A novel arylation of arylacetic acid esters using tertiary arylamines and TiCl4

Article abstract of DOI:10.1016/j.tetlet.2003.10.009

The reactions of arylacetic acid esters with tertiary arylamines in the presence of TiCl₄ give α-arylated products in 65-90% yields, as well as 10-20% yields of the corresponding benzidines.

Full text of DOI:10.1016/j.tetlet.2003.10.009

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8939–8941
A novel arylation of arylacetic acid esters using tertiary
arylamines and TiCl4
Mariappan Periasamy,* N. KishoreBabu and Keela Natarajan Jayakumar
School of Chemistry, University of Hyderabad, Central University PO, Hyderabad 500 046, India
Received 20 August 2003; revised 25 September 2003; accepted 3 October 2003
Abstract—The reactions of arylacetic acid esters with tertiary arylamines in the presence of TiCl4 give a-arylated products in
65–90% yields, as well as 10–20% yields of the corresponding benzidines.
© 2003 Elsevier Ltd. All rights reserved.
In recent years, the TiCl4/R3N reagent system has been
extensively used in organic synthesis.1 This reagent
system is useful for the oxidative coupling of arylacetic
acid esters (Scheme 1).2 N,N-Dialkylanilines also
undergo oxidative coupling in the presence of TiCl4 to
give the corresponding benzidine derivatives (Scheme
1).3
The reaction was found to be general and several other
tertiary arylamines and arylacetic acid esters were
found to give the corresponding cross-coupled products
under these conditions (see Scheme 2). The results are
summarized in Table 1. The formation of the cross-cou-
pled products may be explained by considering cross-
coupling between the titanium enolate of the esters and
the aryltitanium species formed in situ (Scheme 3).
Initially, the reaction of N,N-dialkylarylamines with
TiCl4 would produce aryltitanium intermediates.3 The
TiCl4–ester complex could be deprotonated by the N,N-
dialkylarylamine present which would lead to the for-
mation of titanium enolates that on cross-coupling with
the aryltitanium species produce the corresponding
diarylacetic esters.
We report that arylacetic acid esters react with tertiary
arylamines to give the corresponding cross coupled
products. We observed that the reaction of the aryltita-
nium species with methyl phenylacetate produced the
corresponding a-arylated products in good yields
(Scheme 2). For example, the reaction of N,N-dimethyl-
aniline and methyl phenylacetate with TiCl4 at 0–25°C
for 5 h produced 1a in 89% yield, as well as the
corresponding benzidine derivative (10%).4 The diaryl-
acetic esters were readily separated from the benzidines
by a usual workup.
In this reaction, the arylating agent N,N-dialkylaryl-
amine also acts as a base in the titanium enolate
formation (Scheme 3). We observed that enolizable
Scheme 1.
Keywords: diaryl acetic esters; cross coupling reactions; titanium enolates; aryltitanium.
* Corresponding author.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.009

8940
M. Periasamy et al. / Tetrahedron Letters 44 (2003) 8939–8941
Scheme 2.
Table 1. Reaction of arylacetic acid esters with arylamines
and TiCl4
S. No
ArNR2
Ester
Producta
Yieldb (%)
1
2
3
4
5
6
7
8
9
Ar=Ph,
R=CH3
Ar=Ph,
R=C2H5
Ar=Ph,
R=CH3
Ar=Ph,
R=C2H5
Ar=Ph,
R=CH3
Ar=Ph,
R=C2H5
Ar=1-Np
R=CH3
Ar=1-Np,
R=CH3
Ar=1-Np,
R=CH3
R%=Ph,
R%%=C2H5
R%=Ph,
R%%=C2H5
R%=1-Np,
R%%=CH3
R%=1-Np,
R%%=CH3
R%=Ph,
R%%=CH3
R%=Ph,
R%%=CH3
R%=Ph,
R%%=C2H5
R%=Ph,
R%%=CH3
R%=1-Np,
R%%=CH3
1a
1b
1c
1d
1e
1f
89
90
88
76
86
81
76
65
68
Scheme 3.
Acknowledgements
We are grateful to the DST (New Delhi, India) for
financial support under FIST program. N.K.B. and
K.N.J. are thankful to CSIR for fellowships. Support
of the UGC under the ‘University of Potential for
Excellence’ is gratefully acknowledged.
2a
2b
2c
References
a The products were identified by 1H, 13C NMR and mass spectral
data5 and by comparison with the data reported for compound 1a.6
b In all reactions, TiCl4 (10 mmol), arylamine (7.5 mmol) and the
arylacetic acid ester (2.5 mmol) were used. Yields of products
isolated by column chromatography are based on the amount of
ester used. In all cases, the corresponding benzidine (up to 20%) as
well as small amounts of unidentified mixtures of polar products
were also isolated.
1. (a) Harrison, C. R. Tetrahedron Lett. 1987, 28, 4135; (b)
Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V. J.;
Sheppard, G. S. J. Am. Chem. Soc. 1990, 112, 866; (c)
Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J.
Am. Chem. Soc. 1991, 113, 1047; (d) Crimmins, M. T.;
King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997, 119,
7883; (e) Yoshida, Y.; Hayashi, R.; Sumihara, H.; Tanabe,
Y. Tetrahedron Lett. 1997, 38, 8727 and references cited
therein.
2. (a) Matsumura, Y.; Nishimura, M.; Hiu, H.; Watanabe,
M.; Kise, N. J. Org. Chem. 1996, 61, 2809; (b) Kise, N.;
Tokioka, K.; Aoyama, Y.; Matsumura, Y. J. Org. Chem.
1995, 60, 1100; (c) Kise, N.; Kumada, K.; Terao, Y.;
Ueda, N. Tetrahedron 1998, 54, 2697.
esters like methyl propionate did not react with the
aryltitanium species under these reaction conditions,
possibly due to the weaker basicity of the arylamines
for the formation of enolates.
The synthesis of this new class of a-aryl esters is of
interest because certain diarylacetic acid derivatives are
known to be biologically active.7 This new method of
a-arylation is relatively simple compared to other meth-
ods of a-arylation for esters6 and hence will help in the
synthesis of this important class of organic compounds.
3. Periasamy, M.; Jayakumar, K. N.; Bharathi, P. J. Org.
Chem. 2000, 65, 3548.
4. Representative procedure for the reaction of N,N-dimethyl-
aniline and ethyl phenylacetate with TiCl4: In CH2Cl2 (25
mL), N,N-dimethylaniline (0.9 mL, 7.5 mmol) and ethyl
phenylacetate (0.35 ml, 2.1 mmol) were dissolved at 0°C

