Ni-Catalyzed [8+3] cycloaddition of tropones with 1,1-cyclopropanediesters

Article abstract of DOI:10.1039/c3cc45552a

A variety of cycloheptapyrane derivatives were prepared via Ni-catalyzed formal [8+3] cycloaddition of tropones with 1,1-cyclopropanediesters. The asymmetric version of the process can be achieved using either an enantiomerically enriched cyclopropane as the starting material or a racemic cyclopropane and a chiral Lewis acid.

Full text of DOI:10.1039/c3cc45552a

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Ni-Catalyzed [8+3] cycloaddition of tropones with
1
,1-cyclopropanediesters†
Cite this: Chem. Commun., 2013,
9, 10406
4
Rub e´ n Tejero, Alberto Ponce, Javier Adrio* and Juan C. Carretero*
Received 22nd July 2013,
Accepted 11th September 2013
DOI: 10.1039/c3cc45552a
www.rsc.org/chemcomm
A
variety of cycloheptapyrane derivatives were prepared via provide an easy access to functionalized cycloheptapyrane frame-
15
Ni-catalyzed formal [8+3] cycloaddition of tropones with 1,1-cyclopro- works. As far as we know, examples of such transformation have
panediesters. The asymmetric version of the process can be achieved not been reported to date.
using either an enantiomerically enriched cyclopropane as the starting
material or a racemic cyclopropane and a chiral Lewis acid.
Our initial experiments focused on the identification of an
appropriate Lewis acid. A metal salt screening using 1,1-cyclopro-
panediester 2a as the model substrate and CH
Tropone derivatives have attracted the attention of organic chemists 70 1C was carried out (Table 1). While treatment with MgI
2
Cl
2
as the solvent at
led to no
2
for decades owing to their unique chemical properties and synthetic reaction (entry 1), we were pleased to find out that in the presence
1
versatility. In particular, troponoids have been broadly studied as of 10 mol% Zn(OTf) the formation of the desired product took
2
2
suitable partners in high order cycloadditions, which have become place with 70% conversion (entry 2). Other Lewis acids were able to
powerful tools for synthesis of natural product. Representative promote the reaction (Table 1, entries 3–6). Among them, Yb(OTf)3
examples in this field include [6+4], [4+2] and [8+2] cycloadditions,
as well as the formation of [6+3] cycloadducts in the reaction with 3a in 89% and 91% yields, respectively (entries 5 and 6). The use of
trimethylenemethanes or allylic compounds. In contrast, much other solvents such as toluene, THF, CH CN, DMF or MeOH did
3
less common is the participation of tropones in [8+3] cycloadditions. not improve these results. We also studied the effect of tempera-
3
4
and Ni(ClO
4
)
2
Á6H
2
O provided the best results, affording the product
5
6
16
To the best of our knowledge, the only previous examples are the ture, observing a much lower reactivity at 50 1C. This effect was
II
7
reaction of tropone with the 2-oxyallyl Fe cation, the N-heterocyclic significantly more pronounced in the case of Yb(OTf) (entry 7).
3
8
carbene catalyzed annulation with enals via homoenolate, and Finally, lowering the amount of catalyst to 5 mol% led to a
the cyclization with modified allylic compounds catalyzed by an significant erosion of the reactivity (entry 9).
9
organic–inorganic hybrid with triphenylphosphine groups.
