Zn(OTf)2-catalyzed cyclization of proparyl alcohols with anilines, phenols, and amides for synthesis of indoles, benzofurans, and oxazoles through different annulation mechanisms

Article abstract of DOI:10.1021/jo0606711

Zn(OTf)₂ (10 mol %) catalyzed the cyclization of propargyl alcohols with PhXH (X = O, NH) in hot toluene (100 °C) without additive and gave indole and benzofuran products with different structures. In such transformations, α-carbonyl intermedia

Full text of DOI:10.1021/jo0606711

Zn(OTf)2-Catalyzed Cyclization of Proparyl Alcohols with Anilines,
Phenols, and Amides for Synthesis of Indoles, Benzofurans, and
Oxazoles through Different Annulation Mechanisms
Manyam Praveen Kumar and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua UniVersity, Hsinchu, Taiwan 30043
rsliu@mx.nthu.edu.tw
ReceiVed March 28, 2006
Zn(OTf)2 (10 mol %) catalyzed the cyclization of propargyl alcohols with PhXH (X ) O, NH) in hot
toluene (100 ïC) without additive and gave indole and benzofuran products with different structures. In
such transformations, R-carbonyl intermediates A and C were isolated as reaction intermediates. The
1,2-nitrogen shift in the formation of indole is catalyzed by Zn(OTf)2, and its mechanism has been
elucidated. This catalytic cyclization is also applicable to the synthesis of oxazoles through the cyclization
of propargyl alcohols and amides without a 1,2-nitrogen shift.
Introduction
as a two-carbon building unit for synthesis of heteroaromatic
compounds is practical and intriguing in mechanistic aspects.
There are two distinct pathways depending on the types of
catalysts: (a) an initial propargyl at the C(3)-carbon8a,9 or (b)
amination at the C(2)-carbon10 with a subsequent annulation.
These two catalytic methods have been applied to the synthesis
of furans,9 oxazoles,8a and indoles,10 and their reaction protocols
Indoles and benzofurans are important functionalities in many
pharmacologically active molecules. Metal-catalyzed synthesis
of such heteroaromatic compounds has received considerable
attention.1-8 Most documented methods involve the use of
starting R-functionalized anilines or phenols, which are expen-
sive and not readily available.3-8 The use of propargyl alcohol
(4) Indole synthesis using platinum and gold catalysts: (a) Shimada, T.;
Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 10546. (b)
Alfonsi, M.; Areadi.; Aschi, M.; Bianchi, G.; Marinelli, F. J. Org. Chem.
2005, 70, 2265. (c) Fukuda, Y.; Utimoto, K.; Nozaki, H. Heterocycles 1987,
25, 297.
(1) Recent reviews for indole synthesis: (a) Gribble, G. W. J. Chem.
Soc., Perkin Trans. 1 2000, 1045. (b) Sundberg, R. J. Indoles; Academic
Press: San Diego, 1996. (c) Gilchrist, T. L. J. Chem. Soc., Perkin Trans.
1 1999, 2848.
(2) Reviews for metal-catalyzed of indole and benzofuran synthesis: (a)
Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285. (b) Gribble, G. W.
Contemp. Org. Synth. 1994, 145.
(3) Indole synthesis using palladium catalysts: (a) Willis, M. C.; Brace,
G. N.; Holmes, I. P. Angew. Chem., Int. Ed. 2005, 44, 403. (b) Ackermann,
L. Org. Lett. 2005, 7, 439. (c) Takeda, A.; Kamijo, S.; Yamamoto, Y. J.
Am. Chem. Soc. 2000, 122, 5662. (d) Nazare, M.; Schneider, C.; Linden-
schmidt, A.; Will, D. W. Angew. Chem., Int. Ed. 2004, 43, 4526. (e)
Ackermann, L.; Kaspar, L. T.; Gschrei, C. J. Chem. Commun. 2004, 2824.
