Skeletal diverse synthesis of N-fused polycyclic heterocycles via the sequence of Ugi-type MCR and CuI-catalyzed coupling/tandem Pictet-Spengler reaction

Article abstract of DOI:10.1021/jo202255v

Several diversity-oriented syntheses of N-fused polycyclic heterocycles have been demonstrated but most of them are based on point diversity within the same library and usually involve time-consuming sequential multistep syntheses, which also suffer from

Full text of DOI:10.1021/jo202255v

Article
pubs.acs.org/joc
Skeletal Diverse Synthesis of N-Fused Polycyclic Heterocycles
via the Sequence of Ugi-Type MCR and CuI-Catalyzed
Coupling/Tandem Pictet−Spengler Reaction
Vikas Tyagi,† Shahnawaz Khan,† Vikas Bajpai,† Harsh M. Gauniyal,‡ Brijesh Kumar,‡
and Prem M. S. Chauhan*,†
†Medicinal and Process Chemistry Division and ‡Sophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute,
Lucknow 226 001, India
S
* Supporting Information
ABSTRACT: Several diversity-oriented syntheses of N-fused
polycyclic heterocycles have been demonstrated but most of
them are based on point diversity within the same library and
usually involve time-consuming sequential multistep syntheses,
which also suffer from low yields and/or poor precursor
scopes. We have developed a new strategy for the syntheses of
skeletal diverse N-fused polycyclic compounds via an Ugi-type
MCR followed by a CuI-catalyzed coupling reaction or tandem
Pictet−Spengler reaction. This two-step sequence provides
eight distinct skeleton of fused {6−5−5−6}, {5−5−5−6}, {6−5−6−6}, and {5−5−6−6} ring systems that have applications in
medicinal chemistry and chemical genetics too.
untoward number of aromatic rings in the context of their
ability to provide a quality medicinal chemistry leads.
Several natural products inspired diversity-oriented synthesis of
N-fused polycyclic heterocycles have been demonstrated, but
most of them are based on point diversity within the same library6
and usually involve a time-consuming sequential multistep
synthesis and also suffer from low yields and/or poor precursor
scopes.7
Recently, isocyanide-based multicomponent reactions
(IMCR) followed by other synthetic transformations emerged
as a powerful tool for creating fused multicyclic skeletons.8 As a
part of our program to discover novel heterocycles as anti-
infective agents9 and encouraged by the skeletal diversity of
N-rich polycyclic compounds, we report our efforts toward the
synthesis of skeletal diverse N-fused polycyclic heterocycles
through an Ugi-type MCR (Groebke−Blackburn−Bienayme
reaction)10 (Figure 2) coupled with Cu-catalyzed intramolecular
INTRODUCTION
■
Diversity-oriented synthesis (DOS) with an emphasis on
skeletal diversity has been developed for rapid access to natural
product and druglike small molecules with complex and diverse
molecular structures.1 Pioneering work in skeletal DOS has
been done by Schreiber and co-workers to establish a diverse
collection of nitrogen-containing small molecules with
application in drug discovery and chemical genetics.2 Nitrogen-
containing polycyclic molecules and analogues have attracted
much attention due to their presence in biologically active
natural products and pharmaceuticals. These N-fused poly-
cycles displayed a wide range of biological activities (antifungal/
antibacterial, antineoplastic, anticancer, antiplasmodial, DNA
intercalators).3 For example, columbamine 1, an isoquinoline
alkaloid, showed antiplasmodial, antiamoebic, and cytotoxic
activities; cryptolepine 2 and quindoline 3 are potent anti-
plasmodial indole alkaloids (Figure 1).4 On the other hand, the
Figure 2. Groebke−Blackburn−Bienayme MCR.
C−N bond formation or in situ cyclization through the Pictet−
Spengler reaction.
Figure 1. Some biologically active N-fused polycyclic heterocycles.
N-fused aromatic polycyclic systems having the ability to
increase the DNA intercalation properties5 and contain an
Received: November 2, 2011
Published: January 10, 2012
© 2012 American Chemical Society
1414
dx.doi.org/10.1021/jo202255v | J. Org. Chem. 2012, 77, 1414−1421

The Journal of Organic Chemistry
Article
We envisaged that substrates containing halogen function-
alities such as product 5 can undergo CuI-catalyzed intra-
molecular cyclization for the synthesis of 4, whereas polycyclic
heterocycle 9 can be obtained by the tandem Pictet-Spengler
reaction of 10 and aldehydes. IMCR products 5 and 10 can be
obtained by the reaction of aldehyde, isocyanide and aromatic
heterocyclic 2-aminoazines (Figure 3).
Table 1. Survey of the Reaction Condition for Cu-Catalyzed
Coupling Reaction
a
b
entry
catalyst
ligand
base
yield (%)
c
1
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
0
2
CuTC
CuI
L2
L1
L2
L2
L2
L3
L4
L5
L2
L2
16
45
22
34
72
60
32
16
51
3
4
CuBr
CuI
Figure 3. Retrosynthetic analysis.
5
6
CuI
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
7
RESULTS AND DISCUSSION
■
8
CuI
Initially, the syntheses of Ugi type products 14a−m and 17a−g
(Tables 3 and 5) were achieved by the condensation of
aromatic heterocyclic 2-aminoazines, aldehydes, and isocya-
nides in methanol catalyzed by PTSA (Scheme 1).11
9
CuI
10
11
CuI
d
CuI
Cs2CO3
50
a
Reaction conditions: substrate 14a (1 mmol), catalyst (10 mol %),
Once these IMCR products were synthesized, a set of
experiments were carried out using 14a as the model substrate
to optimize reaction conditions for the metal-catalyzed
intramolecular cyclization reaction, including catalysts, bases,
and solvents. CuI was the best catalyst among all the three
copper catalysts tested as shown in Table 1. Subsequently, the
effect of ligands was further investigated; 1,10-phenanthroline
was found as the most efficient ligand to push the reaction
forward. Cs2CO3 emerged as base of choice for the coupling
reaction among the several bases used (Table 1). When loading
of catalyst was decreased from 10 to 5 mol %, lowering of the
yield from 72% to 50% (Table 1, entry 11) was observed. The
effect of solvent was also investigated, and DMF was found to
be the best solvent at 120 οC (Table 2). Further, the optimized
conditions equally applied for the synthesis of a wide variety of
N-fused polycyclic heterocycles 15a−m starting from IMCRs
14a−m (Table 3).Very good yields were observed for the
ligand (10 mol %), base (2 mmol), solvent (2 mL) under nitrogen
ο
atmosphere, reaction temperature (120 C), reaction time (2 h),
b
c
d
Isolated yield. No addition of catalyst. Loading of catalyst (5 mol %).
2-aminopyridine- and 2-aminopiperazine-based IMCRs 14a−f,
whereas moderate yield of product was obtained in the case of
2-aminopyrimidine- and 2-aminotrizole-based IMCRs 14g and
14h (Table 3).
In recent years, Domling et al. reported an Ugi reaction
(IMCR) followed by a Pictet−Spengler reaction as a powerful
tool for the synthesis of N-fused polycyclic heteocycles.12
Therefore, our aim was shifted toward diversity generation by
the use of Pictet−Spengler reaction. Removal of the tert-butyl
group in IMCR by TFA13 inspired us to use TFA for the efficient
transformation through Pictet−Spengler reaction. In the first
instance, substrate 17a was subjected to 4-methoxybenzaldehyde
using several acidic protocols (Table 4).
