C - H bond functionalization under metalation - Deprotonation process: Regioselective direct arylation of 3-aminoimidazo[1,2-a]pyrazine

Article abstract of DOI:10.1021/jo301065s

Concerted metalation deprotonation (CMD) approach with appropriate proton shuttle precursor, base, and solvent (PivOH - K₂CO₃ - toluene) has rendered a regioselective Pd-catalyzed C6-arylation of 3-aminoimidazo[1,2-α]pyrazine, a therapeutically relevant scaffold accessible by multicomponent reaction. The arylation of this heteroarene suffers from competing C5 and C2′-arylation reactions, while the developed process has virtually eliminated these competing arylations. Density functional calculations for CMD C - H activation at C6, C5, C8, and C2′ sites imply that the energy barrier with distortion energy penalty as major contributing component influences the regioselectivity.

Full text of DOI:10.1021/jo301065s

Note
pubs.acs.org/joc
C−H Bond Functionalization Under Metalation−Deprotonation
Process: Regioselective Direct Arylation of
3‑Aminoimidazo[1,2‑a]pyrazine
Sankar K. Guchhait,* Somnath Kandekar, Maneesh Kashyap, Nikhil Taxak, and Prasad V. Bharatam
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S. A. S. Nagar, Mohali,
160062, Punjab, India
S
* Supporting Information
ABSTRACT: Concerted metalation deprotonation (CMD)
approach with appropriate proton shuttle precursor, base, and
solvent (PivOH−K2CO3−toluene) has rendered a regioselec-
tive Pd-catalyzed C6-arylation of 3-aminoimidazo[1,2-a]pyrazine,
a therapeutically relevant scaffold accessible by multicomponent
reaction. The arylation of this heteroarene suffers from competing
C5 and C2′-arylation reactions, while the developed process has
virtually eliminated these competing arylations. Density functional calculations for CMD C−H activation at C6, C5, C8, and C2′ sites
imply that the energy barrier with distortion energy penalty as major contributing component influences the regioselectivity.
irect arylation of (hetero)arene has recently emerged as
D
an appealing and valuable strategy in organic synthesis.1
In contrast to conventional cross-coupling reactions,2 this
approach does not require additional prefunctionalization of
arenes. It avoids especially the prior preparation and use of
stoichiometric (hetero)arylmetal derivatives. Therefore, these
reactions are atom-economical and produce less waste. How-
ever, regioselective C−H bond functionalization and the practi-
cability of these processes for versatile (hetero)arenes are major
constraints. Regioselective arylation becomes more problematic
for heterocyclic scaffolds possessing multiple closely related
nucleophilic centers and or acidic C−H (s), such as oxazole,
thiazole, imidazole, pyrrole, and indole.1a,3 In the context of
versatility, π-nucleophilic aromatics as direct arylation coupling
partners are common. For these arenes, the C−H bond func-
tionalizations are often proposed to take place via electrophilic
aromatic substitution (SEAr) pathway,4 although Heck-like5
and oxidative C−H insertion6 pathways also have been demon-
strated. In contrast, electron-deficient arenes are less explored.
The concerted metalation deprotonation (CMD) pathway, an
excellent approach introduced by Fagnou7 and a similar proton
abstraction mechanism first proposed by Echavarren and
Maseras,8 has enabled various electron-deficient aromatics as
valid arene coupling partners for direct arylation.9 In this path-
way, several electron-rich heterocycles have also been found
later to be operative.9a,b Herein, we report a novel regioselective
Pd-catalyzed direct C6-arylation reaction of 3-aryl/alkylamino
and 2-aryl/alkyl substituted imidazo[1,2-a]pyrazine, a π-defi-
cient heteroarene, with bromoarene via metalation−deprotonation
process (Figure 1). Several ring nitrogen atoms and the sub-
stitution/functionality present in the scaffold contribute differently
to the electronic and steric factors and can coordinate to Pd-
catalyst. These cause competing arylations of the scaffold at other
sites (such as C2′ and C5). Our developed CMD process with
Figure 1. Arylations of N-fused imidazoles.
pivalate proton shuttle, in situ generated from PivOH−K2CO3,
in toluene solvent has virtually eliminated these competing
arylations. The computational studies indicate that the C−H
activation energy barrier (distortion energy penalty as major
governing component) favored the C6-CMD TS over C2′, C5,
and C8. There are a few methods reported for arylation
reactions of fused imidazo-heterocycles, including C5-arylation
of imidazo[1,5-a]pyrazine via Heck-like pathway, and C3-
arylations of imidazo[1,2-b][1,2,4]triazine and imidazo[1,2-a]-
pyrimidine via SEAr process.10 The present work introduces
CMD-mediated C6-arylation of 3-aminoimidazo[1,2-a]pyrazine, a
therapeutically important motif.
Imidazo[1,2-a]pyrazines and their derivatives with 3-aryl/
alkyl-amine, 2-aryl/alkyl and 6-aryl substitutions have been
found to possess a wide range of bioactivities.11,12 Analogues of
Received: May 26, 2012
Published: August 28, 2012
© 2012 American Chemical Society
8321
dx.doi.org/10.1021/jo301065s | J. Org. Chem. 2012, 77, 8321−8328

The Journal of Organic Chemistry
Note
a
Table 1. Evaluation of Reagents and Conditions for C6-Arylation of 3-Aminoimidazo1,2-a]pyrazine (S)
b
c
entry
catalyst
ligand
additive
PivOH
base
solvent
DMF
P1:P2
yield (%) of P1
d
1
2
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
(t-Bu)2MeP·HBF4
(t-Bu)2MeP·HBF4
(t-Bu)2MeP·HBF4
(t-Bu)2MeP·HBF4
(t-Bu)2MeP·HBF4
(t-Bu)2MeP·HBF4
(t-Bu)2MeP·HBF4
(t-Bu)2MeP·HBF4
(t-Bu)2MeP·HBF4
(t-Bu)2MeP·HBF4
(t-Bu)2MeP·HBF4
(t-Bu)2MeP·HBF4
PPh3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K2CO3
KOAc
1.1:1
1.2:1
4.5:1
4:1
P1:15 (P2:13)
DMF
P1:18 (P2:15)
PivOH
PivOH
PivOH
PivOH
PivOH
toluene
mesitylene
toluene
mesitylene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
e
4
5
49:1
62
e
6
19:1
7
7.3:1
trace
32.3:1
1.2:1
trace
44.4:1
100:0
8
CsOPiv
Ag2CO3
K2CO3
9
PivOH
46
10
11
12
13
PivOH
Mes CO2H
PivOH
K2CO3
47
K2CO3
65
a
Conditions: Additive (30 mol %), base (2 equiv), ligand (20 mol %), imidazopyrazine (1 mmol), 4-bromotoluene (2.5 equiv), Pd catalyst
(10 mol %) and anhydrous solvent were added sequentially to the reaction vessel under N2, and the mixture was heated at 110 °C for
b
c
d
e
24−36 h. Ratio was determined by RP-HPLC analysis. Isolated yield. It formed C5-arylated product in 3% yield. Reaction temperature:
140 °C.
this scaffold represent various marketed drugs such as zolpidem
and zolimidine. C6-Aryl derivatives of these compounds are
normally prepared by a sequence of reactions.11,13 It uses
bromination of 2-aminopyrazine, condensation of 2-amino-
5-bromopyrazine with α-haloketone or with aldehyde and
isocyanide to produce 6-bromo-imidazopyrazine, and the
Suzuki coupling with boronic acid. In addition, bromination of
2-aminopyrazine produces also unwanted regioisomeric bromi-
nated and polybromo derivatives.11e Therefore, inherent advant-
ages of direct arylation chemistry and therapeutic importance
signify 3-aminoimidazo[1,2-a]pyrazine as a useful direct arylation
coupling partner.
