Palladium-catalyzed highly regio-and stereoselective synthesis of 4-alkylidene-4 H -3,1-benzoxazines from N -Acyl-o -alkynylanilines

Article abstract of DOI:10.1021/ol103130s

The highly regio-and stereoselective 6-exo-dig mode cyclization of N-acyl-o-alkynylanilines producing 4-alkylidene-3,1-benzoxazines occurred unpredictably by use of a proper catalyst [Pd(OAc)₂] and an effective additive (acetic acid) under suit

Full text of DOI:10.1021/ol103130s

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1098–1101
Palladium-Catalyzed Highly Regio- and
Stereoselective Synthesis of 4-Alkylidene-
4H-3,1-benzoxazines from N-Acyl-
o-alkynylanilines
Takao Saito,* Shohei Ogawa, Naoya Takei, Noriki Kutsumura, and Takashi Otani
Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka,
Shinjuku-ku, Tokyo 162-8601, Japan
tsaito@rs.kagu.tus.ac.jp
Received December 24, 2010
ABSTRACT
The highly regio- and stereoselective 6-exo-dig mode cyclization of N-acyl-o-alkynylanilines producing 4-alkylidene-3,1-benzoxazines occurred
unpredictably by use of a proper catalyst [Pd(OAc)2] and an effective additive (acetic acid) under suitable reaction conditions.
3,1-Benzoxazines are attractive targets for medicinal
chemists because some 3,1-benzoxazine derivatives are
known to show interesting biological activities and have
been used as potent progesterone-receptor agonists, DNA-
binding antitumor agents,1 human leukocyte elastase
(HLE) inhibitors,2 and C1r serine protease inhibitors, as
well as fungicidal, anti-inflammatory, and anticonvulsant
drugs.3 The indole ring system is among the most important
heterocycles owing to its existence in nature and in many
pharmaceutical agents,4 and numerous methods for syn-
thesizing indoles,5 including functionalization of indoles,5d,6
have been developed. Recent new methodologies for indole
synthesis have involved the catalytic cyclization of a variety
of o-alkynylaniline derivatives as a key step. When a sub-
strate, for example, of type I (N-acylated) is employed
(Scheme 1), formal cyclization in a 5-endo-dig mode yields
indoles (III), while cyclization in a 6-exo-dig mode yields
3,1-benzoxazines (II). Therefore, highly effective regio-
control of the cyclization mode is essential for selective
(1) (a) Zhang, P.; Terefenko, T. A.; Fensome, A.; Zhang, Z.; Zhu, Y.;
Cohen, J.; Winneker, R.; Wrobel, J.; Yardley, J. Bioorg. Med. Chem.
Lett. 2002, 12, 787. (b) Dias, N.; Goossens, J.-F.; Baldeyrou, B.;
Lansiaux, A.; Colson, P.; Di Salvo, A.; Bernal, J.; Turnbull, A.;
Mincher, D. J.; Bailly, C. Bioconjugate Chem. 2005, 16, 949.
(2) Krantz, A.; Spencer, R. W.; Tam, T. F.; Liak, T. J.; Copp, L. L.;
Thomas, E. M.; Rafferty, S. P. J. Med. Chem. 1990, 33, 464.
(3) (a) Hays, S. J.; Caprathe, B. W.; Gilmore, J. L.; Amin, N.;
Emmerling, M. R.; Michael, W.; Nadimpalli, R.; Nath, R.; Raser,
K. J.; Stafford, D.; Watson, D.; Wang, K.; Jaen, J. C. J. Med. Chem.
1998, 41, 1060. (b) Sugiyama, H.; Hosoda, K.; Kumagai, Y.; Takeuchi,
M.; Okada, M. U.S. Patent 4,596,801, 1986. (c) Kobzina, J. W. U.S. Patent
4,030,906, 1977.
(4) For reviews (natural): (a) Higuchi, K.; Kawasaki, T. Nat. Prod.
Rep. 2007, 24, 843. (b) O’Connor, S. E.; Maresh, J. Nat. Prod. Rep. 2006,
23, 532. (c) Brancale, A.; Silvestri, R. Med. Res. Rev. 2007, 27, 209. For
reviews (indole, medicinal): (d) Sundberg, R. J. In Comprehensive Het-
erocyclic Chemistry II; Katritzky, A. R., Rees, C. R., Scriven, E. F. V., Bird,
C. W., Eds.; Pergamon: Oxford, UK, 1996; Vol. 2, p 119. (e) Gribble, G. W.
In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. R.,
Scriven, E. F. V., Bird, C. W., Eds.; Pergamon: Oxford, UK, 1996; Vol. 2,
p 207.
r
10.1021/ol103130s
Published on Web 02/03/2011
2011 American Chemical Society

and/or reaction conditions is attractive to chemists.15 This
prompted us to develop a reaction involving the alternative
pathway of 6-endo-dig mode cyclization of I. We have realized
a highly regio- and stereoselective synthesis of 4-alkylidene-
4H-3,1-benzoxazines II from o-alkynyl-N-carboxanilides I by
seeking a competent catalyst, an effective additive, and appro-
priate reaction conditions. We report the results herein.
