Four-component synthesis of functionalized 2,2′-bipyridines based on the Blaise reaction

Article abstract of DOI:10.1055/s-0030-1260304

In situ C-acylation of the Blaise intermediate - as reported by Lee and coworkers - provides α-acyl-β-enamino esters that are versatile building blocks for the preparation of N-heterocycles. The corresponding N-acylated β-ketoenamides can be employed in the synthesis of 4-hydroxypyridine derivatives. N-Acylation of the α-acyl-β-enamino esters with 2-picolyl chloride furnished β-ketoenamides, and the subsequent TMSOTf/base-promoted intramolecular condensation reaction led to 4-hydroxy-2,2′-bipyridine derivatives. Conversion into 2,2′-bipyrid-4-yl nonaflates allowed further functionalization such as palladium-catalyzed coupling reactions. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260304

LETTER
2311
Four-Component Synthesis of Functionalized 2,2¢-Bipyridines Based on the
Blaise Reaction
A
N
ew Appro
a
u
tionalized 2,
l
2
¢
-
Bipyridine
s
Hommes, Phillip Jungk, Hans-Ulrich Reissig*
Freie Universität Berlin, Institut für Chemie und Biochemie, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received 15 June 2011
Upon treatment with n-butyllithium followed by addition
Abstract: In situ C-acylation of the Blaise intermediate – as report-
ed by Lee and coworkers – provides a-acyl-b-enamino esters that
are versatile building blocks for the preparation of N-heterocycles.
The corresponding N-acylated b-ketoenamides can be employed in
of acetic acid anhydride the intermediates 2 of the Blaise
reaction of ethyl bromoacetate with nitriles 1 are trans-
formed into a-acyl-b-enamino esters 3 (Scheme 1).4a Be-
the synthesis of 4-hydroxypyridine derivatives. N-Acylation of the ing structurally related to b-ketoenamides 4, we
a-acyl-b-enamino esters with 2-picolyl chloride furnished b-keto-
envisioned that N-acylation of the a-acyl-b-enamino es-
enamides, and the subsequent TMSOTf/base-promoted intramolec-
ters 3 (with activated carboxylic acid derivatives) should
ular condensation reaction led to 4-hydroxy-2,2¢-bipyridine
also provide suitable precursors for the TMSOTf-promot-
derivatives. Conversion into 2,2¢-bipyrid-4-yl nonaflates allowed
ed cyclization to 4-hydroxypyridine derivatives.
further functionalization such as palladium-catalyzed coupling re-
actions.
Lee's modification of the Blaise reaction:4a–d
Key words: condensation, 2,2¢-bipyridines, b-ketoenamides, mul-
ticomponent reaction, nonaflates, pyridines
Br
NH2
O
Zn
Zn
BrCH2CO2Et
HN
O
a) n-BuLi
b) Ac2O
r.t., 3 h
R
OEt
RCN
THF
reflux, 1 h
Although being first described at the beginning of the 20th
century, the synthetic potential of the Blaise reaction1 –
the addition of zinc enolates derived from a-halo esters to
nitriles – has not been fully exploited. Despite the broad
availability of suitable starting materials application of
this reaction was limited due to low yields and competing
side reactions. More recently, improved protocols led to
an increased interest.2 Developments and applications of
the Blaise reaction have been reviewed by Rao et al.3 Lee
and coworkers demonstrated that zinc chelate intermedi-
ates such as 2 (Scheme 1) react in situ with electrophiles
to provide valuable precursors for the synthesis of hetero-
cycles like pyrroles,4a,b 2-pyridones,4c or indoles.4d Fol-
lowing our previous work5 on the trimethylsilyl
trifluoromethanesulfonate (TMSOTf) promoted intramo-
lecular condensation of b-ketoenamides 4 to 4-hydroxy-
pyridines 56 we were interested in expanding the substrate
scope for this transformation. In particular we were in-
trigued to extend our method to the synthesis of unsym-
metrically functionalized 2,2¢-bipyridines5f taking into
account the general importance7 of this class of heterocy-
cles in coordination and supramolecular chemistry and in
numerous applications. Various cross-coupling strategies
employing pyridine-containing building blocks and other
de novo approaches for their synthesis have been devel-
oped.8,9 However, new and flexible approaches for the
synthesis of unsymmetrically functionalized 2,2¢-bipy-
ridines are rare.
