Highly regioselective synthesis of substituted tetrahydroquinolines by palladium-catalyzed cyclization of substituted 2-amidophenylmalonates with 1,4-diacetoxybut-2-ene

Article abstract of DOI:10.1016/j.tetlet.2010.09.033

The reaction of 2-amidophenylmalonates with 1,4-diacetoxybut-2-ene in the presence of a palladium catalyst is described. Substituted tetrahydroquinolines having a vinyl group at the 3- or 2-position were synthesized, in which the regioselectivities of the double allylic substitution reactions have been altered depending on the substituent on the amino group.

Full text of DOI:10.1016/j.tetlet.2010.09.033

Tetrahedron Letters 51 (2010) 6008–6010
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly regioselective synthesis of substituted tetrahydroquinolines by
palladium-catalyzed cyclization of substituted 2-amidophenylmalonates
with 1,4-diacetoxybut-2-ene
⇑
Masahiro Yoshida , Yohei Maeyama, Kozo Shishido
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of 2-amidophenylmalonates with 1,4-diacetoxybut-2-ene in the presence of a palladium
catalyst is described. Substituted tetrahydroquinolines having a vinyl group at the 3- or 2-position were
synthesized, in which the regioselectivities of the double allylic substitution reactions have been altered
depending on the substituent on the amino group.
Received 9 August 2010
Revised 3 September 2010
Accepted 10 September 2010
Available online 16 September 2010
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Transition metal-catalyzed nucleophilic allylic substitution reac-
tions have received considerable attention and have been exten-
sively studied due to their versatile and specific reactivities.1
Among them, 2-butene-1,4-diol derivatives, such as the dicarbon-
ate, are attractive substrates for palladium-catalyzed reactions with
nucleophiles. For example, a compound having two nucleophilic
moieties within the molecule reacted with 1,4-diacyloxybut-2-
ene to afford the cyclized product via successive double allylic sub-
stitutions (Scheme 1). Various heterocyclic compounds such as
quinoxalines,2 benzoxazines,3 piperidines,4 morpholines,4,5 benzo-
dioxanes,6 oxazolidinones,7 pyrroles,8 and dihydrofurans9 have
been synthesized by this methodology. In our studies on the palla-
dium-catalyzed cascade cyclizations using compounds containing
two nucleophilic moieties,10 we focused on the nucleophilic activity
of 2-amidophenylmalonates toward the 1,4-diacyloxybut-2-ene. By
introducing nucleophilic nitrogen and carbon moieties within the
molecule, we thought that substituted tetrahydroquinolines, com-
mon structures in many biologically active compounds,11 could be
constructed in one step. Herein, we describe the palladium-cata-
lyzed reaction of 2-amidophenylmalonates 1 with 1,4-diacetoxy-
but-2-ene 2, in which the substituted tetrahydroquinolines 3 or 4
having a vinyl group at the 3- or 2-position have been regioselec-
tively constructed depending on the substituent on the amino group
(Scheme 2).
OCOR
NuH
Nu'H
Nu
cat. Pd(0)
base
+
Nu'
OCOR
Scheme 1.
EWG
N
EWG
NH
OAc
MeO2C
CO2Me
3
cat. Pd(0)
base
or
+
CO2Me
CO2Me
EWG
OAc
N
1
2
MeO2C
CO2Me
4
Scheme 2.
Our initial attempts were carried out using 2-(p-toluenesulfo-
nylamino)phenylmalonate (1a)12 and (Z)-1,4-diacetoxybut-2-ene
(2).13 When 1a and 2 were treated with 5 mol % Pd2(dba)3ÁCHCl3,
tion with various ligands (entries 5–8), we found that 3a could be
produced in 86% yield when DPPP was used as the ligand (entry 7).