With these optimized reaction conditions in hand, we next
Donor–acceptor cyclopropanes are versatile three carbon building studied the scope of the cycloaddition with regard to the
blocks, very useful in organic synthesis due to both their reactivity
10
and availability. The release of strain in the ring opening of the
cyclopropane moiety promotes their reaction with nucleophiles. In
the case of 1,1-cyclopropanediesters the process is facilitated by
coordination of a Lewis acid to the ester moieties. Their synthetic
value has been extensively demonstrated in the preparation of highly
Table 1 Optimization of the reaction conditions
11
substituted carbo- and heterocyclic products via formal [3+2],
12
13
[
3+3] or [3+4] cycloaddition reactions. On the other hand, the
a
Entry
[M]
T (1C)
Conversion (%)
cycloaddition of donor–acceptor cyclopropanes with carbonyl com-
pounds is well established, and efficient metal catalyzed procedures
1
2
3
4
5
6
7
8
9
MgI
Zn(OTf)
Sc(OTf)
Sn(OTf)
Yb(OTf)
Ni(ClO
Yb(OTf)
2
70
70
70
70
70
70
50
50
70
0
70
90
85
>99 (89)
>99 (91)
14
2
have been reported in the last decade. In this context, the
cycloaddition of 1,1-cyclopropanediesters with tropones could
3
2
b
3
b
4
)
2
Á6H
2
O
Departamento de Qu ´ı mica Org a´ nica, Facultad de Ciencias, Universidad Aut o´ noma
de Madrid, Cantoblanco 28049, Madrid, Spain. E-mail: javier.adrio@uam.es,
juancarlos.carretero@uam.es; Fax: +34 914973966
3
25
60
65
Ni(ClO
Ni(ClO
4
)
)
2
2
Á6H
2
2
O
O
c
4
Á6H
†
Electronic supplementary information (ESI) available: Experimental proce-
a
1
b
dures, spectroscopic data and NMR spectra. CCDC 951034. For ESI and crystal-
lographic data in CIF or other electronic format see DOI: 10.1039/c3cc45552a
Determined by H-NMR in the crude reaction mixtures. Isolated
c
yield. 5 mol% of catalyst.
1
0406 Chem. Commun., 2013, 49, 10406--10408
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Table 2 Scope of the reaction with regard to the substitution at the cyclopropane
Scheme 1
Scheme 2
Thus, to evaluate the stereochemical outcome of the reaction the
19
enantiopure cyclopropane (S)-2a (Z99% ee) was subjected to the
reaction with tropone under the optimized conditions (Ni(ClO
H O, CH Cl , 70 1C). The cycloadduct 3a was isolated with a
4
)
2
Á
6
2
2
2
significant loss of enantiomeric purity at 70 1C. In contrast, when
the reactions with cyclopropanes (S)-2a (Z99% ee) and (S)-2d
2
0
(
93% ee) were performed at a lower temperature (55 1C) a much
21
smaller erosion of the enantiomeric integrity was observed (95%
and 88% ee, respectively, Scheme 2). The (R) configuration of the
resulting stereocentre was determined by X-ray diffraction analysis of
(
R)-3d, proving that the process occurs mainly with inversion of the
22
configuration at the benzylic carbon of the cyclopropane unit.
A simplified plausible stepwise mechanism is shown in
II
Scheme 3. Activation of the cyclopropane by the Ni catalyst,
coordination and tropone nucleophilic attack to the benzylic
substituted site would generate the tropilium-type zwitterionic
intermediate 4. Straightforward ring closure leading to pyrane 5
and final 1,3-H shift would afford the cycloadduct 3.
Yields after column chromatography.
substitution at the 1,1-cyclopropanediester (Table 2). Excellent
reactivity was observed from aromatic cyclopropanes regardless
of the electronic nature of the substituent at the aromatic ring
Efficient enantioselective Lewis acid catalyzed processes to
transform racemic donor–acceptor cyclopropanes into enantio-
(adducts 3b–j, 62–92% yield). The sterically more demanding
2
3
merically enriched products have also been reported. In these
processes the achievement of good levels of enantioselectivity
relies on the in situ epimerization of the cyclopropane and the
use of a highly stereodiscriminating chiral ligand.
ortho-substituted aromatic cyclopropanes were also suitable
substrates (products 3k–l) and similar results were obtained
from heteroaryl substituted cyclopropanes (3m–o). Interest-
ingly, the alkenyl cyclopropane 2p (82% yield for 3p), and the
phthaloyl substituted cyclopropane 2q (64% yield for 3q) also
underwent the cycloaddition. Remarkably, the usually less
reactive cyclopropanediester 2r, without substitution at the
adjacent position to the geminal diester, provided the expected
cycloadduct 3r in 83% yield. In contrast, no cycloaddition was
observed when the benzyl substituted cyclopropane 2s was
tested under the same reaction conditions.
