A site selective C-H arylation of free-(NH2) adenines with aryl chlorides: Application to the synthesis of 6,8-disubstituted adenines

Article abstract of DOI:10.1039/b912033e

An efficient site selective method for the direct arylation of free-(NH₂) adenines 1 to provide a range of C-8 arylated adenines 3 in excellent yields is described. This process based on the use of Pd(OH) ₂/C as the catalyst and a st

Full text of DOI:10.1039/b912033e

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A site selective C–H arylation of free-(NH2) adenines with aryl chlorides:
Application to the synthesis of 6,8-disubstituted adenines†
Sophian Sahnoun, Samir Messaoudi, Jean-Daniel Brion and Mouaˆd Alami*
Received 19th June 2009, Accepted 16th July 2009
First published as an Advance Article on the web 14th August 2009
DOI: 10.1039/b912033e
An efficient site selective method for the direct arylation of free-(NH2) adenines 1 to provide a range of
C-8 arylated adenines 3 in excellent yields is described. This process based on the use of Pd(OH)2/C as
the catalyst and a stoichiometric amount of CuI under ligandless conditions is general. It allows the
coupling to proceed with a variety of aryl halides, including for the first time cheaper and less reactive
aryl chlorides. The extension of this process for the sequential preparation of non-symmetrical
C8/N6-arylated adenines 4 is also reported.
synthesis of substituted adenines 3 are based on the construction
Introduction
of the heteroaryl–aryl bond at the 8-position of these heterocycles
Substituted purines have attracted much interest as therapeutics,
by Pd-catalyzed cross-coupling reactions between organometallic
molecular tools and probes for investigating biological systems.1
In addition, they represent a large family of biologically active
molecules and constitute the scaffold for a wide variety of
promising drugs, including kinase inhibitors,2 modulators of
multidrug resistance3 and antineoplastic agents.4 In recent years,
several substituted purines, such as PU24FCl, PU24S, as well
as their 8-arylsulfanyl analogues,5 have been found to be potent
inhibitors of chaperone hsp90, an exciting new target in cancer
drug discovery (Fig. 1).6 This wide range of biological activity
displayed by purines has made them popular synthetic targets.7
reagents with N-protected 8-bromoadenines.9 While these re-
actions are suitable methods, they suffer from being multistep
syntheses requiring the preparation of either or both reagents
and are therefore time-consuming and economically inefficient.
New synthetic strategies such as the direct functionalization
of sp2 C–H bonds are now emerging as viable alternatives to
traditional cross-coupling reactions. In these instances, the need
for preactivating one of the reaction components is circumvented.
Several reviews highlight the broad scope of this strategy, as well
as high functional group tolerance and atom economy.10 However,
this straightforward approach is hindered by the regioselectivity
difficulties particularly with free-(NH2) adenines. Hocek and
Fairlamb described the direct aryl functionalization of free-(NH2)
adenine nucleosides with aryl iodides which give in moderate to
good yields C8-arylated adenosine derivatives together with a
small amount of N6-arylation products.11 This C–H activation
process was further extended by Hocek to N9-protected free-
(NH2) adenines and optimal conditions reported led to a complex
mixture of three major products.12 Besides the desired 8-arylated
adenines formed in low to moderate yields (21–50%), two by-
products were also isolated arising from single and double Pd/
Cu-mediated N6-arylation of starting adenine. Therefore, the site
selective direct arylation of free-(NH2) adenines still remains a
significant synthetic challenge. For this purpose, we sought to use
aryl chlorides in palladium mediated C–H arylation reactions13
as these substrates have traditionally been the least successful
partners in the N-arylation reactions.14
Fig. 1 Adenines used in this study and target structures 3 and 4.
In support of an ongoing medicinal chemistry program toward
hsp90,8 a rapid and versatile access to 8-aryladenines of type 3,
which includes two centers for introduction of diversity into ade-
nine molecule, was required (Fig. 1). Conventional methods for the
Results and discussion
Recently, we described a regioselective and direct C–H arylation
of free-(NH2) adenines to prepare a variety of 8-aryladenines
3 from aryl bromides and iodides under ligandless microwave
activation.15 In this preliminary study, we reported three examples
where the new developed catalyst system also enabled, for the
first time, efficient reaction with cheap and the less reactive aryl
chlorides. Encouraged by this initial discovery, the scope of this
catalyst system with various aryl chlorides as substrates was more
Universite´ Paris-Sud, CNRS, BioCIS UMR 8076, Laboratoire de Chimie
The´rapeutique, Faculte´ de Pharmacie, 5 rue J.-B. Cle´ment, Chaˆtenay-
Malabry, F-92296, France; Fax:
0146835887
+ (33) 0146835828; Tel: +(33)
† Electronic supplementary information (ESI) available: General, exper-
1
imental procedures for starting materials and H and 13C spectra for all
new compounds. See DOI: 10.1039/b912033e
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Table 2 Direct C-8 arylation of adenines 1 with aryl chloridesa
Table 1 Optimization C-8 arylation of 1a with 4-tolyl chloridea
Entry Adenine ArCl
Time (h) Product 3
Yield (%)b
91(86)c
1
2
3
1a
1a
1b
4
Entry [Pd]b
Base
Solvent T (◦C) / Time (h) Yield (%)c
16
16
83(60)cd
77
1
2
3
4
5
6
7
8
9
10
11
12
13
Pd2dba3
Pd/C
Pd(OAc)2
Pd(OH)2/C Cs2CO3
Pd(OAc)2 Cs2CO3
Pd(OH)2/C K2CO3
Pd(OH)2/C Na2CO3
Pd(OH)2/C K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
NMP
NMP
NMP
NMP
DMF
NMP
NMP
NMP
160/16
160/16
160/16
160/16
120 /42
160/16
160/16
160/16
160/16
160/16
160/16
0
0
73
90
0d
51
8
25
0
27
85
0
4
5
6
1c
1c
1a
16
16
4
94
Pd(OH)2/C piperidine NMP
Pd(OH)2/C Cs2CO3
Pd(OH)2/C Cs2CO3
Pd(OH)2/C Cs2CO3
Pd(OH)2/C Cs2CO3
DMF
DMA
Dioxane 160/16
NMP 160 /4
91
93
a 1a (1 equiv), 4-tolyl chloride (1.5 equiv), Pd(OH)2/C (5 mol%), CuI
(1 equiv), Cs2CO3 (2 equiv), NMP, 160 ◦C. b No reaction occurred without
palladium catalyst or copper salt. c Isolated yields. d Hocek conditions.11
90(85)c
deeply investigated. Moreover, the development of this method
on the regiocontrolled C-8 (hetero)arylation of 1 followed by a
N6-(hetero)arylation with various hetero(aryl) halides to furnish
4 will be reported.
