Synthesis of unsymmetrical polysubstituted pyridines from β-sulfonylvinylamines via 1-aza-allyl anion intermediates

Article abstract of DOI:10.1055/s-0031-1289578

A modular synthesis of highly functionalized unsymmetrical pyridines has been developed from reacting β-sulfonylvinylamines with α,β-unsaturated systems in the presence of base via the formation of 1-aza-allyl anion intermediates. Georg Thieme Verlag Stut

Full text of DOI:10.1055/s-0031-1289578

3908
PAPER
Synthesis of Unsymmetrical Polysubstituted Pyridines from
b-Sulfonylvinylamines via 1-Aza-Allyl Anion Intermediates
Synthesis of
U
nsy
h
mmetrical
P
a
olysubstitu
n
ted Pyridines Lau, Gavin Chit Tsui, Mark Lautens*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, M5S 3H6, Canada
Fax +1(416)9468185 ; E-mail: mlautens@chem.utoronto.ca
Received 25 September 2011
amines are reacted with various a,b-unsaturated sub-
strates to form unsymmetrical pyridines (Scheme 1). The
mechanism proposed for this remarkable transformation
can be rationalized by first generating the 1-aza-allyl
anion10 synthon 2 with base followed by Michael addition
of the resulting carbanion11 to chalcone producing imine
3. Additional base facilitates condensation of this imine to
the carbonyl group to form dihydropyridine 4 and upon
deprotonation, tautomerization places the resulting anion
in a stabilized position adjacent to the electron-withdraw-
ing sulfone moiety. Finally, aromatization of 6, via elimi-
nation of sulfinic acid, results in the formation of pyridine
8a.
Abstract: A modular synthesis of highly functionalized unsymmet-
rical pyridines has been developed from reacting b-sulfonylviny-
lamines with a,b-unsaturated systems in the presence of base via the
formation of 1-aza-allyl anion intermediates.
Key words: b-sulfonylvinylamines, 2,4,6-triarylpyridines, 1-aza-
allyl anions, a,b-unsaturated ketones, cascade reactions
Pyridines possessing a 2,4,6-triaryl substitution pattern
are of immense interest owing to their diverse roles in bi-
ology,1,2 material science,3,4 and potential in homoge-
neous catalysis.5 While there have been many reported
protocols6 to form symmetrical pyridine derivatives, the
synthesis of unsymmetrical pyridines is significantly less
developed. Existing methods7 in the construction of un-
symmetrical pyridines typically suffer from low yields,
limited scope, or poor regioselectivity.
For preliminary studies, variation in the type and equiva-
lents of base, temperature, and solvent were screened in
the synthesis of 2,4,6-triphenylpyridine.12 Sodium hy-
droxide proved to be the ideal base as higher temperatures
were tolerated without a reduction in yield, which allowed
for significantly shorter reaction times. With a set of opti-
mized reaction conditions in hand, the scope of unsym-
metrical pyridines was subsequently studied (Table 1).
We were able to illustrate that a diverse array of these de-
Utilizing (Z)-b-sulfonylvinylamine 1 formed from a pre-
viously discovered8 rhodium(I)-catalyzed addition of
arylboronic acids to (arylsulfonyl)acetonitriles and in-
spired by Feringa’s dihydropyridine synthesis,9 we have
developed a cascade reaction in which the resulting
[Rh(cod)OH]2
BINAP
H
PhO2S
NH
R1
R1B(OH)2
PhO2S
NH
base
PhO2S
CN
O
1,4-dioxane, H2O
75 °C
R1
R3
1-aza-allyl anion
(Z)-β-sulfonylvinylamine
2
1
R2
H
R1
H
HN
OH
R3
R1
N
R3
R1
N
base
base
R3
PhO2S
PhO2S
PhO2S
H
H
R2
O
R2
R2
4
3
R1
N
R3
R1
N
R3
R1
N
R3
R1 = 4-ClC6H4
R2 = Ph
R3 = 2-pyridyl
base
– SO2Ph
PhO2S
PhO2S
H
H
R2
R2
R2
5
6
8a
Scheme 1
SYNTHESIS 2011, No. 23, pp 3908–3914
x
x.
x
x
.
