Hexamethyldisilazane-promoted sonogashira reaction of polyfunctionalized N-containing heterocycles

Article abstract of DOI:10.3987/COM-10-S(E)89

1,1,1,3,3,3-Hexamethyldisilazane (HMDS) was found to be an efficient solvent for Sonogashira reaction. For the synthesis of C-nucleosides, Sonogashira reaction of ethynyldeoxyriboside with halogenated pyrimidine or pyridine derivatives could be improved b

Full text of DOI:10.3987/COM-10-S(E)89

HETEROCYCLES, Vol. 82, No. 2, 2011
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HETEROCYCLES, Vol. 82, No. 2, 2011, pp. 1137 - 1141. © The Japan Institute of Heterocyclic Chemistry
Received, 1st July, 2010, Accepted, 13th August, 2010, Published online, 16th August, 2010
DOI: 10.3987/COM-10-S(E)89
HEXAMETHYLDISILAZANE−PROMOTED
REACTION OF POLYFUNCTIONALIZED
HETEROCYCLES
SONOGASHIRA
N-CONTAINING
Masahiko Inouye,* Yasuhiro Doi, Junichi Azuchi, Wataru Shirato, Junya
Chiba, and Hajime Abe*
Graduate School of Pharmaceutical Sciences, University of Toyama, Sugitani
2630, Toyama, 930-0194, Japan. E-mail: inouye@pha.u-toyama.ac.jp
Abstract – 1,1,1,3,3,3-Hexamethyldisilazane (HMDS) was found to be an
efficient solvent for Sonogashira reaction. For the synthesis of C-nucleosides,
Sonogashira reaction of ethynyldeoxyriboside with halogenated pyrimidine or
pyridine derivatives could be improved by the use of an HMDS−DMF mixed
solvent. In situ protection of hydroxy and amino groups by the solvent system
may play an important role for the improvement.
Dedicated to Professor Albert Eschenmoser on the occasion of his 85th birthday
When one would like to assemble two organic moieties by an acetylene bond, Sonogashira reaction is one
of the most versatile strategies.1 However, sometimes undesirable side reactions accompany with the
coupling reaction, such as nucleophilic addition to triple bonds and deprotonation of substituents on
substrates. Common solvents for Sonogashira reaction are organic amines, which can behave as a
nucleophile. When the acidic substituent is deprotonated, its conjugated base may be nucleophilic. It
is also troublesome that the substrates may be labile to bases at long reaction time. Recently, our group
has developed artificial DNAs, in which two kinds of heterocyclic moieties are linked by acetylene
bonds: one is an N-containing heterocycle and the other is a deoxyribose.2,3 During the course of this
study, we sometimes have faced low yields in Sonogashira reaction, and the improvement had to be
required. In this communication, we describe the use of HMDS as an effective promoter as well as a
solvent for Sonogashira reaction of polyfunctionalized N-containing heterocycles. The key to our
success is that in situ protection of the polar substituents took place in this solvent and that the protective
group could be removed during the work-up.

