Direct acylation of aryl chlorides with aldehydes by palladium-pyrrolidine Co-catalysis

Article abstract of DOI:10.1021/ol101466g

A palladium catalyst system has been developed that allows for the direct acylation of aryl chlorides with aldehydes. The choice of ligand, as well as the presence of pyrrolidine and molecular sieves is shown to be critical to the catalysis, which appears to proceed via an enamine intermediate. The reaction was successful for a wide range of aryl chlorides and tolerant of functionality on the aldehyde component, giving easy access to alkyl aryl ketones in modest to good yields.

Full text of DOI:10.1021/ol101466g

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3670-3673
Direct Acylation of Aryl Chlorides with
Aldehydes by Palladium-Pyrrolidine
Co-catalysis
Paul Colbon,† Jiwu Ruan,† Mark Purdie,‡ and Jianliang Xiao*,†
Department of Chemistry, LiVerpool Centre for Materials and Catalysis, UniVersity of
LiVerpool, LiVerpool L69 7ZD, U.K., and AstraZeneca, Bakewell Road,
Loughborough LE11 5RH, U.K.
j.xiao@liV.ac.uk
Received June 25, 2010
ABSTRACT
A palladium catalyst system has been developed that allows for the direct acylation of aryl chlorides with aldehydes. The choice of ligand,
as well as the presence of pyrrolidine and molecular sieves is shown to be critical to the catalysis, which appears to proceed via an enamine
intermediate. The reaction was successful for a wide range of aryl chlorides and tolerant of functionality on the aldehyde component, giving
easy access to alkyl aryl ketones in modest to good yields.
Alkyl aryl ketones are extensively used in the pharmaceutical,
fragrance, dye and agrochemical industries.1 Such com-
pounds are usually synthesized by the traditional Friedel-
Crafts acylation, which involves handling hazardous reagents
and fails with electron-deficient arenes.2 In recent years,
alternative methods have been developed, using catalysts and
allowing easy-to-handle substrates to be employed. Notable
examples include hydroacylation of olefins3 and acylation
of arenes,4 although these reactions generally require che-
lation assistance. Acylation of aryl halides offers another
attractive approach.5-7 However, the initial reports were
limited to aryl iodides in substrate scope and required
bimetallic systems and a chelating auxiliary on the aldehydes.
In related studies, aryl boronate salts have been acylated with
aldehydes to give diaryl ketones,8 which could also be
obtained by coupling of aryl iodides with N-pyrazyl aldi-
mines or N-tert-butylhydrazones followed by hydrolysis.9,10
We recently reported an efficient protocol for the direct
acylation of aryl bromides with aldehydes, which uses
palladium-amine cooperative catalysis, allowing a variety of
alkyl aryl ketones to be readily synthesized.11,12 This method
† University of Liverpool.
(5) Satoh, T.; Itaya, T.; Miura, M.; Nomura, M. Chem. Lett. 1996, 823.
‡ AstraZeneca.
(6) Huang, Y.-C.; Majumdar, K. K.; Cheng, C.-H. J. Org. Chem. 2002,
(1) (a) Franck, H. G.; Stadelhofer, J. W. Industrial Aromatic Chemistry;
Springer-Verlag: Berlin, 1988. (b) Surburg, H.; Panten, J. Common
Fragrance and FlaVor Materials, 5th ed.; Wiley-VCH: Weinheim, Germany,
2006.
67, 1682
.
(7) Ko, S.; Kang, B.; Chang, S. Angew. Chem., Int. Ed. 2005, 44, 455
(8) Pucheault, M.; Darses, S.; Genet, J.-P. J. Am. Chem. Soc. 2004, 126,
.
15356.
(9) Ishiyama, T.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 12043
(10) Takemiya, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 14800
(2) Olah, G. A. Friedel-Crafts Chemistry; Wiley: New York, 1973.
(3) For selected reviews, see: (a) Park, Y. J.; Park, J.-W.; Jun, C.-H.
Acc. Chem. Res. 2008, 41, 222. (b) Willis, M. C. Chem. ReV. 2010, 110,
725.
.
.
(11) Ruan, J.; Saidi, O.; Iggo, J. A.; Xiao, J. J. Am. Chem. Soc. 2008,
130, 10510
.
(4) For direct acylation of arenes, see: (a) Basle, O.; Bidange, J.; Shuai,
Q.; Li, C.-J. AdV. Synth. Catal. 2010, 352, 1145. (b) Jia, X.; Zhang, S.;
Wang, W.; Luo, F.; Cheng, J. Org. Lett. 2009, 11, 3120. (c) Barluenga, J.;
Trincado, M.; Rubio, E.; Gonza´lez, J. M. Angew. Chem., Int. Ed. 2006, 45,
3140.
(12) For similar acylation recently reported, see: (a) Zanardi, A.; Mata,
´
J. A.; Peris, E. Organometallics 2009, 28, 1480. (b) Alvarez-Bercedo, P.;
Flores-Gaspar, A.; Correa, A.; Martin, R. J. Am. Chem. Soc. 2010, 132,
466. (c) Adak, L.; Bhadra, S.; Ranu, B. C. Tetrahedron Lett. 2010, 51,
3811
.
10.1021/ol101466g  2010 American Chemical Society
Published on Web 07/23/2010