(f) Siebeneicher, H.; Bytschkov, I.; Doye, S. Angew. Chem., Int. Ed. 2003,
42, 3042. (g) Zhang, H.-C.; Ye, H.; Moretto, A. F.; Brumfield, K. K.;
Maryanoff, B. E. Org. Lett. 2005, 7, 439. (h) Charrier, N.; Demont, E.;
Dunsdon, R.; Maile, G.; Naylor, A.; Brien, A. O.; Redshaw, S.; Theobald,
P.; Vesey, D.; Walter, D. Synlett 2005, 3072. (i) Kamjio, S.; Yamamoto,
Y. Angew. Chem., Int. Ed. 2003, 41, 3230. (j) Wagaw, S.; Yang, B. H.;
Buchwald, S. L. J. Am. Chem. Soc. 1922, 44, 10251.
(5) Indole synthesis using ruthenium and other metal species: (a)
Tokunaga, M.; Ota, M.; Haga, M.; Wakatsuki, Y. Tetrahedron Lett. 2001,
42, 3865. (b) Nicolaou, K. C.; Lee, S. H.; Estrada, A. A.; Zak, M. Angew.
Chem., Int. Ed. 2005, 44, 3736. (c) Julian, P. L.; Meyer, E. W.; Magnani,
A.; Cole, W. J. Am. Chem. Soc. 1945, 67, 1203. (d) Tsuchimoto, T.;
Matsubayashi, H.; Kaneko, M.; Shirakawa, E.; Kawakami, Y. Angew.
Chem., Int. Ed. 2005, 44, 1336. (e) Taber, D. F.; Tian, W. J. Am. Chem.
Soc. 2006, 126, 1058. (f) Penoni, A.; Palmisano, G.; Kadowaki, A.; Nicholas,
K. M. J. Org. Chem. 2006, 71, 823. (g) Yue, D.; Larock, R. C. Org. Lett.
2004, 6, 1037. (h) Tokuyama, H.; Yamashita, T.; Reding, M. T.; Kaburagi,
Y.; Fukuyama, T. J. Am. Chem. Soc. 1999, 121, 3791. (i) Russell, G. A.;
Yao, C.-F.; Tashtoush, H. I.; Russell, J. E.; Dedolph, D. F. J. Org. Chem.
1991, 56, 663. (j) Isomura, K.; Ayabe, G. I.; Hatano, S.; Taniguchi, H. J.
Chem. Soc., Chem Commun. 1980, 1252. (k) Padwa, A.; Smolanoff, J.;
Tremper, A. J. Org. Chem. 1976, 41, 543. (l) Alper, H,; Prickett, J. E. J.
Chem. Soc., Chem Commun. 1976, 483.
10.1021/jo0606711 CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/23/2006
J. Org. Chem. 2006, 71, 4951-4955
4951

Kumar and Liu
TABLE 1. Zn(OTf)2-Catalyzed Synthesis of Indole Derivatives
SCHEME 1
SCHEME 2
entry
catalysta
solvent
T, °C (time, h)
product (yield, %)b
1
2
3
4
5
6
7
8
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
AuCl3
130 (4)
100 (14)
100 (8)
100 (14)
100 (14)
100 (14)
100 (14)
100 (14)
4a/4a′ ) 4.5 (95)
4a (89)
4a (97)
N.R.
N.R.
benzene
toluene
DCE
DME
toluene
toluene
toluene
PtCl2
Cu(OTf)2
a 10 mol % of catalyst, [substrate] ) 1.3 M. b Products were separated
from a silica column.
are shown in Schemes 1 and 2, respectively. One drawback for
such cyclizations is the use of two catalysts, one to achieve
nucleophilic addition at alkynes and another for a subsequent
cyclization of the resulting intermediates.9,10 In the second
process,10 Ru3(CO)12 is responsible for the initial C(2)-amination
of propargyl alcohols, whereas additive PhNH3X catalyzes both
the isomerization between two R-aminoketone A and A′11 as
well as the cyclization of these two intermediates. This catalytic
process produces two indole regioisomers with a 1,2-nitrogen
migration product 1′ being dominant (1′/1 > 6.0).
TABLE 2. Zn(OTf)2-Catalyzed Synthesis of Indole
Here, we report a new Zn(OTf)2-catalyzed synthesis of
indoles, benzofurans, and oxazoles using propargyl alcohols as
a two-carbon building unit. In contrast with preceding examples,
Zn(OTf)2 activates both the C(2)-addition of propargyl alcohols
and their subsequent cyclizations. Only one regioisomeric
product is obtained for these heteroaromatic compounds, but
indole derivatives are distinct from oxazoles and benzofurans
in cyclization regioselectivity.
