A gold(i)-catalyzed intramolecular oxidation-cyclopropanation sequence of 1,6-enynes: A convenient access to [n.1.0]bicycloalkanes

Article abstract of DOI:10.1039/c1cc14788a

A gold(i)-catalyzed tandem oxidation/cyclopropanation reaction of 1,6-enynes with an external oxidant has been developed. This quite simple and rapid strategy will provide a safe, mild and versatile avenue to numerous carbo- and hetero [n.1.0]bicyclic frameworks.

Full text of DOI:10.1039/c1cc14788a

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COMMUNICATION
A gold(I)-catalyzed intramolecular oxidation–cyclopropanation sequence
of 1,6-enynes: a convenient access to [n.1.0]bicycloalkanesw
Deyun Qiana and Junliang Zhang*ab
Received 3rd August 2011, Accepted 25th August 2011
DOI: 10.1039/c1cc14788a
A gold(I)-catalyzed tandem oxidation/cyclopropanation reaction of
1,6-enynes with an external oxidant has been developed. This quite
simple and rapid strategy will provide a safe, mild and versatile
avenue to numerous carbo- and hetero [n.1.0]bicyclic frameworks.
Cyclopropanes are an important class of compounds, which
play a fundamental role as versatile units in modern synthetic
chemistry.1 Among many methods2 to synthesise these
adducts, the metal-catalyzed cyclopropanation reaction of
olefins with the metal carbenoid via decomposition of diazo
compounds is believed to be an efficient one (eqn (1)).2,3
Scheme 1
Nevertheless, the potentially explosive, hazardous and toxic
characteristics of diazo compounds (or their precursors) may
of pregnant quaternary centers (Scheme 1). In addition, this
limit their applications.4a In past decades, much attention has
quite simple strategy will provide a safe, mild and versatile
been paid to diazo-compounds free accesses.4–8 For example,
avenue to numerous carbo- and heterocyclic frameworks
possessing an intricate architecture.
Sanford et al.5a and Tse et al.5b independently reported an
pioneering example of palladium-catalyzed oxidative cyclization
Our preliminary studies focused on 1,6-enyne 1a. 1a was
subjected to a solution of Ph3PAuCl/AgNTf2 (5 mol%) and
of 1,6-enynes (eqn (2)). However, the gold-catalyzed oxidative
oxidant (2-4 equiv) in dichloroethane (DCE) at 25 oC, the
cyclization of 1,6-enynes with an external oxidant to relative
cyclopropane adducts remains largely unexplored.6 Gratifyingly,
reaction was then run for 12 h. After some attempts, the
the oxidation of alkynes to generate a-oxo gold carbenoids has
a,b-unsaturated ketone 2a rather than the expected product 3a
recently been developed,4a,b,7,8 which may offer a breakthrough
was obtained in 30% isolated yield by the use of pyridine
point. In this respect and by analogy with eqn (1), we surmise that
transiently formed gold carbenoid species A via gold-catalyzed
N-oxide as the external oxidant, along with some recovered
starting material 1a (Scheme 2). This might suggest that this
oxidation of alkynes may subsequently react with a pendant
transformation was consistent with the reactivity expected
olefin to provide an annulated cyclopropane ring system
(eqn (3)).7a,9 Herein, during the course of our ongoing interests
1,2-C–H insertion.8a,b,8d According to this analysis, a keto
from the formation of a gold-carbenoid, by subsequent
of synthesis of [n.1.0]bicycloalkanes10a,b and the gold-carbene10c
carbonyl was introduced to the enyne substrate 1a to give 1b,
chemistry, we report such a tandem oxidation/cyclopropanation
which can be easily prepared from the 3-phenylpropiolic acid,
reaction to provide a strategically alternative route to elaborate
tosyl isocyanate and allyl bromide. Commonly used oxidants such
[n.1.0]bicycloalkanes,11 which are widely found in natural
as sulfur oxides (e.g., Ph2SO), amine oxides, and imine oxides were
products12a and pharmaceutics.12b,c The reaction involves the
inactive for the reaction when using PPh3AuCl/AgNTf2 as
selective formation of two C–C bonds to afford annulated
cyclopropyl ketone derivatives, allowing for facile construction
the catalyst. To our delight, when the pyridine N-oxide was used
as the oxidant, the desired 3-azabicyclo[3.1.0]hexan-2-one 3b
was indeed formed albeit in only 13% NMR yield along with
a Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry, East China Normal University,
3663 N, Zhongshan Road, Shanghai 200062, P. R. China.
E-mail: jlzhang@chem.ecnu.edu.cn; Fax: +86 21-6223-5039
b State key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
P. R. China
w Electronic supplementary information (ESI) available: Representative
experimental procedure and characterization of reaction products.