R
OEt
O
1
2
3
Our previous work:5a–l
O
R1
R1
R1
NH
O
N
HN
R2
TMSOTf
base, Δ
R2
R2
OH
O
R3
R3
R3
4
5
6
Scheme 1 C-Acylation of the Blaise intermediates 2 leading to 3
and TMSOTf/base-promoted intramolecular condensation of b-keto-
enamides 4 to 4-hydroxypyridines 5
Following Lee’s protocol4a we prepared a series of a-acyl-
b-enamino esters 3 that were acylated10 with activated pi-
colinic acid derivatives (Scheme 2). The desired b-keto-
enamides 7a–f were obtained as inseparable mixtures of E
and Z isomers11 in moderate to good yields (Table 1).
O
N
NH2
O
NH
O
a)
b)
RCN
R
OEt
R
OEt
O
O
1a–f
3a–f
(E/Z)-7a–f
Scheme 2 Synthesis of a-acyl-b-enamino esters 3a–f and N-acyla-
tion to b-ketoenamides 7a–f. Reagents and conditions: (a) i) Zn (acti-
vated, 2 equiv), BrCH2CO2Et (1.5 equiv), THF, reflux, 1 h; ii) n-BuLi
(1 equiv), 0 °C; iii) Ac2O (1.3 equiv), r.t., 3 h.4a (b) Method A: 2-
PyCOCl (2 equiv), Et3N (2 equiv), CH2Cl2, 0 °C then r.t., overnight;
method B: 2-PyCOBt12 (1.5 equiv), NaH (1.3 equiv), THF, r.t., over-
night.
SYNLETT 2011, No. 16, pp 2311–2314
x
x
.x
x
.2
0
1
1
Advanced online publication: 13.09.2011
DOI: 10.1055/s-0030-1260304; Art ID: B10911ST
© Georg Thieme Verlag Stuttgart · New York

2312
P. Hommes et al.
LETTER
Table 1 Synthesis and N-Acylation of a-Acyl-b-enamino Esters
3a–f to Intermediates 7a–f
Table 2 TMSOTf/Base-Promoted Cyclization of b-Ketoenamides 7
to Unsymmetrically Substituted 2,2¢-Bipyridine Derivatives 8 or 9
R
Yield of 3
Method for Yield of 7
Isomeric
ratioc
(%)a,b
N-acylation (%)a
O
1) TMSOTf
N
DIPEA
N
DCE, 90 °C, 5 d
Ph
3a: 63
3b: 23d
3c: 51f
3d: 54f
3e: 71
3f: 36g
A
A
A
A
B
A
7a: 87
7b: 42
7c: 50
7d: 61
7e: 71
7f: 83
3.5:1
NH
O
O
N
2) O-nonaflation or
O-methylation
e
R1
OEt
CH2OMe
Me
–
R1
OR2
OEt
3.0:1
4.5:1
4.0:1
16:1
O
7a–f
i-Pr
R2 = Me 8a,e
2 = Nf 9a–f
R
n-Bu
Entry
R1
Derivatization
methylationb
nonaflationc
nonaflationc
nonaflationc
nonaflationc
methylationb
nonaflationc
nonaflationc
Yield (%)a
8a: 67
9a: 70
9b: –d
4-NCC6H4
a Yield of pure compounds after column chromatography.
b For preparation of 3a, 3c, and 3d, also see ref. 4a.
c Ratio determined by 1H NMR spectroscopy.
1
2
3
4
5
6
7
8
7a: Ph
7a: Ph
d For an alternative preparation of 3b, also see ref.13.
