Room-temperature palladium-catalyzed C-H activation: Ortho-carbonylation of aniline derivatives

Article abstract of DOI:10.1002/anie.200805842

Pd and CO - ureally got me! The title reaction proceeds efficiently at 18°C under CO (1 atm) with 5 % [Pd(OTs)₂ (MeCN)₂] as precatalyst. Depending on the solvents used, either anthranilates or cyclic imides can be obtained in high yields (see picture, BQ=benzoquinone, Ts=4-toluenesulfonyl).

Full text of DOI:10.1002/anie.200805842

Communications
DOI: 10.1002/anie.200805842
ꢀ
C H Activation
ꢀ
Room-Temperature Palladium-Catalyzed C H Activation: ortho-
Carbonylation of Aniline Derivatives**
Chris E. Houlden, Marc Hutchby, Chris D. Bailey, J. Gair Ford, Simon N. G. Tyler,
Michel R. Gagnꢀ, Guy C. Lloyd-Jones,* and Kevin I. Booker-Milburn*
ꢀ
The interconversion of Ar H and
ꢀ
Ar FG (FG = functional group) is
an attractive process for the synthe-
sis of functionalized aromatic rings
and the development of transition-
metal catalysts for achieving this
transformation is currently an area
of intense activity. Whilst a range of
efficient catalyst systems have
recently been reported, it is of note
that nearly all of them require high
temperatures and/or powerful oxi-
dants.[1] Indeed, the development of
an effective catalytic protocol for
carbonylation using CO by palladi-
ꢀ
um(II)-mediated C H activation has
long been recognized as being diffi-
cult and only recently has the first
example been reported.[2] Herein we
report a room-temperature, urea-
directed, palladium-catalyzed car-
Scheme 1. Formation and reactions of PdII complex 2. NBS=N-bromosuccinimide,
NCS=N-chlorosuccinimide.
bonylation that provides access to biologically and syntheti-
cally useful anthranilic acid derivatives and heterocycles
under mild conditions.
We recently reported the development of a palladium(II)-
catalyzed 1,2-carboamination of dienes using aryl urea
derivatives.[3] During these investigations, [Pd(OTs)2-
(MeCN)2] (Ts = 4-toluenesulfonyl) was identified as a highly
efficient precatalyst and we proposed that the reaction
ꢀ
proceeded by a urea-directed C H insertion to give a reactive
ꢀ
ꢀ
Pd Ar complex. In subsequent attempts to isolate Pd Ar
complexes, we found that reaction of the m-toluidine urea 1
(Scheme 1) with one equivalent of [Pd(OTs)2(MeCN)2] in
anhydrous THF led to rapid precipitation of the ortho-
palladate 2 as a grey amorphous solid, which was readily
isolated in analytically pure form (79%). Crystallization of 2
from CH2Cl2/petroleum ether afforded the cationic hydrate
complex 3 whose molecular structure was confirmed by X-ray
crystallography (Figure 1).
[*] C. E. Houlden, M. Hutchby, C. D. Bailey, Prof. Dr. G. C. Lloyd-Jones,
Prof. Dr. K. I. Booker-Milburn
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
Fax: (+44)117-929-8611
E-mail: k.booker-milburn@bristol.ac.uk
guy.lloyd-jones@bristol.ac.uk
Prof. Dr. M. R. Gagnꢀ
Department of Chemistry, Caudill and Kenan Laboratories
UNC-Chapel Hill, NC 27599-3290 (USA)
Dr. J. G. Ford
AstraZeneca, Global Process R&D
Silk Road, Macclesfield, Cheshire, SK102NA (UK)
Dr. S. N. G. Tyler
AstraZeneca, Global Process R&D, Avlon Works
Severn Road, Hallen, Bristol BS107ZE (UK)
[**] We thank the EPSRC (GR/R02382 and E061575) and AstraZeneca
for support, the joint EPSRC/AstraZeneca/GlaxoSmithKline/Pfizer
Organic Studentship Initiative, and Dr. M. Haddow for X-ray
crystallography. G.C.L.-J. holds a Royal Society Wolfson Merit Award.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200805842.
Figure 1. Molecular structure of 3 (thermal ellipsoids shown at 50%
probability).
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Chemie
Table 2: Room temperature palladium(II)-catalyzed methoxycarbonyla-
tion.
