Domino Cu-catalyzed C-N coupling/hydroamidation: A highly efficient synthesis of nitrogen heterocycles

Article abstract of DOI:10.1002/anie.200602917

(Chemical Equation Presented) Working in tandem: Highly functionalized pyrroles and pyrazoles can be synthesized from a domino Cu-catalyzed C-N coupling/hydroamidation sequence. The scope and the generality of the method is noteworthy as a wide variety of substituents, either in the alkene or alkyne counterparts, are well tolerated.

Full text of DOI:10.1002/anie.200602917

Angewandte
Chemie
Heterogeneous Catalysis
particularly pyrroles and pyrazoles. Herein, we describe our
study of this approach, which combines an initial Cu-
catalyzed amidation of a haloenyne followed by an intra-
molecular hydroamidation of the latent alkyne in situ[12,13]
(Scheme 1). We also demonstrate that cyclization of the
DOI: 10.1002/anie.200602917
À
Domino Cu-Catalyzed C N Coupling/
Hydroamidation: A Highly Efficient Synthesis of
Nitrogen Heterocycles**
À
initially formed C N coupling product I, which can be readily
isolated, requires the presence of both a base and copper
catalyst.
RubØn Martín, Marta Rodríguez Rivero, and
Stephen L. Buchwald*
Heterocyclic compounds are of great chemical and biological
significance.[1] In particular, nitrogen-containing heterocycles
are structural constituents of many bioactive natural products,
medicinally important compounds, and organic materials.[2]
Recent strategies for the synthesis of heterocycles based on
metal-catalyzed reactions nicely complement the classical
synthetic approaches. Among their advantages is that harsh
conditions are frequently avoided and readily available
starting materials can be utilized.[3] Despite the advances
realized, more flexible and general routes to a variety of
heterocycles are needed. In particular, techniques that can
readily give access to heterocyclic cores with a diverse and
easily manipulated set of substituents are still of critical
importance.
Scheme 1. Synthesis of heterocycles through a domino copper-cata-
lyzed amidation/hydroamidation sequence. TFA=trifluoroacetic acid.
We envisioned that an array of heterocycles could be
synthesized through 5-exo-dig and 5-endo-dig pathways
involving intermediate I. This objective could be achieved
both by varying the nature of the nucleophile as well as the
substitution pattern on the haloenyne precursor. We focused
our attention on the synthesis of pyrroles[14] and pyrazoles[15]
as applications of the Cu-catalyzed vinylation methodol-
ogy.[16] Aseries of ligands were examined for the reaction of
the model substrate (Z)-4-iododec-4-en-6-yne (1) with tert-
butyl carbamate and bis(tert-butyloxycarbonyl)hydrazine
(bis(Boc)hydrazine; Figure 1). The reaction was carried out
in THF with CuI as the precatalyst and Cs2CO3 as the base at
808C for 12 h. Among those examined, 1,2-diamine ligands
show the highest activity, with 20 mol% N,N’-dimethylethyl-
enediamine (ligand g) giving exclusively the desired cascade
products in excellent overall yield. We note that the successful
preparation of 2 represents, to the best of our knowledge, the
first metal-catalyzed coupling of vinyl halides with a hydra-
zide.[17]
The transformation outlined above merits some further
discussion: 1) two different heterocycles could be obtained
from a common starting material; 2) no 6-endo-dig cyclization
was observed using bis(Boc)hydrazine as the nucleophile;
3) although the trans arrangement of the hydrogen and iodide
species in 1 suggests a potential for dehydrohalogenation,
only traces of the undesired bisalkyne were detected.[18]
Encouraged by our initial results, we sought to examine
the scope and the generality of the method. The domino Cu-
catalyzed amidation/hydroamidation of haloenynes[19] with
tert-butyl carbamate shows excellent chemoselectivity, and its
wide scope is evident from the results compiled in Table 1. As
summarized below, different combinations of substituents on
the alkyne and alkene can be used to allow the synthesis of di-
and trisubstituted pyrroles, including those bearing alkene,
ester, silyl ether, and alkyl halide substituents.