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HETEROCYCLES, Vol. 82, No. 2, 2011
As mentioned above, our object was to bind N-containing heterocycles and deoxyribose moieties by an
acetylene bond to form novel C-nucleosides. The ethynyldeoxyribose is represented as
4,4'-dimethoxytrityl- (DMTr-) protected ethynyl 2-deoxy--D-ribofuranoside 1.4,5 A bromopyridone
derivative, 6-amino-5-bromo-2(1H)-pyridone 2 was attempted to couple with this terminal acetylene.
The optimization of reaction conditions is described in Table 1. In triethylamine, no or little coupled
product could be observed (entries 1, 2). On the other hand, when HMDS was used as the solvent,
C-nucleotide 3 and its TMS-protected derivative 4 was obtained (entry 3). The TMS group of 4 was
transferred from HMDS.3c,6,7 Through the optimization, a higher reaction temperature and Pd(0)
catalysts were found to give 3 in a better yield after desilylation (entries 7, 8).8 It is remarkable that the
amino group on the pyridone ring of 3 was protected by dimethylaminomethylene group, which was
transferred from DMF. Products with free NH2 group were not detected, and the DMTr groups were
preserved.
Table 1. Optimization of Sonogashira reaction between 1 and bromopyridone 2
O
NH
DMTrO
DMTrO
1) Pd catalyst, CuI
amine/DMF
H
Br
O
O
N
+
O
N
H
NH2
NMe2
HO
RO
1
2
3: R = H
4: R = TMS
reaction conditions
reagents (mol%)
product [%]a
entry
amine
temp [°C] time [h]
3
4
n.d.b
trace
11
37c
60c
30c
70c
73c
n.d.b
n.d.b
31
Et3N
Et3N
PdCl2(PPh3)2 (1), CuI (1)
1
2
3
4
5
6
7
8
90
90
4.5
3.5
3.5
7
Pd2(dba)3•CHCl3 (4), PPh3 (8), CuI (1)
PdCl2(PPh3)2 (4), CuI (1)
HMDS
HMDS
HMDS
HMDS
HMDS
HMDS
90
Pd(PPh3)4 (4), CuI (1)
90
Pd2(dba)3•CHCl3 (4), PPh3 (8), CuI (1)
PdCl2(PPh3)2 (4), CuI (1)
90
6.5
3.5
2.5
1
120
120
120
Pd(PPh3)4 (4), CuI (1)
Pd2(dba)3•CHCl3 (4), PPh3 (8), CuI (1)
a Isolated yields. b Not detected. c Yields after desilylation by TBAF treatment.
Next, several kinds of iodopyrimidinone derivatives 5a-c were coupled with 1 by Sonogashira reaction in
HMDS/DMF (Table 2).2

HETEROCYCLES, Vol. 82, No. 2, 2011
1139
Table 2. Sonogashira reaction of 1 with iodopyrimidinones 5a-c in HMDS/DMF
O
NH
Y
I
X
DMTrO
DMTrO
H
O
O
Y
Pd catalyst, CuI
X
+
R2N
N
O
NR2
HMDS/DMF
H
RO
HO
6a-c
R = H or TMS
1
5a-c
X/Y = CH/N or N/CH
producta
entry
iodopyrimidine
reaction conditions
N
O
I
N
PdCl2(PPh3)2, CuI,
HMDS/DMF, rt, 16 h
NH
DMTrO
1
O
O
O
H2N
N
O
NH2
H
6a
79%
5a
TMSO
N
NH2
I
1) PdCl2(PPh3)2, CuI,
HMDS/DMF, rt, 15 h
2) NH4OH, pyridine,
rt, 2 h
N
NH
DMTrO
2
3
O
N
NH2
O
O
b
H
6b
85%
5b
HO
I
NH
NR2
Pd2(dba)3, PPh3, CuI
HMDS/DMF,
rt, 3 h then 60 °C, 2.5 h
N
DMTrO
N
O
N
H
N
NMe2
6c'
R2 = H,H 40%
6c R2 = CHNMe2 15%
5c
TMSO
b
a Isolated yields are shown. Yield after desilylation by treatment with NH4OH.
Iodine atoms could be substituted at a room temperature to give targeted C-nucleosides 6a-c in good
yields. The 3'-hydroxy groups on the deoxyribose ring were protected with TMS groups and the DMTr
groups were preserved. These TMS groups must be transferred from HMDS and could be removed
during the work up with aqueous ammonia.
The combination of HMDS and DMF behaved not only as a reaction solvent but also a protecting agent
for polar groups. Probably quite low nucleophilicity of HMDS and in situ protection of reactive groups
would suppress side reactions and improved the product yields. Thus, the combination of HMDS and
DMF was shown to be an efficient solvent system for Sonogashira reaction of polar substrates. These
findings would enlarge the scope of Sonogashira reaction, and the utilization of solvents also as
protecting agents would be an interesting maneuver in organic syntheses.