Scheme 1. Two Step Synthesis of N-Fused Polycyclic Heterocycles
1415
dx.doi.org/10.1021/jo202255v | J. Org. Chem. 2012, 77, 1414−1421

The Journal of Organic Chemistry
Article
Table 2. Screening of Solvent for Coupling Reaction
Table 4. Optimization of Acidic Protocols for Pictet−
Spengler Reaction
entry
solvent
conversion (%)
1
2
3
4
5
DMSO
dioxane
DMF
56
63
72
52
38
entry
solvent
TFA (%)
yields (%)
1
2
3
4
5
DCM
DCM
DCE
DCE
THF
20
50
20
50
50
NR
30
26
71
59
NMP
toluene
It has been found that 50% TFA in DCE at reflux was the
optimal condition for the tandem Pictet−Spengler reaction. We
next explored the efficacy of IMCRs 17a−g (Table 5) to
undergo π-cyclizations with a variety of aldehydes. The electron-
rich trimethoxybenzaldehyde-derived products 17a−e were
found to be reactive in the subsequent Pictet−Spengler ring
closure, and both the 4-chlorobenzaldehyde- and p-anisalde-
hyde-derived products 17f and 17g were observed not to afford
the desired Pictet−Spengler products and instead led only to the
loss of the tert-butyl group to afford 20a and 20b. An interesting
feature of this unique tandem reaction involves de-tert-
butylation, π-cyclization, and aromatization. To the best of our
knowledge, there is no report available on this type of tandem
Pictet−Spengler sequence.
a
Table 3. Two-Step Synthesis of IMCR-Coupling Product
a
Reaction conditions: under nitrogen atmosphere, substrate 14 (1 mmol), CuI (10 mol %), L2 (10 mol %), Cs2CO3 (2 mmol), DMF (2 mL),
b
120 οC, 2−4 h. Isolated yield.
1416
dx.doi.org/10.1021/jo202255v | J. Org. Chem. 2012, 77, 1414−1421

The Journal of Organic Chemistry
Article
a
Table 5. Two-Step Synthesis of IMCR−PS Product
a
b
c
Reaction conditions: substrate 1 (1 mmol), aromatic aldehyde (1.2 mmol), 50% TFA in DCE (5 mL), reflux, 5−6 h. Isolated yield. Only de-tert-
butylated products 20a and 20b were observed; PS = Pictet−Spengler reaction.
was performed over silica gel (230−400 flash). All compounds were
CONCLUSION
■
1
characterized by TLC, H NMR and 13C NMR, MS, and HRMS.
In summary, we have developed a highly efficient approach
for the synthesis of eight distinct skeletal frameworks of fused
{6−5−5−6}, {5−5−5−6}, {6−5−6−6}, and {5−5−6−6} ring
systems of N-rich polycyclic heterocycles via the IMCR-CuI
catalyzed/tandem Pictet−Spengler reaction sequence. This
synthetic approach has various prominent features such as less
reaction steps, good yields and operational simplicity, ultimately
leading to a diverse array of medicinally relevant N-fused
heterocycles. Biological screening of synthesized compounds are
currently under progress in our lab and will be reported in due
course.
General Procedure for the Synthesis of IMCR Products 14a−
m and 17a−g. To the solution of the aromatic heteroarylamine
(1 mmol) and aromatic benzaldehyde (1.2 mmol) in methanol (3 mL)
was added isocyanide (1 mmol) through a microsyringe at room
temperature, and then p-toluenesulfonic acid (20 mol %) was added.
After stirring at room temperature for 15−18 h, the solvent was
removed to obtain crude products on which purification by flash column
chromatography on silica gel (eluent: hexane/EtOAc) afforded Ugi type
product 14a−m and 17a−g in 62−93% yields.
General Procedure for the Synthesis of Coupling Products
15a−m. CuI (10 mol %), 1,10-phenanthroline (10 mol %), Ugi-type
product (14a−m) (1 mmol), and DMF (2 mL) as a solvent were
added to a dry Schlenk tube under nitrogen. The reaction mixture was
stirred and heated at 120 °C for 2−4 h. After completion of the
reaction as indicated by TLC, the resulting mixture was cooled to
room temperature and filtered through a pad of Celite, and the Celite
was rinsed with EtOAc. The solvent was evaporated under reduced
pressure, and the residue was purified by flash column chromatography
on silica gel (eluent: hexane/EtOAc) to afford the corresponding
polycyclic products 15a−m in 49−72% yields.
EXPERIMENTAL SECTION
■
General Experimental Procedures. All reagents and solvents
were purchased from commercial sources and used without purifi-
cation. NMR spectra were recorded with a 200, 300, and
400 MHz spectrometers for H NMR and 50 and 75 MHz for 13C
1
NMR in deuterated solvents with TMS as internal reference (chemical
shifts δ in ppm, coupling constant J in Hz). Multiplicities are reported
as follows: singlet (s), doublet (d), triplet (t), quartet (q), multiplet
(m), and broad singlet (br, s). Melting points were determined in open
capillary tubes on an electrically heated block and are uncorrected.
Mass spectra and HRMS were taken in the ESI positive-ion mode. The
reaction progress was routinely monitored by thin-layer chromatog-
raphy (TLC) on precoated silica gel plates. Column chromatography
General Procedure for the Synthesis of Pictet−Spengler
Products 19a−k. IMCR adduct (17a−g) (1 mmol) was dissolved in
50% TFA in DCE (5 mL), the corresponding aromatic aldehyde
(1.2 mmol) was added, and the reaction mixture was stirred and
refluxed for 5−6 h. The completion of tandem Pictet−Spengler
cyclization was monitored by TLC. After completion, the reaction
mixture was evaporated, and the residue so obtained was neutralized
with saturated NaHCO3. It was then extracted with EtOAc (20 mL),
1417
dx.doi.org/10.1021/jo202255v | J. Org. Chem. 2012, 77, 1414−1421

The Journal of Organic Chemistry
Article
and the combined organic layer was washed with water (10 mL) and
dried over sodium sulfate. EtOAC was evaporated to dryness under
reduced pressure, and the crude obtained was purified by column
chromatography (eluent: CHCl3/MeOH) to afford cyclized products
19a−k in 51−68% yield.
(s, 1H), 1.68−1.51 (m, 5H), 1.12−0.99 (m, 5H) ppm; 13C NMR
(75 MHz, CDCl3) δ 141.2, 139.5, 136.5, 132.9, 132.7, 132.6, 129.2,
127.3, 121.7, 117.1, 111.9, 57.1, 33.7, 25.4, 24.5 ppm; HRMS (ESI)
calcd for C17H19BrN3S [M + H]+ 376.0483, found 376.0530.
1
Compound 14k: oil; yield 87% H NMR (300 MHz, CDCl3) δ
Characterization of Compounds. Compound 14a: solid;
7.65 (d, J = 7.8 Hz, 1H), 7.42−7.28 (m, 4H), 6.79 (d, J = 4.2 Hz, 1H),
2.88 (t, J = 6.6 Hz, 2H), 1.51−1.41(m, 2H), 1.25−1.17 (m, 2H), 0.80
(t, J = 6.9 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 144.1, 141.3,
139.5, 132.8, 132.7, 132.6, 129.2, 127.3, 123.1, 116.8, 112.1, 48.6, 32.2,
19.8, 13.7 ppm; HRMS (ESI) calcd for C15H17BrN3S [M + H]+
350.0327, found 350.0339.
