Gold-catalyzed 1,3-addition of a sp3-hybridized C-H bond to alkenylcarbenoid intermediate

Article abstract of DOI:10.1021/ja807384a

We report stereoselective synthesis of bicyclo[3.2.1]oct-6-en-2-ones through Au(I)-catalyzed cycloisomerization of an allenene-acetal functionality. This cyclization is mechanistically significant because it involves an unprecedented 1,3-addition of a sp<

Full text of DOI:10.1021/ja807384a

Published on Web 11/14/2008
Gold-Catalyzed 1,3-Addition of a sp3-Hybridized C-H Bond to
Alkenylcarbenoid Intermediate
Sabyasachi Bhunia and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua UniVersity, Hsinchu, Taiwan, ROC
Received September 18, 2008; E-mail: rsliu@mx.nthu.edu.tw
One recent advent in modern synthetic chemistry is the generation
We prepared various substrates 1b-l to examine the generality of
the gold-catalyzed synthesis of bicyclo[3.2.1]oct-6-en-2-ones; the
results are summarized in Table 2. Particularly notable is the formation
of a single stereoisomer for the resulting cyclized products 3a-k and
3l despite their molecular complexity. The relative configurations of
ketones 3d and 3e are determined by 1H NOE spectra.6 Entries 1-4
show the suitability of this cycloisomerization for substrates 1b-e
bearing various 3-allen-1-enyl substituents; their resulting ketones 1b-e
were obtained in 68-94% yields. This cycloisomerization is extended
to species 1f-i bearing fluoro and methoxy at the phenyl groups, giving
ketones 3f-i efficiently. The value of this cycloisomerization is also
reflected by its applicability to nonaromatic substrates 1j and 1k, which
gave desired ketones 3j and 3k in 74-78% yields. This catalysis also
works well with species 1l comprising a 1,3-dioxolane group (entry 11).
As shown in Scheme 1, Au(I)-catalyzed cyclization of species
d1-1a shows a complete transfer of deuterium from its D-C(OMe)2
to the olefinic hydrogen of its ketone product d1-3a. For species
of metal carbenoid from an alkyne using Au(I) and Pt(II) catalysts.1
Insertion of a C-H bond into a metal carbenoid is a highly useful
method to form a new carbon-carbon bond, and its widespread use
is highlighted by development of asymmetric catalysis.2a To the best
of our knowledge, reported reactions of a carbenoid-induced C-H
bond activation are restricted strictly to an insertion reaction,2,3 through
a 1,1-addition of the C-H bond to a carbenoid carbon (eq 1). Here,
we report an atypical gold-carbenoid induced cleavage of a sp3-
hybridized C-H bond, which surprisingly undergoes a 1,3-addition
to vinylcarbenoid intermediate (eq 2).
Insertion of a C-H bond into carbenoid:
1,3-Addition of a C-H bond to vinylcarbenoid:
′
d1 -1a, its C(5)-deuterium stayed with the same carbon during the
cycloisomerization. We found no loss of deuterium content for both
′
d1-3a and d1 -3a even though residual water was present.