would be of even greater appeal if it were applicable to aryl
chlorides, as they are cheaper and more widely available than
their bromide or iodide counterparts. Unfortunately, aryl
chlorides proved to be essentially inactive when subjected
to the Pd-dppp catalysis we had developed for aryl bromides
(Vide infra).11 Research from a number of pioneering groups
has led to the discovery of palladium catalysts bearing bulky
and electron-rich phosphine or carbene ligands that exhibit
much enhanced activity toward aryl chlorides.13 We thought
that by ligating palladium with such a ligand we might be
able to force aryl chlorides to enter the acylation reaction.
With this hypothesis in mind, we set out to examine the
acylation of 4-chloroanisole 1a with 3-phenylpropanal 2g
by combining Pd(dba)2 with various ligands under conditions
previously developed for ArBr.11 The results are summarized
in Table 1. After screening several bidentate and monodentate
ligands in DMF, we were delighted to find that the bulky,
electron-rich monophosphine L1 (entry 10)14 led to the
formation of the desired product in 19% isolated yield. The
yield was increased to 53% by raising the reaction temper-
ature to 140 °C (entry 11). A wider range of ligands were
then tested at the increased reaction temperature in order to
find the optimal catalyst system. Surprisingly, all other
monophosphine ligands, except the structurally similar L2
(entry 12), gave poor results, regardless of their steric and
electronic characteristics. Likewise, all of the diphosphine
ligands tested, including the previously successful dppp,11
failed to yield any of the desired product! When investigating
the use of ligands as their stable salts (entries 18, 25, and
26), a small amount of a strong base was added in the hope
to release the free ligand in situ. Unfortunately, these ligands
were also unable to catalyze the desired acylation reaction.
Changing the solvent from DMF to DMA (entry 28)
further enhanced the acylation rate with Pd-L1, resulting in
a 75% isolated yield of the desired ketone 3g. It was found
that 2 equiv of the aldehyde component were required in
order to achieve full conversion of 1a.15 As in the case of
ArBr,11 the presence of the pyrrolidine and 4 Å MS was
critical; no desired reaction occurred in the absence of either
additive.
Table 1. Optimizing Conditions for Acylation of 1a with 2ga
entry
ligand
solvent
temp (°C)
yield (%)b
1
2
3
4
5
6
7
8
-
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
NMP
toluene
dioxane
DMSO
115
115
115
115
115
115
115
115
115
115
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
0
0
0
0
0
0
0
0
0
19
53
50
8
dpppc
dppmc
dppec
L9
L10c
L11
PCy3
PPh3
L1
L1
L2
L3
L4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27h
28
29
30
31
32
0
L5
L6
<5
<5
24
18
0
0
0
0
0
0
0
0
13
75
42
10
<5
16
Q-Phos
P(t-Bu)3·HBF4
dppfc
Binapc
4-OMe-dpppe
4-CF3-dpppf
L7c
d
With the optimized conditions in hand, we then tested the
acylation of 1a with various aldehydes 2a-n. As can be seen
in Table 2, the reactions afforded moderate to good yields
of ketones 3 when subjected to the Pd-L1 catalysis in the
presence of pyrrolidine and 4 Å MS. As in the case of ArBr,
the reaction proved to be tolerant of functionalities on the
aldehyde component (entries 10-13). The substrate scope
was limited, however, to aldehydes without substitution on
the R carbon, although ꢀ substitution did not pose a problem
(e.g., entries 8 and 9). Thus, acylation of 1a with 2-meth-
L8c
L12d g
,
L13d g
,
Pd118
L1
L1
L1
L1
L1
a All reactions were carried out with 1a (1.0 mmol), 2g (2.0 mmol),
pyrrolidine (1.5 mmol), Pd(dba)2 (2 mol %), ligand (6 mol %), and 4 Å
MS (1 g) in 4 mL of solvent. b Isolated yields of ketone; zero indicates no
or trace 3g in the crude 1H NMR spectrum. c 3 mol % of ligand was used.
d 3 mol % of t-BuOK was added. e (4-OMePh)2PCH2CH2CH2P(4-OMePh)2.
f (4-CF3Ph)2PCH2CH2CH2P(4-CF3Ph)2. g 2 mol % of ligand was used. h 2
mol % of Pd118 was used as palladium source.
(13) For selected reviews, see: (a) Fu, G. C. Acc. Chem. Res. 2008, 41,
1555. (b) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461. (c)
Marion, N.; Nolan, S. P. Acc. Chem. Res. 2008, 41, 1440.
(14) (a) Schulz, T.; Torborg, C.; Enthaler, S.; Scha¨ffner, B.; Dumrath,
A.; Spannenberg, A.; Neumann, H.; Bo¨rner, A.; Beller, M. Chem.sEur. J.
2009, 15, 4528. (b) Zapf, A.; Beller, M. Chem. Commun. 2005, 431.
(15) This is due to the competing pathway of aldol condensation, as
well as the limited stability of the aldehyde under the reaction conditions.
Further increase in the amount of aldehyde used did not increase the product
yield.
ylhexanal under the optimized conditions failed to yield any
of the desired ketone.
Org. Lett., Vol. 12, No. 16, 2010
3671

