Sterically hindered benzophenones via rhodium-catalyzed oxidative arylation of aldehydes

Article abstract of DOI:10.1021/jo801460w

(Chemical Equation Presented) Efficient cross-coupling, allowing a straightforward access to congested benzophenones, between aromatic aldehydes and potassium aryltrifluoroborates, is described in the presence of a rhodium/tri-tert-butylphosphane catalyst system and acetone as cosolvent. The use of the stable phosphonium salts of tri-tert-butylphosphane prevented the use of highly oxidizable tri-tert-butylphosphane and allowed a careful control of the stoichiometry with the rhodium.

Full text of DOI:10.1021/jo801460w

of the condensation of an organometallic reagent (lithium,
magnesium) to aldehydes followed by oxidation.6 However,
these reactions, conducted under either highly basic and
nucleophilic or acidic conditions, are incompatible with most
functional groups, and the construction of elaborated benzophe-
nones generally involves further functionalization steps that are
time-consuming and generally low yielding.1-6
Sterically Hindered Benzophenones via
Rhodium-Catalyzed Oxidative Arylation of
Aldehydes
Olivier Chuzel, Alexander Roesch, Jean-Pierre Genet,* and
Sylvain Darses*
Alternatively, the transition-metal-catalyzed reaction of acyl
chlorides or anhydrides with organometallic reagents (mainly
organoboronic acids) has emerged as a promising tool to
construct benzophenone frameworks under milder conditions.7
Another elegant approach, starting from aldehydes, consists of
a transition-metal-catalyzed hydroacylation reaction8 or Heck-
type reaction with aryl halides9 or organoboranes.10,11 Prepara-
tion of hindered benzophenones under mild conditions would
be highly desirable but is still a challenge in organic synthesis.
However, all these reactions, and particularly the highly
desirable mild transition-metal-catalyzed reactions, are limited
to reagents that are sterically unencumbered. The majority of
biologically active benzophenones are sterically congested
substrates2,6 (at least di-ortho-substituted) and are still, and more
efficiently, prepared by the addition of aryllithium or arylmag-
nesium to aldehydes followed by oxidation.12
Laboratoire de Synthe`se Se´lectiVe Organique (UMR 7573,
CNRS), Ecole Nationale Supe´rieure de Chimie de Paris,
11 rue P&M Curie, 75231 Paris cedex 05, France
sylVain-darses@enscp.fr; jean-pierre-genet@enscp.fr
ReceiVed July 4, 2008
Efficient cross-coupling, allowing a straightforward access
to congested benzophenones, between aromatic aldehydes
and potassium aryltrifluoroborates, is described in the pres-
ence of a rhodium/tri-tert-butylphosphane catalyst system and
acetone as cosolvent. The use of the stable phosphonium
salts of tri-tert-butylphosphane prevented the use of highly
oxidizable tri-tert-butylphosphane and allowed a careful
control of the stoichiometry with the rhodium.
We report here a solution to this longstanding limitation: a
direct access to highly congested benzophenones under very
mild conditions. We recently described a straightforward access
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7800 J. Org. Chem. 2008, 73, 7800–7802
10.1021/jo801460w CCC: $40.75 2008 American Chemical Society
Published on Web 08/28/2008