Scheme 2 shows a plausible mechanism to rationalize the stereo-
chemistry of cyclized ketone 3e. In the presence of PPh3AuSbF6,
starting substrate 1e undergoes a known allenene cyclization to give
We prepared substrate 1a bearing a 3-alkenylallene group, which acts
as a precursor for the generation of an alkenylcarbenoid intermediate4,5
in the presence of PtCl2 or PR3AuSbF6 catalyst. As shown in Table 1,
treatment of species 1a with PtCl2/CO (5 mol %) in CH2Cl2 (25 °C, 10
min) gave bicyclo[3.3.0]octene 2a as a single stereoisomer (93% yield).6
Compound 2a appears to arise from a Pt(II)-catalyzed tandem Nazarov/
Nazarov cascade.7 The use of PPh3AuCl/AgOTf gave compound 2a in
69% yield. Notably, PPh3AuCl/AgSbF6 completely altered the cyclization
pathway, giving distinct cycloisomerization products, bicyclo[3.2.1]oct-
6-en-2-one 3a and its dimethoxy derive 3a′, in 52% and 44% yields,
respectively. Hydrolysis of the reaction solution with p-TSA/acetone
provided ketone 3a with the yield up to 92% (entry 4). AgSbF6 alone
gave a complicated mixture of products. Structural elucidation of
compound 3a relies on an X-ray diffraction study of its alcohol derivative
3a-OH, produced from NaBH4 reduction.6
Table 2. Scope for Synthesis of Bicyclo[3.2.1]oct-6-en-2-ones
Table 1. Catalyst-Dependent Cycloisomerization of Substrate 1a
entry
catalyst
time (min) temp (°C)
2a
yield (%) 3a 3a′
1
2
3
4
PtCl2 /CO
10
5
5
25
10
10
10
93
69
AuClPPh3/AgOTf
AuClPPh3/AgSbF6
AuClPPh3/AgSbF6
44
92
52
a
5
a [substrate] ) 0.25 M, 5 mol % PPh3AuCl/AgSbF6,CH2Cl2, 10 °C, 10
min. b p-TSA and acetone were added at the end of reaction for entries
1-10. c Product yields are reported after silica column chromatography.
a Before workup, the reaction mixture was treated with 5% p-TSA in
acetone for 15 min with stirring.
9
16488 J. AM. CHEM. SOC. 2008, 130, 16488–16489
10.1021/ja807384a CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
products. The new concept of this atypical carbenoid-induced C-H
activation warrants further investigation.15
Acknowledgment. The authors wish to thank the National Science
Council, Taiwan, for supporting this work.
Supporting Information Available: Table S1,7 detailed synthesis
of substrate, X-ray data of alcohol 3a-OH, spectral data, and NMR spectra
of new compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) (a) Fu¨rstner, A.; Davies, P. W. Angew Chem. Int. Ed. 2007, 46, 3410. (b)
Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180. (c) Li, J.; Brouwer, C.; He, C.
Chem. ReV. 2008, 108, 3239. (d) Nu´n˜ez, E. J.; Echavarren, A. M. Chem. ReV
2008, 108, 3326. (e) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. ReV. 2008,
108, 3351. (f) Patil, N.; Yamamoto, Y. Chem. ReV. 2008, 108, 3395.
(2) (a) Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861. (b)
Ye, T.; McKervey, M. A. Chem. ReV. 1884, 94, 1091.
Au(I)-alkenyl carbenoid B4,5 that has a phenyl group trans to the
adjacent methyl group to minimize steric hindrance.8 On the basis of
deuterium-labeling and crossover experiments,9 we envisage that
cleavage of the H-C(OMe)2 bond of species B proceeds through an
intramolecular hydride transfer, induced by the AudC carbon to form
Au(I)-η1-allyl species C containing a dimethoxymethyl cation. Herein,
we do not preclude a possibility that the methoxy group of species B
facilitates a 1,3-hydride transfer through its coordination to carbenoid
carbon,10,11 as depicted in state I. A subsequent SE2′ addition of Au(I)-
η1-allyl functionality at this carbocation terminus, opposite the
neighboring methyl group, forms tricyclic species D with its methyl
group on the same side as the adjacent hydrogen and ethyl group.
(3) For C-H insertion by platinum- or gold-carbenoid, see: ref 4b and: (a) Oh,
C. H.; Lee, J. H.; Lee, S. J.; Kim, J. I.; Hong, C. S. Angew Chem., Int. Ed.
2008, 47, 7505. (b) Hashmi, A. S. K.; Scha¨fer, S.; Wo¨lfle, M.; Gil, C. D.;
Fischer, P.; Laguna, A.; Blanco, M. C.; Gimenno, M. C. Angew. Chem.,
Int. Ed. 2007, 46, 6184.
