Nucleophilic arylation of halopurines facilitated by br?nsted acid in fluoroalcohol

Article abstract of DOI:10.3390/molecules24213812

Various aryl-substituted purine derivatives were synthesized through the direct arylation of halopurines with aromatic compounds, facilitated by the combination of triflic acid and fluoroalcohol. This metal-free method is complementary to conventional cou

Full text of DOI:10.3390/molecules24213812

molecules
Communication
Nucleophilic Arylation of Halopurines Facilitated by
Brønsted Acid in Fluoroalcohol
Naoko Takenaga 1,
*
, Toshitaka Shoji 2, Takayuki Menjo 3, Akiko Hirai 2, Shohei Ueda 3,
Kotaro Kikushima 2, Tomonori Hanasaki 3 and Toshifumi Dohi 2,
*
1
Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525–8577,
Japan; ph0088sh@ed.ritsumei.ac.jp (T.S.); akiko.xp@gmail.com (A.H.); kixy@fc.ritsumei.ac.jp (K.K.)
Department of Applied Chemistry, College of Life Sciences, Ritsumeikan University, 1-1-1 Nojihigashi,
Kusatsu, Shiga 525–8577, Japan; sb0067xs@ed.ritsumei.ac.jp (T.M.); sc0029ev@ed.ritsumei.ac.jp (S.U.);
hanasaki@sk.ritsumei.ac.jp (T.H.)
2
3
*
Correspondence: ntakenag@meijo-u.ac.jp (N.T.); td1203@ph.ritsumei.ac.jp (T.D.);
Tel.: +81-052-839-2706 (N.T.); +81-077-561-4908 (T.D.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Gianfranco Favi
Received: 8 October 2019; Accepted: 21 October 2019; Published: 23 October 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: Various aryl-substituted purine derivatives were synthesized through the direct arylation of
halopurines with aromatic compounds, facilitated by the combination of triflic acid and fluoroalcohol.
This metal-free method is complementary to conventional coupling reactions using metal catalysts
and reagents for the syntheses of aryl-substituted purine analogues.
Keywords: purine; nucleobase; aromatic substitution; arylation; fluoroalcohol
1. Introduction
Biogenic purine bases are heteroaromatic compounds that constitute the basic subunits of DNA
and RNA and play a crucial role in biological processes. In addition to these natural nucleosides,
various chemically modified purine nucleosides have recently been discovered, and detailed analyses
of their bioactivities have attracted much attention. Purine derivatives bearing an aryl substituent are
of particular interest among these extensively studied classes of compounds, and their preparation
has gained much attention owing to the promising biological properties of the derivatives, such as
cytotoxicity and antitumor activity [1–3]. In addition, their applications as biological probes have also
been consistent with the synthetic advances in artificial purine compounds [4].
The classical methods for the preparation of purines bearing aryl substituents are based on
heterocyclization; however, the cyclization methodology usually requires multistep procedures.
Consequently, the synthesis of the target aryl purines afforded only moderate to low yields [
recent methods for the synthesis of aryl-substituted purines involve the transition metal-catalyzed
cross-coupling reactions of aryl organometallics (Ar-M) with halopurines (Scheme 1A) [ ]. For
example, Suzuki–Miyaura [ 16], Stille [17 18], Negishi [19], and Kumada [20] coupling reactions have
5]. The
6,7
8
–
,
been frequently used for the preparation of aryl-substituted purines. Indeed, these approaches represent
versatile and reliable synthetic methods; however, these coupling reactions require stoichiometric
amounts of metallic reagents and the protection of the nucleophilic functional groups—such as
the hydroxyl and amino groups—in the substrates. Hence, direct arylation of 6-chloropurines by
electron-rich arenes using a three-fold excess of aluminum chloride (AlCl3) was reported by Guo’s
group as an alternative method for preparing aryl purines in a short synthetic step (Scheme 1B) [21].
Molecules 2019, 24, 3812; doi:10.3390/molecules24213812
www.mdpi.com/journal/molecules

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Scheme 1. General synthetic routes to obtain aryl-substituted purines from halopurines. (
synthesis. (B) Direct synthesis.
A) Stepwise
Despite these synthetic advances brought about by the alternative method, there unfortunately
remain some limitations regarding the structural diversity of the obtainable aryl purines. To the best
of our knowledge, the preparation of N-7-substituted 6-arylpurines has seldom been reported in the
scientific literature [22–24]. To expand the synthetic scope for obtaining highly functionalized aryl
purines with greater structural and steric diversities, developing a new practical method for preparing
a variety of aryl-substituted purines is still necessary. In our continuous study on the development of a
new method for the synthesis of functionalized nucleobases [25–27], we would like to report herein the
metal-free arylation of purine derivatives facilitated by the combination of triflic acid and fluoroalcohol
(Scheme 2).
Scheme 2. Direct arylation of halopurines facilitated by Brønsted acid in fluoroalcohol. ArH: aryl
nucleophile, TfOH: triflic acid.
2. Results and Discussions
Fluoroalcohols, such as 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and 2,2,2-trifluoroethanol (TFE),
possess specific properties that differentiate them from other non-fluorinated alcohols; they are highly
polar [28] and weakly nucleophilic [29] and exhibit remarkable hydrogen-bond donor abilities [30].
Owing to their unique physical properties, these fluoroalcohols can dramatically direct the course
of reactions; thus, as a means of developing new reactions, the authors utilized HFIP and TFE as
attractive and distinctive alternatives to ordinary solvents in hypervalent iodine chemistry [31–33].
