Lewis acid-promoted friedel-crafts alkylation reactions with α-ketophosphate electrophiles

Article abstract of DOI:10.1021/ol100410k

The BF₃·OEt₂-promoted nucleophilic substitution of α-aryl-α-ketophosphates to afford α,α-diaryl ketone products is described. Electron-rich α-ketophosphates perform best, with electron-neutral and electron-poor substrates also tolerated. The reaction is tolerant of a range of aromatic, heteroaromatic, and nonaromatic nucleophiles, with yields ranging from 44% to 84%. Enantioenriched starting material yields racemic product, suggesting an S_N1 pathway via an acylcarbenium ion.

Full text of DOI:10.1021/ol100410k

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1784-1787
Lewis Acid-Promoted Friedel-Crafts
Alkylation Reactions with
r-Ketophosphate Electrophiles
Austin G. Smith and Jeffrey S. Johnson*
Department of Chemistry, UniVersity of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599-3290
jsj@unc.edu
Received February 17, 2010
ABSTRACT
The BF3·OEt2-promoted nucleophilic substitution of r-aryl-r-ketophosphates to afford r,r-diaryl ketone products is described. Electron-rich
r-ketophosphates perform best, with electron-neutral and electron-poor substrates also tolerated. The reaction is tolerant of a range of aromatic,
heteroaromatic, and nonaromatic nucleophiles, with yields ranging from 44% to 84%. Enantioenriched starting material yields racemic product,
suggesting an SN1 pathway via an acylcarbenium ion.
R-Aryl carbonyl compounds have garnered considerable
attention as synthetic targets, most notably in the chemical
production of nonsteroidal anti-inflammatory drugs (NSAIDs).
Common drugs such as naproxen, ibuprofen, fluribiprofen,
and dichlofenac all contain this moiety.1 The Pd(0)-catalyzed
R-arylation of ketones, pioneered concurrently by Buchwald,
Hartwig, and Miura in 1997, has served as the premier route
to these products.2,3 In recent years, this methodology has
been expanded to include esters, amides, aldehydes, and
lactones as carbonyl coupling partners in the presence of an
aryl halide or triflate and a Bronsted base.4,5
whether formation of an Ar-CR bond was possible through
polarity reversal, or umpolung methodology,6 with Friedel-
Crafts alkylation occurring at an electrophilic R-carbon
(Figure 1). Such a route could be envisioned from a substrate
The aforementioned transition metal-catalyzed routes take
advantage of the conventional reactivity patterns of nucleo-
philic ketone enolates and electrophilic Pd(II) intermediates
to arrive at R-arylated carbonyls. We wanted to observe
(1) Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2002, 41, 953–956.
(2) (a) Hamann, B. C.; Hartwig, J. J. Am. Chem. Soc. 1997, 119, 12382–
12383. (b) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,
11108–11109. (c) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew.
Chem., Int. Ed. 1997, 36, 1740–1742
(3) For an example of Pd(0)-catalyzed enolate vinylation, see: Piers,
E.; Marais, P. C. J. Org. Chem. 1990, 55, 3454–3455
(4) For an R-arylation review, see: Culkin, D. A.; Hartwig, J. F. Acc.
Chem. Res. 2003, 36, 234–245
.
Figure 1
. Transition metal-catalyzed enolate arylation (top) and
.
Friedel-Crafts alkylation via an umpolung strategy (bottom).
.
10.1021/ol100410k  2010 American Chemical Society
Published on Web 03/17/2010