À
In the last decade, metal-catalyzed C N bond-forming
reactions[4] have become important methods for the prepara-
tion of nitrogen-containing compounds in both academic and
pharmaceutical laboratories.[5] In recent years, Cu-promoted
processes have evolved into viable alternatives to the more
widely practiced Pd-catalyzed reactions.[6,7] The Cu-based
methods are distinguished by their broad scope, high effi-
ciency, and mild reaction conditions, thus making them
attractive vehicles for further applications.[8]
The development of a method for generating multiple
classes of nitrogen-containing heterocycles from common
building blocks is a highly desirable goal. Previously, Acker-
mann showed that substrates for the Cacchi indole synthesis[9]
can be prepared by Pd- or Cu-catalyzed amination of o-
alkynyl aryl halides.[10] Under the conditions of these coupling
processes, cyclization to the N-benzyl or N-aryl indoles takes
place in an efficient manner.[11] We wondered whether it
would be possible to effect a related transformation as a
means to access other important nitrogen heterocycles,
[*] Dr. R. Martín, Dr. M. Rodríguez Rivero, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18–490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax: (+1)617-253-3297
E-mail: sbuchwal@mit.edu
[**] Generous financial support from the National Institutes of Health
(GM058160) is gratefully acknowledged. R.M. and M.R.R. thank the
Spanish MEC for postdoctoral fellowships. The Bruker Advance
400 MHz NMR spectrometer used in this work was purchased with
funding from the National Institutes of Health (GM 1S10RR13886-
01).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Synthesis of pyrroles through Cu-catalyzed domino amidation/
hydroamidation of haloenynes.[a]
Entry
Product
X
Yield [%][b]
1[c]
2
Br
I
70
74
3
I
84
4
I
83
82
81
5[c]
6[c]
Br
Br
7[d]
I
I
68
52
8
Figure 1. Ligand screening in the domino Cu-catalyzed amidation/
hydroamidation of haloenyne 1.
9
I
78
Although the reaction of a substrate bearing a terminal
alkyne led to decomposition, the synthetic equivalent of this
transformation can be accomplished by the use of a trime-
thylsilyl (TMS) group, which masks the terminal acetylene
and is deprotected in situ (Table 1, entry 7).[20] Thus, not only
2,5- but also 2,3-disubstitution on the pyrrole core can be
achieved, albeit in lower yield. Although the Cu-catalyzed
coupling of primary amides with vinyl halides bearing an a-
electron-withdrawing group has little precedent,[21] we were
pleased to find that the cascade reaction took place, with
cleavage of the carbamate group, thus providing the depro-
tected pyrroles in excellent overall yield (Table 1, entries 5
and 6). Although this study focused on the use of iodoenynes,
we also demonstrated that bromoenynes could be used if the
reaction was carried out in toluene at 1108C (Table 1,
entries 1, 5, 6, 13, and 14). Polyheterocylic compounds could
also be prepared in high yields by introducing a heterocyclic
moiety either in the alkene or alkyne counterpart (Table 1,
entries 13–15).
To extend the scope of this methodology to the synthesis
of pyrazoles, the reaction of several iodoenynes was evaluated
under the optimized conditions using bis(Boc)hydrazine as
the nucleophilic component (Table 2). In this case, simple
treatment of the intermediate II with trifluoroacetic acid
(Scheme 1), with no need for isolation, afforded the free
pyrazoles (for simplicity, represented as one tautomer) in
good-to-excellent overall yields. Although the hydroamida-
tion reaction could theoretically proceed through two possi-
ble pathways, 5-exo-dig or 6-endo-dig, exclusive formation of
the five-membered ring was observed in all cases. It is worth
noting that mono-, di- and trisubstituted pyrazoles can be
10
11
I
I
85
91
12
I
95
83
74
71
13[c]
14[c]
15
Br
Br
I
[a] Reaction conditions: haloenyne (1.0 equiv), NH2Boc (1.2 equiv), CuI
(5 mol%), N,N’-dimethylethylenediamine (20 mol%), Cs2CO3
(2.0 equiv), THF (0.5m). [b] Yields of the isolated products are the
average of two runs and are estimated to be over 95% pure by 1H NMR
spectroscopic and GC analysis. [c] Using K2CO3 (2.0 equiv) and toluene
(0.5m) at 1108C. [d] R3 =TMS. TBS=tert-butyldimethylsilyl, TIPS=tri-
isopropylsilyl.
accessed through this route. As in the case of pyrroles, alkenes
and alkynes with a wide variety of substituents are viable
reaction components. Moreover, despite acidic treatment of
II, many functional groups, such as alkyl halides, esters, benzyl
ethers, and even silyl ethers, are well tolerated in the reaction.