In initial experiment, a model reaction of 3-tert-butylamino-2-
phenylimidazopyrazine with bromotoluene was performed
using Snieckus’s method10a for C5-arylation of imidazo[1,5-a]-
pyrazine (Table 1, entry 1). However, it provided 6-arylated
product (P1), 2′-arylated product (P2), and 5-arylated product
in 15, 13, and 3% yields, respectively. The reactions were then
carried out following methods reported for arylation of other
fused imidazo-heterocycles, imidazopyrimidine, imidazopyrida-
zine, and imidazo-triazine.10 All of them led to the formation of
C6, C2′, and C5 arylated products in similar yields. These
methods with a few variations of palladium sources and ligands
could improve in neither regioselectivity nor synthetic con-
version. CMD approach was then considered for investigation.
In initial investigations, reactions were performed with addi-
tional use of PivOH as proton shuttle precursor in various
solvents. Gratifyingly, in each reaction, the competing C5-
arylation could be avoided. Although 2′-arylated product (P2)
formed along with 6-arylated product (P1), the use of toluene
as solvent significantly improved the regioselectivity for C6-
arylation. Compared to polar solvents, apolar solvents were
found to be more effective. Increasing the reaction temperature
using mesitylene solvent was of no advantage. The competing
C2′-arylation took place plausibly by directed C2′−H bond
functionalization through 3-amino or imidazole ring nitrogen−
palladium coordination.1 Variation in base was then inves-
tigated. To our delight, the use of K2CO3 base replacing
Cs2CO3 provided high regioselectivity and C6-arylated product
in 62% isolated yield. K2CO3 was found to be superior to
acetate. Use of CsOPiv (without PivOH) or the reaction
performed in absence of base resulted in trace conversion.
These imply that the choice of base is important. The CMD
process was found to be essential. The reaction without PivOH
resulted in almost loss of regioselectivity, less reaction con-
version, and a complex mixture of products on prolonging the
reaction (entry 10). 2-Mesitylenecarboxylate as proton shuttle
was found to be inferior to pivalate. Various ligands and palla-
dium sources were then evaluated. Interestingly, the combina-
tion of PPh3−Pd(OAc)2 with PivOH−K2CO3 afforded the
formation of only 6-arylated product in 65% isolated yield and
no 2′-arylated product (entry 13). Compared to aryl bromide,
aryl iodide lowered the conversion. This might be due to
poisoning of the catalyst by accumulated iodide in the reaction
medium. With aryl iodide, the use of Ag2CO3 replacing K2CO3
enhanced desired arylation,10a,14 but its use was found not
imperative.
With the optimized protocol in hand, we next set out to
explore its scope. Versatile 3-aryl/alkylamino and 2-aryl/alkyl
substituted imidazo[1,2-a]pyrazines were prepared by
Groebke−Blackburn−Bienayme
́
multicomponent reaction.15,16
These imidazopyrazines in reaction with various aryl bromides
provided C6-arylated products in moderate to good yields
(Tables 2 and 3). In each case, the reaction provided the regio-
selective C6-arylation product with negligible or no (0−2%)
2′-arylated product, although the conversion was not complete.
The 3-arylamine motifs of imidazopyrazine (products 9−11,
Table 3) remained intact, although they are susceptible toward
possible direct arylation at 2′-position of 3-arylamine facilitated
by electrophilic palladation or fused nitrogen coordination to
8322
dx.doi.org/10.1021/jo301065s | J. Org. Chem. 2012, 77, 8321−8328

The Journal of Organic Chemistry
Note
Table 2. C6-Arylation of 3-Aminoimidazopyrazine (S) with
Various Bromoarenes
Table 3. Synthesis of Versatile C6-Aryl Derivatives of
3-Aminoimidazopyrazine with Diverse Substitutions
a
a
Conditions: Imidazopyrazine (1 mmol), bromoarene (2.5 equiv),
Pd(OAc)2 (10 mol %), PPh3 (20 mol %), PivOH (30 mol %), K2CO3
b
(2 equiv), 110 °C, N2. Isolated yield.
catalyst. This direct arylation was also chemoselective with the
fact that no C−N bond formation reaction (Buchwald−
Hartwig coupling) was observed. Both electron-donating
and -withdrawing groups on aryl bromides were compatible.
The tolerance of functionalities such as chloro, cyano, nitro,
methoxy, amine, and gratifyingly, even aldehyde in this protocol
provides opportunity of their various further chemical
manipulation in products.
The crucial role of pivalate as proton shuttle in this regio-
selective direct arylation implies that the arene C−H bond
functionalization underwent plausibly via CMD mechanism
(Figure 2). The lack of electronic effect (EWG vs EDG) of
bromoarenes on the reactivity/regioselectivity in arylation rules
out the possibility of sole electrophilic palladation. The oxida-
tive addition of aryl bromide to Pd(0) forms ArPdBr, which
in reaction with PivOK generates ArPd(OPiv) complex (A).
This complex induces C6−H bond activation of imidazopyr-
azine and forms complex (B), which subsequently produces
aryl-Pd-imidazopyrazine complex (C). Its reductive elimina-
Figure 2. Proposed mechanism (CMD pathway).
tion produces C6-arylated imidazopyrazine and regenerates
Pd(0).
To gain insight into the reasons for C6-selectivity, computa-
tional studies were performed for C−H activation energy barriers
of CMD TSs (for details, see the Supporting Information).
The energy barriers associated with C−H activations at
different sites (C5, C6, C8 and C2′) were calculated by
8323
dx.doi.org/10.1021/jo301065s | J. Org. Chem. 2012, 77, 8321−8328

The Journal of Organic Chemistry
Note
density functional theory (DFT) with the B3LYP exchange-
correlation functional similar to that used by Fagnou and co-
workers (see the Supporting Information). The lowest energy
barrier (24.11 kcal mol−1) was observed for C6-TS (Figure 3),
site selectivity and synthetically useful conversion. The studies
of distortion and interaction energies and bond index for
CMD process were in agreement with experimental results.