7b: CH2OMe
7c: Me
e Compound 7b could not be obtained in pure form and the isomeric
ratio could not be determined by 1H NMR spectroscopy.
f Nitriles 1c and 1d were used as solvent in the Blaise reaction (yields
of 3c and 3d refer to BrCH2CO2Et).
9c: 67
9d: 33
8e: 70
9e: 61
9f: 62
7d: i-Pr
g Twice the amounts of reagents were used in the modified Blaise re-
action [compound 3g was isolated in 21% yield as byproduct (also see
Scheme 4)].
7e: n-Bu
7e: n-Bu
7f: 4-NCC6H4
Gratifyingly, the mixtures of E- and Z-configured b-ke-
toenamides 7 (except 7b) cyclized in the desired manner:
treatment with TMSOTf in the presence of Hünig base
(DIPEA) and heating for 5 days in 1,2-dichloroethane
(DCE) provided the desired 4-hydroxy-2,2¢-bipyridines
(Table 2). However, their isolation directly after the cy-
clization posed to be rather difficult: separation from the
ammonium salt generated from Hünig base and trifluo-
romethanesulfonic acid (formed after aqueous workup)
was tedious, requiring several runs of column chromatog-
raphy. This problem was solved when the crude 4-hy-
droxy-2,2¢-bipyridines were directly O-alkylated to 8, or
more conveniently O-nonaflated to 9.14,15
a Yields of pure products after column chromatography.
b MeI, K2CO3, acetone, reflux, overnight.
c NaH, Nf2O, THF, r.t., overnight.16
d Decomposition of starting material.
for 9f
N
N
N
N
F
B(OH)2
a)
R
R
ONf
OEt
O
O
OEt
F
9
10, 99%
The decreased polarity of 2,2¢-bipyrid-4-yl nonaflates 9
allows their facile chromatographic purification. An addi-
tional advantage of this protocol is the direct preparation
of precursors for subsequent metal-catalyzed coupling re-
actions. Although the overall yields for the synthesis of
2,2¢-bipyridine derivatives 8 or 9 are sometimes only
moderate, the readiness and simplicity of the protocol is
remarkable. No systematic optimizations have so far been
attempted.
for 9c
c), 12
R = 4-NCC6H4
b)
for 9a
n-Pr
N
N
12
N
R
N
R
We performed a few typical subsequent palladium-cata-
lyzed transformations employing the obtained 2,2¢-bipy-
rid-4-yl nonaflates 9 in order to demonstrate their
synthetic potential (Scheme 3). Reduction of nonaflate 9a
by formic acid and triethylamine17 provided 2,2¢-bipyri-
dine derivative 11 in moderate yield. Suzuki coupling of
nonaflate 9f with 4-fluorophenyl boronic acid furnished
2,2¢-bipyridine 10 and Sonogashira reaction of 9c with
alkyne 12 led to 2,2¢-bipyridine 13, both in excellent
yields.
O
OEt
O
OEt
n-Pr
11, 50%
13, 97%
R = Me
R = Ph
Scheme 3 Subsequent transformations of the 2,2¢-bipyrid-4-yl no-
naflates 9. Reagents and conditions: (a) K2CO3, Pd(PPh3)4 (5 mol%),
DMF, 80 °C, 3 h; (b) HCO2H, Et3N, dppp (20 mol%), Pd(OAc)2 (10
mol%), DMF, 80 °C, 2 h; (c) CuI (5 mol%), Pd(PPh3)2Cl2 (5 mol%),
DMF–Et3N (1:1), 60 °C, overnight.