7
1b
16
64
Initial studies were performed by using adenine 1a and 4-
tolyl chloride as model substrates. As summarized in Table 1,
the screening conditions revealed that the source of palladium
used has an important influence on the outcome of the present
reaction. Thus, the use of Pd/C or Pd2(dba)3 did not promote the
C–H arylation reaction (entries 1 and 2), while in the presence
of Pd(OAc)2 the reaction led to 3a in a satisfactory 73% yield
(entry 3). We were delighted to find that the catalytic activity of
Pd(OH)2/C16 proved to be superior to Pd(OAc)2 leading to 3a
with an excellent 90% yield (entry 4). It should be noted that no
reaction occurred when 1a was reacted with 4-tolyl chloride under
Hocek conditions (entry 5); only starting material was recovered.
The screening reactions were continued with respect to the base
and solvent. Evaluation of bases revealed that Cs2CO3 is superior
to all other choices (entries 6–9). Optimization with respect to the
solvent showed that the reaction proceeds best in NMP. In the
presence of other polar solvents such as DMA, the C–H arylation
also proved to be effective providing 3a in a similar yield (85%,
entry 11). Finally, the best conditions were found to require: 4-
tolyl chloride (1.5 equiv), Pd(OH)2/C (5 mol%), CuI (1 equiv) and
Cs2CO3 (2 equiv) at 160 ◦C for 4 h furnishing 3a in 91% yield
(entry 13).
8
9
1c
1d
16
24
77
54
10
11
1a
1c
32
4
62
55(56)c
a Substrate (1 equiv), ArCl (1.5 equiv), Cs2CO3 (2 equiv), Pd(OH)2/C
(5 mol %), CuI (1 equiv), 160 ◦C. b Isolated yields. c Yield between brackets
refers to C–H arylation under MWI. See ESI† for details. d A 22% of
methoxy substituent deprotection product was isolated as side product.
With an effective catalytic system in hand, we probed its scope in
the direct C8-arylation of various N9-substituted adenines 1. The
results summarized in Table 2, show that the optimized conditions
described above proved to be general for the coupling with a large
variety of electron-rich and electron-deficient aryl chlorides. In
addition, there was little effect of the substitution pattern of the
aryl chloride with respect to yield or selectivity. One can note that
4-chlorobenzonitrile reacted with 1c to provide concomitantly 3h
in a good yield as the arylated adenine with hydration of the
nitrile function (entry 8). Running the reaction from 1d bearing an
sp2-carbon–chlorine bond, the C–H arylation gave selectively 3i
in 54% yield (entry 9).
As depicted in entry 11, heteroaromatic chlorides could be
employed in this direct arylation reaction as well. Thus, 2-
chloropyridine gave rise to the heteroarylated adenine 3k in 55%
yield. Finally, as demonstrated in entries 1, 2, 6 and 11, microwave
heating is also effective for direct arylation of adenines 1. The
expected coupling products 3 were isolated in similar yields as
those of conventional heating but with shorter reaction times
(~1 h). The lower yield observed with 4-chloroanisole (entry 2, 60%
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vs. 83%) is due to the formation of side product (22%) resulting
from deprotection of the methoxy substituent.
C-8 arylation compound together with a notable amount of N6-
arylated byproduct. These results clearly demonstrate that aryl
chlorides are more suitable partners than the corresponding iodo
and bromo derivatives for the site selective direct arylation of free-
(NH2) adenines (Table 2, entries 3–5).
Attention was next focused on this direct arylation using aryl
iodides and bromides as arene coupling partners. As shown
in Table 3, this method was equally efficient with electron-
rich and electron-deficient aryl bromides and iodides, suggesting
that the substrate scope of this method is high. A variety of
8-aryladenines 3 were thus obtained in 33–95% yields. One can
note that the lower yield observed with ortho and meta substituted
aryl iodides (entries 5 and 7) is due to the formation of the
Being given the high efficiency of the synthesis of C8-substituted
adenines 3, we expected that the newly developed procedure
would serve as an extremely useful and quick route to obtain
N6-arylated adenine derivatives 4. These classes of substituted
heterocyclic compounds offer a high degree of structural diversity
and have proven to be broadly useful as biologically active
compounds.1 In this context, we were pleased to observe that
optimal reaction conditions for the N-arylation of adenines 3
were found to be similar than those of the C–H arylation reaction,
using Pd(OH)2/C as the palladium source, Xantphos as the ligand,
Cs2CO3 as the base and NMP as the solvent. These conditions
proved to be effective with a wide range of aryl bromides and
iodides furnishing non-symmetrical adenines 4a–g in good yields
(Table 4).
Table 3 Arylation of 1a and 2a with aryl iodides and bromidesa
Entry
1
Adenine
ArX
Product
Yield (%)b
78
1a
2
3
4
5
6
1a
1a
1a
1a
1a
90
55
80
42c
95
Table 4 N6-arylation of adenines 3 with aryl halidesa
Entry Adenine ArX
Product 4
Yield (%)b
60
1
2
3
4
3b
3b
3k
3s
58
44
87
7
8
1a
1a
1a
1a
1a
2a
33c
44
68
43
82
61
5
6
7
3a
3a
3e
61
66
60c
9
10
11
12
a Substrate (1 equiv), ArX (1.5 equiv), Cs2CO3 (2 equiv), Pd(OH)2/C
(5 mol%), CuI (1 equiv), NMP, 160 ◦C, MWI. See the ESI for details.†
b Isolated yields. c Accompanied by 35% of C8/N6-diarylated byproduct.
a Substrate (1 equiv), ArX (1.05 equiv), Cs2CO3 (2 equiv), Pd(OH)2/C
(5 mol%), Xantphos (10 mol%), NMP, 160 ◦C, 16 h. See the ESI for
details.† b Isolated yields. c Run with 2 equiv of ArBr.
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To obviate direct manipulation and purification of 3, we next
examined a one-pot Pd-catalyzed C-arylation/N6-amination cou-
pling sequence as it would be economically and environmentally
advantageous over multistep syntheses (Scheme 1). In a typical
experiment, we achieved this transformation in a one-pot way by
mixing, in the first step, 1a with 4-tolyl chloride as partner under
optimal reaction conditions. After completion of the C8-arylation
step, 3-iodoanisole (1.05 equiv) and ◦Xantphos (10 mol%) in NMP
were introduced and heated at 160 C for 16 h. Thus, under this
protocol, we were pleased to observe that the reaction worked well
and provided the desired 4h in a 49% yield, despite the fact that
the reaction conditions had never been optimized.
purification of the residue by silica gel column chromatography
gave the desired product.