2
0
1
1
Advanced online publication: 27.10.2011
DOI: 10.1055/s-0031-1289578; Art ID: Z92211SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Unsymmetrical Polysubstituted Pyridines
3909
sirable pyridines could be synthesized in moderate to ly useful handles for construction of increasingly complex
good yields. This reaction provides access to structurally pyridines and allows for further functionalization such as
novel bipyridyl derivatives that may serve as tri- and bi- the introduction of chiral components for potential appli-
dentate ligands in homogeneous catalysis. In addition, the cations in asymmetric catalysis.
presence of halogenated substituents provides synthetical-
Table 1 Synthesis of Unsymmetrical Pyridines
X
PhO2S
NH2
O
R2
N
NaOH (3.0 equiv)
R1
R2
+
Y
1,4-dioxane (0.11 M)
75 °C, 2.5 h
(1.5 equiv)
R1, R2 = Ph or heteroaryl
Y
R1
8a–k
X
X = Cl, H
or
Y = OMe
Entry
Substrate
Product
Yield (%)a
Cl
N
N
O
N
1
78
7a
8a
MeO
N
N
O
N
2
75b
7a
8b
Br
MeO
N
N
O
N
Br
3
73b
Br
7b
Br
N
8c
Br
N
O
N
Br
4
85b
Br
7b
Br
8d
Synthesis 2011, No. 23, 3908–3914 © Thieme Stuttgart · New York

3910
C. Lau et al.
PAPER
Table 1 Synthesis of Unsymmetrical Pyridines (continued)
X
PhO2S
NH2
O
R2
N
NaOH (3.0 equiv)
R1
R2
+
Y
1,4-dioxane (0.11 M)
75 °C, 2.5 h
(1.5 equiv)
R1, R2 = Ph or heteroaryl
Y
R1
8a–k
X
X = Cl, H
or
Y = OMe
Entry
Substrate
Product
Yield (%)a
Br
N
Cl
N
O
N
Br
5
87b
Br
7b
Br
N
8e
Cl
O
6
72
MeO
7c
OMe
N
8f
Cl
Cl
Cl
O
7
8
9
72
64
55
O
O
7d
8g
N
O
S
S
7e
8h
N
O
O
O
S
S
7f
8i
Synthesis 2011, No. 23, 3908–3914 © Thieme Stuttgart · New York

PAPER
Synthesis of Unsymmetrical Polysubstituted Pyridines
3911
Table 1 Synthesis of Unsymmetrical Pyridines (continued)
X
PhO2S
NH2
O
R2
N
NaOH (3.0 equiv)
R1
R2
+
Y
1,4-dioxane (0.11 M)
75 °C, 2.5 h
(1.5 equiv)
R1, R2 = Ph or heteroaryl
Y
R1
8a–k
X
X = Cl, H
or
Y = OMe
Entry
Substrate
Product
Yield (%)a
N
O
O
81b
O
10
S
S
7f
8j
Cl
t-Bu
N
O
72c
t-Bu
11
7g
8k
a Isolated yields.
b Reaction performed at r.t. over 14 h.
c KOH was used and the mixture heated at 75 °C over 5 h.
Investigations pertaining to the synthesis of diaryl- 4, and 6) whereas nitro substituents led to low yields (en-
monoalkyl substituted unsymmetrical pyridines showed tries 2 and 5). On the other hand, electron-donating, elec-
that alkylated product 8k can be formed from a,b-unsatur- tron-withdrawing, and chloride substituents on 9 were all
ated substrate 7g in 72% yield. Variants of 7g possessing tolerated to afford the desired product in good yields (en-
a-hydrogens such as isopropyl and methyl groups resulted tries 7–9).
in significantly lower yields, and occurrence of aldol con-
densations was observed especially at room temperature.
synthesized in good yields. In addition to the incorpora-
Heteroaryl containing pyridines were also successfully
We also investigated the effects of the aryl substituent tion of typical heteroaryl groups (furyl, thienyl, and py-
groups on (Z)-b-sulfonylvinylamine 9 and chalcone deriv- ridyl), the reaction also allows introduction of two furyl
atives (Table 2). In general, electron-rich and chloride substituents in the final product (entry 13) as well as an
substituents resulted in good yields (Table 2, entries 1, 3, unprotected pyrrole group (entry 12).