We next attempted the reactions using the 2-amidophenylmal-
onates 1b–f having various electron-withdrawing groups on the
amino group (Table 2).14 When the sulfonamide-type substrates
1b and 1c having a benzenesulfonyl- and a 2-naphthalenesulfonyl
group were subjected to the reactions with 2, the 3-vinyltetrahy-
droquinolines 3b and 3c were produced in 89% and 55% yield,
respectively (entries 1 and 2). On the other hand, it is interesting
to note that the 2-vinyltetrahydroquinoline 4d was produced
t
20 mol % DPPE and BuOK in THF under reflux for 2 h, the 3-vinyl-
tetrahydroquinoline 3a was obtained in 27% yield (Table 1, entry
1). By changing the base (entries 2–4), the yield of 3a was
improved to 79% with K2CO3 (entry 4). After further experimenta-
⇑
Corresponding author. Tel./fax: +81 88 6337294.
E-mail address: yoshida@ph.tokushima-u.ac.jp (M. Yoshida).
0040-4039/$ - see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.033

M. Yoshida et al. / Tetrahedron Letters 51 (2010) 6008–6010
6009
Table 1
Effect of base and ligand
4d was low (27%), it was dramatically improved to 74% by carrying
out the reaction in the presence of ( )-BINAP as the ligand (entry
4). Similar results were obtained in the reactions of other carba-
mate-type substrates. Thus, compounds 1e and 1f, containing a
methoxycarbonyl and a t-butoxycarbonyl (Boc) group, were regio-
selectively transformed to the corresponding 2-vinyltetrahydro-
quinolines 4e and 4f in 66% and 82% yield, respectively (entries 5
and 6). From these results, it is now clear that the regiochemical
course of the reaction is altered depending on the electron-with-
drawing group on the amine.
5 mol %
Pd2(dba)3·CHCl3
20 mol % ligand
Ts
OAc
OAc
Ts
N
NH
+
CO2Me
base, THF, reflux
2 h
MeO2C
CO2Me
CO2Me
1a
2
3a
Entry
Base
Ligand
Yield of 3a (%)
1
2
3
4
5
6
7
8
tBuOK
Et3N
DPPE
DPPE
DPPE
DPPE
DPPF
DPPB
DPPP
27
22
58
79
61
68
86
36
A plausible mechanism for the cyclization is shown in Scheme
3. On reacting with the palladium catalyst, 1,4-diacetoxybut-2-
ene 2 is converted to the p-allylpalladium complex 5, which is fur-
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
ther subjected to the reaction with the 2-amidophenylmalonate 1.
When the sulfonamide-type substrate was used, the corresponding
aza-anion 6 was selectively generated because of the strong elec-
tron-withdrawing character of the sulfonyl group.15 As a result,
the nucleophilic attack of the sulfonamide initially occurs to afford
the intermediate 7, which further reacts with the malonate moiety
in the presence of palladium to produce the 3-vinyltetrahydro-
quinolines 3 in a regioselective manner. On the other hand, the
malonate anion 8 would be predominantly produced in the case
of the carbamate-type substrate,15 which would lead to the forma-
tion of the 2-vinyltetrahydroquinolines 4 via the intermediate 9.16
We next carried out a study of the substrate scope. When the
tosylamides 1g and 1h, containing methyl and methoxy groups
on the aromatic ring, were subjected to the reactions with 2, the
( )-BINAP
Table 2
Reactions using substrates 1b–f with 2
EWG
OAc
NH
5 mol % Pd2(dba)3·CHCl3
20 mol % ligand
+
CO2Me
K2CO3, THF, reflux, 2 h
CO2Me
1b–1f
OAc
2
EWG
EWG
N
N
5 mol %
Pd2(dba)3·CHCl3
20 mol % DPPP
Ts
OAc
Ts
N
+
R
NH
R
+
MeO2C
CO2Me
CO2Me
CO2Me
MeO2C
4d–4f
Yields (%)
CO2Me
K2CO3, THF, reflux
2 h
3b–3d
MeO2C CO2Me
OAc
Entry
EWG
1g R = Me
1h R = OMe
3g R = Me
86%
2
3
4
3h R = OMe 92%
1a
2a
3a
4b
5b
6b
Benzenesulfonyl (1b)
89
55
7
14
–
—
—
27
74
66
82
2-Naphthalenesulfonyl (1c)
Benzyloxycarbonyl (Cbz) (1d)
Benzyloxycarbonyl (Cbz) (1d)
Methoxycarbonyl (1e)
5 mol %
Pd2(dba)3·CHCl3
20 mol % BINAP
Boc
NH
OAc
Boc
N
R
R
t-Butoxycarbonyl (Boc) (1f)
—
+
CO2Me
CO2Me
K2CO3, THF, reflux
2 h
a
DPPP was used as the ligand.