General procedure for direct arylation of N9-substituted adenines
1 with aryles halides under microwave irradiation. A flame-
dried resealable 2–5 mL Pyrex reaction vessel was charged with
the solid reactant(s): Pd(OH)2/C (20% on carbon) (5.0 mol%),
CuI (1.0 mmol), N9-substituted adenine (1.0 mmol), aryl halide
(1.5 mmol) and Cs2CO3 (2.0 mmol). The reaction vessel was
capped with a rubber septum, evacuated and backfilled with argon;
this evacuation/backfill sequence was repeated one additional
time. The liquid reactant(s) and NMP (6 mL per mmol) were
added through the septum. The septum was replaced with a Teflon
screwcap. The reaction vessel was sealed, then placed in the Emrys
Optimizer and exposed to microwave irradiation according to the
following specifications: temperature: 160 ◦C; time: (see tables);
fixed hold time: on; sample absorption: high; pre-stirring: 60 s. The
resulting suspension was cooled to room temperature and filtered
through a pad of Celite eluting with CH2Cl2/MeOH (7 : 3), and the
inorganic salts were removed. The filtrate was concentrated and
purification of the residue by silica gel column chromatography
gave the desired product.
Scheme 1 One-pot synthesis of C8, N6-disubstituted adenine 4h. (a):
1a (1.0 equiv), 4-chlorotoluene (1.5 equiv), Pd(OH)2/C (5 mol %), CuI
(1 equiv), Cs2CO3 (2.0 equiv), NMP, 160 ◦C, 4 h. (b): 3-iodoanisole
(1.05 equiv), Xantphos (10 mol%), NMP (2 mL), 160 ◦C, 12 h.
Compound 3a. Yield: 91% (287 mg); white solid; mp: 188–
190 ◦C; TLC: Rf 0.32 (CH2Cl2/MeOH: 95/5); IR (neat): n(cm-1)
3145, 2357, 1639, 1597, 1453, 1329, 1298, 1184, 1108, 1074, 1022,
Conclusion
1
In summary, we demonstrated that N6-free-(NH2) adenines can be
selectively arylated at the 8-position with a variety of aryl halides
including cheaper and generally more available aryl chlorides in
the presence of Pd(OH)2/CuI system, with Cs2CO3 as the base and
NMP as the solvent under ligandless conditions. This is the first
general method for N6-free adenines arylation with aryl chlorides
to provide C-8 arylated adenines in good to excellent yields.
Sequential combination of C8-direct arylation using aryl chlorides
and N6-arylation reaction using aryl bromides and iodides proved
to be useful for the rapid construction of disubstituted adenines
in good yields. We believe that this methodology should find
broad applications in synthetic organic chemistry, as well as the
combinatorial and pharmaceutical sciences. The synthesis of a
library of new adenine derivatives 3 as well as 4 as potential hsp90
inhibitors will be reported in due course.
826, 729, 694; H NMR (300 MHz, CDCl3): d 8.38 (s, 1H), 7.46
(d, 2H, J = 8.1 Hz),7.27 (m, 3H), 7.23 (d, 2H, J = 8.0 Hz),
7,07 (m, 2H), 5,97 (s, 2H, NH), 5,45 (s, 2H), 2,40 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 155.1, 153.0, 151.8, 151.8, 140.6, 136.4,
129.5 (2C), 128.9 (2C), 128.8 (2C), 127.8, 126.6 (2C), 126.5, 119.1,
46.9, 21.4; m/z MS (ES+) (M+H+) 316; Anal. Calcd for C19H17N5
(315,15): C 72.36, H 5.43, N 22.21; found: C 72.64, H 5.69, N
22.65.
Compound 3b. Yield: 83% (275 mg); beige solid; mp: 104–
106 ◦C; TLC: Rf 0.29 (CH2Cl2/MeOH: 95/5); IR (neat): n(cm-1)
3157, 1661, 1606, 1530, 1458, 1332, 1298, 1266, 1179, 1031, 834,
727, 694; 1H NMR (300 MHz, CDCl3): d 8.40 (s, 1H), 7.53 (d, 2H,
J = 8.5 Hz), 7.28 (m, 3H), 7.09 (m, 2H), 6.96 (d, 2H, J = 8.5 Hz),
5.92 (s, 2H, NH), 5.47 (s, 2H), 3.86 (s, 3H); 13C NMR (75 MHz,
DMSO d6): d 160.3, 155.5, 152.4, 151.3, 150.0, 137.0, 130.1 (2C),
128.6 (2C), 127.3, 126.1 (2C), 121.9, 118.4, 114.1 (2C), 55.2, 46.0;
m/z MS (ES+) (M+H)+ 332; Anal. Calcd for C19H17N5O (331,14):
C 68.87, H, 5.17, N, 21.13; found: C 69.01, H, 5.34, N, 21.24.
Experimental details
General experimental
Compound 3c. Yield: 77% (241 mg); white solid; mp: 139–
141 ◦C; TLC: Rf 0.26 (CH2Cl2/MeOH: 95/5); IR (neat): n(cm-1)
3308, 3119, 2931, 1661, 1594, 1572, 1479, 1350, 1322, 1257, 1219,
1116, 1023, 883, 787, 1H NMR (300 MHz, CDCl3): d 1.05 (t, 3H,
J = 7.0 Hz), 3.37 (q, 2H, J = 7.0 Hz), 3.86 (m, 5H), 4.42 (t, 2H,
J = 5.4 Hz), 6.26 (s, 2H, NH), 7,04 (m, 1H), 7,39 (m, 3H), 8,34
(s, 1H); 13C NMR (75 MHz, CDCl3): d 14.9, 44.0, 55.4, 66.6, 68.0,
114.9, 116.2, 119.3, 121.9, 129.8, 130.9, 151.5, 151.8, 152.5, 155.3,
159.7; m/z MS (ES+) (M+ h)+ 314; Anal. Calcd for C16H19N5O2
(313,15): C 61.33, H 6.11, N 22.35; found: C 61.61, H 6.24, N
22.67.
General procedure for direct arylation of N9-substituted adenines
1 with aryl chlorides. A flame-dried resealable 2–5 mL Pyrex
reaction vessel was charged with the solid reactant(s): Pd(OH)2/C
(20% on carbon) (5.0 mol%), CuI (1.0 mmol), N9-substituted
adenine 2 (1.0 mmol), aryl chloride (1.5 mmol) and Cs2CO3
(2.0 mmol). The reaction vessel was capped with a rubber septum,
evacuated and backfilled with argon; this evacuation/backfill
sequence was repeated one additional time. The liquid reactant(s)
and NMP (6 mL per mmol) were added through the septum. The
septum was replaced with a Teflon screwcap. The reaction vessel
was sealed, and then heated at 160 ◦C; time: (see Table 2). The
resulting suspension was cooled to room temperature and filtered
through a pad of Celite eluting with CH2Cl2/MeOH (7 : 3), and the
inorganic salts were removed. The filtrate was concentrated and
Compound 3d. Yield: 94% (325 mg); beige solid; mp: 157–
◦
159 C; TLC: Rf 0.45 (CH2Cl2/MeOH: 9/1); IR (neat): n(cm-1)
3321, 3139, 1664, 1647, 1597, 1565, 1513, 1302, 1246, 1178, 1030,
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1
846; H NMR (300 MHz, DMSO-d6): d 8.36 (bs, 1H), 7.40 (m,
1299, 1202, 1051, 886, 881; 1H NMR (300 MHz, CDCl3): d 8.39 (s,
1H); 7.30 (m, 7H), 6.74 (d, 1H, J = 7.5 Hz), 6.27 (s, 2H, NH), 5.58
(s, 2H), 13C NMR (75 MHz, CDCl3): d 162.7 (d, J = 248.1 Hz),
155.5, 153.4, 152.0, 150.1, 133.6, 132.0, 131.2 (d, J = 8.1 Hz), 130.7
(d, J = 8.3 Hz), 129.8, 129.1, 127.4, 127.0, 124.2, 119.3,117.4 (d,
J = 21.1 Hz), 116.0 (d, J = 23.4 Hz), 44.9; m/z MS (ES+) (M+ h)+
354; Anal. Calcd for C18H13ClFN5 (353,08): C 61.11, H 3.70, N
19.80; found: C 61.22, H 3.83, N 19.98.
