Zinc-catalyzed reactions of ethenetricarboxylates with 2- (trimethylsilylethynyl)anilines leading to bridged quinoline derivatives

Article abstract of DOI:10.1021/ol900960q

Zinc Lewis acid-catalyzed cyclization of thenetricarboxylate derivatives 1 with 2-ethynylanilines has been examined. Reaction of 1,1-diethyl 2-fert-butyl ethenetricarboxylate 1 b with 2-(trimethylsilylethynyl)aniline substrates In the presence of Zn(OTf)<

Full text of DOI:10.1021/ol900960q

ORGANIC
LETTERS
2
009
Vol. 11, No. 13
796-2799
Zinc-Catalyzed Reactions of
Ethenetricarboxylates with
2
2-(Trimethylsilylethynyl)anilines Leading
to Bridged Quinoline Derivatives
,
†
†,‡
Shoko Yamazaki,* Satoshi Morikawa, Kazuya Miyazaki,
†
†
†
Masachika Takebayashi, Yuko Yamamoto, Tsumoru Morimoto,
‡
‡
Kiyomi Kakiuchi, and Yuji Mikata
§
Department of Chemistry, Nara UniVersity of Education, Takabatake-cho, Nara
30-8528, Japan, Graduate School of Materials Science, Nara Institute of Science and
6
Technology (NAIST), Takayama, Ikoma, Nara 630-0192, Japan, and KYOUSEI Science
Center, Nara Women’s UniVersity, Nara 630-8506, Japan
yamazaks@nara-edu.ac.jp
Received May 1, 2009
ABSTRACT
Zinc Lewis acid-catalyzed cyclization of ethenetricarboxylate derivatives 1 with 2-ethynylanilines has been examined. Reaction of 1,1-diethyl
-tert-butyl ethenetricarboxylate 1b with 2-(trimethylsilylethynyl)aniline substrates in the presence of Zn(OTf) gave bridged quinoline derivatives
2
2
in 43-85% yield. The reaction of 1b with 2′-aminoacetophenone also gave the bridged quinoline derivative in 41% yield. Thermal reaction of
bridged quinolines (180-190 °C) afforded indole derivatives in moderate to good yields.
Benzo-annulated six- and five-membered nitrogen-containing
heterocyclic systems such as quinolines and indoles are an
important class of compounds. They are present in many
biologically active compounds. Many efforts have been
devoted to the development of new synthetic methods to
construct quinolines and indoles in recent years.
We have recently reported zinc and indium-promoted
formal [3 + 2] cycloadditions of ethenetricarboxylates 1 with
propargylamines to afford methylenepyrrolidines (Scheme
3
,4
1
,2
†
Nara University of Education.
Nara Institute of Science and Technology.
Nara Women’s University.
‡
(3) For recent examples of synthesis of quinolines, see: (a) Madapa, S.;
Tusi, Z.; Batra, S. Curr. Org. Chem. 2008, 12, 1116. (b) Kouznetsov, V. V.;
Mendez, L. Y. V.; Gomez, C. M. M. Curr. Org. Chem. 2005, 9, 141. (c)
Yan, M.-C.; Tu, Z.; Lin, C.; Ko, S.; Hsu, J.; Yao, C.-F. J. Org. Chem.
2004, 69, 1565. (d) Sakai, N.; Annaka, K.; Konakahara, T. J. Org. Chem.
2006, 71, 3653. (e) Arcadi, A.; Aschi, M.; Marinelli, F.; Verdecchia, M.
Tetrahedron 2008, 64, 5354. (f) Xiao, F.; Chen, Y.; Liu, Y.; Wang, J.
Tetrahedron 2008, 64, 2755. (g) Mierde, H. V.; Voort, P. V. D.; Verpoort,
F. Tetrahedron Lett. 2009, 50, 201. (h) Qi, C.; Zheng, Q.; Hua, R.
Tetrahedron 2009, 65, 1316. (i) Likhar, P. R.; Subhas, M. S.; Roy, S.;
Kantam, M. L.; Sridhar, B.; Seth, R. K.; Biswas, S. Org. Biomol. Chem.