TABLE 1. Rhodium-Catalyzed Formation of Congested
Benzophenones from Aldehydesa
SCHEME 1. Rhodium-Catalyzed Formation of Congested
Benzophenones
entry
Ar1CHO
Ar2BF3K
yieldb
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1c
1d
1h
1g
1i
2a
2a
2b
2a
2a
2a
2d
2c
2f
97%c (3aa)
98% (3aa)
87% (3ab)
94% (3ba)
69% (3ca)
79% (3da)
77% (3hd)
48% (3gc)
52%d (3if)
9
70%d e (3if)
,
10
11
12
13
14
15
16
17
18
1i
2f
1e
1j
1i
1j
1i
1i
1e
1j
2a
2e
2a
2a
2e
2c
2c
2c
76% (3ea)
90% (3je)
62% (3ia)
76% (3ja)
45%d (3ie)
31%d,f (3ic)
59% (3ec)
65% (3jc)
to benzophenones via the rhodium-catalyzed coupling of orga-
noboron reagents, and particularly potassium organotrifluoro-
borates,13,14 with aldehydes using inexpensive acetone as hydride
acceptor.10a However, the presence of ortho-substituents on both
reaction partners generally prevented the formation of ben-
zophenones, low yields, or absence of reactivity being observed,
as well as reproducibility problems. Moreover, the use of
unstable P(t-Bu)3 as a ligand, which is readily oxidized,
prevented a careful control of the stoichiometry of the ligand
compared to rhodium. We wondered if the use of stable, easily
handled, and commercially available phosphonium salt HP-
a Reactions conducted using 0.5 mmol of 1, 2 equiv of 2 with 1.5 mol
% of [Rh(CH2CH2)2Cl]2, 3 mol % of HP(t-Bu)3BF4, and 3 mol % of
K2CO3 at 80 °C in 2.5 mL of 1,4-dioxane/acetone 4:1. b Isolated yield
of ketone. c Using 3 mol % of i-Pr2NEt in place of K2CO3. d Reaction
conducted at 100 °C. e Using 6 mol % of HP(t-Bu)3BF4 and 6 mol % of
K2CO3. f Formation of 46% of (2,6-dimethylphenyl)(2-methoxynaph-
thalen-1-yl)methanol.
SCHEME 2. Low Catalytic Loading in the
Rhodium-Catalyzed Formation of Benzophenones
15
(t-Bu)3BF4 would provide a solution to previous limitations.
Several bases, used in catalytic amount, were evaluated to
release the free phosphane ligand in the rhodium-catalyzed
reaction of potassium 2-methylphenyltrifluoroborate (2a) with
4-methoxybenzaldehyde (1a) (Scheme 1). Potassium carbonate
and diisopropylethylamine were found to be suitable (Table 1,
entries 1 and 2), affording nearly quantitative yield of ortho-
substituted benzophenone 3aa in a dioxane/acetone mixture at
80 °C and in less than 1 h. Because of its low cost and ease of
handling, potassium carbonate was selected to liberate the ligand
from its salt.
SCHEME 3. Rhodium-Catalyzed Addition of Potassium
Alkenyltrifluoroborates
Indeed, using 1 equiv of P(t-Bu)3 as its phosphonium salt
compared to rhodium, high yields of mono- and di-ortho-
substituted benzophenones were achieved in the reaction of
various potassium aryltrifluoroborates and aldehydes (Scheme
1, Table 1, entries 1-10). Heterocyclic aldehydes, such as
thiophene (1b), furan (1d), pyrrole (1g), or indole (1h) deriva-
tives, underwent clean reaction with different ortho-substituted
trifluoroborate salts, affording straightforward access to hetero-
cyclic benzophenones (entries 4 and 5 and 7 and 8) whose
preparation, using conventional reactions, is not obvious. In the
same way, acidic phenol functional groups were tolerated (entry
6). For certain substrates, an increase of the reaction temperature
to 100 °C, as well as an increase of the amount of P(t-Bu)3
compared to rhodium, allowed a significant increase in the yields
(entries 9 and 10).
pleased to find that tri- and even tetra-ortho-substituted ben-
zophenones were readily accessed in moderate to good yields
using this reaction (entries 11-18). For example, reaction of
1j, a di-ortho-substituted aldehyde, with 2e afforded the tri-
ortho-substituted ketone 3je in 90% yield, and on reaction with
2c, tetra-ortho-substituted benzophenone 3jc was obtained in
65% yield (entries 12 and 18). Slightly lower yields were
observed in the formation of some sterically hindered tetra-
ortho-substituted benzophenones because of competitive forma-
tion of carbinol with those congested substrates (entry 16).
However, yields ranging from 31 to 65% (entries 16-18) were
achieved for the direct preparation of tetra-ortho-substituted
benzophenones from aldehydes using this one-step reaction.
Indeed, it appeared that the only competitive methods to this
reaction are the condensation of aryllithium or arylmagnesium
to acyl chlorides or aldehydes followed by oxidation, reactions
occurring under highly basic conditions that are incompatible
with hydroxyl, carbonyl, cyano, and other labile functional
groups. It is also important to note that all the reactions were
complete within less than 1 h in the presence of 3 mol % of
catalyst. However, reactions conducted on aliphatic aldehydes
failed to give any detectable traces of ketone: only carbinols
were obtained in moderate yield.
We wondered if these conditions would be amenable for the
construction of highly congested benzophenones. We were
(13) Reviews: (a) Darses, S.; Genet, J.-P. Eur. J. Org. Chem. 2003, 4313.
(b) Molander, G. A.; Figueroa, R. Aldrichimica Acta 2005, 38, 49. (c) Molander,
G. A.; Ellis, N. M. Acc. Chem. Res. 2007, 40, 275. (d) Stefani, H. A.; Cella, R.;
Vieira, A. S. Tetrahedron 2007, 63, 3623. (e) Darses, S.; Genet, J.-P. Chem.
ReV. 2008, 108, 288.
(14) For some Rh-catalyzed reactions involving RBF3K, see: (a) Navarre,
L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004, 43, 719. (b) Pucheault,
M.; Darses, S.; Genet, J.-P. Chem. Commun. 2005, 4714. (c) Navarre, L.;
Martinez, R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130, 6159.
(15) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
J. Org. Chem. Vol. 73, No. 19, 2008 7801