1
yield 93%; mp = 127−130 οC; H NMR (300 MHz, CDCl3) δ 8.33
(d, J = 6.9 Hz, 1H), 7.68−7.63 (m, 2H), 7.57 (d, J = 9.0 Hz, 1H), 7.43
(t, J = 6.9 Hz, 1H), 7.26−7.14 (m, 2H), 6.82 (t, J = 6.3 Hz, 1H), 3.22
(br s, 1H), 0.93(s, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ 141.9,
139.0, 136.7, 133.0, 132.6, 129.4, 127.4, 124.6, 124.3, 123.6, 122.6,
117.3, 111.4, 55.7, 29.9 ppm; HRMS (ESI) calcd for C17H19BrN3 [M +
H]+ 344.0762, found 344.0731.
1
Compound 14l: solid; yield 86%; mp = 120−125 °C; H NMR
(300 MHz, CDCl3) δ 8.19 (d, J = 6.9 Hz, 1H), 7.67 (t, J = 7.8 Hz,
2H), 7.42 (t, J = 7.2 Hz, 1H), 7.25−7.19 (m, 2H), 6.65 (d, J = 6.3 Hz,
1H), 3.18 (br, s, 1H), 2.39 (s, 3H), 0.93 (s, 9H) ppm; 13C NMR
(75 MHz, CDCl3) δ 138.7, 137.0, 134.9, 133.0, 132.5, 129.2, 127.4,
124.1, 122.8, 122.7, 115.7, 114.0, 55.6, 29.9, 21.2 ppm; HRMS (ESI)
calcd for C18H21BrN3 [M + H]+ 358.0918, found 358.0964.
Compound 14b: semisolid; yield 89% 1H NMR (300 MHz,
CDCl3) δ 8.17 (d, J = 6.0 Hz, 1H), 7.67−7.55 (m, 3H), 7.43 (t, J = 6.9
Hz, 1H), 7.28−7.14 (m, 2H), 6.84 (t, J = 6.0 Hz, 1H), 2.68 (s, 1H),
1.68−1.47 (m, 5H), 1.06 (s, 5H) ppm; 13C NMR (75 MHz, CDCl3) δ
140.3, 131.7, 131.5, 128.2, 126.3, 126.2, 124.8, 122.6, 122.5, 121.9,
121.8, 116.4, 110.4, 55.3, 32.7, 24.6, 23.4 ppm; HRMS (ESI) calcd for
C19H21BrN3 [M + H]+ 370.0918, found 370.0906.
1
Compound 14m: solid; yield 80%; mp = 130−135 °C; H NMR
(300 MHz, CDCl3) δ 8.45 (s, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.55−
7.39 (m, 2H), 7.33−7.23 (m, 2H), 0.95 (s, 9H) ppm, 13C NMR
(75 MHz, CDCl3) δ 140.6, 140.1, 136.4, 133.2, 133.0, 130.0, 128.1,
127.9, 125.2, 124.1, 122.9, 118.4, 107.0, 56.2, 30.3 ppm; HRMS (ESI)
calcd for C17H18Br2N3 [M + H]+ 421.9867, found 421.9904.
Compound 15a: solid; yield 72%; mp = 125−128 °C; FT-IR (KBr)
ν (cm−1) 3409, 2932, 1632, 1220, 771; 1H NMR (300 MHz, CDCl3) δ
8.59 (d, J = 7.2 Hz, 1H), 8.15 (d, J = 6.9 Hz, 1H), 7.93 (d, J = 7.8 Hz,
1H), 7.78 (d, J = 9.0 Hz, 1H), 7.33−7.26 (m, 2H), 0.7.18−7.12 (m,
1H), 6.87−6.83 (m, 1H), 1.97 (s, 9H) ppm; 13C NMR (75 MHz,
CDCl3) δ 146.4, 142.4, 131.3, 123.8, 123.4, 121.6, 119.8, 119.4, 119.3,
118.7, 114.8, 111.0, 58.6, 32.5 ppm; HRMS (ESI) calcd for C17H18N3
[M + H]+ 264.1500, found 264.1490.
1
Compound 14c: oil; yield 91%; H NMR (300 MHz, CDCl3) δ
8.07 (s, 1H), 7.58−7.49 (m, 3H), 7.34−7.28 (m, 1H), 7.19−7.06 (m,
2H), 6.73 (s, 1H), 3.34 (br s, 1H), 2.76 (s, 2H), 1.39−1.16 (m, 4H),
0.71 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 141.1, 136.0, 135.6,
132.6, 132.5, 129.3, 127.1, 123.4, 123.3, 122.5, 117.5, 111.5, 47.8, 32.4,
19.8, 13.6 ppm; HRMS (ESI) calcd for C17H19BrN3 [M + H]+
344.0762, found 344.0790.
Compound 14d: semisolid; yield 65%; 1H NMR (300 MHz,
CDCl3) δ 8.18 (d, J = 6.6 Hz, 1H), 7.68−7.56 (m, 3H), 7.42 (t, J = 7.2
Hz, 1H), 7.24−7.14 (m, 2H), 6.87 (t, J = 6.3 Hz, 1H), 3.57 (s, 4H),
2.91 (s, 2H), 2.38 (t, J = 5.4 Hz, 2H), 2.19 (s, 4H) ppm; 13C NMR
(50 MHz, CDCl3) δ 141.3, 135.9, 135.1, 132.8,132.7, 129.5, 127.4,
123.8, 123.5, 122.7, 117.7, 111.9, 66.9, 57.5, 53.2, 44.3 ppm; HRMS
(ESI) calcd for C19H22BrN4O [M + H]+ 401.0977, found 401.0970.
Compound 14e: semisolid; yield 87%; 1H NMR (300 MHz,
DMSO-d6) δ 8.86−8.83 (m, 1H), 8.53−8.51 (m, 1H), 7.75 (d, J =
7.5 Hz, 1H), 7.64 (d, J = 6.0 Hz, 1H), 7.49 (t, J = 6.6 Hz, 1H), 7.37−
7.32 (m, 1H), 7.09−7.06 (m, 1H), 4.09 (br s, 1H), 0.87 (s, 9H) ppm;
13C NMR (75 MHz, DMSO-d6) δ 150.6, 144.2, 140.1, 135.9, 133.2,
133.1, 132.7, 130.5, 127.9, 123.8, 123.2, 109.0, 55.5, 29.9 ppm; HRMS
(ESI) calcd for C16H18BrN4 [M + H]+ 345.0715, found 345.0723.
Compound 14f: semisolid; yield 82%; 1H NMR (300 MHz,
CDCl3) δ 8.07−7.84 (m, 2H), 7.69−7.55 (m, 3H), 7.42−7.29 (m,
2H), 4.54 (br s, 1H), 2.88 (s, 2H), 1.33−1.19 (m, 4H), 0.76 (s, 3H)
ppm; 13C NMR (75 MHz, CDCl3) δ 142.8, 137.7, 134.7, 134.1, 132.8,
132.6, 130.2, 127.5, 123.3, 47.3, 32.4, 19.8, 13.6 ppm; HRMS (ESI)
calcd for C16H18BrN4 [M + H]+ 345.0714, found 345.0729.