In these studies, we unexpectedly discovered the metal-free SNAr-type arylation of heteroaromatic
diaryliodonium salts by nucleophilic aromatic compounds facilitated by Lewis and Brønsted acids, i.e.,
boron trifluoride, trimethylsilyl triflate, and triflic acid (TfOH), in fluoroalcohols [34–36]. Golding’s
group also reported that the combination of trifluoroacetic acid (TFA) and TFE allowed the amination
of halopurines by various substituted anilines under metal-free conditions; this method involves C–N
bond formation [37–40]. Meanwhile, the metal-free nucleophilic arylation of halopurines involving
C–C bond formation has not been reported.
In a pilot experiment, we first examined the SNAr-type coupling reaction of 6-chloropurine 1a
initiated by a Brønsted acid [34,35], using methyl indole 2a as an aromatic nucleophile in HFIP as the
model case (Table 1). In order to optimize the coupling reaction, varying equivalents (Entries 1–4) of
TfOH were used, and the desired arylation product of purine 3aa was obtained in excellent yield when
we used 0.5 to 1.0 equiv. of TfOH for the reactions (Entries 3 and 4). The usage of alternative Brønsted
acids as additives, such as H3PO4, p-TsOH, and even TFA [37–40], was not as effective and provided
inferior results in comparison with the use of TfOH. The fluoroalcohol HFIP plays an essential role in
the reaction, and a solvent mixture of HFIP and 1,2-dichloroethane (DCE) did not smoothly produce
the coupling product 3aa. (Entry 5). Also, the replacement of HFIP with TFE and the use of methanol
and acetonitrile as the solvent instead of HFIP yielded low or null amounts of product 3aa.

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Table 1. Optimization of the reaction conditions a.
Yield (%) b
Entry
Solvent
TfOH
1
2
3
4
5
HFIP
HFIP
HFIP
0.1 equiv.
0.2 equiv.
0.5 equiv.
1.0 equiv.
1.0 equiv.
8
54
89
quant.
60
HFIP
HFIP/DCE = 9:1
a
Reaction conditions: The reactions were performed using chloropurine 1a (0.50 mmol), 1-methylindole 2a
(0.55 mmol), and TfOH in solvent (0.1 M). b Determined by 1H-NMR using nitromethane as an internal standard.
HFIP: hexafluoroisopropanol, DCE: 1,2-dichloroethane.
To evaluate the generality of the reaction system, the substrate scope under the optimized reaction
conditions was examined (Table 2). The reaction of N-protected 9-benzyl-6-chloro-9H-purine 1b cleanly
favored the corresponding product 3ba with good yield. When non-N-protected indoles 2b
–d were
subjected to analogous reaction conditions, the desired products 3bb bd were also obtained in excellent
–
yields. However, it was revealed that the reaction of indoles bearing electron-withdrawing groups,
such as 5-nitroindole 2e, did not proceed under these reaction conditions due to the deactivation of
the aromatic nucleophile by hydrogen bonding with HFIP [41–43]. Furthermore, other electron-rich
arenes were as compatible as the aromatic nucleophiles; similarly, good results were obtained from the
coupling reactions with 1-naphthol 2f, 1-methoxynaphthalene 2g, several alkoxybenzenes 2h
resorcinol 2j.
,i, and
Table 2. Scope of substrates a.
3aa: quant.
3bd: 90%
3ba: 82%
3be: n.r
3bb: quant.
3af: 97%
3bc: 96%
3ag: 85%
3bg: 92%
3bh: quant.
3bi: quant.
3bj: quant.
a
All the reactions were performed using chloropurine
1 (0.50 mmol), indole or aromatic nucleophile 2 (0.55 mmol),
and TfOH (0.5 mmol, 1.0 equiv.) in HFIP (0.1 M) at 60 ◦C. The yields after isolation are indicated.

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One of the significant advantages of the present reaction system is the production of structural
and sterically diverse N-7-substituted 6-arylpurines; these arylpurines are not easily accessible by other
synthetic methods [22–24]. As a result, the proposed reaction conditions were also utilized for the
coupling of 7-benzyl-6-chloro-7H-purine 1c with indole 2k and naphthalene nucleophile 2f to afford
the corresponding 6-arylated N-7-substituted purines 3ck and 3cf in good yields (Scheme 3).
Scheme 3. Synthesis of 7-substituted 6-aryl purines.
When using p-anisidine
chemoselective N-arylation of halopurines at the 6 position under mild temperature (Scheme 4) [37].
We subjected 9H-chloropurine 1d and aniline
to our optimized conditions at 60 ◦C, obtaining selective
N-arylation that smoothly provided N-(4-methoxyphenyl)-9H-purine-6-amine in 79% yield, without
4 as a substrate, our reaction system with TfOH became valuable for the
4
5
the formation of the C-arylated purine coupling product 50. On the other hand, Guo’s group previously
reported the reaction of purines and anilines or naphthylamines in the presence of a three-fold excess
of AlCl3 in DCE, which alternatively gave the C-arylated coupling products and likewise the biaryl
50
[21]. Therefore, our reaction system is complementary to the AlCl3-mediated coupling reaction [21]
for the syntheses of C6-aryl-substituted purine derivatives in view of product selectivity.
Scheme 4. Formation of different products using Brønsted acid and aluminum chloride as activators.
The success of the metal-free coupling reaction relies on the use of HFIP as the solvent. Although
the precise role of HFIP [44 46] remains unclear, we presume that HFIP can increase the acidity of
TfOH (Brønsted acid activation by H-bond donor) to enhance the reactivity of halopurine electrophiles
through the purine nitrogen atoms [47 50]. Importantly, HFIP offers a means of improving the
–
–
leaving group ability of the chloride atom in the purine substrates through hydrogen bonding as
well as solvation [51]. Recently, such unique role of fluoroalcohol as the H-bond donor has been
discussed in several Brønsted acid catalyzed reactions in regard to its ability to accelerate substitution
processes [37,47–51]. Interestingly, these cases would involve intermediates activated by hydrogen
bonding with fluoroalcohol, and, with our present system, the formation of a similar intermediate
would also be expected to facilitate the aromatic substitution reactions.