This work has rendered for the first time the inclusion of
3-aminoimidazo[1,2-a]pyrazine, a therapeutically relevant scaf-
fold accessible by multicomponent reaction, in the array of
(hetero)arene direct arylation coupling partners, and will
potentially replace the usually followed multistep synthesis of
6-aryl derivatives of 3-aminoimidazo[1,2-a]pyrazines via
bromo-intermediates.
Figure 3. (A) Calculated energy barriers (ΔE‡gas) of activation (in kcal
EXPERIMENTAL SECTION
■
mol−1) for CMD TSs. (B) C6-CMD TS structure.
1
General Considerations. The H and 13C spectra were recorded
in CDCl3/DMSO-d6/CD3OD solvents on 400/500 MHz spectrom-
eter using TMS as internal standard. HRMS was measured using TOF
analyzer. Melting points determined are uncorrected.
which correlated with the experimental results. Computation
considering implicit solvent conditions (toluene) using IEFPCM
model also showed lowest barrier for C6-TS (27.06 kcal/mol)
relative to other sites (C5, C8 and C2′). The range of barrier
differences for C6, C5 and C8 (ΔE‡gas; 1.14−2.81 kcal mol−1
and ΔE‡solv; 1.07−2.60 kcal mol−1) was found to be in accordance
with the reported range of 0.7−6 kcal mol−1 for a variety of
arenes.7,9a
Representative Experimental Procedure for Synthesis of
N-(tert-Butyl)-2-phenyl-6-(4-tolyl)imidazo[1,2-a]pyrazin-3-amine
(Table 2, entry 1). PivOH (30 mg, 30 mol %), K2CO3 (276 mg,
2 mmol), PPh3 (52 mg, 20 mol %), and N-tert-butyl-2-phenylimidazo-
[1,2-a]pyrazin-3-amine (266 mg, 1 mmol) were taken subsequently
in a round-bottom flask under N2. To this mixture were added
4-bromotoluene (427 mg, 2.5 mmol), Pd(OAc)2 (22 mg, 10 mol %)
and anhydrous toluene (3 mL). The mixture was then stirred at 110 °C
for 24 h (monitored by TLC). The resultant mixture was taken in
EtOAc and washed with water. The organic solution was dried with
anhydrous Na2SO4 and concentrated in rotatory evaporator under a
vacuum. The column chromatographic purification of crude mixture
on silica gel eluting with hexane−EtOAc (4:1) provided N-(tert-
butyl)-2-phenyl-6-(4-tolyl)imidazo[1,2-a]pyrazin-3-amine (231 mg,
65% yield).
The analysis of distortion−interaction energy was studied
(Table 4). The distortion energy (Edist) is the energy associated
with distortion of arene and Pd-catalyst from their ground
states to form corresponding CMD TS geometries. The inter-
action energy (Eint) is the energy associated with interaction
between arene and Pd-catalyst in the TS. Wiberg bond index
(BPd−C) shows covalent bond interaction. The lower Edist was
observed for C6-CMD TS as compared to C5, C8, and C2′.
The more facile distortions in arene and Pd-complex for C6 TS
could be attributed to ring nitrogen atoms and substitutions of
the scaffold favoring to C6-site (Figure 3B). The gain due to
small Edist penalty for C6 was higher than the loss from less
negative Eint value. The CAr−Pd covalent interaction, quantified
by the Pd−CAr bond order (BPd−C6), was higher for C6 than
C5, C8 and C2′. In contrast, higher Edist were observed in case
of C5 and C8, which offsets the gain due to larger Eint values.
These signify the lower energy barrier for C6−H activation,
which is in correlation with the experimental regioselectivity.
The C2′−H TS is favored by neither Edist cost nor Eint gain.
The arylation at C2′ as competing side reaction took place
plausibly by directed C2′−H bond functionalization through
3-amino or imidazole ring nitrogen−palladium coordination.1
We next set out to gain insight into superior efficiency of pivalate
as proton shuttle to mesitylenecarboxylate and carbonate. The
energy barriers of activation for CMD TSs with corresponding
proton shuttles were evaluated. The relatively higher energies
(ΔE‡gas) of activation for mesitylenecarboxylate (28.60 kcal
mol−1) and carbonate (36.70 kcal mol−1) compared to pivalate
correlated with the experimental results.
All arylation reactions (Table 2 and 3) were carried out following
this experimental procedure.
1. N-tert-Butyl-2-phenyl-6-4-(tolyl)imidazo[1,2-a]pyrazin-3-
amine (Table 2, Entry 1). Yellow semisolid: 231 mg, 65% yield; IR
(neat) νmax = 3449, 2922, 1580, 1459 cm−1; H NMR (400 MHz,
1
CDCl3) δ = 8.99 (s, 1H), 8.13 (d, J = 7.28 Hz, 2H), 7.65 (s, 1H),
7.43−7.38 (m, 6H), 7.34−7.32 (m, 1H), 2.48 (s, 3H), 2.47 (brs, NH),
0.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ = 142.7, 142.3, 139.7,
138.1, 134.6, 131.3, 131.2, 129.5, 129.4 (2CH), 129.0 (2CH), 128.6
(2CH), 128.2 (2CH), 128.0, 127.1, 57.0, 29.3 (3CH3), 21.4; MS
(APCI) m/z 357 (MH+); HRMS (ESI) calcd for C23H24N4Na [M +
Na]+ 379.1893, found m/z 379.1903.
2. N-tert-Butyl-2-(4′-methylbiphenyl-2-yl)imidazo[1,2-a]pyrazin-
3-amine (Side Product, P2). White semisolid: IR (neat) νmax
=
1
3338, 2918, 1607, 1459 cm−1; H NMR (400 MHz, CDCl3) δ = 9.02
(d, J = 1.4 Hz, 1H), 7.97 (dd, J = 4.6 Hz, 1.4 Hz, 1H), 7.82−7.78 (m,
2H), 7.48−7.43 (m, 3H), 7.07 (m, 4H), 2.33 (s, 3H), 0.73 (s, 9H);
13C NMR (100 MHz, CDCl3) δ = 143.0, 142.9, 140.5, 138.2, 137.6,
137.2, 132.8, 131.9, 129.8, 129.5 (2CH), 128.8, 128.7 (2CH), 128.6,
127.7, 125.8, 116.4, 55.8, 29.4, 21.2; MS (APCI) m/z 357 (MH+);
HRMS (ESI) calcd for C23H24N4Na [M + Na]+ 379.1893, found m/z
379.1882.
In conclusion, we have discovered a novel regioselective
Pd-catalyzed direct C6-arylation of versatile substituted
3-aminoimidazo[1,2-a]pyrazines with various bromoarenes.