N-Acyl-o-alkynylanilines 1, the key substrates bearing
various substituents (R1, R2, R3), were prepared in good
yields from 2-iodoanilines via the Sonogashira coupling
reaction with 1-alkynes, followed by acylation with acyl
chlorides (Scheme 2).
Scheme 1. Cyclizations of 6-Exo-dig vs 5-Endo-dig Mode
preparation of either indoles (III) or 3,1-benzoxazines (II).
A survey of the literature on SciFinder Scholar (up to
December 2010) for both reactions reveals, surprisingly,
that there are only 4 reports7,8 in which the formation of 3,1-
benzoxazines (II and congeners) from I is described, despite
146 reports demonstrating the transformation to indoles
(III and congeners) and a vast number of examples of indole
formation if the N-substituent of I are not limited to an acyl
group (R2CdO).5,9-14
Scheme 2. Preparation of Substrates 1
The development of methodologies for the highly selec-
tive synthesis of different products from the same starting
materials by simple modification of catalysts/promoters
€
ꢀ
(5) For reviews (indole synthesis): (a) Kruger (nee Alex), K.; Tillack,
A.; Beller, M. Adv. Synth. Catal. 2008, 350, 2153. (b) Humphrey, G. R.;
Kuethe, J. T. Chem. Rev. 2006, 106, 2875. (c) Zeni, G.; Larock, R. C.
Chem. Rev. 2006, 106, 4644. (d) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005,
105, 2873. (e) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285. (f)
Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127. (g) Gilchrist,
T. L. J. Chem. Soc., Perkin Trans. 1 2001, 2491. (h) Gribble, G. W. J.
Chem. Soc., Perkin Trans. 1 2000, 1045. (i) Patil, N. T.; Yamamoto, Y.
Chem. Rev. 2008, 108, 3395 (sec. 2.3). Recent reports: (j) Cacchi, S.;
Fabrizi, G.; Goggiamani, A.; Perboni, A.; Sferrazza, A.; Stabile, P. Org.
Lett. 2010, 12, 3279. (k) Kothandaraman, P.; Rao, W.; Foo, S. J.; Chan,
P. W. H. Angew. Chem., Int. Ed. 2010, 49, 4619. (l) Bernini, R.; Fabrizi,
G.; Sferrazza, A.; Cacchi, S. Angew. Chem., Int. Ed. 2009, 48, 8078. (m)
Yu, W.; Du, Y.; Zhao, K. Org. Lett. 2009, 11, 2417. (n) (Oxindoles):
Miura, T.; Toyoshima, T.; Ito, Y.; Murakami, M. Chem. Lett. 2009, 38,
Initially, to examine the regioselectivity (6-exo-dig vs
5-endo-dig cyclization mode) of the reaction to be con-
trolled, we selected palladium catalysts and screened them
in a model reaction of 2-(3,3-dimethyl-1-butynyl)phenyl-
acetamide (1a) and benzamide (1c). The results are shown
in Table 1. In the presence of Pd(dba)2, Pd(PPh3)4, PdCl2-
(PPh3)2, or Pd(PPh3)4/K2CO3, the reaction proceeded very
slowly at room temperature even by use of 20 mol % of the
catalyst and appreciable amounts of the starting material
1a remained (runs 1-3), while at higher temperatures, the
formation of indoles 3a/c predominated (runs 4-6). In
addition, the PdCl2 catalyst clearly promoted the forma-
tion of indoles 3a/c (runs 7 and 8). Interestingly, Pd-
(OCOCF3)2 preferentially provided 3,1-benzoxazine 2a
(58% yield) along with a small amount of indole 3a (6%)
(run 9). We finally found that Pd(OAc)2 was most efficient
in controlling the regioselectivity of the formation of 3,1-
benzoxazines 2a/c in the model reaction in an acetonitrile
solution (runs 10-12).
ꢀ
1174. (o) Cantagrel, G.; de Carne-Carnavalet, B.; Meyer, C.; Cossy, J.
€
Org. Lett. 2009, 11, 4262. (p) Jia, Y.-X.; Kundig, E. P. Angew. Chem.,
Int. Ed. 2009, 48, 1636.
