An efficient access to 2,3-diarylimidazo[1,2-a]pyridines via imidazo[1,2-a]pyridin-2-yl triflate through a Suzuki cross-coupling reaction-direct arylation sequence

Article abstract of DOI:10.1016/j.tetlet.2011.11.015

An efficient method to prepare 2,3-diarylimidazo[1,2-a]pyridines is described. The procedure involves a Suzuki cross-coupling reaction followed by a direct arylation at position 3. Imidazo[1,2-a]pyridin-2-yl triflate was identified as a suitable coupling partner, permitting access to a variety of highly functionalized 2,3-diarylimidazo[1,2-a]pyridines.

Full text of DOI:10.1016/j.tetlet.2011.11.015

Tetrahedron Letters 53 (2012) 297–300
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient access to 2,3-diarylimidazo[1,2-a]pyridines via
imidazo[1,2-a]pyridin-2-yl triflate through a Suzuki cross-coupling
reaction-direct arylation sequence
⇑
⇑
Sophie Marhadour, Marc-Antoine Bazin , Pascal Marchand
Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections, de l’Immunité et du Cancer, IICiMed EA 1155,
UFR de Sciences Pharmaceutiques et Biologiques, 1 rue Gaston Veil, 44035 Nantes, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method to prepare 2,3-diarylimidazo[1,2-a]pyridines is described. The procedure involves a
Suzuki cross-coupling reaction followed by a direct arylation at position 3. Imidazo[1,2-a]pyridin-2-yl tri-
flate was identified as a suitable coupling partner, permitting access to a variety of highly functionalized
2,3-diarylimidazo[1,2-a]pyridines.
Received 5 October 2011
Revised 27 October 2011
Accepted 4 November 2011
Available online 10 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Imidazo[1,2-a]pyridines
Suzuki–Miyaura reaction
Direct arylation
2,3-Diarylimidazo[1,2-]pyridines
Triflate
Imidazo[1,2-a]pyridines are a class of nitrogen bridgehead het-
erocycles which have received considerable attention due to their
interesting biological activities.1 Moreover, 2,3-diarylimidazo[1,2-
a]pyridines 1 (Fig. 1) have shown antiprotozoal,2 antiviral,3 and
anti-apoptotic4 activities, and have attracted attention as liver X
receptor agonists5 and kinase inhibitors.6 The increased interest
in this class of compounds led us to envisage an efficient synthetic
method. To the best of our knowledge, the access to highly func-
tionalized 2,3-diarylimidazo[1,2-a]pyridines has not yet been de-
scribed in the literature.
followed by a two-step process including Pd-catalysed Suzuki–
Miyaura and direct arylation reactions.
R
N
2
N
3
Initially, 2-arylimidazo[1,2-a]pyridine cores must be built up.
The most common route for the preparation of such compounds in-
volves condensation between 2-aminopyridine and 2-bromoaceto-
phenone.7 However, such strategy is limited by the commercial
availability of 2-bromoacetophenones. Thus, we envisaged that a
Pd-catalysed Suzuki cross-coupling reaction could proceed at posi-
tion 2 with an appropriate coupling partner.
R'
Figure 1. 2,3-Diarylimidazo[1,2-a]pyridines 1.
N
N
Ar
Ar
N
N
A retrosynthetic strategy for the synthesis of 2,3-diarylimi-
dazo[1,2-a]pyridines is outlined in Scheme 1. Targeted compounds
1 could be obtained from 2-halogenoimidazo[1,2-a]pyridines 3,
readily available from commercially-available 2-aminopyridine
2
(het)Ar'
1
NH2
N
X
N
N
⇑
Corresponding authors. Tel.: +33 240 411 114; fax: +33 240 412 876 (M.-A.B.);
tel.: +33 240 412 874; fax: +33 240 412 876 (P.M.).
3
E-mail addresses: marc-antoine.bazin@univ-nantes.fr (M.-A. Bazin), pascal.
marchand@univ-nantes.fr (P. Marchand).
