Facile and chemoselective rhodium-catalysed intramolecular hydroacylation of α,α-disubstituted 4-alkylidenecyclopropanals

Article abstract of DOI:10.1039/c1cc14626b

Mild intramolecular hydroacylation of α,α-disubstituted 4-alkylidenecyclopropanals has been developed, avoiding decarbonylation and affording cycloheptenones in good yields. The reaction is chemoselective in favour of the alkylidenecyclopropane moiety when potential alkene or alkyne acceptors are tethered to the substrate.

Full text of DOI:10.1039/c1cc14626b

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COMMUNICATION
Facile and chemoselective rhodium-catalysed intramolecular
hydroacylation of a,a-disubstituted 4-alkylidenecyclopropanalsw
´
¨
Damien Crepin, Coralie Tugny, James H. Murray and Christophe Aıssa*
Received 28th July 2011, Accepted 18th August 2011
DOI: 10.1039/c1cc14626b
Mild intramolecular hydroacylation of a,a-disubstituted 4-alkylidene-
cyclopropanals has been developed, avoiding decarbonylation and
affording cycloheptenones in good yields. The reaction is chemo-
selective in favour of the alkylidenecyclopropane moiety when
potential alkene or alkyne acceptors are tethered to the substrate.
Rhodium-catalysed intramolecular hydroacylation is a remark-
able example of atom-economical transformation.1–3 Early
experimental studies suggest that migratory insertion of the
terminal olefin into the rhodium–hydrogen bond of acyl-
hydridorhodium A leads to both pentarhodacycle B and hexa-
rhodacycle C (Scheme 1).4 Moreover, more recent theoretical
studies conducted with non-substituted 4-pentenal suggest
that pentarhodacycles B are the key intermediates leading to
Scheme 2 Smooth formation of a,a-disubstituted cycloheptenones.
a: [Rh((ꢀ)-BINAP)]BF4 (10 mol%),8 acetone, 21 1C, 12 h. Positive
decarbonylation of the substrate whilst hexarhodacycles C
would undergo productive carbon–carbon reductive elimination.5
To the extent that the Thorpe–Ingold effect6 would favour the
predominant formation of rhodacycle intermediates B over
hexarhodacycle C from a,a-disubstituted aldehydes (R1, R2 a H),
these mechanistic considerations are in good accordance with
the notorious reluctance of a,a-disubstituted aliphatic aldehydes
to undergo intramolecular hydroacylation.2b,c,7 Hence, relatively
harsh reaction conditions are often required to promote the
charge and ligand sphere on rhodium are omitted for simplicity.
usually low yielding formation of cyclopentanones,2c,7 with rare
exceptions,7c,e and products resulting from side reactions such
as carbon–carbon double bond migration and decarbonylation
have been observed.2c,7b
We found that treatment of a,a-disubstituted aldehyde 1
with [Rh((ꢀ)-BINAP)]BF4 (10 mol%) (BINAP = 2,20-
bis(disphenylphosphino-1,10-binaphthyl)) in acetone at room
temperature led to the smooth formation of cycloheptenone
2 in 89% isolated yield whilst no cyclopentanone was
observed (Scheme 2).8 This result is in good accordance with
the previous reasoning and suggests that migratory insertion
of the alkylidenecyclopropane moiety in A1 and formation
of pentarhodacycle intermediate B1 prevail over migratory
insertion of the terminal olefin and formation of hexarhoda-
cycle C1. Swift ring enlargement and reductive elimination
would then divert B1 from the decarbonylative pathway.
Presumably, the release of strain energy during the migratory
insertion from A1 toward B1 and during the subsequent ring
enlargement plays an important role in favouring this productive
reaction pathway.
Scheme 1 Formation of pentarhodacycle and hexarhodacycle inter-
mediates from a,a-disubstituted aliphatic aldehydes.