Results and Discussions
In a typical operation, aniline 2a was heated with neat
1-pentyn-3-ol 3a in equal proportion (130 °C, 4 h) in the
(6) Benzofuran synthesis using palladium catalysts: (a) Zhang, H.;
Ferreira, E. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2004, 43, 6144. (b)
Willis, M. C.; Taylor, D.; Gilmore, A. T. Org. Lett. 2004, 6, 4755. (c) Hu,
Y.; Nawoschik, K. J.; Liao, Y.; Ma, J.; Fathi, R.; Yang, Z. J. Org. Chem.
2004, 69, 2235. (d) Youn, S. W.; Eom, J, I. Org. Lett. 2005, 7, 3355. (e)
Xie, X.; Chen, B.; Lu, J.; Han, J.; She, X.; Pan, X. Tetrahedron Lett. 2004,
45, 6235. (f) Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham, K. K. C. J.
Org. Chem. 1995, 60, 3270.
(7) Benzofuran synthesis using other metal catalysts: (a) Fu¨rstner, A.;
Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024. (b) Li, X.; Chianese,
A. R.; Vogel, T.; Crabtree, R. H. Org. Lett. 2005, 7, 5437. (c) Nakamura,
I.; Mizushima, Y.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 15022. (d)
Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292.
(8) For general synthesis of oxazole derivatives, see: (a) Milton, M. D.;
Inada, Y.; Nishibayashi, Y.; Uemura, S. Chem. Commun. 2004, 2712. (b)
Keni, M.; Tepe, J. J. J. Org. Chem. 2005, 70, 4211. (c) Pulici, M.; Quartieri,
F.; Felder, E. R. J. Comb. Chem. 2005, 7, 463. (d) Clapham, B.; Lee, S.-
H.; Koch, G.; Zimmermann, J.; Janda, K. D. Tetrahedron Lett. 2002, 43,
5407. (e) Wipf, P.; Miller. C. P. J. Org. Chem. 1993, 58, 3604. (f) Spanka,
C.; Clapham, B.; Janda, K. D. J. Org. Chem. 2002, 67, 3045. (g) Cunico,
R. F.; Kuan, C. P. J. Org. Chem. 1992, 57, 3331. (h) Whitney S. E.;
Rickborn, B. J. Org. Chem. 1991, 56, 3058.
a 10 mol % of catalyst, toluene, 100 °C, [substrate] ) 1.1 M. b Products
were separated from a silica column.
presence of Zn(OTf)2 (10 mol %), giving two isomeric indoles
4a and 4a′ (4a/4a′ ) 4.5) as shown in Table 1. The structure
1
of species 4a was indicated by H-NOE and confirmed by
comparison of its NMR data to those of authentic samples.12
The use of benzene and toluene as reaction solvents in a sealed
tube gave only indole 4a according to NMR analysis (entries 2
and 3). This Zn(OTf)2-catalyzed cyclization is highly sensitive
to solvents, and starting aniline was recovered in 68% and 75%
yield using dichloroethane (DCE) and dimethoxyethane (DME)
as solvents (entries 4 and 5). Among other π-alkyne activators
(entries 6-8), only Cu(OTf)2 were found to be equally efficient
for such indole synthesis (86% yield).
(9) (a) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Milton, M. D.; Hidai,
M.; Uemura, S. Angew. Chem., Int. Ed. 2003, 42, 2681. (b) Nishibayashi,
Y.; Milton, M. D.; Inada, Y.; Yohsikawa, M.; Wakiji, I.; Hidai, M.; Uemura,
S. Chem. Eur. J. 2005, 11, 1433.
(10) Tokunaga, M.; Ota, M.; Haga, M.-A.; Wakatsuki, Y. Tetrahedron
Lett. 2001, 42, 3865.
Table 2 shows additional examples of the Zn(OTf)2-catalyzed
indole synthesis using various anilines and propargyl alcohols.
