3-(Dichloroacetyl)chromone; A new building block for the synthesis of formylated purine isosteres: Design and Synthesis of Fused -(formyl)pyridines

Article abstract of DOI:10.1055/s-0030-1258364

The first synthesis of 3-(dichloroacetyl)chromone from 3-(dimethylamino)-1- (2-hydroxyphenyl)propen-1-one and dichloroacetyl chloride is described. The reaction of electron-rich aminoheterocycles with 3-(dichloroacetyl)chromone provides a set of diverse f

Full text of DOI:10.1055/s-0030-1258364

PAPER
469
3-(Dichloroacetyl)chromone; A New Building Block for the Synthesis of For-
mylated Purine Isosteres: Design and Synthesis of Fused a-(Formyl)pyridines
Viktor O. Iaroshenko,*a,b Satenik Mkrtchyan,a Gagik Ghazaryan,a,c Ani Hakobyan,a,c Aneela Maalik,a Linda Supe,a
Alexander Villinger,a Andrei Tolmachev,b,d Dmytro Ostrovskyi,a Vyacheslav Ya. Sosnovskikh,e
Tariel V. Ghochikyan,c Peter Langer*a,f
a
Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: viktor.iaroshenko@uni-rostock.de; E-mail: iva108@googlemail.com
National Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33, 01033, Ukraine
b
Fax +380(44)5373253; E-mail: yaroshenko@enamine.net
Faculty of Chemistry, Yerevan State University, Alex Manoogian 1, 0025 Yerevan, Armenia
Enamine Ltd., 23 A. Matrosova st., 01103 Kyiv, Ukraine
Department of Chemistry, Ural State University, 51 Lenina Ave., 620083 Ekaterinburg, Russian Federation
c
d
e
f
Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 21 October 2010
vestigate the reaction of amines 1–10 with building block
11.
Abstract: The first synthesis of 3-(dichloroacetyl)chromone from
3-(dimethylamino)-1-(2-hydroxyphenyl)propen-1-one and dichlo-
roacetyl chloride is described. The reaction of electron-rich amino-
heterocycles with 3-(dichloroacetyl)chromone provides a set of
diverse fused pyridines bearing the CHCl2-substituent at the a-posi-
tion of the pyridine core. Subsequent hydrolysis leads to the forma-
tion of annulated a-(formyl)pyridines.
Unfortunately, many reactions of 11 with aminoheterocy-
cles did not give satisfactory results as, in most cases,
complex product mixtures were formed which could not
be separated by preparative column chromatography.
Only amines 1a and 5 reacted smoothly with 11 leading to
pyridine ring annulation. In these cases, the reactions gave
6-(dichloromethyl)-2-phenyl-1,2-dihydro-3H-pyrazo-
lo[3,4-b]pyridin-3-one (12) and 5-(dichloromethyl)-1-
methyl-3-phenyl-1,3-dihydro-2H-imidazo[4,5-b]pyridine-
2-thione (13) bearing a CHCl2 substituent located at the a-
position of the annulated pyridine ring.
Key words: 3-(dichloroacetyl)chromone, 4H-1-benzopyran-4-one,
heterocyclic amines, fused pyridines, annulation reactions
Purine isosteres and purine-like scaffolds are of consider-
able interest as major privileged scaffolds1 often used in
medicinal chemistry and drug design. In the past decade,
functionalized derivatives of purine isosteres have proved
to be of high pharmacological importance as lead struc-
tures and synthetic building blocks in medicinal and agri-
cultural chemistry.2–8
O
NC
S
N
R1
Alk2N
NH2
NH2
N
R
NH2
N
R2
N
1a R1 = Ph, R2 = H
1b R1 = Me, R2 = H
1c R1 = H, R2 = Me
At the same time, purine-like scaffolds, bearing a carbon-
yl function9 at the 2-position of the purine core, are con-
sidered as a promising heterocyclic platform for the
design of inosine 5¢-monophosphate dehydrogenase
(IMPDH) inhibitors. IMPDH is considered as an impor-
tant target enzyme for drug design.9,10 In our present study
we have developed a preparative approach to purine iso-
steres bearing a formyl function located at the 2-position
of the purine/pseudo-purine core.
2a R = 4-MeOC6H4CH2 3a Alk2N = piperidino
2b R = c-Hex
2c R = t-Bu
3b Alk2N = morpholino
3c Alk2N = NMe2
O
Me
R1
N
N
N
S
N
N
NH2
O
N
NH2
NH2
Ph
Ph
R2
4
5
6a R1 = H, R2 = H
6b R1 = Me, R2 = Me
6c R1 = H, R2 = Me
Retrosynthetically, structures of this type can be assem-
bled by annulation of the a-formyl-substituted pyridine
ring with an aminoheterocyclic moiety. As 1,3-C,N-dinu-
cleophiles, which are suitable for this purpose, we envis-
aged electron-rich hetarylamines 1–10 (Figure 1) and 1,1-
dichloro-4-ethoxybut-3-en-2-one (11)11 as a 1,3-C,C-di-
electrophile. With this concept in hand, we began to in-
OMe
Me2N
NH2
MeO
NH2
7
8
OMe
MeO
MeO
MeO
MeO
NH2
NH2
SYNTHESIS 2011, No. 3, pp 0469–0479
x
x
.
x
x
.2
0
1
1
9
10
Advanced online publication: 15.12.2010
DOI: 10.1055/s-0030-1258364; Art ID: P15910SS
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Structures of the 1,3-C,N-dinucleophiles used

470
V. O. Iaroshenko et al.
PAPER
At the same time, aminothiazole 3a reacts with 11 form- CF2Cl analogues.12 The structures of intermediate 16 as
ing a mixture of two regioisomers 14a and 15a in a ratio well as 5-(dichloromethyl)thiazolo[4,5-b]pyridine 15a
of 3:1. The mixture of two regioisomers was successfully were confirmed by an X-ray crystal structure analysis13
separated by preparative column chromatography. A sim- (Figures 2 and 3).
ilar reaction of 3b with 11 gave a mixture of 14b and 15b
in a ratio ~3:1.
With this demotivating result in hand, we had to changed
our initial strategy and thus we directed our attention to-
In contrast, in the case of aminopyrrole 2c, the reaction wards the employment of 3-(dichloroacetyl)chromone [3-
proceeded as a two-step process with the formation of in- (dichloroacetyl)-4H-1-benzopyran-4-one, 22], which can
termediate 16 which was then cyclized to give pyridine be considered as a masked 1,3-C,C-dielectrophile.
17. This reaction was carried out under harsh conditions,
namely, melting under an inert atmosphere at 180 °C for
three hours. Base mediated hydrolysis (KOH, MeOH) af-
forded the corresponding formyl derivatives 18–21 in
moderate yields (Scheme 1, Table 1).
O
Ph
S
N
N
CHCl2
N
H
12
Me
CHCl2
O
N
i
N
CHCl2
CHCl2
N
Figure 2 Molecular structure of compound 16
OEt
Ph
11
13
In recent years, the use of 3-substituted chromones in the
synthesis of various heterocycles has received much at-
tention. The synthetic utility of these compounds with
formyl,14 acetyl,15 trifluoroacetyl,16 methoxalyl,17 cy-
ano,18 and nitro19 groups located at the 3-position primari-
ly derives from the reactivity of the three electron-
deficient centers, i. e. carbon atoms C2 and C4 of the
chromone moiety and the substituent attached to carbon
C3. Reactions of 3-substituted chromones with nucleo-
philes, which possess several reactive centers, can lead to
several products and are, therefore, of interest from the
point of view of their chemo- and regioselectivity.