( )-BINAP was used as the ligand.
b
MeO2C CO2Me
OAc
1i R = Me
1j R = OMe
4i R = Me
71%
2
4j R = OMe 85%
predominantly when the benzyloxycarbonyl (Cbz)-substituted
Scheme 4.
substrate 1d was used (entry 3). Although the yield of the resulting
SO2R
N
SO2R
SO2R
N
SO2R
N
CO2Me
CO2Me
N
Pd(0)
Pd(0)
Pd+
6
– Pd(0)
MeO2C
MeO2C
OAc
MeO2C
MeO2C CO2Me
OAc
OAc
MeO2C
Pd+
3
Pd(0)
7
R'O2C
N
CO2R'
N
R'O2C
NH
OAc
OAc
CO2R'
NH
2
5
Pd+
– Pd(0)
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
CO2Me
CO2Me
9
4
8
Scheme 3.

6010
M. Yoshida et al. / Tetrahedron Letters 51 (2010) 6008–6010
Fadel, R.; Sinou, D. Tetrahedron: Asymmetry 2000, 11, 3561; (c) Yang, S.-C.; Lai,
EWG
NH
OAc
H.-C.; Tsai, Y.-C. Tetrahedron Lett. 2004, 45, 2693.
5 mol % Pd2(dba)3·CHCl3
20 mol % DPPP or BINAP
4. (a) Tsuda, T.; Kiyoi, T.; Saegusa, T. J. Org. Chem. 1990, 55, 3388; (b) Uozumi, Y.;
Tanahashi, A.; Hayashi, T. J. Org. Chem. 1993, 58, 6826; (c) Yamazaki, A.; Achiwa,
K. Tetrahedron: Asymmetry 1995, 6, 1021.
+
CO2Me
CO2Me
K2CO3, THF, reflux, 2 h
5. Thorey, C.; Wilken, J.; Hénin, F.; Martens, J.; Mehler, T.; Muzart, J. Tetrahedron
Lett. 1995, 36, 5527.
OAc
10
6. Massacret, M.; Goux, C.; Lhoste, P.; Sinou, D. Tetrahedron Lett. 1994, 35, 6093.
7. (a) Hayashi, T.; Yamamoto, A.; Ito, Y. Tetrahedron Lett. 1987, 28, 4837; (b)
Hayashi, T.; Yamamoto, A.; Ito, Y. Tetrahedron Lett. 1988, 29, 99; (c) Moreno-
Mañas, M.; Morral, L.; Pleixats, R.; Villarroya, S. Eur. J. Org. Chem. 1999, 181; (d)
Tanimori, S.; Kirihata, M. Tetrahedron Lett. 2000, 41, 6785.
1a EWG = Ts
1f EWG = Boc
Ts
Boc
N
N
8. Murahashi, S.-I.; Shimamura, T.; Moritani, I. J. Chem. Soc., Chem. Commun. 1974,
931.
or
9. (a) Hayashi, T.; Yamamoto, A.; Ito, Y. Tetrahedron Lett. 1988, 29, 669; (b)
Hayashi, T.; Ohno, A.; Lu, A. S.-J.; Matsumoto, Y.; Fukuyo, E.; Yanagi, K. J. Am.
Chem. Soc. 1994, 116, 4221; (c) Sakamoto, M.; Shimizu, I.; Yamamoto, A. Bull.
Chem. Soc. Jpn. 1996, 69, 1065; (d) Nomura, N.; Tsurugi, K.; Okada, M. Angew.
Chem., Int. Ed. 2001, 40, 1932; (e) Murakami, H.; Matsui, Y.; Ozawa, F.; Yoshifuji,
M. J. Organomet. Chem. 2006, 691, 3151.
10. (a) Yoshida, M.; Higuchi, M.; Shishido, K. Tetrahedron Lett. 2008, 49, 1678; (b)
Yoshida, M.; Higuchi, M.; Shishido, K. Org. Lett. 2009, 11, 4752; (c) Yoshida, M.;
Higuchi, M.; Shishido, K. Tetrahedron 2010, 66, 2675.