CMD process was found to be crucial in accomplishing the
Table 4. Analysis of Distortion/Interaction Energies for CMD TSs with Pivalate
site
ΔE‡
ΔE‡
ΔG‡
ΔG‡
Edist(ArH)
Edist(PdL
Eint
BPd−C
gas
solv
gas
solv
C5
C6
C8
C2′
25.25
24.11
26.92
48.76
28.13
27.06
29.66
51.06
40.52
40.31
41.01
65.71
43.41
48.56
40.89
53.09
2.79
22.76
18.29
23.08
34.30
−46.06
−35.08
−49.26
11.65
0.357
0.369
0.169
0.201
43.26
43.75
68.01
8324
dx.doi.org/10.1021/jo301065s | J. Org. Chem. 2012, 77, 8321−8328

The Journal of Organic Chemistry
Note
(brs, NH), 0.34 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ = 161.1,
143.1, 141.7 (2CH), 137.2, 134.3, 132.3 (d, J = 8 Hz), 131.2 (d, J = 25
Hz), 128.6, 128.5 (2CH), 128.1 (d, J = 3 Hz), 128.0 (2CH), 127.9,
126.9, 115.5 (d, J = 22 Hz), 114.2 (d, J = 21 Hz), 55.5. 28.9 (3CH3);
MS (APCI) m/z 361 (MH+); HRMS (ESI) calcd for C22H21FN4Na
+
[M + Na] 383.1642, found m/z 383.1634.
7. N-(tert-Butyl)-6-(4-cyanophenyl)-2-phenylimidazo[1,2-a]-
pyrazin-3-amine (Table 2, Entry 6). Yellow semisolid: 198 mg, 54%
1
yield; IR (neat) νmax = 3420, 2935, 2257, 1645, 1432 cm−1; H NMR
(400 MHz, DMSO-d6) δ = 9.01 (s, 1H), 8.07 (d, J = 7.44 Hz, 2H),
7.95 (d, J = 7.56 Hz, 2H), 7.85 (d, J = 7.52 Hz, 2H), 7.79 (s, 1H), 7.43
(t, J = 7.0 Hz, 2H), 7.37−7.34 (m, 1H), 4.08 (brs, NH), 0.31 (s, 9H);
13C NMR (100 MHz, DMSO-d6) δ = 143.6, 142.4, 136.9, 136.4, 134.1,
131.9, 131.1 (2CH), 130.9 (2CH), 130.3, 128.6 (2CH), 128.1 (2CH),
128.0, 127.1, 118.7, 111.0, 55.4, 28.8 (3CH3); MS (APCI) m/z 368
(MH+); HRMS (ESI) calcd for C23H21N5Na [M + Na]+ 390.1689,
found m/z 390.1693.
3. N-tert-Butyl-2,6-diphenylimidazo[1,2-a]pyrazin-3-amine
(Table 2, Entry 2). Yellow semisolid: 201 mg, 59% yield; IR (neat)
νmax = 3435, 2924, 1606, 1459 cm−1; 1H NMR (400 MHz, CDCl3) δ =
9.01 (s, 1H), 8.11 (d, J = 7.04 Hz, 2H), 7.68 (s, 1H), 7.59−7.53 (m,
5H), 7.44−7.40 (m, 2H), 7.35−7.33 (m, 1H), 2.43 (brs, NH), 0.46 (s,
9H); 13C NMR (100 MHz, CDCl3) δ = 143.0, 142.6, 138.1, 134.6,
132.5, 131.5, 131.1, 129.5, 129.2 (2CH), 128.7 (2CH), 128.6 (2CH),
128.2 (2CH), 128.1, 127.1, 57.0, 29.7 (3CH3); MS (APCI) m/z 343
(MH+); HRMS (ESI) calcd for C22H22N4Na [M + Na]+ 365.1737,
found m/z 365.1745.
8. N-(tert-Butyl)-6-(4-nitrophenyl)-2-phenylimidazo[1,2-a]-
pyrazin-3-amine (Table 2, Entry 7). Yellow semisolid: 201 mg, 52%
4. N-tert-Butyl-6-(naphthalen-1-yl)-2-phenylimidazo[1,2-a]-
pyrazin-3-amine (Table 2, Entry 3). Yellow semisolid: 204 mg, 52%
1
yield; IR (neat) νmax = 3451, 2925, 1592, 1443 cm−1; H NMR (400
MHz, CDCl3) δ = 9.07 (s, 1H), 8.40 (dd, J = 6.92 Hz, 1.8 Hz, 2H),
7.90 (d, J = 7.16 Hz, 2H), 7.78 (s, 1H), 7.74 (dd, J = 6.84 Hz, 1.92 Hz,
2H), 7.49−7.45 (m, 2H), 7.41−7.39 (m, 1H), 2.70 (brs, NH), 0.43 (s,
9H); 13C NMR (100 MHz, CDCl3) δ = 147.8, 144.5, 143.5, 138.5,
137.6, 134.0, 132.5, 130.6 (2CH), 129.6, 128.6 (4CH), 128.5, 127.0,
122.9 (2CH), 57.2, 29.2 (3CH3); MS (APCI) m/z 388 (MH+);
HRMS (ESI) calcd for C22H21N5NaO2 [M + Na]+ 410.1587, found
m/z 410.1576.
1
yield; IR (neat) νmax = 3313, 2926, 1610, 1472 cm−1; H NMR (400
MHz, CDCl3) δ = 9.10 (s, 1H), 8.06 (d, J = 8.44 Hz, 1H), 8.02−7.98
(m, 3H), 7.83 (s, 1H), 7.73−7.65 (m, 2H), 7.59−7.57 (m, 1H), 7.47
(t, J = 7.2 Hz, 1H), 7.38 (m, 2H), 7.31 (d, J = 7.3 Hz, 1H), 7.21 (d, J =
8.4 Hz, 1H), 0.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ = 143.3,
143.0, 137.8, 134.6, 133.0, 132.2, 132.0, 130.3, 130.0, 129.7, 129.1,
128.9, 128.7 (2CH), 128.2, 128.1 (2CH), 127.8, 127.1, 126.9, 125.3,
124.2, 56.0, 29.3 (3CH3), MS (APCI) m/z 393 (MH+); HRMS (ESI)
calcd for C26H24N4Na [M + Na]+ 415.1893, found m/z 415.1896.
5. N-tert-Butyl-6-(4-chlorophenyl)-2-phenylimidazo[1,2-a]-
pyrazin-3-amine (Table 2, Entry 4). Yellow semisolid: 229 mg, 61%
9. N-(tert-Butyl)-6-(4-formylphenyl)-2-phenylimidazo[1,2-a]-
pyrazin-3-amine (Table 2, Entry 8). Yellow semisolid: 177 mg, 48%
1
yield; IR (neat) νmax = 3391, 2920, 1702, 1601, 1444 cm−1; H NMR
(400 MHz, CDCl3) δ = 10.14 (s, 1H), 9.05 (s, 1H), 8.07 (d, J = 7.92
Hz, 2H), 7.99 (d, J = 7.32 Hz, 2H), 7.77 (s, 1H), 7.73 (d, J = 7.92 Hz,
2H), 7.47−7.44 (m, 2H), 7.39−7.37 (m, 1H), 2.56 (brs, NH), 0.43 (s,
9H); 13C NMR (100 MHz, CDCl3) δ = 191.3, 144.0, 143.2, 138.1,
137.8, 136.4, 134.1, 132.2, 130.3, 130.1 (2CH), 129.3 (2CH), 128.6
(2CH), 128.4 (2CH), 128.2, 127.0, 57.0, 29.3 (3CH3); MS (APCI)
m/z 371 (MH+); HRMS (ESI) calcd for C23H22N4NaO [M + Na]+
393.1686, found m/z 393.1704.