S
N
Alk2N
N
14a Alk2N = piperidino
14b Alk2N = morpholino
S
Alk2N
N
CHCl2
N
15a Alk2N = piperidino
15b Alk2N = morpholino
CHCl2
NC
NC
11
NH
O
ii
iii
N
N
N
t-Bu
CHCl2
t-Bu
16
17
19
O
N
N
H
CHO
NC
Ph
CHO
CHO
N
N
N
t-Bu
18
S
S
N
N
N
N
CHO
N
N
20
21
Scheme 1 Reagents and conditions: (i) aminoheterocycle [1a (12),
5 (13), 3a (14a/15a), 3b (14b/15b)], DMF, 120 °C, 12 h, under argon;
(ii) 2c (16), DMF, 60 °C, 12 h; (iii) 180 °C, 5 h, under argon.
Figure 3 Molecular structure of compound 15a
Chromones, having electron-withdrawing substituents at
the 3-position, undergo reactions with dinucleophiles at
the 2-position of the chromone system, followed by in-
tramolecular cyclization via another electrophilic cen-
ters.14–19 Using 3-(perfluoroacyl)chromones as 1,3-
The structure of the heteroannulated pyridines was estab-
lished by means of 1D and 2D NMR spectroscopy. The
spectroscopic features of all CHCl2-heteropyridines are in
good agreement with previously synthesized CF3 and
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PAPER
Synthesis of Fused a-(Formyl)pyridines
471
O
O
dielectrophiles and electron-rich aminoheterocycles as
1,3-dinucleophiles, we have recently developed formal [3
+ 3] cycloaromatization reactions which allow the regio-
controlled synthesis of pyrimidines16c and fused py-
ridines.16d These products can be considered as purine
isosteres and are of a great interest as privileged scaffolds
in medicinal chemistry and drug design.1–8,20 Such an ap-
proach has been also used for the synthesis of fluorinated
pyrazolo[3,4-b]pyridines, pyrazolo[3,4-d]pyrimidines,
and a-carboline nucleosides.21 This method makes use of
easily prepared reagents and is particularly suitable for a
combinatorial approach to the synthesis of fused py-
ridines.
O
OH
Cl2HC
NH2NHR
i
CHCl2
R
N
N
O
22
23a R = Me (83%)
23b R = Ph (75%)
Scheme 3 Reagents and conditions: (i): toluene, reflux, 3–5 h.
romethyl)-1H-pyrazoles 23a,b (Scheme 3). The structure
of scaffold 23b was unambiguously confirmed by X-ray
single crystal analysis (Figure 4). Concerning pyrazole
23a, the exact structure was established by 2D NMR ex-
periments. In the NOESY spectrum we observed the
cross-peak between protons at d = 3.92 (1-Me) and 7.56
(5-CHCl2), this can be accepted as a proof for structure
23a, where the methyl and dichloromethyl groups are sit-
uated near to each other.
O
O
OH
O
ClCOCCl2H
Py
CHCl2
NMe2
O
22
Scheme 2 Synthesis of 3-(dichloroacetyl)chromone (22)
Since 3-formyl- and 3-(trifluoroacetyl)chromones have
been shown to react with heterocyclic amines to give the
corresponding heteroannulated pyridines,16d,22 it was ex-
pected that Michael addition of these 1,3-C,N-dinucleo-
philes to a powerful Michael acceptor, such as 3-
(dichloroacetyl)chromone (22), followed by ring closure
and aromatization could provide a direct route to purine
isosteres bearing a dichloromethyl group that could then
be converted into the formyl23 or trichloromethyl24
groups. In addition, dichloromethyl-substituted heterocy-
clic compounds are precursors of hetarylchlorocarbenes,
which add to the double bond of alkenes to form cyclopro-
pane derivatives.25 However, it is difficult to prepare
dichloromethylazines by direct chlorination of the corre-
sponding methylazines as this reaction usually affords a
mixture of mono-, di-, and trichloromethylazines.26 In
connection with this, and in view of the unique biological
properties displayed by many purine isostere analogues,1–8,20
we have focused our attention on chromone 22 as a new
polydentate electrophilic substrate for the synthesis of
dichloromethylated fused pyridines. This chromone, de-
spite its potential interest as a building block in organic
synthesis, has received little attention. In contrast to the
well-known 3-(polyfluoroacyl)chromones,16 no data on
the preparation and chemical properties of 22 have been
reported to date.
Figure 4 Molecular structure of pyrazole 23b
Next, we extended our studies to the application of 1,3-di-
nucleophiles, such as the previously mentioned electron-
rich aminoheterocycles and anilines 1–10. We recently
prepared a wide range of fluorinated fused pyridines by
reaction of 3-(trifluoroacetyl)chromones with heterocy-
clic amines and, although two competitive routes were ob-
served in acetic acid, the reaction pathways could be
controlled with respect to the prevalent a-(trifluorometh-
yl)pyridine derivatives.16d As an extension of this, we de-
cided to investigate whether this reaction could be applied
to chromone 22. We found that the reaction of 22 with
amines 1–8 gave a set of diverse heteroannulated py-
ridines 24a–p, bearing a dichloromethyl substituent at the
a-position of the pyridine core, in 60–93% yields
(Scheme 4, Table 1). The reactions were carried out in
acetic acid (reflux for 2–5 h) or, alternatively, in N,N-di-
methylformamide using the water scavenger chlorotri-
methylsilane. In contrast to the analogous reactions of 3-
(trifluoroacetyl)chromones, chromone 22 showed better
regioselectivity.
It is known that 3-substituted chromones are available by
reaction of 3-(dimethylamino)-1-(2-hydroxyphenyl)pro-
pen-1-one with various electrophiles.27 We have found
that 3-(dichloroacetyl)chromone (22) can be prepared in
75% yield by reaction of 3-(dimethylamino)-1-(2-hydroxy-
phenyl)propen-1-one with dichloroacetyl chloride in py-
ridine (Scheme 2).