4H), 7.17 (s, 2H, NH), 6.94 (d, 2H, J = 8.4 Hz), 6.81 (d, 2H, J =
8.3 Hz), 5.40 (s, 2H), 3.69 (s, 3H), 2.35 (s, 3H); 13C NMR (75 MHz,
DMSO-d6): d 158.2, 137.4, 129.9, 129.5, 129.0, 128.6, 128.0, 127.5
(2C), 125.4, 113.6 (2C), 54.7, 45.3, 20.3; m/z MS (ES+) (M+H)+
346; Anal. Calcd for C20H19N5O1 (345,16): C, 69.55, H 5.54, N
20.28; found: C, 69.62, H 5.74, N 20.32.
Compound 3e. Yield: 93% (321 mg); beige solid; mp: 238–
◦
240 C; TLC: Rf 0.44 (CH2Cl2/MeOH: 9/1); IR (neat): n(cm-1)
Compound 3j. Yield: 62% 213 mg); beige solid; mp: 169–
171 ◦C; TLC: Rf 0.28 (CH2Cl2/MeOH: 95/5); IR (neat): n(cm-1)
3832, 3464, 3382, 3303, 3113, 2204, 1663, 1591, 1575, 1495, 1448,
3313, 1638, 1611, 1584, 1480, 1335, 1301, 1243, 1182, 1035, 779,
735, 657; H NMR (300 MHz, CDCl3): d 8.44 (s, 1H), 7.32 (m,
1
1
4H),6.85 (d, 2H, J = 8.6 Hz), 6.69 (d, 2H, J = 8.5 Hz), 5.93 (s, 2H,
NH), 5.15 (s, 2H), 3.73 (s, 3H), 1.99 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 159.2, 155.1, 152.8, 151.0, 150.9, 138.3, 130.6, 130.3,
130.0, 129.4, 129.2 (2C), 128.2, 125.8, 119.0, 113.8 (2C), 55.2, 46.0,
19.4; m/z MS (ES+) (M+H)+ 346; Anal. Calcd for C20H19N5O
(345,16): C 69.55, H 5.54, N 20.28; found: C 69.70, H 5.72, N
20.31.
1407, 1357, 1329, 1283, 1237, 1013, 955, 846, 816, 721, 692; H
NMR (300 MHz, CDCl3): d 8,43 (s, 1H), 8,12 (s, 1H), 8,08 (d, 1H,
J = 7.8 Hz), 7,82 (d, 1H, J = 7.7 Hz), 7,57 (dd, 1H, J = 7.7 Hz, J =
7.8 Hz), 7,29 (m, 3H),7.01 (m, 2H), 6.05 (s, 2H, NH), 5.50 (s, 2H),
2.45 (s, 3H); 13C NMR (75 MHz, CDCl3): d 197.0, 155.4, 153.3,
152.1, 150.5, 137.5, 136.2, 133.4, 130.1, 129.7, 129.3, 129.0 (3C),
128.0, 126.4 (2C), 119.4, 47.0, 26.4; m/z MS (ES+) (M+H)+ 344;
Anal. Calcd for C20H17N5O (343,14): C 69.96, H 4.99, N 20.40;
found: C 70.12, H 5.13, N 20.61.
Compound 3f. Yield: 90% (316 mg); beige solid; mp: 184–
186 ◦C; TLC: Rf 0.30 (CH2Cl2/MeOH: 95/5); IR (neat): n(cm-1)
3337, 3164, 1610, 1606, 1572, 1496, 1454, 1450, 1432, 1322, 1315,
Compound 3k. Yield: 55% (183 mg); beige solid; mp: 161–
163 ◦C; TLC: Rf 0.34 (CH2Cl2/MeOH: 95/5); IR (neat): n(cm-1)
3354, 3105, 2926, 2204, 2150, 1656, 1592, 1586, 1504, 1500,1462,
1427, 1336, 1300, 1286, 1253, 1175, 1096, 1035, 818, 794; 1H NMR
(300 MHz, CDCl3): d 8.69 (brd, 1H, J = 4.8 Hz), 8.42 (s, 1H), 8.21
(d, 1H, J = 8.0 Hz), 7.78 (td, 1H, J = 7.9 Hz, J = 1.4 Hz),7.33
(dd, 1H, J = 7.5 Hz, J = 4.9 Hz), 7.20 (d, 2H, J = 8.6 Hz), 6.71
(d, 2H, J = 8.6 Hz), 6.08 (s, 2H), 5.94 (s, 2H, NH), 3.70 (s, 3H);
13C NMR (75 MHz, CDCl3): d 158.9, 155.4,153.4, 152.3, 150.0,
148.7, 147.9, 136.8, 129.7, 129.2 (2C), 124.1, 123.9, 119.4, 113.7
(2C), 55.1, 46.9; m/z MS (ES+) (M+H)+ 333; Anal. Calcd for
C18H16N6O1 (332,14): C 65.05, H 4.85, N 25.29; found: C 65.18, H
4.98, N 25.37.
1
800, 775, 722, 695; H NMR (300 MHz, CDCl3): d 8.44 (s, 1H),
7.99 (d, 1H, J = 8.1 Hz), 7.92 (d, 1H, J = 8.2 Hz),7.47 (m,
5H), 7.07 (m, 3H), 6.78 (m, 2H), 6.18 (s, 2H, NH), 5.21 (s, 2H);
13C NMR (75 MHz, CDCl3): d 155.3, 153.1, 151.3, 150.3, 136.0,
133.5, 131.9, 130.7, 128.8, 128.4, 128.4 (2C), 127.7, 127.4 (3C),
127.1, 126.5,124.8 (2C), 119.3, 46.8; m/z MS (ES+) (M+ h)+ 352;
Anal. Calcd for C220H17N5 (351,15): C 75.19, H 4.88, N 19.93;
found: C 75.22, H 4.96, N 20.10.
