Benzofurans prepared by C-H bond functionalization with acylsilanes

Article abstract of DOI:10.1002/anie.200804854

(Chemical Equation Presented) Instant carbenes - that's hot: The thermal 1,2-Brook rearrangement of acylsilanes generates siloxycarbene intermediates that can undergo intramolecular C-H bond insertion to provide benzofuran derivatives. This metal-free tan

Full text of DOI:10.1002/anie.200804854

Communications
DOI: 10.1002/anie.200804854
À
C H Functionalization
À
Benzofurans Prepared by C H Bond Functionalization with
Acylsilanes**
Zengming Shen and Vy M. Dong*
Dedicated to Professor Adrian Brook on the occasion of his 85th birthday
The functionalization of inert carbon–hydrogen bonds has
emerged as an exciting strategy in organic synthesis as it
enables unconventional and remarkable bond-forming reac-
tions.[1] Within the broad field of C H bond functionalization,
À
À
the insertion of carbenes into C H bonds is arguably the best
À
Scheme 1. Proposed mechanism for intramolecular C H bond func-
tionalization of acylsilanes.
À
À
approach for directly elaborating a C H bond into a C C
bond.[2] However, this strategy remains limited by the
methods and precursors available for generating carbene
intermediates. While many creative carbene insertions have
been accomplished, the vast majority of these processes have
focused on diazocarbonyl compounds as the carbene pre-
both academic and industrial settings,[7] we chose microwave
irradiation to induce the desired thermal Brook rearrange-
ment. A variety of high-boiling solvents were examined
(Table 1). In accordance with our mechanistic design, irradi-
cursors.[2] Herein, we report a novel and operationally simple
strategy for functionalizing benzylic sp -hybridized C H
bonds. This method features the use of siloxycarbenes
generated directly from acylsilanes by a microwave-assisted
Brook rearrangement.
3
À
Table 1: Solvent effects on the microwave-assisted Brook rearrange-
ment.[a]
À
Our strategy for C H bond functionalization is inspired
by Adrian Brookꢀs discovery of the unique ability of
acylsilanes to undergo thermal and photochemically induced
1,2 silicon-to-oxygen migration.[3] The Brook rearrangement
of acylsilanes has been featured in a range of umpolung
processes with the acylsilanes acting as a carbonyl anion
equivalent.[4] However, the synthetic utility of acylsilanes as
siloxycarbene precursors has remained virtually unexplored
since these seminal reports.[3] Inspired by these accounts, we
envisioned that a thermally induced Brook rearrangement
would generate a transient siloxycarbene that would undergo
Entry 1[a]
Solvent
2a [%][b]
3a [%][b]
4a [%][b]
cis/trans[c]
1
2
3
4
5
6
o-dichlorobenzene
nitrobenzene
ethyl benzoate
DMSO
NMP
diethylene glycol
diethyl ether
92 (72:28)
>99 (67:33)
–
–
–
–
–
–
72
80
–
4
–
27
20
50
22
–
À
rapid insertion to a neighboring C H bond (Scheme 1).
Notably, this Brook rearrangement/insertion cascade would
allow rapid access to important heterocyclic motifs[5] includ-
ing dihydrobenzofurans. Few methods for making 2-phenyl-3-
hydroxydihydrobenzofurans exist.[5a,6] Furthermore, methods
such as the photoinduced cyclization of o-benzyloxybenzal-
dehyde[6] are plagued by competing radical pathways.
[a] Reaction conditions: substrate 1a (0.05m), 2508C, 5 min under
microwave irradiation. [b] Yield was determined from the 1H NMR
spectrum yield with 1,3,5-trimethoxybenzene as the internal standard.
1
[c] Determined by H NMR spectroscopy.
Our studies began with acylsilane 1a derived from readily
available methyl salicylate. Based on its demonstrated
effectiveness for promoting a range of chemical processes in
ation of 1a at 2508C in o-dichlorobenzene for 5 min resulted
in formation of the expected 3-silyloxy-2,3-dihydrobenzo-
furan 2a in excellent yield (92%) and good stereoselectivity
(cis/trans 72:28; Table 1, entry 1). The major isomer was
identified to be the cis diastereomer 2a by single-crystal X-ray
analysis.[8] Microwave heating of 1a in nitrobenzene provided
2a in quantitative yield, albeit with lower diastereoselectivity
(cis/trans 67:33) (Table 1, entry 2).[9] A significant solvent
effect was observed: when the reaction was conducted in ethyl
benzoate (Table 1, entry 3) or DMSO (entry 4), the benzo-
furan product 3a was obtained as the major product (72%
and 80% yield, respectively). Formation of the benzofuran
presumably occurs by loss of silanol from 2a. The use of N-
methylpyrrolidinone (NMP) and diethylene glycol diethyl
[*] Dr. Z. Shen, Prof. V. M. Dong
Department of Chemistry, University of Toronto
80 St. George Street, Toronto, ON, M5S 3H6 (Canada)
E-mail: vdong@chem.utoronto.ca
Homepage: http://www.chem.utoronto.ca/staff/vdong
[**] Financial support was provided by the University of Toronto, the
Canadian Foundation for Innovation, Ontario Research Foundation,
NSERC, and Boehringer Ingelheim.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804854.