Entries 1-4 show the applicability of this cyclization to
propargyl alcohols 3b-e bearing various R substituents (R )
(11) (a) Mohlau, R. Chem. Ber. 1881, 14, 171. (b) Bischler, A. Chem.
Ber. 1892, 25, 2860.
(12) Fu¨rstner, A.; Hupperts, A. J. Am. Chem. Soc. 1995, 117, 4468.
4952 J. Org. Chem., Vol. 71, No. 13, 2006

Zn(OTf)2-Catalyzed Cyclization of Proparyl Alcohols
TABLE 3. Zn(OTf)2-Catalyzed Synthesis of Benzofurans
SCHEME 3
a [TpRu] ) TpRuPPh3(CH3CN)2PF6; 10 mol % of catalyst, toluene, 100
b
°C, [substrate] ) 0.75 M. Products were separated from a silica column.
TABLE 4. Zn(OTf)2-Catalyzed Synthesis of Oxazole Derivatives
a 10 mol % of catalyst, toluene, 100 °C, [substrate] ) 0.75 M. b Products
were separated from a silica column.
i
iPr, Bu, Ph, 2-naphthyl); the resulting indole products 4b-e
were obtained in 71-91% yields. Entries 5-7 show the
compatibility of this method with various anilines 2b-d having
a methyl at the C(2), C(3), and C(4) positions; the corresponding
indole products 4f-h were obtained in 78-93% yields. This
indole synthesis is successfully extensible to 1-aminonaphtha-
lene, which gave indole 4i in 93% yield (entry 8). The structure
of 4b was identified by 1H-NOE spectra,13 whereas the
molecular structure of compound 4h has been elucidated by
X-ray diffraction methods.14
a 10 mol % of catalyst, toluene, 100 °C, [substrate] ) 0.75 M. b Products
were separated from a silica column.
We extended this Zn(OTf)2-catalyzed cyclization to catalytic
synthesis of benzofurans using phenols and propargyl alcohols,
and the examples are summarized in Table 3. Cyclization of
phenol 6a with 3-phenyl-1-propyn-3-ol 3d using Zn(OTf)2 (10
mol %) in hot toluene (100 °C, 16 h) afforded benzofuran 7a
in 86% yields (entry 1). This method is compatible with various
phenols 6b, 6c, and 6d, which gave the corresponding benzo-
furans 7b, 7c, and 7d with yields exceeding 91% (entries 2-4).
Entries 5 and 6 provide additional examples for cyclization of
various 3-phenyl-1-propyn-3-ols 3f and 3g with suitable phenols,
which gave desired products 7e and 7f in 85-94% yields.
Among these benzofurans, the structure of species 7a was
identified by 1H-NOE effects;13 its NMR spectra are consistent
with literature data.15 These benzofurans differ notably from
indole products in their structures because the former has a C(1)-
methyl and the latter has a C(2)-methyl group.
The value of this Zn(OTf)2-catalyzed reaction is demonstrated
also by its applicability to the synthesis of oxazoles through
the cyclization of propargyl alcohols with amides. As shown
in Scheme 3, treatment of 3-phenyl-1-propyn-3-ol with benza-
mide with Zn(OTf)2 (10 mol %) in hot toluene (100 °C) gave
oxazole 9a in only 28% yield, but the presence of cocatalyst
TpRuPPh3(CH3CN)2PF6 (10%)16 greatly enhanced the catalytic
activity, giving oxazole with 95% yield. Use of TpRuPPh3(CH3-
CN)2PF6 alone in catalytic cyclization led only to the recovery
of starting amide 8a and propargyl alcohol 3d. These results
indicate that Zn(OTf)2 is responsible for the C(2)-amination of
propargyl alcohols and that TpRuPPh3(CH3CN)2PF6 is more
active for the subsequent cyclization.
Table 4 shows a generalization of the catalytic oxazole
synthesis with various amides and propargyl alcohols; the
reactions were performed in hot toluene (100 °C, 5 h) using
Zn(OTf)2 and TpRuPPh3(CH3CN)2PF6 at 10 mol % loading.