However, it has been proposed that the turnover number
of rhodium-catalysed hydroacylation of 4-pentenals can be
improved by suppressing the decarbonylation pathway, either
in the presence of ethylene4a or by coordination of another
olefin.4b Accordingly, we wondered whether a second olefin
must be tethered to a,a-disubstituted 4-alkylidenecyclopropanes
in order to observe smooth conversion. Conversely, would the
University of Liverpool, Chemistry Department, Crown Street,
L69 7ZD, Liverpool, UK. E-mail: aissa@liverpool.ac.uk;
Fax: +44 151 794 3588; Tel: +44 151 795 2170
w Electronic supplementary information (ESI) available: Detailed
description of experimental procedures and characterisation of new
compounds. See DOI: 10.1039/c1cc14626b
c
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Table 1 General preparation of a,a-disubstituted cycloheptenonesa
Entry R1
R2
Product Time/h Yieldb (%)
1
2
3
4
5
6
Ph
Ph
CH2OTBS
CH2OTBS
CH2OCH2Ph Me
CH2Opiv Me
Me
Me
Me
4a
4a
4b
2
14
2
3
4
85c
86d
87
CH2Ph 4c
93
77
4d
4e
8
54e
Scheme 4 Bidirectional formation of spiro-1,3-bisketone. Reaction
conditions: a: (COCl)2, DMSO, Et3N, CH2Cl2; b: [Rh((ꢀ)-BINAP)]-
BF4 (10 mol%),8 acetone, 21 1C, 82% over two steps; c: TBSCl, DMAP,
Et3N, CH2Cl2, 83%; d: (COCl)2, DMSO, Et3N, CH2Cl2, 97%;
e: [Rh((ꢀ)-BINAP)]BF4 (10 mol%),8 acetone, 60 1C, 88%; f: TBAF,
THF, 85%; g: (COCl)2, DMSO, Et3N, CH2Cl2; h: [Rh((ꢀ)-BINAP)]BF4
(10 mol%),8 acetone, 60 1C, incomplete conversion.
a
All reactions were performed at 60 1C except otherwise noted. The
active catalyst was prepared prior to use by hydrogenation of
[Rh(nbd)2]BF4 (10 mol%) (nbd = norbornadiene) in the presence of
c
(ꢀ)-BINAP (10 mol%) at room temperature.8 b Isolated yields. At
d
e
21 1C. 3 mol% of catalyst was used. 15 mol% of catalyst was
used.TBS = tert-butyldimethylsilyl. Piv = pivaloate.
reaction be similarly chemoselective if the second tethered
olefin in 1 is replaced by other alkenes or an alkyne?
manipulations of diol 8 into aldehyde 11, followed by a first
intramolecular hydroacylation giving ketone 12 in 88% yield,
and further functional group manipulations toward 13, which
revealed itself very difficult to handle and led to irreproducible
results during the second incomplete intramolecular hydro-
acylation toward 10.
We first examined the generality of the transformation
depicted in Scheme 2 with substrates which did not pose
an issue of chemoselectivity and found that treatment of
aldehydes 3a–d led to the formation of a,a-disubstituted
cycloheptenones 4a–d in good to excellent isolated yields
(Table 1). In general, reactions were complete within few
hours. As shown with 4a (entries 1 and 2), it was possible to
decrease the catalyst loading from 10 mol% to 3 mol%
without observing a decrease of isolated yield, although the
reaction rate was slower. Alkyl and phenyl substituents were
suitable for the reaction (entries 1–5). Moreover, silyl and
benzyl ethers were also tolerated (entries 3–5). Conversely,
aldehyde 3e was not stable at room temperature, even in the
absence of a catalyst, which explains the lower yield obtained
with this substrate (entry 6).
Having established that a tethered olefin is not required for
the reaction to proceed smoothly, we then turned our attention
to the study of the chemoselectivity of this reaction when several
carbon–carbon multiple bonds present in the substrate are
capable of undergoing intramolecular migratory insertion into the
rhodium–hydrogen bond of acylhydridorhodium intermediates.