The first step of the reaction leading to 24 apparently in-
volves an attack of the internal enamine b-carbon (in gen-
eral, this atom is more nucleophilic than the primary
amino group) at C2 of 22 with concomitant opening of the
pyrone ring (1,4-addition, intermediate A). Subsequent
intramolecular attack of the amino group at the dichloro-
acetyl group leads to the fused pyridines 24. The alterna-
To investigate the reactivity of 22 we studied its reaction
with methyl- and phenylhydrazines, which resulted in a
regioselective synthesis of the 1-substituted 5-(dichlo-
Synthesis 2011, No. 3, 469–479 © Thieme Stuttgart · New York

472
V. O. Iaroshenko et al.
PAPER
OH
O
O
O
O
H2N
1–8
CHCl2
CHCl2
i
O
A
22
H2N
N
OH
O
OH
Figure 5 Molecular structure of compound 24g
O
CHCl2
N
CHCl2
25
24a–p
The structures of pyridines 24 and 26 were confirmed by
1H and 13C NMR spectroscopy and mass-spectrometry
and are in good agreement with earlier synthesized hetero-
cyclic patterns16d,22 (Table 1). The 1H NMR spectra of 24
exhibit a singlet of the pyridine proton at d = 8.0–8.5; in
addition, all protons of the benzene ring are shifted to
higher field and, hence, opening of the pyrone ring took
place under the action of aminoheterocycles. Moreover,
we have established the structure of 6-(dichloromethyl)-
3-methyl-1-phenyl-5-salicyloyl-1H-pyrazolo[3,4-b]pyri-
dine (24g) by X-ray single crystal analysis (Figure 5).13
Scheme 4 Reagents and conditions: (i) AcOH, reflux, 2–5 h (for 1–
4, 6); DMF, TMSCl, 100 °C (for 5, 7, 8).
tive cyclization of A, involving the amino group and the
carbonyl carbon atom connected to the benzene ring, does
not occur, and no formation of the corresponding 5H-
chromeno[4,3-b]pyridines 25 was detected (Scheme 4).
The reaction of chromone 22 with heterocyclic amines
makes this compound very useful for the synthesis of nov-
el dichloromethylated pyridines. Taking into account that
the salicyloyl substituent can easily be transformed via
Dakin reaction into a carboxy group;28 this is also a meth-
od for preparing new derivatives of fused nicotinic acid
with potential biological activity. However, it is necessary
to mentioned that not all electron-rich amines reacted with
22 with the formation of the corresponding pyridines; in
the case of 9 and 10 the reaction failed.
OH
OH
O
O
i
CHCl2
N
CHO
N
24a–p
26a–f
The transformation of the dichloromethyl into the formyl
group was successfully conducted in methanol with four
equivalents of potassium hydroxide under reflux
(Scheme 5). The reaction delivers a set of a-(formyl)py-
ridines 26 in good yields after drying under vacuum at 50–
60 °C for three hours.
Scheme 5 Reagents and conditions: (i) (a) MeOH, KOH, reflux, 2
h; (b) concd HCl.
Table 1 Yields and Characteristic Data for Heteroannulated Pyridines
Product
Yielda (%) Mpb (°C) IR (ATR, cm–1), 1H and 13C NMR [d, J (Hz)], MS m/z (%), HRMS (ESI)
87
298–300 IR: 3368 (w), 3335 (s), 3185 (s), 1668 (w), 1622 (s), 1614 (s), 1597 (m), 1589
(m), 1518 (s), 1496 (s), 1485 (s).
O
1H (DMSO-d6): 7.27–7.32 (m, 2 H, Ph), 7.49–7.53 (m, 3 H, Ph), 7.55 (s, 1 H,
CHCl2), 7.88–7.91 (m, 1 H), 8.38 (d, 3J = 7.9, 1 H), 11.95 (s, 1 H, NH).
13C (DMSO-d6): 71.3, 111.2, 114.7, 119.7, 125.6, 129.1, 135.7, 136.7, 156.3,
157.6, 160.2.
Ph
N
N
CHCl2
N
H
12
MS: 293 (M+, 100), 260 (10), 230 (18), 229 (12), 225 (16), 196 (14), 156 (20),
105 (19), 77 (72), 73 (10), 69 (14), 57 (11), 51 (12), 44 (21), 43 (13).
HRMS: m/z [M]+ calcd for C13H9Cl2N3O: 293.0121; found: 293.0123.
69
255–256 IR: 1664 (m), 1562 (s), 1440 (w).
Me
1H (CDCl3): 3.86 (s, 3 H, Me), 6.65 (s, 1 H, CHCl2), 7.52 (d, 3J = 8.2, 1 H), 7.57–
7.63 (m, 5 H, Ph), 7.75 (d, 3J = 8.2, 1 H).
N
S
13C (CDCl3): 31.2, 71.2, 116.3, 116.7, 126.7, 128.2, 129.1, 129.2, 134.1, 144.1,
152.2, 173.1.
N
N
CHCl2
Ph
MS: 324 (M+, 15), 323 (40), 308 (62), 231 (100), 196 (25), 161 (41), 148 (12).
HRMS: m/z [M+ + 1] calcd for C14H11Cl2N3S: 324.0588; found: 324.0587.
13
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Synthesis of Fused a-(Formyl)pyridines
473
Table 1 Yields and Characteristic Data for Heteroannulated Pyridines (continued)
Product
Yielda (%) Mpb (°C) IR (ATR, cm–1), 1H and 13C NMR [d, J (Hz)], MS m/z (%), HRMS (ESI)
65
61
20
183–185 1H (CDCl3): 1.61 (br s, 6 H), 3.79 (br s, 4 H), 6.77 (s, 1 H, CHCl2), 7.11 (d,
CHCl2
3J = 4.2, 1 H), 8.34 (d, 1 H, 3J = 4.2).
S
N
N
N
14a
211–213 1H (CDCl3): 3.73 (br s, 4 H), 3.87 (br s, 4 H), 6.74 (s, 1 H, CHCl2), 7.15 (d, 1 H,
CHCl2
3J = 4.2), 8.30 (d, 1 H, 3J = 4.2).
S
O
N
N
N
N
14b
145–146 IR: 1586 (m), 1567 (m), 1529 (s), 1441 (m).
1H (CDCl3): 1.70 (s, 6 H), 3.67 (s, 4 H), 6.72 (s, 1 H, CHCl2), 7.42 (d, 3J = 7.7,
1 H), 7.90 (d, 3J = 7.7, 1 H).
S
N
N
CHCl2
13C NMR (CDCl3): 24.1, 25.3, 49.6, 69.6, 112.4, 121.2, 140.3, 146.9, 166.7,
169.9.
15a
MS: 301 (M+, 27), 266 (M+ – Cl, 23), 247 (11), 233 (16), 198 (16), 177 (11), 156
(59), 129 (16), 95 (28), 81 (46), 69 (100), 57 (38).
HRMS: m/z [M]+ calcd for C12H13Cl2N3S: 301.02018; found: 301.01977.
18
83
171–173 IR: 1564 (m), 1523 (s), 1464 (w).
S
1H (CDCl3): 3.72–3.73 (m, 4 H), 3.81–3.83 (m, 4 H), 6.74 (s, 1 H, CHCl2), 7.49
(d, 3J = 8.0, 1 H), 7.98 (d, 3J = 8.0, 1 H).
O
N
N
N
CHCl2
13C (CDCl3): 48.1, 65.9, 71.5, 113.4, 125.4, 130.0, 155.1, 162.6, 170.6.
MS: 303 (M+, 75), 268 (63), 246 (100), 210 (93), 183 (11), 156 (40), 120 (14),
95 (15), 69 (13).
15b
HRMS: m/z [M]+ calcd for C11H11Cl2N3OS: 302.99944; found: 302.99935.
135–136 IR: 3156 (w), 1640 (m), 1574 (s), 1516 (m), 1477 (m).
1H (CDCl3): 1.64 (s, 9 H, t-Bu), 5.72 (d, 3J = 7.7, 1 H, =CH), 5.90 (s, 1 H,
CHCl2), 6.19 (m, 1 H, =CHN), 7.12–7.19 (m, 2 H, pyr), 11.39 (d, 3J = 11.0, 1 H,
NH).