M. Periasamy et al. / Tetrahedron Letters 44 (2003) 8939–8941
8941
under N2. TiCl4 (2.2 mL of 1:1 solution of TiCl4/CH2Cl2,
10 mmol) in CH2Cl2 (10 mL) was added dropwise over 5
min. The reaction mixture was stirred at 0°C for 0.5 h and
at 0–25°C for 5 h. Saturated aqueous K2CO3 (10 mL) was
added and the mixture stirred for 0.5 h. The reaction
mixture was filtered through a Buchner funnel, the organic
layer was separated and the aqueous layer was extracted
with CH2Cl2 (2×25 mL). The combined organic extracts
were washed with brine (10 mL) and dried over anhydrous
MgSO4. The solvent was removed and the residue was
chromatographed on a silica gel column. The unreacted
amine was eluted using 1:99 EtOAc/hexane mixture. The
N,N,N%,N%-tetramethylbenzidine (0.089 g, 10%) and
aminoester 1a (0.528 g, 89%) were eluted next.
134.2, 131.9, 129.8, 129.1, 128.1, 126.6, 126.3, 125.7, 125.6,
123.5, 112.8, 53.0, 52.4, 40.6. 1d: 13C NMR (l ppm) 174.0,
147.2, 135.5, 134.1, 129.9, 129.0, 127.9, 126.5, 126.3, 125.6,
125.5, 124.4, 123.4, 112.0, 52.8, 52.3, 44.4, 12.7. 1e: 13C
NMR (l ppm) 173.6, 149.9, 139.6, 129.4, 128.6, 127.4,
127.1, 126.5, 112.7, 56.3, 52.2, 40.6. 1f: 13C NMR (l ppm)
173.5, 147.1, 139.6, 129.5, 128.5, 128.5, 127.0, 125.2, 111.8,
56.2, 52.1, 44.3, 12.6. 2a: 13C NMR (l ppm) 173.0, 150.7,
138.4, 132.9, 129.3, 129.0, 128.6, 127.2, 126.3, 126.2, 125.0,
124.9, 123.6, 113.5, 61.2, 53.5, 45.2, 14.2. 2b: 13C NMR (l
ppm) 173.5, 150.8, 138.3, 132.9, 129.3, 129.0, 128.6, 127.3,
126.3, 125.1, 124.9, 123.6, 113.5, 53.4, 52.4, 45.2. 2c: 13C
NMR (l ppm) 173.8, 150.8, 134.4, 134.1, 132.9, 131.8,
129.4, 129.0, 128.2, 127.7, 126.7, 125.7, 125.6, 125.2, 123.4,
123.1, 113.7, 52.5, 50.1, 45.3.
5. Representative spectral data: 13C NMR (50 MHz, CDCl3)
spectral data for compounds 1a–2c. 1a: 13C NMR (l ppm)
173.0, 149.8, 139.7, 129.3, 128.5, 128.5, 126.9, 126.8, 112.7,
60.9, 56.4, 40.6, 14.2. 1b: 13C NMR (l ppm) 173.1, 147.0,
139.8, 129.5, 128.5, 128.4, 126.9, 125.5, 111.9, 60.9, 56.3,
44.4, 14.2, 12.6. 1c: 13C NMR (l ppm) 173.9, 150.0, 135.5,
6. Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001,
123, 7996.
7. Lednicer, D.; Mitscher, L. A. Organic Chemistry of Drug
Synthesis; John Wiley & Sons: New York, 1977; pp.
85–99.