O
N
Ph
N
Ph
PhO2S
NH2
Ph
base (3.0 equiv)
dioxane (0.11 M)
Ph
+
+
SO2Ph
9a
12
Ph
13
Ph
14
(1.5 equiv)
NaOH
KOH
55%
71%
42%
–
at 75 °C, 2.5 h
at r.t., 12 h
20%
14%
NaOMe
NaOH
KOH
NaOMe
41%
15%
42%
35%
57%
27%
Scheme 2
Synthesis 2011, No. 23, 3908–3914 © Thieme Stuttgart · New York

3912
C. Lau et al.
PAPER
Table 2 Scope of Chalcones and b-Sulfonylvinylamines
heterocycles as well as ligands for catalysis. The utility of
these compounds are currently under investigation.
R3
N
R1
O
NaOH (3.0 equiv)
PhO2S
NH2
R1
+
R2
R3
1,4-dioxane (0.11 M)
75 °C, 2.5 h
TLC was performed with Silicycle normal phase glass plates (0.25
mm, 60-A pore size, 230–400 mesh). Purification of reaction prod-
ucts was generally done by flash chromatography with Silicycle
Ultra-Pure 230–400 mesh silica gel. 1H NMR and 13C NMR spectra
were recorded at 23 °C with a Varian Mercury 400 (400 MHz/100
MHz) NMR spectrometer equipped with a Nalorac4N-400 probe, or
a Varian 400 (400 MHz/100 MHz) NMR spectrometer equipped
with ATB8123-400 probe. IR spectra were obtained using a Perkin-
Elmer Spectrum 1000 FT-IR spectrometer as a neat film on a NaCl
plate. High-resolution mass spectra were obtained from a SI2 Mi-
cromass 70S-250 mass spectrometer (EI) or an ABI/Sciex Qstar
mass spectrometer (ESI). Melting points were taken on a Fisher–
Johns melting point apparatus and are uncorrected.
R2
R1 = Ph, 9a
(1.5 equiv)
= 4-MeOC6H4, 9b R2, R3 = aryl or heteroaryl
= 4-F3CC6H4, 9c
10a–n
= 4-ClC6H4, 9d
Entry R1
R2
R3
Yield (%)a
10a, 86
10b, 34b
10c, 93
10d, 85
10e, 20
10f, 95
10g, 80
10h, 70
10i, 90
1
2
Ph
4-MeOC6H4
4-O2NC6H4
4-ClC6H4
Ph
Ph
Ph
Ph
3
Ph
Ph
4
Ph
4-MeOC6H4
4-O2NC6H4
4-ClC6H4
Ph
Polysubstituted Pyridine Derivatives 8; General Procedure
To a 2-dram vial equipped with a magnetic stir bar was added the b-
sulfonylvinylamine (0.20 mmol) followed by the a,b-unsaturated
substrate (0.30 mmol) and 1,4-dioxane (1.8 mL). The reaction was
allowed to stir for 5 min before adding the appropriate base (0.60
mmol) as a solid and heated in a 75 °C oil bath for 2.5 h. The solvent
was removed in vacuo and the crude was purified by flash column
chromatography on silica gel (hexanes–EtOAc, 9:1) (Table 1).
5
Ph
Ph
6
Ph
Ph
7
4-MeOC6H4
Ph
8
4-F3CC6H4
Ph
Ph
9
4-ClC6H4
Ph
Ph
8a
10
11
12
13
14
Ph
Ph
Ph
Ph
Ph
2-furyl
2-thienyl
2-pyrrolyl
2-furyl
Ph
Ph
10j, 77
10k, 87
10l, 81
Yellow solid; yield: 54 mg (78%); mp 135–136 °C.
Ph
IR (film): 3085, 3058, 3036, 2962, 2928, 1601, 1567, 1550, 1474,
1442, 1402, 1383, 1102, 1091, 1013, 824, 795, 744, 695, 671, 619,
496 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.71 (m, 1 H), 8.62–8.66 (m, 2 H),
8.14 (d, J = 8.0 Hz, 2 H), 7.93 (d, J = 2.0 Hz, 1 H), 7.77–7.87 (m, 3
H), 7.45–7.54 (m, 5 H), 7.33 (m, 1 H).