Scheme 1. Retrosynthetic pathway of 2,3-diarylimidazo[1,2-a]pyridines 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.015

298
S. Marhadour et al. / Tetrahedron Letters 53 (2012) 297–300
N
N
N
NH2
NH
CO2H
Direct arylation
ii
i
X
N
N
N
N
N
Path b
2a
Halogenation
4
Ar = Ph, 7a
Ar
3a : X = Cl
3b : X = Br
Ar = 4-pyridyl, 7b
. HBr
NH
CO2Et
. HBr
Suzuki-Miyaura
N
N
cross-coupling reaction
N
N
iii
iv
Path a
OTf
+
N
R = Br, 6a
R = I, 6b
R
N
O
3c
N
Scheme 4. Synthesis of 7a–b from 2a.
5
Scheme 2. Synthesis of 3a–c. Reagents and conditions: (i) ClCH2CO2H, Et3N, H2O,
90 °C, 5 h, then EtOH, 5 °C, 2 h, 71%; (ii) X = Cl, POCl3, toluene, reflux, 16 h, 88%;
X = Br, POBr3, toluene, reflux, 16 h, 9%; (iii) BrCH2CO2Et, 0 °C?rt, 15 min, then EtOH,
reflux, 18 h; (iv) PhNTf2, Et3N, toluene, reflux, 20 h, 67% (two steps).
Table 2
Synthesis of 7a–b via halogenation-Suzuki–Miyaura coupling sequence (path a)
Entry Substrate Conditions
Product Yielda
(%)
1
2
3
2a
2a
6a
NBS, MeCN, rt, 2 h
NIS, MeCN, rt, 1 h
6a
6b
7a
95
73
90
N
N
PhB(OH)2
PhB(OH)2, Pd(PPh3)4, Na2CO3,
dioxane–H2O 2:1, 110 °C, 2 h
(4-Pyridyl)boronic acid pinacol ester, 7b
Pd(PPh3)4, Na2CO3, dioxane–H2O 2:1,
110 °C, 2 h
PhB(OH)2, Pd(PPh3)4, Na2CO3,
dioxane–H2O 2:1, sealed tube, reflux,
12 h
(4-Pyridyl)boronic acid pinacol ester, 7b
Pd(PPh3)4, Na2CO3, dioxane–H2O 2:1,
sealed tube, reflux, 12 h
R
N
N
Na2CO3, Pd(PPh3)4,
solvent, heat
4
5
6
6a
6b
6b
93
93
95
3a, R = Cl
3b, R = Br
3c, R = OTf
2a
7a
Scheme 3. Synthesis of 2a.
We first started with the synthesis of 2-halogenoimidazo[1,2-
a]pyridines from 2-aminopyridine (Scheme 2). 2-Aminopyridine
was reacted with chloroacetic acid to afford acetic acid derivative
4 in a good yield. Subsequent cyclization with POCl3 and POBr3,
respectively, led to 2-chloroimidazo[1,2-a]pyridine 3a and its bro-
minated analogue 3b.8 These conditions proved to be successful for
3a but afforded a very low yield of 3b (extraction failure). We next
decided to prepare imidazo[1,2-a]pyridin-2-yl triflate9 3c which
could be an efficient coupling partner in the Suzuki–Miyaura
cross-coupling reaction. Thus, 2-aminopyridine reacted with ethyl
bromoacetate to give 5, as a mixture of the expected product and a
non-cyclized intermediate. Subsequent treatment with N-phenyl-
bis(trifluoromethanesulfonimide) led to 3c in a satisfactory yield
(67%, two steps).10
a
Isolated yield.
Table 3
Synthesis of 7a–b via direct arylation (path b)
Entry Substrate Conditions
Product Yielda
(%)
1
2
3
2a
2a
2a
PhBr, Pd(OAc)2, PPh3, K2CO3, dioxane– 7a
37b
EtOH, MW, 130 °C, 1 h
PhBr, Pd(OAc)2, PCy3ꢀHBF4, PivOH,
K2CO3, DMA, sealed tube, 100 °C, 16 h
4-Bromopyridine hydrobromide,
Pd(OAc)2, PCy3.HBF4, PivOH, K2CO3,
DMA, sealed tube, 100 °C, 16 h
7a
7b
95
85
With these suitable substrates in our hand, the Suzuki–Miyaura
reaction of 3a, 3b and 3c with phenylboronic acid afforded 2-
phenylimidazo[1,2-a]pyridine 2a (Scheme 3 and Table 1).