Compound 3g. Yield: 64% (225 mg); white solid; mp: 170–
172 ◦C; TLC: Rf 0.27 (CH2Cl2/MeOH: 95/5); IR (neat): n(cm-1)
3381, 3156, 2893, 2204, 1645, 1599, 1582, 1462, 1411, 1323, 1169,
1
1119, 1070, 1019, 899, 854, 839; H NMR (300 MHz, CDCl3): d
8.37 (s, 1H), 8.05 (d, 2H, J = 8.0 Hz), 7,77 (d, 2H, J = 8.1 Hz), 6.17
(s, 2H, NH), 4.41 (t, 2H, J = 5.1 Hz), 3.89 (t, 2H, J = 5.1 Hz),
3.38 (q, 2H, J = 7.0 Hz), 1.06 (t, 3H, J = 7.0 Hz); 13C NMR
(75 MHz, CDCl3): d 155.4; 152.9, 151.6, 150.6, 133.4, 131.8 (q,
J = 32.8 Hz), 130.2 (2C), 125.6 (2C), 123.8 (q, J = 272.4 Hz),
119.5, 68.1, 66.7, 44.3, 14.9; m/z MS (ES+) (M+ h)+ 352; Anal.
Calcd for C16H16F3N5O (351,13): C 54.70, H 4.59, N 19.93; found:
C 54.81, H 4.63, N 20.10.
Compound 3l. Yield: 55% (215 mg); beige brown solid; mp:
189–191 ◦C; TLC: Rf 0.22 (CH2Cl2/MeOH: 95/5); IR (neat):
n(cm-1) 3155, 1662, 1589, 1461, 1417, 1356, 1326, 1298, 1241,
1124, 1025, 992, 852; 1H NMR (300 MHz, CDCl3): d 3.66 (s, 6H),
3.88 (s, 3H), 5.50 (s, 2H), 6.00 (s, 2H, NH), 6.78 (s, 2H), 7.13 (m,
2H), 7.31 (m, 3H), 8.42 (s, 1H), 13C NMR (75 MHz, CDCl3): d
47.0, 55.9 (2C), 60.9, 106.2 (2C), 124.5, 126.1 (2C), 127.8, 129.0
(2C), 136.7, 139.7, 151.9, 153.4 (2C); m/z MS (ES+) (M+H)+ 392;
Anal. Calcd for C21H21N5O3 (391,16): C 64.44, H 5.41, N 17.89;
found: C 64.61, H 5.56, N 17.98.
Compound 3h. Yield: 77% (288 mg); white solid; mp: 173–
175 ◦C; TLC: Rf 0.10 (CH2Cl2/MeOH: 95/5)); IR (neat): n(cm-1)
3314, 3139, 2918, 2187, 1640, 1600, 1513, 1459, 1330, 1288, 1247,
Compound 3m. Yield: 80% (253 mg); beige solid; mp: 170–
172 ◦C; TLC: Rf 0.19 (CH2Cl2/MeOH: 95/5); IR (neat): n(cm-1)
3127, 1654, 1606, 1451, 1331, 1300, 1184, 835, 729, 695; 1H NMR
(300 MHz, DMSO-d6): d 8.12 (s, 1H), 7.36 (d, 2H, J = 8.4 Hz),
7.25 (m, 5H), 7,01 (d, 2H, J = 7.3 Hz), 6.59 (d, 2H, J = 8.4 Hz),
5.58 (s, 2H), 5.45 (s, 2H); 13C NMR (75 MHz, DMSO-d6): d 155.2,
152.0, 151.3, 150.9, 150.3, 137.3, 129.7 (2C), 128.6 (2C), 127.2,
126.2 (2C), 118.3, 116.3, 113.3 (2C), 46.1; m/z MS (ES+) (M+H)+
317; Anal. Calcd for C18H16N6 (316,14): C 68.34, H 5.10, N 26.56;
found: C 68.64, H 5.19, N 26.70.
1
1177, 1030, 862, 722; H NMR (300 MHz, DMSO-d6): d 8.22
(s, 1H), 8.09 (s, 1H, CONH), 8.00 (d, 2H, J = 8.4 Hz), 7.79 (d,
2H, J = 8.4 Hz), 7,51 (s, 1H, CONH), 7.41 (s, 2H, NH),6.92 (d,
2H, J = 8.7 Hz), 6.80 (d, 2H, J = 8.7 Hz), 5.46 (s, 2H), 3.67 (s,
3H); 13C NMR (75 MHz, DMSO-d6): d 167.1, 158.4, 155.8, 152.9,
151.3, 148.9, 135.0, 132.3, 128.7, 128.5 (2C), 127.7 (4C), 118.6,
114.0 (2C), 54.9, 45.6; m/z MS (ES+) (M+ h)+ 375; Anal. Calcd
for C20H18N6O2 (374,15): C 64.16, H 4.85, N 22.45; found: C 64.21,
H 4.99, N 22.52.
Compound 3i. Yield: 54% (191 mg); white solid; mp: 198–
200 ◦C; TLC: Rf 0.28 (CH2Cl2/MeOH: 95/5); IR (neat): n(cm-1)
3315, 3140, 2188, 2066, 1656, 1595, 1586, 1458, 1373, 1348, 1323,
Compound 3n. Yield: 33% (109 mg); beige solid; mp: 145–
147 ◦C; TLC: Rf 0.28 (CH2Cl2/MeOH: 95/5); IR (neat): n(cm-1)
3141, 2355, 1650, 1596, 1580, 1454, 1327, 1300, 1261, 1220, 1041,
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1
869, 864, 726, 696; H NMR (300 MHz, CDCl3): d 8.39 (s, 1H),
126.9 (d, J = 3.1 Hz), 126.6 (2C), 126.1 (d, J = 3.3 Hz), 123.5 (q,
J = 272.5 Hz), 47.1; RMN 13C (100 MHz, CDCl3): d (ppm): 155.5,
153.2, 152.0, 150.1, 136.0, 130.5, 129.4, 129.0 (2C), 132.2, 131.4
(q, J = 32.9 Hz), 128.1, 126.8 (d, J = 3.0 Hz), 126.6 (2C), 126.1 (d,
J = 3.4 Hz),123.5 (q, J = 272.7 Hz), 47.1; m/z MS (ES+H)+ 370;
Anal. Calcd for C19H14F3N5 (369,12): C 61.79, H 3.82, N 18.96;
found: C 61.96, H 3.96, N 19.16.
7.31 (m, 4H), 7.09 (m, 5H), 6.49 (s, 2H, NH), 5.48 (s, 2H), 3.69
(s, 2H); 13C NMR (75 MHz, CDCl3): d 159.6, 155.4, 153.0, 151.7,
151.4, 136.4, 130.5, 129.9, 128.8 (2C), 127.7, 126.5 (2C), 121.3,
119.1, 116.7, 113.8, 55.1, 46.1; m/z MS (ES+) (M+H)+ 332; Anal.