(6) (a) Joucla, L.; Djakovitch, L.; Bandini, M. Adv. Synth. Catal.
2009, 351, 673. (b) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed.
2009, 48, 9608.
(7) (a) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843 (2-
aryl and 2-heteroaryl indole synthesis). (b) Cacchi, S.; Fabrizi, G.;
Marinelli, F.; Moro, L.; Pace, P. Synlett 1997, 1363 (3-aryl indole
synthesis). (c) Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 1999, 401
(2-arylquinoline synthesis). (d) Costa, M.; Ca, N. D.; Gabriele, B.;
Massera, C.; Salerno, G.; Soliani, M. J. Org. Chem. 2004, 69, 2469
(benzoxazine, quinolin-2-one, and quinolin-4-one synthesis).
(8) In refs 7a-7c, 3,1-benzoxazines having specific substituents were
formed as less favored byproduct in the synthesis of indoles7a,b or
quinolines.7c The reaction7d is a direct synthetic approach from I to
3,1-benzoxazines with the substituent R2 of an aryl or alkenyl group.
However, the method suffered from the demand of relatively high
pressure of [CO þ O2] (24 bar) and from that the 3,1-benzoxazines were
formed as a mixture of E- and Z-isomers contaminated with a minor
amount of the TMS-eliminated starting materials.
To effectively accelerate the reaction and to obtain
2a selectively in high yield, the Pd(OAc)2-catalyzed
(12) Ipy2BF3: Barluenga, J.; Trincado, M.; Rubio, E.; Gonzalez, J.
Angew. Chem., Int. Ed. 2003, 42, 2406.
(13) tBuOK: Sun, L.-P.; Huang, X.-H.; Dai, W.-M. Tetrahedron
2004, 60, 10983.
(9) Pd: (a) Rudisill, D. E.; Stille, J. K. J. Org. Chem. 1989, 54, 5856.
(b) Iritani, K.; Matsubara, S.; Utimoto, K. Tetrahedron Lett. 1988, 29,
1799. (c) Taylor, E. C.; Katz, A. H.; Salgado-Zamora, H.; McKillop, A.
Tetrahedron Lett. 1985, 26, 5963. (d) Ye, S.; Ding, Q.; Wang, Z.; Zhou,
H.; Wu, J. Org. Biomol. Chem. 2008, 6, 4406. (e) Ambrogio, I.; Cacchi,
S.; Fabrizi, G. Org. Lett. 2006, 8, 2083. (f) Arcadi, A.; Cacchi, S.; Fabrizi,
G.; Marinelli, F.; Parisi, L. M. J. Org. Chem. 2005, 70, 6213. (g) Cacchi,
S.; Fabrizi, G.; Pace, P. J. Org. Chem. 1998, 63, 1001.
(14) InBr3: (a) Sakai, N.; Annaka, K.; Fujita, A.; Sato, A.; Konakahara,
T. J. Org. Chem. 2008, 73, 4160. (b) Sakai, N.; Annaka, K.; Konakahara, T.
Tetrahedron Lett. 2006, 47, 631.
(15) For selected recent examples, see: (a) Bianchi, G.; Chiarini, M.;
Marinelli, F.; Rossi, L.; Arcadi, A. Adv. Synth. Catal. 2010, 352, 136. (b)
ꢀ
Gimeno, A.; Medio-Simon, M.; Ramırez de Arellano, C.; Asencio, G.;
´
Cuenca, A. B. Org. Lett. 2010, 12, 1900. (c) Li, L.; Wang, M.; Zhang, X.;
Jiang, Y.; Ma, D. Org. Lett. 2009, 11, 1309. (d) Xiao, Y.; Zhang, J. Chem.
Commun. 2009, 3594. (e) Masters, K.-S.; Flynn, B. L. Adv. Synth. Catal.
2009, 351, 530. (f) Liu, L.; Zhang, J. Angew. Chem., Int. Ed. 2009, 48,
6093. (g) Wang, H.; Liu, L.; Wang, Y.; Peng, C.; Zhang, J.; Zhu, Q.
Tetrahedron Lett. 2009, 50, 6841 and references cited therein. For our
previous examples, see: (h) Saito, T.; Ohmori, H.; Furuno, E.; Motoki,
S. J. Chem. Soc., Chem. Commun. 1992, 22 (thermal electrocyclization).
(i) Saito, T.; Ohmori, H.; Ohkubo, T.; Motoki, S. J. Chem. Soc., Chem.
Commun. 1993, 1802 (Lewis acid-induced intramolecular Diels-Alder).
(10) Pt: Shimada, T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem.