Compound 15b: semisolid; yield 67% FT-IR (neat) ν (cm−1) 3462,
1
3419, 2360, 2360, 1638, 1220, 771; H NMR (300 MHz, CDCl3) δ
8.47 (d, J = 6.90 Hz, 1H), 8.15 (d, J = 7.5 Hz, 1H), 7.76 (d, J = 9.3 Hz,
1H), 7.60 (d, J = 8.1 Hz, 1H), 7.40 (t, J = 7.2 Hz, 1H),7.30−7.25
(m,1H), 7.15−7.10 (m,1H), 6.89 (t, J = 6.3 Hz, 1H), 4.67−4.56 (m,
1H), 2.16−2.07 (m, 6H), 1.95−1.90 (m, 1H) 1.63−1.38 (m, 3H)
ppm; 13C NMR (75 MHz, CDCl3) δ 145.5, 140.8, 131.9, 130.0, 123.2,
122.6, 121.4, 119.7, 119.6, 118.7, 117.9, 111.2, 111.0, 55.9, 33.5, 26.2,
25.4 ppm; HRMS (ESI) calcd for C19H20N3 [M + H]+ 290.1657,
found 290.1654.
Compound 15c: semisolid; yield 71%; FT-IR (neat) ν (cm−1) 3418,
2929, 1634, 1220, 771; 1H NMR (300 MHz, CDCl3) δ 8.21 (d, J = 6.6
Hz, 1H), 8.10 (d, J = 7.5 Hz, 1H), 7.73 (d, J = 9.3 Hz, 1H), 7.40−7.32
(m, 2H), 7.25 (d, J = 6.6 Hz, 1H), 7.13 (m, 1H), 6.86 (t, J = 6.6 Hz,
1H), 4.44 (t, J = 6.9 Hz, 2H), 1.87−1.78 (m, 2H), 1.42−1.30 (m, 2H),
0.94 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 139.9,
128.6, 127.9, 122.6, 121.7, 120.7, 119.0, 118.8, 116.8, 116.1, 111.0,
108.9, 43.4, 32.1, 19.2, 12.8 ppm; HRMS (ESI) calcd for C17H18N3
[M + H]+ 264.1500, found 264.1501.
1
Compound 14g: solid; yield 75%; mp = 119−122 °C; H NMR
(300 MHz, CDCl3) δ 8.64 (d, J = 6.6 Hz, 1H), 8.62−8.54 (m, 1H),
7.74 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.45 (t, J = 7.5 Hz,
1H), 7.29−7.24 (m, 1H), 6.92−6.88 (m, 1H), 0.92 (s, 9H) ppm; 13C
NMR (75 MHz, CDCl3) δ 149.8, 144.9, 140.4, 135.9, 133.3, 132.6,
131.3, 129.8, 127.6, 123.1, 122.4, 108.2,55.9, 29.9 ppm; HRMS (ESI)
calcd for C16H18BrN4 [M + H]+ 345.0715, found 345.0718.
Compound 15d: semisolid; yield 52%; FT-IR (neat) ν (cm−1)
1
3426, 2366, 1638, 1220,772; H NMR (300 MHz, CDCl3) δ 8.41−
8.32 (m, 1H), 8.03 (d, J = 7.2 Hz, 2H), 7.75 (d, J = 9.0 Hz, 1H), 7.49−
7.41 (m, 2H), 7.34−7.32 (m, 1H), 6.97−6.93 (m, 1H), 3.83−3.80
(m, 4H), 3.19 (s, 2H), 2.75−2.72 (m, 2H), 2.69−2.62 (m, 4H) ppm;
13C NMR (75 MHz, CDCl3) δ 146.1, 141.0, 135.9, 134.3, 133.8, 128.6,
127.4, 127.1, 126.4, 124.3, 122.5, 117.1, 111.9, 66.7, 58.2, 53.6, 43.9
ppm; HRMS (ESI) calcd for C19H21N4O1 [M + H]+ 321.1715, found
321.1730.
1
Compound 14h: solid; yield 62%; mp = 170−173 οC; H NMR
(300 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.62
(d, J = 7.5 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H),
3.95 (br s, 1H), 0.96 (s, 9H) ppm; 13C NMR (75 MHz, DMSO-d6) δ
153.3, 148.2, 133.9, 133.2, 131.6, 131.1, 128.0, 124.5, 123.0, 121.7,
54.4, 30.2 ppm; HRMS (ESI) calcd for C14H17BrN5 [M + H]+
334.0667, found 334.0674.
Compound 15e: semisolid; yield 61%; FT-IR (KBr) ν (cm−1) 3419,
1
1
Compound 14i: solid; yield 85%; mp = 129−132 °C; H NMR
2364, 1634, 770; H NMR (300 MHz, CDCl3) δ 9.18 (s, 1H), 8.43
(300 MHz, CDCl3) δ 7.62 (t, J = 8.1 Hz, 2H), 7.42−7.34 (m, 2H),
7.21 (d, J = 6.6 Hz, 1H), 6.75 (s, 1H), 0.92 (s, 9H) ppm; 13C NMR
(75 MHz, CDCl3) δ 145.1, 139.4, 136.6, 132.9, 132.6, 129.1, 127.4,
126.8, 122.5, 117.9, 111.6, 55.3, 29.9 ppm; HRMS (ESI) calcd for
C15H17BrN3S [M + H]+ 350.0326, found 350.0342.
(d, J = 4.8 Hz, 1H), 8.20 (d, J = 7.2 Hz, 1H), 7.95−7.87 (m, 2H),
7.40−7.28 (m, 2H), 1.99 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
144.5, 143.5, 141.2, 136.0, 131.1, 128.0, 125.1, 120.4, 120.3, 118.6,
116.2, 114.8, 58.8, 32.4; HRMS (ESI) calcd for C16H17N4 [M + H]+
265.1453, found 265.1452.
Compound 15f: solid; yield 63%; mp = 120−123 °C; FT-IR (KBr)
ν (cm−1) 3418, 1634, 1220, 771; 1H NMR (300 MHz, CDCl3)
δ 9.12 (s, 1H), 8.15 (d, J = 7.5 Hz, 1H), 8.06 (d, J = 3.6 Hz, 1H), 7.86
Compound 14j: semisolid; yield 79%; 1H NMR (300 MHz,
CDCl3) δ 7.66 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.40 (t,
J = 6.3 Hz, 2H), 7.25−7.20 (m, 1H), 6.80 (d, J = 4.5 Hz, 1H), 2.70
1418
dx.doi.org/10.1021/jo202255v | J. Org. Chem. 2012, 77, 1414−1421

The Journal of Organic Chemistry
Article
(d, J = 3.9 Hz, 1H), 7.46−7.39 (m, 2H), 7.33−7.28 (m, 1H), 4.43 (t,
J = 6.9 Hz, 2H), 1.90−1.81 (m, 2H), 1.41−1.32 (m, 2H), 0.96 (t, J =
7.2 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 143.6, 142.3, 139.6,
133.3, 129.8, 127.6, 124.8, 120.2, 120.0, 117.1, 114.0, 109.8, 44.1, 32.7,
20.0, 13.6 ppm; HRMS (ESI) calcd for C16H17N4 [M + H]+ 265.1453,
found 265.1447.
HRMS (ESI) calcd for C21H28N3O3 [M + H]+ 370.2130, found
370.2136.
Compound 17c: solid; yield 79%; mp = 215−218 °C; H NMR
1
(300 MHz, CDCl3) δ 8.59 (s, 1H), 7.25 (s, 2H), 7.19−7.12 (m, 2H),
3.89 (s, 3H), 3.79 (s, 6H), 1.06 (s, 9H) ppm; 13C NMR (75 MHz,
CDCl3) δ 153.2, 142.2, 140.2, 139.3, 135.3, 134.0, 128.8, 125.7, 105.2,
60.8, 56.3, 56.1, 30.6 ppm; HRMS (ESI) calcd for C20H25BrN3O3
[M + H]+ 434.1079, found 434.1099.