with a sufficient nucleofuge in place adjacent to the carbonyl
functionality (Figure 2).
method would provide a simple route to R,R-diaryl ketones.
R-Acylcarbenium ions have been trapped in solution by
treating R-halobenzyl ketones with AgSbF6 in the presence
of phenol and methanol.13,14
We initially tested this reaction design by subjecting
R-ketophosphate 1 to a number of readily available and
inexpensive Lewis acids in the presence of anisole in CH2Cl2
(Table 1). We observed the desired product 2a regardless of
Table 1. Initial Reaction Conditions for the Coupling of
R-Ketophosphate 1 with Anisolea
Figure 2. Umpolung approach to R,R-dialkyl carbonyls.
An umpolung R-alkylation route has precedent. In 2004,
Ready and Malosh described the copper-catalyzed cross-
coupling of primary and secondary organozinc halides with
R-chloroketones, providing R-branched ketones in high
yields with inversion of configuration at the R-carbon.7
In 2008, Breit and Studte described a zinc-catalyzed
stereospecific sp3-sp3 cross-coupling reaction involving
alkyl Grignard reagents and R-hydroxy ester triflates.8 The
umpolung alkylation route becomes especially attractive
if the needed functionality (i.e., nucleofuge) can be directly
installed in conjunction with another synthetic operation.
In this context, we noted a potential connection to our
previous work demonstrating that cyanide-catalyzed ad-
ditions of acyl phosphonates to aldehydes provide R-keto
phosphate products (Figure 2).9,10 Acyl phosphonates are
easily prepared in one step via the Michaelis-Arbuzov
reaction, rendering them a convenient acyl donor. The
“phospha-benzoin” reaction forms a C-C bond and installs
a potential nucleofuge in a concomitant fashion. In principle,
R-substitution reactions are feasible directly on these benzoin
products with no prior functional group manipulation re-
quired, distinguishing this cross-benzoin route from those
conducted with aldehydes, acyl silanes, or benzils as acyl
donors.11,12
entry
Lewis acid
solvent
yield (%)b
1
2
3
TiCl4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
66
67
66
66
61
59
76
80
71
99
85
74
66
0
BF3·OEt2
TMSOTf
ZnCl2
4
5c
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
6d
7e
8
9
CCl4
CH3CN
(CH2)2Cl2
benzene
1,2-DME
10
11
12
13
14-19f
toluene
f
a Reactions were performed on 0.15 mmol scale, using 1.0 equiv of
Lewis acid in CH2Cl2 (1.5 mL) at 23 °C for 5 h. b Isolated yields obtained
after flash chromatography. c Reaction performed at 80 °C for 5 h. d Reaction
performed on 0.15 mmol scale, using 10 mol % catalyst loading. e Entries
7-13 were performed on 0.0285 mmol scale, using 100 mol % of BF3·OEt2
in the specified solvent (0.29 mL) at 23 °C for 5 h. Yields were calculated
by 1H NMR with mesitylene as an internal standard. f Entries 14-19:
t
acetone, BuOMe, Et2O, THF, DMF, DMA.
the Lewis acid tried. Performing the reaction at elevated
temperatures did not increase the yield for this substrate
(entry 5, Table 1). The reaction was catalytic in Lewis acid.
Product formation was seen in 59% yield when 10 mol %
BF3·OEt2 was used (entry 6, Table 1); however, significantly
longer reaction times and diminished yields for a number of
different substrates led us to examine the reaction scope using
a full equivalent of BF3·OEt2.
Reaction conditions with different solvents were also
explored. Several polar aprotic solvents yielded no desired
product, and only R-ketophosphate 1 was recovered (entries
14-19); strongly Lewis basic solvents quelled catalyst
reactivity, but the reaction was tolerant of more moderate
Lewis bases without competitive Ritter-type reactivity (entry
9). Arene alkylation proceeded in less polar solvents as well
as chlorinated solvents, with 1,2-dichloroethane being su-
perior (entry 10).
We hypothesized that treating an R-ketophosphate with
an appropriate Lewis acid could promote phosphate group
ionization and generate an R-acylcarbenium ion that could
be subsequently trapped by an arene nucleophile. Such a
(5) For selected examples in synthesis, see: (a) Liu, X.; Hartwig, J. F.
J. Am. Chem. Soc. 2004, 126, 5182–5191. (b) Martin, R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2007, 46, 7236–7239. (c) Hama, T.; Hartwig, J. F.
Org. Lett. 2008, 10, 1549–1552. (d) Vo, G. D.; Hartwig, J. F. Angew. Chem.,
Int. Ed. 2008, 47, 2127–2130. For alternative methods, see: (e) Milne, J. E.;
Murry, J. A.; King, A.; Larsen, R. D. J. Org. Chem. 2009, 74, 445–447,
and references cited therein.
(6) Seebach, D. Angew. Chem., Int. Ed. 1979, 18, 239–336.
(7) Malosh, C. F.; Ready, J. M. J. Am. Chem. Soc. 2004, 126, 12040–
12041.
(8) Studte, C.; Breit, B. Angew. Chem., Int. Ed. 2008, 47, 5451–5455.
(9) Bausch, C. C.; Johnson, J. S. AdV. Synth. Catal. 2005, 347, 1207–
1211.
(10) Demir, A. S.; Reis, O.; Igdir, A. C.; Esiringu, I.; Eymur, S. J. Org.
Chem. 2005, 70, 10584–10587.
(11) Linghu, X.; Bausch, C. C.; Johnson, J. S. J. Am. Chem. Soc. 2005,
127, 1833–1840.
After initial optimization, we investigated the scope and
generality of both nucleophile and R-ketophosphate electro-
(12) Demir, A. S.; Reis, O. Tetrahedron 2004, 60, 3803–3811.
Org. Lett., Vol. 12, No. 8, 2010
1785

