Reaction of arynes with amino acid esters

Article abstract of DOI:10.1039/c1cc11234a

An efficient route to a variety of 2-phenylindolin-3-ones from amino acid methyl esters has been developed. The reaction of amino acid methyl esters with benzyne prepared from 2-(trimethylsilyl)phenyl triflate and CsF gave 2-phenylindolin-3-ones in moderate to good yields.

Full text of DOI:10.1039/c1cc11234a

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COMMUNICATION
Reaction of arynes with amino acid estersw
Kentaro Okuma,*a Nahoko Matsunaga,a Noriyoshi Nagahora,a Kosei Shiojia and
Yoshinobu Yokomorib
Received 2nd March 2011, Accepted 25th March 2011
DOI: 10.1039/c1cc11234a
An efficient route to a variety of 2-phenylindolin-3-ones from
amino acid methyl esters has been developed. The reaction
of amino acid methyl esters with benzyne prepared from
2-(trimethylsilyl)phenyl triflate and CsF gave 2-phenylindolin-
3-ones in moderate to good yields.
Scheme 1
Arynes are novel reaction intermediates that react with dienes
or 1,3-dipoles to give the corresponding cycloadducts.1
Recently, many researchers have reported the reaction of
benzyne prepared from 2-(trimethylsilyl)phenyl triflate (1a)
or benzenediazonium carboxylate with imines,2 aminobenzoate,3
2-aminobenzophenones,4 azides5 and diazo compounds,6
which provides a variety of N-containing cycloadducts, such
as acridines, acridones, triazoles and indazoles. Formally, the
reaction proceeds through the [2+2], [3+2], or [4+2] manner.
Simple amines, such as aniline and triethylamine, react
with benzyne to afford N-phenylated products.7 Meanwhile,
complex amines, such as enamides,8 allylamines,9 imidazoles,10
pyrroles,11 amides,12 oxaza adamantine,13 and dienyl
amides,14 give insertion products, cycloadducts, or N-arylated
products. However, there is no report on the cycloaddition
reaction of benzyne with amino acid esters (2). The reported
example of the reaction of benzyne with 2-phenylglycine ethyl
ester afforded N-phenyl-2-phenylglycine ethyl ester, an
N-phenylation product.15 As far as we know, there is only
one cycloaddition reaction of amino acid derivatives with
benzyne, i.e. the reaction of N-protected exomethyleneamino
acid methyl esters (enamides), which afforded the corresponding
indolines and isoquinolines.16 These results prompted us to
envision another transformation involving amino acid esters
but through cycloaddition, which would provide indolin-3-one
derivatives, as shown in Scheme 1. We report herein a direct
route to 2-phenylindolin-3-ones via the aryne cycloaddition
reaction with amino acid esters.2
Scheme 2
We began our study by reacting L-alanine methyl ester (2a)
with benzyne generated from triflate 1a and CsF (Scheme 2,
Table 1). The reaction of ester 2a with triflate 1a (1 equiv.) and
CsF gave 2-methyl-2-phenylindolin-3-one (3a) in 30% yield
(entry 1). A small amount of N-phenylalanine methyl ester
(4a) was also isolated. Triflate 1a (2.2 equiv.), CsF (4 equiv.)
and 2a in acetonitrile gave the best yield of 3a (65%; entry 2).
A larger amount of 1a (3–4 equiv.) furnished a complicated
reaction mixture that resulted in the isolation of indolin-3-one
3a in decreased yields (46–48%) (entries 3 and 4). When
the reaction was carried out by using tetrabutylammonium
fluoride (TBAF) or tetrabutylammonium difluorotriphenyl-
silicate (TBAT) as the fluoride source, 4a was obtained in 62
and 64% yields, respectively (entries 5 and 6).
When KF was used as the fluoride source in the presence of
18-crown-6 (18-C-6), 3a was obtained in 32% yield along with
4a (35%) (entry 7), suggesting that CsF and KF play an
important role in the formation of indolin-3-one 3a.
a Department of Chemistry, Faculty of Science, Fukuoka University,
Jonan-ku, Fukuoka 814-0180, Japan.
Table 1 Reaction of triflate 1a with L-alanine methyl ester 2a