2009, 7, 85. (j) Sandelier, M. J.; DeShong, P. Org. Lett. 2007, 9, 3209. (k)
Janza, B.; Studer, A. Org. Lett. 2006, 8, 1875. (l) Tanaka, S.; Yasuda, M.;
Baba, A. J. Org. Chem. 2006, 71, 800. (m) Jia, C.-S.; Zhang, Z.; Tu, S.-J.;
§
(
1) For quinolines, see: (a) Balasubramanian, M.; Keay, J. G. In
ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 5, p 245. (b) Gabriele,
B.; Mancuso, R.; Salerno, G.; Ruffolo, G.; Plastina, P. J. Org. Chem. 2007,
7
2, 6873, and references cited therein
.
(
2) For indoles, see: (a) Gribble, G. W. In ComprehensiVe Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1996; Vol. 5, p 207. (b) Brossi, A.; Holmes, H. L.;
Manske, R. H. F. The Alkaloids: Chemistry and Pharmacology; Academic
Press: New York, 2001. (c) The Chemistry of Heterocyclic Compounds,
Part 4; Vol. 25, Indoles: The Monoterpenoid Indole Alkaloids; Saxton, J. E.,
Ed.; Wiley: New York, 1983. (d) Monoterpenoid Indole Alkaloids:
Supplement to Part 4; Saxton, J. E., Ed.; Wiley: Chichester, 1994
.
Wang, G.-W. Org. Biomol. Chem. 2006, 4, 104.
10.1021/ol900960q CCC: $40.75
Published on Web 06/11/2009
 2009 American Chemical Society

5
1
). In these reactions, the Lewis acid possibly coordinates
to both carbonyl groups and alkynes. The highly electrophilic
reactivity of ethenetricarboxylates 1 led to an efficient one-
pot reaction. In this study, 2-ethynylanilines 2 were examined
to extend this method to six-membered rings 3, and as a
result a new reaction to give bridged quinoline derivatives
4
has been found (Scheme 1).
Table 1. Reaction of 1b,c with 2-Ethynylanilines 2a,b
Lewis temp reaction
4a
Scheme 1
a
a
entry
R
Y
acid
(°C) time (h) (yield %)
t
1
2
3
4
5
6
a
1b Bu 2a H
ZnBr
2
80
80
80
80
50
50
16
3
19
3
7
7
35
50
38
58
43
58
t
1b Bu 2a H
Zn(OTf)
ZnBr
Zn(OTf)
ZnBr
Zn(OTf)
2
t
1b Bu 2b Si(CH
3
)
3
2
t
1b Bu 2b Si(CH
1c H 2a H
1c H 2a H
3
)
3
2
2
2
Optimum reaction condition is shown.
analysis of its 4-chloro analogue 4c (see the Supporting
t
Information for details). Apparently, Bu and TMS groups
were lost under the reaction conditions.
To obtain some insights into the mechanism, reactions
7
between a substrate bearing a free CO
2
H 1c and 2-ethyny-
laniline 2a were examined. In the reactions, the compound
a was obtained in 43-58% yield (Table 1, entries 5-6).
The results suggest that the free acid (or its anion) is the
4
The reaction of ethenetricarboxylates 1 and 2-ethynyla-
nilines 2 as the one-carbon homologues for propargylamines
real reaction intermediates in the formation of 4a (Scheme
was examined in the presence of zinc Lewis acids (0.2 equiv)
t
2
). It is difficult to predict when Bu or TMS groups are
5
(
2
8
eq 1). Reaction of triethyl ethenetricarboxylate 1a and
removed precisely in the reaction of 1b with 2a or 2b, since
amine addition may be fast and reversible. In any case,
intermediate B is formed from intermediate A, and then C-C
bond formation occurs, followed by O-C bond formation.