Compound 15g: semisolid; yield 56%; FT-IR (neat) ν (cm−1)
1
3470, 2364, 1631, 1219, 771; H NMR (300 MHz, CDCl3) δ 8.55−
1
Compound 17d: solid; yield 86%; mp = 140−143 °C; H NMR
8.48 (m, 2H), 7.99 (d, J = 7.2, 2H), 7.46−7.28 (m, 3H), 1.04 (s, 9H)
ppm; 13C NMR (75 MHz, CDCl3) δ 150.6, 148.4, 134.9, 133.6, 130.2,
127.5, 127.4, 127.3, 126.9, 124.6, 106.9, 55.7, 29.4 ppm; HRMS (ESI)
calcd for C16H17N4 [M + H]+ 265.1453, found 265.1456.
(300 MHz, CDCl3) δ 9.03 (s,1H), 8.14 (d, J = 3.3 Hz, 1H), 7.90 (d,
J = 4.5 Hz, 1H), 7.29 (s, 2H), 3.97 (s, 6H), 3.92 (s, 3H), 1.12 (s, 9H)
ppm; 13C NMR (75 MHz, CDCl3) δ 153.2,143.1, 141.9, 138.2, 137.0,
129.5, 129.0, 124.6, 116.1, 105.5, 61.0, 56.9, 56.3, 30.5 ppm; HRMS
(ESI) calcd for C19H25N4O3 [M + H]+ 357.1926, found 357.1976.
Compound 17e: semisolid; yield 79% 1H NMR (300 MHz,
CDCl3) δ 7.37 (d, J = 4.5 Hz, 1H), 7.29 (s, 2H), 6.75 (d, J = 4.5 Hz,
1H), 3.92 (s, 6H), 3.88 (s, 3H),1.13 (s, 9H) ppm; 13C NMR (75 MHz,
CDCl3) δ 152.9, 145.4, 139.6, 137.0, 130.5, 125.0, 117.8, 111.7, 104.4,
60.9, 56.1, 55.7, 30.4 ppm; HRMS (ESI) calcd for C18H24N3O3S
[M + H]+ 362.1538, found 362.1599.
Compound 15h: solid; yield 49% mp =152−155 °Cy FT-IR (KBr)
1
ν (cm−1) 3415, 2364, 1632, 1218, 771; H NMR (300 MHz, DMSO-
d6) δ 12.3 (br, s, 1H), 7.94 (s, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.65−
7.62 (m, 1H), 7.23−7.14 (m, 2H), 1.92 (s, 9H) ppm; 13C NMR
(75 MHz, CDCl3) δ 158.7, 157.5, 140.7, 129.0, 126.6, 124.7, 122.2,
120.8, 120.7, 119.9, 63.2, 35.7 ppm; HRMS (ESI) calcd for C14H16N5
[M + H]+ 254.1405, found 254.1412.
Compound 15i: semisolid; yield 68%; FT-IR (neat) ν (cm−1) 3421,
2338, 1629, 1219, 772; 1H NMR (300 MHz, CDCl3) δ 7.99−7.96 (m,
1H), 7.80−7.77 (m, 2H), 7.25−7.20 (m, 2H), 6.80 (d, J = 4.8 Hz,
1H), 1.92 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ 148.1, 137.8,
133.4, 129.7, 120.9, 118.8, 118.5, 117.5, 113.5, 108.3, 56.9, 30.5 ppm;
HRMS (ESI) calcd for C15H16N3S1 [M + H]+ 270.1064, found
270.1073.
1
Compound 17f: solid; yield 82%; mp = 142−145 °C; H NMR
(300 MHz, CDCl3) δ 8.17 (d, J = 6.9 Hz, 1H), 7.91 (d, J = 8.7 Hz,
2H), 7.54 (d, J = 9 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.15−7.09 (m,
1H), 6.77−6.72 (m, 1H), 1.02 (s, 9H) ppm; 13C NMR (75 MHz,
CDCl3) δ 143.5, 141.4, 138.5, 137.6, 133.7, 131.6, 130.2, 124.4, 123.3,
116.7, 111.5, 106.6, 105.4, 52.8, 30.4 ppm; HRMS (ESI) calcd for
C17H19ClN3 [M + H]+ 300.1268, found 300.1284.
Compound 15j: semisolid; yield 64%; FT-IR (neat) ν (cm−1) 3416,
1
Compound 17g: solid; yield 87%; mp = 130−133 °C; H NMR
1
2367, 1637, 1220, 771; H NMR (300 MHz, CDCl3) δ 8.06 (dd, J =
(300 MHz, CDCl3) δ 8.19 (d, J = 6.9 Hz, 1H), 7.86 (d, J = 9.0 Hz,
2H), 7.53 (d, J = 9.0 Hz, 1H), 7.11−7.06 (m, 1H), 6.96 (d, J = 8.7 Hz,
2H), 6.72 (t, J = 6.6 Hz, 1H), 3.82 (s, 3H), 1.02 (s, 9H) ppm; 13C
NMR (75 MHz, CDCl3) δ 159.0, 141.6, 138.9, 129.3, 127.3, 124.1,
123.4, 122.9, 116.8, 113.6, 111.3, 56.3, 55.2, 30.3 ppm; HRMS (ESI)
calcd for C18H22N3O [M + H]+ 296.1763, found 296.1774.
23.7, 7.5 Hz, 1H), 7.76 (d, J = 4.8 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H),
7.32−7.21 (m, 2H), 6.84 (d, J = 4.8 Hz, 1H), 4.51−4.43 (m, 1H),
2.31−1.80 (m, 7H), 1.64−1.35 (m, 3H) ppm; 13C NMR (75 MHz,
CDCl3) δ 147.0, 137.0, 132.0, 128.6, 120.7, 118.7, 117.3, 117.3, 116.2,
109.4, 109.1, 53.9, 32.7, 25.0, 24.6 ppm; HRMS (ESI) calcd for
C17H18N3S1 [M + H]+ 296.1221, found 296.1203.
Compound 19a: solid; yield 56% mp = 170−173 °C; FT-IR (KBr)
ν (cm−1): 3423, 2364, 1635, 1219, 839, 771; 1H NMR (300 MHz,
CDCl3) δ 9.12 (d, J = 5.7 Hz, 1H), 8.69 (s, 1H), 8.34 (br s, 1H), 8.02
(br s, 1H), 7.49 (s, 5H), 4.28 (s, 3H), 3.98 (s, 3H), 3.42 (s, 3H) ppm;
13C NMR (75 MHz, CDCl3) δ 158.0, 154.5, 150.5, 143.3, 140.0, 138.3,
134.4, 133.2, 131.5, 129.1, 126.6, 124.2, 123.4, 121.1, 117.1, 115.3,
113.2, 113.1, 100.1, 60.4, 60.3, 56.8 ppm; HRMS (ESI) calcd for
C23H19Cl1N3O3 [M + H]+ 420.1114, found 420.1103.
Compound 15k: semisolid; yield 62%; FT-IR (Neat) ν (cm−1)
1
3442, 2359, 1612, 1119, 773; H NMR (300 MHz, CDCl3) δ 7.95−
7.92 (m, 1H), 7.42 (d, J = 4.5 Hz, 1H), 7.30−7.18 (m, 3H), 6.71 (d,
J = 4.5 Hz,1H), 4.17 (t, J = 6.9 Hz, 2H), 1.79−1.69 (m, 2H), 1.33−
1.21 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCl3) δ 147.6, 138.2, 131.5, 130.3, 121.5, 119.6, 118.4, 118.2, 115.3,
110.7, 109.7, 44.3, 32.4, 20.2, 13.7 ppm; HRMS (ESI) calcd for
C15H16N3S1 [M + H]+ 270.1064, found 270.1071.