Calcd for C19H16N5O (331,14): C 68.87, H 5.17, N 21.13; found: C
68.98, H 5.31, N 21.30.
Compound 3t. Yield: 61% (192 mg); beige solid; mp: 163–
165 ◦C; TLC: Rf 0.28 (CH2Cl2/MeOH: 95/5); IR (neat): n(cm-1)
3314, 3188, 1615, 1586, 1497, 1474, 1431, 1423, 1359, 1265, 1140,
Compound 3o. Yield: 42% (132 mg); white solid; mp: 160–
162 ◦C; TLC: Rf 0.29 (CH2Cl2/MeOH: 95/5); IR (neat): n(cm-1)
3163, 1650, 1595, 1475, 1455, 1370, 1323, 1068, 723, 696, 657; 1H
NMR (300 MHz, CDCl3): d 8.42 (s, 1H), 7.42 (m, 1H), 7.22 (m,
6H), 6.91 (m, 2H), 6.34 (s, 2H, NH), 5.22 (s, 2H), 1.97 (s, 3H);
13C NMR (75 MHz, CDCl3): d 155.3, 152.9, 150.9, 150.8, 138.3,
135.9, 130.5, 130.3, 129.9, 129.2, 128.4 (2C), 127.8, 127.6 (2C),
125.8, 118.9, 46.5, 19.3; m/z MS (ES+) (M+H)+ 316; Anal. Calcd
for C19H17N5 (315,15): C 72.36, H 5.43, N 22.21; found: C 72.63,
H 5.54, N 22.32.
1
909, 826, 798, 727; H NMR (300 MHz, CDCl3): d 8.75 (s, 1H),
7.49 (d, 2H, J = 7.9 Hz),7.29 (m, 3H), 7.23 (d, 2H, J = 7.8 Hz),
7.09 (m, 2H), 5.38 (s, 2H), 5.1 (s, 2H, NH), 2.40 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 155.3, 156.1, 159.8, 155.3, 153.5, 148.8, 140.5,
136.4, 129.4 (2C), 128.8 (4C),127.8, 127.7, 126.5 (2C), 46.4, 21.3;
m/z MS (ES+) (M+H)+ 316; Anal. Anal. Calcd for C19H17N5
(315,15): C 72.36, H 5.43, N 22.21; found: C 72.63, H 5.75,
N 22.41.
Compound 3p. Yield: 44% (132 mg); light brown solid; mp:
138–140 ◦C; TLC: Rf 0.29 (CH2Cl2/MeOH: 95/5); IR (neat):
n(cm-1) 3314, 2926, 1654, 1596, 1455, 1372, 1332, 1296, 1074,
1032, 727, 696, 664; 1H NMR (300 MHz, CDCl3): d 8.40 (s, 1H),
7.58 (m, 2H), 7.45 (m, 3H), 7.28 (m, 3H), 7.07 (m, 2H), 6.53 (s, 2H,
NH), 5.47 (s, 2H); 13C NMR (75 MHz, CDCl3): d 155.3, 153.0,
151.7, 151.5, 136.3, 130.2, 129.4, 129.0 (2C), 128.8 (4C), 127.8,
126.6 (2C), 119.1, 46.9; m/z MS (ES+) (M+H)+ 302; Anal. Calcd
for C18H15N5 (301,13): C 71.74, H 5.02, N 23.24; found: C 71.96,
H 5.11, N 23.31.
General procedure for N-arylation of adenines 3 with various
bromides and iodides
A flame-dried resealable Schlenk tube was charged with the
solid reactant(s): Pd(OH)2/C (5 mol%), Xantphos (10 mol%),
1.05 mmol of the aryl iodides/bromides, 1.0 mmol of adenines
3 and Cs2CO3 (2 mmol). The Schlenk tube was capped with
a rubber septum, evacuated and backfilled with argon; this
evacuation/backfill sequence was repeated one additional time.
The liquid reactant(s) and NMP (6 mL) were added through the
septum. The septum was replaced with a teflon screwcap. The
Schlenk tube was sealed, and the mixture was stirred at 160 ◦C for
16 h. The resulting suspension was cooled to room temperature
and filtered through celite eluting with ethyl acetate, and the
inorganic salts were removed. The filtrate was concentrated and
purification of the residue by silica gel column chromatography
gave the desired product.
Compound 3q. Yield: 68% (222 mg); white solid; mp: 215–
217 ◦C; TLC: Rf 0.31 (CH2Cl2/MeOH: 95/5); IR (neat): n(cm-1)
3373, 3168, 2228, 1648, 1593, 1580, 1527, 1490, 1461, 1408, 1310,
1302, 1277, 1110, 1065, 1019, 849, 720, 714, 694; 1H NMR
(300 MHz, CDCl3): d 8.43 (s, 1H), 7.73 (s, 4H), 7.29 (m, 3H),
7.05 (m, 2H), 6.07 (s, 2H, NH), 5.50 (s, 2H); 13C NMR (75 MHz,
CDCl3): d 155.5, 153.6, 152.1, 149.4, 135.8, 133.9, 132.5 (2C),
129.6 (2C), 129.1 (2C), 128.1, 126.4 (2C), 118.0, 113.9, 47.1; m/z
MS (ES+) (M+H)+ 327; Anal. Calcd for C19H14N6 (326,13): C
69.92, H 4.32, N 25.75; found: C 69.99, H 4.42, N 25.83.
Compound 4a. Yield: 60% (262 mg); white solid; mp: 188–
190 ◦C; TLC: Rf 0.30 (EtOAc/c-hexane: 7/3); IR (neat): n(cm-1)
3406, 3027, 2944, 2840, 1610, 1577, 1522, 1482, 1453, 1423, 1375,
1353, 1330, 1312, 1292, 1255, 1180, 1168, 1105, 1049, 1024, 831;
1H NMR (300 MHz, CDCl3): d 8.80 (m, 1H),. 8,59 (s, 1H), 8.30
(s, 1H), 7.59 (d, 2H, J = 8.6 Hz), 7.29 (m, 3H), 7.08 (m, 4H),
6.98 (m, 1H), 6.98 (d, 2H, J = 8.6 Hz),5.51 (s, 2H), 3.95 (s, 3H),
3.87 (s, 3H); RMN 13C (75 MHz, CDCl3): d 161.1, 152.5, 151.7,
151.6, 151.4, 148.5, 136.5, 130.6 (2C), 128.9 (2C), 128.5, 127.7,
126.5 (2C), 122.6, 121.9, 120.8, 120.6, 120.0, 114.3 (2C), 110.0,
55.6, 55.4, 46.9; m/z MS (ES+) (M+H)+ 438; Anal. Calcd for
C26H23N5O2 (437,19): C 71.38, H 5.30, N 16.01; found: C 71.57, H
5.43, N 16.21.