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3. Conclusions
In conclusion, we have developed a new metal-free coupling method of halopurines for the
syntheses for diverse C6-aryl-substituted purine derivatives based on Brønsted acid activation. The
combination of TfOH and HFIP is an efficient and practical methodology for the direct nucleophilic
arylation of halopurines under mild conditions. We have elucidated that the unique properties of
HFIP (hydrogen-bonding formation and weak nucleophilicity) could facilitate the direct arylation of
halopurines by various nucleophilic arene molecules. Further investigations on the utilization of the
obtained purine biaryls are currently underway in our research group.
4. Experimental Section
The melting points (mp) are uncorrected. The 1H-NMR (and 13C-NMR) spectra of the coupling
products
400 MHz (100 MHz for 13C-NMR) in DMSO-d6 at 25 ◦C with tetramethylsilane as the internal standard.
The data are reported as follows: chemical shift in part per million ( ), multiplicity (s = singlet,
3 and 5 were recorded by a JEOL JMN-400 spectrometer (JEOL Ltd., Tokyo, Japan) operating at
δ
d = doublet, t = triplet, q = quartet, br = broad singlet, m = multiplet), integration, and coupling
constant (Hz). The infrared spectra (IR) were obtained using a Hitachi 270–50 spectrometer (Hitachi
Ltd., Tokyo, Japan); absorptions are reported in reciprocal centimeters (cm−1) for representative
peaks. High-resolution mass spectra were measured with a Thermo Scientific Exactive Plus Orbitrap
(Thermo Fisher Scientific., Inc., Waltham, MA, USA). All chemicals used in this study are commercially
available and were used without further purification. Regarding fluoroalcohol, we used commercial
water-containing hexafluoroisopropanol (HFIP) as supplied for the reactions.
4.1. General Procedure for Brønsted Acid Catalyzed Arylation of Halopurines in Fluoroalcohol (Table 2 and
Scheme 3)
To a stirred solution of chloropurine
1
(0.50 mmol) in hexafluoroisopropanol (5 mL), aromatic
L, 0.5 mmol, 1 equiv)
nucleophile (0.55 mmol, 1.1 equiv) and trifluoromethanesulfonic acid (TfOH, 44
2
µ
were successively added. The resulting mixture was stirred at 60 ◦C for 24 h. After completion of the
reaction checked by TLC, the reaction mixture was poured into sat. NaHCO3 aqueous. The resultant
solution was extracted with ethyl acetate, dried with solid sodium sulfate, and then concentrated. The
residue was purified by short-column chromatography on silica gel using hexane-ethyl acetate as the
eluent to give the purine aromatic-linked compound 3 in the indicated yield in Table 2 or Scheme 3.
◦
Compound 6-(1-methyl-1H-indol-3-yl)-7H-purine (3aa). A yellow powder, mp 346–350 C. IR: 3647,
1
1732 cm−1. H-NMR (400 MHz, DMSO-d6)
δ
3.95 (s, 3H), 7.21–7.31 (m, 2H), 7.55 (d, J = 7.9 Hz, 1H),
33.1,
8.49 (s, 1H), 8.81–8.84 (m, 2H), 8.97 (s, 1H), 13.4 (bs, 1H) ppm; 13C-NMR (100 MHz, DMSO-d6)
δ
110.4 (x 2), 121.0, 122.4, 122.9, 126.2, 128.0, 136.2, 137.2, 142.7, 151.3, 152.1, 152.3 ppm; HRMS (DART):
Calcd. for C14H12N5 [M + H]+: 250.1087, found: 250.1087.
Compound 6-(1-methyl-1H-indol-3-yl)-9-phenylmethyl)-9H-purine (3ba) [21]. A yellow powder, mp
1
163–166 ◦C. IR: 3047, 2932, 1581, 1536, 1498, 1475 cm−1. H-NMR (400 MHz, DMSO-d6)
δ
3.96 (s, 3H),
5.51(s, 2H), 7.23–7.59 (m, 7H), 7.57 (d, 1H, J = 7.8 Hz), 8.68 (s, 1H), 8.80 (d, 1H, J = 7.8 Hz), 8.86 (s, 1H),
8.96 (s, 1H) ppm; 13C-NMR (100 MHz, DMSO-d6)
δ
33.0, 54.9, 110.2, 110.3, 121.1, 122.5, 122.8, 126.2,
127.6, 127.8, 128.1, 128.7, 136.3, 136.8, 137.2, 144.4, 150.3, 152.3, 152.7 ppm.
Compound 6-(1H-indol-3-yl)-9-phenylmethyl-9H-purine (3bb) [21]. A yellow powder, mp 178–180 ◦C.
IR: 3631, 1688 cm−1
.
1H-NMR (400 MHz, DMSO-d6)
δ
5.51 (s, 2H), 7.17–7.41 (m, 7H), 7.52 (d, 1H,
J = 6.8 Hz), 8.66 (s, 1H), 8.76–8.89 (m, 2H), 8.99 (s, 1H), 12.0 (s, 1H) ppm; 13C-NMR (100 MHz, DMSO-d6)
46.3, 111.2, 112.0, 120.9, 122.4, 122.7, 125.7, 127.9, 128.4, 128.8, 132.8, 136.6, 136.9, 144.5, 150.3, 152.3,
δ
153.1 ppm.