Ph
2-furyl
2-pyridyl
10m, 88
10n, 75
a Isolated yields.
b Obtained in 57% yield with KOH.
13C NMR (100 MHz, CDCl3): d = 156.60, 156.37, 156.08, 150.67,
149.33, 138.82, 138.11, 137.10, 135.39, 129.31, 129.26, 129.13,
128.55, 127.46, 124.12, 121.67, 118.43, 118.01.
HRMS (ESI): m/z calcd for C22H15ClN2 [MH+]: 343.0924; found:
343.1002.
When a tetralone-based a,b-unsaturated system 12 (a
‘fused’ chalcone substrate) was reacted with b-sulfonylvi-
nylamine 9a under the previously optimized reactions
conditions, the expected polycyclic product 13 was ob-
tained in 55% yield (Scheme 2).
8b
Colorless oil; yield: 51 mg (75%).
IR (film): 3059, 3032, 3008, 2960, 2936, 2835, 1603, 1584, 1550,
1492, 1394, 1246, 1119, 761, 620 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.70 (m, 1 H), 8.62 (m, 2 H), 8.14
(d, J = 1.6 Hz, 1 H), 8.03 (dd, J = 9.2, 1.6 Hz, 1 H), 7.78–7.85 (m,
3 H), 7.36–7.55 (m, 4 H), 7.30 (m, 1 H), 7.14 (dt, J = 7.2, 0.8 Hz, 1
H), 7.05 (d, J = 7.6 Hz, 1 H), 3.89 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 157.51, 156.80, 156.32, 155.95,
149.23, 149.21, 139.27, 137.02, 131.73, 130.25, 129.50, 129.15,
128.98, 127.58, 123.83, 123.50, 121.73, 121.31, 117.34, 111.83,
56.00.
However, at room temperature, we observed formation of
sulfonylated product 14. In order to determine if the sul-
fonylated compound is a potential intermediate along the
mechanistic pathway leading to formation of 13, pure 14
was subjected to the optimized conditions, and only start-
ing material was recovered. This observation shows that
14 is not an intermediate of 13 and implies that 14 could
possibly be a kinetic product formed from an oxidation
process formally removing hydrogen leading to its arom-
atization. Potassium hydroxide afforded the highest yield
of either the desired product 13 (71%) or the sulfonylated
product 14 (57%) when the appropriate reaction condi-
tions were applied.
HRMS (ESI): m/z calcd for C23H18N2O [MH+]: 339.1419; found:
339.1499.
8c
White solid; yield: 72 mg (73%); mp 161–162 °C.
In summary, we have developed a modular synthesis of
unsymmetrical polysubstituted pyridines, which tolerates
a wide variety of functionality. This has led to the synthe-
sis of novel pyridine products, which are potentially use-
ful building blocks in the design of more complex
IR (film): 3050, 3006, 2960, 2935, 2909, 2856, 2834, 1649, 1635,
1604, 1575, 1553, 1543, 1492, 1407, 1383, 1245, 1125, 1073, 1010,
800, 672 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.56 (dd, J = 7.6, 0.8 Hz, 1 H),
8.51 (d, J = 1.6 Hz, 1 H), 8.10 (d, J = 1.6 Hz, 1 H), 7.99 (dd, J = 6.0,
1.6 Hz, 1 H), 7.60–7.69 (m, 5 H), 7.49 (dd, J = 8.0, 0.8 Hz, 1 H),
Synthesis 2011, No. 23, 3908–3914 © Thieme Stuttgart · New York

PAPER
Synthesis of Unsymmetrical Polysubstituted Pyridines
3913
7.38–7.45 (m, 1 H), 7.14 (dt, J = 7.6, 0.8 Hz, 1 H), 7.04 (d, J = 8 Hz,
HRMS (ESI): m/z calcd for C21H14ClNO [MH+]: 332.0764; found:
1 H), 3.89 (s, 3 H).
332.0842.