-ethynylaniline 2a in the presence of ZnBr
2 2
or Zn(OTf) at
0 °C in ClCH CH Cl or 110 °C in toluene gave no
2
2
cycloadducts such as 3 (in Scheme 1) efficiently and gave a
complex mixture, possibly containing a noncyclized aniline
adduct. Then, a Lewis acid-catalyzed cyclization of ethen-
etricarboxylate derivative 1a with 2-(trimethysilylethynyl)a-
niline 2b was examined, since Zn-catalyzed reaction of 1a
Scheme 2
and silyl substituted propargyl alcohols gave tetrahydrofurans
6
efficiently. However, ZnBr
2
or Zn(OTf)
2
catalyzed reaction
of 1a with 2b also gave a complex mixture containing a
noncyclized adduct. Next, the reaction of tert-butyl ester 1b
and 2a-b was examined. The ZnBr
2
and Zn(OTf)
2
catalyzed
reaction of 1b and 2a in ClCH CH
2
2
Cl at 80 °C gave an
unexpected compound 4a as a major isolable product in 35
and 50% yields, respectively (eq 1 and Table 1, entries 1-2).
Interestingly, the ZnBr
2 2
and Zn(OTf) catalyzed reaction of
1
b and 2b also gave 4a in 38 and 58% yields, respectively
(
entries 3-4).
The structure of 4a was determined by spectroscopic
techniques and confirmed on the basis of the X-ray diffraction
(4) For recent examples of synthesis of indoles, see: (a) Cui, S.-L.; Wang,
J.; Wang, Y.-G. J. Am. Chem. Soc. 2008, 130, 13526. (b) El Kaim, L.;
Gizzi, M.; Grimaud, L. Org. Lett. 2008, 10, 3417. (c) Zhang, Y.; Donahue,
J. P.; Li, C.-J. Org. Lett. 2007, 9, 627. (d) Yue, D.; Yao, T.; Larock, R. C.
J. Org. Chem. 2006, 71, 62.
The reaction of 2-(phenylethynyl)aniline or 2-(1-hexyny-
l)aniline with 1b in the presence of Zn(OTf)
2
was also
examined. However, it gave a complex mixture.
(
5) Morikawa, S.; Yamazaki, S.; Furusaki, Y.; Amano, N.; Zenke, K.;
Kakiuchi, K. J. Org. Chem. 2006, 71, 3540.
(
6) Morikawa, S.; Yamazaki, S.; Tsukada, M.; Izuhara, S.; Morimoto,
(7) (a) Kelly, T. R. Tetrahedron Lett. 1973, 437. (b) Yamazaki, S.;
Ohmitsu, K.; Ohi, K.; Otsubo, T.; Moriyama, K. Org. Lett. 2005, 7, 759.
T.; Kakiuchi, K. J. Org. Chem. 2007, 72, 6459.
Org. Lett., Vol. 11, No. 13, 2009
2797

Next, the reaction of 1b and 2′-aminoacetophenone 5, as
another possible reaction intermediate for eq 1, was also
examined (eq 2). The reaction 1b and 5 in the presence of
Table 2. Reaction of 1b with 2-(Trimethylsilylethynyl)-anilines
2
Zn(OTf)
2
2 2
(0.2 equiv) at 80 °C in ClCH CH Cl for 3 h also
reaction
time (h)
yield
(%)
gave 4a in 41% yield. A possible reaction path including
stepwise C-C and O-C bond formations is shown in
Scheme 3. The yield of 4a is lower than that of the reaction
a
entry
Z
b
1
2
3
4
5
6
7
a
2b
2c
2d
2e
2f
H
3
16
18
3
18
18
16
4a
4c
4d
4e
4f
58
77
c
of 1b and 2a. The reactions of 2a or 2b with Zn(OTf)
C in ClCH CH Cl gave complex mixtures, possibly con-
taining a small amount of 5. The amine adduct of 5 to 1b
C, in Scheme 3) may also be a reaction intermediate in
2
at 80
4-Cl
4-CN
2
85
69
61
43
62
°
2
2
8
4-CO Me
4-NO
4-Me
5-Cl
2
(
2g
4g
4h
9
Scheme 2.
2h
b
c
Optimum reaction time is shown. In Table 1. Reaction of 1b and
c in the presence of 0.2 equiv ZnBr for 3 h in ClCH CH Cl at 80 °C also
gave 4c in 76% yield.
2
2
2
2
gave decarboxylated diesters 6 along with further decar-
boxylated monoesters 7 (eq 4, Table 3). The first formation
of cyclopropane intermediates E by loss of CO is assumed.