Entries 1-4 include additional examples for the cyclization of
benzamide 8a with various 3-phenyl-1-propyn-3-ols 3f-i, which
gave oxazole products 9b-e with yields up to 88-95%. Entries
5 and 6 show the applicability of this catalytic reaction to
n-caproamide 8b and 2-methylacrylamide 8c, and the corre-
sponding oxazoles 9f,g were obtained in 90% and 95% yields,
respectively. The structure of oxazole 9c has been characterized
by X-ray diffraction study,14 which reveals that these oxazole
products closely resemble benzofurans 7a-f in their skeletal
structure; both compounds have a methyl group at the C(1)
carbon, which is the carbon being attacked by phenol and amide
nucleophiles. In contrast, indole derivatives 4a-h have a methyl
group located at the C(2)-carbon, rather than the C(1)-carbon.
Scheme 4 shows our efforts to elucidate the reaction mech-
anism of the indole synthesis via isolation of reaction intermedi-
(16) TpRuPPh3(CH3CN)2PF6 is considered to be a mild Lewis acid; see
the following examples of catalysis using this catalyst: (a) Chan, W.-C.;
Lau, C.-P.; Chen, Y.-Z.; Fang, Y.-Q.; Ng, S.-M.; Jia, G. Organometallics
1997, 16, 34. (b) Madhushaw, R. J.; Lin, M.-Y.; Abu Sohel, S. M.; Liu,
R.-S. J. Am. Chem. Soc. 2004, 126, 6895. (c) Odedra, A.; Wu, C.-J.; Pratap,
T. B.; Huang, C.-W.; Ran, Y.-F.; Liu, R.-S. J. Am. Chem. Soc. 2005, 12,
3406. (d) Lin, M.-Y.; Maddirala, S. J.; Liu, R.-S. Org. Lett. 2005, 7, 1745.
(13) The 1H NOE effects of key compounds 4a, 4b, 7a, and 7b are
provided in the Supporting Information.
(14) The X-ray structural data of compounds 4h and 9c are provided in
the Supporting Information.
(15) Katritzky, A. R.; Ji, Y.; Fang, Y.; Prakash, I. J. Org. Chem. 2001,
66, 5613.
J. Org. Chem, Vol. 71, No. 13, 2006 4953

Kumar and Liu
SCHEME 4
SCHEME 6
SCHEME 7
SCHEME 5
catalyzed by Zn(OTf)2. This hypothesis is supported by Zn-
(OTf)2-catalyzed conversion of R-carbonyl amide 10b to oxazole
9f as depicted in Scheme 5. The Zn(OTf)2-catalyzed isomer-
ization between species 10a and 10a′ is remarkable since we
observed no analogous reaction in the oxazole and benzofuran
synthesis. This isomerization mechanism differs from those
using PhNH3X catalyst in the Ru3(CO)12-catalyzed indole
synthesis as depicted in Scheme 2. Scheme 6 rationalizes the
observed chemoselectivity in indole synthesis. The equilibrium
between R-amino ketones 10a and 10a′ is thought to be fast
and reversible according to our observation in Scheme 4. The
preference for formation of indole 4a is the faster rate in
cyclization of ketone 10a relative to that of its regioisomer 10a′
(k1 > k1′). Scheme 7 also shows a plausible mechanism for
mutual isomerization between ketones 10a and 10a′. We propose
that Zn(OTf)2 initially coordinates to ketone 10a′ to generate
carbocation (I), and this species subsequently produces aziridine
intermediate (II) via an intramolecular nitrogen attack. The R3-
NH+ functionality of species (II) enhances the opening of an
aziridine ring via its tethered oxygen attack, giving epoxide (III),
which ultimately yielded the other R-haloketone 10a following
the epoxide-ketone rearrangement.17 Relative to phenol and
amide nucleophiles, the aniline nitrogen has a greater nucleo-
philicity to generate aziridine intermediate I, which might
account for the observed 1,2-nitrogen shift in the indole
synthesis.