We noticed that 2-chloroimidazo[1,2-a]pyridine 3a was less
reactive than the corresponding bromide 3b (Table 1, entries 1
and 2). Interestingly, triflate 3c proved to be effective in the cou-
pling reaction carried out in a sealed tube with a shorter time (en-
try 3). No difference was observed when the reaction was
performed in 1,4-dioxane (entry 4). Thus these results prompted
us to employ imidazo[1,2-a]pyridin-2-yl triflate 3c as a substrate
for further Suzuki–Miyaura cross-coupling reaction at position 2
of the scaffold.
a
Isolated yield.
b
Significant amount of starting material (41%, UPLC-MS) was remaining.
We next investigated the preparation of 2,3-diarylimidazo[1,2-
a]pyridines 1 through two methods. Initially, we thought that a
halogenation-Suzuki–Miyaura coupling sequence11 could give the
desired products (Scheme 4, path a). Halogenation with NBS or
NIS in acetonitrile afforded easily the compounds 6a and 6b, pre-
cursors for a Suzuki–Miyaura coupling reaction (Table 2, entries
1 and 2). This reaction was carried out using phenylboronic acid
and (4-pyridyl)boronic acid pinacol ester as Suzuki coupling part-
ners in a heterogeneous mixture of 1,4-dioxane, water, sodium car-
Table 1
Synthesis of 2a
bonate,
in
the
presence
of
catalytic
amount
of
Entry Substrate Conditions
Yield of 2aa
tetrakis(triphenylphosphine)palladium(0). The corresponding cou-
pling products 7a and 7b were both isolated in excellent yields
(90–95%) (entries 3–6).
In addition, this method was compared to a palladium-cata-
lysed direct arylation reaction starting from 2-phenylimi-
dazo[1,2-a]pyridine 2a (Scheme 4, path b). Following the
procedure described by Guillaumet,12 we observed that a signifi-
cant amount of the starting material remained (Table 3, entry 1).
(%)
1
2
3
4
3a
3b
3c
3c
DME–H2O 2:1, reflux, sealed tube, 6 h
DME–H2O 2:1, reflux, sealed tube, 6 h
DME–H2O 2:1, 100 °C, sealed tube, 4 h
Dioxane–H2O 2:1, 100 °C, sealed tube,
7 h
25
51
46
43
a
Isolated yield.

S. Marhadour et al. / Tetrahedron Letters 53 (2012) 297–300
299
(het)Ar'Br, Pd(OAc)2,
N
N
N
ArB(OH)2, Pd(PPh3)4,
PCy3.HBF4, PivOH,
Ar
OTf
Ar
N
N
N
K2CO3, DMA,
Na2CO3, dioxane-H2O 2:1,
sealed tube, 100 °C
sealed tube, 100 °C
3c
(het)Ar'
2a-i
1a-p
Scheme 5. Synthesis of 1a–p from triflate 3c through Suzuki coupling-direct arylation sequence.
