Facile synthesis of 9-(arenethenyl)purines via Heck reaction of 9-vinylpurines and aryl halides

Article abstract of DOI:10.1016/j.tetlet.2007.08.008

The first example of a Heck reaction with 9-vinylpurines and aryl halides is described. It gives exclusively E-9-(arenethenyl)purines in high yields. Subsequent hydrogenation furnishes 9-(arenethyl)purines quantitatively.

Full text of DOI:10.1016/j.tetlet.2007.08.008

Tetrahedron Letters 48 (2007) 7388–7391
Facile synthesis of 9-(arenethenyl)purines via Heck reaction of
9-vinylpurines and aryl halides
Wei-Sheng Huang,* Yihan Wang, Raji Sundaramoorthi, R. Mathew Thomas, David Wen,
Shuangying Liu, Scott P. Lentini, Sasmita Das, Geetha Banda, Tomi K. Sawyer and
William C. Shakespeare
ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139, United States
Received 6 July 2007; accepted 1 August 2007
Available online 6 August 2007
Abstract—The first example of a Heck reaction with 9-vinylpurines and aryl halides is described. It gives exclusively E-9-(arenethen-
yl)purines in high yields. Subsequent hydrogenation furnishes 9-(arenethyl)purines quantitatively.
Ó 2007 Elsevier Ltd. All rights reserved.
In one of our kinase inhibitor drug discovery programs
we required ready access to E-9-(arenethenyl)purines 1,
particularly those bearing further substitution on the
terminal phenyl group. Literature methods for the prep-
aration of 1 are based on the Horner–Wadsworth–
Emmons (HWE) reaction of N9-phosphorylmethylpurine
and benzaldehydes.1,2 In addition to limited availability
of functionalized benzaldehydes, this transformation
usually yields a mixture of Z- and E-isomers, which
can result in separation difficulties in some cases. More-
over, the preparation of necessary HWE reagents is not
trivial and the strongly basic conditions are often incom-
patible with many functional groups. Very recently, a
single example of a copper-mediated coupling of an
alkenyl boronic acid with 9H-purine was reported to
provide the alkenylation product in high yield.3 The dif-
ficulty in extending this methodology more broadly in
the synthesis of 1 is that several synthetic steps are
required for the preparation of suitably functionalized
alkenyl boronic acids. We envisaged that a Heck reac-
tion of 9-vinylpurine and aryl halides could be an effi-
cient way of making 1 considering the excellent
functional group compatibility in this reaction and
abundant availability of various poly-functionalized aryl
halides (Table 1). To our knowledge, Heck reactions of
9-vinylpurines have not been reported.
The preparation of 9-vinylpurines is well documented in
the literature.4 Thus, commercially available 6-chloro
and 2,6-dichloropurine were easily converted to their
corresponding N9-vinyl derivatives 2a and 2e by reacting
both with excessive vinyl acetate in the presence of cat-
alytic amounts of H2SO4 and Hg(OAc)2. Subsequent
displacement of the chloride at C-6 in 2a or 2e by
methylamine, cyclopropylamine, or (4-dimethylphos-
phonyl)aniline gave 2b–d, f, respectively. All aromatic
halides 3 used in our studies were commercially avail-
able except 3a and 3d, which were prepared by coupling
the requisite acids and amines.
We began our investigations by reacting 2b and 3b at
100 °C in DMF utilizing Pd(OAc)2/P(o-tol)3 as the cat-
alyst system and (i-Pr)2NEt as the base. The reaction
proceeded smoothly despite the steric hindrance of 3b,
giving the desired product 1b in high yield and exclu-
sively as the E geometrical isomer. The regioisomer
resulting from arylation at a position, a product
reported in similar Heck reactions of vinyl ethers or N-
vinyl amides/imides,5 was not observed. Encouraged by
these preliminary results we expanded the scope of our
investigations to other substrates 2 and 3. As outlined
in Table 1, good to excellent yields were obtained from
all reactions, which were not optimized. Most reactions
proceeded to completion after heating at 100 °C for
15 h, and in each case, crude HPLC traces indicated
conversion to a single product that was determined to
result from b-attack and be exclusively the E-isomer.
Both aromatic iodides and bromides were suitable
Keywords: 9-Vinylpurine; Heck reaction; 9-(Arenethenyl)purine;
9-(Arenethyl)purine.
*
Corresponding author. E-mail: wei-sheng.hunag@ariad.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.008