NC
NH
O
N
13C (CDCl3): 30.0, 57.9, 69.7, 90.6, 91.8, 103.3, 116.2, 123.9, 131.8, 151.8,
188.4.
t-Bu
CHCl2
16
MS: 299 (M+, 11), 243 (16), 173 (10), 160 (100), 144 (18), 57 (38). HRMS (EI):
m/z [M]+ calcd for C13H15Cl2N3O: 299.05867; found: 299.05821.
77
177–179 IR: 2212 (s), 1688 (w), 1597 (w), 1573 (w), 1520 (m), 1469 (w).
1H (CDCl3): 1.82 (s, 9 H, t-Bu), 6.81 (s, 1 H, CHCl2), 7.65 (d, 3J = 4.6, 1 H),
7.94 (s, 1 H), 8.10 (d, 3J = 4.6, 1 H).
CHCl2
N
NC
13C (CDCl3): 29.0, 59.0, 71.9, 114.8, 117.2, 121.8, 129.3, 134.7, 144.9, 145.0,
152.0.
N
t-Bu
MS: 281 (M+, 15), 225 (40), 190 (100), 154 (14), 57 (10).
HRMS: m/z [M+ 1]+ calcd for C13H13Cl2N3: 282.0559; found: 282.0557.
17
88
71
332–335 1H (DMSO-d6): 7.20–7.28 (m, 2 H, Ph), 7.40–7.49 (m, 3 H, Ph), 7.80–7.87 (m,
1 H), 8.36 (d, 3J = 8.0, 1 H), 10.05 (s, 1 H, CHO), 11.95 (s, 1 H, NH).
13C (DMSO-d6): 112.3, 114.9, 120.1, 126.6, 129.4, 135.9, 137.0, 156.3, 157.6,
160.2, 191.2.
O
Ph
N
N
CHO
N
CHO
N
MS: 239 (M+, 80), 210 (18), 230 (18), 229 (12), 132 (34).
HRMS: m/z [M]+ calcd for C13H9N3O2: 239.0721; found: 239.0723.
H
18
191–192 IR: 2212 (s), 1738 (w), 1597 (w), 1573 (w), 1520 (m), 1469 (w).
1H (CDCl3): 1.81 (s, 9 H, t-Bu), 7.50 (d, 3J = 4.9, 1 H), 7.90 (s, 1 H), 7.95 (d,
3J = 4.9, 1 H), 10.01 (s, 1 H, CHO).
NC
13C (CDCl3): 29.0, 59.0, 113.8, 117.2, 122.6, 129.9, 134.7, 144.9, 145.0, 152.0,
190.0.
N
t-Bu
MS: 227 (M+, 35), 170 (60), 144 (100), 115 (14).
HRMS: m/z [M + 1]+ calcd for C13H13ON3: 227.1123; found: 227.1124.
19
63
195–197 IR: 1731 (m), 1531 (s), 1570 (w), 1488 (w).
1H (CDCl3): 1.78 (s, 6 H), 3.64 (s, 4 H), 7.49 (d, 3J = 4.5, 1 H), 7.98 (d, 3J = 4.5,
1 H), 10.11 (s, 1 H, CHO).
CHO
N
S
N
N
13C (CDCl3): 24.0, 25.7, 48.3, 114.0, 125.9, 130.5, 155.9, 162.0, 172.9, 185.5.
20
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474
V. O. Iaroshenko et al.
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Table 1 Yields and Characteristic Data for Heteroannulated Pyridines (continued)
Product
Yielda (%) Mpb (°C) IR (ATR, cm–1), 1H and 13C NMR [d, J (Hz)], MS m/z (%), HRMS (ESI)
69
174–175 IR: 1736 (m), 1567 (m), 1529 (s), 1441 (m).
S
N
1H (CDCl3): 1.71 (s, 6 H), 3.69 (s, 4 H), 7.37 (d, 3J = 7.9, 1 H), 7.85 (d, 3J = 7.9,
1 H), 10.02 (s, 1 H, CHO).
N
N
CHO
13C (CDCl3): 24.2, 25.4, 49.6, 113.4, 121.9, 141.3, 147.0, 166.7, 170.4, 192.6.
MS: 247 (M+, 36), 218 (32), 148 (100), 134 (16).
21
HRMS: m/z [M]+ calcd for C12H13N3OS: 247.0869; found: 247.0864.
75
173–174 IR: 1700 (m), 1643 (s), 1611 (s), 1591 (w), 1550 (s), 1463 (s).
1H (CDCl3): 7.50–7.57 (m, 2 H, H6, H8), 7.58 (s, 1 H, CHCl2), 7.74–7.81 (m, 1
H, H7), 8.28–8.31 (m, 1 H, H5), 8.76 (s, 1 H, H2),
O
O
O
CHCl2
13C (CDCl3): 69.0, 117.4, 117.9, 123.6, 125.6, 125.9, 134.1, 154.7, 162.6, 173.2,
183.8.
MS: 255 (M+, 1), 221 (34), 173 (M+ – CHCl2, 100), 121 (35).
HRMS: m/z [M]+ calcd for C11H6Cl2O3: 255.96885; found: 255.96875.
22
83
75
189–190 IR: 1621 (m), 1580 (m), 1528 (m), 1481 (m).
O
OH
Cl2HC
1H (DMSO-d6): 3.92 (s, 3 H, Me), 6.90–7.01 (m, 2 H, H5, H3), 7.41–7.51 (m, 2
H, H4, H6), 7.56 (s, 1 H, CHCl2), 8.22 (s, 1 H, =CH), 10.60 (s, 1 H, OH).
13C (DMSO-d6): 39.2, 63.9, 116.8, 117.1, 119.1, 124.8, 130.0, 133.6, 137.6,
150.1, 157.3, 189.8.
Me
N
N
23a
MS: 284 (M+, 26), 249 (40), 213 (83), 185 (32), 129 (16), 120 (100), 92 (20).
HRMS: [M+ – 1] calcd for C12H10Cl2N2O2: 283.0047; found: 283.0053.
177–179 IR: 1621 (w), 1581 (m), 1531 (m), 1485 (m).
O
OH
Cl2HC
1H (DMSO-d6): 6.96–7.05 (m, 2 H, H5, H3), 7.48–7.59 (m, 2 H, H4, H6), 7.61–
7.69 (m, 5 H, Ph), 7.73 (s, 1 H, CHCl2), 7.97 (s, 1 H, =CH), 10.80 (s, 1 H, OH).
13C (DMSO-d6): 59.3, 117.2, 119.3, 119.5, 124.4, 126.9, 129.2, 130.0, 130.8,
134.4, 138.8, 141.1, 142.0, 157.9, 191.1.
Ph
N
N
MS: 346 (M+, 20), 311 (24), 275 (21), 263 (M+ – CHCl2, 100), 247 (10), 191
(14), 155 (17), 120 (72), 92 (11), 77 (28), 65 (11).
23b
HRMS: m/z [M + 1]+ calcd for C17H12Cl2N2O2: 347.0349; found: 347.0354.
77
88
199–200 IR: 1661 (m), 1617 (s), 1597 (s), 1485 (m).