Table 4
Synthesis of 1a-pa
Entry
Compd
Ar
Time
Yieldb (%)
Compd
(het) Ar0
Time
Yieldb (%)
1
2
3
4
5
6
7
8
2a
2b
2c
C6H5
3-ClC6H4
3,5-(Cl)2C6H3
7 h
6 h
45 min
43
45
35
1a
1b
1c
1d
1ec
1f
1g
1h
1i
4-(NO2)C6H4
C6H5
C6H5
3-Pyridyl
C6H5
3-Pyridyl
C6H5
3-Pyridyl
3-(NO2)C6H4
3-(MeO)C6H4
C6H5
C6H5
C6H5
36 h
21 h
18 h
15 h
31 h
14 h
15 h
15 h
16 h
72 h
13 h
18 h
10 h
18 h
72 h
21 h
93
83
83
69
64
85
60
56
92
44
27
15
81
67
40
84
2d
2e
2-FC6H4
4-FC6H4
1 h
1 h
97
41
9
10
11
12
13
14
15
16
1jd
1k
1lc
1m
1n
1od
1pe
2f
2g
2h
4-(CO2Et)C6H4
4-(NO2)C6H4
4-(MeO)C6H4
45 min
4 h
45 min
9
26
78
3-(NO2)C6H4
3-(MeO)C6H4
C6H5
2i
2-(MeO)C6H4
1 h
94
a
Direct arylation conditions: 2a–i 1 equiv, (het) Ar0Br 1 equiv, Pd(OAc)2 2 mol %, PCy3.HBF4 4 mol %, PivOH 0.3 equiv, K2CO3 1.5 equiv, DMA, sealed tube, 100 °C.
Isolated yield.
b
c
Reagents and conditions: Pd(OAc)2 4 mol %, PCy3.HBF4 8 mol %, PivOH 0.6 equiv.
d
e
Reagents and conditions: (het) Ar0Br 3.0 equiv, Pd(OAc)2 8 mol %, PCy3.HBF4 16 mol %, PivOH 1.2 equiv, K2CO3 2.0 equiv.
Reagents and conditions: (het) Ar0Br 1.3 equiv, Pd(OAc)2 4 mol %, PCy3ꢀHBF4 8 mol %.
The reaction did not proceed to completion even after 2 h. We tried
conditions to provide products 1g, 1i, 1m and 1n in good yields
(entries 7, 9, 13 and 14). In contrast, with both substrates, use of
3-bromoanisole gave the corresponding products in lower yields
(40% and 44%) even if an excess of reagents was added (entries
10 and 15). Finally, compounds 2 bearing electron-poor substitu-
ent (i.e. ester or nitro group) were found to proceed in lower yields
for direct arylation with bromobenzene (entries 11 and 12). Based
on these results, C-3 direct arylation of 2-arylimidazo[1,2-a]pyri-
dines 2 is influenced by electronic effects of the ring in position 2.
In summary, we have developed a straightforward method for
the synthesis of 2,3-diarylimidazo[1,2-a]pyridines from imi-
dazo[1,2-a]pyridin-2-yl triflate readily available from 2-aminopyr-
idine. These compounds were prepared via a Suzuki–Miyaura
cross-coupling reaction and a subsequent direct arylation, making
the route attractive for accessing these functionalized heterocycles.
Further applications to the synthesis of bioactive compounds is in
progress in our laboratory.
to improve the yield of this direct arylation using Fagnou’s condi-
tions.13 The yield was significantly increased (95%) using bromo-
benzene in a sealed tube for 16 h (entry 2). Heteroarylation using
4-bromopyridine hydrobromide occurred in the same way (entry
3). Finally, although the two methods afforded similar results for
the access to 2,3-diarylimidazo[1,2-a]pyridines 1, direct arylation
single-step remained preferable.
With optimal conditions in hand, we explored the scope of the
Suzuki–Miyaura coupling-direct arylation sequence starting from
imidazo[1,2-a]pyridin-2-yl triflate 3c with a variety of aryl boronic
acids and aryl bromides (Scheme 5 and Table 4).14 The Suzuki
cross-coupling is compatible with a variety of aryl groups and pro-
ceeded in various yields (9–97%) depending on the influence of the
electronic properties of the coupling partner. The electron-defi-
cient aryl boronic acids were coupled in low to moderate yields.
For instance, compounds bearing halogens (2b, 2c, 2e) were ob-
tained in moderate yields (35–45%) whereas 2-fluorophenyl boro-
nic acid afforded unexpectedly 2d in an excellent yield (97%, entry
5). Ester 2f and nitro derivative 2g proceeded in low yields (entries
11 and 12). Nevertheless, compounds 2h and 2i bearing a methoxy
donating group were obtained in good yields (78–94%, entries 13
and 16).