Synlett 2011, No. 16, 2311–2314 © Thieme Stuttgart · New York

LETTER
A New Approach to Functionalized 2,2¢-Bipyridines
2313
In addition to monoaddition product 3f the modified
Blaise reaction of terephthalodinitrile 1f also afforded the
bis-b-enamino ester 3g with 21% yield (Scheme 4). N-
Acylation leading to 7g was challenging due to the poor
solubility of precursor 3g in all solvents examined. The
subsequent TMSOTf/base-promoted cyclization followed
by nonaflation allowed the synthesis of bis-2,2¢-bipyridyl
nonaflate 9g in low overall yield (Scheme 4). Although
further optimization should be possible this first example
nevertheless demonstrates that the presented approach al-
lows a simple and very rapid access to fairly complex
compounds with 2,2¢-bipyridyl moieties.
O
1) TMSOTf
DIPEA
NH
O
O
N
O
DCE, reflux, 5 d
Ph
OEt
Ph
ONf
OEt
2) NaH, Nf2O
THF, r.t., overnight
41%
14
15
Scheme 5 Synthesis of pyrid-4-yl nonaflate 15
for the preparation of unsymmetrically functionalized
2,2¢-bipyridine derivatives has been discovered. The in-
troduction of the nonaflyl group in 4-position allows
metal-catalyzed coupling reactions providing ideal build-
ing blocks for more complex architectures.
EtO
O
EtO
O
N
H
N
NH2
O
O
O
O
O
O
Acknowledgment
2-PyCOCl (6 equiv)
The authors thank the Center for Supramolecular Interaction (Freie
Universität Berlin), the Deutsche Forschungsgemeinschaft (GK
1582), and the Bayer Schering Pharma AG for financial support.
We gratefully acknowledge the help of Dr. R. Zimmer during pre-
paration of this manuscript.
DCE, Et3N
reflux, 1 d
36%
NH2
N
H
N
EtO
O
3g
EtO
O
7g
References and Notes
mixture of (E/Z) isomers
(1) (a) Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901, 132,
478. (b) Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901,
132, 987. (c) Blaise, E. E.; Courtot, A. P. Bull. Soc. Chim.
Fr. 1906, 35, 589.
(2) Benetti, S.; Romagnoli, R. Chem. Rev. 1995, 95, 1065.
(3) Rao, H. S. P.; Rafi, S.; Padmavathy, K. Tetrahedron 2008,
64, 8037.
1) TMSOTf
DIPEA
DCE, reflux, 5 d
2) NaH, Nf2O, THF
r.t., overnight
26%
(4) (a) Chun, Y. S.; Lee, K. K.; Ko, Y. O.; Shin, H.; Lee, S.
Chem. Commun. 2008, 5098. (b) Ko, Y. O.; Chun, Y. S.;
Park, C.-L.; Kim, Y.; Shin, H.; Ahn, S.; Hong, J.; Lee, S.
Org. Biomol. Chem. 2009, 7, 1132. (c) Chun, Y. S.; Ryu, K.
Y.; Ko, Y. O.; Hong, J. Y.; Hong, J.; Shin, H.; Lee, S. J. Org.
Chem. 2009, 74, 7556. (d) Kim, J. H.; Lee, S. Org. Lett.
2011, 13, 1351.
NfO
CO2Et
EtO2C
ONf
N
N
N
N
9g
(5) (a) Review: Lechel, T.; Reissig, H.-U. Pure Appl. Chem.
2010, 82, 1835. For original publications: (b) Flögel, O.;
Dash, J.; Brüdgam, I.; Hartl, H.; Reissig, H.-U. Chem. Eur.
J. 2004, 10, 4283. (c) Dash, J.; Lechel, T.; Reissig, H.-U.
Org. Lett. 2007, 9, 5541. (d) Lechel, T.; Dash, J.; Brüdgam,
I.; Reissig, H.-U. Eur. J. Org. Chem. 2008, 3647.
(e) Eidamshaus, C.; Reissig, H.-U. Adv. Synth. Catal. 2009,
351, 1162. (f) Dash, J.; Reissig, H.-U. Chem. Eur. J. 2009,
15, 6811. (g) Lechel, T.; Brüdgam, I.; Reissig, H.-U.
