Deoxybenzoins from Stille carbonylative cross-couplings using molybdenum hexacarbonyl

Article abstract of DOI:10.1016/j.tetlet.2010.10.115

Stille-type carbonylative cross-couplings, employing palladium catalysis and Mo(CO)₆ as the carbon monoxide carrier, were used for the preparation of deoxybenzoins. Straightforward transformations were conveniently performed in closed vessels at 100 °C, providing the products in good yields. Benzyl bromides and chlorides were used as coupling partners with aryl and heteroaryl stannanes. This mild three-component carbonylation employs the destabilizing agent DBU to promote smooth release of carbon monoxide from Mo(CO)₆, which made this protocol operationally simple and minimized the formation of Stille diarylmethane products.

Full text of DOI:10.1016/j.tetlet.2010.10.115

Tetrahedron Letters 51 (2010) 6886–6889
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Deoxybenzoins from Stille carbonylative cross-couplings using
molybdenum hexacarbonyl
⇑
Jonas Sävmarker, Jonas Lindh, Peter Nilsson
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Center, Uppsala University, PO Box 574, SE-751 23 Uppsala, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Stille-type carbonylative cross-couplings, employing palladium catalysis and Mo(CO)6 as the carbon
monoxide carrier, were used for the preparation of deoxybenzoins. Straightforward transformations were
conveniently performed in closed vessels at 100 °C, providing the products in good yields. Benzyl bro-
mides and chlorides were used as coupling partners with aryl and heteroaryl stannanes. This mild
three-component carbonylation employs the destabilizing agent DBU to promote smooth release of car-
bon monoxide from Mo(CO)6, which made this protocol operationally simple and minimized the forma-
tion of Stille diarylmethane products.
Received 13 September 2010
Revised 6 October 2010
Accepted 22 October 2010
Available online 30 October 2010
Keywords:
Stille
Molybdenum hexacarbonyl
Deoxybenzoins
Palladium
Ó 2010 Elsevier Ltd. All rights reserved.
1,2-Diarylated ethanones (deoxybenzoins) are a common motif
among approved pharmaceuticals such as the anti-inflammatory
Bermoprofen,1 in oxacarbazepine2 (anticonvulsant) and in analge-
sics such as Narceine.3 Deoxybenzoins are also important building
blocks in heterocyclic chemistry (e.g., formation of isoxazoles,4
strates. Our original protocol using 10 mol % of the palladium
catalyst, PdCl2(dppf)ꢀCH2Cl2, one equivalent of Mo(CO)6, and
10 mol % of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) in DMF is a
very robust protocol for diarylketone synthesis employing aryl
triflates and bromides in couplings with various aryl stannanes.13
Thus, there was a clear incentive to examine additional organo-
halide moieties, prone to undergo oxidative addition to palladium,
in order to further extend the methodology.
Initially, we decided to investigate a set of suitable moieties
lacking activated b-hydrogens (Scheme 1).19 The first attempts
using simple vinyl bromide and methyl iodide proved unsuccessful
with only a trace amount of carbonylation product formed.
According to LC–MS the organohalides were consumed and
benzophenone was formed as the major product. However,
employing the styryl substrates, cis/trans-b-bromostyrene (50:50)
and 2-bromoindene produced 72% and 33% yields of carbonylation
pyrazoles,1 and indoles5). The synthesis, via the direct
a-arylation
of acetophenones has, during the past decade enjoyed a renais-
sance due to the discovery of the simple two-component coupling
between acetophenones and a suitable Ar-X reagent (X is com-
monly a halogen) under palladium catalysis.6,7 Classically, this type
of reaction is performed using a
-halo carbonyl compounds8 or pre-
formed enolates.9 Modern methods also include other approaches
such as the Negishi coupling of benzyl zinc derivatives to aroyl
chlorides.10
Previously, our group developed a methodology relying on
sequential Heck-arylations of enol ethers to obtain deoxybenzoins
after hydrolysis.11 In addition to a cobalt-catalyzed carbonylation12
procedure to access symmetrical diarylketones using solid
Co2(CO)8 and microwaves, we have developed a Stille carbonyla-
tive cross-coupling method13 to obtain a variety of unsymmetrical
diarylketones. Synthetic advantages of the Stille carbonylation
reaction include: the wide functional group tolerance exhibited
by organostannanes, thus increasing the number of available build-
ing blocks, the three-component14 nature of this coupling, and
additionally, the convenience of non-gaseous substrates.15–18
Herein, we present an investigation of the scope and limitation
of a Stille carbonylation protocol using vinyl and alkyl halide sub-
products, respectively.
a
-Bromostyrene was productive (ꢁ60%
yield) but could not be separated from the major side product
benzophenone. Substrates such as allyl and cinnamyl bromides
furnished less than 10% yields. A plausible explanation is that a
p
-allyl mechanism is competing with the carbonylative catalytic
cycle.20 It should be noted that, in addition to palladium, molybde-
num carbonyls are also known to form
p
-allyl complexes and may
O
[Pd], Mo(CO)6
PhSnBu3
+
R'-X
DBU, DMF
100 °C, 16 h
Ph
R'
1a
⇑
Corresponding author. Tel.: +46 184714338; fax: +46 18 4714474.
E-mail address: peter.nilsson@orgfarm.uu.se (P. Nilsson).
Scheme 1. Carbonylative coupling of phenyl stannane with different electrophiles
(R0 = vinyl, methyl, styryl, allyl; X = Br, and I).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.115