CCDC 838005. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1cc14788a
Scheme 2
c
11152 Chem. Commun., 2011, 47, 11152–11154
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low conversion (see ESIw, Table S1). The addition of 1.2
equivalents of acid MsOH afforded a slightly better yield
(Table S1w, entry 2).13 Then, we tuned the steric and electronic
properties of gold catalysts and N-oxides. Gratifyingly, the
combination of 5 mol% of IPrAuCl/AgNTf2 bearing a strong
s-donating NHC ligand and 2-bromopyridine N-oxide in DCE
at 60 1C resulted in a sharp increase in yield (Table S1w, entry
5). It was noteworthy that a side product 4 via the hydrolysis
of 1b was formed when 2-bromopyridine N-oxide was used as
the oxidant (Table S1w, entries 4–9). Notably, replacing
2-bromopyridine N-oxide with 4-acetylpyridine N-oxide generated
bicyclo[3.1.0]hexan-2-one 3b in 63% and 64% NMR yields using
MsOH and HNTf2, respectively, without any competitive
formation of the side product after 21 h (Table S1w, entries
10–21). The use of PPh3AuCl/AgSbF6 gave the desired
product 3b with 52% yield (Table S1w, entry 11). This yield
could be further improved to 73% after 36 h and 81% yield by
higher catalyst loading respectively (Table S1w, entries 15 and 16).
Different solvents were further tested, but failed to improve
the process (Table S1w, entries 18–19). No reaction occurred in
the absence of gold catalysts (Table S1w, entry 20). Besides,
treatment of 1b with other transition-metal complexes such as
Rh2(OAc)4, PtCl2 and Pd(OAc)2,2 which have been reported
to catalyze cycloisomerization of enynes well, could not efficiently
promote this reaction (Table S1w, entries 22–24). Finally, the
relatively mild and cheap MsOH was selected as an optimal
additive due to more general functionality tolerance.13
their potential-yielding conversion to lactam 3f exemplifies a
synthetically challenging diastereoselective construction of
two vicinal quaternary carbon centers.14 The structure and
relative stereochemistry of bicyclic 3f were confirmed by X-ray
crystallography analysis. The 1,2-disubstituted alkene species 1g
(E/Z = 4.2:1) was also tolerated, producing bicyclo[3.1.0]hexan-
2-one 3g as a 4.2:1 mixture of diastereoisomers (Table 1, entry
6). By introducing a phenyl or two methyl groups at the
terminal position of alkene, however, only a complicated
mixture could be obtained, respectively.
After further examination, 8-methylquinoline N-oxide8b as
the external oxidant was found to be more effective in some
cases owing to mild reaction conditions: no acid, faster reaction
rate and room temperature. For example, the yield of 3h could
be further improved from 46% (Table 1, entry 7) to 53% by
using 8-methylquinoline N-oxide instead of 4-acetyl pyridine
N-oxide as oxidant (Table 2, entry 1). Importantly, aryl and alkyl
groups were well tolerated on the alkyne component. Further-
more, a variety of N-protecting groups such as benzyl, sulfonyl
and methyl were also compatible (Table 2, entries 1–4, and 10).
Analogously, substitution at the alkene moiety was also
Table 2 Scope of gold(I)-catalyzed oxidative-cyclopropanation of
1 in the presence of quinoline N-oxidesa
Under the optimal reaction conditions, a series of nitrogen
linked 1,6-enynes 1 were prepared and examined (Table 1).
Diverse bicyclo[3.1.0] ring systems (i.e., lactams) could be
constructed in 40–81% yields. Apparently, a general trend
can be deduced on the basis of the results of a series of enynes
with a para-substituted group on aromatic R1 (e.g., entries
1–4), the more electron-rich the aryl group, the more efficient
the reaction was found, which may be due to the more stability
of the cyclopropane under the identical conditions. The
introduction of a naphthalene group at the alkyne component
might inhibit the cyclopropanation step. We next turned to
study the scope of substitution at the alkene moiety.