1
7
To test this alternative, we explored the Ni-catalyzed reaction
of racemic cyclopropane (Æ)-2a in the presence of a chiral
2
4
ligand. After screening a variety of chiral ligands, we found
that the combination of Ni(ClO ) Á6H O with the commercially
4 2
2
Next, to gain some insight into the stereochemical issues of the
process, we performed several experiments. It has been reported
that a number of formal cycloaddition processes involving
1
,1-cyclopropanediesters take place by stereospecific attack of
1
8
the nucleophile on the activated site of the cyclopropane.
Consequently, the use of an enantiomerically enriched cyclopropane
could lead to an enantioenriched cycloadduct by inversion at the
substituted carbon centre. Loss of enantiomeric excess could result
by opening/closing of the cyclopropane via formation of an open
planar zwitterionic intermediate (Scheme 1).
Scheme 3
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4
5
(a) L. Isakovic, J. A. Ashenhurst and J. L. Gleason, Org. Lett., 2001,
3
4
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1
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Scheme 4
6
7
8
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9
C. Chen, X. Shao, K. Yao, W. Shangguan, T. Kawaguchi and
K. Shimazu, Langmuir, 2011, 27, 11958.
1
0 For reviews on donor–acceptor cyclopropanes: (a) C. A. Carson and
M. A. Kerr, Chem. Soc. Rev., 2009, 38, 3051; (b) M. Yu and
B. L. Pagenkopf, Tetrahedron, 2005, 61, 321; (c) H.-U. Reissig and
R. Zimmer, Chem. Rev., 2003, 103, 1151.
1
1 (a) H. Xiong, H. Xu, S. Liao, Z. Xie and Y. Tang, J. Am. Chem. Soc.,
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P. Hensenne, S. Schroeder and M. Niggemann, Org. Lett., 2013,
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Y. V. Nelyubina, Y. V. Tomilov and S. L. Ioffe, Org. Lett., 2013,
Scheme 5
available MeObiphep ligand 6 catalyzed the [8+3] cycloaddition,
affording the cycloadduct (S)-3a in 68% yield and 80% ee
(
Scheme 4).
1
1
This result suggests that the Ni(ClO
4
)
2
Á6H
2
O/MeObiphep 6
1
(
1
5, 350; (b) L. Wu and M. Shi, Chem.–Eur. J., 2010, 16, 1149;
c) T. P. Lebold, A. B. Leduc and M. A. Kerr, Org. Lett., 2009,
1, 3770; (d) C. Perreault, S. R. Goudreau, L. E. Zimmer and
catalyst system facilitates the enantiomer interconversion in the
starting cyclopropane through the open zwitterionic intermediate.
