Gold-Catalyzed Intermolecular Nitrene Transfer from 2H-Azirines to Ynamides: A Direct Approach to Polysubstituted Pyrroles

Article abstract of DOI:10.1021/ol503172h

(Chemical Equation Presented). An effective gold-catalyzed intermolecular nitrene transfer by the reaction of 2H-azirines and ynamides is reported, which provides highly substituted pyrroles in a straightforward manner. This transformation proceeds under mild conditions and gives the polysubstituted pyrroles in good-to-excellent yields. Preliminary results indicate that a nongold carbenoid pathway is preferred for current pyrrole synthesis.

Full text of DOI:10.1021/ol503172h

Letter
pubs.acs.org/OrgLett
Gold-Catalyzed Intermolecular Nitrene Transfer from 2H‑Azirines to
Ynamides: A Direct Approach to Polysubstituted Pyrroles
Lei Zhu,† Yinghua Yu,† Zhifeng Mao, and Xueliang Huang*
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences,
Yangqiao West Road 155#, Fuzhou, Fujian, China, 350002
S
* Supporting Information
ABSTRACT: An effective gold-catalyzed intermolecular nitrene transfer by the reaction of 2H-azirines and ynamides is
reported, which provides highly substituted pyrroles in a straightforward manner. This transformation proceeds under mild
conditions and gives the polysubstituted pyrroles in good-to-excellent yields. Preliminary results indicate that a nongold
carbenoid pathway is preferred for current pyrrole synthesis.
olysubstituted pyrrole derivatives have found broad
application in organic synthesis and material science. In
Scheme 1. Pyrrole Synthesis via Gold-Catalyzed Nitrene
Transfer
P
addition, they exhibit diverse biological and therapeutic activities
(Figure 1).1 The most frequently used method to synthesize
Figure 1. Examples of biologically and therapeutically active molecules
containing pyrrole scaffold.
reported recently, which release 1 equiv of pyridine as a
byproduct.10,11−13
pyrrole units relies on the classical Hantzsch, Paal−Knorr
procedure. Although a variety of methods have been recently
developed for the synthesis of functionalized pyrrole deriva-
tives,2,3 direct access to polyfuctionalized pyrroles from readily
available feedstocks, especially in an atom and step economic
manner, still remains challenging and highly desirable.
Recently, homogeneous gold-catalyzed reactions of alkynes
with nucleophiles have been recognized as one of the most
powerful and useful tools in organic synthesis.4,5 In particular, the
discovery of the formation of α-carbonyl gold carbenoids
through oxygen transfer has led to the development of numerous
useful synthetic transformations.6 Compared with the generation
of α-Oxo gold carbenoids, gold-catalyzed nitrene transfer is still
far from being fully explored. Intramolecular gold-catalyzed
nitrene transfer reactions of alkynes with tethered azide moieties
have been achieved by the research groups of Toste (Scheme
1a),7 Zhang,8 and Gagosz.9 For the intermolecular nitrene
transfer, only a few examples on gold-catalyzed intermolecular
reactions of iminopyridium ylides with activated alkynes were
2H-Azirine, which can be readily prepared by Neber reaction
or elimination of dinitrogen from vinyl azide, has been widely
applied in N-heterocycles synthesis.14,15 Compared with azide,
2H-azirine is sufficiently stable, easy to handle, and thus could be
considered as a better reagent for nitrene transfer. It possesses
high ring strain, and the nitrogen atom in imino moiety is mildly
nucleophilic. So, treatment of 2H-azirine 2 with an activated
alkyne 1 may lead to formation of zwitterion intermediate A
(Scheme 1b). More importantly, the potential side reaction
azide−alkyne Huisgen cycloaddition can be avoided. In this
context, we envisioned that treatment of alkyne 1 with 2H-azirine
2 in the presence of a proper gold catalyst would afford
multisubstituted pyrrole 3 in an atom economic manner, as all