1.5 mol %), HP(t-Bu)3BF4 (4.4 mg, 3.0 mol %), K2CO3 (2.1 mg,
3.0 mol %), and potassium 2-naphthyltrifluoroborate 2f (234 mg,
1.0 mmol, 2.0 equiv) were introduced successively, placed under
argon atmosphere, and dissolved in 1 mL of freshly degazed 1,4-
dioxane. After 15 min, aldehyde 1i (93 mg, 0.5 mmol) in solution
in 0.5 mL of anhydrous degazed acetone and 1 mL of dioxane were
added, and the reaction mixture was heated at the indicated
temperature. After the reaction was complete, solvents were
removed under reduced pressure and the crude product purified by
chromatography on silica gel to afford 81 mg of a light yellow
solid (52% yield): Rf (Ch/AcOEt, 90:10) ) 0.41; flash chromatog-
raphy eluent cyclohexane/AcOEt 98:2; 1H NMR (300 MHz, CDCl3)
δ 3.83 (3H, s), 7.33-7.42 (3H, m), 7.45-7.52 (1H, m), 7.55-7.65
(2H, m), 7.80 (1H, d, 3J ) 8.1 Hz), 7.85-7.95 (3H, m), 8.01 (1H,
d, J ) 9.0 Hz), 8.12 (1H, dd, J ) 8.4 Hz, J ) 1.7 Hz), 8.24
(1H, s); 13C NMR (75 MHz, CDCl3) δ 56.6, 113.2, 123.1, 124.2,
124.6, 126.6, 127.5, 127.8, 128.2, 128.5, 128.6, 128.9, 129.8, 131.3,
131.9, 132.3, 132.7, 135.5, 136.0, 154.2, 197.7; EI-MS m/z ) 312
[M]+ (100%); HRMS (EI) calcd for C22H16O2 312.1150, found
312.1146.
To demonstrate further the synthetic usefulness of this
procedure, a reaction was conducted using lower catalyst
loading. Indeed, reaction of aldehyde 1a and potassium aryl-
trifluoroborate 2a in the presence of 0.25 mol % of rhodium
dimer catalyst afforded the expected benzophenone 3aa in
quantitative yield (Scheme 2).
Contrary to the reaction with potassium aryltrifluoroborates,
the reaction of aldehydes with alkenyltrifluoroborates did not
yield the expected R,ꢀ-unsaturated ketone, but a saturated
product. Indeed, reaction of 1a with potassium styryltrifluo-
roborate (2g) under optimized conditions afforded ketone 3ag
in 77% yield (Scheme 3) because the generated intermediate
enone is a better hydride acceptor than acetone.10a,b
We have described for the first time a straightforward access
to congested benzophenone frameworks starting from readily
available aryl aldehydes and potassium aryltrifluoroborates. This
reaction, occurring under neutral conditions, allowed the direct
formation of di-, tri-, and even tetra-ortho-substituted benzophe-
nones under operationally simple conditions, thanks to the use
of stable phosphonium salt of P(t-Bu)3. This reaction, operation-
ally simple and providing efficient alternative for the construc-
tion of benzophenones, would be useful in organic synthesis.
3
3
4
Acknowledgment. This work was supported by the Centre
National de la Recherche Scientifique (CNRS).
Supporting Information Available: Experimental proce-
dures and description and NMR spectra of compounds 3aa-3jc.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental Section
General Procedure for the Synthesis of Benzophenones:
Preparation of (2-Methoxy-1-naphthyl)-(2-naphthyl)methanone
(3if), entry 9. In a septum-capped vial, [Rh(C2H4)2Cl]2 (2.9 mg,
JO801460W
7802 J. Org. Chem. Vol. 73, No. 19, 2008