Compound 3r. Yield: 43% (149 mg); yellow solid; mp: 236–
238 ◦C; TLC: Rf 0.30 (CH2Cl2/MeOH: 95/5); IR (neat): n(cm-1)
3479, 3070, 2158, 1665, 1593, 1568, 1520, 1341, 1292, 1105, 1064,
975, 856, 734, 707; 1H NMR (300 MHz, CDCl3): d 8.32 (d, 2H, J =
8.9 Hz), 8.23 (s, 1H), 7.99 (d, 2H, J = 8.9 Hz), 7.55 (s, 2H, NH),
7.24 (m, 3H), 6.99 (m, 2H), 5.59 (s, 2H); 13C NMR (75 MHz,
CDCl3): d 155.3, 156.1, 153.3, 151.5, 147.7, 147.4, 136.5, 135.8,
129.8 (2C), 128.6 (2C), 127.5, 126.3 (2C), 123.8 (2C), 118.8, 46.1;
m/z MS (ES+) (M+H)+ 347; Anal. Calcd for C18H14N6O2 (346,12):
C 62.42, H 4.07, N 24.27; found: C 62.60, H 4.19, N 24.19.
Compound 3s. Yield: 82% (303 mg); beige solid; mp: 172–
Compound 4b. Yield: 58% (253 mg); beige solid; mp: 148–
150 ◦C; TLC: Rf 0.29 (EtOAc/c-hexane: 7/3); IR (neat): n(cm-1)
3396, 2920, 1626, 1608, 1578, 1536, 1495, 1470, 1455, 1420, 1380,
1357, 1336, 1306, 1280, 1256, 1198, 1175, 1157, 1116, 1078, 1029,
981, 956, 934, 844, 822, 791, 777, 734; 1H NMR (300 MHz,
CDCl3): d 8.61 (s, 1H), 7.86 (s, 1H), 7.68 (s, 1H), 7.60 (d, 2H,
J = 8.4 Hz), 7.34 (m, 5H),7.14 (d, 1H, J = 6.5 Hz), 7.01 (d, 2H,
J = 8.4 Hz), 6.70 (d, 2H, J = 7.9 Hz), 5.54 (s, 2H), 3.90 (s, 6H);
RMN 13C (75 MHz, CDCl3): d 161.3, 160.2, 152.6, 151.9, 151.6,
◦
174 C; TLC: Rf 0.31 (CH2Cl2/MeOH: 95/5); IR (neat): n(cm-1)
3140, 2927, 2359, 1659, 1601, 1570, 1497, 1452, 1420, 1377, 1356,
1325, 1300, 1242, 1167, 1122, 1099, 1076, 982, 914, 840, 821, 727,
1
695, 681; H NMR (300 MHz, Acetone-d6): d 8.29 (s, 1H), 8.00
(m, 2H), 7.84 (d, 1H, J = 7.9 Hz), 7.73 (dd, 1H, J = 8.1 Hz, J =
8.0 Hz), 7.28 (m, 3H), 7.11 (m, 2H),6.83 (s, 2H, NH), 5.62 (s, 2H);
13C NMR (75 MHz, CDCl3): d 15.4, 153.5, 152.0, 150.0, 136.0,
132.2, 131.4 (q, J = 33.0 Hz), 130.5; 129.4; 129.0 (2C), 128.1;
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151.5, 140.1, 136.4, 130.6 (2C), 129.7, 128.9 (2C), 127.8, 126.6
(2C), 121.6, 120.0, 114.4 (2C), 112.4, 108.8, 106.1, 55.4, 55.3, 47.0;
m/z MS (ES+) (M+H)+ 438; Anal. Calcd for C26H23N5O2 (437,19):
C 71.38, H 5.30, N 16.01; found: C 71.65, H 5.43, N 16.21.
Compound 4g. Yield: 61% (304 mg); light brown solid; mp:
92–94 ◦C; TLC: Rf 0.36 (CH2Cl2/MeOH: 9/1); IR (neat): n(cm-1)
2361, 1611, 1563, 1513, 1470, 1427, 1336, 1304, 1281, 1249, 1177,
1091, 1033, 908, 850; 1H NMR (300 MHz, CDCl3): d 8.71 (s, 1H),
8.39 (brs, 2H), 7.68 (t, 2H, J = 7.5 Hz), 7.23 (m, 8H), 6.87 (d,
2H, J = 8.4 Hz), 6.70 (d, 2H, J = 8.5 Hz), 5.22 (s, 2H), 3.74 (s,
3H), 1.86 (s, 3H); RMN 13C (75 MHz, CDCl3): d 159.1, 156.2,
153.6, 153.3, 152.0, 151.9, 148.7, 138.7, 137.7 (2C), 130.6, 130.0,
129.7, 129.2 (3C), 129.0, 128.1, 125.3, 124.1, 120.6, 120.3, 113.8
(4C), 55.2, 46.1, 19.6; m/z MS (ES+) (M+H)+ 500; Anal. Calcd for
C30H25N7O1 (499,21): C 72.13, H 5.04, N 19.63; found:. C 72.35,
H 5.23, N 19.91.
Compound 4c. Yield: 44% (211 mg); beige solid; mp: 171–
173 ◦C; TLC: Rf 0.16 (EtOAc/c-hexane: 7/3); IR (neat): n(cm-1)
3568, 3411, 2985, 1703, 1624, 1607, 1578, 1512, 1462, 1421, 1404,
1379, 1339, 1274, 1240, 1189, 1174, 1103, 1030, 938, 901, 852,
1
823, 793, 766; H NMR (300 MHz, CDCl3): d 8.71 (brs, 1H),
8.64 (s, 1H), 8.24 (d, 1H, J = 7.5 Hz), 8.06 (m, 3H), 7.95 (d, 2H,
J = 8.6 Hz), 7.79 (t, 1H, J = 7.7 Hz), 7.35 (m, 1H), 7.24 (d,
2H, J = 8.5 Hz), 6.73 (d, 2H, J = 8.5 Hz), 6.12 (s, 2H),4.37 (q,
2H, J = 7.1 Hz), 3.59 (s, 3H),1.40 (t, 3H, J = 7.1 Hz); RMN
13C (75 MHz, CDCl3): d 166.2, 158.9, 152.9, 152.1, 151.4, 149.7,
148.7, 148.3, 143.1, 136.8, 130.8 (2C), 129.4, 129.2 (2C), 124.6,
124.3, 124.0, 120.4, 118.7 (2C), 113.7 (2C), 60.7, 55.1, 47.0, 14.3;
m/z MS (ES+) (M+H)+ 481; Anal. Calcd for C27H24N6O3 (480,19):
C 67.49, H 5.03, N 17.49; found: C 67.60, H 5.13, N 17.51.