atoms are fused into 3 during the nitrene transfer process (A → B
→ 3). Recently, Gagosz et al. reported a gold-catalyzed pyridine
Received: October 30, 2014
© XXXX American Chemical Society
A
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Letter
synthesis from 2-propargyl-2H-azirine.16 Herein we describe a
facile approach to another important one-ring heterocycle,
pyrrole, by gold-catalyzed intermolecular [3 + 2] cycloaddition of
2H-azirine and ynamide under mild conditions. It is worthwhile
to mention that our hypothesis is mechanistically distinct from
previously reported procedures for multiply substituted pyrrole
synthesis from 2H-azirines and activated ketones (vide
infra).15a−c
a
Scheme 4. Reaction Scope of Ynamides with 2H-Azirine 2a
After initial investigation and evaluation of reaction parame-
ters,17 we found that the reaction of ynamide18,19 1a and 2H-
azirine 2a, conducted with 3 mol % of gold complex E in CH2Cl2
at rt, afforded the desired pyrrole 3a in nearly quantitative yield
(Scheme 2). Consequently the effects of the amide moiety were
Scheme 2. Gold Complex E Catalyzed Formal [3 + 2]
Cycloaddition of 2H-Azirine 2a and Ynamide 1a
Scheme 3. Scope of the Ynamides Bearing Different Amides
a
Groups
a
b
Yields reported are for pure, isolated compounds. 5 mol % E was
employed.
a methyl or chloro group at the meta position of the phenyl ring
reacted well with 2a, giving the corresponding pyrroles (3p and
3q) in high yields. Of note, ynamides possessing ortho
substituents were well tolerated in the reactions; pyrroles 3r
and 3s were isolated in 87% and 89% yields, respectively. In
addition, the reaction also worked well for thiophenyl substituted
ynamide, furnishing pyrrole 3t in high yield. Interestingly,
replacement of the aryl ynamide with styryl or cyclopropyl
ynamide had no significant influence on the reaction (3u and 3v).
When the ynamide bearing a trimethylsilyl group at the terminal
position of the triple bond was employed for this reaction, an in
situ desilylation took place, and pyrrole 3w was obtained in 62%
yield.
With the ynamide 1b as the model electrophile, we studied the
scope of 2H-azirines for this reaction and the results are listed in
Scheme 5. The reaction was first examined by variation of R3 on
the CN double bond moiety. Introducing an electron-
donating (3x, 3y, and 3aa) or electron-withdrawing (3z) group
on the phenyl ring had no significant influence, and the
corresponding pyrroles were obtained in excellent yields (up to
99%). Furyl, naphthyl, and alkenyl groups were tolerated as well,
affording pyrroles 3ab, 3ac, and 3ad in good to excellent yields.
Replacement of the aryl group with an alkyl substituent also led
to the effective formation of the corresponding pyrrole by
carrying out the reaction at elevated temperature (3ae). In
contrast, the reaction was sensitive to the electronic nature of
substituent R4. With electron-withdrawing groups (e.g., ester,
chloro) at the para position of the phenyl ring, high efficiencies of
the reactions were maintained (3ag and 3ah). When a methyl
group was placed at the para position of the phenyl ring, the
reaction was significantly slow (3af), presumably due to the
a
Yields reported are for pure, isolated compounds.
evaluated (Scheme 3). In general, the reactions of ynamides
bearing a variety of protecting groups proceeded well, giving the
desired products (3b−3g) in moderate to high yields. The
ynamide possessing an Ns (p-NO2C6H4SO2, 1h) is not
compatible with current reaction conditions. The structure of
3b was confirmed by single-crystal X-ray analysis. Notably,
according to our mechanistic hypothesis (Scheme 1b), the allylic
group in ynamide 1i should be able to intercept the carbenoid
intermediate. In contrast, pyrrole 3i was solely obtained, with no
observation of the expected cyclopropane,20 which might suggest
a different mechanistic perspective as depicted in Scheme 1b
(vide infra).