1H (DMSO-d6): 6.96–7.02 (m, 2 H), 7.32 (t, J = 7.1, 1 H), 7.48–7.57 (m, 4 H),
7.67 (s, 1 H, CHCl2), 7.88 (d, J = 8.0, 2 H), 8.20 (s, 1 H, Py), 10.62 (s, 1 H, OH).
13C (DMSO-d6): 68.8, 109.3, 117.2, 119.5, 120.0, 123.8, 124.8, 126.0, 129.2,
131.6, 135.1, 136.3, 137.0, 155.3, 156.8, 158.1, 158.2, 195.6.
MS: 413 (M+, 5), 78 (96), 63 (100), 44 (12).
OH
O
N
O
Ph
N
HRMS: m/z [M + 1]+ calcd for C20H13Cl2N3O3: 414.0407; found: 414.0409.
N
CHCl2
H
24a
178–179 IR: 1706 (w), 1622 (m), 1477 (m).
1H (DMSO-d6): 3.46 (s, 3 H, NMe), 6.94–7.00 (m, 2 H, H3¢, H5¢), 7.43–7.53 (m,
2 H, H6¢, H4¢), 7.67 (s, 1 H, CHCl2), 8.10 (s, 1 H, Py), 10.53 (s, 1 H, OH), 12.53
(br s, 1 H, NH).
OH
O
13C (DMSO-d6): 30.5, 68.9, 117.1, 119.4, 123.5, 124.1, 131.4, 134.9, 136.6,
153.4, 156.9, 157.3, 157.8, 172.0, 195.8.
O
Me
N
N
MS: 351 (M+, 64), 316 (M+ – Cl, 100), 281 (89), 268 (M+ – CHCl2, 96), 252 (26),
231 (11), 121 (88).
N
CHCl2
H
24b
HRMS: m/z [M + 1] calcd for C15H11Cl2N3O3: 352.0250; found: 352.0249.
78
179–181 IR: 1712 (w), 1599 (m), 1574 (m), 1495 (w), 1479 (w).
1H (DMSO-d6): 3.92 (s, 3 H, NMe), 6.95–7.01 (m, 2 H, H3¢, H5¢), 7.43–7.53 (m,
2 H, H6¢, H4¢), 7.74 (s, 1 H, CHCl2), 8.28 (s, 1 H, Py), 10.51 (s, 1 H, OH), 11.56
(br s, 1 H, NH).
OH
O
O
13C (DMSO-d6): 33.2, 69.3, 104.1, 117.2, 119.3, 122.7, 124.4, 131.4, 134.6,
134.9, 148.7, 153.6, 154.3, 157.8, 172.0, 196.5.
HN
N
MS: 351 (M+, 29), 316 (M+ – Cl, 100), 281 (74), 268 (M+ – CHCl2, 57), 252 (22),
196 (12), 121 (52).
N
CHCl2
Me
24c
HRMS: m/z [M + 1] calcd for C15H11Cl2N3O3: 352.0250; found: 352.0247.
Synthesis 2011, No. 3, 469–479 © Thieme Stuttgart · New York

PAPER
Synthesis of Fused a-(Formyl)pyridines
475
Table 1 Yields and Characteristic Data for Heteroannulated Pyridines (continued)
Product
Yielda (%) Mpb (°C) IR (ATR, cm–1), 1H and 13C NMR [d, J (Hz)], MS m/z (%), HRMS (ESI)
93
238–240 IR: 1621 (m), 1603 (s), 1550 (w), 1513 (s), 1483 (w).
1H (CDCl3): 3.80 (s, 3 H, MeO), 5.54 (s, 2 H, CH2), 6.85–6.93 (m, 3 H), 7.12 (d,
J = 8.3, 1 H), 7.21 (s, 1 H, CHCl2), 7.31 (dd, J = 8.2, 1.5, 1 H), 7.39–7.43 (m, 2
H), 7.55–7.61 (m, 1 H), 7.88 (s, 1 H, Py), 8.08 (s, 1 H, =CHN), 11.79 (s, 1 H,
OH).
OH
NC
O
13C (CDCl3): 49.1, 55.3, 68.6, 86.1, 113.9, 114.6, 118.9, 119.1, 119.4, 119.5,
125.7, 126.9, 129.6, 130.3, 133.3, 137.7, 137.8, 146.1, 150.6, 160.0, 163.7,
200.2.
N
PMB
24d
N
CHCl2
MS: 465 (M+, 22), 430 (14), 395 (25), 382 (M+ – CHCl2, 13), 121 (2-
HOC6H4CO, 100), 77 (19).
HRMS: m/z [M + 1] calcd for C24H17Cl2N3O3: 466.072; found: 466.0722.
84
174–176 IR: 2219 (m), 1621 (s), 1601 (m), 1553 (w), 1521 (w), 1480 (w).
1H (DMSO-d6): 1.15–2.10 (m, 10 H, 5 CH2), 4.71–4.86 (m, 1 H, NCH), 6.95–
7.02 (m, 2 H, H5¢, H3¢), 7.46 (dd, J = 7.8, 1.7, 1 H, H6¢), 7.53–7.58 (m, 1 H,
H4¢), 7.57 (s, 1 H, CHCl2), 8.20 (s, 1 H, Py), 8.90 (s, 1 H, =CHN), 10.77 (s, 1 H,
OH).
OH
NC
O
13C (DMSO-d6): 24.8, 25.1, 32.0, 55.2, 69.4, 84.0, 114.5, 117.4, 119.1, 119.4,
123.2, 126.5, 129.9, 132.1, 135.7, 139.3, 145.2, 149.0, 159.0, 197.2.
MS: 427 (M+, 12), 392 (81), 357 (23), 344 (M+ – CHCl2, 67), 309 (13), 275 (41),
262 (100), 246 (43), 207 (27), 121 (16).
N
c-Hex
24e
N
CHCl2
HRMS: m/z [M + 1]+ calcd for C22H19Cl2N3O2: 428.0927; found: 428.0924.
79
200–202 IR: 1624 (m), 1601 (m), 1519 (w), 1483 (w).
1H (DMSO-d6): 1.85 (s, 9 H, t-Bu), 6.95–7.02 (m, 2 H), 7.48 (dd, J = 7.8, 1.6, 1
H), 7.52–7.58 (m, 1 H), 7.60 (s, 1 H, CHCl2), 8.17 (s, 1 H, Py), 8.80 (s, 1 H,
=CHN), 10.75 (s, 1 H, OH).
OH
NC
13C (DMSO-d6): 28.5, 59.3, 69.5, 83.1, 114.7, 117.4, 119.4, 120.2, 123.2, 125.8,
129.7, 132.0, 135.6, 139.7, 145.8, 148.3, 158.9, 197.1.
O
MS: 401 (M+, 10), 366 (36), 318 (40), 310 (28), 275 (32), 274 (32), 262 (100),
246 (32), 218 (11), 121 (10).
N
t-Bu
N
CHCl2
HRMS: m/z [M]+ calcd for C20H17Cl2N3O2: 401.0669; found: 401.0670.
24f
69
86
73
205-206
IR: 1620 (m), 1592 (m), 1559 (w), 1510 (w), 1497 (w), 1482 (w).