With a ready supply of 2 in hand we explored its reactivity
towards
a range of coupling partners and reagents
(Scheme 1).[4,5] Methoxycarbonylation[6] (CO/MeOH) and
ꢀ
arylation (Ph M, M = B, Sn, etc.) were found to be effective
for the formation of the anthranilic ester 4 and biaryl 5
respectively. Interestingly, carbonylation of 2 in the absence
of MeOH led to the instantaneous formation of the cyclic
imidate 6 by internal nucleophilic capture of the intermediate
acyl palladate.[7]
Entry
9
R
R’
R’’
10
Yield [%]
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9 f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
9q
9r
Me
Et
iPr
Me
Et
iPr
H
H
H
H
H
H
H
H
10a 88 (97)[a]
10b 76
10c 55 (75)[b]
10d 75
The ability to selectively convert 2 into either anthranilate
4 or cyclic imidate 6 by stoichiometric reaction with either
CO/MeOH or CO, led us to focus on developing these into
catalytic processes. After a brief optimization study, it was
found that a range of aryl urea derivatives (7) underwent
rapid carbonylation ([Pd(OTs)2(MeCN)2], 5 mol%), benzo-
quinone (BQ, 2 equivalents), TsOH (1 equivalent), CO
(1 atm), CH2Cl2, reaction time ꢁ 5 hours) at ambient temper-
ature (188C) to afford cyclic imidates[8] (8) in moderate to
good yields (Table 1). In contrast to the reactions of aniline-
derived urea derivatives with dienes,[3] this procedure did not
require anhydrous conditions, although TsOH was essential
for catalytic turnover. Prolonged reaction times resulted in
lower yields, which are presumably a reflection of the acid
sensitivity of the imidate products 8.
morpholine
H
Me
Et
iPr
tBu
Bn
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
10e 61
10 f 81
10g 90
10h 88
10i 85
10j 88
10k 84
10l 78
H
H
H
H
9
H
10
11
12
13
14
15
16
17
18
19
20
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
o-Me
m-Me
p-Me
o-MeO
m-MeO
p-MeO
p-CF3
m-Br
p-Br
o,p-Me
p-CO2Me
10m 15 (40)[c]
10n 26 (60)[c]
10o 31 (80)[c]
10p 5 (30)[c]
10q 70
10r 40
9 s
9t
10 s 56
10t 36 (46)[c]
Table 1: Room-temperature palladium(II)-catalyzed ortho-carbonylation
of aryl urea derivatives.
21
54
[a] Reactions conducted with 10 mol% precatalyst. [b] Reaction con-
ducted in 100% MeOH with 3 equiv BQ. [c] Reactions conducted at
508C.
Entry
7
R
R’
8
Yield [%]
example, the p-CF3-bearing substrate 9p gave only traces of
anthranilate product (Table 2, entry 16) at ambient temper-
ature, although a 30% yield of 10p could be obtained at 508C.
The p-CO2Me analogue (9t) benefited similarly (Table 2,
entry 20), which reinforced the conclusion that the palladi-
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7 f
Me
Et
iPr
Me
Et
iPr
8a
8b
8c
8d
8e
8 f
67 (75)[a]
50
40
49
34
40
66
85
morpholine
Me
Et
iPr
tBu
H
H
H
H
ꢀ
um(II)-catalyzed C H activation sequence is electrophilic in
7g
7h
8g
8h
nature.[3] Interestingly, all three MeO isomers (Table 2,
entries 13–15) reacted inefficiently at 188C but gave moder-
ate to excellent yields of anthranilates at 508C. The 1-
naphthylamine derivative (Table 2, entry 21) gave only
cyclized imidate 11 (see below). Significantly, acetanilide
failed to undergo reaction even at 508C. This latter result
highlights the powerful activation effect of the urea moiety
with this precatalyst.[3,11]
[a] Reaction conducted with 10 mol% precatalyst.
When these palladium(II)-catalyzed reactions were con-
ducted in MeOH as solvent instead of CH2Cl2, methoxycar-
bonylation gave the desired anthranilate, but yields were
compromised by contamination with significant quantities of
an unidentified resinous material.[9] After screening a variety
of cosolvents, we found that dilution of the MeOH with THF
(1:1) gave excellent results with minimal by-product forma-
tion. It was also found that the amount of TsOH could be
reduced to 0.5 equivalents. These conditions were then
In certain cases, the transient formation of cyclic imidates
(8) was observed by TLC, which raised the question of
whether ester formation (10) proceeds by direct solvolysis of
an acyl palladate (12!10) or by a postcatalytic methanolysis
of the imidate (13!10). Control experiments[12] demon-
strated that the imidates are very labile[8] under the meth-
anolic carbonylation conditions and that the likely mecha-
applied to
a variety of substituted aniline derivatives
(Table 2) and generally gave excellent yields of anthranilates
10. The reaction proceeded readily at room temperature with
short reaction times and was unaffected by substitution on the
non-aryl urea nitrogen atom. The reaction was generally
tolerant of substitution in the aniline ring, although highly
electron-withdrawing substituents were troublesome.[10] For
ꢀ
nism for the formation of 10 from 9 is by a C H insertion,
carbonylation, cyclization, and solvolytic ring-opening
sequence (Scheme 2).