Table 2. Acylation of 1a with Aldehydes 2a-na
Table 3. Acylation of Aryl Chlorides 1b-o with 2ga
a Reactions were carried out with 1a (1.0 mmol), 2a-n (2.0 mmol),
pyrrolidine (1.5 mmol), 4 Å MS (1 g), Pd(dba)2 (2 mol %), and L1 (6 mol
%) in 4 mL of DMA at 140 °C for 4 h. b Isolated yields. c 4 mol % of
Pd(dba)2 and 12 mol % of L1 were used.
a The conditions were the same as in Table 2. No 4a, which would be
the same as 3g. b Isolated yields. c 4 mol % of Pd(dba)2 and 12 mol % of
L1 were used.
We next extended the acylation to a series of aryl chlorides
coupling with the aldehyde 2g. As summarized in Table 3,
the reaction afforded moderate to good yields of ketones 4,
particularly when electron-rich aryl chlorides were used.
However, as previously found for ArBr,11 the presence of
ortho (entries 9 and 10) or electron-withdrawing substituents
(entries 4 and 5) on the aryl ring resulted in lower yields. It
should be noted that the moderate success of the electron-
deficient substrates 1e and 1f is a significant improvement,
as the equivalent ArBr were completely inactive under the
previously reported Pd-dppp catalysis.11 Unfortunately, acyl-
ation of heterocyclic chlorides, such as 2-chlorothiophene
and 2-chloropyridine, did not occur under the same condi-
tions.
3672
Org. Lett., Vol. 12, No. 16, 2010