Acknowledgment
The financial support from the Région des Pays de la Loire is
gratefully acknowledged.
We next explored direct arylation of substrates 2a–i with vari-
ous aryl bromides. Reactions proceeded in good yields with bromo-
benzene and 3-bromopyridine (Table 4, entries 2–6). When 2-
phenylimidazo[1,2-a]pyridine 2a reacted with an electron-defi-
cient aryl bromide (i.e., 4-nitrobenzene), direct arylation was
accomplished in a better yield (entry 1). Substrates 2e and 2h
underwent direct arylation with various aryl bromides to probe
the influence of an electron-deficient group on the phenyl ring or
an electron-rich one. It is noteworthy that 3-bromonitrobenzene
and bromobenzene were suitable coupling partners under classical
References and notes
1. Enguehard-Gueiffier, C.; Gueiffier, A. Mini-Rev. Med. Chem. 2007, 7, 888–899.
2. (a) Biftu, T.; Feng, D.; Fisher, M.; Liang, G.-B.; Qian, X.; Scribner, A.; Dennis, R.;
Lee, S.; Liberator, P. A.; Brown, C.; Gurnett, A.; Leavitt, P. S.; Thompson, D.;
Mathew, J.; Misura, A.; Samaras, S.; Tamas, T.; Sina, J. F.; McNulty, K. A.;
McKnight, C. G.; Schmatz, D. M.; Wyvratt, M. Bioorg. Med. Chem. Lett. 2006, 16,
2479–2483; (b) Scribner, A.; Dennis, R.; Lee, S.; Ouvry, G.; Perrey, D.; Fisher, M.;
Wyvratt, M.; Leavitt, P.; Liberator, P.; Gurnett, A.; Brown, C.; Mathew, J.;
Thompson, D.; Schmatz, D.; Biftu, T. Eur. J. Med. Chem. 2008, 43, 1123–1151.
3. (a) Gudmundsson, K. S.; Johns, B. A. Org. Lett. 2003, 5, 1369–1372; (b)
Gudmundsson, K. S.; Johns, B. A. Bioorg. Med. Chem. Lett. 2007, 17, 2735–2739.

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S. Marhadour et al. / Tetrahedron Letters 53 (2012) 297–300
4. Enguehard-Gueiffier, C.; Fauvelle, F.; Debouzy, J.-C.; Peinnequin, A.; Thery, I.;
14. Representative Suzuki coupling-direct halogenation sequence procedure: 2-(3,5-
dichlorophenyl)-3-(3-pyridyl)imidazo[1,2-a]pyridine (1d). To 10 mL vial
with magnetic stir bar was added triflate (400 mg, 1.5 mmol), 3,5-
Dabouis, V.; Gueiffier, A. Eur. J. Pharm. Sci. 2005, 24, 219–227.
5. Singhaus, R. R.; Bernotas, R. C.; Steffan, R.; Matelan, E.; Quinet, E.; Nambi, P.;
Feingold, I.; Huselton, C.; Wilhelmsson, A.; Goos-Nilsson, A.; Wrobel, J. Bioorg.
Med. Chem. Lett. 2010, 20, 521–525.
6. (a) Follot, S.; Debouzy, J.-C.; Crouzier, D.; Enguehard-Gueiffier, C.; Gueiffier, A.;
Nachon, F.; Lefebvre, B.; Fauvelle, F. Eur. J. Med. Chem. 2009, 44, 3509–3518; (b)
Colletti, S. L.; Frie, J. L.; Dixon, E. C.; Singh, S. B.; Choi, B. K.; Scapin, G.;
Fitzgerald, C. E.; Kumar, S.; Nichols, E. A.; O’Keefe, S. J.; O’Neill, E. A.; Porter, G.;
Samuel, K.; Schmatz, D. M.; Schwartz, C. D.; Shoop, W. L.; Thompson, C. M.;
Thompson, J. E.; Wang, R.; Woods, A.; Zaller, D. M.; Doherty, J. B. J. Med. Chem.