Compound 6-(5-methyl-1H-indol-3-yl)-9-phenylmethyl-9H-purine (3bc). A brown liquid, IR: 3649, 1690,
1
1559, 1540 cm–1. H-NMR (400 MHz, DMSO-d6)
δ 2.36 (s, 3H), 5.45 (s, 2H), 7.08 (d, J = 8.3 Hz, 1H),

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7.26
−
7.36 (m, 6H), 8.53 (s, 1H), 8.59 (s, 1H), 8.82 (s, 1H), 8.90 (s, 1H), 11.8 (s, 1H) ppm; 13C-NMR
(100 MHz, DMSO-d6)
δ
21.5, 46.0, 110.8, 111.7, 122.3, 124.0, 126.0, 127.6, 127.9, 128.3, 128.8, 129.5, 132.9,
+
135.0, 136.9, 144.3, 150.2, 152.3, 153.2 ppm; HRMS (DART): Calcd. for C21H18N5 [M + H]+: 340.1557,
found: 340.1557.
Compound 6-(5-methoxy-1H-indol-3-yl)-9-phenylmethyl-9H-purine (3bd). A brown solid, mp 229–231 ◦C.
1
IR: 3595, 1704, 1559, 1508, 1437 cm−1. H-NMR (400 MHz, DMSO-d6)
δ 3.89 (s, 3H), 5.57 (s, 2H), 6.92 (d,
1H, J = 8.6 Hz), 7.31–7.49 (m, 6H), 8.38 (s, 1H), 8.71 (s, 1H), 8.93 (s, 1H), 9.01 (s, 1H), 11.9 (s, 1H) ppm;
13C-NMR (100 MHz, DMSO-d6)
δ 46.3, 55.4, 104.6, 111.0, 112.2, 112.7, 126.4, 127.6, 127.9, 128.2, 128.8,
131.6, 133.2, 136.9, 144.3, 150.2, 152.3, 153.2, 154.7 ppm; HRMS (DART): Calcd. for C21H18N5O+ [M +
H]+: 356.1506, found: 356.1507.
Compound 4-(7H-purin-6-yl)-naphthalene-1-ol (3af). A yellow powder, mp 204–208 ◦C. IR: 3650, 1541 cm−1
1H-NMR (400 MHz, DMSO-d6)
7.09 (d, 1H, J = 8.6 Hz), 7.51–7.57 (m, 2H), 8.06–8.63 (m, 4H), 9.06 (s,
.
δ
1H), 10.8 (bs, 1H), 13.3 (bs, 1H) ppm; 13C-NMR (100 MHz, DMSO-d6)
δ 107.8, 122.6, 123.5, 125.0, 125.3,
125.8, 127.3, 131.4, 132.2, 152.0, 155.5 ppm; HRMS (DART): Calcd. for C15H11N4O+ [M + H]+: 263.0927,
found: 263.0928.
Compound 6-(4-methoxynaphthalen-1-yl)-7H-purine (3ag). A yellow powder, mp 170–172 ◦C. IR: 3629,
1
1704, 1542, 1508 cm–1. H-NMR (400 MHz, DMSO-d6)
δ 4.06 (s, 3H), 7.16 (d, 1H, J = 8.6 Hz), 7.49–7.59
(m, 2H), 8.22–8.30 (m, 3H), 8.58 (bs, 1H), 9.02 (s, 1H), 13.6 (bs, 1H) ppm; 13C-NMR (100 MHz, DMSO-d6)
δ
56.0, 103.9, 121.7, 124.8, 125.0, 125.6, 127.1, 131.5, 151.6, 156.3 ppm; HRMS (DART): Calcd. for
C16H13N4O+ [M + H]+: 277.1084, found: 277.1082.
Compoun◦d 6-(4-methoxynaphthalen-1-yl)-9-phenylmethyl-9H-purine (3bg) [21]. A white solid, mp
. δ 4.02 (s, 3H), 5.55 (s,
1H-NMR (400 MHz, DMSO-d6)
197–198 C. IR: 3672, 2968, 1507 cm−1
2H), 7.12 (d, 1H, J = 8.0 Hz), 7.24–7.36 (m, 3H), 7.42 (d, 2H, J = 7.4 Hz), 7.48–7.55 (m, 2H), 8.13 (d, 1H,
J = 8.6 Hz), 8.24–8.28 (m, 1H), 8.44–8.49 (m, 1H), 8.75 (s, 1H), 9.09 (s, 1H) ppm; 13C-NMR (100 MHz,
DMSO-d6) δ 46.5, 55.8, 103.8, 121.7, 124.5, 125.0, 125.4, 125.9, 127.0, 127.8, 127.9, 128.7, 131.6, 131.8, 136.5,
146.1, 151.7, 151.8, 156.4, 156.5 ppm.
Compound 6-(1,3,5-trimethoxyphen-4-yl)-9-phenylmethyl-9H-purine (3bh) [21]. A white solid, mp
1
251–253 ◦C. IR: 3650, 1698 cm−1. H-NMR (400 MHz, DMSO-d6)
δ 3.58 (s, 6H), 3.84 (s, 3H), 5.49 (s, 2H),
6.35 (s, 2H), 7.27–7.47 (m, 5H), 8.61 (s, 1H), 8.90 (s, 1H) ppm; 13C-NMR (100 MHz, DMSO-d6)
δ 46.6,
55.5, 55.7, 91.0, 106.6, 128.1, 128.8, 133.6, 136.6, 145.7, 150.8, 151.8, 154.2, 158.7, 162.0 ppm.
Compound 6-(1,3-dimethoxyphen-4-yl)-9-phenylmethyl-9H-purine (3bi) [52]. A white solid, mp 125–127 ◦C.