W.-S. Huang et al. / Tetrahedron Letters 48 (2007) 7388–7391
Table 1. Heck reaction of N-vinylpurines 2 and aryl halides 3
7389
R6
R6
N
N7
N9
5
1N
R2
X
8
N
N
4
N
+
FG
R2
N
3
α
β
FG
2
3
1
2
3
1
Yield (%)
I
I
R2
H
R6
Cl
2a
2b
3a
1a
81a
H
N
N
O
CF3
H
NHMe
3b
3c
1b
1c
86b
58b
I
CHO
I
O
3d
1d
82b
N
H
CF3
I
H
H
2c
2d
3e
3a
1e
1f
66b
88b
HN
HN
OH
Br
O
P
62b
74b
Me
Me
3f
1g
1h
N
H
I
I
3g
NH2
Cl
Cl
Cl
2e
2f
3h
3b
1i
1j
78c
70d
OH
HN
a 5 mol % Pd[P(t-Bu)3]2, 120 mol % (i-Pr)2NEt, DMF, 100 °C, 5 h.
b 2.5 mol % Pd(OAc)2, 5 mol % P(o-tol)3, 120 mol % (i-Pr)2NEt, DMF, 100 °C, 15 h.
c 5 mol % Pd[P(t-Bu)3]2, 120 mol % (i-Pr)2NEt, DMF, microwave, 150 °C, 20 min.
d 15 mol % Pd(OAc)2, 30 mol % P(o-tol)3, 360 mol % (i-Pr)2NEt, DMF, microwave, 90 °C, 10 min.
coupling partners. Most reactions were run with conven-
tional heating but microwave-assisted reactions worked
equally well.
rides.6a Several alternate conditions consisting of differ-
ent Pd, ligand and base combinations gave low
conversions and/or complex mixtures.7 However, fur-
ther screening led to the identification of a very efficient
catalyst for this reaction, Pd[P(t-Bu)3]2,8 which fur-
nished 1a in high yield. This catalyst was also success-
fully applied to the reaction of 2e and 3h, where the Cl
at C-2 was again found to be benign.
Heck reactions of 2a, e and f were of particular interest
since Cl substitution by SNAr and/or palladium-medi-
ated cross-coupling reactions offer the potential for fur-
ther elaboration at either C-2 and/or C-6 on the purine
template.6 Gratifyingly, the reaction of 2f and 3b fur-
nished 1j in high yield, suggesting that the Cl at C-2
did not interfere with the Heck reaction. To the con-
trary, the reaction of 2a and 3a yielded complex mix-
tures under general reaction conditions, presumably
resulting from interfering chemistry at C-6 despite the
increased reactivity of aromatic iodides relative to chlo-
rides in these reactions. This result is consistent with the
increased reactivity at C-6 relative to C-2 on the purine
template in mechanistically relevant metal-catalyzed
cross-coupling reactions of the corresponding chlo-
As expected, many functional groups, which would be
incompatible with standard HWE conditions, including
NH2, alcoholic OH, phenolic OH, indolyl NH, amide
NH, and aldehydes, were tolerated in this reaction.
The presence of these functional groups and their incor-
poration without the need for protection highlights the
synthetic utility of this reaction as further derivatization
to more complex purines was often desired. For exam-
ple, 1h was coupled with 5-cyclopropylisoxazole-3-carb-
oxylic acid or 2-picolinic acid under standard amide