MeO2C
CO2Me
MeO2C
CO2Me
3a 81% (from 1a)
4f 57% (from 1f)
Scheme 5.
3-vinyltetrahydroquinolines 3g and 3h were produced in 86% and
92% yield, respectively (Scheme 4). Similarly, the reactions of the
carbamates 1i and 1j bearing methyl and methoxy groups on the
aromatic ring also proceeded to give the 2-vinyltetrahydroquino-
lines 4i and 4j in 71% and 85% yield, respectively. When (E)-1,4-
diacetoxybut-2-ene (10) was reacted with the tosylamide 1a and
the t-butoxy carbamate 1f, the corresponding products 3a and 4f
were obtained in 81% and 57% yield, respectively (Scheme 5). This
11. Katrizky, A.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031. and
references therein.
12. The substrate 1a was prepared from dimethyl (2-nitrophenyl)malonate via
hydrogenetion of the nitro group followed by tosylation of the resulting amino
moiety. Other substrates 1b–j also were prepared by the similar method.
13. General
amidophenylmalonates with 1,4-diacetoxybut-2-ene: To a stirred solution of
the sulfonamide 1a (30 mg, 0.079 mmol) and 1,4-diacetoxybut-2-ene
(16.4 mg, 0.095 mmol) in THF (2 mL) were added Pd2(dba)3ÁCHCl3 (4.1 mg,
3.95 mol), dppp (6.5 mg, 15.8 mol), and K2CO3 (43.7 mg, 0.318 mmol) at rt,
procedure
for
the
palladium-catalyzed
reaction
of
2-
2
l
l
and stirring was continued for 30 min at the same temperature under an argon
atmosphere. The reaction mixture was then allowed to heat to 80 °C, and
stirred for 2 h. After filtration of the reaction mixture using a small amount of
silica gel followed by concentration, the residue was chromatographed on
silica gel with hexane/AcOEt (80:20, v/v) as eluent to give the 3-
vinyltetrahydroquinoline 3a (29.3 mg, 86%) as colorless prisms. Compound
3a: mp 111.7–113.8 °C (AcOEt/Hex/CHCl3);. IR (KBr) 2953, 1746, 1721, 1489,
implies that the reactions occurred via the common
p-allylpalla-
dium intermediate 5 regardless of the stereochemistry of the sub-
strate 2.
In summary, the studies described above have resulted in the
regioselective synthesis of vinyltetrahydroquinolines by a palla-
dium-catalyzed cyclization between the 2-amidophenylmalonates
and 1,4-diacetoxybut-2-ene. The regioselectivity of the reaction
can be altered depending on the substituent on the amino group.
1361, 1240, 1178, 1099, 1028 cmÀ1 1H NMR (400 MHz, CDCl3) d 2.39 (s, 3H),
;
2.98 (dt, J = 4.0, 9.0 Hz, 1H), 3.56 (s, 3H), 3.64 (s, 3H), 3.99 (dd, J = 9.0, 13.2 Hz,
1H), 4.09 (dd, J = 4.0, 13.2 Hz, 1H), 5.10 (dd, J = 0.8, 17.2 Hz, 1H), 5.15 (dd,
J = 0.8, 10.4 Hz, 1H), 5.86 (ddd, J = 9.0, 10.4, 17.2 Hz, 1H), 7.09 (dt, J = 0.8, 7.8 Hz,
1H), 7.23 (d, J = 8.8 Hz, 2H), 7.27 (dt, J = 1.2, 7.8 Hz, 1H), 7.33 (dd, J = 1.2, 7.8 Hz,
1H), 7.57 (d, J = 8.8 Hz, 2H), 7.82 (dd, J = 0.8, 7.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 21.4 (CH3), 43.0 (CH), 47.6 (CH2), 52.5 (CH3), 52.7 (CH3), 60.8 (Cq),
119.0 (CH2), 122.6 (CH), 124.0 (CH), 124.5 (Cq), 127.2 (CH), 128.6 (CH), 129.6
(CH), 131.1 (CH), 134.2 (CH), 136.3 (Cq), 136.5 (Cq), 143.8 (Cq), 169.2 (Cq),
169.9 (Cq); HRMS (ESI) m/z calcd for C22H24NO6S [M++H+] 430.1324, found
430.1320.