1
yield; IR (neat) νmax = 3390, 2967, 1533, 1478 cm−1; H NMR (400
MHz, CDCl3) δ = 8.93 (s, 1H), 7.93 (d, J = 7.12 Hz, 2H), 7.59 (s,
1H), 7.46 (d, J = 8.6 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7.37−7.34 (m,
2H), 7.29−7.27 (m, 1H), 2.43 (brs, NH), 0.40 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ = 143.5, 142.8, 138.0, 135.4, 134.4, 131.8, 130.8,
130.7 (2CH), 130.3, 128.6 (2CH), 128.5 (2CH), 128.3 (2CH), 128.2,
126.9, 57.0, 29.5 (3CH3); MS (APCI) m/z 377 (MH+); HRMS (ESI)
calcd for C22H21ClN4Na [M + Na]+ 399.1347, found m/z 399.1366.
6. N-(tert-Butyl)-6-(4-fluorophenyl)-2-phenylimidazo[1,2-a]-
pyrazin-3-amine (Table 2, Entry 5). Yellow semisolid: 172 mg, 48%
10. N-(tert-Butyl)-6-(4-methoxyphenyl)-2-phenylimidazo[1,2-a]-
pyrazin-3-amine (Table 2, Entry 9). Yellow semisolid: 189 mg, 51%
yield; IR (neat) νmax = 3438, 2924, 1633, 1468 cm−1; H NMR (400
MHz, CDCl3) δ = 8.98 (s, 1H), 8.11 (d, J = 7.48 Hz, 2H), 7.63 (s,
1H), 7.47−7.40 (m, 4H), 7.34−7.32 (m, 1H), 7.11 (d, J = 8.56 Hz,
2H), 3.91 (s, 3H), 2.52 (brs, NH), 0.50 (s, 9H); 13C NMR (100 MHz,
1
1
yield; IR (neat) νmax = 3442, 2923, 1613, 1472, 1275 cm−1; H NMR
(400 MHz, DMSO-d6) δ = 8.96 (s, 1H), 8.08 (d, J = 6.84 Hz, 2H),
7.71−7.66 (m, 3H), 7.43 (t, J = 6.9 Hz, 2H), 7.36−7.32 (m, 3H), 3.86
8325
dx.doi.org/10.1021/jo301065s | J. Org. Chem. 2012, 77, 8321−8328

The Journal of Organic Chemistry
Note
CDCl3) δ = 160.5, 142.7, 142.2, 138.2, 134.6, 131.3, 131.1, 130.5
(2CH), 128.6 (2CH), 128.2 (2CH), 128.0, 127.1, 124.6, 114.1 (2CH),
57.1, 55.6, 29.4 (3CH3); MS (APCI) m/z 373 (MH+); HRMS (ESI)
calcd for C23H24N4NaO [M + Na]+ 395.1842, found m/z 395.1857.
11. N-(tert-Butyl)-6-(3,5-dimethoxyphenyl)-2-phenylimidazo[1,2-
a]pyrazin-3-amine (Table 2, Entry 10). Yellow semisolid: 185 mg,
126.5, 126.1, 126.0, 57.2, 29.4 (3CH3), 21.4; MS (APCI) m/z 407
(MH+); HRMS (ESI) calcd for C27H26N4Na [M + Na]+ 429.2050,
found m/z 429.2064.
4. N-(tert-Butyl)-2-(4-chlorophenyl)-6-phenylimidazo[1,2-a]-
pyrazin-3-amine (Table 3, Entry 4). Yellow semisolid: 221 mg, 59%
yield; IR (neat) νmax = 3438, 2925, 1620, 1456 cm−1; H NMR (400
1
1
46% yield; IR (neat) νmax = 3438, 2927, 1629, 1345 cm−1; H NMR
MHz, CDCl3) δ = 9.0 (s, 1H), 8.13 (dd, J = 6.8 Hz, 1.8 Hz, 2H), 7.69
(s, 1H), 7.60−7.56 (m, 3H), 7.54−7.52 (m, 2H), 7.39 (dd, J = 6.8 Hz,
1.8 Hz, 2H), 2.38 (brs, NH), 0.49 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ = 142.7, 141.6, 138.2, 133.9, 133.1, 132.4, 131.6, 131.0,
129.8 (2CH), 129.6, 129.0 (2CH), 128.9 (2CH), 128.4 (2CH), 127.1,
57.2, 29.4 (3CH3); MS (APCI) m/z 377 (MH+); HRMS (ESI) calcd
for C22H21ClN4Na [M + Na]+ 399.1347, found m/z 399.1341.
5. N-(tert-Butyl)-2-(naphthalen-2-yl)-6-phenylimidazo[1,2-a]-
pyrazin-3-amine (Table 3, Entry 5). Yellow semisolid: 250 mg, 64%
(400 MHz, CDCl3) δ = 8.99 (s, 1H), 8.15 (d, J = 7.08 Hz, 2H), 7.70
(s, 1H), 7.43−7.40 (m, 2H), 7.34−7.32 (m, 1H), 6.66−6.62 (m, 3H),
3.87 (s, 6H), 2.64 (brs, NH), 0.55 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ = 161.2 (2C), 142.7, 142.6, 138.1, 134.6, 134.1, 131.1, 130.7,
128.6 (2CH), 128.2 (2CH), 128.1, 127.3, 107.3 (2CH), 101.1, 56.9,
55.8 (2CH3), 29.5 (3CH3); MS (APCI) m/z 403(MH+); HRMS
(ESI) calcd for C24H26N4NaO2 [M + Na]+ 425.1948, found m/z
425.1968.
Table 3. 1. N-tert-Butyl-2-propyl-6-(p-tolyl)imidazo[1,2-a]pyrazin-
3-amine (Table 3, Entry 1). Yellow semisolid: 228 mg, 71% yield; IR
1
yield; IR (neat) νmax = 3390, 2926,1611, 1415 cm−1; H NMR (400
MHz, CDCl3) δ = 9.05 (s, 1H), 8.65 (s, 1H), 8.32 (dd, J = 8.6 Hz, 1.48
Hz, 1H), 7.93−7.91 (m, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.85−7.82 (m,
1H), 7.70 (s, 1H), 7.61−7.55 (m, 5H), 7.49−7.46 (m, 2H), 2.50 (brs,
NH), 0.50 (s, 9H); 13C NMR (100 MHz, CDCl3) δ = 142.64, 142.6,
138.3, 133.4, 133.1, 132.5, 132.1, 131.6, 131.1, 129.6, 129.1 (2CH),
128.9 (2CH), 128.4, 127.66, 127.63, 127.62, 127.4, 126.5, 126.1, 126.0,
57.2, 29.3 (3CH3); MS (APCI) m/z 393 (MH+); HRMS (ESI) calcd
for C26H24N4Na [M + Na]+ 415.1893, found m/z 415.1882.