1
IR: 3671, 1707 cm−1. H-NMR (400 MHz, DMSO-d6)
δ 3.74 (s, 3H), 3.83 (s, 3H), 5.50 (s, 2H), 6.66 (d,
1H, J = 8.8 Hz), 6.73 (s, 1H), 7.24–7.42 (m, 5H), 7.53 (d, 1H, J = 8.3 Hz), 8.66 (s, 1H), 8.93 (s, 1H) ppm;
13C-NMR (100 MHz, DMSO-d6)
δ
46.5, 55.4, 55.7, 98.9, 105.2, 117.8, 127.8, 128.0, 128.8, 131.9, 132.5,
136.7, 145.6, 151.1, 151.8, 155.4, 158.8, 162.0 ppm.
Compound 4-(9-phenylmethyl-9H-purin-6-yl)-benzene-1,3-diol (3bj) [21]. A yellow solid, mp 250–253 ◦C.
1
IR: 3691, 2983, 1686, 1507, 1318 cm−1. H-NMR (400 MHz, DMSO-d6)
δ 5.47 (s, 2H), 6.36 (s, 1H), 6.48 (d,
1H, J = 8.8 Hz), 7.20–7.34 (m, 5H), 8.72 (s, 1H), 8.79 (s, 1H), 9.21 (d, 1H, J = 8.8 Hz), 14.6 (s, 1H) ppm;
13C-NMR (100 MHz, DMSO-d6) δ 46.6, 103.3, 106.4, 108.2, 109.1, 127.8, 128.8, 133.8, 136.5, 145.6, 149.5,
151.1, 154.4, 158.6, 162.5, 163.5 ppm.
Compound 6-(1-phenyl-1H-indol-3-yl)-7-phenylmethyl-7H-purine (3ck). A yellow powder, mp 191–194 ◦C.
1
IR: 1693, 1521 cm−1. H-NMR (400 MHz, DMSO-d6)
δ
5.54 (s, 2H), 7.26–7.39 (m, 7H), 7.49–7.74 (m, 6H),
46.4, 110.9, 112.8,
8.72 (s, 1H), 8.91–8.95 (m, 2H), 9.14 (s, 1H) ppm; 13C-NMR (100 MHz, DMSO-d6)
δ
122.1, 123.2, 123.6, 124.5, 126.8, 127.6, 127.7, 127.9, 128.8, 130.1, 134.5, 136.0, 136.7, 138.2, 143.3, 145.0,
150.5, 152.0, 152.3 ppm. HRMS (DART): Calcd. for C26H20N5 [M + H]+: 402.1713, found: 402.1713.

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Compound 4-(7-phenylmethyl-7H-purin-6-yl)-naphthalene-1-ol (3cf). A yellow powder, mp 259–263 ◦C. IR:
1
3613, 2980, 1697 cm−1. H-NMR (400 MHz, DMSO-d6)
δ 4.96-5.04 (m, 2H), 6.18 (d, 2H, J = 7.3 Hz), 6.77
(t, 2H, J = 7.3 Hz), 6.86 (t, 1H, J = 7.3 Hz), 6.93 (d, 1H, J = 7.8 Hz), 7.18 (d, 1H, J = 8.3 Hz), 7.26 (t, 2H,
J = 5.4 Hz), 7.42 (t, 1H, J = 7.3 Hz), 8.22 (d, 1H, J = 8.3 Hz), 8.91 (s, 1H), 9.04 (s, 1H), 10.7 (bs, 1H) ppm;
13C-NMR (100 MHz, DMSO-d6) δ 49.8, 107.0, 122.2, 123.4, 123.6, 124.3, 124.7, 124.9, 125.7, 126.9, 127.3,
127.9, 128.8, 132.3, 135.6, 150.8, 151.7, 152.0, 154.9, 161.6 ppm; HRMS (DART): Calcd. for C22H17N4O+
[M + H]+: 353.1397, found: 353.1395.
4.2. General Procedure for Brønsted Acid Catalyzed N-Coupling of Aniline Derivatives to Halopurines in
Fluoroalcohol (Scheme 4)
To a stirred solution of 9H-chloropurine 1d (77.3 mg, 0.50 mmol) in hexafluoroisopropanol (5
mL) p-methoxyaniline
µ
4 (67.8 mg, 0.55 mmol, 1.1 equiv) and trifluoromethanesulfonic acid (TfOH, 44
L, 0.5 mmol, 1 equiv) were successively added. The resulting mixture was stirred at 60 ◦C for 24 h.
After completion of the reaction checked by TLC, the reaction mixture was poured into sat. NaHCO3
aqueous. The resultant solution was extracted with ethyl acetate, dried with solid sodium sulfate, and
then concentrated. The residue was purified by short-column chromatography on silica gel using
hexane-ethyl acetate as the eluent to give N-(4-methoxyphenyl)-9H-purine-6-amine
5
in 79% yield
(95.3 mg, 0.395 mmol) as a white powder.
◦
Compound N-(4-methoxyphenyl)-9H-purine-6-amine (
5
) [53]. A white solid, mp 266–267 C. IR: 3673,
1
3630 cm−1. H-NMR (400 MHz, DMSO-d6)
δ
3.33 (s, 3H), 6.89 (d, 2H, J = 9.3 Hz), 7.79 (d, 2H, J = 8.8 Hz),
8.22 (s, 1H), 8.29 (s, 1H), 9.61 (s, 1H), 13.1 (bs, 1H) ppm; 13C-NMR (100 MHz, DMSO-d6)
δ 55.2, 113.6,
119.2, 122.4, 132.8, 139.5, 150.2, 151.9, 154.9, 159.7 ppm.