E-mail: kokuma@fukuoka-u.ac.jp; Fax: +81-92-865-6030;
Tel: +81-92-871-6631
Entry
1a (eq.)
Additive
t/h
3a
4a
b National Defense Academy, Hashirimizu, Yokosuka,
239-8686, Japan.
1
2
3
4
5
6
7
1
2.2
3
4
2
CsF (1 eq.)
CsF (4 eq.)
CsF (6 eq.)
CsF (8 eq.)
TBAF (3 eq.)
TBAT (3 eq.)
KF (4 eq.)/18-C-6
16
16
16
16
3
30
65
48
46
0
3
10
9
E-mail: yokomori@nda.ac.jp; Fax: +81-46-844-5901;
Tel: +81-46-841-3810
w Electronic supplementary information (ESI) available: Detailed
experimental procedures and analytical data. CCDC 815166. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c1cc11234a
8
62
64
35
2
2
5
16
27
32
c
5822 Chem. Commun., 2011, 47, 5822–5824
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Table 2 Reaction of amino acid methyl esters 2 with triflate 1a
Amino acid
Entry methyl ester
Yielda
(%)
Product
1
65
26
Scheme 3
Indolin-3-ones (3) are interesting compounds because of
their biological and pharmaceutical activities. Recent work
includes the formation of 2,2-disubstituted indolin-3-ones,17
the Claisen rearrangement of indolin-3-ones,18 the intramolecular
cyclization of 2-aminochalcones,19 and the synthesis of
indirubin-N-glycosides.20 In particular, indolin-3-ones having
a quaternary center at the 2-position are potentially useful
intermediates for the synthesis of alkaloids and pharmaceutical
agents.21 The present result provides a simple and efficient
route for the synthesis of indolin-3-ones.
2c
3
4
5
70
72
71
Interestingly, when aspartic acid methyl ester (2b) was
treated with triflate 1a (2.4 equiv.) and CsF (4 equiv.) at rt
for 15 h, N-phenylaspartic acid methyl ester (4b) and (Z)-
methyl 2-(3-oxoindolin-2-ylidene)acetate (5a) were obtained in
11 and 51% yields, respectively (Scheme 3). The 1H NMR
spectrum of 5a features an olefinic proton signal that appears
at 6.20 ppm as a singlet. The stereochemistry of 5a (Z-form)
was determined by X-ray spectroscopic analysis (Fig. 1).22
A variety of functionally substituted amino acid methyl
esters (2c–2i) underwent this chemistry to afford moderate to
good yields of indolin-3-ones 3. The results are shown in
Table 2. Glycine methyl ester (2c) afforded only N-phenylglycine
methyl ester (4c) (entry 1). Proline methyl ester (2d) also
afforded N-phenylated product 4d in low yield, suggesting
that a secondary amino acid reacts with benzyne more slowly
than a primary amino acid (entry 2). Valine (2e), leucine (2f)
and isoleucine (2g) methyl esters gave cycloadducts, 2-isopropyl-
2-phenylindolin-3-one (3b), 2-isobutyl-2-phenylindolin-3-one
(3c) and 2-isobutyl-2-phenylindolin-3-one (3d) in good yields,
respectively (entries 3–5). When tyrosine methyl ester (2h) was
used as substrate, 2-(4-phenoxylphenyl)-2-phenylindolin-3-
one (6) was obtained in 72% yield (entry 6) upon reaction
with 3 mol equiv. benzyne. When phenylalanine methyl ester
(2i) was used as substrate, corresponding cycloadduct (3e) and
6
65
26
32
7
a
b
Isolated yield. Reaction conditions: 0.5 mmol of amino acid methyl
ester, 2.2 equiv. of triflate 1a, and 4.4 equiv. of CsF in 6 mL of MeCN
c
at room temperature for 20 h. Starting 2d was recovered in
62% yield.
(Z)-2-benzylideneindolin-3-one (5b) were obtained in 26 and
32% yields, respectively (entry 7). In this case, no N-phenyl-
ation product was obtained.
Thus, the cycloaddition reaction may proceed as follows:
benzyne initially reacts with methyl ester to afford indolin-3-
one a and this, in turn, enolizes to give 3-hydroxyindole b.
3-Hydroxyindole b further reacts with another benzyne via the
ene reaction to afford 2-phenylindolin-3-one 3. As the ene
reaction occurs very rapidly, initial adduct a could not be
isolated. Actually, obtained products 3 are racemic ([a]D = 0).
Fig. 1 ORTEP drawing of 5a.
c
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Chem. Commun., 2011, 47, 5822–5824 5823