The synthetic utility of the urea anthranilates was further
demonstrated by their cyclization to form quinazolinones, a
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Communications
sequence for aniline derivatives. The reaction proceeds
efficiently under CO (1 atm), at room temperature (188C),
and with 5% catalyst loadings. Key features of the reaction
are the use of [Pd(OTs)2(MeCN)2] as precatalyst and the
powerful activating effect of the aniline–urea moiety (com-
pare Table 2, entry 1 (88%) versus acetanilide (0%)). The
reaction conditions can be easily manipulated to produce
either cyclic imidates (8) or methyl anthranilates (10). The use
ꢀ
of N-aryl urea derivatives that bear a terminal N H moiety
allows the generation of quinazolinones by in situ base-
mediated cyclization of the methoxycarbonylated products.
Finally, we have demonstrated the unique ability of the
Scheme 2. Mechanism of ester formation: direct solvolysis versus
imidate formation. a) For reagents see Table 2, 1.5 h, 95%.
ꢀ
diisopropyl urea moiety to function as a C H-activating and
-directing group that can be removed under neutral con-
ditions, which represents the selective hydrolysis of a urea
group in the presence of an ester group. We anticipate that
these reactions will be of substantial utility for the preparation
of anthranilic acids, and their derivatives, under mild con-
ditions from the corresponding aniline.
key heterocyclic pharmacophore in numerous drug substan-
ces.[13] Indeed, carbonylation of 9i followed by the addition of
potassium carbonate[14] and heating afforded the quinazoli-
none 14 in 80% overall yield in a one-pot sequence from 9i
(Scheme 3). Both 9e and 9 f reacted similarly to afford the
corresponding quinazolinones in 57 and 70% yields, respec- Experimental Section
General procedure for methoxycarbonylation: A Radleyꢀs reduced-
tively.
volume reaction vessel (10 mL) equipped with a stirring bar was
charged with the desired urea derivative (1 mmol), benzoquinone
(2 mmol), [Pd(OTs)2(MeCN)2] (5 mol%), tosic acid monohydrate
(0.5 mmol), THF (0.5 mL), and methanol (0.5 mL). The vessel was
connected to a Schlenk line and was briefly evacuated and stirred at
room temperature (188C), followed by charging with CO to 1 atm.
This cycle was repeated three times and the vessel left open to a
dynamic atmosphere of CO (1 atm). The reaction mixture was then
stirred at 188C and monitored by TLC. On completion (2–5 h), the
reaction mixture was concentrated in vacuo, the residue dissolved in
CH2Cl2 and washed with HCl (1m). The organic layer was then
washed with water, dried over MgSO4, filtered and concentrated
in vacuo. Purification by flash chromatography (10–40% EtOAc/
petroleum ether afforded the pure products.
Scheme 3. One-pot carbonylation–cyclization route to quinazolinones.
Finally, we investigated conditions for the selective
cleavage of the urea moiety to provide convenient access to
the methyl anthranilates and anthranilic acids. During this
study we made the observation that aniline diisopropyl urea
derivatives undergo an unprecedented facile solvolysis in
methanol under neutral conditions.[15] Remarkably, we found
that simply heating 10c in water gave methyl anthranilate 15
in 85% yield with no ester hydrolysis. The unusual reactivity
of the diisopropyl urea moiety was further highlighted by the
lack of reaction of 10a and 10b under identical conditions.
Reaction of 10c with NaOH (1m) gave anthranilic acid 16 in
excellent yield, which highlighted the diisopropyl urea moiety
Received: December 1, 2008
Published online: January 23, 2009
ꢀ
Keywords: C H activation · carbonylation · heterocycles ·
heterogeneous catalysis · palladium
.
[1] a) F. Kakiuchi, T. Kochi, Synthesis 2008, 3013 – 3039; b) D.
Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174 –
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C. Campeau, D. R. Stuart, K. Fagnou, Aldrichimica Acta 2007,
40, 35.
ꢀ
as an efficient “traceless” ortho-directing C H activating
group for anilines (Scheme 4).
[2] During the preparation of this manuscript Yu and Giri reported
the first palladium(II)-catalyzed ortho carbonylation of benzoic
In summary, we have described a highly efficient,
palladium(II)-catalyzed, and ortho-selective carbonylation
ꢀ
and phenylacetic acids by C H insertion: R. Giri, J-Q. Yu, J.