Beilstein J. Org. Chem. 2010, 6, No. 42. (h) Lechel, T.;
Dash, J.; Eidamshaus, C.; Brüdgam, I.; Lentz, D.; Reissig,
H.-U. Org. Biomol. Chem. 2010, 8, 3007. (i) Lechel, T.;
Dash, J.; Hommes, P.; Lentz, D.; Reissig, H.-U. J. Org.
Chem. 2010, 75, 726. (j) Bera, M. K.; Reissig, H.-U.
Synthesis 2010, 2129. (k) Eidamshaus, C.; Kumar, R.; Bera,
M. K.; Reissig, H.-U. Beilstein J. Org. Chem. 2011, 7, 962.
(l) Eidamshaus, C.; Reissig, H.-U. Eur. J. Org. Chem. 2011,
DOI: 10.1002/ejoc.201100681.
Scheme 4 Synthesis of phenylene bridged bis(2,2¢-bipyrid-4-yl)
derivative 9g
The modified Blaise reaction of benzonitrile 1a was also
performed with longer reaction times. In addition to the
expected product 3a we also obtained b-ketoenamide 14
in 8% yield formed by partial N-acylation of 3a with the
excess of Ac2O. Treatment of compound 14 with
TMSOTf and base followed by nonaflation afforded the
pyrid-4-yl nonaflate 15 in moderate yield (Scheme 5), in-
dicating that the presented approach is not limited to the
synthesis of 2,2¢-bipyridine derivatives, but may also be
utilized for the synthesis of highly functionalized pyridine
derivatives in general if other N-acylating components are
used.
(6) For a proposed mechanism, see ref. 5l.
We demonstrated that Lee's modification of the Blaise re-
action followed by N-acylation provides highly suitable
precursors for the TMSOTf/base-promoted intramolecu-
lar condensation affording 4-hydroxypyridine derivatives
in moderate to good yields. Moreover, a flexible method
(7) (a) Lehn, J.-M. Supramolecular Chemistry – Concepts and
Perspectives; VCH: Weinheim, 1995. Selected reviews:
(b) Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev. 2000,
100, 3553. (c) Schubert, U. S.; Eschbaumer, C. Angew.
Chem. Int. Ed. 2002, 41, 2892; Angew. Chem. 2002, 114,
3016. (d) Fletcher, N. C. J. Chem. Soc., Perkin Trans. 1
Synlett 2011, No. 16, 2311–2314 © Thieme Stuttgart · New York

2314
P. Hommes et al.
LETTER
2002, 1831. (e) Ye, B.-H.; Tong, M.-L.; Chen, X.-M. Coord.
Chem. Rev. 2005, 249, 545.
during N-acylation or chromatography of the b-keto-
enamides 7 is currently unclear.
(8) For reviews, see: (a) Kröhnke, F. Synthesis 1976, 1.
(b) Summers, L. A. The Bipyridines, In Advances in
Heterocyclic Chemistry, Vol. 35; Katritzky, A. R., Ed.;
Academic Press: Orlando, FL, 1984, 281. (c) Chelucci, G.;
Thummel, R. P. Chem. Rev. 2002, 102, 3129. (d) Varela,
J. A.; Saá, C. Chem. Rev. 2003, 103, 3787. (e) Newkome,
G. R.; Patri, A. K.; Holder, E.; Schubert, U. S. Eur. J. Org.
Chem. 2004, 235. (f) Hapke, M.; Brandt, L.; Lützen, A.
Chem. Soc. Rev. 2008, 37, 2782.
(9) Selected recent examples: (a) Altuna-Urquijo, M.; Gehre,
A.; Stanforth, S. P.; Tarbit, B. Tetrahedron 2009, 65, 975.