Acknowledgment
This study was supported in part by a Grant-in-Aid for the
Encouragement of Young Scientists (B) from the Japan Society for
the Promotion of Science (JSPS), the Uehara Memorial Foundation,
the Takeda Science Foundation, and the Program for Promotion of
Basic and Applied Research for Innovations in the Bio-oriented
Industry (BRAIN). We are grateful to Dr. Tatsusada Yoshida for
helpful suggestions about pKa calculations.
14. By following the same procedure described in ref 13, the 2-
vinyltetrahydroquinoline 4f was prepared from 1f and 2 in the presence of
BINAP in 82% yield as colorless needles: mp 103.9–105.6 °C (AcOEt/Hex/
CHCl3); IR (KBr) 2980, 1740, 1694, 1491, 1250, 1160, 1132, 1071 cmÀ1 1H NMR
;
(400 MHz, CDCl3) d 1.46 (s, 9H), 2.13 (dd, J = 9.6, 13.6 Hz, 1H), 2.99 (dd, J = 8.0,
13.6 Hz, 1H), 3.68 (s, 3H), 3.87 (s, 3H), 4.86 (tddd, J = 1.2, 6.4, 8.0, 9.6 Hz, 1H),
5.07 (td, J = 1.2, 10.4 Hz, 1H), 5.17 (td, J = 1.2, 17.2 Hz, 1H), 5.68 (ddd, J = 6.4,
10.4, 17.2 Hz, 1H), 7.04 (dd, J = 1.6, 7.6 Hz, 1H), 7.10 (dt, J = 1.6, 7.6 Hz, 1H), 7.29
(dt, J = 0.8, 7.6 Hz, 1H), 7.49 (dd, J = 0.8, 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 28.2 (CH3), 38.8 (CH2), 53.00 (CH3), 53.03 (CH3), 53.2 (CH), 57.8 (Cq), 81.0
(Cq), 115.1 (CH2), 124.4 (CH), 125.4 (CH), 126.8 (CH), 127.9 (CH), 131.3 (Cq),
136.4 (Cq), 137.4 (CH), 153.3 (Cq), 170.1 (Cq), 170.3 (Cq); HRMS (ESI) m/z calcd
for C20H25NO6Na [M++Na+] 398.1580, found 398.1582.
References and notes
1. (a) Tsuji, J. Palladium Reagents and Catalysts: New Perspectives for the 21st
Century; Wiley: New York, 2004. p 431; (b) Davis, J. A.. In Comprehensive
Organometallic Chemistry II; Able, E. W., Stone, F. G. A., Wilkinson, G., Eds.;
Pergamon: Oxford, 1995; Vol. 9, p 291; (c) Godleski, S. A.. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: New York, 1991; Vol.
3, p 585.
2. (a) Massacret, M.; Lhoste, P.; Sinou, D. Eur. J. Org. Chem. 1999, 129; (b) Yang, S.-
C.; Shue, Y.-J.; Liu, P.-C. Organometallics 2002, 21, 2013; (c) Yang, S.-C.; Liu, P.-
C.; Feng, W.-H. Tetrahedron Lett. 2004, 45, 4951.
15. The pKa values of the tosylamide and the malonate moiety in 1a, using the
ChemAxon’s pKa calculation method are 7.37 and 10.17, respectively. On the
other hand, the pKa value of the tert-butoxycarbamate group in 1f is 11.68.
16. For examples showing the difference in reactivity between sulfonamides and
carbamates, see: (a) Ishikawa, T.; Aikawa, T.; Watanabe, S.; Saito, S. Org. Lett.
2006, 8, 3881; (b) Chataingner, I.; Panel, C.; Gérard, H.; Piettre, S. R. Chem.
Commun. 2007, 3288.
3. (a) Yamazaki, A.; Achiwa, I.; Achiwa, K. Tetrahedron: Asymmetry 1996, 7, 403;
(b) Massacret, M.; Lakhmiri, R.; Lhoste, P.; Nguefack, C.; Abdelouahab, F. B. B.;