C-H bond functionalization via hydride transfer: Lewis acid catalyzed alkylation reactions by direct interamolecular coupling of sp3 C-H bonds and reactive alkenyl oxocarbenium intermediates

Full text of DOI:10.1021/ja806068h

Published on Web 12/19/2008
C-H Bond Functionalization via Hydride Transfer: Lewis Acid Catalyzed
Alkylation Reactions by Direct Intramolecular Coupling of sp3 C-H Bonds
and Reactive Alkenyl Oxocarbenium Intermediates
Kevin M. McQuaid and Dalibor Sames*
Department of Chemistry Columbia UniVersity, New York, New York 10027
Received August 1, 2008; E-mail: sames@chem.columbia.edu
Scheme 1. Compensating Lower Reactivity of C-H Bonds by
Increasing the Activation of the Alkene
C-H bond functionalization enables strategically new approaches
to complex organic compounds including biologically active agents,
research probes and functional organic materials.1 Catalytic coupling
of sp3 C-H bonds and alkenes is an attractive strategy as it provides
an overall alkylation of saturated carbon centers under nonbasic
conditions. To complement transition metal-catalyzed processes,2 we
have developed a conceptually different approach to direct coupling
of sp3 C-H bonds and alkenes based on Lewis acid-promoted hydride
transfer (Scheme 1A).3 Although acid-triggered hydride transfer
reactions are known, there are only a few processes where hydride
transfer is coupled to C-C bond formation in a predictable manner.4
We here report a simple and economical method, based on the
generation of highly activated alkenyl-oxocarbenium intermediates,
which expands the scope and efficiency of hydride transfer-initiated
cyclization reactions and avoids the use of transition metal catalysts.
We have previously found that in the cyclization reactions shown
in Scheme 1A, substrates with less reactive C-H bonds (reactivity
can be estimated by considering the cation-stabilizing ability of adjacent
groups) required the use of expensive transition metal Lewis acids
such as PtCl4, or were altogether resistant to the hydride transfer.3 We
now provide additional evidence for this finding, illustrated by substrate
1 which undergoes a very slow cyclization under the preferred
conditions (BF3 ·Et2O, CH2Cl2, RT), taking four days to afford a low
yield of product 2 (Scheme 1B). To address this problem and avoid
the use of expensive Lewis acids, we examined the reactivity of the
corresponding alkenyl acetals, inspired by the high reactivity of alkenyl-
oxocarbenium intermediates toward Diels-Alder reactions and other
transformations.5 When submitted to the standard reaction conditions,
acetal 3 was consumed within one hour, providing a good yield of the
cyclic product 4; direct comparison of acetal 3 to the corresponding
aldehyde 1 revealed a dramatic increase in both reactivity and chemical
yield, as well as an improvement in diastereoselectivity. Remarkably,
a primary ether can undergo alkylation in the R-position at room
temperature!
The mechanistic rationale is depicted in Scheme 2; boron trifluoride
etherate opens the cyclic acetal, generating the oxocarbenium inter-
mediate II, which activates the conjugated double bond for the hydride
abstraction. Subsequent to the hydride transfer step, the resulting
oxocarbenium-enolether intermediate III undergoes rapid C-C bond
formation and the new oxocarbenium species reforms the acetal,
producing the desired product V and the Lewis acid catalyst. The
observed stereoselectivity can be explained by the favorable transition
state, IV, where all substituents are in equatorial positions.
a Isolated yield of diastereomeric mixtures. Diastereomeric ratio determined
by 1H NMR. b Contained varying amounts (<5%) of hydrolyzed products.
Scheme 2. Proposed Mechanistic Rationale
(90%, >20:1, Table 1). The acetal moiety also enabled efficient
cyclization of the allyl ether 7 and the crotyl ether 9 (Table 1, entries
2 and 3).6 As indicated by the cyclization of the ethyl ether 3 (Scheme
1B), less reactive alkyl ethers also underwent the desired cyclization
in high yield and excellent stereoselectivity, including the more
hindered isopropyl ether 11 and cyclohexyl ether 13, both readily
available from 2-propanol and cyclohexanol, respectively (Table 1,
entries 4 and 5). Comparable yields and stereoselectivity were obtained
with lower catalyst loading, which required longer reaction times (5
mol% BF3 ·Et2O, Table 1, entry 4). Other Lewis and protic acids were
examined (e.g., TMSOTf, TiCl4, Bi(OTf)3, MsOH) and proved inferior
to BF3 ·Et2O in terms of obtained yields (by >20%).
To explore the alkylation reaction in a more complex structural
context and to examine the effect of other chirality elements in the
molecule, we synthesized substrate 15 from (-)-menthol (Figure 1).
Under the standard reaction conditions, this compound gave product
16 as the only observed diastereomer. The molecular structure was
confirmed by X-ray analysis (Figure 1). Apparently, the stereoselec-
tivity of the C-C bond forming step is controlled by the adjacent center
We next examined the reactivity of different C-H bonds (in the
R-position to the ether oxygen) in the context of alkenyl acetal and
ketal substrates (Table 1). These compounds are readily available in
few synthetic steps where the alkenyl acetal moiety is installed by the
cross-metathesis between the homoallylic ether or alcohol and com-
mercially available 2-vinyl-1,3-dioxolane (or 2-methyl-2-vinyl-1,3-
dioxolane, Supporting Information). The activated benzyl ether 5
affords the cyclized product in excellent yield and diastereoselectivity
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402 J. AM. CHEM. SOC. 2009, 131, 402–403
10.1021/ja806068h CCC: $40.75
2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Ethylene Glycol Serves as an Organocatalyst.