Author Contributions: N.T. and T.D. conceived and designed the experiments and directed the project; N.T., T.S.,
T.M., A.H., and S.U. performed the experiments; T.D. and K.K. analyzed the data and checked the experimental
details; T.H. contributed to critical discussion and presentation of the results; N.T. and T.D. wrote the paper.
Funding: This work was supported by JSPS KAKENHI Grant Number 16K18854. T.D. acknowledges the support
from JSPS KAKENHI (C) Grant Number 19K05466 and the Ritsumeikan Global Innovation Research Organization
(R-GIRO) project.
Acknowledgments: We thank Central Glass Co., Ltd., for the generous gift of fluoroalcohol.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
Legraverend, M.; Grierson, D.S. The purines: Potent and versatile small molecule inhibitors and modulators
of key biological targets. Bioorg. Med. Chem. 2006, 14, 3987–4006. [CrossRef] [PubMed]
Bakkestuen, A.K.; Gundersen, L.L.; Utenova, B.T. Synthesis, biological activity, and SAR of antimycobacterial
9-aryl-, 9-arylsulfonyl-, and 9-benzyl-6-(2-furyl)purines. J. Med. Chem. 2005, 48, 2710–2723. [CrossRef]
[PubMed]
2.
3.
4.
Hocek, M.; Naus, P.; Pohl, R.; Votruba, I.; Furman, P.A.; Tharnish, P.M.; Otto, M.J. Cytostatic 6-arylpurine
nucleosides. 6. SAR in anti-HCV and cytostatic activity of extended series of 6-hetarylpurine ribonucleosides.
J. Med. Chem. 2005, 48, 5869–5873. [CrossRef] [PubMed]
Storr, T.E.; Strohmeier, J.A.; Baumann, C.G.; Fairlamb, I.J.S. A sequential direct arylation/Suzuki–Miyaura
cross-coupling transformation of unprotected 20-deoxyadenosine affords a novel class of fluorescent
analogues. Chem. Commun. 2010, 46, 6470–6472. [CrossRef] [PubMed]
5.
6.
7.
Shaw, G. Comprehensive Heterocyclic Chemistry; Katritzky, A.R., Rees, C.W., Eds.; Pergamon Press: Oxford,
UK, 1984; Volume 5, pp. 501–597.
Agrofoglio, L.A.; Gillaizeau, I.; Saito, Y. Palladium-assisted routes to nucleosides. Chem. Rev. 2003, 103,
1875–1916. [CrossRef]
Hocek, M. Synthesis of purines bearing carbon substituents in positions 2, 6 or 8 by metal- or
organometal-mediated C–C bond-forming reaction. Eur. J. Org. Chem. 2003, 245–254. [CrossRef]

Molecules 2019, 24, 3812
8 of 10
8.
9.
Lakshman, M.K.; Hilmer, J.H.; Martin, J.Q.; Keeler, J.C.; Dinh, Y.Q.; Ngassa, F.N.; Russon, L.M. Palladium
catalysis for the synthesis of hydrophobic C-6 and C-2 aryl 20-deoxynucleosides. Comparison of C–C versus
C–N bond formation as well as C-6 versus C-2 reactivity. J. Am. Chem. Soc. 2001, 123, 7779–7787. [CrossRef]
Hocek, M.; Holy, A.; Votruba, I.; Dvorakova, H. Synthesis and cytostatic activity of substituted 6-phenylpurine
bases and nucleosides: Application of the Suzuki-Miyaura cross-coupling reactions of 6-chloropurine
derivatives with phenylboronic acids. J. Med. Chem. 2000, 43, 1817–1825. [CrossRef]
10. Cerna, I.; Pohl, R.; Klepetarova, B.; Hocek, M. Synthesis of 6,8,9-tri- and 2,6,8,9-tetrasubstituted purines by a
combination of the Suzuki cross-coupling, N-arylation, and direct C–H arylation reactions. J. Org. Chem.
2008, 73, 9048–9054. [CrossRef]
11. Lakshman, M.K.; Thomson, P.F.; Nuqui, M.A.; Hilmer, J.H.; Sevova, N.; Boggess, B. Facile Pd-catalyzed
cross-coupling of 20-deoxyguanosine O6-arylsulfonates with arylboronic acids. Org. Lett. 2002, 4, 1479–1482.
[CrossRef]
12. Gunda, P.; Russon, L.M.; Lakshman, M.K. Pd-catalyzed amination of nucleoside arylsulfonates to yield
N6-aryl-2,6-diaminopurine nucleosides. Angew. Chem. Int. Ed. 2004, 43, 6372–6377. [CrossRef] [PubMed]
13. Lakshman, M.K.; Gunda, P.; Pradhan, P. Mild and room temperature C–C bond forming reactions of
nucleoside C-6 arylsulfonates. J. Org. Chem. 2005, 70, 10329–10335. [CrossRef] [PubMed]
14. Liu, J.; Robins, M.J. Fluoro, alkylsulfanyl, and alkylsulfonyl leaving groups in suzuki cross-coupling reactions
of purine 20-deoxynucleosides and nucleosides. Org. Lett. 2005, 7, 1149–1151. [CrossRef] [PubMed]
15. Liu, J.; Robins, M.J. Azoles as Suzuki cross-coupling leaving groups: Syntheses of 6-arylpurine
20-deoxynucleosides and nucleosides from 6-(imidazol-1-yl)- and 6-(1,2,4-triazol-4-yl)purine derivatives.
Org. Lett. 2004, 6, 3421–3423. [CrossRef] [PubMed]
16. Kang, F.A.; Sui, Z.; Murray, W.V. Pd-catalyzed direct arylation of tautomerizable heterocycles with aryl
boronic acids via C-OH bond activation using phosphonium salts. J. Am. Chem. Soc. 2008, 130, 11300–11302.