phile in this transformation. Table 2 summarizes the range
of nucleophiles employed in this system. Both aromatic and
heteroaromatic nucleophiles were tolerated (entries 1-3, 7,
and 8, Table 2), with varying reaction times depending on
the nucleophile employed. Several nonarene nucleophiles
performed well in this system (entries 4-6 and 9). The
potassium trifluoroborate styrenyl salt15 added cleanly in
acetonitrile at 90 °C when ZnCl2 was used as the Lewis acid,
delivering the trans olefin in 60% yield (entry 4). This
reaction allowed for incorporation of a nonaryl sp2-hybridized
carbon center at the R-position. TMSN3 was well-tolerated
under the reaction conditions, providing the R-azido ketone
in 81% yield (entry 5). Silyl enol ether and acetylacetone
addition were also feasible, delivering 1,4-diketone products
in promising yields (entries 6 and 9).
Table 2. Nucleophilic Substitution to 1a
Table 3 summarizes the scope of the electrophile with
anisole as the nucleophile. Para-substituted aromatic sub-
Table 3. Scope of the R-Ketophosphatea
% yield
entry
R1
Ph
Ph
Ph
Ph
Ph
R2
temp (°C) time (h) (product)b
1c
2
4-MeOPh
2-thienyl
2-naphthyl
4-ClPh
23
23
85
85
85
23
5
1.5
3.5
17
17
0.5
73 (3a)
48 (3b)
61 (3c)
51 (3d)
54 (3e)
71 (3f)
3d e
,
4d f
,
5d f
Ph
,
6
4-ClPh 4-MeOPh
a Reactions were performed on a 0.29 mmol scale, using 1.0 equiv of
BF3·OEt2 and 10.0 equiv of anisole in (CH2)2Cl2 (2.85 mL) unless otherwise
noted. b Isolated yield after column chromatography, results averaged over
at least two trials. c Reaction performed in DCM. d Reaction performed in
a Teflon seal-capped vial. e Ortho-addition product isolated in 7% yield.
f Ortho-addition product isolated in 8% yield.
strates and heteroaromatic substrates were tolerated (entries
1 and 2, Table 3), and the alkylation also progressed in the
absence of a strong electron-donating group on the ring
(entries 3-5). Heating the reaction to 85 °C allowed for
successful ionization of the R-phosphate group in the absence
of an electron-donating aryl substituent. Elevated tempera-
tures did result in trace ortho-addition product when anisole
was employed as the nucleophile; however, this minor
product was easily separated from the para-addition product
with silica gel chromatography.
The relatively equal success of a number of Lewis acids
(Table 1, entries 1-4) in the initial arene alkylation screen
led us to question whether the dialkyl phosphoric acid
generated as a byproduct in the reaction was the true
promoter of this transformation. To test this, 1 was subjected
to a full equivalent of analogous dibutyl phosphoric acid and
10 equivalents of anisole in (CH2)2Cl2 (Figure 3). Little
a Reactions were performed on a 0.29 mmol scale, using 1.0 equiv of
BF3·OEt2 and 10.0 equiv of nucleophile at 23 °C in (CH2)2Cl2 (2.85 mL)
unless otherwise noted. b Isolated yield after flash chromatography, results
averaged over at least two trials. c Reaction was performed in CH3CN (2.85
mL) at 90 °C in a Teflon seal-capped vial, using 1.0 equiv of ZnCl2 and
3.0 equiv of nucleophile. d Reaction was performed in CH2Cl2 (2.85 mL).
e Reaction was performed at 80 °C in a Teflon seal-capped vial, using 1.0
equiv of ZnCl2. f Reaction performed in CH2Cl2. g Reaction was performed
with 5.0 equiv of nucleophile.
(13) Begue, J.-P.; Charpentier-Morize, M. Acc. Chem. Res. 1980, 13,
207–212.
(14) Kulkarni, G. C.; Karmarkar, S. N.; Kelkar, S. L.; Wadia, M. S.
Tetrahedron 1988, 16, 5189–5198.
(15) Molander, G. A.; Bernardi, C. R. J. Org. Chem. 2002, 67, 8424–
8429.
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Org. Lett., Vol. 12, No. 8, 2010

23 °C (Figure 3), the enantiomeric ratio of the resulting
product was 50:50, thus suggesting an SN1 mechanistic
pathway that proceeded through a 2° acyl carbenium ion.
In summary, we have discovered a Lewis acid-promoted
route to R,R-diaryl ketones that proceeds in one step from
an easily prepared R-ketophosphate and invokes an umpolung
strategy to induce arene alkylation at the R-carbon. The
reaction proceeds at room temperature with sufficiently
electron-rich R-ketophosphates; electron-neutral and electron-
poor R-ketophosphates react upon heating. The cationic
intermediate can be successfully trapped with both hetero-
atom and nonaromatic nucleophiles. Development of an
asymmetric variant of this methodology is currently ongoing
in our laboratory.
Acknowledgment. This research was supported by the
National Institutes of Health (National Institute of General
Medical Sciences, no. GM068443) and Novartis (Early
Career Award to J.S.J.).
Figure 3. Control experiments: (a) dialkyl phosphoric acid does
not promote this reaction; (b) enantioenriched starting material
yields racemic product.
Supporting Information Available: Experimental pro-
cedures and spectroscopic and analytical data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
desired product was observed upon heating the reaction to
80 °C for 22 h (<2% yield), allowing us to rule out the dialkyl
phosphoric acid byproduct as the reaction promoter.
When enantioenriched R-ketophosphate 48 was treated
with furan (10 equiv) and BF3·OEt2 (1 equiv) in CH2Cl2 at
OL100410K
Org. Lett., Vol. 12, No. 8, 2010
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