Table 1. Cyclization of Alkenyl Acetal/Ketal Substrates
a Conditions A: BF3 ·Et2O (0.5 equiv). Conditions B: BF3 ·Et2O (0.5
equiv) and ethylene glycol (0.2 equiv). Reactions performed at 50 °C.
Isolated yield as an average of three runs. Diastereomeric ratio determined
by NMR or GC. b Reaction run at room temperature.
addition of ethylene glycol, affording bicyclic product 22 in 79% yield
as a single diastereoisomer.
a Reactions performed at 0.02-0.03 M in CH2Cl2 with BF3 ·Et2O (0.5
equiv.) at room temperature (<1 h). The major diastereomer is shown.
b Isolated yield as an average of three runs. c Diastereomeric ratio
determined by 1H NMR or GC. d Isolated yield using 0.05 equivalents of
BF3 ·Et2O after 3 h.
The use of boron trifluoride etherate as the Lewis acid and ethylene
glycol as the organocatalyst provides a highly active catalytic system,
presumably via the in situ formation of alkenyl-oxocarbenium inter-
mediates, which eliminates the need for expensive transition metal
Lewis acids or the preparation of acetal/ketal substrates.7,8 This binary
catalytic system expands the scope and improves the efficiency of the
hydride transfer-initiated alkylation reactions.
Acknowledgment. This work was supported by the National
Institute of General Medical Sciences (NIGMS). We thank Dr. S. J.
Pastine for helpful discussions and Professor G. Parkin’s group for
the X-ray analysis (Columbia University, CHE-0619638).
Supporting Information Available: Experimental procedures and
spectroscopic data for starting materials and products. X-ray data for
compound 16 and 22. This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 1. Cyclization of menthol-derived alkenyl acetal 15. Molecular structure
of product 16 as revealed by X-ray analysis. Selected hydrogen atoms have
been added for clarity.
bearing the isopropyl group. This example illustrates the synthetic
power of the hydride transfer-triggered cyclization: a tertiary center is
transformed in one step into a quaternary ether center under mild
conditions and with excellent stereocontrol, providing a novel and
structurally complex spirocyclic product from a readily available terpene.
We next considered the idea of generating the key alkenyl-
oxocarbenium intermediate (such as II, Scheme 2) from a ketone and
ethylene glycol in situ, which would eliminate the need for preparation
of the corresponding ketal. Indeed, addition of ethylene glycol to boron
trifluoride etherate in dichloromethane had a dramatic effect on the
reaction rate as demonstrated in the cyclization of enone 17; the reaction
was complete in less than 12 h, while the same conditions in the
absence of ethylene glycol required 96 h to reach completion (Table
2, the rate plot is shown in the Supporting Information). Optimization
of the reaction conditions showed that best results were obtained with
0.2 equivalents of ethylene glycol under standard conditions; other
diols including chiral diols were investigated and found to be less
effective than ethylene glycol (Supporting Information). Examining
the ethylene glycol effect with the benzyl ether substrate 19 showed
not only a 5-fold increase in rate, but also an improvement in the
isolated yield and stereoselectivity (Table 2, entry 2). Finally, the slow
trans-annular cyclization of cyclohexenone 21 was accelerated by the
References
(1) (a) Godula, K.; Sames, D. Science 2006, 312, 67–72. (b) Davies, H. M. L.
Angew. Chem., Int. Ed. 2006, 45, 6422–6425.
(2) (a) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077–1101. (b)
DeBoef, B.; Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004, 126, 6556–
6557. (c) Shi, L.; Tu, Y.-Q.; Wang, M.; Zhang, F.-M.; Fan, C.-A.; Zhao,
Y.-M.; Xia, W.-J. J. Am. Chem. Soc. 2005, 127, 10836–10837.
(3) Pastine, S. J.; McQuaid, K. M.; Sames, D. J. Am. Chem. Soc. 2005, 127,
12180–12181.
(4) The tert-amino effect cyclizations: (a) Verboom, W.; Reinhoudt, D. N.; Visser,
R.; Harkema, S. J. Org. Chem. 1984, 49, 269–276. Recent review: (b) Ma´tyus,
´
P.; Elia´s, O.; Tapolcsa´nyi, P.; Polonka-Ba´lint, A.; Hala´sz-Dajka, B. Synthesis
2006, 16, 2625–2639. Formation of carbocycles: (c) Atkinson, R. S.; Green,
R. H. J. Chem. Soc., Perkin Tans. 1 1974, 394–401.
(5) (a) Gassman, P. G.; Singleton, D. A.; Wilwerding, J. J.; Chavan, S. P. J. Am.
Chem. Soc. 1987, 109, 2182–2184. (b) Roush, W. R.; Gillis, H. R.; Essenfeld,
A. P. J. Org. Chem. 1984, 49, 4674–4682. Review: (c) Harmata, M.;
Rashatasakhon, P. Tetrahedron 2003, 59, 2371–2395.
(6) For oxidative alkylation of benzyl and allyl ethers using an external oxidant,
see: Tu, W.; Liu, L.; Floreancig, P. E. Angew. Chem., Int. Ed. 2008, 47, 4184–
4187.
(7) For enantioselective hydride reduction of R,ꢀ-unsaturated aldehydes and ketones
using amine organocatalysts, see: (a) Ouellet, S. G.; Tuttle, J. B.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2005, 127, 32–33. (b) Ouellet, S. G.; Walji,
A. M.; MacMillan, D. W. C. Acc. Chem. Res. 2007, 40, 1327–1339.
(8) Unfortunately, the amine organocatalysts were not able to catalyze the
intramolecular alkylation reactions discussed in this paper.
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