Am. Chem. Soc. 2008, 130, 14082.
[3] C. E. Houlden, C. D. Bailey, J. G. Ford, M. R. Gagnꢁ, G. C.
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10066.
[4] For the stoichiometric reaction of aryl–PdII–amide complexes,
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ꢀ
[5] For palladium-catalyzed C H activation reactions with phenyl
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Scheme 4. Facile hydrolysis of an aryl diisopropyl urea.
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2002; b) J.-R. Wang, C.-T. Yang, L. Liu, Q-X. Guo, Tetrahedron
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these cases, which confirmed the superiority of the [Pd(OTs)2-
ꢀ
(MeCN)2] precatalyst system for mild and selective C H
activation (Ref. [3]).
[12] Pure 8a was subjected to the reaction conditions from Table 2.
After 1.5 hours, all of 8a was consumed and the ester 10a was
isolated in 95% yield.
[13] For recent reports on synthesis and biological activity of
2,4(1H,3H)-quinazolinediones see: a) Z. Li, H. H. Huang, H.
Sun, H. Jiang, H. Liu, J. Comb. Chem. 2008, 10, 484; b) C.
Larksarp, H. Alper, J. Org. Chem. 2000, 65, 2773, and references
therein.
[14] For the formation of quinazolinediones from basic condensation
of ortho-ester aryl urea groups, see: E. P. Papadopoulos, C. D.
Torres, J. Heterocycl. Chem. 1982, 19, 269.
[15] To the best of our knowledge, solvolysis of urea derivatives
requires relatively harsh conditions, for example, high temper-
atures, strongly acidic or basic conditions, metal catalysis etc:
a) J. Wang, Q. Li, W. Dong, M. Kang, X. Wang, S. Peng, Appl.
Catal. 2004, 261, 191; b) N. V. Kaminskaia, N. M. Kostꢂc, Inorg.
Chem. 1998, 37, 4302; c) N. R. Ayyanger, A. R. Choudhary, U. R.
Kalkote, A. A. Natu, Chem. Ind. 1998, 599. In contrast, we have
found that aryl diisopropylamino ureas undergo solvolysis under
particularly mild conditions. This is clearly a property imparted
by the diisopropylamino group, and not a consequence of
(contaminant) palladium catalysis as the following (palladium-
free) example demonstrates: Capasso et al have demonstrated
[6] For CO insertion into palladacycles, see: a) J. Dupont, C.
Consorti, J. Spencer, Chem. Rev. 2005, 105, 2527; b) A. D.
Ryabov, Synthesis 1985, 233.
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lium intermediates, see: a) R. C. Larock, C. A. Fellows, J. Am.
Chem. Soc. 1982, 104, 1900; b) A. Krantz, R. W. Spencer, T. F.
Tam, T. Liak, US Patent 4,665,070, 1987; c) A. Krantz, R. W.
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Rafferty, J. Med. Chem. 1990, 33, 464.
[8] For the synthesis, biological activity, and reactions of 2-hetero-
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Chem. 2000, 37, 1369, and references therein.
[9] PdII/CO has been used for the manufacture of polymers from
diols. From NMR studies we suggest that polycarbonate
oligomers are formed from hydroquinone repeating units and
methanol termini: a) M. Okamoto, J. Sugiyama, T. Yamamoto, J.
Appl. Polym. Sci. 2008, 110, 3902; b) K. Okuyama, J. Sugiyama,
R. Nagahata, M. Asai, M. Ueda, K. Takeuchi, Macromolecules
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that phenyldimethyl urea derivatives undergo hydrolysis under
acidic or basic conditions via phenylisocyanate intermediates: S.
Salvestrini, P. DiCerbo, S. Capasso, J. Chem. Soc. Perkin Trans. 2
2002, 1889. We propose that the ease with which phenyldiiso-
propyl urea derivatives undergo solvolysis may be a result of the
leaving group ability of diisopropylamine being enhanced by the
steric compression afforded by the isopropyl groups. Further
mechanistic investigation is ongoing and will be reported in due
course.
[10] The p-NO2 derivative failed to react altogether.
[11] We also found that methoxycarbonylation could be achieved
with a) PdCl2 (10 mol%), BQ (3 equiv), CO, MeOH/THF (1:1)
at 608C and b) Pd(OAc)2 (5 mol%), BQ (2 equiv), and TsOH
(1 equiv) at 188C (see the Supporting Information for full
details). However, significantly lower yields were obtained in
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