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Angewandte
Chemie
ether resulted in protodesilylation to form aldehyde 4a as the
major product (Table 1, entries 5 and 6).
We next examined the scope of acylsilane substrates by
varying the substituents on the aromatic ring and the alkoxy
chain (Table 2). The desired 2,3-dihydrobenzofuran 2a could
trans 25:75; Table 2, entry 8). However, under these reaction
conditions, alkoxy-substituted derivatives 1j and 1k do not
[11]
À
undergo the corresponding aliphatic C H bond insertion.
Remarkably, by simply using DMSO as the solvent, we
could access benzofuran derivatives efficiently; this cascade
sequence requires three distinct steps (Brook rearrangement,
À
C H bond insertion, and loss of silanol) (Table 3). The
À
Table 2: Microwave-assisted Brook rearrangement/C H bond insertion
yielding 2,3-dihydrobenzofurans.[a]
Table 3: Cascade route to benzofurans consisting of Brook rearrange-
[a]
À
ment, C H bond insertion, and desiloxylation.
Entry
1
Product
Yield [%][b]
87
cis/trans[c]
2a
2b
2c
2d
2e
72:28
Entry
Product
Yield [%][b]
2
3
4
5
72
89
74
91
67:33
70:30
69:31
74:26
1
2
3
4
3a
3c
3d
3e
3 f
64
65
67
61
5
64
6
7
8
3g
3h
3i
50
74
38
6
2 f
82
74:26
7
8
9
2g
2h
2i
81
53
31
76:24
25:75
76:24
[a] Reaction conditions: substrate (0.2 mmol), o-dichlorobenzene
(2 mL), 2508C, 10 min, under microwave irradiation. [b] Yield of isolated
product.
[a] Reaction conditions: substrate (0.2 mmol), o-dichlorobenzene
(2 mL), 2508C, 10 min, under microwave irradiation. [b] Yield of isolated
product. [c] Determined by 1H NMR spectroscopy.
competing byproduct formed is the aldehyde that results from
protodesilylation of the acylsilane precursor. Additives such
as 4 ꢁ molecular sieves, CaH2 (1 equiv), and trimethylsilyl
chloride (1 equiv) were ineffective at inhibiting this decom-
position. Different substituents (e.g., CH3, Cl, and Br) were
tolerated on the aromatic ring and the corresponding
benzofurans (3c, 3e–3g) were obtained in 50 to 65% yield
(Table 3, entries 2 and 4–6). The naphthyl-based acylsilane
was transformed into product 3d in 67% yield (Table 3,
entry 3). Notably, the sulfur-containing heterocycle 3h could
be obtained in 74% yield (Table 3, entry 7). The 2-furyl
substituent was tolerated to some extent as 3i was isolated in
38% yield (Table 3, entry 8).
be isolated in good yield (87%; Table 2, entry 1).[10] The
sterically bulkier dimethylphenylsilyl substituent could also
be tolerated in this process to provide the corresponding
dihydrobenzofuran 2b (72% yield, cis/trans 67:33; Table 2,
entry 2). A number of substrates investigated (including those
with Me-, Cl-, and Br-substituted aromatic rings) underwent
À
tandem Brook rearrangement and C H bond insertion to
provide the corresponding 2,3-dihydrobenzofurans in good to
excellent yields (81–92%; Table 2, entries 3 and 5–7) with
moderate diastereocontrol (cis/trans 70:30 to 76:24). Notably,
these products were generated efficiently after microwave
irradiation for less than 10 minutes.
In summary, we have designed and executed a new
approach to forming 2,3-dihydrobenzofuran and benzofuran
À
derivatives under microwave irradiation. This C H bond-
The 2-furylmethoxy substituent was not well tolerated in
this process, and product 2i was obtained in 31% yield (cis/
trans 74:26; Table 2, entry 9). The sulfur-containing 2,3-dihy-
drobenzothiophene could also be synthesized (53% yield, cis/
functionalization strategy involves a thermally induced Brook
rearrangement to form a putative siloxycarbene intermediate.