[CrossRef]
17. Langli, G.; Gundersen, L.-L.; Rise, F. Regiochemistry in Stille couplings of 2,6-dihalopurines. Tetrahedron
1996, 52, 5625–5638. [CrossRef]
18. Havelková, M.; Dvorˇák, D.; Hocek, M. Covalent analogues of DNA base-pairs and triplets. Part 3: Synthesis of
1,4- and 1,3-bis(purin-6-yl)benzenes and 1-(1,3-dimethyluracil-5-yl)-3 or 4-(purin-9-yl)benzenes. Tetrahedron
2002, 58, 7431–7435. [CrossRef]
19. Gundersen, L.L.; Langli, G.; Rise, F. Regioselective Pd-mediated coupling between 2,6-dichloropurines and
organometallic reagents. Tetrahedron Lett. 1995, 36, 1945–1948. [CrossRef]
20. Furstner, A.; Leitner, A.; Mendez, M.; Krause, H. Iron-catalyzed cross-coupling reactions. J. Am. Chem. Soc.
2002, 124, 13856–13863. [CrossRef]
21. Guo, H.-M.; Li, P.; Niu, H.-Y.; Wang, D.-C.; Qu, G.-R. Direct synthesis of 6-arylpurines by reaction of
6-chloropurines with activated aromatics. J. Org. Chem. 2010, 75, 6016–6018. [CrossRef]
22. Edenhofer, A. Novel route to imidazoles, and their use for the synthesis of purines and
4,6-dihydro-1,2-dimethyl-8-phenylimidazo[4,5-e]-1,4-diazepin-5(1H)-one. Helv. Chim. Acta 1975, 58,
2192–2209. [CrossRef]
23. Gundersen, L.-L.; Bakkestuen, A.K.; Aasen, J.; Overas, H.; Rise, F. 6-Halopurines in palladium-catalyzed
coupling with organotin and organozinc reagents. Tetrahedron 1994, 50, 9743–9756. [CrossRef]
24. Havelkova, M.; Hocek, M.; Cesnek, M.; Dvorak, D. The Suzuki-Miyaura cross-coupling reactions of
6-halopurines with boronic acids leading to 6-aryl- and 6-alkenylpurines. Synlett 1999, 1145–1147. [CrossRef]
25. Takenaga, N.; Ueda, S.; Hayashi, T.; Dohi, T.; Kitagaki, S. Facile synthesis of stable uracil-iodonium(III) salts
with various counterions. Heterocycles 2018, 97, 1248–1256. [CrossRef]
26. Takenaga, N.; Ueda, S.; Hayashi, T.; Dohi, T.; Kitagaki, S. Vicinal functionalization of uracil heterocycles with
base activation of iodonium(III) salts. Heterocycles 2019, 99, 865–874. [CrossRef]
27. Takenaga, N.; Hayashi, T.; Ueda, S.; Satake, H.; Yamada, Y.; Kodama, T.; Dohi, T. Synthesis of
uracil-iodonium(III) salts for practical utilization as nucleobase synthetic modules. Molecules 2019, 24,
3034. [CrossRef]
28. Reichardt, C. Empirical parameters of solvent polarity as linear free-energy relationships. Angew. Chem. Int.
Ed. Engl. 1979, 18, 98–110. [CrossRef]
29. Schadt, F.L.; Bentley, T.W.; Schleyer, P.V.R. The SN2-SN1 spectrum. 2. Quantitative treatments of nucleophilic
solvent assistance. A scale of solvent nucleophilicities. J. Am. Chem. Soc. 1976, 98, 7667–7675. [CrossRef]

Molecules 2019, 24, 3812
9 of 10
30. Kamlet, M.J.; Abbound, J.L.M.; Abraham, M.H.; Taft, R.W. Linear solvation energy relationships. 23. A
comprehensive collection of the solvatochromic parameters, .pi*., alpha., and .beta., and some methods for
simplifying the generalized solvatochromic equation. J. Org. Chem. 1983, 48, 2877–2887. [CrossRef]
31. Dohi, T.; Yamaoka, N.; Kita, Y. Fluoroalcohols: Versatile solvents in hypervalent iodine chemistry and
syntheses of diaryliodonium(III) salts. Tetrahedron 2010, 66, 5775–5785. [CrossRef]
32. Kamitanaka, T.; Morimoto, K.; Tsuboshima, K.; Koseki, D.; Takamuro, H.; Dohi, T.; Kita, Y. Efficient coupling
reaction of quinone monoacetal with phenols leading to phenol biaryls. Angew. Chem. Int. Ed. 2016, 55,
15535–15538. [CrossRef] [PubMed]
33. Dohi, T.; Ito, M.; Morimoto, K.; Minamitsuji, Y.; Takenaga, N.; Kita, Y. Versatile direct dehydrative approach
for diaryliodonium(III) salts in fluoroalcohol media. Chem. Commun. 2007, 4152–4154. [CrossRef] [PubMed]
34. Dohi, T.; Ito, M.; Yamaoka, N.; Morimoto, K.; Fujioka, H.; Kita, Y. Unusual ipso substitution of diaryliodonium
bromides initiated by a single-electron-transfer oxidizing process. Angew. Chem. Int. Ed. 2010, 49, 3334–3337.
[CrossRef] [PubMed]
35. Yamaoka, N.; Sumida, K.; Itani, I.; Kubo, H.; Ohnishi, Y.; Sekiguchi, S.; Dohi, T.; Kita, Y. Single-electron-transfer
(SET)-induced oxidative biaryl coupling by polyalkoxybenzene-derived diaryliodonium(III) salts. Chem.