Of particular relevance is substrate 1f (Table 1, entry 5), since
Entry
Enyne
Productb
Entry
Enyne
Productb
Table 1 Scope of gold(I)-catalyzed oxidation–cyclopropanation of
1 in the presence of pyridine N-oxidesa
Entry
X
R1/R2/R3 (1)
Time/h Isolated yieldb (%)
1c
2
3
4
5
6
7
8
NTs Ph/H/H (1b)
NTs 4-MeC6H4/H/H (1c)
NTs 4-MeOC6H4//H/H (1d)
36
48
48
3b (71)
3c (73)
3d (81)
3e (40)
3f (59)
3g (61)
3h (46)
nd
NTs 1-Naphthylene/H/H (1e) 40
NTs Ph/Me/H (1f)
NTs Ph/H/Me (1g)
NBn Ph/H/H (1h)
NTs Bu/H/H (1i)
72
70
1
12
a
b
Reactions were conducted at 0.2 mmol scale of 1. Isolated yield
a
b
Reactions were conducted at 0.2 mmol scale of 1. Isolated yield
c
(average of two runs). Reaction time (16 h). Reaction time (24 h).
e
d
c
(average of two runs). HNTf2 in place of MsOH.
7.5 mol% of catalyst was used, Au to AgNTf2 = 1 : 1.
c
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Chem. Commun., 2011, 47, 11152–11154 11153

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explored. The reaction of methallyl derivative 1n furnished
bicyclo[3.1.0]hexan-2-one 3n in 60% yield possessing two adjacent
quaternary centers at the ring junction (Table 2, entry 7).
Introduction of a benzyl group at the homoallylic position was
also successful, producing bicyclo[3.1.0] ring species 3o as a
1 : 1.5 mixture of two diastereoisomers (Table 2, entry 8). More-
over, [4.1.0]bicyclic 3q could be obtained in a moderate yield.
To further explore the scope of this transformation, the
ester 1r was subjected to the reaction conditions. However, the
desired 3-oxabicyclo [3.1.0]hexan-2-one 3r was not detected at
all under various reaction conditions, instead, an unexpected
product 5 was isolated in 51% yield employing L3(AuCl)2/
AgSbF6 (L3 = MeO-DTBM-BIPHEP) as catalyst (Scheme 3).
Several inferences can be drawn from these studies: (a) the
s-trans conformation of ester 1r is more stable due to the
well-known stereoelectronic effects.15 (b) In general, the cyclization
of enynes catalyzed by gold proceeds through the mono-
coordination to the alkyne rather than biscoordination to
both the alkyne and alkene at the same time, which other
transition-metal often does.5,6 (c) The transient a-oxo gold
carbenoid species was formed, which would undergo competitively
intermolecular O–H insertion with MsOH prior to the intra-
molecular cyclopropanation leading to product 5.8a,b
N-oxide or 8-methylquinoline N-oxide as external oxidant has
been developed. Regarding the mechanism, the expected a-oxo
gold carbenoid was believed to be formed, which can undergo an
intramolecular cyclopropanation with a pedant alkene or
insertion of the H–X bond. This strategy will provide a safe, mild
and versatile avenue to a lot of carbo- and hetero[n.1.0]bicyclic
frameworks. Further studies on the scope, asymmetric catalysis
and synthetic applications of this new process are underway.
