yields but good enantioselectivity. The absolute
configuration of 10t was established unambiguously by single
crystal x-ray analysis. The configuration of the other 1H pyrroles
was assigned by analogy.
stereoselectivity.
Table 1. Optimization of the Reaction Conditions.[a]
entry
catalyst
11a
11b
11c
11d
11e
11f
solvent
10 yield (%)[b]
ee (%)[c]
<5
1
2
p-xylene
25
26
65
40
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
CHCl3
3
37
4
26
30
17
5
5
45
6
64
7
8[d]
11f
83
60
55
11f
86
CHCl3
[a] Reaction conditions: 1a (0.1 mmol), 2b (0.1 mmol), 20 mol% of 11 in CHCl3
(1.0 mL) at 24 °C for 24 h. [b] Isolated yield. [c] Determined by HPLC
Chiralpak IC. [d] 0.15 mmol of 2b was used.
Scheme 6. Scope of enantioenriched 1H pyrroles.[a]
We then turned our attention to the realization of
enantioselective pyrrole synthesis under chiral phosphine
catalysis. We initiated our optimization of reaction conditions to
promote the model reaction between 1a and 2b (Table 1).[12] The
use of commercially available chiral phosphine catalysts were
To validate our proposed mechanism shown in Scheme 5a,
we reacted α-benzyl substituted isocyanoacetate 2c with
allenote 1a (Scheme 7), the reaction of which should stop at the
2H pyrrole stage (corresponding to intermediate V in Scheme 5b)
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[1]
[2]
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as the following hydride shift cannot take place. To our delight,
we were able to obtain the desired compound 12, albeit in a
small amount. This nonetheless provides significant support for
the the reaction pathway shown in Scheme 5b. The
configuration of 12 was unambiguously assigned by single
crystal x-ray analysis. The low yield of the reaction is attributed
to low conversion, possibly due more steric hindrance from
substituted isocyanide 2c. We believe that a number of
regioisomers were formed in the reaction. However, our
attempts to isolate and assign other isomers of the reaction
proved futile. Efforts to further explore this reaction is currently
underway.
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Scheme 7. Synthesis of 2H pyrrole 12.
Conclusions
In conclusion, we have detailed the enantioselective
synthesis of 3H pyrroles from the reaction of isocyanoacetates
and allenoates under silver catalysis as well as a one-pot,
sequential cyclisation to produce unprecedented bicyclic
imidazolines in
a
highly stereoselective fashion. The
enantioselective variant of 1H pyrrole synthesis with the use of
amino acid-derived phosphine is also disclosed. Both methods
use simple procedures and are able to tolerate a good range of
functional groups. Efforts to further extend the utility of these
reactions are underway.
[4]
For selected reactions with α,β-unsaturated carbonyls: (a) Song, J.;
Guo, C.; Chen, P.-H.; Yu, J.; Luo, S.-W.; Gong, L.-Z., Chem. Eur. J.
2011, 17, 7786-7790; (b) Bai, J.-F.; Wang, L.-L.; Peng, L.; Guo, Y.-L.;
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Experimental Section
To
a 10 mL vial charged with catalyst 11f (0.02 mmol) and p-
toluenesulfonylmethyl isocyanide 2b (0.15 mmol) was added anhydrous
CHCl3 (1.0 mL), followed by allenoate (0.1 mmol). The reaction mixture
was then stirred at ambient temperature for 24 h, concentrated and
purified by column chromatography (hexanes/ethyl acetate) to afford
product 10.
[5]
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Zard, S. Z., Tetrahedron 1990, 46, 7587-7598; (b) Kamijo, S.;
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X.; Yao, Q.; Yu, P., Chem. Asian J. 2016, 11, 2121-2125; (j) Peng, X.-
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Acknowledgements
We are grateful for the generous financial support from A*STAR
SERC (R-143-000-648-305) and the Singapore Economic
Development Board and GlaxoSmithKline (R-143-000-564-592),
and the National Natural Science Foundation of China
(21402150).
Keywords: silver catalysis • phosphine catalysis • pyrroles •
imidazolines • enantioselectivity
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Germaine Kok Pui Yann, Pan-Lin Shao,
Jia-Yu Liao, Siti Nur Fairuz Bte Sheikh
Ismail, Weijun Yao, Yixin Lu and Yu Zhao
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Divergent, Enantioselective Synthesis of
Pyrroles, 3H Pyrroles and Bicyclic
Imidazolines by Ag- or P-Catalyzed [3 +
2] Cycloaddition of Allenoates with
Activated Isocyanides
We report herein our detailed investigation of divergent, stereoselective formal [3 + 2]
cycloadditions of allenoates with activated isocyanides catalyzed by silver or phosphine-
based catalysts. Silver catalysis is capable of delivering a range of 3H-pyrroles in high
stereoselectivities. These enantioenriched heterocycles can either undergo sequential
cyclisation with isocyanoacetates to deliver unprecedented bicyclic imidazolines with
excellent yields and stereoselectivity or undergo unusual aromatization pathways leading
to poly-substituted pyrroles. On the other hand, a simple mix-and-go procedure using an
amino acid-derived phosphine as the catalyst produces pyrroles bearing a benzylic
stereocenter with good enantioselectivity.
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