7390
W.-S. Huang et al. / Tetrahedron Letters 48 (2007) 7388–7391
bond formation condition (EDCI/HOBt), furnishing
amides 4a and 4b in high yields, respectively.
as opposed to substituted benzaldehydes (HWE reac-
tion) substantially increased the pool of diverse starting
materials and provided access to a number of products
bearing reactive functionalities without the need for pro-
tection/de-protection strategies.
1h
4a
H
O
O
P
R =
N
NH
N
O
N
N
N
References and notes
O
N
1. (a) Boesen, T.; Madsen, C.; Henriksen, U.; Dahl, O. J.
Chem. Soc., Perkin Trans. 1 2000, 2015, and references
cited therein; (b) Cornforth, J.; Wilson, J. R. H. J. Chem.
Soc., Perkin Trans. 1 1994, 1897.
2. Guan, H.-P.; Qiu, Y.-L.; Ksebati, M. B.; Kern, E. R.;
Zemlicka, J. Tetrahedron 2002, 58, 6047, and references
cited therein.
4b
R
NH
Since several N9-(arenethyl)purine compounds have
been reported as potent dual Src/Abl kinase inhibitors9
(e.g., AP23464 has an IC50 < 1 nM against Src kinase),
we were also interested in converting the Heck coupling
product 1 to its saturated analog. As such, 1d was
smoothly hydrogenated to 5 using standard conditions
(H2, Pd/C, EtOAc). Despite a 2-step procedure, this
Heck-hydrogenation route to N9-(arenethyl)purines still
offers significant advantages over the existing methods
for the following considerations: (i) de novo construc-
tion of N9-substituted purines requires early incorpora-
3. Jacobsen, M. F.; Knudsen, M. M.; Gothelf, K. V. J. Org.
Chem. 2006, 71, 9183.
4. (a) Pitha, J.; Ts’o, P. O. P. J. Org. Chem. 1968, 33, 1341;
(b) Taddei, M.; Ciapetti, P. Tetrahedron 1998, 54, 11305.
5. (a) Ziegler, C. B., Jr.; Heck, R. F. J. Org. Chem. 1978, 43,
2949; (b) Busacca, C. A.; Johnson, R. E.; Swestock, J. J.
Org. Chem. 1993, 58, 3239; (c) Datta, G. K.; von Schenck,
H.; Hallberg, A.; Larhed, M. J. Org. Chem. 2006, 71,
3896.
tion of N-9 substituents in
a lengthy reaction
6. (a) Hocek, M. Eur. J. Org. Chem. 2003, 245; (b) Chen, J.;
Grim, M.; Rock, C.; Chan, K. Tetrahedron Lett. 1989, 30,
5543; (c) Tanji, K.; Kubota, H.; Yamamoto, Y.; Higash-
ino, T. Chem. Pharm. Bull. 1987, 35, 4972; (d) Ding, S.;
Gray, N. S.; Wu, X.; Ding, Q.; Schultz, P. G. J. Am.
Chem. Soc. 2002, 124, 1594; (e) Hocek, M.; Votruba, I.;
Dvorakova, H. Tetrahedron 2003, 59, 607; (f) Hocek, M.;
Dvorakova, H. J. Org. Chem. 2003, 68, 5773; (g) Wan, Z.;
Boehm, J. C.; Bower, M. J.; Kassis, S.; Lee, J. C.; Zhao,
B.; Adams, J. L. Bioorg. Med. Chem. Lett. 2003, 13, 1191;
(h) Altmann, E.; Cowan-Jacob, S. W.; Missbach, M. J.
Med. Chem. 2004, 47, 5833; (i) Hocek, M.; Pohl, R.
Synthesis 2004, 2869.
7. Catalysts investigated: 2.5 mol % Pd2(dba)3/5 mol %
Pd[P(t-Bu)3]2, 5 mol % Pd2(dba)3/10 mol % P(o-tol)3.
8. Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719.
9. (a) Azam, M.; Nardi, V.; Shakespeare, W. C.; Metcalf, C.
A., III; Bohacek, R. S.; Wang, Y.; Sundaramoorthi, R.;
Sliz, P.; Veach, D. R.; Bornmann, W. G.; Clarkson, B.;
Dalgarno, D. C.; Sawyer, T. K.; Daley, G. Q. Proc. Natl.
Acad. Sci. U.S.A. 2006, 103, 9244; (b) Brunton, V. G.;
Avizienyte, E.; Fincham, V. J.; Serrels, B.; Metcalf, C. A.,
Jr.; Sawyer, T. K.; Frame, M. C. Cancer Res. 2005, 65,
1335; (c) O’Hare, T.; Pollock, R.; Stoffregen, E. P.; Keats,
J. A.; Abdullah, O. M.; Moseson, E. M.; Rivera, V. M.;
Tang, H.; Metcalf, C. A., III; Bohacek, R. S.; Wang, Y.;
Sundaramoorthi, R.; Shakespeare, W. C.; Dalgarno, D.;
Clackson, T.; Sawyer, T. K.; Deininger, M. W.; Druker,
B. J. Blood 2004, 104, 2532; (d) Dalgarno, D.; Stehle, T.;
Narula, S.; Schelling, P.; van Schravendijk, M. R.; Adams,
S.; Andrade, L.; Keats, J.; Ram, M.; Jin, L.; Grossman,
T.; MacNe il, I.; Metcalf, C., III; Shakespeare, W.; Wang,
Y.; Keenan, T.; Sundaramoorthi, R.; Bohacek, R.; Weig-
ele, M.; Sawyer, T. Chem. Biol. Drug Des. 2006, 67, 46.
10. Schaeffer, H. J.; Odin, E.; Bittner, S. J. Pharm. Sci. 1971,
60, 1184.
sequence,10 (ii) SN2 alkylation of 9H-purine with (2-
haloethyl)arenes is often accompanied with significant
b-elimination11 and the pool of commercially available
(2-haloethyl)arenes is very limited, (iii) Mitsunobu reac-
tions of 9H-purine with alcohols suffer from tedious
preparation of (2-hydroxyethyl)arenes and poor yields
due to b-elimination,12 (iv) functional group compatibil-
ities of these existing methods are generally poor.
O
P
NH
N
NH
N
N
N
N
N
N
N
NH
N
N
N
N
O
O
N
H
N
H
CF3
CF3
OH
AP23464
1d
5
To access N9-(arenethyl)purine directly from 2, a reduc-
tive Heck coupling of 2b and iodobenzene in the pres-
ence of HCO2H was attempted.13 Unfortunately, this
reaction did not yield the desired hydroarylation prod-
uct but generated a small amount of Heck product 1,
with the major product being 6-(methylamino)-9-ethyl-
purine. This result suggests that the insertion of ArPdX
complex into N9-vinyl of 2 is slow and that the reduction
of 9-vinylpurine by HCO2H itself predominates, yield-
ing 9-ethylpurine in a manner similar to the reduction
of an enamine in the Leuchart–Wallach reaction.14
In summary, we have demonstrated that 9-vinylpurines
undergo Heck reactions cleanly and efficiently with a
variety of substituted aryl halides.15 Through this reac-
tion, a number of highly potent, purine-based dual
Src/Abl kinase inhibitors bearing 9-(arenethenyl) sub-
stituents were prepared.16 Subsequent hydrogenation
of the Heck reaction products gave rapid access to 9-
(arenethyl)purines. Importantly, the use of aryl halides
11. Raboisson, P.; Lugnier, C.; Muller, C.; Reimund, J.-M.;
Schultz, D.; Pinna, G.; Le Bec, A.; Basaran, H.; Desaubry,
L.; Gaudiot, F.; Seloum, M.; Bourguignon, J.-J. Eur. J.
Med. Chem. 2003, 38, 199.
12. Toyota, A.; Katagir, N.; Kaneko, C. Heterocycles 1993,
36, 1625.
13. Cacchi, S.; Palmieri, G. Synthesis 1984, 575.