(neat) νmax = 3380, 2961, 1613,1482 cm−1; 1H NMR (400 MHz,
CDCl3) δ = 8.89 (s, 1H), 7.62 (s, 1H), 7.34 (m, 4H), 2.79 (t, J = 7.8
Hz, 2H), 2.46 (s, 3H), 2.35 (brs, NH), 1.90−1.84 (m, 2H), 1.04−1.01
(t, J = 7.36 Hz, 3H), 0.63 (s, 9H); 13C NMR (100 MHz, CDCl3) δ =
145.9, 141.4, 139.4, 138.1, 131.2, 131.1, 129.5, 129.3 (2CH), 128.9
(2CH), 126.7, 55.9, 30.1, 29.3 (3CH3), 22.6, 21.3, 14.3; MS (APCI)
m/z 323 (MH+); HRMS (ESI) calcd for C20H26N4Na [M + Na]+
345.2050, found m/z 345.2055.
6. N-(tert-Butyl)-6-(4-chlorophenyl)-2-(naphthalen-2-yl)imidazo-
[1,2-a]pyrazin-3-amine (Table 3, Entry 6). Yellow semisolid: 277 mg,
2. N-(tert-Butyl)-6-(4-chlorophenyl)-2-propylimidazo[1,2-a]-
pyrazin-3-amine (Table 3, Entry 2). Yellow semisolid: 232 mg, 68%
65% yield; IR (neat) νmax = 3437, 2925, 1605, 1461 cm−1; H NMR
1
1
yield; IR (neat) νmax = 3389, 2962, 1533, 1478 cm−1; H NMR (400
(400 MHz, CDCl3) δ = 9.06 (s, 1H), 8.56 (s, 1H), 8.22 (dd, J = 8.52
Hz, 1.6 Hz, 1H), 7.94−7.89 (m, 2H), 7.86−7.84 (m, 1H), 7.69 (s,
1H), 7.59−7.57 (m, 2H), 7.52−7.48 (m, 4H), 2.54 (brs, NH), 0.50 (s,
9H); 13C NMR (100 MHz, CDCl3) δ = 143.3, 142.8, 138.1, 135.6,
133.4, 133.2, 131.8, 131.7, 130.8, 130.6 (2CH), 130.3, 128.7 (3CH),
128.4, 127.8, 127.7 (2CH), 127.2, 126.3, 126.2, 57.2, 29.4 (3CH3); MS
(APCI) m/z 427(MH+); HRMS (ESI) calcd for C26H23ClN4Na [M +
Na]+ 449.1503, found m/z 449.1503.
MHz, CDCl3) δ = 8.91 (s, 1H), 7.64 (s, 1H), 7.48 (dd, J = 8.30 Hz,
1.12 Hz, 2H), 7.42 (d, J = 8.28 Hz, 2H), 2.81−2.77 (m, 2H), 2.36 (brs,
NH), 1.90−1.84 (m, 2H), 1.03 (t, J = 7.24 Hz, 3H), 0.66 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ = 146.1, 141.7, 137.9, 135.1, 131.6, 131.1
(2CH), 130.6, 130.3, 128.0 (2CH), 126.7, 55.9, 30.0, 29.5 (3CH3),
22.6, 14.3; MS (APCI) m/z 343 (MH+); HRMS (ESI) calcd for
C19H23ClN4Na [M + Na]+ 365.1503, found m/z 365.1512.
3. N-tert-Butyl-2-(naphthalen-2-yl)-6-(p-tolyl)imidazo[1,2-a]-
pyrazin-3-amine (Table 3, Entry 3). Yellow semisolid: 247 mg, 61%
7. N-Cyclohexyl-2-(4-methoxyphenyl)-6-phenylimidazo[1,2-a]-
pyrazin-3-amine (Table 3, Entry 7). Yellow semisolid: 286 mg, 72%
1
1
yield; IR (neat) νmax = 3391, 2969, 1598, 1479 cm−1; H NMR (400
yield; IR (neat) νmax = 3380, 2927, 1610, 1448, 1250 cm−1; H NMR
MHz, CDCl3) δ = 9.04 (s, 1H), 8.67 (s, 1H), 8.35 (dd, J = 8.7 Hz, 1.64
Hz, 1H), 7.93−7.91 (m, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.84−7.81 (m,
1H), 7.66 (s, 1H), 7.47−7.46 (m, 2H), 7.44−7.39 (m, 4H), 2.54 (brs,
NH), 2.48 (s, 3H), 0.49 (s, 9H); 13C NMR (100 MHz, CDCl3) δ =
142.4, 142.3, 139.8, 138.3, 133.4, 133.1, 132.2, 131.4, 131.2, 129.52
(2CH), 129.49, 128.9 (2CH), 128.4, 127.64, 127.58 (2CH), 127.5,
(400 MHz, CDCl3) δ = 8.96 (s, 1H), 8.12 (d, J = 8.72 Hz, 2H), 7.61
(s, 1H), 7.55 (m, 5H), 6.96 (d, J = 8.68 Hz, 2H), 3.85 (s, 3H), 2.51 (d,
J = 6.08 Hz, NH), 2.26−2.21 (m, 1H), 1.37−1.34 (m, 3H), 1.02−0.99
(m, 2H), 0.84−0.79(m, 3H), 0.59−0.50 (m, 2H); 13C NMR (100
MHz, CDCl3) δ = 159.4, 142.2, 139.3, 137.5, 131.8, 130.6, 130.3,
129.6, 129.4 (2CH), 129.1(2CH), 128.4 (2CH), 127.5, 126.5, 113.7
8326
dx.doi.org/10.1021/jo301065s | J. Org. Chem. 2012, 77, 8321−8328

The Journal of Organic Chemistry
Note
(2CH), 57.3, 55.2, 33.7 (2CH2), 25.5, 24.6 (2CH2); MS (APCI) m/z
399 (MH+); HRMS (ESI) calcd for C25H26N4NaO [M + Na]+
421.1999, found m/z 421.1998.
8. N-Cyclohexyl-2-(4-chlorophenyl)-6-phenylimidazo[1,2-a]-
pyrazin-3-amine (Table 3, Entry 8). Yellow semisolid: 297 mg, 74%
120.1, 90.8 (2CH), 61.1 (OCH3), 55.9 (2OCH3); MS (APCI) m/z
515 (MH+); HRMS (ESI) calcd for C28H23ClN4NaO4 [M + Na]+
537.1306, found m/z 537.1318.