(b) Gutz, C.; Lützen, A. Synthesis 2010, 85. (c) Kremer, C.;
Lützen, A. Synthesis 2011, 210. (d) Duric, S.; Tzschucke,
C. C. Org. Lett. 2011, 13, 2310.
(12) 2-PyCOBt = 1H-1,2,3-benzotriazol-1-yl(pyrid-2-yl)-
methanone; for its preparation, see: (a) Katritzky, A. R.; He,
H.-Y.; Suzuki, K. J. Org. Chem. 2000, 65, 8210. For a
review on N-acylbenzotriazoles, see: (b) Katritzky, A. R.;
Suzuki, K.; Wang, Z. Synlett 2005, 1656.
(13) Takaya, H.; Naota, T.; Murahashi, S.-I. J. Am. Chem. Soc.
1998, 120, 4244.
(14) For a review on aryl and alkenyl nonaflates, see:
Högermeier, J.; Reissig, H.-U. Adv. Synth. Catal. 2009, 351,
2747.
(15) Representative Procedure for the Cyclization of
b-Ketoenamides Followed by Nonaflation of the Crude
Product – 5-Ethoxycarbonyl-6-phenyl-2,2¢-bipyrid-4-yl
Nonaflate (9a)
(10) Representative Procedure for the N-Acylation of a-Acyl-
b-enamino Esters with 2-Picolyl Chloride: Ethyl 3-oxo-2-
[phenyl(picolinamido)methylene]butanoate (7a)
TMSOTf (0.94 mL, 5.17 mmol) was added dropwise to a
solution of b-ketoenamide 7a (350 mg, 1.03 mmol) and
DIPEA (0.68 mL, 4.14 mmol) in DCE (25 mL) under argon.
The mixture was stirred for 5 d at 90 °C in a sealed tube. All
volatile components were removed under reduced pressure,
the crude product was dissolved in THF (15 mL) and treated
with an excess of NaH (309 mg, 7.73 mmol, 60% in mineral
oil, washed with hexane prior to use). After addition of Nf2O
(778 mg, 1.34 mmol) the mixture was stirred overnight at r.t.
and then quenched by slow addition of sat. aq NH4Cl
solution (20 mL). The layers were separated, and the
aqueous layer was extracted three times with CH2Cl2 (20
mL). The combined organic layers were dried with Na2SO4,
and after filtration the solvent was removed under reduced
pressure. Purification of the crude product by flash
chromatography (silica gel, hexane–EtOAc = 40:1 → 20:1)
afforded 434 mg (70%) of 9a as colorless oil. IR (ATR):
3070 (=CH), 2985, 2940–2930, 2905 (CH), 1735 (C=O),
1600, 1575, 1545 (C=C, C=N) cm–1. 1H NMR (500 MHz,
CDCl3): d = 1.15 (t, J = 7.1 Hz, 3 H, CH3), 4.26 (q, J = 7.1
Hz, 2 H, OCH2), 7.40 (ddd, J = 7.8, 4.7, 0.8 Hz, 1 H, 5¢-H),
7.47–7.50, 7.71–7.74 (2 m, 3 H, 2 H, Ph), 7.85 (td, J = 7.8,
1.3 Hz, 1 H, 4¢-H), 8.49 (s, 1 H, 3-H), 8.54 (dbr, J = 7.8 Hz,
1 H, 3¢-H), 8.74 (ddd, J = 4.7, 1.3, 0.8 Hz, 1 H, 6¢-H) ppm.
13C NMR (126 MHz, CDCl3): d = 13.5 (q, CH3), 62.6 (t,
OCH2), 111.2 (d, C-3), 121.7 (d, C-5), 121.9 (s, C-3¢), 125.1
(d, C-5¢), 128.5, 128.6, 129.6 (3 d, Ph), 137.2 (d, C-4¢), 138.5
(s, Ph), 149.4 (d, C-6¢), 153.5, 155.0, 159.1, 159.4 (4 s, C-2,
C-2¢, C-4, C-6), 164.2 (s, CO2Et) ppm. 19F NMR (471 MHz,
CDCl3): d = –125.6 (td, J = 13.7, 4.4 Hz, 2 F, CF2), –120.5
(mc, 2 F, CF2), –108.7 (t, J = 13.7 Hz, 2 F, CF2), –80.5 (t,
J = 9.7 Hz, 3 F, CF3) ppm. HRMS (ESI-TOF): m/z calcd for
C23H16F9N2O5S [M + H]+: 603.0636; found: 603.0629. Anal.
calcd for C23H15F9N2O5S (602.4): C, 45.86; H, 2.51; N, 4.65;
S, 5.32. Found: C, 45.75; H, 2.51; N, 4.69; S, 5.47.