Compound 19b: solid; yield 68%; mp = 167−170 °C; FT-IR (KBr)
ν (cm−1) 3487, 2361, 1631, 771; 1H NMR (300 MHz, CDCl3) δ 9.13
(s, 1H), 8.02 (s,1H), 7.84 (br s, 1H), 7.54 (s, 3H), 7.02 (s, 3H), 4.18
(s, 3H), 3.98 (s, 3H), 3.93 (s, 3H), 3.39 (s, 3H) ppm; 13C NMR
(75 MHz, CDCl3) δ 159.0, 157.0, 152.4, 151.6, 146.0, 142.5, 140.8,
139.2, 136.2, 130.2, 129.6, 128.3, 124.4, 117.4, 117.2, 117.1, 114.0,
112.6, 111.7, 98.4, 61.2, 61.0, 56.5, 55.3 ppm; HRMS (ESI) calcd for
C24H22N3O4 [M + H]+ 416.1610, found 416.1619.
Compound 15l: solid; yield 63%; mp =150−152 °C; FT-IR (KBr)
ν (cm−1) 3404, 3221, 1641, 1217, 768; 1H NMR (300 MHz, CDCl3) δ
8.12 (d, J = 6.9 Hz, 1H), 7.92 (d, J = 6.9 Hz, 2H), 7.46 (t, J = 7.5 Hz,
2H), 7.34 (d, J = 9.0 Hz, 1H), 6.63 (d, J = 6.9 Hz, 1H), 2.40 (s,
3H), 1.04 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ 142.3, 138.8,
135.2, 135.1, 132.7, 128.2, 128.1, 127.2, 122.7, 115.6, 114.0, 56.3, 30.3,
21.2 ppm; HRMS (ESI). for C18H20N3 [M + H]+ 278.1657, found
278.1664.
Compound 15m: solid; yield 59%; mp = 170−173 °C; FT-IR
(KBr) ν (cm−1): 2871, 1217, 760; 1H NMR (300 MHz, CDCl3) δ 8.35
(s, 1H), 7.89 (d, J = 7.2 Hz, 2H), 7.46−7.42 (m, 2H), 7.36−7.31 (m,
1H), 7.21−7.17 (m, 1H), 1.05 (s, 9H) ppm; 13C NMR (75 MHz,
CDCl3) δ 140.3, 134.8, 128.3, 128.1, 127.6, 127.3, 123.8, 123.7, 106.2,
118.0, 56.5, 30.3 ppm; HRMS (ESI) calcd for C17H17BrN3 [M + H]+
342.0606, found 342.0615.
Compound 19c: semisolid; yield 62% FT-IR (neat) ν (cm−1) 3438,
1
1635, 1472 751; H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 6.8
Hz, 1H), 7.91 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz,
2H), 7.27 (d, J = 7.6 Hz, 2H), 7.14 (t, J = 6.8 Hz, 2H), 4.10 (s, 3H),
3.83 (s, 3H), 3.27 (s, 3H), 2.42 (s, 3H) ppm; 13C NMR (75 MHz,
CDCl3) δ 156.9, 152.4, 151.6, 146.4, 142.3, 140.9, 136.8, 134.7, 130.9,
130.7, 129.1,128.7, 128.5, 127.8, 124.4, 117.3, 117.0, 111.3, 98.1, 61.1,
61.0, 56.4, 21.3 ppm; HRMS (ESI) calcd for C24H22N3O3 [M + H]+
400.1661, found 400.1660.
Compound 17a: semisolid; yield 91%; 1H NMR (300 MHz,
CDCl3) δ 8.16 (d, J = 6.3 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.25 (s,
2H), 7.12 (t, J = 6.9 Hz, 1H), 6.76 (t, J = 6.6 Hz, 1H), 3.90 (s, 6H),
3.85 (s, 3H), 1.05 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ 152.9,
141.4, 138.5, 137.4, 130.2, 124.4, 123.3, 123.2, 116.7, 111.5, 105.3,
60.8, 56.2, 56.1, 30.4 ppm; HRMS (ESI) calcd for C20H26N3O3 [M +
H]+ 356.1974, found 356.1992.
Compound 19d: semisolid; yield 51%; FT-IR (neat) ν (cm−1)
1
3480, 2935, 2340, 1216, 762 H NMR (300 MHz, CDCl3) δ 8.52 (d,
J = 6.6 Hz, 1H), 7.96 (d, J = 7.8 Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H),
7.66 (d, J = 9.0 Hz, 1H), 7.36 (d, J = 6.9 Hz, 1H), 7.04−6.96 (m, 2H),
3.94 (s, 3H), 3.85 (s, 6H) ppm, 13C NMR (75 MHz, CDCl3) δ 154.1,
152.9, 140.7, 132.9, 128.5, 126.5, 123.7, 119.6, 118.8, 117.9, 114.2,
113.4, 105.9, 61.3, 56.5 ppm; HRMS (ESI) calcd for C24H19N4O3
[M + H]+ 411.1457, found 411.1465.
Compound 19e: solid; yield 62%; mp = 150−158 °C; FT-IR (KBr)
ν (cm−1) 3442, 2904, 1214, 762 1H NMR (300 MHz, CDCl3) δ
8.92 (d, J = 6.9 Hz, 1H), 8.02 (s, 1H), 7.85 (d, J = 9.3 Hz, 1H), 7.52
Compound 17b: semisolid; yield 86% 1H NMR (300 MHz,
CDCl3) δ 8.08 (d, J = 6.9 Hz, 1H), 7.26 (d, J = 4.5 Hz, 2H), 6.64−6.60
(m, 2H), 3.94 (s, 6H), 3.89 (s, 3H), 2.39 (s, 3H), 1.09 (s, 9H) ppm,
13C NMR (75 MHz, CDCl3) δ 153.3, 153.0, 141.8, 137.7, 135.9, 122.7,
122.6, 115.1, 114.5, 105.5, 103.9, 60.9, 56.3, 56.2, 30.5, 21.2 ppm;
1419
dx.doi.org/10.1021/jo202255v | J. Org. Chem. 2012, 77, 1414−1421

The Journal of Organic Chemistry
Article
(d, J = 8.1 Hz, 3H), 7.32 (d, J = 7.8 Hz, 2H), 6.99 (t, J = 6.9 Hz, 1H),
4.17 (s, 3H), 3.96 (s, 3H), 3.37 (s, 3H), 2.81 (q, J = 7.5 Hz, 2H), 1.36
(t, J = 3.9 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 156.9, 152.6,
151.7, 146.4, 143.2, 142.4, 141.2, 134.8, 130.8, 128.8, 128.5, 126.6,
124.4, 117.4, 117.1, 111.3, 106.3, 98.1, 61.1, 61.0, 56.4, 28.8, 15.7 ppm;
HRMS (ESI) calcd for C25H24N3O3 [M + H]+ 414.1817, found
414.1849.
