Gold(I)-catalyzed formation of 3-pyrazolines through cycloaddition of diaziridine to alkynes

Article abstract of DOI:10.1021/ol202452b

This work reports the high-yield formation of pyrazoline derivatives mediated by gold(I) catalysts. The reaction utilizes a diaziridine, which has seen only limited usage in organic methodology. Mechanistic studies suggest a gold-mediated opening of the d

Full text of DOI:10.1021/ol202452b

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5842–5845
Gold(I)-Catalyzed Formation of
3-Pyrazolines through Cycloaddition of
Diaziridine to Alkynes
David A. Capretto, Chad Brouwer, Catherine B. Poor, and Chuan He*
Department of Chemistry and Institute for Biophysical Dynamics,
The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, United States
chuanhe@uchicago.edu
Received September 9, 2011
ABSTRACT
This work reports the high-yield formation of pyrazoline derivatives mediated by gold(I) catalysts. The reaction utilizes a diaziridine, which has
seen only limited usage in organic methodology. Mechanistic studies suggest a gold-mediated opening of the diazridine ring, alkyne insertion, and
finally an intramolecular hydroamination to furnish the product.
Pyrazolines have been heavily investigated due to their
occurrence in a number of biologically active molecules.
Various pyrazolines have exhibited antibacterial, anti-
amoebic, antitumor, anti-inflammatory, antidepressant,
and MAO-inhibitory activities.1 It is therefore important
to be able to access them through methods that are rapid,
cost-effective, and atom-economical. Pyrazolines are typi-
cally synthesized by the condensation/addition of hydrazines
onto R,β-unsaturated carbonyl compounds.2,3 More re-
cently, azomethine iminies have been used to form pyrazo-
line-containing scaffolds via cycloaddition onto alkynes.4
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^
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10.1021/ol202452b
Published on Web 10/11/2011
2011 American Chemical Society