12. N-Butyl-6-(4-chlorophenyl)-2-phenylimidazo[1,2-a]pyrazin-3-
amine (Table 3, Entry 12). Yellow oil: 199 mg, 53% yield; IR (neat)
1
yield; IR (neat) νmax = 3336, 2927, 1631, 1488 cm−1; H NMR (400
MHz, CDCl3) δ = 8.98 (s, 1H), 8.16 (dd, J = 6.76 Hz, 1.92 Hz, 2H),
7.64 (s, 1H), 7.63−7.53 (m, 5H), 7.40 (dd, J = 6.76 Hz, 1.92 Hz, 2H),
2.48 (d, J = 5.84 Hz, NH), 2.28−2.21 (m, 1H), 1.38−1.34 (m, 3H),
1.01−0.98 (m, 2H), 0.84−0.76 (m, 3H), 0.59−0.50 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ = 142.7, 138.1, 137.6, 133.7, 132.4, 131.6,
130.7, 130.4, 129.9, 129.4 (2CH), 129.0 (2CH), 128.6 (2CH), 128.5
(2CH), 128.1, 57.5, 32.7 (2CH2), 25.4, 24.6 (2CH2); MS (APCI) m/z
403 (MH+); HRMS (ESI) calcd for C24H23ClN4Na [M + Na]+
425.1503, found m/z 425.1504.
νmax = 3402, 2967, 1653, 1275 cm−1; 1H NMR (500 MHz, CDCl3) δ =
8.97 (s, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.60 (s, 1H), 7.55−7.51 (m,
4H), 7.46−7.43 (m, 2H), 7.36−7.34 (m, 1H), 2.41 (m, 2H), 1.74 (brs,
NH), 0.96−0.92 (m, 4H), 0.72−0.69 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ = 143.0, 137.9, 137.1, 136.1, 133.5, 131.0 (2CH), 130.6,
130.0, 129.7, 129.4, 128.8 (2CH), 128.5 (2CH), 128.2, 127.5 (2CH),
49.1, 31.8, 19.8, 13.8; MS (APCI) m/z 377 (MH+); HRMS (ESI)
calcd for C22H21ClN4Na [M + Na]+ 399.1347, found m/z 399.1340.
9. 2-(4-Chlorophenyl)-6-phenyl-N-(3,4,5-trimethoxyphenyl)-
imidazo[1,2-a]pyrazin-3-amine (Table 3, Entry 9). Yellow semisolid:
ASSOCIATED CONTENT
■
S
* Supporting Information
Details of computational studies and 1H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
243 mg, 50% yield; IR (neat) νmax = 3420, 2923, 1607, 1445, 1219
cm−1; 1H NMR (400 MHz, CDCl3) δ = 9.10 (s, 1H), 8.04 (d, J = 7.76
Hz, 2H), 7.66 (s, 1H), 7.42−7.40 (m, 1H), 7.36−7.32 (m, 4H), 7.25−
7.23 (m, 2H), 5.06 (s, 2H), 4.70 (brs, NH), 3.71 (s, 3H), 3.51 (s, 6H);
13C NMR (100 MHz, CDCl3) δ = 153.7 (2C), 142.9, 141.7, 140.2,
138.5, 134.6, 131.8, 131.3, 131.0, 130.9, 130.8, 129.3 (2CH), 129.2,
128.9 (2CH), 128.7 (2CH), 128.0 (2CH), 120.5, 91.0 (2CH), 61.0
(OCH3), 55.8 (2OCH3); MS (APCI) m/z 487 (MH+); HRMS (ESI)
calcd for C27H23ClN4NaO3 [M + Na]+ 509.1356, found m/z 509.1357.
10. 2-(4-Chlorophenyl)-N-(4-methoxyphenyl)-6-(4-
formylphenyl)imidazo[1,2-a]pyrazin-3-amine (Table 3, Entry 9).
AUTHOR INFORMATION
Corresponding Author
*Tel: 91 (0)172 2214683. Fax: 91 (0)172 2214692. E-mail:
skguchhait@niper.ac.in.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from DST, New
Delhi, for this investigation.
■
REFERENCES
■
(1) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107,
174−238. (b) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110,
1147−1169. (c) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew.
Chem., Int. Ed. 2009, 48, 9792−9826. (d) Chen, X.; Engle, K. M.;
Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094−5115.
(2) (a) Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6722−6737.
(b) Negishi, E-i Angew. Chem., Int. Ed. 2011, 50, 6738−6764.
(3) (a) Strotman, N. A.; Chobanian, H. R.; Guo, Y.; He, J.; Wilson, J.
E. Org. Lett. 2010, 12, 3578−3581. (b) Ohnmacht, S. A.; Mamone, P.;
Culshaw, A. J.; Greaney, M. F. Chem. Commun. 2008, 44, 1241−1243.
(c) Turner, G. L.; Morris, J. A.; Greaney, M. F. Angew. Chem., Int. Ed.
2007, 46, 7996−8000. (d) Roger, J.; Doucet, H. Adv. Synth. Catal.
2009, 351, 1977−1990. (e) Joucla, L.; Djakovitch, L. Adv. Synth. Catal.
2009, 351, 673−714.
(4) (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura,
M. Bull. Chem. Soc. Jpn. 1998, 71, 467−473. (b) Lane, B. S.; Brown, M.
A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050−8057. (c) Park, C.-
H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan, V. Org. Lett.
2004, 6, 1159−1162.
(5) (a) Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.; Javadi,
G. J.; Cai, D.; Larsen, R. D. Org. Lett. 2003, 5, 4835−4837. (b) Wang,
Yellow semisolid: 254 mg, 56% yield; IR (neat) νmax = 3392, 2917,
1
1701, 1604, 1445 cm−1; H NMR (400 MHz, CDCl3) δ = 10.03 (s,
1H), 9.13 (s, 1H), 7.98 (d, J = 8.28 Hz, 2H), 7.75 (d, J = 7.78 Hz, 2H),
7.67 (s, 1H), 7.38 (d, J = 7.78 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 6.49
(d, J = 8.52 Hz, 2H), 5.79 (d, J = 8.52 Hz, 2H), 4.71 (brs, NH), 3.68
(s, 3H); 13C NMR (100 MHz, CDCl3) δ = 191.3, 153.8, 143.5, 141.9,
138.4, 137.2, 136.6, 136.4, 134.7, 130.9 (1CH, 1C), 130.2, 130.0
(2CH), 128.9 (2CH), 128.7 (2CH), 128.5(2CH), 120.9, 114.7
(2CH), 114.1(2CH), 55.6; MS (APCI) m/z 455 (MH+); HRMS
(ESI) calcd for C26H19ClN4NaO2 [M + Na]+ 477.1094, found m/z
477.1079.