Eur. J. 2013, 19, 15004–15011. [CrossRef]
36. Dohi, T.; Ueda, S.; Hirai, A.; Kojima, Y.; Morimoto, K.; Kita, Y. Selective aryl radical transfers into
N-heteroaromatics from diaryliodonoium salts with trimethoxybenzene auxiliary. Heterocycles 2017, 95,
1272–1284. [CrossRef]
37. Carbin, B.; Coxon, C.R.; Lebraud, H.; Elliott, K.J.; Matheson, C.J.; Meschini, E.; Roberts, A.R.; Turner, D.M.;
Wong, C.; Cano, C.; et al. Trifluoroacetic acid in 2,2,2-trifluoroethanol facilitates SNAr reactions of heterocycles
with arylamines. Chem. Eur. J. 2014, 20, 2311–2317. [CrossRef]
38. Whitfield, H.J.; Griffin, R.J.; Hardcastle, I.R.; Henderson, A.; Meneyrol, J.; Mesguiche, V.; Sayle, K.L.;
Golding, B.T. Facilitation of addition–elimination reactions in pyrimidines and purines using trifluoroacetic
acid in trifluoroethanol. Chem. Commun. 2003, 2802–2803. [CrossRef]
39. Marchetti, F.; Cano, C.; Curtin, N.J.; Golding, B.T.; Griffin, R.J.; Haggerty, K.; Newell, D.R.; Parsons, R.J.;
Payne, S.L.; Wang, L.Z.; et al. Synthesis and biological evaluation of 5-substituted O4-alkylpyrimidines as
CDK2 inhibitors. Org. Biomol. Chem. 2010, 8, 2397–2407. [CrossRef]
40. Wong, C.; Griffin, R.J.; Hardcastle, I.R.; Northen, J.S.; Wang, L.Z.; Golding, B.T. Synthesis of sulfonamide-based
kinase inhibitors from sulfonates by exploiting the abrogated SN2 reactivity of 2,2,2-trifluoroethoxysulfonates.
Org. Biomol. Chem. 2010, 8, 2457–2464. [CrossRef]
41.
B
égu
é, J.; Bonnet-delpon, D.; Crousse, B. Fluorinated alcohols: A new medium for selective and clean
reaction. Synlett 2004, 18–29. [CrossRef]
42. Shuklov, I.A.; Dubrovina, N.V.; Boerner, A. Fluorinated alcohols as solvents, cosolvents and additives in
homogeneous catalysis. Synthesis 2007, 2925–2943. [CrossRef]
43. Baeza, A.; Najera, C. Recent advances in the direct nucleophilic substitution of allylic alcohols through
SN1-type reactions. Synthesis 2014, 46, 25–34. [CrossRef]
44. Berkessel, A.; Adrio, J.A. Dramatic acceleration of olefin epoxidation in fluorinated alcohols: Activation of
hydrogen peroxide by multiple H-bond networks. J. Am. Chem. Soc. 2006, 128, 13412–13420. [CrossRef]
[PubMed]
45. Colomer, I.; Chamberlain, A.E.R.; Haughey, M.B.; Donohoe, T.J. Hexafluoroisopropanol as a highly versatile
solvent. Nat. Rev. Chem. 2017, 1, 0088. [CrossRef]
46. Zhou, Z.; Cheng, Q.-Q.; Kürti, L. Aza-Rubottom oxidation: Synthetic access to primary α-aminoketones. J.
Am. Chem. Soc. 2019, 141, 2242–2246. [CrossRef] [PubMed]
47. Liu, J.; Robins, M.J. SNAr displacements with 6-(fluoro, chloro, bromo, iodo, and alkylsulfonyl)purine
nucleosides: Synthesis, kinetics, and mechanism. J. Am. Chem. Soc. 2007, 129, 5962–5968. [CrossRef]
[PubMed]
48. Vukovic, V.D.; Richmond, E.; Wolf, E.; Moran, J. Catalytic Friedel-Crafts reactions of highly electronically
deactivated benzylic alcohols. Angew. Chem. Int. Ed. 2017, 56, 3085–3089. [CrossRef]
49. Liu, W.; Wang, H.; Li, C.-J. Metal-free markovnikov-type alkyne hydration under mild conditions. Org. Lett.
2016, 18, 2184–2187. [CrossRef]
50. Dohi, T.; Hu, Y.; Kamitanaka, T.; Washimi, N.; Kita, Y. [3 + 2] Coupling of quinone monoacetals by combined
acid-hydrogen bond donor. Org. Lett. 2011, 13, 4814–4817. [CrossRef]

Molecules 2019, 24, 3812
10 of 10
51. Lee, J.W.; Oliveira, M.T.; Jang, H.B.; Lee, S.; Chi, D.Y.; Kim, D.W.; Song, C.E. Hydrogen-bond promoted
nucleophilic fluorination: Concept, mechanism and applications in positron emission tomography. Chem.
Soc. Rev. 2016, 45, 4638–4650. [CrossRef]
52. Braendvang, M.; Gundersen, L.-L. Selective anti-tubercular purines: Synthesis and chemotherapeutic
properties of 6-aryl- and 6-heteroaryl-9-benzylpurines. Bioorg. Med. Chem. 2005, 13, 6360–6373. [CrossRef]
53. Wang, X.; Han, C.; Wu, K.; Luo, L.; Wang, Y.; Du, X.; He, Q.; Ye, F. Design, synthesis and ability of non-gold
complexed substituted purine derivatives to inhibit LPS-induced inflammatory response. Eur. J. Med. Chem.
2018, 149, 10–21. [CrossRef]
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