1H (DMSO-d6): 2.61 (s, 3 H, Me), 6.96–7.03 (m, 2 H), 7.34–7.40 (m, 1 H), 7.51–
7.64 (m, 5 H), 8.36 (dd, J = 8.7, 0.9, 2 H), 8.53 (s, 1 H, Py), 10.81 (s, 1 H, OH).
13C (DMSO-d6): 12.2, 69.5, 116.2, 117.5, 119.4, 119.9, 123.0, 126.0, 128.3,
129.3, 132.1, 133.5, 135.8, 138.6, 144.5, 148.8, 153.5, 159.2, 196.8.
MS: 411 (M+, 74), 376 (90), 341 (99), 328 (M+ – CHCl2, 100), 312 (41), 291
(32), 256 (21), 179 (12), 121 (25), 77 (43).
OH
O
N
N
N
CHCl2
Ph
HRMS: m/z [M + 1] calcd for C21H15Cl2N3O2: 412.0614; found: 412.0618.
24g
233–235 IR: 1735 (w), 1624 (m), 1598 (m), 1500 (m), 1483 (w).
1H (CDCl3): 3.56 (s, 3 H, Me), 6.88 (t, J = 7.1, 1 H), 6.97–7.05 (m, 2 H), 7.32
(s, 1 H, CHCl2), 7.48 (d, J = 8.0, 1 H), 7.58–7.64 (m, 5 H), 8.00 (s, 1 H, Py),
11.03 (s, 1 H, OH).
OH
Me
13C (DMSO-d6): 31.4, 69.2, 116.4, 117.7, 119.4, 122.2, 126.4, 127.8, 128.4,
129.0, 129.1, 132.6, 134.2, 136.5, 145.8, 146.7, 160.1, 173.3, 197.1.
MS: 444 (M+, 7), 373 (59), 360 (M+ – CHCl2, 100), 344 (24), 298 (10).
HRMS: m/z [M + 1] calcd for C21H15Cl2N3O2S: 444.0335; found: 444.0334.
N
O
S
N
N
CHCl2
Ph
24h
244–245 IR: 1620 (w), 1602 (m), 1556 (s), 1505 (w), 1478 (w).
1H (DMSO-d6): 3.25 (s, 6 H, 2 Me), 6.93–7.00 (m, 2 H, H5¢, H3¢), 7.42 (dd,
J = 7.8, 1.6, 1 H, H6¢), 7.51 (s, 1 H, CHCl2), 7.48–7.54 (m, 1 H, H4¢), 8.29 (s, 1
H, Py), 10.64 (s, 1 H, OH).
OH
13C (DMSO-d6): 39.8, 69.4, 117.3, 119.3, 123.1, 123.8, 125.9, 131.5, 131.6,
135.0, 151.7, 158.3, 165.4, 172.6, 196.6.
S
O
CHCl2
Me2N
N
MS: 381 (M+, 35), 346 (73), 311 (69), 298 (M+ – CHCl2, 100), 282 (64), 268
(12), 263 (14), 261 (21), 226 (15), 121 (11).
N
24i
HRMS: m/z [M]+ m/z [M + 1] calcd for C16H13Cl2N3O2S: 382.0178; found:
382.0181.
Synthesis 2011, No. 3, 469–479 © Thieme Stuttgart · New York

476
V. O. Iaroshenko et al.
PAPER
Table 1 Yields and Characteristic Data for Heteroannulated Pyridines (continued)
Yielda (%) Mpb (°C) IR (ATR, cm–1), 1H and 13C NMR [d, J (Hz)], MS m/z (%), HRMS (ESI)
Product
70
226–228 IR: 1620 (w), 1599 (w), 1544 (m), 1505 (m), 1485 (m).
1H (CDCl3): 3.72–3.76 (m, 8 H), 6.93–7.00 (m, 2 H, H5¢, H3¢), 7.43 (dd, J = 7.8,
1.6, 1 H, H6¢), 7.49–7.52 (m, 2 H, CHCl2, H4¢), 8.33 (s, 1 H, Py), 10.64 (s, 1 H,
OH).
OH
13C (CDCl3): 48.7, 66.2, 68.3, 118.8, 119.3, 119.6, 123.1, 125.2, 129.7, 133.1,
137.6, 152.7, 163.4. 165.5, 172.0, 199.8.
S
N
O
O
N
MS: 423 (M+, 33), 390 (25), 389 (21), 388 (70), 387 (20), 354 (11), 353 (48),
352 (21), 342 (15), 341 (47), 340 (M+ – CHCl2, 100), 324 (32), 303 (14), 296
(16), 266 (12), 246 (11), 121 (14).
N
CHCl2
24j
HRMS: m/z [M + 1]+ calcd for C18H15Cl2N3O3S: 424.0827; found: 424.0286.
74
263–264 IR: 1617 (m), 1594 (w), 1538 (s), 1503 (m), 1482 (w).
1H (CDCl3): 1.72 (m, 6 H), 3.73 (m, 4 H), 6.84 (td, J = 8.1, 1.0, 1 H, H5¢), 7.01
(s, 1 H, CHCl2), 7.06 (dd, J = 8.4, 0.7, 1 H, H3¢), 7.32 (dd, J = 8.0, 1.6, 1 H, H6¢),
7.49–7.54 (m, 1 H, H4¢), 7.81 (s, 1 H, Py), 11.78 (s, 1 H, OH).
13C (CDCl3): 24.0, 25.4, 50.0, 68.4, 118.7, 119.2, 119.6, 122.4, 125.4, 129.2,
133.1, 137.4, 152.5, 163.3, 166.1, 171.5, 199.9.
OH
S
O
N
N
MS: 421 (M+, 16), 386 (22), 351 (81), 338 (M+ – CHCl2, 100), 322 (47), 295
(16), 268 (13), 121 (14), 84 (13), 69 (16).
N
CHCl2
24k
HRMS: m/z [M + 1]+ calcd for C19H17Cl2N3O2S: 422.0491; found: 422.0494.
69
237–238 IR: 3176 (w), 3051 (w), 1682 (s), 1603 (s), 1574 (s), 1504 (w), 1481 (m).
1H (DMSO-d6): 6.96–7.01 (m, 2 H), 7.45–7.54 (m, 2 H), 7.56 (s, 1 H, CHCl2),
8.20 (s, 1 H, Py), 10.59 (s, 1 H, OH), 11.68 (s, 1 H, NH), 12.28 (s, 1 H, NH).
13C (DMSO-d6): 68.1, 110.4, 117.2, 119.5, 123.8, 126.0, 131.4, 135.3, 139.5,
150.2, 153.6, 158.0, 158.1, 161.2, 194.8.
O
OH
HN
O
MS: 366 (M+, 2), 330 (69), 295 (62), 282 (M+ – CHCl2, 100), 266 (11), 239 (11),
223 (7), 196 (8), 121 (22), 69 (14), 57 (10), 44 (15).
O
N
H
N
CHCl2
HRMS: m/z [M – 1]+ calcd for C15H9Cl2N3O4: 363.9897; found: 363.9914.
24l
71
235–236 IR: 3330 (w), 3035 (w), 1732 (m), 1699 (s), 1596 (s), 1567 (m), 1475 (m).