(4) (a) Lee, J. H.; Toste, F. D. Angew Chem., Int. Ed. 2007, 46, 912. (b) Funami,
H.; Kusama, H.; Iwasawa, N. Angew Chem., Int. Ed. 2007, 46, 909. (c)
Lemie`re, G.; Gandon, V.; Cariou, K.; Fukuyama, T.; Dhimane, A. -L.;
Fensterbank, L.; Malacria, M. Org. Lett. 2007, 9, 2207. (d) Gandon, V.;
Lemiere, G.; Hours, A.; Fensterbank, L.; Malacria, M. Angew. Chem., Int.
Ed. 2008, 47, 7534.
(5) The carbenoid character of alkenylcarbenoid B is demonstrated by its
cyclopropanation and C-H insertion. See ref. 4b and 4c.
Scheme 2
(6) X-ray structures and spectral data of alcohol 3a-OH, and 1H NOE NMR
spectra of key compounds are provided in Supporting Information.
(7) A mechanism of formation of product 2a is proposed below, comprising
two consecutive Nazarov cyclizations. Additional five examples of this
PtCl2-catalyzed bicyclo[3.3.0]octene synthesis with their spectral data, are
provided in Table S1 and Supporting Information.
(8) Formation of carbenoid B from of cis-1e in Scheme 2 likely involves a cisftrans
isomerization of gold-π-allene intermediate before Nazarov cyclization .
Scheme 3
(9) Treatment of a 1:1 mixture of d1-1a (> 97% deuterium content) and 1c
with PPh3AuCl/AgSbF6 in CH2Cl2 gave only d1-3a and 3c without
formation of 3a and d1-3c.
(10) In rhodium-carbenoid chemistry,11 heteroatoms show pronounced as-
sistance for a 1,2-migration of substituents (Stevens rearrangement), but
the assistance for a 1,3-hydride shift is unknown.
(11) (a) Roskamp, M.; Johnson, C. R. J. Am. Chem. Soc. 1986, 108, 6062. (b)
Doyle, M. P.; Tamblyn, W. H.; Bagheri, V. J. Org. Chem. 1981, 46, 5094.
(12) (a) Marion, N.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2750. (b)
Zhang, L. J. Am. Chem. Soc. 2005, 127, 16804. (c) Shi, F.-Q.; Li, X.; Xia,
Y.; Zhang, L.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 15503.
(13) Bicyclo[3.2.1]oct-6-en-2-ones, given in this work, are key intermediates
for bioactive (-)-cytisine; see: Coe, J. W.; Vetelino; Bashore, C. G.; Wirtz,
M. C.; Brooks, P. R.; Arnold, E. P.; Lebel, L. A.; Fox, C. B.; Sands, S. B.;
Davis, T. I., Schulz, D. W.; Rollema, H.; Tingley, F., D., III; O’Neill, B.
T, Bioorg. Med. Chem. Lett. 2005, 15, 2974.
The versatility of this cycloisomerization is highlighted by the
transformation of substrates 4a and 4b into cyclized ketones 5a and
5b in a tandem cascade. In the presence of PtCl2/CO or PPh3AuSbF6
catalysts, 4a and 4b initially form allenylacetate species E through a
1,3-acetate shift,12 which subsequently undergo a carbeniod formation
and C-H activation cascade. Interestingly, PtCl2/CO is superior to
PPh3AuSbF6 in cyclization efficiency, giving 5a and 5b in 81% and
67% yields, respectively.
′
(14) We exclude the possibility that the C-H activation of species d1 -1a arises
from a 1,5-hydrogen shift of cyclopentadiene F because of its inconsistency
with our deuterium-labeling experiment .
In summary, we report stereoselective synthesis of bicyclo[3.2.1]oct-
6-en-2-ones,13 through Au(I)-catalyzed cycloisomerization of allenene-
acetal functionality. This cyclization is mechanistically significant
because it involves an unprecedented 1,3-addition of a sp3-hybridized
C-H bond to vinylcarbenoid moiety.14 Before our work, activation
of a C-H bond with metal carbenoids only leads to C-H insertion
(15) Our data suggest that the 3,4-disubstituents of the 1,2,4-triene moieties of
substrates are necessary to this C-H activation.
JA807384A
9
J. AM. CHEM. SOC. VOL. 130, NO. 49, 2008 16489