The current protocol for pyrrole synthesis is efficient, as a wide
array of ynamides undergo formal [2 + 3] cycloaddition with 2H-
azirine 2a at ambient temperature using E as the catalyst in DCM
(Scheme 4). Both electron-donating (products 3j−m) and
-withdrawing substituents (products 3n and 3o) at the para
position of the aryl ring were tolerated. The ynamides containing
B
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Letter
a
Scheme 5. Reaction Scope of 2H-Azirine with Ynamides 1b
Scheme 6. Mechanistic Rationale for the Pyrrole Synthesis
This electronic stabilization accounts for the slow reaction rates
of azirines 2ae, 2af, and 2ai. Elimination of the cationic gold(I)
catalyst and liberation of 3H-pyrrole 4 complete the catalytic
cycle.
Because vinyl azide has been widely used for the synthesis of
multiply functionalized pyrrole24 and it is a precursor of 2H-
azirine, we also studied the reaction of vinyl azide 5a with
ynamide 1b in the presence of catalyst E (3 mol %) at rt. This
reaction afforded pyrrole 3b in only moderate yield (eq 2).
Although less efficient, to the best of our knowledge, this
represents the first example of gold-catalyzed intermolecular
nitrene transfer from an organic azide to an alkyne.
a
b
Yields reported are for pure, isolated compounds. The concentration
c
d
is 0.3 M. The reaction was run in toluene at 110 °C. 5 mol % E was
employed.
enhanced stability of intermediate A (Scheme 1b) and thus
resulted in a slower ring expansion of the 2H-azirine core.
Similarly, when R4 is an alkyl group (R4 = Me, 3ai), higher
reaction temperature was required to reach full conversion in a
reasonable reaction time. Unambiguous evidence of the
regioselectivity was established by single-crystal X-ray analysis
of pyrroles 3ae and 3aj,21 which ruled out the mechanistic
pathway related to previous reports (vide supra).15a−c,22
In summary, we have reported a gold-catalyzed formal [3 + 2]
cycloaddition of 2H-azirines with ynamides, which provides a
straightforward approach to fully substituted pyrroles in good to
excellent yields. The current transformation features mild
reaction conditions, low catalyst loadings, a broad substrate
scope, and atom economy.25 Additional studies to elucidate the
mechanism and to distinguish the reactivities between vinyl azide
and 2H-azirine are underway in our laboratory.
To gain more information on the mechanism, ynamide 1x was
prepared and subjected to the current transformation (eq 1).
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and data; NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
Pyrrole 3ak was obtained in 39% isolated yield. Combining the
results we obtained from the reactions of ynamides 1i and 1v (cf.
products 3i and 3v), a plausible mechanistic rationale22 for
current pyrrole synthesis is depicted in Scheme 6. The reaction is
initiated by gold(I) activation of an ynamide, generating highly
electrophilic keteniminium intermediate I, which reacts with 2H-
azirine 2 to afford zwitterion intermediate II. At this stage, an
intramolecular nucleophilic addition of an enamine to the azirine
moiety would lead to the formation of a pyrrole core (IV)
(pathway a). Alternatively, ring opening of the three-member
ring may lead to the formation of a gold-carbenoid III which is in
equilibrium with cationic intermediate III′. Similarly, direct ring
opening of II also gives III′. Cyclization of III′ would afford IV
(pathway b). No observation of cyclopropane (cf. the reaction of
ynamide 1i)20,23 may be due to a rapid ring closure from III′ to
IV. When R4 is more electron-donating, intermediate II is more
stable, thus leading to a slower formation of intermediate IV.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: huangxl@fjirsm.ac.cn.
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21402197) and Fujian Institute of Research on the
Structure of Matter, Chinese Academy of Sciences for financial
support. We also thank Prof. Jian Zhang and Prof. Fei Wang from
Fujian Institute of Research on the Structure of Matter, Chinese
Academy of Sciences for crystallographic analysis. Prof. Nuno
C
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Letter
(13) Echavarren and co-workers reported a gold-catalyzed tetrazoles
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D
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