13C NMR (100 MHz, CDCl3): d = 157.81, 157.45, 156.16, 154.82,
148.16, 141.70, 139.34, 137.99, 132.37, 131.65, 130.50, 129.16,
128.96, 128.18, 123.71, 123.52, 121.32, 120.38, 117.30, 111.80,
55.98.
HRMS (ESI): m/z calcd for C23H16Br2N2O [MH+]: 494.9629; found:
494.9717.
8h
White solid; yield: 47 mg (64%); mp 145–147 °C.
IR (film): 3106, 3085, 3065, 3039, 2953, 2923, 2851, 1580, 1574,
1527, 1436, 1424, 1102, 1092, 1014 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.06–8.16 (m, 4 H), 7.86 (d,
J = 1.6 Hz, 1 H), 7.81 (d, J = 1.6 Hz, 1 H), 7.60 (dd, J = 2.4, 1.6 Hz,
1 H), 7.42–7.55 (m, 6 H), 7.17 (dd, J = 4.0, 1.6 Hz, 1 H).
8d
White solid; yield: 79 mg (85%); mp 177–180 °C.
13C NMR (100 MHz, CDCl3): d = 158.04, 156.65, 143.37, 141.95,
139.40, 137.99, 135.47, 129.49, 129.09, 128.97, 128.65, 128.58,
127.30, 127.29, 125.58, 115.76, 115.25.
HRMS (ESI): m/z calcd for C21H14ClNS [MH+]: 348.0535; found:
348.0608.
IR (film): 3100, 3050, 3015, 2980, 2962, 2925, 2854, 1604, 1598,
1574, 1551, 1490, 1408, 1383, 1123, 1074, 1009, 822, 799, 773,
692, 642 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.61 (dd, J = 7.6, 0.4 Hz, 1 H),
8.51 (d, J = 1.2 Hz, 1 H), 8.15 (m, 2 H), 7.9 (d, J = 1.6 Hz, 1 H), 7.69
(t, J = 7.6 Hz, 1 H), 7.64 (s, 4 H), 7.42–7.55 (m, 4 H).
8i
Orange solid; yield: 39 mg (55%); mp 122–123 °C.
13C NMR (100 MHz, CDCl3): d = 157.37, 154.81, 149.22, 141.56,
139.21, 139.03, 137.47, 132.26, 129.36, 128.86, 128.83, 128.20,
127.08, 123.59, 120.23, 118.67, 117.53.
IR (film): 3112, 3073, 2955, 2924, 2853, 1608, 1577, 1572, 1548,
1424, 1405, 1221, 1093, 1013, 828, 754, 744, 703, 592, 556 cm–1.
HRMS (ESI): m/z calcd for C22H14Br2N2 [MH+]: 464.9524; found:
464.9615.
1H NMR (400 MHz, CDCl3): d = 8.05 (m, 2 H), 7.84 (d, J = 1.6 Hz,
1 H), 7.72 (d, J = 1.6 Hz, 1 H), 7.60 (dd, J = 2.6, 1.2 Hz, 1 H), 7.57
(dd, J = 2.6, 1.0 Hz, 1 H), 7.42–7.48 (m, 3 H), 7.22 (dd, J = 2.6, 0.8
Hz, 1 H), 7.16 (dd, J = 3.6, 1.6 Hz, 1 H), 6.57 (dd, J = 2.0, 1.6 Hz,
1 H).
8e
White solid; yield: 87 mg (87%); mp 210–213 °C.
IR (film): 3099, 3054, 3020, 2991, 2943, 2915, 2888, 1654, 1635,
1623, 1616, 1604, 834, 817, 798, 729, 694, 579 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.57 (dd, J = 7.6, 0.8 Hz, 1 H),
8.52 (d, J = 1.2 Hz, 1 H), 8.09 (m, 2 H), 7.86 (d, J = 1.6 Hz, 1 H),
7.69 (t, J = 7.6 Hz, 1 H), 7.64 (s, 4 H), 7.52 (dd, J = 7.8, 1.2 Hz, 1
H), 7.48 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 156.61, 153.78, 149.94, 143.43,
143.04, 141.53, 137.57, 135.34, 128.90, 128.44, 128.37, 127.18,
125.52, 114.81, 113.40, 112.17, 109.32.