124.1, 117.8, 117.2, 114.9, 114.6, 113.0, 55.6 ppm; HRMS (ESI) calcd
for C14H14N3O [M + H]+ 240.1137, found 240.1142.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra of all the compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Compound 19f: semisolid; yield 59% FT-IR (neat) ν (cm−1) 3415,
2943, 2314, 1607, 1126, 769,1H NMR (300 MHz, CDCl3) δ 8.92 (d,
J = 6.9 Hz, 1H), 8.0 (s, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.75 (s, 1H),
7.60−7.49 (m, 4H), 7.08−6.99 (m, 1H), 4.18 (s, 3H), 3.97 (s, 3H),
3.46 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 157.6, 151.6, 146.6,
146.0, 142.8, 132.0, 130.5, 130.3, 129.0, 127.9, 124.8, 121.5, 117.6,
112.3, 98.6, 61.5, 61.2, 56.9 ppm; HRMS (ESI) calcd for
C23H19BrN3O3 [M + H]+ 464.0610, found 464.0622.
AUTHOR INFORMATION
Corresponding Author
*Email: premsc58@hotmail.com, prem_chauhan_2000@
yahoo.com.
■
Notes
Compound 19g: solid; yield 56%; mp = 140−144 °C; FT-IR (KBr)
ν (cm−1) 3480, 2960, 2343, 1607, 1120, 760,1H NMR (300 MHz,
CDCl3) δ 8.96 (d, J = 6.9 Hz, 1H), 8.25 (s, 2H), 7.46 (d, J = 7.8 Hz,
2H), 7.32−7.19 (m, 3H), 4.21 (s, 3H), 3.97 (s, 3H), 3.40 (s, 3H),
2.68(s, 3H), 2.49 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 158.5,
156.2, 151.7, 148.0, 143.9, 141.8, 139.8,137.7, 132.6, 128.5, 127.9,
124.4, 123.9, 121.8, 118.4, 118.1, 113.0, 99.5, 61.2, 56.8, 22.3, 21.3
ppm; HRMS (ESI) calcd for C25H24N3O3 [M + H]+ 414.1817, found
414.1797.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
V.T. and S.K. are thankful to the University Grant Commission,
New Delhi, for financial support in the form of SRF. We also
acknowledge SAIF-CDRI for providing spectral and analytical
data. CDRI communication no. is 8185.
Compound 19h: solid; yield 62%; mp = 125−128 °C; FT-IR (KBr)
ν (cm−1) 3480, 2935, 1216, 928, 762, 670; 1H NMR (300 MHz,
CDCl3) δ 9.04 (s, 1H), 7.97 (s, 1H), 7.71−7.67 (m, 1H), 7.53−7.46
(m, 3H), 7.29 (s, 2H), 4.18 (s, 3H), 3.96 (s, 3H), 3.40 (s, 3H), 2.49 (s,
3H) ppm; 13C NMR (75 MHz, CDCl3) δ 157.4, 153.7, 152.1, 145.0,
142.8, 141.2, 137.3, 134.8, 132.4, 131.6, 128.9, 128.2, 124.9, 118.5,
117.5, 106.0, 98.3, 61.5, 61.4, 56.8, 21.7 ppm; HRMS (ESI) calcd for
C24H21BrN3O3 [M + H]+ 478.0766, found 478.0800.
REFERENCES
■
(1) (a) Spring, D. R. Org. Biomol. Chem. 2003, 1, 3867.
(b) Strausberg, R. L.; Schreiber, S. L. Science 2003, 300, 294.
(c) Burke, M. D.; Schreiber, S. L. Angew Chem., Int. Ed. 2004, 43, 46.
(d) Smith, A. B. III; Han, H.; Kim, W. S. Org. Lett. 2011, 13, 3328.
(e) Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 5, 709.
(f) Sore, H. F.; Blackwell, D. T.; MacDonald, S. J. F.; Spring, D. R. Org.
Lett. 2010, 12, 2806.
(2) (a) Pizzirani, D.; Kaya, T.; Clemons, P. A.; Schreiber, S. L Org.
Lett. 2010, 12, 2822. (b) Schreiber, S. L. ChemBioChem 2009, 10, 26.
(c) Schreiber, S. L. Nature 2009, 153.
(3) (a) Katritzky, A. R.; Tymoshenko, D. O.; Monteux, D.;
Vvedensky, V.; Nikonov, G.; Cooper, C. B.; Deshpande, M. J. Org.
Chem. 2000, 65, 8059. (b) Maryanoff, B. E.; McComsey, D. F.; Ho,
W.; Shank, R. P.; Dubinsky, B. Bioorg. Med. Chem. Lett. 1996, 6, 333.
(c) Reitz, A. B.; Gauthier, D. A.; Ho, W.; Maryanoff, B. E. Tetrahedron
2000, 56, 8809. (d) Rida, S. M.; Soliman, F. S. G.; Badawey, E.; Kappe, T.
J. Heterocycl. Chem. 1988, 25, 1725. (e) Rida, S. M.; Soliman, F. S. G.;
Badawey, E.; El-Ghazzawi, E.; Kader, O.; Kappe, T. J. Heterocycl. Chem.
1988, 25, 1087. (f) Badawey, E.; Kappe, T. Eur. J. Med. Chem. 1995,
30, 327. (g) El-Hawash, S. A. M.; Badawey, E.; Kappe, T. Pharmazie
1999, 54, 341.
(4) (a) Arzel, E.; Rocca, P.; Grellier, P.; Labaeïd, M.; Frappie, F.;
́
Gueritte, F.; Gaspard, C.; Marsais, F.; Godard, A.; Queguiner, G
J. Med. Chem. 2001, 44, 949. (b) Lauria, A.; Patella, C.; Dattolo, G.;
Almerico, A. M. J. Med. Chem. 2008, 51, 2037. (c) Lisa., D. V.; Magno,
S. M.; Ornella, G.; Marini, A. M.; Settimo, F. D.; Salerno, S.; Motta,
C. L.; Simorini, F.; Taliani, S.; Lavecchia, A.; Giovanni, C. D.; Brancato,
G.; Barone, V.; Novellino, E. J. Med. Chem. 2009, 52, 5429.
(5) (a) Pastor, P.; Siro, G. J.; García-Navío, J. L.; Vaquero, J. J.;
Alvarez-Builla, J,; Gago, F.; Pascual-Teresa, B. D.; Pastor, M.; Rodrigo,
M. M. J. Org. Chem. 1997, 62, 5476. (b) Venkatesh, C.; Sundaram, G.
S. M.; Ila, H.; Junjappa, H. J. Org. Chem. 2006, 71, 1281.
(6) (a) Mamane, V.; Fort, Y. Tetrahedron Lett. 2006, 47, 2337.
(b) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 10, 1551. (c) Murarka,
S; Zhang, C.; Konieczynska, M. D.; Seidel, D. Org. Lett. 2009, 1, 129.
(d) Cai, Q.; Li, Z.; Wei, J.; Fu, L.; Ha, C.; Pei, D.; Ding., K Org. Lett.
2010, 7, 1500. (e) Du, D.; Li, L.; Wang, Z. J. Org. Chem. 2009, 74,
4379. (f) Martins, A.; Lautens, M. J. Org. Chem. 2008, 73, 8705.
(g) Palacios, F.; Alonso, C.; Amezua, P.; Rubiales, G. J. Org. Chem.
2002, 67, 1941.
Compound 19i: solid; yield 60%; mp = 210−213 °C; FT-IR (KBr)
1
ν (cm−1) 3415, 2933, 2360, 1607, 1126, 769; H NMR (400 MHz,
DMSO-d6) δ 9.41 (s, 1H), 8.97−8.96 (m, 1H), 8.12 (d, J = 4 Hz, 1H),
7.99 (s, 1H), 7.54 (s, 4H), 4.13 (s, 3H), 3.85 (s, 3H), 3.33 (s, 3H)
ppm; 13C NMR (75 MHz, CDCl3) δ 157.7, 154.0, 151.7, 144.7, 143.0,
141.8, 140.5, 133.9, 133.6, 132.0, 130.0, 129.0, 128.5, 127.4, 117.2,
116.7, 98.4, 61.2, 61.0, 56.5 ppm; HRMS (ESI) calcd for
C22H18Cl1N4O3 [M + H]+ 421.1067, found 421.1044.