2003, 46, 349–352.
a
a
5
dichlorophenylboronic acid (344 mg, 1.8 mmol), Na2CO3 (382 mg, 3.6 mmol)
and Pd(PPh3)4 (5% mol, 87 mg) in a mixture 1,4-dioxane–water (4 mL, 2:1). The
vial was sealed and purged with argon through the septum inlet for 5 min. The
suspension was then heated at 100 °C for 45 min. After cooling, the resulting
mixture was diluted with EtOAc, filtered through Celite and washed with
EtOAc. Water was added and the organic layer was extracted twice with EtOAc.
The combined organic layers were washed with water, dried over Na2SO4,
filtered and concentrated under vacuum. The crude product was purified by
silica gel chromatography using petroleum ether/EtOAc (9:1) as eluent.
7. Zhu, D.; Chen, J.; Wu, D.; Liu, M.; Ding, J.; Wu, H. J. Chem. Res. 2009, 84–86.
8. Maxwell, B. D.; Boyé, O. G.; Ohta, K. J. Label. Compd. Radiopharm. 2005, 48, 397–
406.
9. Thompson, F.; Mailliet, P.; Ruxer, J.-M.; Goulaouic, H.; Vallee, F.; Minoux, H.;
Pilorge, F.; Bertin, L.; Hourcade, S. FR 2 907 453, 2008; Chem. Abstr. 2008, 148,
495926.
10. Imidazo[1,2-a]pyridin-2-yl triflate (3c). At 0 °C, 2-aminopyridine (8.37 g,
89 mmol) was added portionwise to ethyl bromoacetate (34.5 mL,
311 mmol). The reaction mixture was stirred for 30 min at room
temperature. The precipitate was collected and washed with diisopropylic
ether. Then, a solution of the crude product in absolute ethanol (200 mL) was
refluxed for 18 h. The reaction mixture was cooled to room temperature for 2 h
and to 0 °C for 1 h. The precipitate was collected and washed with diisopropylic
ether to give 18.24 g of the crude product 5. This material was used in the next
reaction without further purification.
Trituration
with
diisopropylic
ether
afforded
2-(3,5-
dichlorophenyl)imidazo[1,2-a]pyridine 2c as a white powder (138 mg, 35%
yield). Mp 142–143 °C; 1H NMR (400 MHz, DMSO-d6) d 8.63 (s, 1 H), 8.57 (d,
J = 6.8 Hz, 1 H), 8.04 (d, J = 2.0 Hz, 2 H), 7.63 (d, J = 8.6 Hz, 1 H), 7.58 (t,
J = 2.0 Hz, 1 H), 7.33 (ddd, J = 8.6 Hz, J = 7.2 Hz, J = 1.2 Hz, 1 H), 6.97 (ddd,
J = 7.2 Hz, J = 6.8 Hz, J = 1.2 Hz, 1 H); 13C NMR (100 MHz, DMSO-d6)d 144.88,
141.38, 137.51, 134.54, 127.13, 126.79, 125.68, 123.88, 116.83, 112.78, 110.81;
IR (KBr) d 3483, 3375, 2924, 1723, 1600, 1370, 1282, 1252, 1126, 1098, 800,
754 cmꢂ1; MS (ESI) m/z (%): 263.0 (100) [M+H]+, 265.0 (88) [M+H+2]+, 267.0
(16) [M+H+4]+; Anal. Calcd for C13H8Cl2N2: C 59.34; H 3.06; N 10.65. Found: C
58.96; H 3.12; N 10.25.