Substitution of the alkene moiety did not change the chemo-
selectivity initially observed with 1. Hence, treating aldehydes
14a–c with the rhodium catalyst at room temperature afforded
cycloheptenones 15a–c in good isolated yields (Table 2, entries
1–3). As it was the case for 9, aldehydes 14a and b obtained after
Swern oxidation10 were not purified otherwise than by CuSO4
aqueous work up,9 this procedure giving better results over two
steps with those substrates. It is noteworthy that unsubstituted
4-pentenal gave the fastest turnovers in Bosnich’s initial
studies on intramolecular hydroacylation catalysed by cationic
rhodium catalysts.2c Hence, the exclusive formation of cyclo-
heptenone 15a from 14a, as opposed to the possible formation
of a cyclopentanone, attests to the chemoselectivity of the
reaction in favour of the alkylidenecyclopropane moiety. This
complete chemoselectivity does not appear to depend on the
substitution in the a position of the starting aldehyde, since
cycloheptenone 15d was obtained exclusively from aldehyde
14d in much shorter time (entry 4). Finally, we examined the
chemoselectivity of the reaction in the presence of an alkyne
with substrate 14e. Partial decomposition and incomplete
conversion were observed after twelve hours. Nevertheless,
cycloheptenone 15e was obtained in 58% isolated yield (entry 5).
Incomplete conversion and a complex mixture of products were
also obtained when aldehyde 14f, tethered to a simple methyl-
substituted alkyne, was treated with [Rh((ꢀ)-BINAP)]BF4.
However, using [Rh(dppf)]BF4 as a catalyst restored the
A similar instability was observed with 1,3-keto-aldehyde 6
and 1,3-bisaldehyde 9 derived from oxidation of diols 5 and 8,
respectively (Schemes 3 and 4). However, it was possible to
treat 6 and 9 with the optimised catalyst after only minimal
purification by filtration over celite and aqueous work up using a
saturated solution of CuSO4,9 respectively, enabling the rapid
formation of spiro-bisketones 7 and 10 in 80% and 82%
isolated yields over two steps, respectively. It is noteworthy that
the bidirectional intramolecular hydroacylation of 9 into 10
represents an advantageous synthetic shortcut when compared
to the longer linear sequence consisting of functional group
Scheme 3 Formation of spiro-1,3-bisketone. Reaction conditions:
a: Dess–Martin periodinane, NaHCO3, CH2Cl2; b: [Rh(BINAP)]BF4
(10 mol%),6 acetone, 60 1C.
c
10958 Chem. Commun., 2011, 47, 10957–10959
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Table 2 Chemoselectivity favouring alkylidenecyclopropanes over
alkenes and alkynesa
carbon–carbon bond formation in the case of alkylidenecyclo-
propanals whereas decarbonylation and double bond migration
are the dominant pathways in the case of 4-pentenals.2c,7b
Moreover, the reaction is chemoselective in favour of the
alkylidenecyclopropane moiety when an alkene or an alkyne
are tethered to the substrate, a fact which remained to be
established before the present study.
Yieldb
(%)
Entry Substrate
Product
1
75c,d
Financial support from EPSRC (DTA studentship to D.C.),
City of Paris (Scholarship to C.T.), RCUK (Fellowship to C.A.),
and the University of Liverpool is acknowledged. The authors
are also grateful to the EPSRC National Mass Spectrometry
Service Centre in Swansea for some HRMS measurements.
2
70c
Notes and references
1 For reviews, see: (a) M. C. Willis, Chem. Rev., 2010, 110, 725;
(b) G. C. Fu, in Modern Rhodium-Catalyzed Organic Reactions,
ed. P. A. Evans, Wiley-VCH, New York, 2005, p. 85.
2 For selected examples, see: (a) K. Sakai, J. Ido, O. Oda and
N. Nakamura, Tetrahedron Lett., 1972, 13, 1287; (b) R. C. Larock,
K. Oertle and G. F. Potter, J. Am. Chem. Soc., 1980, 102, 190;
(c) D. P. Fairlie and B. Bosnich, Organometallics, 1988, 7, 936;
(d) A. D. Aloise, M. E. Layton and M. D. Shair, J. Am. Chem. Soc.,
2000, 122, 12610; (e) Y. Sato, Y. Oonishi and M. Mori, Angew.
Chem., Int. Ed., 2002, 41, 1218; (f) K. Tanaka and G. C. Fu, J. Am.