Notes and references
1 For selected reviews, see: (a) H. Lebel, J. F. Marcoux, C. Molinaro
and A. B. Charette, Chem. Rev., 2003, 103, 977; (b) F. Brackmann
and A. de Meijere, Chem. Rev., 2007, 107, 4538; (c) A. Reichelt and
S. F. Martin, Acc. Chem. Res., 2006, 39, 433.
2 For recent mini-reviews, see: (a) K. Ota, S. I. Lee, J.-M. Tang,
M. Takachi, H. Nakai, T. Morimoto, H. Sakurai, K. Kataoka and
N. Chatani, J. Am. Chem. Soc., 2009, 131, 15203; (b) J. A. Bull and
A. B. Charette, J. Am. Chem. Soc., 2010, 132, 1895.
3 G. Maas, Chem. Soc. Rev., 2004, 33, 183, and references therein.
4 (a) H.-S. Yeom, J.-E. Lee and S. Shin, Angew. Chem., Int. Ed., 2008,
47, 7040; (b) N. Bremeyer, S. C. Smith, S. V. Ley and M. J. Gaunt,
Angew. Chem., Int. Ed., 2004, 43, 2681; (c) B. M. Trost and
A. S. K. Hashmi, J. Am. Chem. Soc., 1994, 116, 2183.
5 (a) L. L. Welbes, T. W. Lyons, K. A. Cychosz and M. S. Sanford,
J. Am. Chem. Soc., 2007, 129, 5836; (b) X. Tong, M. Beller and
M. K. Tse, J. Am. Chem. Soc., 2007, 129, 4906.
6 For selected reviews, see: (a) E. Jimenez-Nu´ nez and
´
A plausible catalytic cycle of this gold-catalyzed oxidative
cyclopropanation is outlined in Scheme 4. A linear mono-
coordination of the alkyne moiety of enynes 1 to the gold
species would give the corresponding intermediate IA, which is
oxidized by external pyridine/quinoline N-oxides. The resulting
a-oxo gold carbenoid IB would undergo an intramolecular
cyclopropanation to give the target product 3.6–9,16
A. M. Echavarren, Chem. Rev., 2008, 108, 3326; (b) Z. Li,
C. Brouwer and C. He, Chem. Rev., 2008, 108, 3239;
(c) V. Michelet, P. Y. Toullec and J. P. Genet, Angew. Chem.,
´
Int. Ed., 2008, 47, 4268; (d) A. Furstner, Chem. Soc. Rev., 2009,
¨
38, 3208; (e) N. D. Shapiro and F. D. Toste, Synlett, 2010, 675;
(f) A. S. K. Hashmi, Angew. Chem., Int. Ed., 2010, 49, 5232.
7 Using sulfoxides as external oxidants, selected examples:
(a) C. A. Witham, P. Mauleon, N. D. Shapiro, B. D. Sherry and
´
F. D. Toste, J. Am. Chem. Soc., 2007, 129, 5838; (b) C.-W. Li,
K. Pati, G.-Y. Lin, S. M. Abu Sohel, H.-H. Hung and R.-S. Liu,
Angew. Chem., Int. Ed., 2010, 49, 9891, and references therein.
8 For nitrogen-based oxides, see: (a) L. Ye, W. He and L. Zhang,
J. Am. Chem. Soc., 2010, 132, 8550; (b) W. He, C. Li and L. Zhang,
J. Am. Chem. Soc., 2011, 133, 8482, and references therein;
(c) H. S. Yeom, Y. Lee, J. Jeong, E. So, S. Hwang, J. E. Lee,
S. S. Lee and S. Shin, Angew. Chem., Int. Ed., 2010, 49, 1611;
(d) P. W. Davies, A. Cremonesi and N. Martin, Chem. Commun.,
2011, 47, 379; (e) D. Vasu, H.-H. Hung, S. Bhunia, S. A. Gawade,
A. Das and R.-S. Liu, Angew. Chem., Int. Ed., 2011, 50, 6911.
9 For selected examples of intermolecular and intramolecular cyclo-
In summary, an efficient gold(I)-catalyzed intramolecular
oxidative-cyclopropanation sequence of enynes with pyridine
propanation of olefins with gold carbenes, see: P. Patricia Pe
E. Herrero-Gomez, D. T. Hog, N. J. A. Martin, F. Maseras and
A. M. Echavarren, Chem. Sci., 2011, 2, 141, and references therein.
rez-Galan,
´ ´
´
10 (a) J.-J. Feng and J. Zhang, J. Am. Chem. Soc., 2011, 133, 7304;
(b) Z. Chen and J. Zhang, Chem.–Asian J., 2009, 351, 3083;
(c) T. Wang and J. Zhang, Dalton Trans., 2010, 39, 4270.
11 During our preparation of this manuscript, Liu et al. reported a
gold(I)-catalyzed oxidation–cyclization of enynes, in which no
electron-deficient alkyne has been studied, see: ref. 8e.
12 (a) H.-W. Liu and C. T. Walsh, In The Chemistry of the
Cyclopropyl Group, ed. Z. Rappoport, John Wiley & Sons Ltd.,
New York, 1987, pp. 959–1025; (b) A. B. Bueno, et al., J. Med.
Chem., 2005, 48, 5305; (c) M. D. McBriar, et al., J. Med. Chem.,
2006, 49, 2294.
Scheme 3
13 Basic pyridine species formed during the reaction might deactiva-
teLAuNTf, addition of acids to improve the reaction see: ref. 8a;
also see: A. S. K. Hashmi, Catal. Today, 2007, 122, 211. For the
control experiments regarding acid stability, see ESIw.
14 B. M. Trost, A. Breder, B. M. O’Keefe, M. Rao and A. W. Franz,
J. Am. Chem. Soc., 2011, 133, 4766.
15 A. J. Kirby, Stereoelectronic Effects, Oxford University Press, New
York, 1996.
16 An alternative mechanism suggested by a referee through the
oxidative rearrangements of 1,6-enynes may be possible, see:
ref. 7a.
Scheme 4
c
11154 Chem. Commun., 2011, 47, 11152–11154
This journal is The Royal Society of Chemistry 2011