1H (DMSO-d6): 3.58 (s, 3 H, Me), 6.97–7.01 (m, 2 H, H5¢, H3¢), 7.46 (dd,
J = 8.1 1.7, 1 H, H6¢), 7.51–7.57 (m, 1 H, H4¢), 7.62 (s, 1 H, CHCl2), 8.32 (s, 1
H, Py), 10.57 (s, 1 H, OH), 11.94 (s, 1 H, NH).
O
OH
HN
O
13C (DMSO-d6): 28.5, 68.4, 111.5, 117.2, 119.5, 123.6, 125.6, 131.4, 135.3,
139.6, 150.5, 152.8, 157.4, 157.9, 160.2, 194.6.
MS: 380 (M+, 2), 344 (42), 309 (52), 296 (M+ – CHCl2, 100), 280 (12), 121 (21).
HRMS: m/z [M]+ calcd for C16H11Cl2N3O4: 379.0121; found: 379.0115.
O
N
N
CHCl2
Me
24m
77
196–197 IR: 1712 (m), 1666 (m), 1656 (m), 1628 (m), 1601 (s), 1572 (m), 1485 (m).
1H (DMSO-d6): 3.28 (s, 3 H, Me), 3.66 (s, 3 H, Me), 6.96–7.01 (m, 2 H, H5¢,
H3¢), 7.47 (dd, J = 8.2, 1.6, 1 H, H6¢), 7.51–7.57 (m, 1 H, H4¢), 7.61 (s, 1 H,
CHCl2), 8.25 (s, 1 H, Py), 10.57 (s, 1 H, OH).
O
N
OH
Me
O
13C (DMSO-d6): 28.5, 29.4, 68.4, 110.6, 117.2, 119.5, 123.6, 125.9, 131.4,
135.4, 140.1, 150.8, 151.4, 157.3, 158.0, 160.0, 194.5.
N
O
MS: 394 (M+, 3), 358 (99), 310 (M+ – CHCl2, 100), 294 (21), 120 (44), 69 (11).
HRMS: m/z [M]+ calcd for C17H13Cl2N3O4: 393.0278; found: 393.0271.
N
CHCl2
Me
24n
72
188–189 IR: 1620 (s), 1600 (s), 1571 (m), 1480 (w).
1H (DMSO-d6): 3.92 (s, 3 H, MeO), 3.99 (s, 3 H, MeO), 6.80 (s, 1 H), 6.96–7.01
(m, 2 H, H5¢, H3¢), 7.16 (s, 1 H), 7.47–7.53 (m, 2 H, H6¢, H4¢), 7.70 (s, 1 H,
CHCl2), 8.41 (s, 1 H, Py), 10.55 (s, 1 H, OH).
OMe
OH
13C (DMSO-d6): 56.1, 56.4, 69.3, 93.7, 100.3, 114.3, 117.2, 119.4, 123.9, 125.5,
131.5, 134.0, 135.0, 149.7, 154.1, 156.0, 158.1, 163.9, 196.5.
MS: 391 (M+, 47), 356 (M+ – Cl, 100), 339 (10), 321 (49), 292 (21), 271 (42),
236 (22), 206 (12), 121 (23), 65 (13).
O
MeO
N
CHCl2
24o
HRMS: m/z [M + 1]+ calcd for C19H15Cl2NO4: 392.0451; found: 392.0457.
Synthesis 2011, No. 3, 469–479 © Thieme Stuttgart · New York

PAPER
Synthesis of Fused a-(Formyl)pyridines
477
Table 1 Yields and Characteristic Data for Heteroannulated Pyridines (continued)
Product
Yielda (%) Mpb (°C) IR (ATR, cm–1), 1H and 13C NMR [d, J (Hz)], MS m/z (%), HRMS (ESI)
60
186–188 IR: 1614 (w), 1576 (m), 1505 (m), 1479 (w).
1H (DMSO-d6): 3.14 (s, 6 H, 2 Me), 6.94–7.02 (m, 2 H), 7.05 (d, J = 2.5, 1 H),
7.37 (dd, J = 9.2, 2.5, 1 H), 7.44–7.54 (m, 2 H), 7.71 (s, 1 H, CHCl2), 7.89 (d,
J = 9.2, 1 H), 8.25 (s, 1 H, Py), 10.61 (s, 1 H, OH).
OH
O
13C (DMSO-d6): 39.9, 69.7, 104.7, 117.2, 118.0, 118.2, 119.3, 123.4, 124.0,
129.8, 131.5, 134.7, 139.8, 149.4, 153.0, 153.7, 158.3, 197.0.
MS: 374 (M+, 100), 339 (37), 322 (18), 291 (54), 207 (18), 137 (17).
HRMS: m/z [M]+ calcd for C19H16Cl2N2O2: 374.0655; found: 374.0658.
Me2N
N
CHCl2
24p
72
169–171 1H (DMSO-d6): 3.82 (s, 3 H, MeO), 5.51 (s, 2 H, CH2), 6.92–6.98 (m, 3 H), 7.23
(d, J = 8.1, 1 H), 7.39 (dd, J = 8.0, 1.4, 1 H), 7.42–7.48 (m, 2 H), 7.57–7.63 (m,
1 H), 7.93 (s, 1 H, Py), 8.18 (s, 1 H, =CHN), 10.09 (s, 1 H, CHO), 11.79 (s, 1 H,
OH).
OH
NC
13C (DMSO-d6): 49.1, 55.3, 86.5, 114.6, 114.9, 119.2, 119.9, 120.4, 120.6,
125.8, 127.0, 129.9, 130.6, 133.7, 138.1, 138.4, 146.2, 150.6, 160.6, 164.0,
192.0, 200.2.
O
N
PMB
26a
N
CHO
MS: 411 (M+, 32), 380 (24), 354 (31), 325 (13), 248 (100).
HRMS: m/z [M + 1]+ calcd for C24H17N3O4: 412.1256; found: 412.1253.
81
155–157 1H (DMSO-d6): 2.63 (s, 3 H, Me), 7.02–7.11 (m, 2 H), 7.40–7.48 (m, 1 H), 7.61–
7.68 (m, 4 H), 8.51 (dd, J = 8.4, 1.0, 2 H), 8.43 (s, 1 H, Py), 10.08 (s, 1 H, CHO),
10.81 (s, 1 H, OH).
OH
13C (DMSO-d6): 12.2, 117.2, 118.5, 119.9, 120.1, 123.6, 126.4, 128.9, 130.2,
132.4, 133.9, 136.1, 138.8, 145.5, 149.0, 153.5, 159.3, 191.8, 196.8.
MS: 357 (M+, 34), 342 (80), 325 (79), 296 (100), 312 (41), 219 (42), 191 (21).
HRMS: m/z [M + 1]+ calcd for C21H15N3O3: 358.1161; found: 358.1162.
O
CHO
N
N
N
Ph
26b
70
183–184 1H (DMSO-d6): 3.55 (s, 3 H, Me), 6.93 (t, J = 7.2, 1 H), 7.00–7.07 (m, 2 H), 7.61
(d, J = 8.1, 1 H), 7.61–7.69 (m, 5 H), 8.22 (s, 1 H, Py), 10.08 (s, 1 H, CHO),
11.03 (s, 1 H, OH).
OH
Me
13C (DMSO-d6): 31.4, 116.9, 118.7, 119.3, 123.2, 126.4, 129.0, 129.4, 130.0,
131.1, 132.6, 134.2, 137.5, 145.8, 146.7, 161.1, 173.3, 192.2, 197.1.