Chem. Soc., 2001, 123, 11492; (g) H. D. Bendorf, C. M. Colella,
E. C. Dixon, M. Marchetti, A. N. Matunokis, J. D. Musselman and
T. A. Tiley, Tetrahedron Lett., 2002, 43, 7031; (h) K. Takeishi,
K. Sugishima, K. Sasaki and K. Tanaka, Chem.–Eur. J., 2004,
10, 5681; (i) M. M. Coulter, P. K. Dornan and V. M. Dong,
J. Am. Chem. Soc., 2009, 131, 6932.
3
4
75
99e
3 (a) C. Aıssa and A. Furstner, J. Am. Chem. Soc., 2007, 129, 14836;
(b) D. Crepin, J. Dawick and C. Aıssa, Angew. Chem., Int. Ed.,
2010, 49, 620.
4 (a) R. Campbell Jr., C. F. Lochow, K. P. Vora and R. G. Miller,
J. Am. Chem. Soc., 1980, 102, 5824–5830; (b) D. P. Fairlie and
B. Bosnich, Organometallics, 1988, 7, 946.
5
58
5 I. F. D. Hyatt, H. K. Anderson, A. T. Morehead Jr. and
A. L. Sargent, Organometallics, 2008, 27, 135.
6 (a) R. M. Beesley, C. K. Ingold and J. F. Thorpe, J. Chem. Soc.
Trans., 1915, 107, 1080; (b) M. E. Jung and J. Gervay, J. Am.
Chem. Soc., 1991, 113, 224.
a
b
[Rh((ꢀ)-BINAP)]BF4 (10 mol%),8 acetone, 21 1C, 12 h. Isolated
c
yields. Yield over two steps including Swern oxidation for the
e
preparation of the aldehyde. 4 h. NMR yield after 1 h.
d
7 (a) B. R. James and C. G. Young, J. Chem. Soc., Chem. Commun.,
1983, 1215; (b) T. Sattelkau and P. Eilbracht, Tetrahedron Lett.,
1998, 39, 9647; (c) M. Rolandsgard, S. Baldawi, D. Sirbu,
V. Bjørnstad, C. Rømming and K. Undheim, Tetrahedron, 2005,
61, 4129; (d) S. Mukherjee and B. List, J. Am. Chem. Soc., 2007,
129, 11336; (e) V. Bjørnstad and K. Undheim, Synthesis, 2008, 962.
8 Representative procedure: a Teflon-screw Schlenk flask equipped
with a small stirring bar was charged with [Rh(nbd)2]BF4 (4.4 mg,
0.0117 mmol), (ꢀ)-BINAP (7.8 mg, 0.0117 mmol), and acetone
(2.3 mL) under N2 before bubbling H2 (4.8 mL, 0.199 mmol) via a
syringe before closing the flask under N2. After stirring for 1h at
room temperature, this solution was added to aldehyde 1a (28 mg,
0.117 mmol) in another Teflon-screw Schlenk flask before closing
the flask under N2. After stirring for 12h at room temperature, the
mixture was allowed to cool before evaporation. Purification by
flash chromatography (petroleum ether/ethyl acetate: 250/1) gave
ketone 2 (25 mg, 89%) as white solid.
chemoselectivity and cycloheptenone 15f was obtained in good
isolated yield (Scheme 5), whilst catalysts prepared with other
bisphosphines (e.g. dppe, dppp, dppb) were mostly inactive.11
In conclusion, we have demonstrated that rhodium-catalysed
intramolecular hydroacylation of a,a-disubstituted 4-alkylidene-
cyclopropanals is a smooth process in contrast to the same
reaction conducted on a,a-disubstituted 4-pentenals. In both
cases, a pentarhodacycle intermediate is likely formed prefer-
entially. This intermediate can rearrange toward productive
9 M. L. Grachan, M. T. Tudge and E. N. Jacobsen, Angew. Chem.,
Int. Ed., 2008, 47, 1469.
10 A. J. Mancuso, S.-L. Huang and D. Swern, J. Org. Chem., 1978,
43, 2980.
11 dppf = 1,10- bis(diphenylphosphino)-ferrocene, dppe = 1,2-bis-
(diphenylphosphino)-ethane, dppp = 1,3-bis(diphenylphosphino)-
propane, dppb = 1,4-bis(diphenylphosphino)-butane. We thank
one of the referees for suggesting this experiment.
Scheme 5 Alternative reaction conditions for chemoselective hydro-
acylation of alkylidenecyclopropanes in the presence of simple internal
alkyne.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10957–10959 10959