Compound 19j: semisolid; yield 63%; FT-IR (neat) ν (cm−1) 3439,
1
2923, 2363, 1636, 771; H NMR (400 MHz, DMSO-d6) δ 9.38 (s,
1H), 8.94 (d, J = 4.4 Hz, 1H), 8.10 (d, J = 4.4 Hz, 1H), 7.97 (s, 1H),
7.41 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 4.13 (s, 3H), 3.83
(s, 3H), 3.29 (s, 3H), 2.43 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3)
δ 157.5, 155.7, 152.1, 144.6, 143.0, 140.6, 140.3, 139.2, 137.3, 134.0,
131.8, 129.1, 128.4, 128.3, 127.9, 117.5, 116.8, 114.0, 98.4, 61.2, 61.1,
56.5, 21.3 ppm; HRMS (ESI) calcd for C23H21N4O3 [M + H]+
401.1613, found 401.1595.
Compound 19k: solid; yield 52%; mp = 160−163 °C; FT-IR (KBr)
1
ν (cm−1) 2362, 1262, 1098,1028, 805; H NMR (400 MHz, DMSO-
d6) δ 8.41 (d, J = 4.4 Hz, 1H), 7.73 (s, 1H), 7.48 (s, 4H), 7.45 (d, J =
4.4 Hz, 1H), 4.07 (s, 3H), 3.80 (s, 3H), 3.29 (s, 3H) ppm; 13C NMR
(75 MHz, CDCl3) δ 158.0, 153.1, 152.2, 151.0, 142.6, 141.4, 134.9,
133.6, 130.0, 127.4, 126.8, 117.9, 116.5, 114.4, 97.6, 61.2, 60.9, 56.5
ppm; HRMS (ESI) calcd for C21H17ClN3O3S1 [M + H]+ 426.0679,
found 426.066.
Compound 20a: solid; yield 72%; mp = 110−113 °C; FT-IR (KBr)
1
ν (cm−1) 3466, 2363, 1635, 1220, 771; H NMR (300 MHz, DMSO-
d6) δ 8.29 (d, J = 6.9 Hz, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 9.0
Hz, 1H), 7.61 (d, J = 8.7 Hz, 2H), 7.47−7.42 (m, 1H), 7.11 (t, J = 6.8
Hz, 1H) ppm; 13C NMR (75 MHz, DMSO-d6) δ 157.5, 157.1, 142.9,
133.3, 132.0, 129.3, 128.7, 126.7, 124.4, 117.5, 113.5 ppm; HRMS
(ESI) calcd for C13H11Cl1N3 [M + H]+ 244.0641, found 244.0640.
Compound 20b: solid; yield 69%; mp = 122−125 °C; FT-IR (KBr)
1
ν (cm−1) 3449, 1634, 1219, 771; H NMR (300 MHz, DMSO-d6) δ
8.22 (d, J = 6.6 Hz, 1H), 7.90 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 9.0 Hz,
1H), 7.39 (t, J = 6.9 Hz, 1H), 7.09−6.99 (m, 3H), 3.82 (s, 3H) ppm;
13C NMR (75 MHz, DMSO-d6) δ 159.8, 142.7, 128.4, 126.1, 125.7,
(7) (a) Stanslas, J.; Hagan, D. J.; Ellis, M. J.; Turner, C.; Carmichael,
J.; Ward, W.; Hammonds, T. R.; Stevens, M. F. G. J. Med. Chem. 2000,
43, 1563. (b) Li, A.; Gilbert, T. M.; Klumpp, D. A. J. Org. Chem. 2008,
1420
dx.doi.org/10.1021/jo202255v | J. Org. Chem. 2012, 77, 1414−1421

The Journal of Organic Chemistry
Article
73, 3654. (c) Kouznetsov, V. V.; Mendez, L. Y. V.; Gomez, C. M. M.
Curr. Org. Chem 2005, 9, 141. (d) Benincori, T.; Sannicolo,
́
F.
J. Heterocycl. Chem. 1988, 25, 1029. (e) Hranjec, M.; Kralj, M.;
̂
́ ́
M.; Suman, L.; Pavelic, K.; Karminski-Zamola, G.
Piantanida, I.; Sedic,
J. Med. Chem. 2007, 50, 5696.
(8) (a) Ma, Z.; Xiang, Z.; Luo, T.; Lu, K.; Xu, Z.; Chen, J.; Yang, Z
J. Comb. Chem. 2006, 8, 69. (b) Ilyin, A.; Kysil, V.; Krasavin, M.;
Kurashvili, I.; Ivachtchenko, A. V. J. Org. Chem. 2006, 71, 9544.
(c) Riva, R; Banfi, L.; Basso, A.; Cerulli, V.; Guanti, G.; Pani, M. J. Org.
Chem. 2010, 15, 5134. (d) Guchhait, S. K.; Madaan, C. Org. Biomol.
Chem. 2010, 8, 3631. (e) Erb, W.; Neuville, L.; Zhu, J. J. Org. Chem.
2009, 74, 3109. (f) Kaïm, L. EI; Gizzi, M.; Grimaud, L. Org. Lett. 2008,
10, 3417. (g) Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Org.
Lett. 2007, 9, 4223. (h) Kaïm, L. EI.; Grimaud, L.; Wagschal, S. J. Org.
Chem. 2010, 75, 5343. (i) Bonnaterre, F.; Bois-Choussy, M.; Zhu.
J. Org. Lett. 2006, 19, 4351. (j) Hulme, C.; Ma, L.; Romano, J. J.;
Morton, G.; Tang, S.-Y.; Cherrier, M.-P.; Choi, S.; Salvino, J.;
Labaudiniere, R. Tetrahedron Lett. 2000, 41, 1889. (k) Gracias, V.;
Moore, J. D.; Djuric, S. W. Tetrahedron Lett. 2004, 45, 417.
(9) (a) Porwal, S.; Chauhan, S .S.; Chauhan, P. M. S.; Shakya, N.;
Verma, A.; Gupta, S. J. Med. Chem. 2009, 19, 5793. (b) Srivastava, S.
K.; Agarwal, A.; Chauhan, P. M. S.; Agarwal, S. K.; Bhaduri, A. P.;
Singh, S. N.; Fatima, N.; Chatterjee, R. K. J. Med. Chem. 1999, 42,
1667.
(10) (a) Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661.
(b) Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.; Tsai, S.
Tetrahedron Lett. 1998, 39, 3635. (c) Bienayme, H.; Bouzid, K.
Angew.Chem., Int. Ed. 1998, 37, 2234.
(11) Shaabani, A.; Soleimani, E.; Khavasi, H. R. J. Comb. Chem. 2008,
10, 442.
(12) (a) Wang, W.; Ollio, S.; Herdtweck, E.; Domling, A. J. Org.
̈
Chem. 2011, 76, 637. (b) Wang, W.; Herdtweck, E.; Domling, A.
Chem. Commun. 2010, 46, 770.
̈
(13) Che, C; Xiang, J.; Wang, G. X.; Fathi, R.; Quan, J. M.; Yang, Z.
J. Comb. Chem. 2007, 9, 982.
1421
dx.doi.org/10.1021/jo202255v | J. Org. Chem. 2012, 77, 1414−1421