Regioselective synthesis of oxepinones and azepinones by gold-catalyzed cycloisomerization of functionalyzed cyclopropyl alkynes

Article abstract of DOI:10.1039/c3cc46238b

A regioselective synthesis of oxepinones and azepinones in good to excellent yields from alkynylcyclopropanecarboxylic acid derivatives is described. This novel cycloisomerization cascade process consists of a nucleophilic addition followed by a cyclopropane ring-opening, where both donor and acceptor groups are required as substituents of the cyclopropane ring.

Full text of DOI:10.1039/c3cc46238b

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Regioselective synthesis of oxepinones and azepinones
by gold-catalyzed cycloisomerization of functionalyzed
cyclopropyl alkynes†
Cite this: Chem. Commun., 2013,
4
9, 11185
Received 14th August 2013,
Accepted 9th October 2013
a
b
b
Jes u´ s M. Fern a´ ndez-Garc ´ı a, Patricia Garc ´ı a-Garc ´ı a, Manuel A. Fern a´ ndez-Rodr ´ı guez,
a
a
Alexandra P e´ rez-Anes and Enrique Aguilar*
DOI: 10.1039/c3cc46238b
www.rsc.org/chemcomm
A regioselective synthesis of oxepinones and azepinones in good
to excellent yields from alkynylcyclopropanecarboxylic acid deri-
vatives is described. This novel cycloisomerization cascade process
consists of a nucleophilic addition followed by a cyclopropane
ring-opening, where both donor and acceptor groups are required
as substituents of the cyclopropane ring.
Fig. 1 Proposed synthetic strategy.
The synthesis of seven-membered cyclic compounds remains as a
Compound 1a was selected as a model system for checking the
highly challenging task in organic synthesis, despite the blooming viability of the proposed strategy and a variety of parameters were
1
development of powerful tools such as the RCM methodology. In screened. Due to the highly functionalized nature of the starting
particular, very few methods have been developed for the synthesis material several alternative reactions may occur, which makes the
of the oxepin-2-one skeleton, even though it is present in natural control of the selectivity an important issue in this transformation.
2
products displaying remarkable biological activities. On the other Thus, up to four side products 3–6 were observed in variable
12a
hand, gold-catalyzed cycloadditions and cycloisomerizations have amounts using different catalysts (Scheme 1). Gratifyingly, the
3
been widely explored in recent years. In this regard, we have combination IPrAuCl–AgOTs led to a completely selective reaction
employed gold catalysis to prepare six-membered heterocycles allowing the isolation of desired oxepin-2-one 2a in a remarkable
4
5
(
pyridines and dihydropyridones) and carbocycles from push–pull 90% yield provided that strictly anhydrous conditions are employed
6
conjugated dienynes. Alkynyl cyclopropanes have also recently [both gold and silver complexes (or essentially, the hygroscopic
served as starting materials for gold-catalyzed transformations. In silver salt) were lyophilised prior to carrying out the reaction, and
7
12b
this context, we envisioned that alkynyl cyclopropanes bearing MS of 4 Å were used] (Scheme 1).
donor–acceptor (DA) substituents in the cyclopropane ring (push–
With the proof of concept established, the scope of the reaction
pull cyclopropanes) might offer a straightforward access to the was checked. The optimized conditions shown to be useful for a wide
oxepin-2-one skeleton, via an intramolecular cascade reaction invol- range of DA alkynylcyclopropane carboxylic acids (Table 1). Thus,
ving a regioselective 6-endo nucleophilic attack of the carboxy group good to excellent yields were reached for oxepinones bearing aromatic
8
9
and the opening of the cyclopropyl ring (Fig. 1). Cascade reactions substitutents with electron-donating (2b–e) or electron-withdrawing
are some of the most useful strategies for achieving synthetic groups (2f,g) either in the para (2b–d,f,g), meta (2c) or ortho (2e)
10
efficiency, and on the other hand, mild reaction conditions should position, as well as heteroaromatics (2h). Alkenyl substituents
be expected for this transformation due to the intrinsic vulnerability
11
of DA cyclopropanes to undergo ring-opening reactions.
a
Instituto Universitario de Qu ´ı mica Organomet a´ lica ‘‘Enrique Moles’’,
Departamento de Qu ´ı mica Org a´ nica e Inorg a´ nica, Universidad de Oviedo, C/Juli a´ n
Claver ´ı a, 8, 33006, Oviedo, Spain. E-mail: eah@uniovi.es; Fax: +34-985-103-446
A´ rea de Qu ´ı mica Org a´ nica, Departamento de Qu ´ı mica, Facultad de Ciencias,
b
Universidad de Burgos, Pza. Misael Ba n˜ uelos, s/n, 09001, Burgos, Spain
†
Electronic supplementary information (ESI) available: Full experimental details
(
including the catalyst lyophilisation process), optimization of the reaction
conditions, a proposal to explain the lack of reactivity of trans-DA alkynylcyclo-
1
13
propanes, and copies of H- and C-NMR spectra of both new starting materials
and reaction products. See DOI: 10.1039/c3cc46238b
Scheme 1 Proof of concept.
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Chem. Commun., 2013, 49, 11185--11187 11185