HRMS (ESI): m/z calcd for C19H12ClNOS [MH+]: 338.0328; found:
338.0400.
8j
13C NMR (100 MHz, CDCl3): d = 157.34, 156.31, 155.09, 149.60,
141.79, 139.40, 137.61, 137.47, 135.68, 132.49, 129.18, 129.01,
128.50, 123.91, 120.35, 118.56, 117.96.
HRMS (ESI): m/z calcd for C22H13Br2ClN2 [MH+]: 498.9134;
found: 498.9213.
Orange solid; yield: 49 mg (81%); mp 96–97 °C.
IR (film): 3108, 3087, 3066, 3040, 3012, 2957, 2924, 2853, 1612,
1549, 1538, 1525, 1016, 742, 693 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.12 (m, 2 H), 7.84 (s, 1 H), 7.77
(s, 1 H), 7.61 (d, J = 4.0 Hz, 1 H), 7.56 (s, 1 H), 7.40–7.53 (m, 4 H),
7.24 (m, 1 H), 7.16 (m, 1 H), 6.56 (m, 1 H).
8f
Yellow solid; yield: 54 mg (72%); mp 164–166 °C.
13C NMR (100 MHz, CDCl3): d = 157.91, 154.00, 149.91, 143.31,
142.89, 141.78, 139.20, 129.23, 128.74, 128.40, 127.12, 127.03,
125.41, 115.15, 113.21, 112.15, 109.21.
IR (film): 3084, 3063, 3039, 3004, 2958, 2932, 2836, 1700, 1583,
1428, 1291, 1237, 1180, 1090, 1031, 1013, 776, 755, 693, 570 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.10–8.20 (m, 4 H), 7.85 (d,
J = 1.6 Hz, 1 H), 7.79 (d, J = 1.6 Hz, 1 H), 7.68 (m, 2 H), 7.41–7.54
(m, 5 H), 7.01–7.07 (m, 2 H), 3.88 (s, 3 H).
HRMS (ESI): m/z calcd for C19H13NOS [MH+]: 304.0718; found:
304.0790.
8k
13C NMR (100 MHz, CDCl3): d = 160.77, 157.77, 156.39, 150.03,
139.74, 138.33, 135.28, 131.31, 129.31, 129.06, 128.94, 128.59,
128.54, 127.32, 117.06, 116.54, 114.79, 55.66.
HRMS (ESI): m/z calcd for C24H18ClNO [MH+]: 372.1077; found:
372.1155.
Colorless oil; yield: 46 mg (72%).
IR (film): 3075, 3053, 2962, 2924, 2899, 1656, 1635, 1604, 1595,
1551, 1492, 1403, 1091, 1012, 877, 734, 697, 616, 588, 575 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.09 (m, 2 H), 7.71 (d, J = 1.6 Hz,
1 H), 7.66 (m, 2 H), 7.41–7.53 (m, 6 H), 1.47 (s, 9 H).
8g
13C NMR (100 MHz, CDCl3): d = 169.92, 155.06, 149.89, 139.73,
138.60, 135.00, 129.25, 128.97, 128.96, 128.46, 127.42, 116.29,
115.50, 38.09, 30.53.
HRMS (ESI): m/z calcd for C21H20ClN [MH+]: 322.1284; found:
322.1354.
Orange solid; yield: 48 mg (72%); mp 135–137 °C.
IR (film): 3117, 3086, 3063, 3038, 2922, 2850, 1611, 1546, 1490,
1012, 832, 736, 693 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.10–8.20 (m, 4 H), 7.91 (d,
J = 1.6 Hz, 1 H), 7.88 (d, J = 1.6 Hz, 1 H), 7.57–7.59 (m, 1 H),
7.42–7.54 (m, 5 H), 6.97 (dd, J = 4.0, 1.6 Hz, 1 H), 6.57 (dd, J = 4.0,
2.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 157.81, 156.45, 151.99, 143.93,
139.48, 139.39, 138.07, 135.40, 129.42, 129.05, 128.93, 128.53,
127.25, 113.43, 112.92, 112.38, 108.86.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Synthesis 2011, No. 23, 3908–3914 © Thieme Stuttgart · New York

3914
C. Lau et al.
PAPER
(6) Condensation of 1,5-diketones with formamide-formic
Acknowledgment
acid: (a) Chubb, F.; Hay, A. S.; Sandin, R. B. J. Am. Chem.