We previously suggested that the acylation may take place
via a Heck-type pathway.11 A possible catalytic cycle is
depicted in Scheme 1. Pyrrolidine plays two roles in the
be obtained by reacting 1a with 2g using 20 mol %
pyrrolidine and 1 equiv KF under otherwise identical
conditions to those above (Table 2);17 this resulted in a 51%
isolated yield of 3g.
The pyrrolidinyl moiety of the enamine is critical for the
desired acylation. It polarizes the CdC double bond, which
facilitates the ꢀ carbon coordination to Pd(II) and the
migration of the aryl group to the R carbon, thereby
furnishing the R arylated product.18 In line with this view,
the arylation of 6 led to a mixture of R and ꢀ arylated
enamides (Scheme 3). The formation of these relatively stable
Scheme 1. Proposed Acylation Mechanism
Scheme 3. Arylation of Enamide 6
regioisomers is most likely a result of the electron-withdraw-
ing effect of the carbonyl group, which renders the CdC
double bond less polarized. When using a bidentate ligand
under ionizing conditions, however, the R product can be
exclusively obtained from 6.19
In summary, we have discovered a catalyst system that
allows for the direct acylation of a wide range of aryl
chlorides with various aldehydes, including those bearing
functionalities. In contrast to the acylation of ArBr effected
by Pd-dppp and pyrrolidine, the reaction of ArCl necessitates
an electron-rich monophosphine ligand and a higher tem-
perature.
reaction: one is to form an enamine in a catalytic fashion
and the other to neutralize the acid HX.11 The in situ
formation of the enamine from the aldehyde is a key element
of the catalytic cycle. If instead pyrrolidine deprotonated the
aldehyde, R arylation might result.16 To determine if the
enamine is involved in the acylation, we carried out a reaction
starting from a preformed enamine 5. Under the conditions
established (Table 2), the ketone 3c was indeed formed
(Scheme 2), thus supporting the intermediacy of enamine.
Acknowledgment. The authors thank the EPSRC (EP/
F000316) and AstraZeneca for support.
Scheme 2. Arylation of Preformed Enamine 5
Supporting Information Available: Experimental details
and analytical data (NMR, IR, MS). This material is available
free of charge via the Internet at http://pubs.acs.org.
OL101466G
(17) A prolonged reaction time of 6 h was required to achieve full
conversion with respect to 1a.
A higher yield was obtained when using bromoanisole under
the previously developed conditions.11 In both cases, how-
ever, the isolated yield was somewhat lower than starting
with hexanal. As with the acylation of ArBr,11 the coupling
of ArCl with aldehydes becomes catalytic in the amine in
the presence of an additional base. Thus, the ketone 3g could
(18) (a) Henriksen, S. T.; Norrby, P.-O.; Kaukoranta, P.; Andersson,
P. G. J. Am. Chem. Soc. 2008, 130, 10414. (b) Amatore, C.; Godin, B.;
Jutand, A.; Lemaˆıtre, F. Chem.sEur. J. 2007, 13, 2002. (c) Deeth, R. J.;
Smith, A.; Brown, J. M. J. Am. Chem. Soc. 2004, 126, 7144.
(19) (a) Hyder, Z.; Ruan, J.; Xiao, J. Chem.sEur. J. 2008, 14, 5555.
(b) Mo, J.; Xiao, J. Angew. Chem., Int. Ed. 2006, 45, 4152. (c) Mo, J.; Xu,
L.; Xiao, J. J. Am. Chem. Soc. 2005, 127, 751. (d) Hansen, A. L.; Skrydstrup,
T. J. Org. Chem. 2005, 70, 5997. (e) Andappan, M. M. S.; Nilsson, P.;
Von Schenck, H.; Larhed, M. J. Org. Chem. 2004, 69, 5212. (f) Vallin,
K. S. A.; Zhang, Q.; Larhed, M.; Curran, D. P.; Hallberg, A. J. Org. Chem.
2003, 68, 6639. (g) Tu, T.; Hou, X.-L.; Dai, L.-X. Org. Lett. 2003, 5, 3651.
(h) Cabri, W.; Candiani, I.; Bedeschi, A.; Santi, R. J. Org. Chem. 1992,
57, 3558.
(16) For R arylation of aldehydes, see: (a) Martin, R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2007, 46, 7236. (b) Martin, R.; Buchwald, S. L.
Org. Lett. 2008, 10, 4561. (c) Vo, G. D.; Hartwig, J. F. Angew. Chem., Int.
Ed. 2008, 47, 2127. (d) Johansson, C. C. C.; Colacot, T. J. Angew. Chem.,
Int. Ed. 2010, 49, 676.
Org. Lett., Vol. 12, No. 16, 2010
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