11. 2-(4-Chlorophenyl)-6-(4-formylphenyl)-N-(3,4,5-
trimethoxyphenyl)imidazo[1,2-a]pyrazin-3-amine (Table 3, Entry
11). Yellow semisolid: 267 mg, 52% yield; IR (neat) νmax = 3401, 2928,
1
1698, 1599, 1431 cm−1; H NMR (400 MHz, CDCl3) δ = 10.03 (s,
1H), 9.15 (s, 1H), 8.00 (d, J = 7.76 Hz, 2H), 7.79 (d, J = 7.12 Hz, 2H),
7.71 (s, 1H), 7.41−7.37 (m, 4H), 5.03 (s, 2H), 4.80 (brs, NH), 3.72
(s, 3H), 3.47 (s, 6H); 13C NMR (100 MHz, CDCl3) δ = 191.2, 153.9
(2C), 143.6, 142.3, 139.9, 138.5, 136.6, 136.4, 134.9, 132.0, 131.0,
130.8, 130.2, 130.1 (2CH), 129.0 (2CH), 128.7 (2CH), 128.6 (2CH),
8327
dx.doi.org/10.1021/jo301065s | J. Org. Chem. 2012, 77, 8321−8328

The Journal of Organic Chemistry
Note
J.-X.; McCubbin, J. A.; Jin, M.; Laufer, R. S.; Mao, Y.; Crew, A. P.;
Mulvihill, M. J.; Snieckus, V. Org. Lett. 2008, 10, 2923−2926.
(6) Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc.
2002, 124, 5286−5287.
(7) (a) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 8754−8756. (b) Lafrance, M.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 16496−16497.
(8) García-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A.
M. J. Am. Chem. Soc. 2006, 128, 1066−1067.
(9) (a) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Org. Chem. 2012,
́
77, 658−668. (b) Liegault, B.; Lapointe, D.; Caron, L.; Vlassova, A.;
Fagnou, K. J. Org. Chem. 2009, 74, 1826−1834. (c) Gorelsky, S. I.;
Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848−10849.
(d) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118−1126.
(e) Potavathri, S.; Pereira, K. C.; Gorelsky, S. I.; Pike, A.; LeBris, A. P.;
DeBoef, B. J. Am. Chem. Soc. 2010, 132, 14676−14681. (f) Campeau,
L.-C.; Bertrand-Laperle, M.; Leclerc, J.-P.; Villemure, E.; Gorelsky, S.
I.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3276−3277. (g) Caron, L.;
Campeau, L.-C.; Fagnou, K. Org. Lett. 2008, 10, 4533−4536.
(10) (a) Wang, J.-X.; McCubbin, J. A.; Jin, M.; Laufer, R. S.; Mao, Y.;
Crew, A. P.; Mulvihill, M. J.; Snieckus, V. Org. Lett. 2008, 10, 2923−
2926. (b) Gauthier, D. R., Jr.; Limanto, J.; Devine, P. N.; Desmond, R.
A.; Szumigala, R. H., Jr.; Foster, B. S.; Volante, R. P. J. Org. Chem.
2005, 70, 5938−5945. (c) Li, W.; Nelson, D. P.; Jensen, M. S.;
Hoerrner, R. S.; Javadi, G. J.; Cai, D.; Larsen, R. D. Org. Lett. 2003, 5,
4835−4837. (d) El Akkaoui, A.; Berteina-Raboin, S.; Mouaddib, A.;
Guillaumet, G. Eur. J. Org. Chem. 2010, 862−871.
(11) (a) Demirayak, S.; Kayagil, I.; Yurttas, L. Eur. J. Med. Chem.
2011, 46, 411−416. (b) Mitchell, S. A.; Danca, M. D.; Blomgren, P. A.;
Darrow, J. W.; Currie, K. S.; Kropf, J. E.; Lee, S. H.; Gallion, S. L.;
Xiong, J. M.; Pippin, D. A.; DeSimone, R. W.; Brittelli, D. R.; Eustice,
D. C.; Bourret, A.; Hill-Drzewi, M.; Maciejewski, P. M.; Elkin, L. L.
Bioorg. Med. Chem. Lett. 2009, 19, 6991−6995. (c) Vitse, O.; Laurent,
F.; Pocock, T. M.; Benezech, V.; Zanik, L.; Elliott, K. R.; Subra, G.;
Portet, K.; Bompart, J.; Chapat, J. P.; Small, R. C.; Michel, A.; Bonnet,
P. A. Bioorg. Med. Chem. 1999, 7, 1059−1065. (d) Zimmermann, P. J.;
Brehm, C.; Buhr, W.; Palmer, A. M.; Volz, J.; Simon, W. A. Bioorg.
Med. Chem. 2008, 16, 536−541. (e) Galcera Contour, M.-O.; Poitout,
L.; Moinet, C.; Morgan, B.; Gordon, T.; Roubert, P.; Thurieau, C.
Bioorg. Med. Chem. Lett. 2001, 11, 741−745.
(12) For our works: (a) Baviskar, A. T.; Madaan, C.; Preet, R.;
Mohapatra, P.; Jain, V.; Agarwal, A.; Guchhait, S. K.; Kundu, C. N.;
Banerjee, U. C.; Bharatam, P. V. J. Med. Chem. 2011, 54, 5013−5030.
(13) (a) Odell, L. R.; Nilsson, M. T.; Gising, J.; Lagerlund, O.;
Muthas, D.; Nordqvist, A.; Karlen, A.; Larhed, M. Bioorg. Med. Chem.
Lett. 2009, 19, 4790−4793. (b) Pastor, F. J.; Martinez, G. S.;
Oyarzabal, S. T. WO PCT Int. Appl. 2010, 2010119264 A1.
(14) (a) For similar observation in other arylations: Campeau, L.-C.;
Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581−
590. (b) Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006, 46,
7781−7786.
(15) These Ugi-type MCRs were first reported in 1998. (a) Groebke,
K.; Weber, L.; Mehlin, F. Synlett 1998, 661−663. (b) Blackburn, C.;
Guan, B.; Fleming, K.; Shiosaki, K.; Tsai, S. Tetrahedron Lett. 1998, 39,
3635−3638. (c) Bienayme, H.; Bouzid, K. Angew. Chem., Int. Ed. 1998,
37, 2234−2237.
(16) For our publications in this area: (a) Guchhait, S. K.;
Chandgude, A. L.; Priyadarshani, G. J. Org. Chem. 2012, 77, 4438−
4444. (b) Guchhait, S. K.; Madaan, C. Org. Biomol. Chem. 2010, 8,
3631−3634. (c) Guchhait, S. K.; Madaan, C. Synlett 2009, 628−632.
(d) Guchhait, S. K.; Madaan, C.; Thakkar, B. S. Synthesis 2009, 3293−
3300. (e) Guchhait, S. K.; Madaan, C. Tetrahedron Lett. 2011, 52, 56−
58. (f) Baviskar, A. T.; Madaan, C.; Preet, R.; Mohapatra, P.; Jain, V.;
Agarwal, A.; Guchhait, S. K.; Kundu, C. N.; Banerjee, U. C.; Bharatam,
P. V. J. Med. Chem. 2011, 54, 5013−5030.
8328
dx.doi.org/10.1021/jo301065s | J. Org. Chem. 2012, 77, 8321−8328