Soc. 1953, 75, 6042. Chichibabin method: (b) Dilthey, W.
J. Prakt. Chem. 1921, 102, 209. (c) Lombard, R.; Stephen,
J. P. Bull. Soc. Chim. Fr. 1958, 1458. (d) Zecher, W.;
Kröhnke, F. Chem. Ber. 1961, 94, 690. (e) Frank, R. L.;
Steven, R. P. J. Am. Chem. Soc. 1949, 71, 2629. Reaction
of N-phenacylpyridinium salts and a,b-unsaturated ketones:
(f) Kröhnke, F.; Zecher, W. Angew. Chem., Int. Ed. Engl.
1962, 1, 626. (g) Kröhnke, F. Synthesis 1976, 1. Reaction
of N-phosphinylethanimines with aldehydes:
(h) Kobayashi, T.; Kakiuchi, H.; Kato, H. Bull. Chem. Soc.
Jpn. 1991, 64, 392. Reaction of lithiated b-enaminophos-
phonates with chalcones: (i) Palacios, F.; Retana de A., M.
O.; Oyarzabal, J. Tetrahedron Lett. 1996, 37, 4577.
Reaction of acetophenones, benzaldehydes, and NH4OAc
under solvent-free or microwave conditions: (j) Cave, G.
W. V.; Raston, C. L. Chem. Commun. 2000, 2199. (k) Tu,
S.; Li, T.; Shi, F.; Fang, F.; Zhu, S.; Wei, X.; Zong, Z. Chem.
Lett. 2005, 34, 732.
This research was supported by the Natural Sciences and Enginee-
ring Research Council of Canada (NSERC), Merck (Industrial Re-
search Chair), and the University of Toronto.
References
(1) Applications as anticancer agents: (a) Basnet, A.; Thapa, P.;
Karki, R.; Na, Y.; Jahng, Y.; Jeong, B. S.; Jeong, T. C.; Lee,
C. S.; Lee, E. S. Bioorg. Med. Chem. 2007, 15, 4351.
(b) Zhao, L. X.; Moon, Y. S.; Basnet, A.; Kim, E. K.; Cho,
W. J.; Jahng, Y.; Park, J. G.; Jeong, T. C.; Cho, W. J.; Choi,
S. U.; Lee, C. O.; Lee, S. Y.; Lee, C. S.; Lee, E. S. Bioorg.
Med. Chem. Lett. 2004, 14, 1333. (c) Zhao, L. X.; Kim, T.
S.; Ahn, S. H.; Kim, T. H.; Kim, E. K.; Cho, W. J.; Choi, H.;
Lee, C. S.; Kim, J. A.; Jeong, T. C.; Chang, C. J.; Lee, E. S.
Bioorg. Med. Chem. Lett. 2001, 11, 2659. (d) Carter, P. J.;
Cheng, C. C.; Thorp, H. H. J. Am. Chem. Soc. 1998, 120,
632.
(7) Reaction of pyridinium salts and a,b-unsaturated ketones:
(a) Yan, C.-G.; Cai, X.-M.; Wang, Q.-F.; Wang, T.-Y.;
Zheng, M. Org. Biomol. Chem. 2007, 5, 945. (b) Malik, S.;
Pandey, K. J. Chem. Eng. Data 1983, 28, 430. (c) Also see
refs. 1a,b. Lewis acid catalyzed reaction of w-pyrrolidino-
acetophenone with chalcone under microwave conditions:
(d) Borthakur, M.; Dutta, M.; Gogoi, S.; Bouruah, R. C.
Synlett 2008, 3125. Reaction of a,b-unsaturated imines with
sodium enolates of methyl aryl ketones: (e) Kiselyov, A. S.
Tetrahedron Lett. 1995, 36, 9297. Diels–Alder reaction:
(f) Diring, S.; Retailleau, P.; Ziessel, R. J. Org. Chem. 2007,
72, 10181.