2
Considering that the compounds 1c and 2a are prepared
7
10
from 1b and 2b, respectively, and comparing the yields,
the use of 1b and 2b is an effective way in view of reducing
synthesis steps. Preparation of functionalized 2-(trimethyl-
silylethynyl)anilines are also conveniently prepared using a
Then, the resulting cyclopropylindolines E may be trans-
formed to alkylated indoles 6, similar to the reported
1
2
examples for rhodium catalyzed carbenoid insertion.
2
Formation of byproducts 7 may occur by contaminated H O
3
d,10,11
Sonogashira-coupling reaction.
On the other hand,
1
3
in situ. Thus, heating compound 4c and 1 equiv of water
functionalized 2′-aminoacetophenones are not easily
1
4
1
b
gave compound 7c as a major product (entry 2).
accessible, although 2′-aminoacetophenone 5 is com-
mercially available.
The reaction of various 2-ethynylaniline derivatives 2 was
also examined and they also gave the bridged quinoline
products 4 (eq 3, Table 2). 4-CN-Derivative 2d gave the
product 4b in up to 85% yield, and it seems that aniline
substituted with electron-withdrawing groups give somewhat
better yields (entries 2-5, 7). They might suppress side
reactions such as aromatic substitutions.
Scheme 3
Table 3. Thermal Reaction of 4
temp reaction
entry
Z
(°C)
time (h)
6 (%)
7 (%)
a
b
a
a
a
1
2
3
4
5
a
4c 4-Cl
4c 4-Cl
4d 4-CN
4e 4-CO
4h 5-Cl
180
180
190
180
180
18
18
16
5
6c (68) 7c (8)
7c (83)
6d (56) 7d (12)
6e (43) 7e (8)
6h (49) 7h (12)
2
Me
5
Compound 4 (0.5-0.8 mmol) was heated in a closed vessel (50 mL).
Compound 4c and 1 equiv of water were heated under nitrogen.
b
In summary, the zinc triflate-catalyzed reaction of 1,1-
diethyl 2-tert-butyl ethenetricarboxylate 1b or 1,1-diethyl
2
-hydrogen ethenetricarboxylate 1c with 2-ethynylanilines
1
5
2
a,b gave a bridged quinoline derivative 4a. The reaction
of 1c with 2′-aminoacetophenone also gave 4a. Reaction of
Next, the thermal reaction of the bridged compounds 4
was examined. Heating 4 at 180-190 °C without solvent
1b with various 2-(trimethylsilylethynyl)aniline substrates 2
in the presence of Zn(OTf)
2
gave bridged quinoline deriva-
2798
Org. Lett., Vol. 11, No. 13, 2009

tives 4. Furthermore, thermal reaction of 4 gave indole
derivatives 6.
Thus, a new reaction to construct bridged quinoline
derivatives 4 was studied. Investigation of the detailed
reaction mechanism and further transformation of the
products to potentially useful compounds are ongoing.
Supporting Information Available: Additional experi-
mental procedure, spectral data and crystallographic data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL900960Q
Acknowledgment. This work was supported by the
Ministry of Education, Culture, Sports, Science, and Tech-
nology of the Japanese Government. We thank Ms. Y.
Nishikawa, Mr. S. Katao, and Mr. F. Asanoma (Nara Institute
of Science and Technology) for assistance in obtaining
HRMS data and elemental analyses.
(
15) Typical experimental procedure (Table 1, Entry 4). To a solution
of 1b (107 mg, 0.39 mmol) in 1,2-dichloroethane (0.72 mL) was added
-(trimethylsilylethynyl)aniline (2b) (74 mg, 0.39 mmol) and Zn(OTf) (29
2
2
mg, 0.08 mmol). The mixture was heated at 80 °C and stirred for 3 h. The
reaction mixture was cooled to 0 °C and quenched with water. The mixture
3
was diluted with dichloromethane and then saturated aqueous NaHCO was
added. The organic phase was extracted with dichloromethane, dried
(Na SO ), and evaporated in Vacuo. The residue was purified by column
chromatography over silica gel with hexane-ether as eluent to give 4a (76
mg, 58%). 4a: R ) 0.1 (hexane-ether ) 1 : 1); Colorless crystals; mp
124-125 °C; H NMR (400 MHz, CDCl ) δ (ppm) 1.02 (t, J ) 7.1 Hz,
1
(
8) The H NMR spectra of the product mixtures show the peaks of 5.