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the synthesis of functionalized indolin-3-ones. The reaction
realizes the one-pot synthesis of 2-phenylindolin-3-ones from
amino acid esters.
Notes and references
1 For recent reviews, see: H. Yoshida, J. Ohshita and A. Kunai, Bull.
Chem. Soc. Jpn., 2010, 83, 199; D. Pena, D. Perez and E. Guitian,
Angew. Chem., Int. Ed., 2006, 45, 3579; C. R. Becer,
R. Hoogenboom and U. S. Schubert, Angew. Chem., Int. Ed.,
2009, 48, 4900; R. Sanz, Org. Prep. Proced. Int., 2008, 40,
215.
2 W.-G. Shou, Y.-Y. Yang and Y.-G. Wang, J. Org. Chem., 2007,
72, 9241; A. A. Aly, N. K. Mohamad, A. A. Hassen and A.-F.
E. Mourad, Tetrahedron, 1999, 55, 1111; H. Yoshida,
H. Fukushima, J. Ohshita and A. Kunai, J. Am. Chem. Soc.,
2006, 128, 11040; J. Nakayama, H. Midorikawa and M. Yoshida,
Bull. Chem. Soc. Jpn., 1975, 48, 1063.
3 J. Zhao and R. C. Larock, J. Org. Chem., 2007, 72, 583.
4 F. Shi, J. P. Waldo, Y. Chen and R. C. Larock, Org. Lett., 2008,
10, 2409; K. Yoon, S. M. Ha and K. Kim, J. Org. Chem., 2005, 70,
5741.
Scheme 4
5 S. Chandrasekhar, M. Seenaiah, C. L. Rao and C. R. Reddy,
Tetrahedron, 2008, 64, 11325; F. Shi, J. P. Waldo, Y. Chen and
R. C. Larock, Org. Lett., 2008, 10, 2409.
6 For a review, see Y. Hari, T. Shioiri and T. Aoyama, Yuki Gosei
Kagaku Kyokaishi, 2009, 67, 357.
7 G. Wittig and E. Benz, Chem. Ber., 1959, 92, 1999; See also W. Lin,
I. Sapountzis and P. Knochel, Angew. Chem., Int. Ed., 2005, 44,
4258; S. Dixon, X. Wang, K. S. Lam and M. J. Kurth, Tetrahedron
Lett., 2005, 46, 7443; Z. Liu and R. C. Larock, Org. Lett., 2003, 5,
4673.
8 J. B. Feltenberger, H. Ryuji, Y. Tang, E. S. C. Babiash and
R. P. Hsung, Org. Lett., 2009, 11, 3666.
9 A. A. Cant, G. H. V. Bertrand, J. L. Henderson, L. Roberts and
M. F. Greaney, Angew. Chem., Int. Ed., 2009, 48, 5199.
10 C. Xie and Y. Zhang, Org. Lett., 2007, 9, 781.
11 H. A. McManus, M. J. Fleming and M. Lautens, Angew. Chem.,
Int. Ed., 2007, 46, 433.
12 D. G. Pintori and M. F. Greaney, Org. Lett., 2010, 12, 168.
13 D. L. Goanvic and M. A. Tius, J. Org. Chem., 2006, 71, 7800.
14 C. Dockendorff, S. Sahli, M. Olsen, L. Mihau and M. Lautens,
J. Am. Chem. Soc., 2005, 127, 15028.
The formation of 5 can be explained as follows: 3-hydroxy-
lindole b further reacts with another benzyne to give 5
and benzene (Scheme 4). A similar oxidation mechanism of
benzyne adducts was found in the reaction of benzyne with
anilines and aldehydes.2 Abonia et al. have also reported the
formation of indolinone arylidene derivatives by the intra-
molecular cyclization of 2-aminochalcones via a similar oxidation
mechanism.19
To confirm the presence of 2-alkylindan-3-one, the reaction
of independently synthesized indolin-3-one with triflate 1a in
the presence of CsF was carried out and 3f was formed in 76%
yield (Scheme 5).
4,5-Disubstituted aryne derived from 1b also reacted with
leucine methyl ester 2f to give the corresponding cycloadduct
3g in 75% yield (Scheme 6).
In summary, we have reported that the aryne cycloaddition
reaction with amino acid methyl esters is a useful method for
15 Z. Liu and R. C. Larock, J. Org. Chem., 2006, 71, 3198.
16 C. D. Gilmore, K. M. Allan and B. M. Stoltz, J. Am. Chem. Soc.,
2008, 130, 1558.
17 P. N. Wyrembak and A. D. Hamilton, J. Am. Chem. Soc., 2009,
131, 4566.
18 T. Kawasaki, W. Takamiya, N. Okamoto, M. Nagaoka and
T. Hirayama, Tetrahedron Lett., 2006, 47, 5379.
19 R. Abonia, P. Cuerbo, J. Castillo, B. Insuasty, J. Quiroga,
M. Nogueras and J. Cobo, Tetrahedron Lett., 2008, 49, 5028.
20 S. Libnow, K. Methling, M. Hein, D. Michalik, M. Harms,
K. Wende, A. Flemming, M. Koeckerling, H. Reinke,
P. J. Bednarski, M. Lalk and P. Langer, Bioorg. Med. Chem.,
2008, 16, 5570.
Scheme 5
21 B. Witkop, J. Am. Chem. Soc., 1950, 72, 633; D. Lednicer and
D. E. Emmer, J. Heterocycl. Chem., 1970, 7, 575; B. Robinson,
U. Zubir and M. Pak, J. Sci. Ind. Res., 1976, 19, 214; C. Berti,
L. Greci and L. Marchetti, J. Chem. Soc., Perkin Trans. 2, 1979,
233; G. Tommasi, P. Bruni, L. Greci, P. Sgarabotto and L. Right,
J. Chem. Soc., Perkin Trans. 1, 1999, 681.
22 Crystal data for ompound 5a: Cu-Ka radiation, monoclinic, P21/c,
a = 13.1450(11), b = 5.3200(4), c = 17.294(2) A, b = 127.636
(4)1, Z = 4, 1507 measured reflections, 1046 independent
reflections, 675 observed reflections, R= 0.0740, wR = 0.1934.
Scheme 6
c
5824 Chem. Commun., 2011, 47, 5822–5824
This journal is The Royal Society of Chemistry 2011