In this manner, this protocol provides rapid and modular
access to a variety of nitrogen-containing heterocycles with
different substitution patterns.
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Table 2: Synthesis of pyrazoles through Cu-catalyzed domino amidation-
hydroamidation of iodoenynes.[a]
Entry
1
Product
Yield [%][b]
92
Scheme 2. Possible mechanisms for the domino reaction.
2
3
4
5
6
7
8
93
83
81
72
78
89
86
To probe the reaction mechanism of our method, the
reaction of vinyl iodide 1 with tert-butyl carbamate and
bis(Boc)hydrazine was stopped after 4 h at 808C (Scheme 3).
Scheme 3. Mechanistic insight by trapping the intermediates in the
Cu-catalyzed domino process. a) CuI (5 mol%), N,N’-dimethyl-
ethylenediamine (20 mol%), Cs2CO3 (1.5 equiv), THF (0.5m), 808C,
4 h.
9[c]
66
72
As shown below, the only compounds detected by NMR
spectroscopy of the crude reaction mixture were the corre-
À
sponding C N coupling intermediates 4 and 5 along with
significant amounts of the final cascade product.[22] Remark-
ably, 4 and 5 could be obtained in analytically pure form by
carrying out the reactions at room temperature and 408C in
59 and 48% yields of the isolated products, respectively. Full
conversion into the desired cascade products was observed by
resubjecting 4 and 5 to the reaction conditions for an
additional 4 h. Interestingly, the treatment of 4 and 5 with
either CuI (5 mol%) or Cs2CO3 (1.5 equiv) under otherwise
identical conditions resulted in reisolated starting materials;
not even traces of the final cascade products were observed.
Only the combination of catalyst with base was effective, thus
suggesting that the intramolecular hydroamidation is both a
copper-catalyzed[23] and base-assisted process. These results
10
[a] Reaction conditions: iodoenyne (1.0 equiv), NHBoc–NHBoc
(1.2 equiv), CuI (5 mol%), N,N’-dimethylethylenediamine (20 mol%),
Cs2CO3 (1.5 equiv), THF (0.5m). [b] Yields of the isolated products are
the average of two runs and are estimated to be over 95% pure by
1H NMR spectroscopic and GC analysis. [c] Ligand: trans-1,2-cyclohex-
anediamine (20 mol%).
In principle, two different mechanisms can be envisioned
À
for these domino processes: 1) initial C N coupling followed
by intramolecular hydroamidation of the alkyne portion of I
or 2) intermolecular hydroamidation and subsequent intra-
molecular amidation (Scheme 2). Experiments performed by
Ackermann in his synthesis of indoles indicated that a
mechanism consisting of an intermolecular hydroamination
À
strongly support a mechanism involving an initial C N
coupling followed by intramolecular hydroamidation of the
latent alkyne (top pathway, Scheme 2).[24]
In conclusion, a general, highly flexible, and efficient Cu-
À
À
and a subsequent intramolecular metal-catalyzed C N bond-
forming process was predominantly operative, although no
catalyzed domino C N coupling/hydroamidation reaction has
been developed. The transformation constitutes a straightfor-
ward alternative to the existing methodology for the prepa-
isolation of the proposed intermediate was reported.[10]
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Communications
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ration of pyrroles and pyrazoles. Amechanism in which the
metal acts with dual roles, thus facilitating both amidation and
hydroamidation reactions is proposed. Further studies on
synthetic applications of these important and related trans-
formations are currently in progress.
Received: July 21, 2006
Published online: September 29, 2006
Keywords: amidation · copper · domino reactions ·
.
heterocycles · hydroamidation
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À
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À
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À
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