In this regard, the stability of the enantioenriched cyclopropane
S)-2a in the absence of tropone was studied. In the presence of
Ni(ClO O (S)-2a was recovered after 24 hours without loss of
A. B. Charette, Org. Lett., 2008, 10, 689.
3 (a) Y. Bai, J. Fang, J. Ren and Z. Wang, Chem.–Eur. J., 2009, 15, 8975;
(
(
b) A. Ivanova, E. M. Budynina, Y. K. Grishin, I. V. Trushkov and
4
)
2
Á6H
2
P. V. Verteletskii, Angew. Chem., Int. Ed., 2008, 47, 1107.
enantiomeric purity (Scheme 5, eqn (1)). In contrast, after treatment 14 For very recent examples, see: (a) G. Yang, Y. Sun, Y. Shen, Z. Chai,
S. Zhou, J. Chu and J. Chai, J. Org. Chem., 2013, 78, 5393;
of (S)-2a (Z99% ee) with Ni(ClO
for 1 h cyclopropane 2a was isolated in 46% yield as a racemic
4
)
2
Á6H
2
O/MeObiphep 6 (10 mol%)
(b) S. Haubenreisser, P. Hensenne, S. Schroeder and M. Niggemann,
Org. Lett., 2013, 15, 2262; (c) A. G. Smith, M. C. Slade and J. S. Johnson,
Org. Lett., 2011, 13, 1996; (d) G. Yang, Y. Shen, K. Li, Y. Sun and Y. Hue,
J. Org. Chem., 2011, 76, 299. See also ref. 17.
5 Cycloheptapyrane scaffold is found in several natural products.
R. F. Angawi, D. C. Swenson, J. B. Gloer and D. T. Wicklow, J. Nat.
Prod., 2005, 68, 212.
25
compound (Scheme 5, eqn (2)). These results further support that
the catalyst system Ni(ClO ) Á6H O/MeObiphep 6 promotes the
4
2
2
1
cyclopropane epimerization process.
In summary, we have developed an efficient nickel-catalyzed
methodology for the preparation of cycloheptapyranes via formal
8+3] cycloaddition of tropones with donor–acceptor cyclopro-
panes. Enantiomerically enriched cycloadducts can be obtained
either using enantiopure cyclopropanes or the combination of a
racemic cyclopropane and an appropriate chiral ligand.
Financial support of this work by the Ministerio de Econom ´ı a y
Competitividad (MINECO, CTQ2009-07791 and CTQ2012-35790)
and the Consejer ´ı a de Educaci o´ n de la Comunidad de Madrid (project
1
1
6 See ESI† for details.
7 (a) F. Benfatti, F. de Nanteuil and J. Waser, Chem.–Eur. J., 2012,
[
1
8, 4844; (b) F. Benfatti, F. de Nanteuil and J. Waser, Org. Lett., 2012,
14, 386; (c) F. de Nanteuil and J. Waser, Angew. Chem., Int. Ed., 2011,
0, 12075.
5
1
1
8 K. Sapeta and M. A. Kerr, J. Org. Chem., 2007, 72, 8597. See also ref. 17a.
9 (S)-2a was prepared following the procedure described by P. D. Pohlhaus,
S. D. Sanders, A. T. Parsons, W. Li and J. S. Johnson, J. Am. Chem. Soc.,
2008, 130, 8642.
2
0 For the synthesis of (S)-2d, see: C. Deng, L. J. Wang, J. Zhu and
Y. Tang, Angew Chem., Int. Ed., 2012, 51, 11620.
AVANCAT; S2009/PPQ-1634) is acknowledged. A. P. thanks the MEC 21 These data are in agreement with the results obtained by Keer in the
cycloaddition of nitrones with enantioenriched cyclopropanes, in
which higher ee values were observed when the temperature
decreases, see ref. 18.
2 CCDC 951034.
for a FPU grant. We thank Takasago Company (Dr Taichiro Touge)
for a generous loan of Segphos chiral ligands.
2
Notes and references
23 (a) S. M. Wales, M. M. Walker and J. S. Johnson, Org. Lett., 2013,
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1
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(a) B. Hu, S. Xing, J. Ren and Z. Wang, Tetrahedron, 2010, 66, 5671; 24 See ESI† for details.
(
(
b) P. Li and H. Yamamoto, Chem. Commun., 2010, 46, 6294; 25 The reaction at 70 1C for 24 h led to a complex decomposition
c) B. M. Trost and P. J. McDougall, Org. Lett., 2009, 11, 3782.
reaction mixture in which the starting material was not detected.
1
0408 Chem. Commun., 2013, 49, 10406--10408
This journal is c The Royal Society of Chemistry 2013