Table 1. Catalyst Screen for Pyrazoline Formationa
Scheme 1. Cycloaddition of Diaziridine to Alkynes To Con-
struct 3-Pyrazolines
entry
catalyst
none
temp
equiv 1a
yield (%)b
An intramolecular iodocyclization was also recently re-
ported in which the use of propargylic hydrazides yielded
1-iodo-3-pyrazolines.5 Even with recent developments,
there are limited waysto synthesize the pyrazoline scaffold.
We propose a different strategy of accessing pyrazolines
through the use of diaziridines, the dinitrogen analogues of
the more familiar three-membered aziridines. We envi-
sioned either a tandem event wherein diaziridine would
open and then react with an alkyne in a formal [3 þ 2]
cycloaddition or a concerted process to yield the same
product (see Scheme 1). Metal catalysts, especially π-acids
such as gold ions, may mediate such reactions. In addition,
gold complexes have recently been established as superior
catalysts for the addition of nitrogen and oxygen nucleo-
philes to unsaturated hydrocarbons.6
1
2
100 °C
rt
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
1.0
1.0
2.0
5.0
2.0
no reactionc
no reaction
degradation
no reaction
no reactiond
41 (4a)
TfOH
3
TfOH
50 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
50 °C
rt
4
CuCl
5
CuI
6
AgOTf
7
AuCl3
30 (4a)
8
Zn(OTf)2
23 (4a)
9
Cu(OTf)2
20 (4a)
10
11
12
13
14
15
16
Ph3AuCl/AgOTf
Ph3AuCl/AgOTf
Ph3AuCl/AgOTf
Ph3AuCl/AgOTf
Ph3AuCl/AgOTf
Ph3AuNTf2
Ph3AuNTf2
89 (3a)
85 (3a)
35 (3a)
70 °C
70 °C
70 °C
70 °C
58 (3a)
85 (3a)
85 (3a)
85 (3a)
Reactivity reports of diaziridines are limited and
most revolve around the use of activated substrates such
as ketenes, cyclopropenones, isocyanates, maleimides, or
highly tailored diaziridines.7 There have also been a few
reports of Lewis-acid-catalyzed cycloaddition reactions
with similarly activated substrates.8 Shi and co-workers
haveutilizeddiaziridinones, analoguesofdiaziridines, with
palladium and copper catalysts to perform R-aminations
and diaminations of dienes, esters, and ketones.9 Com-
pared to other systems, in our reaction system, the diazir-
idine is minimally modified and the alkynes are not activated
by electronics, strain, etc.4a,b In this paper, we report the
first gold(I)-catalyzed cycloaddition of this diaziridine
onto alkynes, giving high yields of 3-pyrazolines. In our
a Reactions performed with 0.25 mmol 2. b Yield of isolated product.
c Reaction was run for five days. d Reaction run with 0.5 equiv of
Cy2NMe.
initial studies, we sought to utilize a diaziridine that is
readily accessible and, under the right conditions, exhibits
high reactivity. We employed diaziridine 2, in which the
two nitrogens are modified with benzyl and carbamate
groups. 2 is readily synthesized in two high-yielding steps
beginning from cheap and commercially available cyclo-
hexanone and benzylamine and is column and air-stable.
Initial optimizations were carried out between 2 and
phenylacetylene 1a (Table 1). Entries 1ꢀ3 in Table 1 ruled
out both thermal and simple acid-catalyzed reactions.
Entries 4 and 5 in Table 1 attempted to mimic conditions
used to cyclize azomethine imine intermediates, but with
no success.4a,b
Surprisingly, the use of copper, zinc, silver, and gold(III)
catalysts (Table 1, entries 6ꢀ9) led to insertion of the
alkyne into the ring-opened diaziridine (product 4a). We
reason that, due to the presence of the carbamate group on
one of the nitrogen atoms of the diaziridine 2, the CꢀN
bond is polarized which may facilitate thermal ring open-
ing followed by metal-catalyzed insertion of an acetylide
species. Further optimization showed that Ph3PAuNTf2
provided a cleaner reaction and slightly higher yields in
comparison to the Ph3PAuCl/AgOTf system.10
(7) (a) Syroeshkina, Y. S.; Kuznetsov, V. V.; Kachala, V. V.; Makhova,
N. N. J. Heterocycl. Chem. 2009, 46, 1195–1202. (b) Syroeshikina, Y. S.;
Kachala, V. V.; Ovchinnikov, I. V.; Kuznetsov, V. V.; Nelyubina, Y. V.;
Lyssenko, K. A.; Makhova, N. N. Mendeleev Commun. 2009, 19, 276–278.
(c) Syroeshkina, Y. S.; Kuznetsov, V. V.; Struchkova, M. I.; Epishina,
M. A.; Makhova, N. N. Mendeleev Commun. 2008, 18, 207–208.
(d) Shevtsov, A. V.; Petukhova, V. Y.; Strelenko, Y. A.; Lyssenko,
K. A.; Makhova, N. N.; Tartakovsky, V. A. Russ. Chem. Bull. 2005,
54, 1021–1031. (e) Shevtsov, A. V.; Petukhova, V. Y.; Strelenko,
Y. A.; Lyssenko, K. A.; Fedyanin, I. V.; Makhova, N. N. Mendeleev
Commun. 2003, 13, 221–223. (f) Shevtsov, A. V.; Kuznetsov, V. V.;
Molotov, S. I.; Lyssenko, K. A.; Makhova, N. N. Russ. Chem. Bull.
2006, 55, 554–558. (g) Molchanov, A. P.; Sipkin, D. I.; Koptelov,
Y. B.; Kopf, J.; Kostikov, R. R. Russ. J. Org. Chem. 2004, 40, 67–78.
(h) Koptelov, Y. B.; Saik, S. P.; Molchanov, A. P. Chem. Heterocycl.
Compd. 2008, 44, 860–867. (i) Ortega, H.; Ahmed, S.; Alper, H.
Synthesis 2007, 23, 3683–3691.
With the reaction conditions optimized, we studied the
scope of the reaction. As shown in Table 2, both aryl and
aliphatic alkynes react, but it is clear that electron-poor
(8) (a) Ohshiro, Y.; Komatsu, M.; Yamamoto, Y.; Takaki, K.;
Agawa, T. Chem. Lett. 1974, 3, 383–384. (b) Koptelov, Y. B. Russ. J.
Org. Chem. 2006, 42, 1510–1515. (c) Syroeshkina, Y. S.; Kuznetsov,
V. V.; Lyssenko, K. A.; Makhova, N. N. Mendeleev Commun. 2008, 18,
42–44.
(9) (a) Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 762–
763. (b) Zhao, B.; Du, H.; Shi, Y. J. Am. Chem. Soc. 2008, 130, 7220–
7221. (c) Zhao, B.; Du, H.; Shi, Y. J. Am. Chem. Soc. 2009, 74, 4411–
4413.
(10) For a description of metal triflimidates as catalysts in organic
~
synthesis, see:Antoniotti, S.; Dalla, V.; Dunach, E. Angew. Chem., Int.
Ed. 2010, 49, 7860–7888.
Org. Lett., Vol. 13, No. 21, 2011
5843