W.-S. Huang et al. / Tetrahedron Letters 48 (2007) 7388–7391
7391
1
14. DeBenneville, P. L.; Macartney, J. H. J. Am. Chem. Soc.
1950, 72, 3073.
as a white solid, mp 232 °C. MS [M+H]+ 480; H NMR
(DMSO-d6, 300 MHz): d 11.44 (s, 1H), 8.72 (s, 1H), 8.69
(s, 1H), 8.59 (s, 1H), 8.38 (m, 2H), 8.05 (m, 1H), 8.03 (d,
1H, J = 14.7 Hz), 7.87 (d, 1H, J = 7.9 Hz), 7.81 (d, 1H,
J = 14.7 Hz), 7.55 (d, 1H, J = 4.1 Hz), 7.42 (d, 1H,
J = 8.0 Hz), 3.09 (m, 1H), 2.43 (s, 3H), 0.74 (m, 2H),
0.66 (m, 2H).
15. General procedure: a solution of 2c (1.01 g, 5 mmol), 3a
(2.23 g, 5.5 mmol), Pd(OAc)2 (28 mg, 0.125 mmol), P(o-
tol)3 (76 mg, 0.25 mmol) in DMF (10 mL) was degassed by
bubbling N2 for 10 min. (i-Pr)2NEt (2.60 mL, 15 mmol)
was added under N2. The resulting solution was stirred at
100 °C for 15 h. Water was added and the aqueous layer
was extracted with EtOAc. The combined organic layers
were dried over Na2SO4, concentrated on a rotavap, and
then subjected to silica gel column chromatography (5%
MeOH/CH2Cl2), yielding 2.19 g of the desired product 1f
16. Wang, Y.; Huang, W.-S.; Sundaramoorthi, R.; Zhu, X.;
Thomas, R. M.; Shakespeare, W. C.; Dalgarno, D. C.;
Sawyer, T. K. WO 2007021937, 2007; Chem. Abstr. 2007,
146, 274129.