(2) Applications as chemosensors: (a) Yang, Q. Z.; Wu, L. Z.;
Zhang, H.; Chen, B.; Wu, Z. X.; Zhang, L. P.; Tung, C. H.
Inorg. Chem. 2004, 43, 5195. (b) Siu, P. K. M.; Lai, S. W.;
Lu, W.; Zhu, N.; Che, C. M. Eur. J. Inorg. Chem. 2003,
2749. (c) Wong, K. H.; Chan, M. C. W.; Che, C. M. Chem.
Eur. J. 1999, 5, 2845.
(3) Applications as optoelectronic devices: (a) Liu, R.; Chang,
J.; Xiao, Q.; Li, Y.; Chen, H.; Zhu, H. Dyes Pigm. 2011, 88,
88. (b) Chen, J. L.; Chang, S. Y.; Chi, Y.; Chen, K.; Cheng,
Y. M.; Lin, C. W.; Lee, G. H.; Chou, P. T.; Wu, C. H.; Shih,
P. I.; Shu, C. F. Chem. Asian J. 2008, 3, 2112. (c)Williams,
J. A. G. Top. Curr. Chem. 2007, 281, 205. (d) Chou, P. T.;
Chi, Y. Chem. Eur. J. 2007, 13, 380. (e) Yan, B. P.;
Cheung, C. C. C.; Kui, S. C. F.; Xiang, H. F.; Roy, V. A. L.;
Xu, S. J.; Che, C. M. Adv. Mater. 2007, 19, 3599. (f) Yan,
B. P.; Cheung, C. C. C.; Kui, S. C. F.; Roy, V. A. L.; Che, C.
M.; Xu, S. J. Appl. Phys. Lett. 2007, 91, 63508. (g) Chou,
P. T.; Chi, Y. Eur. J. Inorg. Chem. 2006, 3319. (h)Sun, W.;
Zhu, H.; Barron, P. M. Chem. Mater. 2006, 18, 2602.
(4) Applications as semi-conductors: (a) Lu, W.; Roy, V. A. L.;
Che, C. M. Chem. Commun. 2006, 3972. (b) Kaes, C.; Katz,
A.; Hosseini, M. W. Chem. Rev. 2000, 100, 3553.
(8) Tsui, G. C.; Glenadel, Q.; Lau, C.; Lautens, M. Org. Lett.
2011, 13, 208.
(9) Feringa, B. L. J. Chem. Soc., Chem Commun. 1985, 466.
(10) References outlining the importance of 1-aza-allyl anions
and applications in heterocyclic synthesis: (a) Enamines:
Their Synthesis, Structure and Reactions; Cook, A. G., Ed.;
Marcel Dekker: New York, 1969. (b) House, H. O. Modern
Synthetic Reactions, 2nd ed; W. A. Benjamin, Inc.: Menlo
Park, 1972. (c) Mangelinckx, S.; Giubellina, N.; Kimpe, N.
D. Chem. Rev. 2004, 104, 2353. (d) Job, A.; Janeck, C. F.;
Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002, 58,
2253. (e) Caro, C. F.; Lappert, M. F.; Merle, P. G. Coord.
Chem. Rev. 2001, 605, 219. (f) Semmelhack, M. F. In
Comprehensive Organic Synthesis, Vol. 2; Trost, B. M.;
Fleming, I., Eds.; Pergamon Press: Oxford, 1991.
(5) (a) Carrasco, A. C.; Pidko, E. A.; Masdeu-Bulto, A. M.;
Lutz, M.; Spek, A. L.; Vogt, D.; Müller, C. New J. Chem.
2010, 34, 1547. (b) Eryazici, I.; Moorefield, C. N.; Durmus,
S.; Newkome, G. R. J. Org. Chem. 2006, 71, 1009.
(g) Whitesell, J. K.; Whitesell, M. A. Synthesis 1983, 517.
(h) Hickmott, P. W. Tetrahedron 1982, 38, 3363.
(11) Initial C-alkylation at the b-carbon of 1-aza-allyl anions is
typically observed over N-alkylation; see ref. 10c.
(12) See Supporting Information for additional details relating to
the optimization process.
Synthesis 2011, No. 23, 3908–3914 © Thieme Stuttgart · New York