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Table 1 Scope of the reaction
a
Entry
1
Product
X
R
Yield
2b
O
p-(C
6
H
4
)-OMe
78
2
2c
O
84
3
4
5
6
7
2d
2e
2f
2g
2h
O
O
O
O
O
p-(C
o-(C H
6 4
6
H
4
)-Me
)-Me
)-Cl
92
72
75
86
62
p-(C
p-(C
6
H
H
4
6
4
)-CF
3
Thiophen-2-yl
8
9
2i
O
82
2j
2k
2l
2m
2m
2n
O
O
O
O
O
O
O
NH
NMe
N-p-(C
n-Bu
Cyclopentyl
t-Bu
E-styryl
E-styryl
H
89
87
74
Scheme 2 Proposed mechanism.
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
b
30
c
75
d
30
We have obtained some evidence that led us to consider Via A as
the most probable route (see Table 1, entries 12–15). First, reaction
of substrate 1m under the optimized reaction conditions afforded a
c,d
2n
H
Ph
71
e
16a
16b
16c
85
e
o-(C
p-(C
6
H
H
4
)-Me
)-Me
76
e
1
: 1 ratio of oxepinone 2m and bicyclo[4.1.0]lactone 7 (entry 12),
6
H
4
)-OMe
6
4
62
although 2m could be selectively obtained in good yield when the
reaction was performed at reflux (entry 13).
a
c
b
Isolated yields. Bicyclo[4.1.0]lactone 7 (30%) was also isolated.
d
Reactions carried out in refluxing dichloromethane. Combined yield
of non-separated 2n and 8 (ratio 2n/8: 54/46, entry 14; 52/48, entry 15).
Reactions carried out in 1,2-dichloroethane (DCE) at 110 1C.
On the other hand, DA cyclopropane 1n, bearing a terminal
alkyne moiety, led to a mixture of oxepinone 2n and bicyclo[3.1.0]-
lactone 8, coming from a 5-exo-dig cyclization, in an almost 1 : 1 ratio,
both at room temperature and at reflux (Table 1, entries 14 and 15).
The latter results are not surprising as, in gold-catalyzed reactions, the
e
15
5-exo-dig cyclization is expected to be favoured for terminal alkynes.
The structural features of lactones 7 and 8, which retain the
cyclopropane moiety, as well as the absence of 7 in the reaction of
were also tolerated (2i), as well as primary, secondary or tertiary 1m performed at reflux support the assumption that the nucleophilic
alkyl groups (2j–l). Remarkably, in all these examples the process addition to the triple bond takes place prior to the opening of the
took place with complete regioselectivity without the formation of cyclopropane ring. Moreover, the diastereomeric DA cyclopropanes
the corresponding 5-exo adducts.
bearing the alkynyl group and the carboxylic acid in relative trans
13
In our proposed mechanism, we suggest an initial activation of positions remain unaltered under the optimized reaction condi-
the triple bond of 1 by complexation of the gold catalyst to form tions, which is also in agreement with proposed Via A.
intermediate I (Scheme 2). This intermediate may evolve by three Next we turned our attention to evaluate the role of the
12c
different routes. According to Via A a regioselective 6-endo-dig nucleo- substituents of the cyclopropane in the efficiency of the trans-
philic addition of the carboxylic acid to the activated triple bond in I, formation. As pointed out before, we expected the DA nature of
which is probably favoured over the 5-exo-dig by coordination of the the cyclopropane to be a requirement for the ring opening
14
methoxy group with the metal atom, would lead to II. A subsequent under such mild conditions. To test our hypothesis, alkynyl
cyclopropane ring-opening would render seven-membered ring inter- cyclopropane 9, which does not present an electron-donating
mediate III, which after a final protodemetalation would give product group in its structure, and 10, which lacks an electron-
2
and would regenerate the catalyst. Alternatively, as stated in Via B, withdrawing substituent, were prepared and subjected to the
cyclopropane ring-opening may occur prior to the nucleophilic attack optimized reaction conditions (Scheme 3). Bicyclic products
to the triple bond on I and the formation of III would take place still bearing the cyclopropane ring (11–14) were isolated in
through acyclic intermediate IV. Finally, a concerted mechanism these experiments, even at 50 1C, thus supporting our thesis.
implying a simultaneous nucleophilic attack and ring-opening could Moreover, the higher levels of regioselectivity observed for the
also operate (Via C).
cycloisomerization of substrates 1 and 10 in comparison with 9
1
1186 Chem. Commun., 2013, 49, 11185--11187
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Scheme 3 Reactions with non-DA alkynyl cyclopropanes.
(
(
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seem to support the coordination between the methoxy group