Soc. 2004, 126, 10546.
(11) Cu: (a) Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004,
69, 1126. (b) Hiroya, K.; Itoh, S.; Ozawa, M.; Kanamori, Y.; Sakamoto,
T. Tetrahedron Lett. 2002, 43, 1277. TBAF: (c) Yasuhara, A.; Suzuki,
N.; Yoshino, T.; Takeda, Y.; Sakamoto, T. Tetrahedron Lett. 2002, 43,
6579. (d) Yasuhara, A.; Kanamori, Y.; Kaneko, M.; Numata, A.;
Kondo, Y.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999, 529.
Org. Lett., Vol. 13, No. 5, 2011
1099

Table 1. Screening of Palladium Catalystsa
yield,b %
run
1
substrate
catalyst (mol %)
Pd(dba)2 (20)
conditions
1a/c
2a/c
3a/c
1a
THF
98
rt, 7 d
THF
2
3
1a
1a
1a
1c
1c
1a
1c
1a
1a
1a
1c
Pd(PPh3)4 (20)
PdCl2(PPh3)2 (20)
PdCl2(PPh3)2 (20)
PdCl2(PPh3)2 (20)
Pd(PPh3)4 (10)/K2CO3
PdCl2 (20)
96
85
18
trace
10
50
68
76
82
96
6
rt, 7 d
THF
rt, 7 d
DMF
4
reflux, 25 h
DMF
5
reflux, 25 h
toluene
reflux, 4 d
THF
6
7
rt, 2 d
MeCN
rt, 12 h
THF
8
PdCl2 (10)
9
Pd(OCOCF3)2 (20)
Pd(OAc)2 (20)
27
58
72
87
87
rt, 7 d
THF
10
11
12
rt, 3 d
MeCN
rt, 3 d
MeCN
rt, 2 d
Pd(OAc)2 (10)
Pd(OAc)2 (10)
a Reaction was carried out in the presence of Pd catalyst in each solvent (1.0 mL) with substrate 1a/c (0.24 mmol). b Yields of isolated 1a/c, 2a/c, and 3a/c.
reaction was further examined in the presence of an
additive in refluxing acetonitrile (Table 2). Additives
such as MnO2, CuO, Cu(OAc)2, and AcONa were not
sufficiently effective, as the starting material 1a still
remained after 10 h, although benzoxazine 2a was
obtained in appreciable amounts by use of 20 mol %
of the catalyst (runs 1-4). Compound 4a was formed in
variable amounts from 2a by hydrolysis during the
reaction and/or separation/purification procedure. Ac-
tually, when 2a was treated with acidic water, 4a was
formed exclusively. AcOH (300 mol %) as an additive
clearly accelerated the reaction to produce 2a in 72%
yield and the hydrolyzed form 4a in 18% yield in 2.5 h
with consumption of the starting material 1a in the
presence of 10 mol % of Pd(OAc)2 (run 5). However,
the reaction in the absence of Pd(OAc)2 did not yield any
product even in the presence of AcOH (300 mol %).
Reducing the amount of AcOH to 200 mol % slightly
improved the yield of 2a (75%; run 6). The reaction in
the presence of 100 mol % of AcOH for 2.5 h gave the
best result; benzoxazine 2a was exclusively obtained in
83% yield without formation of 4a (run 7). In the
reaction with 50 mol % AcOH (run 8) for 2.5 h, 1a was
not completely consumed, but a prolonged reaction time
(10 h) under acidic conditions caused hydrolysis of some of
the preformed 2a to give 4a (run 9). The reaction in the
absence of any additive in refluxing acetonitrile for 12 h
produced 2a exclusively in 92% yield, although 30 mol %
of Pd(OAc)2 was required (run 10).
After establishing the optimized reaction conditions
(Table 2, run 7), we examined the generality of this inter-
esting 6-endo-dig mode cyclization using substrates 1 bear-
ing a variety of alkyl and aryl substituents in R1 and R2
(Table 3) and Me and Cl substituents in R3 (Scheme 3). A
tolerable range of the substituted 3,1-benzoxazines 216 was
obtained in good-to-excellent yields (62-90%, not thor-
oughly optimized) within a reasonable reaction time
(0.2-5 h). In the reaction of the R1-unsubstituted sub-
t
strates 1 (R1 = H, R2 = Me, Bu, Ph, p-NO2C6H4), the
(16) The structures of 4-methylene-4H-3,1-benzoxazines 2 were de-
termined spectroscopycally (1H NMR, 13C NMR, IR, HRMS) and
confirmed by X-ray crystallography of 2d and 2r: The crystallographic
coordinates for 2r have been deposited with the Cambridge Crystal-
lographic Data Centre; deposition no. 769241. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre, 12 Union Rd., Cambridge CB2 1EZ, UK or via www.ccdc.cam.
ac.uk/conts/retrieving.html. (see the Supporting Information). Noe was
also observed between the olefinic-H and the peri-position-H of the
benzene ring of 2, suggesting the Z-configuration.