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ACKNOWLEDGEMENTS
This work was partially supported by a Grant-in-Aid for Scientific Research on Innovative Areas
"Emergence in Chemistry (No. 2010)" from the Ministry of Education, Culture, Sports, Science and
Technology (MEXT), Japan.
REFERENCES AND NOTES
1. For reviews for Sonogashira reaction, see: K. Sonogashira, 'Metal-catalyzed Cross-coupling
Reactions,' ed. by F. Diederich and P. J, Stang, WILEY-VCH, Weinheim, 1998, pp. 203−229; R.
Chinchilla and C. Najera, Chem. Rev., 2007, 107, 874.
2. Y. Doi, J. Chiba, T. Morikawa, and M. Inouye, J. Am. Chem. Soc., 2008, 130, 8762.
3. For recent synthetic examples of alkynyl C-nucleosides by Sonogashira reaction, see: (a) T. Bobula,
M. Hocek, and M. Kotora, Tetrahedron, 2010, 66, 530; (b) M. F. A. Adamo and R. Pergoli, Org.
Lett., 2007, 9, 4443; (c) D. Heinrich, T. Wagner, and U. Diederichsen, Org. Lett., 2007, 9, 5311. In
ref. 3c, a two-step procedure (persilylation of 5-iodocytosine in HMDS and Sonogashira reaction in
DIPEA/DMF) was reported.
4. M. Takase, T. Morikawa, H. Abe, and M. Inouye, Org. Lett., 2003, 5, 625.
5. K. Fujimoto, S. Aizawa, I. Oota, J. Chiba, and M. Inouye, Chem. Eur. J., 2010, 16, 2401; K.
Fujimoto, S. Yamada, and M. Inouye Chem. Commun., 2009, 7164; J. Chiba, S. Takeshima, K.
Mishima, H. Maeda, Y. Nanai, K. Mizuno, and M. Inouye, Chem. Eur. J., 2007, 13, 8124.
6. HMDS is known to work as a silylating agent with the presence of acidic catalysts: P. G. M. Wuts
and T. W. Greene, 'Protective Groups in Organic Synthesis,' A John Wiley & Sons, Inc., Hoboken,
2007, p. 171.
7. For recent examples of persilylation of thiouracil derivatives in HMDS solutions, see: N. A.
Al-Awadi, Y. A. Ibrahim, and M. R. Ibrahim, Carbohyd. Res., 2009, 344, 2322. M. Carlucci, E.
Kierzek, A. Olejnik, D. H. Turner, and R. Kierzek, Biochemistry, 2009, 48, 10882. See also ref. 3c.
8. The preparation of 3. Typical procedure for Sonogashira reaction in HMDS−DMF (entry 8 in
Table 1). A mixture of 2-(4,4'-dimethoxytrityloxymethyl)-3-hydroxytetrahydrofuran 12 (50 mg,
0.11 mmol), 6-amino-5-bromo-2(1H)-pyridone 2 (21 mg, 0.11 mmol), Pd2(dba)3•CHCl3 (4.4 mg, 4.5
mol), CuI (0.22 mg, 1.1 mol), PPh3 (2.4 mg, 9 mol), HMDS (0.5 mL), DMF (0.5 mL) was
stirred at 120 °C for 1 h under an argon atmosphere. The resulting mixture was diluted with THF
(50 mL) and AcOEt (50 mL), and subsequently washed with brine × 3, a 1% citric acid solution, a
saturated aqueous NaHCO3 solution, and brine once more. The organic layer was concentrated
with a rotary evaporator, and the resulting residue was dissolved with THF (2 mL) and water (0.1
mL), and TBAF (1.0 M in THF, 0.12 mL) was added. After stirring at room temperature for 2 h,

HETEROCYCLES, Vol. 82, No. 2, 2011
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the mixture was concentrated with a rotary evaporator. The resulting residue was subjected to
silica gel column chromatography (eluent: CH2Cl2/MeOH 20:1) to obtain
=
(2R,3S,5R)-5-(6-(dimethylaminomethyleneamino)-2(1H)-pyridinon-5-ylethynyl)-2-(4,4'-dimethoxy-
trityloxymethyl)-3-hydroxytetrahydrofuran (3, 50 mg, 73%) as a brown viscous oil. IR (KBr) 
3399, 2927, 2223, 1637, 1577 cm−1; 1H NMR (300 MHz, CDCl3)  8.27 (s, 1H), 7.43 (d, J = 8.7 Hz,
2 H), 7.33−7.14 (m, 8 H), 6.79 (d, J = 8.4 Hz, 4 H), 5.98 (d, J = 9.3 Hz, 1 H), 4.96 (t, J = 8.0 Hz, 1
H), 4.40 (s, 1 H), 3.98 (s, 1 H), 3.75 (s, 6 H), 3.34−3.02 (m, 2 H), 3.11 (s, 3 H), 3.08 (s, 3 H),
2.21−2.18 (m, 2 H); HRMS (ESI) Calcd for C36H37N3NaO6 (M + Na+): 630.2580; Found: 630.2598.