MS: 389 (M+, 5), 312 (39), 297 (100), 268 (10).
N
O
S
N
HRMS: m/z [M + 1]+ calcd for C21H15N3O3S: 390.0688; found: 390.0689.
N
CHO
Ph
26c
65
80
143–145 1H (DMSO-d6): 1.73 (m, 6 H), 3.75 (m, 4 H), 6.79 (td, J = 8.0, 0.9, 1 H, H5¢),
7.11 (dd, J = 8.3, 0.8, 1 H, H3¢), 7.42 (dd, J = 8.0 1.6, 1 H, H6¢), 7.51–7.57 (m,
1 H, H4¢), 7.91 (s, 1 H, Py), 10.11 (s, 1 H, CHO), 11.70 (s, 1 H, OH).
13C (DMSO-d6): 24.0, 25.4, 50.0, 119.7, 120.2, 120.8, 122.9, 126.4, 129.9,
134.1, 138.4, 152.6, 163.3, 166.9, 171.5, 191.6, 199.9.
OH
S
N
O
MS: 367 (M+, 16), 338 (32), 321 (71), 244 (100), 216 (46).
N
HRMS: m/z [M + 1]+ calcd for C19H17N3O3S: 368.1223; found: 368.1229.
N
CHO
26d
221–223 1H (DMSO-d6): 3.30 (s, 3 H, Me), 3.70 (s, 3 H, Me), 7.01–7.07 (m, 2 H, H5¢,
H3¢), 7.51 (dd, J = 8.1, 1.5, 1 H, H6¢), 7.54–7.59 (m, 1 H, H4¢), 8.33 (s, 1 H, Py),
10.02 (s, 1 H, CHO), 10.59 (s, 1 H, OH).
O
OH
13C (DMSO-d6): 28.5, 29.4, 110.6, 117.4, 119.8, 124.2, 126.2, 131.6, 135.9,
141.2, 151.1, 152.1, 157.9, 158.1, 160.0, 192.7, 194.5.
Me
O
N
O
MS: 339 (M+, 9), 324 (69), 309 (100), 292 (23), 263 (14).
HRMS: m/z [M]+ calcd for C17H13N3O5: 339.0986; found: 339.0988.
N
N
CHO
Me
26e
77
223–225 1H (DMSO-d6): 3.98 (s, 3 H, MeO), 4.00 (s, 3 H, MeO), 6.87 (s, 1 H), 7.01–7.06
(m, 2 H, H5¢, H3¢), 7.25 (s, 1 H), 7.51–7.58 (m, 2 H, H6¢, H4¢), 8.36 (s, 1 H, Py),
10.13 (s, 1H, CHO), 10.55 (s, 1 H, OH).
OMe
OH
13C (DMSO-d6): 56.1, 56.4, 94.7, 100.9, 114.7, 117.6, 119.7, 124.2, 125.9,
132.1, 134.0, 135.6, 150.1, 154.1, 156.0, 158.2, 163.9, 191.6, 196.5.
MS: 337 (M+, 27), 306 (40), 370 (100), 253 (36), 224 (12), 196 (11).
HRMS: m/z [M]+ calcd for C19H15NO5: 337.1229; found: 337.1227.
O
MeO
N
CHO
26f
a Yields refer to pure isolated product.
b Melting points are uncorrected.
Synthesis 2011, No. 3, 469–479 © Thieme Stuttgart · New York

478
V. O. Iaroshenko et al.
PAPER
Heteroannulated Pyridines 24 in Acetic Acid; General Proce-
dure
In summary, we have reported the first synthesis of 3-
(dichloroacetyl)chromone. The one-pot cyclocondensa-
tion reaction of this new building block with electron-rich
aminoheterocycles afforded a variety of fused a-
(formyl)pyridines.
3-(Dichloroacetyl)-4H-1-benzopyran-4-one (22, 310 mg, 1.2
mmol) and the corresponding amine (1.56 mmol) were dissolved in
AcOH (20 mL) and heated under reflux in an inert atmosphere for
2–5 h (controlled by TLC). Then the soln was evaporated under re-
duced pressure, treated with H2O, filtered, dried in air, and recrys-
tallized from an appropriate solvent or subjected to column
chromatography (silica gel).
All solvents were purified and dried by standard methods. NMR
spectra were recorded on a Jeol JNM-LA 400, Varian VXR-300, or
Varian Mercury-400, Bruker 600 spectrometer: 1H and 13C signals
(300, 400 and 100 MHz, respectively) were recorded with TMS as
an internal standard; 19F (282.2 and 376.2 MHz) with CFCl3 as in-
ternal standard. IR spectra were recorded on a Perkin Elmer FT IR
1600 spectrophotometer for samples in KBr discs. Mass spectra
were obtained on a Hewlett-Packard HP GC/MS 5890/5972 instru-
ment (EI, 70 eV) by GC inlet or on a MX-1321 instrument (EI, 70
eV) by direct inlet. Column chromatography was performed on sil-
ica gel (63–200 mesh, Merck). Silica gel Merck 60F254 plates were
used for TLC.
Heteroannulated Pyridines 24 in DMF/TMSCl; General Proce-
dure
In the pressure tube, amine (1.56 mmol) and 3-(dichloroacetyl)-4H-
1-benzopyran-4-one (22, 310 mg, 1.2 mmol) in an inert atmosphere
were dissolved in anhyd DMF (8 mL) and TMSCl (1 mL) was add-
ed. The mixture was heated at 100 °C for 5–7 h (controlled by TLC).
Then the soln was evaporated under reduced pressure, treated with
H2O, filtered, dried in air, and recrystallized from an appropriate
solvent or subjected to column chromatography (silica gel).
a-Formylpyridines 18–21, 26; General Procedure
Heteroannulated Pyridines 12–15; General Procedure
Fused pyridine 24 (1 mmol) and KOH (4 mmol) were dissolved in
MeOH (10 mL) and heated under reflux for 2 h (under argon atmo-
sphere). Then the mixture was diluted with 10 M HCl (5 mL), the
solid that formed was washed with H2O, filtered, dried under vacu-
um at 60 °C for 3 h, and recrystallized from an appropriate solvent
or subjected to column chromatography (silica gel).
The heterocyclic amine (4 mmol) and 11 (0.81 g, 4.4 mmol) were
dissolved in anhyd DMF (10 mL) and heated under an inert atmo-
sphere at 120 °C for 12 h. The soln was evaporated under reduced
pressure, treated with H2O, dried under reduced pressure, and the
residue was subjected to column chromatography (silica gel).
1-tert-Butyl-5-{[(Z)-4,4-dichloro-3-oxobut-1-enyl]amino}-1H-
pyrrole-3-carbonitrile (16)
2-Amino-1-tert-butyl-1H-pyrrole-4-carbonitrile (2c, 0.66 g,
References
4
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mL) and heated under an inert atmosphere at 60 °C for 12 h. The
soln was evaporated under reduced pressure, treated with H2O,
dried under reduced pressure, and the residue was subjected to col-
umn chromatography (silica gel).
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Synthesis 2011, No. 3, 469–479 © Thieme Stuttgart · New York