ates after brief periods of reactions. As depicted in eq 1,
treatment of pen-1-tyn-3-ol 3a with aniline 2a and Zn(OTf)2
(10 mol %) in hot toluene for a brief period (100 °C, 5 h) gave
a mixture of isomeric ketones 10a and 10a′ (10a′/10a ) 3.1,
67%), indicating that the indole synthesis is initiated by a C(2)-
amination of an alcohol. In this case, two isomeric R-amino
ketones 10a and 10a′ (10a/10a′ ) 3.1) were obtained, and this
mixture was isolated, purified, and subsequently heated with
Zn(OTf)2 (10 mol %) in hot toluene (100 °C, 11 h), eventually
yielding two isomeric indoles 4a′ and 4a in 95% yields (4a/4a′
) 6.0). In separated experiments, we succeeded in obtaining a
single R-amino ketone 10a or 10a′ according to the protocol in
eq 2 (Scheme 4). Notably, these two R-amino ketones notably
produced the same composition of indoles 4a′ and 4a efficiently
upon heating each species alone withZn(OTf)2. After a brief
period (85 °C, 5 h), we found that species 10a became
isomerized to the other R-amino ketones 10a′ in a ratio of 10a/
10a′ ) 1.1. These observations imply that Zn(OTf)2 is active
not only for cyclization of R-amino ketones 10a or 10a′ to give
mainly indole 4a′ but also for rapid isomerization between
R-amino ketones 10a and 10a′.
We also elucidated the mechanistic pathway for Zn(OTf)2-
catalyzed synthesis of benzofurans and oxazoles, which have
different structures from indole synthesis. As shown in Scheme
5, heating a mixture of amide 8b with alcohol 3i with Zn(OTf)2
in hot toluene (100 °C, 3 h) produced R-carbonyl amide 10b
(64%) and oxazole 9f (27%). In contrast with the indole
synthesis, we found no other isomeric R-carbonyl amide
corresponding to a 1,2-nitrogen shift. Heating compound 10b
with Zn(OTf)2 (10 mol %) and TpRuPPh3(CH3CN)2PF6 (10 mol
%) gave only oxazole 9f in 96% yield.
Conclusion
With Zn(OTf)2 as catalyst, we achieved synthesis of indole,
benzofuran, and oxazole through cyclization of propargyl
alcohols with anilines, phenols, and amides. The skeletal
structures of indole products differ from those of benzofurans
and oxazoles. We have elucidated the mechanism of formation
of indole and oxazole products, in which Zn(OTf)2 catalyzes
the C(2)-addition of aniline and amide nucleophiles to propargyl
alcohol moieties. For indole formation, Zn(OTf)2 is active for
In the indole synthesis, species 4a arises primarily from
intramolecular cyclization of R-amino ketone intermediate 10a
(17) Rickborn, B. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, Part 3.3, p 733.
4954 J. Org. Chem., Vol. 71, No. 13, 2006

Zn(OTf)2-Catalyzed Cyclization of Proparyl Alcohols
bicarbonate (305 mg, 3.63 mmol), and water (65 mg, 3.63 mmol),
and the reaction mixture was heated at 80 °C for 10 h. The solvent
was evaporated, extracted with diethyl ether, dried over MgSO4,
concentrated, and finally chromatographed through a silica column
to give 3-phenylaminopentan-2-one (10a) as a yellow oil (430 mg,
2.42 mmol, 80%): IR (neat, cm-1) 3419 (s), 3048 (w), 1718 (s),
1617 (w), 1568 (s), 1376 (s), 1141 (s); 1H NMR (400 MHz, CDCl3)
δ 7.15 (t, J ) 7.6 Hz, 2H), 6.69 (t, J ) 7.6 Hz, 1H), 6.65 (d, J )
7.6 Hz, 2H), 4.34 (br s NH, 1H), 3.96 (t, J ) 6 Hz, 1H), 2.16 (s,
3H), 1.98-1.87 (m, 1H), 1.78-1.68 (m, 1H), 0.92 (t, J ) 7.6 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 210.0, 146.7, 129.3, 117.7,
112.8, 64.1, 26.1, 24.5, 9.3; HMRS calcd for C11H15NO 177.1154,
found 177.1153.