and the gold atom suggested in Via A.
(
e) C.-W. Li, K. Patti, G.-Y. Lin, S. M. A. Sohel, H.-H. Hung and
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Then, we decided to explore if this type of sequential
1
6
reaction could also be used to prepare azepinones. To our
delight, alkynyl cyclopropanamides 15 proved to be active
although they required warming at 110 1C to form azepinones
16 in good isolated yields (Table 1, entries 16–18). In these
9
708–9709. For recent examples of alkynyl cyclopropanes in gold
preliminary results, azepinones bearing N-H (16a), N-alkyl (16b)
and N-aryl (16c) groups have been prepared. Not surprisingly,
harsh conditions were required for the gold-catalyzed reaction
sequence, probably due to difficulties associated with the
catalyzed transformations where the cyclopropyl group does not open
up: (k) W. Yang, Y. Yu, T. Zhang, M. M. Hansmann, D. Pfl ¨a sterer and
A. S. K. Hashmi, Adv. Synth. Catal., 2013, 355, 2037–2043; (l) A. S. K.
Hashmi, W. Yang, Y. Yu, M. M. Hansmann, M. Rudolph and
F. Rominger, Angew. Chem., Int. Ed., 2013, 52, 1329–1332.
1
7
intramolecular triple bond amidation step, but in all cases
the regioselectivity was complete towards the 6-endo-dig isomer.
In conclusion, we have developed a novel cascade reaction
consisting of a sequential intramolecular nucleophilic addition/
cyclopropane ring-opening on alkynyl DA-cyclopropanes leading
to oxepin-2-ones in excellent yields. The cascade process takes place
at room temperature with complete regioselectivity provided that
the cyclopropane ring bears both donor and acceptor substituents.
Moreover, the developed strategy could also be employed for the
8 J. Barluenga, M. A. Fern ´a ndez-Rodr ´ı guez, P. Garc ´ı a-Garc ´ı a,
E. Aguilar and I. Merino, Chem.–Eur. J., 2006, 12, 303–313.
9
For reviews on gold-catalyzed reactions involving ring-expansion:
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67–780. In only a few cases, a direct gold-catalyzed formation of
(
(
7
seven-membered rings has ever been achieved: (d) D. Pfl ¨a sterer,
P. Dolbundalchok, S. Rafique, M. Rudolph, F. Rominger and A. S. K.
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1
0 T. Yang, L. Campbell and D. J. Dixon, J. Am. Chem. Soc., 2007, 129,
12070–12071.
synthesis of other seven-membered heterocyclic compounds as we 11 For an account highlighting the employment of DA-cyclopropanes
for the total synthesis of indoline alkaloids, see: (a) D. Zhang,
H. Song and Y. Qin, Acc. Chem. Res., 2011, 44, 447–457. For selected
reviews on DA-cyclopropanes, see:; (b) M. Yu and B. L. Pagenkopf,
have demonstrated with isolobal azepin-2-ones.
Generous financial support from the Spanish MINECO and
the Principality of Asturias (Grants CTQ2010-16790 and FC-11-
COF-11-14) is acknowledged. P. G.-G. and M. A. F.-R. are grateful
to the Spanish Government for Juan de la Cierva and Ram ´o n y
Cajal contracts.
Tetrahedron, 2005, 61, 321–347; (c) H.-U. Reissig and R. Zimmer,
Chem. Rev., 2003, 103, 1151–1196.
2 See ESI† for details on: (a) optimization of the reaction conditions;
1
(
b) the catalyst lyophilisation process; (c) a proposal to explain the
lack of reactivity of trans-DA alkynylcyclopropanes.
3 A. S. K. Hashmi, Angew. Chem., Int. Ed., 2010, 49, 5232–5241.
1
Notes and references
14 The influence of coordinating groups in the regioselectivity of the
addition of nucleophiles to alkynyl cyclopropanes has been pre-
viously proposed: see ref. 7f.
1
2
3
Selected recent reviews on the synthesis of medium-ring hetero-
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J. Barluenga, WILEY-VCH, Weinheim, 2011, vol. 4, pp. 1865–1988;
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D. Garayalde, E. G o´ mez-Bengoa, X. Huang, A. Goeke and C. Nevado,
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(
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8
85–888; (b) A. Saouf, F. M. Guerra, J. J. Rubal, F. J. Moreno-Dorado, 16 For the gold-catalyzed synthesis of azepinones, see: A. S. K. Hashmi,
M. Akssira, F. Mellouki, M. Lopez, A. J. Pujadas, Z. D. Jorge and W. Yang and F. Rominger, Adv. Synth. Catal., 2012, 354, 1273–1279.
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2
Selected recent reviews in gold chemistry: (a) H. A. Wegner
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This journal is c The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 11185--11187 11187