Solvents play a critical role in product selectivity. We are
currently focused on identifying catalysts to promote this new
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[4] Recent reports of acylsilanes as acyl-anion equivalents: a) R.
Unger, T. Cohen, I. Marek, Org. Lett. 2005, 7, 5313 – 5316; b) X.
Linghu, C. C. Bausch, J. S. Johnson, J. Am. Chem. Soc. 2005, 127,
1833 – 1840; c) A. E. Mattson, K. A. Scheidt, J. Am. Chem. Soc.
2007, 129, 4508 – 4509; d) A. E. Mattson, A. R. Bharadwaj, K. A.
Scheidt, J. Am. Chem. Soc. 2004, 126, 2314 – 2315.
[5] a) M. Yus, F. Foubelo, Adv. Heterocycl. Chem. 2006, 91, 135 –
158; b) B. Gerard, R. Cencic, J. Pelletier, J. A. Porco, Jr., Angew.
Chem. 2007, 119, 7977; Angew. Chem. Int. Ed. 2007, 46, 7831 –
7834.
[6] a) E. M. Sharshira, T. Horaguchi, J. Heterocycl. Chem. 1997, 34,
1837 – 1849; b) T. Horaguchi, C. Tsukada, E. Hasegawa, T.
Shimizu, T. Suzuki, K. Tanemura, J. Heterocycl. Chem. 1991, 28,
1261 – 1272; c) S. P. Pappas, J. B. Blackwell, Jr., Tetrahedron Lett.
1966, 7, 1171 – 1175.
transformation and further exploring the use of acylsilanes as
carbene precursors.
Experimental Section
À
Representative procedure for microwave-assisted siloxycarbene C H
bond insertion in o-dichlorobenzene: A solution of 1a (0.20 mmol,
56.8 mg) in anhydrous o-dichlorobenzene (2.0 mL) was heated to
2508C under microwave irradiation in a sealed 5 mL vial (Biotage)
for 10 min. The reaction mixture was then passed through a column of
silica gel (eluted with 100% pentanes until all the o-dichlorobenzene
was removed, followed by elution with 10% EtOAc/pentanes) to
afford the diastereomers 2a in 87% yield. (cis/trans = 72:28). See the
Supporting Information for details.
[7] See: a) Microwaves in Organic and Medicinal Chemistry (Eds.:
C. O. Kappe, A. Stadler), Wiley-VCH, Weinheim 2005; b) M.
Nꢂchter, B. Ondruschka, W. Bonrath, A. Gum, Green Chem.
2004, 6, 128 – 141.
Received: October 5, 2008
Published online: December 12, 2008
[8] Removal of the silicon group from 2a results in cis-2,3-dihydro-
2-phenylbenzofuran-3-ol (5a), a derivative whose structure was
determined by single-crystal X-ray analysis. See the Supporting
Information for details.
[9] When a solution of 1a in toluene was heated in an oil bath at
1508C for 4 days, 2,3-dihydrobenzofuran 2a was obtained in
84% yield (determined by 1H NMR spectroscopy) and 75:25 cis/
trans selectivity.
[10] Reactions in freshly distilled o-dichlorobenzene afford higher
yields presumably because trace water can promote the decom-
position of the acylsilane to the aldehyde; see a) A. G. Brook,
T. J. D. Vandersar, W. Limburg, Can. J. Chem. 1978, 56, 2758;
b) A. G. Brook, N. V. Schwartz, J. Org. Chem. 1962, 27, 2311 –
2315.
À
Keywords: acylsilanes · Brook rearrangement · C H insertion ·
carbenes
.
À
[1] For reviews on C H functionalization: a) K. R. Campos, Chem.
Soc. Rev. 2007, 36, 1069 – 1084; b) V. Ritleng, C. Sirlin, M.
Pfeffer, Chem. Rev. 2002, 102, 1731 – 1769; c) M. Lersch, M.
Tilset, Chem. Rev. 2005, 105, 2471 – 2526.
[2] For a review of diazo compounds as carbene precursors:
H. M. L. Davies, R. E. J. Beckwith, Chem. Rev. 2003, 103,
2861 – 2903.
[3] At 3508C, pivaloyltrimethylsilane undergoes rearrangement and
À
C H bond insertion to form cyclopropanes; see a) A. R.
Bassindale, A. G. Brook, J. Harris, J. Organomet. Chem. 1975,
90, C6 – C8; b) A. G. Brook, Acc. Chem. Res. 1974, 7, 77 – 84.
[11] See the Supporting Information for structures and spectroscopic
data of 1j and 1k.
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