(5) Procedure for Preparation of R-Amino Ketone (10a′). To
an aqueous ethanol (5 mL) solution of 2-bromopentan-3-one18 (500
mg, 3.03 mmol) were added aniline (338 mg, 3.63 mmol), sodium
bicarbonate (305 mg, 3.63 mmol), and water (65 mg, 3.63 mmol),
and the reaction mixture was heated at 80 °C for 9 h. The solvent
was evaporated, extracted with diethyl ether, dried over MgSO4,
concentrated, and chromatographed through a silica column to give
2-phenylaminopentan-3-one (10a′) as a yellow oil (441 mg, 2.49
mmol, 82%): IR (neat, cm-1) 3416(s), 3047(w), 1721(s), 1614-
(w), 1569(s), 1378(s), 1145(s); 1H NMR (400 MHz, CDCl3) δ 7.15
(t, J ) 7.6 Hz, 2H), 6.69 (t, J ) 7.6 Hz, 1H), 6.65 (d, J ) 7.6 Hz,
2H), 4.34 (br s, NH, 1H), 4.07 (q, J ) 6.8 Hz, 1H), 2.58-2.47 (m,
2H), 1.38 (d, J ) 7.2 Hz, 3H), 1.05 (t, J ) 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 212.7, 146.4, 129.3, 117.8, 112.9, 57.8, 31.5,
18.1, 7.5; HMRS calcd for C11H15NO 177.1154, found 177.1153.
Procedure for Preparation of R-Carbonyl Amide (10b). To a
toluene solution (0.80 mL) of hexanamide (8b) (85 mg, 0.74 mmol)
were added 1-(4-methoxyphenyl)prop-2-yn-1-ol (3i) (100 mg, 0.61
mmol), zinc triflate (22 mg, 0.06 mmol), and TpRuPPh3(CH3-
CN)2PF6 (47 mg, 0.06 mmol), and the reaction mixture was heated
at 100 °C for 5 h. The solution was filtered over a short silica bed,
washed with diethyl ether (5 mL), and concentrated to give
4-methyl-2,5-diphenyloxazole (10b) as a yellow oil (109 mg, 0.39
mmol, 64%): IR (neat, cm-1) 3419 (s), 3048 (w), 3001 (s), 1718
(s), 1676 (s), 1617 (w), 1568 (s), 1452 (s), 1376 (s); 1H NMR (400
MHz, CDCl3) δ 7.19 (dd, J ) 8.4, 2.0 Hz, 2H), 6.85 (dd, J ) 8.4,
2.0 Hz, 2H), 6.71 (d, J ) 6.0 Hz, 1H), 5.47 (d, J ) 5.4 Hz, 1H),
3.76 (s, 3H), 2.16 (t, J ) 6.8 Hz, 2H), 2.07 (s, 3H), 1.60 ∼ 1.52
(m, 2H), 1.30-1.20 (m, 4H), 0.83 (t, J ) 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 203.9, 172.3, 159.7, 129.1, 128.5, 114.5, 62.6,
55.2, 36.3, 31.3, 27.0, 25.1, 22.3, 13.8; HMRS calcd for C16H23-
NO2 277.1678, found 277.1679.
not only the intramolecular cyclization of R-amino ketone
intermediates but also for the isomerization of R-amino ketone
intermediates through a 1,2-nitrogen shift. Zn(OTf)2 shows
similar reaction pathways for benzofuran and oxazole syntheses
except that the resulting R-carbonyl intermediates do not
undergo isomerization in the presence of Zn(OTf)2 catalyst.
Experimental Section
(1) Procedure for Catalytic Synthesis of Indole (4a). To a
toluene solution (0.80 mL) of aniline (132 mg, 1.4 mmol) were
added pent-1-yn-3-ol (3a) (100 mg, 1.1 mmol) and zinc triflate
(43 mg, 0.01 mmol); the reaction mixture was heated at 100 °C
for 8 h. The solution was filtered over a short silica bed, washed
with diethyl ether (5 mL), and concentrated under reduced pressure
to afford 3-ethyl-2-methyl-1H indol (4a) as colorless crystals (mp
38-40 °C, 184 mg, 1.15 mmol, 97%): IR (neat, cm-1) 3418 (s),
1
3041 (w), 1569 (s), 1609 (w), 1371 (s), 1087 (s); H NMR (400
MHz, CDCl3) δ 7.62 (br, 1H), 7.55 (dd, J ) 6.8, 2.4 Hz, 1H), 7.28
(dd, J ) 6.8, 2.4 Hz, 1H), 7.12-7.20 (m, 2H), 2.76 (q, J ) 8.0
Hz, 2H), 2.29 (s, 3H), 1.31 (t, J ) 7.6 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 136.4, 135.0, 129.4, 120.8, 118.9, 117.9, 110.1,
106.0, 19.3, 13.9, 8.2; HRMS calcd for C11H13N 159.1048, found
159.1047.