General procedure for one-pot synthesis of C8, N6-disubstituted
adenine 4h
A flame-dried resealable 2–5 mL Pyrex reaction vessel was charged
with the solid reactant(s): Pd(OH)2/C (20% on carbon) (5.0 mol
%), CuI (1.0 mmol), N9-substituted adenine (1.0 mmol), aryl
chloride (1.5 mmol) and Cs2CO3 (2.0 mmol). The reaction vessel
was capped with a rubber septum, evacuated and backfilled
with argon; this evacuation/backfill sequence was repeated one
additional time. NMP (6 mL) was added through the septum. The
septum was replaced with a Teflon screwcap. The reaction vessel
was sealed, and then heated at 160 ◦C for 4 h. Then, the resulting
suspension was cooled to room temperature and a solution of
Pd(OH)2/C (5 mol%) and Xantphos (10 mol%) in NMP (1 mL)
was added through the septum. The septum was replaced with
a Teflon screwcap and the reaction vessel was sealed, and then
heated at 160 ◦C for 16 h. The resulting suspension was cooled to
room temperature and filtered through a pad of celite eluting with
CH2Cl2/MeOH (7 : 3), and the inorganic salts were removed. The
filtrate was concentrated and purification of the residue by silica
gel column chromatography gave the desired product.
Compound 4d. Yield: 87% (417 mg); white solid; mp: 162–
164 ◦C; TLC: Rf 0.48 (EtOAc/c-hexane: 7/3); IR (neat): n(cm-1)
3392, 3037, 2205, 1965, 1621, 1579, 1526, 1492, 1476, 1383, 1352,
1323, 1298, 1248, 1163, 1136, 1088, 1071, 1038, 910, 846, 822, 797,
1H NMR (300 MHz, CDCl3): d 8.62 (s, 1H), 7.83 (m, 6H), 7.59 (t,
1H, J = 7.7 Hz),7.31 (m, 5H), 7.11 (m, 2H), 5.52 (s, 2H); RMN 13
C
(75 MHz, CDCl3): d 153.2; 151.8, 151.7, 150.2, 137.3, 135.9, 132.2,
131.5 (q, J = 32.9 Hz), 129.5; 129.0 (2C), 129.0 (2C), 128.4, 128.1,
127.0 (d, J = 3.2 Hz), 126.6 (2C), 126.1 (d, J = 3.5 Hz), 123.5
(q, J = 272.8 Hz), 121.7, 121.4 (2C), 120.1, 47.2; m/z MS (ES+)
(M+H)+ 480; Anal. Calcd for C25H17ClF3N5 (479,11): C 62.57, H
3.57, N 14.59; found: C62.60, H 3.63, N 14.60.
Compound 4e. Yield: 61% (269 mg); white solid; mp: 172–
174 ◦C; TLC: Rf 0.55 (EtOAc/c-hexane: 7/3); IR (neat): n(cm-1)
3751, 3559, 3427, 3028, 2356, 1631, 1608, 1593, 1573, 1536, 1502,
1471, 1407, 1374, 1358, 1327, 1275, 1185, 1114, 1094, 1031, 977,
Compound 4h. Yield: 40% (169 mg); white solid; mp: 112–
114 ◦C; TLC: Rf 0.27 (EtOAc/c-hexane: 7/3); IR (neat): n(cm-1)
3376, 1721, 1691, 1603, 1515, 1390, 1250, 1221, 1192, 1022, 996,
1
1
827, 789, 772, 724, 693; H NMR (300 MHz, CDCl3): d 8.53 (s,
941, 889, 826; H NMR (300 MHz, CDCl3): d 8.58 (s, 1H), 7.84
1H), 8.29 (s, 1H), 8.13 (m, 2H),7.91 (m, 1H), 7.76 (d, 1H, J =
8.2 Hz), 77.54 (m, 5H),.29 (m, 5H), 7.13 (d, 2H, J = 7.6 Hz),
5.52 (s, 2H), 2.43 (s, 3H); RMN 13C (75 MHz, CDCl3): d 153.0,
152.9, 152.1, 151.7, 140.5, 136.4, 134.4, 133.2, 129.5 (2C), 129.0
(2C), 128.9 (2C), 128.6, 128.2, 127.8, 126.6 (2C), 126.5, 126.1,
126.0, 125.7, 125.5, 121.7, 121.1, 120.2, 47.0, 21.4; m/z MS (ES+)
(M+H)+ 442; Anal. Calcd for C29H23N5 (441,2): C 78.89, H 5.25,
N 15.86; found: C 79.01 H 5.43, N15.89.
(brs, 1H), 7.65 (m, 1H), 7.50 (d, 2H, J = 8.0 Hz),7.31 (m, 7H), 7.1
(m, 2H), 6.67 (m, 1H), 5.50 (s, 2H), 3.86 (s, 3H), 2.42 (s, 3H); RMN
13C (75 MHz, CDCl3): d 160.1, 152.7, 151.8, 151.5, 151.2, 140.8,
140.1, 138.8, 136.2, 129.6, 129.5, 129.0, 128.8 (2C), 127.9, 126.6
(2C), 126.2, 123.4, 120.3, 112.5, 109.0, 106.1, 55.3, 47.0, 21.4; m/z
MS (ES+) (M+H)+ 422; Anal. Calcd for C26H23N5O1 (421,19): C
74.09, H 5.50, N 16.62; found: C 74.26, H 5.43, N16.51
Acknowledgements
Compound 4f. Yield: 66% (259 mg); white solid; mp: 200–
202 ◦C; TLC: Rf 0.21 (EtOAc/c-hexane: 7/3); IR (neat): n(cm-1)
3030, 2785, 2372, 1633, 1576, 1533, 1479, 1457, 1413, 1377, 1326,
The authors thank the CNRS for support of this research and
MRES for a doctoral fellowship to S.S. Thanks also to E. Morvan
for her help in the NMR experiments.
1
1290, 1031, 1023, 824, 794, 727, 696, 615, H NMR (300 MHz,
CDCl3): d 2.43 (s, 3H), 5.52 (s, 2H), 7.10 (m, 2H), 7.32 (m, 6H),
7.51 (d, 2H, J = 8.2 Hz), 7.92 (s, 1H), 8.36 (brs, 1H), 8.52 (m, 1H),
8.59 (s, 1H), 8.94 (brs, 1H); RMN 13C (75 MHz, CDCl3): d 21.4,
47.1, 120.2, 123.6, 126.3, 126.6 (2C), 127.1, 127.9, 128.9 (2C),
129.0 (2C), 129.6 (2C), 136.0, 136.2, 140.8, 141.3, 143.9, 151.4,
151.8, 152.4, 152.5; m/z MS (ES+) (M+H)+ 393; Anal. Calcd for
C24H20N6 (392,17): C 73.45, H 5.14, N 21.41; found: C 73.63, H
5.25, N 21.87.
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