2
4
However, isolation of 5 was unsuccessful. The efficiency of zinc catalysts
in promoting the loss of TMS in the reaction conditions was also examined.
f
1
The reaction of 4-(trimethylsilylethynyl)aniline with Zn(OTf)
2
gave 4′-
3
aminoacetophenone in 47% isolated yield. On the other hand, the reaction
of (trimethylsilylethynyl)benzene did not change under the reaction condi-
tions. The detailed mechanism of loss of TMS is under investigation.
3H), 1.33 (t, J ) 7.1 Hz, 3H), 1.98 (s, 3H), 3.77-4.05 (m, 1H), 4.07-4.15
(m, 1H), 4.35 (q, J ) 7.1 Hz, 2H), 4.48 (bd, J ) 1.8 Hz, 1H), 4.80 (bs,
1H), 6.61 (dd, J ) 8.1 Hz, 1.1 Hz, 1H), 6.81 (td, J ) 7.6, 1.2 Hz, 1H),
7.17 (ddd, J ) 8.1, 7.3, 1.5 Hz, 1H), 7.34 (dd, J ) 7.9, 1.3 Hz, 1H). Selected
NOEs are between δ 4.80 (NH) and δ 4.48 (CHN), 6.61 (Ar) and between
(
9) 2′-Aminoacetophenone 5 and the amine adduct C are possibly formed
in situ from Zn-catalyzed water addition to the triple bond of 2-ethynyla-
nilines. The effect of water in situ will be investigated in due course.
1
3
3 3
δ 1.98 (CH ) and δ 7.34 (Ar).; C NMR (100.6 MHz, CDCl ) δ (ppm)
(
10) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1989, 30,
581.
11) Ezquerra, J.; Pedregal, C.; Lamas, C.; Barluenga, J.; P e´ rez, M.;
Garc ´ı a-Mart ´ı n, M. A.; Gonz a´ lez, J. M. J. Org. Chem. 1996, 61, 5804.
12) (a) Gibe, R.; Kerr, M. A. J. Org. Chem. 2002, 67, 6247. (b) Salim,
13.67 (q), 14.06 (q), 17.64 (q), 58.58 (d), 60.62 (s), 61.87 (t), 63.08 (t),
84.49 (s), 115.10 (d), 119.17 (d), 123.87 (s), 124.69 (d), 130.48 (d), 139.93
(s), 165.02 (s), 167.70 (s), 169.65 (s). Selected HMBC correlations are
2
(
between δ 4.48 (CHN) and δ 60.62 (C(CO
(OCMe), between δ 1.98 (CH ) and δ 84.49 (OCMe), 123.87 (Ar), 60.62
(C(CO Et) ), and between δ 7.34 (CH(Ar)) and δ 84.49 (OCMe).; IR (KBr)
3380, 2981, 1791, 1756, 1733, 1612, 1483, 1391, 1367, 1287, 1241, 1196,
1036 cm ; MS (EI) m/z 333 (M , 85), 26 (41), 216 (100%); HRMS M
333.1214 (calcd for C17 333.1212); Anal. Calcd for C17 : C,
61.25; H, 5.75; N, 4.20. Found: C, 61.00; H, 5.61; N, 4.22.
2 2
Et) ), 139.93 (Ar), 84.49
(
3
M.; Capretta, F. Tetrahedron 2000, 56, 8063.
2
2
(
(
13) Krapcho, A. P. Synthesis 1982, 805, 893.
-
1
+
+
14) For a recent example of synthesis of indole-2-acetic esters, see:
Gabriele, B.; Mancuso, R.; Salerno, G.; Lupinacci, E.; Ruffolo, G.; Costa,
M. J. Org. Chem. 2008, 73, 4971.
H
19NO
6
H19NO
6
Org. Lett., Vol. 11, No. 13, 2009
2799