(2) Procedure for Catalytic Synthesis of Benzofuran (7a). To
a toluene solution (0.80 mL) of phenol (87 mg, 0.92 mmol) were
added 1-phenyl-prop-2-yn-1-ol (3d) (100 mg, 0.75 mmol) and zinc
triflate (27 mg, 0.075 mmol); the reaction mixture was heated at
100 °C. The reaction was monitored by TLC. After completion,
the reaction mixture was filtered over a short silica bed and
concentrated under reduced pressure to give 2-methyl-3-phenyl-
benzofuran (7a) as colorless plates (mp 93-95 °C (lit.8b mp 93-
95 °C), 136 mg, 0.65 mmol, 86%): IR (neat, cm-1) 3417 (s), 3046
1
(w), 2973 (w), 1602 (s), 1379, 1261 (m), 743 (s); H NMR (400
MHz, CDCl3) δ 7.58-7.56 (d, J ) 8.4 Hz, 1H), 7.51-7.43 (m,
5H), 7.37-7.33 (m,1H), 7.27-7.19 (m, 2H), 2.53 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 154.0, 151.2, 132.8, 128.9, 128.7, 126.5,
123.5, 122.5, 119.3, 116.8, 110.7, 12.8; HMRS calcd for C15H12O
208.0888, found 208.0884.
(3) Procedure for Catalytic Synthesis of Oxazole (9a). To a
toluene solution (0.80 mL) of benzamide (8a) (110 mg, 0.90 mmol)
were added 1-phenylprop-2-yn-1-ol (3d) (100 mg, 0.75 mmol), zinc
triflate (27 mg, 0.075 mmol), and TpRuPPh3(CH3CN)2PF6 (57 mg,
0.075 mmol), and the reaction mixture was heated at 100 °C for 5
h. The solution was filtered over a short silica bed and concentrated
under reduced pressure to give 4-methyl-2,5-diphenyloxazole (9a)
as colorless crystals (mp 77-79 °C (lit.15 78-80 °C), 170 mg, 0.72
mmol, 95%): IR (neat, cm-1) 3349(w), 3038(m), 2936(s), 1636-
Acknowledgment. We thank the National Science Council,
Taiwan, for support of this work.
1
(w), 1612(w), 1583(w), 1377(s); H NMR (400 MHz, CDCl3) δ
Supporting Information Available: Spectral data for com-
pounds 3a,c,e-i, 4b-i, 7b-f, 9b-g, NOE map of 4a,b, 7a,b, and
X-ray data for compounds 4h and 9c. This material is available
free of charge via the Internet at http://pubs.acs.org.
8.06 (dd, J ) 7.8, 1.2 Hz, 2H), 7.72 (dd, J ) 7.8, 1.2 Hz, 2H),
7.45 ∼ 7.41 (m, 6H), 2.60 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 159.3, 143.9, 135.9, 132.2, 129.9, 128.6, 128.5, 127.6, 127.2,
126.8, 126.1, 11.9; HMRS calcd for C16H13NO 235.0997, found
235.0998.
JO0606711
(4) Procedure for Preparation of R-Amino Ketone (10a). To
an aqueous ethanol (5 mL) solution of 3-bromopentan-2-one18 (500
mg, 3.03 mmol) were added aniline (338 mg, 3.63 mmol), sodium
(18) (a) Gnichtel, H.; Sinell, M. Lieb Ann. Chem. 1988, 9, 919. (b) Sanna,
P.; Savelli, F. J. Heterocycl. Chem. 1984, 21, 297.
J. Org. Chem, Vol. 71, No. 13, 2006 4955