(16) Nf2O = nonafluorobutanesulfonic acid anhydride;
nonaflation employing nonafluorobutanesulfonyl fluoride
(NfF) was slow and incomplete.
SOCl2 (0.29 mL, 4.00 mmol) was added dropwise to a
solution of 2-picolinic acid (492 mg, 4.00 mmol), and Et3N
(0.55 mL, 4.00 mmol) in CH2Cl2 (13 mL) under an argon
atmosphere. After addition of catalytic amounts of DMF the
mixture was stirred for 4 h at r.t. A solution of a-acyl-b-
enamino ester 3a (467 mg, 2.00 mmol) in CH2Cl2 (7 mL)
was added at 0 °C. While stirring overnight the mixture was
allowed to warm up to r.t. (in some cases conversion of the
starting material was complete after a few hours) and sat. aq
NaHCO3 solution (20 mL) was added. The layers were
separated, and the aqueous layer was extracted three times
with CH2Cl2 (20 mL). The combined organic layers were
dried with Na2SO4, and after filtration the solvent was
removed under reduced pressure. Purification of the crude
product by flash chromatography (silica gel, hexane–
EtOAc = 4:1 → 2:1) afforded 590 mg (87%) of 7a (major/
minor isomer ca. 3.5:1) as brownish oil. IR (ATR): 3170
(NH), 3060 (=CH), 2980, 2930 (CH), 1710 (C=O), 1650,
1550 (C=C, C=N) cm–1. Chemical shifts are listed for the
major isomer only.1H NMR (500 MHz, CDCl3): d = 0.83 (t,
J = 7.1 Hz, 3 H, CH3), 2.39 (s, 3 H, COCH3), 3.84 (q, J = 7.1
Hz, 2 H, OCH2), 7.33–7.44 (m, 5 H, Ph), 7.48 (ddd, J = 7.7,
4.5, 1.0 Hz, 1 H, 5¢-H), 7.82 (td, J = 7.7, 1.7 Hz, 1 H, 4¢-H),
8.04 (dbr, J = 7.7 Hz, 1 H, 3¢-H), 8.78 (dbr, J = 4.5 Hz, 1 H,
6¢-H) ppm; the NH signal could not be detected. 13C NMR
(126 MHz, CDCl3): d = 13.4 (q, CH3), 29.7 (q, COCH3),
61.2 (t, OCH2), 116.7 (s, CCOCH3), 123.2 (d, C-3¢), 127.0
(d, C-5¢), 127.5, 127.9, 129.3, 134.5 (3 d, s, Ph), 137.4 (d, C-
4¢), 148.8 (d, C-6¢), 149.2 (s, C-2¢), 153.4 (s, CNH), 163.3 (s,
CONH), 168.0 (s, CO2Et), 197.3 (s, COCH3) ppm. HRMS
(ESI-TOF): m/z calcd for C19H18N2O4Na [M + Na]+:
361.1164; found: 361.1166. Anal. calcd for C19H18N2O4
(338.4): C, 67.44; H, 5.36; N, 8.28; found: C, 66.80; H, 5.28;
N, 8.16.
(11) Whether already the a-acyl-b-enamino esters 3 were isolated
as mixtures of E and Z isomers (no isomerization could be
detected by NMR spectroscopy), or isomerization occurred
(17) Cacchi, S.; Ciattini, P. G.; Morera, E.; Otar, G. Tetrahedron
Lett. 1986, 27, 5541.
Synlett 2011, No. 16, 2311–2314 © Thieme Stuttgart · New York

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