J. Sävmarker et al. / Tetrahedron Letters 51 (2010) 6886–6889
6887
tion of the benzyl halide. Purification was straightforward follow-
ing
standard procedure.24 The effective CO concentration
O
X
Ar'
[Pd], Mo(CO)6
ArSnBu3
+
a
Ar'
Ar
DBU, DMF
100 °C, 16 h
X=Br 2a-l
X=Cl 3a-k
appeared sufficient as no direct Stille coupling product was ob-
served. Coupling of benzyl bromide with phenylstannane delivered
deoxybenzoin in an encouraging 72% yield. A small temperature/
time investigation using microwave25 heating indicated lower
yields at elevated temperatures (Table 1, entry 1). Benzyl chloride
performed slightly better, producing an increased yield (81%)
under standard conditions (entry 2). Electron-rich 4-methoxybenz-
yls reacted smoothly to give satisfactory yields with both the
4a-p
1a-e
Scheme 2. Carbonylative coupling of arylstannanes with different benzyl halides
furnishing deoxybenzoins.
also undergo oxidative addition in rare cases.21,22 However, the
major product formed was yet again benzophenone. Further
screening of organohalides led to the benzylic halides, with the
prospect of direct assembly of deoxybenzoins. Somewhat expect-
bromide and chloride (entries 3 and 4). The weakly
r-donating
4-methylbenzyl bromide 2c furnished a slightly higher yield
(73%, entry 5). Moving the methoxy-substituent to the meta posi-
tion improved the outcome indicating the weak influence of elec-
tronic factors (entry 6). Accordingly, the highest yields from the
bromides were obtained using strong electron-withdrawing
groups as in entries 7 and 10. As expected, trifluoromethyl substi-
tuted benzyl chloride 3i reacted smoothly (entry 11). Unfortu-
edly, devoid of high C–X bond energy23 and diminished
p-allyl
likelihood, benzyl halides were indeed found to be compatible
substrates with our present carbonylation protocol to provide
deoxybenzoins in a very versatile and straightforward fashion
(Scheme 2).
All the reactions in Table 1 were performed in sealed vessels
and typically run overnight at 100 °C enabling complete consump-
nately,
a carboxylate moiety was not compatible with this
Table 1
Carbonylative cross-coupling of organostannanes with different electrophilesa producing 4a–p via the reaction depicted in Scheme 2
Entry
1
R-SnBu3
R
R0-X
Reaction time (h)
Product RCOR0
Isolated yield (%)
16
72
53
67
51
O
0.5 (140 °C)c
Ph
1a
1a
1a
Benzyl bromide
2a
3a
2b
4a
4a
4b
1 (140 °C)c
1 (160 °C)c
Ph
O
Ph
O
2
3
Ph
Ph
Benzyl chloride
16
16
81
53
OMe
OMe
4-Methoxybenzyl bromide
Ph
O
4
Ph
1a
4-Methoxybenzyl chloride
3b
16
4b
61
Ph
O
5
6
Ph
Ph
1a
1a
4-Methylbenzyl bromide
3-Methoxybenzyl bromide
2c
16
16
4c
73
62
Ph
O
2d
4d
Ph
OMe
F
O
Ph
O
7
Ph
1a
3,5-Difluorobenzyl bromide
2e
16
4e
81
F
COOH
8
9
Ph
Ph
1a
1a
(4-Carboxy)benzyl bromide
2f
16
16
4f
No product
65
Ph
O
COOMe
(4-Methoxycarbonyl)benzyl chloride
3g
4g
Ph
O
O
Ph
10
Ph
1a
(4-Benzoyl)benzyl bromide
2h
16
4h
76
70
Ph
O
11
12
Ph
Ph
1a
1a
(3-Trifluoromethyl)benzyl chloride
4-Chlorobenzyl chloride
3i
3j
16
16
4i
4j
Ph
O
CF3
Cl
68b
Ph
(continued on next page)