To a 10 mL vial with a magnetic stir bar was added 2c (280 mg, 1.1 mmol), 3-
bromopyridine (168 mg, 1.1 mmol), Pd(OAc)2 (2% mol, 5 mg), PCy3.HBF4
(4% mol, 16 mg), PivOH (33 mg, 0.3 mmol) and K2CO3 (221 mg, 1.6 mmol) in
DMA (4 mL). The vial was sealed and purged with argon through the septum
inlet for 10 min. The suspension was then heated at 100 °C for 15 h. After
cooling, the resulting mixture was diluted with EtOAc and water and the
organic layer was extracted twice with EtOAc. The combined organic layers
were washed with brine and water, dried over Na2SO4, filtered and
concentrated under vacuum. The crude product was purified by silica gel
chromatography using petroleum ether/EtOAc (4:1) as eluent. Trituration with
diisopropylic ether afforded 2-(3,5-dichlorophenyl)-3-(3-pyridyl)imidazo[1,2-
a]pyridine 1d as a beige powder (250 mg, 69% yield). Mp 155–156 °C; 1H NMR
(400 MHz, DMSO-d6) d 8.83 (dd, J = 5.0 Hz, J = 1.6 Hz, 1 H), 8.76 (d, J = 1.6 Hz, 1
H), 8.15 (d, J = 7.4 Hz, 1 H), 8.10 (ddd, J = 8.0 Hz, J = 1.6 Hz, J = 1.6 Hz, 1 H), 7.76
(d, J = 8.2 Hz, 1 H), 7.71 (ddd, J = 8.0 Hz, J = 5.0 Hz, J = 0.8 Hz, 1 H), 7.58 (t,
To a solution of compound 5 (5.0 g, 21 mmol) in toluene (300 mL) was added
N-phenyl-bis(trifluoromethanesulfonimide)
(13.0 g,
37 mmol)
and
triethylamine (5 mL). The reaction was refluxed. Triethylamine (2 ꢁ 12.5 mL)
was then added after 2 and 4 h respectively. The reaction mixture was refluxed
for 12 h, cooled to room temperature and poured into water. The aqueous layer
was extracted twice with ethyl acetate. The combined organic extracts were
dried over Na2SO4, filtered and concentrated under vacuum. The crude product
was purified by silica gel chromatography (eluent: petroleum ether/EtOAc 9:1)
to give 3c as a white powder (3.91 g, 67% yield, two steps). Mp 62–63 °C; 1H
NMR (400 MHz, DMSO-d6) d 8.64 (d, J = 6.8 Hz, 1 H), 8.25 (s, 1 H), 7.68 (d,
J = 8.4 Hz, 1 H), 7.48 (ddd, J = 8.4 Hz, J = 7.0 Hz, J = 1.2 Hz, 1 H), 7.14 (ddd,
J = 7.0 Hz, J = 6.8 Hz, J = 1.2 Hz, 1 H); 13C NMR (100 MHz, DMSO-d6) d 146.76,
140.15, 127.69, 126.92, 118.17 (q, J = 319 Hz), 116.78, 113.92, 101.48; IR (KBr)
d 3158, 3053, 1508, 1429, 1361, 1219, 1137, 995, 882, 799 cmꢂ1; MS (ESI) m/z
(%): 267.0 (83) [M+H]+, 133.8 (100).
J = 2.0 Hz,
1 H), 7.51 (d, J = 2.0 Hz, 2 H), 7.44 (ddd, J = 8.2 Hz, J = 6.6 Hz,
J = 0.8 Hz, 1 H), 7.00 (ddd, J = 7.4 Hz, J = 6.6 Hz, J = 0.8 Hz, 1 H); 13C NMR
(100 MHz, DMSO-d6) d 151.14, 150.39, 144.52, 139.17, 138.63, 137.40, 134.16,
126.93, 126.38, 125.61, 124.86, 124.52, 124.26, 118.75, 117.09, 113.44; IR (KBr)
d 3422, 2925, 2364, 2345, 1589, 1561, 1371, 1345, 1256, 1112, 860, 800,
739 cmꢂ1; MS (ESI) m/z (%): 340.0 (100) [M+H]+, 342.0 (70) [M+H+2]+, 343.0
(12) [M+H+3]+, 344.0 (12) [M+H+4]+; Anal. Calcd for C18H11Cl2N3: C 63.55; H
3.26; N 12.35. Found: C 63.89; H 3.59; N 12.54.
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