Table 2. Substrate Scope for Pyrazoline Formation
Figure 1. ORTEP representations of 4a and 3g.
final cycloaddition product 3a in the gold-catalyzed pro-
cess, but further proof was warranted.
The structure and connectivity of the product was
demonstrated conclusively by an X-ray structure of 3g
(Figure 1), the thiophene-functionalized pyrazoline. We
also obtained a crystal structure of insertion product 4a,
which can be isolated when other catalysts are used (vide
supra).11 This led us to hypothesize that the alkyne inser-
tion product was possibly an intermediate in the catalytic
reaction. Treatment of 4a with 10 mol % of Ph3PAuNTf2
at room temperature afforded 3a in near quantitative yield
(Scheme 2). Postulating that a gold-acetylide species may
be involved in the reaction, we synthesized the (pheny-
lethynyl)(triphenylphosphine)gold species. We expected
this intermediate to react stoichiometrically with 2 and
lead to product. Much to our surprise, we only recovered
the original gold-acetylide species, even with the addition
of catalytic Ph3PAuNTf2 (Scheme 3).12 This ruled out the
role of a discrete metal-acetylide species in the reaction.
a Yields are from isolated products. b Reaction run at room
temperature.
Scheme 3. AlkynylꢀGold Intermediate Does Not Participate in
the Cycloaddition Reaction
Scheme 2. Gold-Catalyzed Cyclization of Compound 4a
Surveying the reactivity pattern in Table 1, we hypothe-
sized that the addition of a metal salt may facilitate the
opening of the diaziridine ring. The existence of product 4a
as well as the ability of gold to cyclize product 4a to yield
product 3a led us to the proposed mechanism shown in
Scheme 4. In this case, gold facilitates the low-temperature
opening of the diaziridine intermediate, followed by inser-
tionofthe alkyne intothe cationic carbon center. While the
second species is drawn with the gold center in a trigonal
substrates give higher yields (Table 2, entries 1ꢀ6). As we
hypothesized, gold(I) performed the cycloaddition reac-
tion leading to the target product 3a. Thiophene does not
poison the catalyst, and good yields were seen with 3-ethy-
nylthiophene (entry 7). Entry 12 shows that so far our
reaction is limited to terminal alkynes. One possible argu-
ment is that steric hindrance might come into play for this
reactivity pattern; however, even the use of 2-butyne as
substrategaveno yield of pyrazoline. Thisrequirementof a
terminal alkyne for the reaction suggests a mechanism with
a terminal alkyne insertion step followed by cyclization.
We speculated that product 4a is an intermediate to the
(11) See Supporting Information for details on both crystal
structures.
(12) See Supporting Information for further details on the conditions
tested.
5844
Org. Lett., Vol. 13, No. 21, 2011

Scheme 4. Mechanistic Proposal for the Cycloaddition Reaction
geometry, it may also be a linear complex along the Pꢀ
Auꢀalkyne axis with minor interaction with the diaziri-
dine motif. The linear geometry is by far the most popular
gold coordination motif; however, the trigonal geometry
has been shown to be a valid structure in a number of
coordination environments.13 Finally, the gold(I) center
performs an intramolecular hydroamination reaction be-
tween the alkyne and the hydrazine fragment, leading
to the pyrazoline product. It explains why other metal
salts do not yield the pyrazoline framework but instead
intermediate 4.
and that gold(I) is a superior catalyst to mediate the
reaction. Diaziridines can be readily prepared and are
reactive under the appropriate conditions. With more
investigation, we believe that this organic motif could
be used for various intra- and intermolecular additions
to unsaturated substrates, leading to a variety of valuable
nitrogen-containing heterocycles.
Acknowledgment. This work was supported by the
National Science Foundation (CHE-0922998). We thank
Ian Steele (University of Chicago) for X-ray crystallogra-
phy, Dr. C.-J. Qin (University of Chicago) for mass spectra,
and the Notre Dame Mass Spectrometry and Proteomics
Facility for high-resolution mass measurements.
We have shown in this study that diaziridines are valu-
able synthons for the formation of nitrogen heterocycles,
ꢀ
(13) For examples of trigonal gold complexes, see: (a) Perez-Galan,
P; Delpont, N.; Herrero-Gomez, E.; Maseras, F.; Echavarren, A. M.
ꢀ
ꢀ
Supporting Information Available. Experiment details
and compound characterization data. This material is
available free of charge via the Internet at http://pubs.acs.
org.
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(e) Schmidbaur, H.; Schier, A. Organometallics 2010, 29, 2–23.
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