6888
J. Sävmarker et al. / Tetrahedron Letters 51 (2010) 6886–6889
Table 1 (continued)
Entry
R-SnBu3
R
R0-X
Reaction time (h)
16
Product RCOR0
Isolated yield (%)
66b
Br
Br
O
13
Ph
1a
4-Bromobenzyl bromide
2k
4k
Ph
O
O
14
15
Ph
Ph
1a
1a
4-Bromobenzyl chloride
3-Chlorobenzyl bromide
3k
2l
16
16
4k
4l
65b
73b
Ph
Ph
Cl
O
O
Ph
Ph
16
3-Pyridyl
1b
Benzyl bromide
2a
16
4m
No product
N
17
18
19
2-Pyridyl
2-Thienyl
2-Furyl
1c
1d
1e
Benzyl bromide
Benzyl bromide
Benzyl bromide
2a
2a
2a
16
16
16
4n
4o
4p
No product
N
O
Ph
Ph
54
42
S
O
O
a
The reaction was conducted in closed vessels at 100 °C on a 1 mmol scale (2a–f, h, k, l or 3a, b, g, and i–k) with 1.4 equiv of 1a–e, 10 mol % PdCl2(dppf)2ꢀCH2Cl2, 1 equiv of
Mo(CO)6, and 10 mol % DBU in DMF (2 mL).
b
1.1 equiv of 1a.
c
The reaction vessel was subjected to microwave heating at the specified temperature.
reaction protocol as no product could be isolated (entry 8). This can
be attributed to interfering coordination to palladium by the car-
boxylate. The analogous methyl ester 3g worked well (entry 9).
The chemoselectivity for activation of the C(sp2)-X and C(sp3)-X
bond was in complete favor of the benzylic halogen as was evident
from entries 7 and 12ꢂ15.23,26,27 This is an important finding as
halogens are ubiquitous aromatic substituents in many synthetic
routes. A slightly smaller excess (1.1 equiv) of arylstannane was
used in entries 12–15 to prevent further reaction with the aryl ha-
lide product. Overall benzyl chlorides performed slightly better or
equally well compared to the corresponding bromides (cf. entries
1–4, 13, and 14).
Acknowledgments
We would like to thank Dr. Luke Odell for critically reviewing
this manuscript and the Knut and Alice Wallenberg Foundation
for helpful support of this investigation.
Supplementary data
Supplementary data (a detailed experimental procedure and
spectra from LC–MS, GC–MS and NMR) associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.
2010.10.115.
In contrast to our previous report13 heteroaromatic stannanes
such as the 3- and 2-pyridines 1b and 1c were incompatible with
this protocol, yielding no products (entries 16 and 17). Competing
benzylation of the pyridine nitrogen seems to be the cause as a ra-
pid production of destannylated N-benzylpyridinium salt was de-
tected by LC–MS. However, non-nucleophilic heteroaromatics
such as thiophene and furan furnished workable yields (entries
18 and 19). Product 4o can be found as a motif in the antihistamine
pharmaceutical ketotifen.
References and notes
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In conclusion, we have successfully developed a convenient and
flexible protocol for carbonylative Stille couplings employing a so-
lid CO-source. Benzyl bromides and chlorides showed broad scope
producing high yields of products and also allowed couplings with
some heteroaromatic stannanes. To the best of our knowledge, this
is the first report where a carbonylative Stille cross-coupling is
used in the production of deoxybenzoins. A broad array of 1,2-ary-
lated ethanones were produced, in good to high yields, employing
a single standard protocol for both benzyl chlorides and bromides.
Further investigations are currently ongoing in our laboratory to
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24. Typical experimental procedure: To a vial (2–5 mL) containing a Teflon coated
stirring bar was added benzyl halide (1.0 mmol), aryltributyltin (1.4 mmol),
PdCl2(dppf)2ꢀCH2Cl2 (81.7 mg, 0.1 mmol), Mo(CO)6 (264 mg, 1.0 mmol), DBU
(15 mg, 0.1 mmol), and DMF (2 mL). The vial was then sealed under air, placed
in a heating block, and stirred at 100 °C for 16 h. After cooling, the mixture was
diluted with CH2Cl2 (10 mL) and then washed with 0.1 M NaOH (aq, 10 mL).
The organic phase was separated, filtered through Florisil, and concentrated in
vacuo. The residue was purified by silica chromatography, eluting with
pentane/EtOAc (9:1) to furnish the pure products in the yields specified in
Table 1.
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