1100
Org. Lett., Vol. 13, No. 5, 2011

Table 2. Screening of Additivesa
Scheme 3. Palladium-Catalyzed Cyclization of 1 To Yield 2
yield,b %
run Pd(OAc)2, mol % additive (mol %) time, h
1a
2a 4a
Scheme 4. A Possible Mechanism for the Palladium Acetate-
Catalyzed Cyclization of 1 To Produce 2
1
2
20
20
20
20
10
10
10
10
10
30
MnO2 (300)
CuO (300)
Cu(OAc)2 (40)
AcONa (300)
AcOH (300)
AcOH (200)
AcOH (100)
AcOH (50)
AcOH (50)
none
10
10
10
10
9
39
58
10
68 17
42 10
39
3
4
62
5
2.5
72 18
75 12
83
6
2.5
2.5
2.5
7
8
28
56
9
10
12
35 55
92
10
a Reaction was carried out in refluxing MeCN (1.0 mL) with
substrate 1a (0.24 mmol) in the presence of 10-30 mol % of Pd(OAc)2
and 50-300 mol % of AcOH. b Yields of isolated 1a, 2a, and 4a.
3,1-benzoxazines 2 formed tended to hydrolyze to afford
compounds 4 (R1 = H), and only 3,1-benzoxazine 2u
(R2 = p-NO2C6H4) was isolated, albeit in 25% yield, when
the reaction was carried out in the absence of AcOH under
the conditions of Table 1, run 11, for 7 d.
Table 3. Palladium-Catalyzed Regioselective Cyclization of
Various N-Acyl-o-alkynylanilines 1to Produce 3,1-Benzoxazines 2a
Although the precise mechanism for this reaction is not
clear, a plausible mechanism is illustrated in Scheme 4.
Initially, the catalyst Pd(OAc)2 attacks the alkyne π-bond
of 1 to form a palladium π-complex. The 6-exo-dig mode
cyclization by the intramolecular nucleophilic attack of the
relatively harder carbonyl oxygen rather than the nitrogen
at the alkyne carbon (the former is harder than the latter)
occurs preferentially, together with elimination of AcOH
to form a palladium σ-complex. The AcOH added in
adjusted amounts (100 mol %) promotes the catalytic
cycle by accelerating the formation of 2 and regeneration
of the Pd(OAc)2 catalyst from the σ-complex without
hydrolysis of 2 formed under the optimized conditions.
The existence of the σ-complex is supported by the ob-
servation that in the presence of methyl acrylate the
reaction yielded the Michael addition product 5.
run
R1
R2
1
time, h product yield,b %
1
2
tBu
Me
nPr
Me
tBu
Ph
1a
1b
1c
2.5
0.5
0.5
1
2a
2b
2c
2d
2e
2f
83
70
75
90
77
70
77
72
65
89
74
65
65
89
79
72
67
72
3
4
p-NO2C6H4 1d
5
Me
tBu
Ph
1e
1f
0.5
0.5
0.2
0.5
0.5
0.5
1
6
7
1g
2g
2h
2i
8
p-NO2C6H4 1h
9
Me
tBu
Ph
1i
1j
10
11
12
2j
1k
2k
2l
In conclusion, we have developed a Pd(OAc)2-catalyzed
new, straightforward and highly regio- and stereoselective
synthetic method for 4-alkylidene-4H-3,1-benzoxazines
from readily available o-alkynyl-N-carboxanilides. A fur-
ther investigation directed toward the utilization of this
reaction and elucidation of the regioselectivity is in progress.
p-MeOC6H4 1l
1
13 Ph
14
Me
tBu
Ph
1m
3
2m
2n
2o
2p
2q
2r
1n
1o
0.5
1
15
16
p-NO2C6H4 1p
1q
p-NO2C6H4 1r
1.5
3
17 p-MeOC6H4 Me
18
10
Supporting Information Available. Typical experimen-
1
tal procedure, spectroscopic data, and copies of H and
13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
a Reaction was carried out in refluxing MeCN (1.0 mL) with
substrate 1 (0.24 mmol) in the presence of 10 mol % of Pd(OAc)2 and
100 mol % of AcOH. b Yields of isolated 2.
Org. Lett., Vol. 13, No. 5, 2011
1101