An unexpected cyclization discovered during the synthesis of 8-substituted purines from a 4,5-diaminopyrimidine

Article abstract of DOI:10.1016/j.tetlet.2008.01.095

Attempted conversion of 4-chloro-5-(N-4-bromobutanoyl)amino-6-phenethylaminopyrimidine (2) to 6-chloro-8-[1-(3-bromo)propyl]-9-phenethylpurine (1) under standard cyclization conditions did not give the targeted product. Instead, an unexpected cyclization

Full text of DOI:10.1016/j.tetlet.2008.01.095

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Tetrahedron Letters 49 (2008) 2143–2145
An unexpected cyclization discovered during the synthesis
of 8-substituted purines from a 4,5-diaminopyrimidine
Qun Dang *, Robert M. Rydzewski, Daniel K. Cashion, Mark D. Erion
Department of Medicinal Chemistry, Metabasis Therapeutics, Inc., 11119 North Torrey Pines Road, La Jolla, CA 92037, United States
Received 15 November 2007; revised 15 January 2008; accepted 24 January 2008
Available online 30 January 2008
Abstract
Attempted conversion of 4-chloro-5-(N-4-bromobutanoyl)amino-6-phenethylaminopyrimidine (2) to 6-chloro-8-[1-(3-bromo)propyl]-
9-phenethylpurine (1) under standard cyclization conditions did not give the targeted product. Instead, an unexpected cyclization
occurred to give 6-chloro-5-[1-(3-hydroxy)propyl]-9-phenethylpurine (3), which can be viewed as a hydrolysis product of the resulting
halide. The cyclization reaction was optimized and compound 3 was prepared in excellent yield. A mechanism involving transient gen-
eration of a spiro-tetrahydrofuran is also proposed.
Ó 2008 Elsevier Ltd. All rights reserved.
Cl
Inhibitors of fructose 1,6-bisphosphatase (FBPase)
represent a new class of potential drug candidates for the
treatment of type 2 diabetes.1 Despite efforts dating back
over two decades, no suitable drug candidates were identi-
fied until recently when our structure-guided drug design
approach successfully predicted that critical AMP-binding
interactions could be achieved by a phosphonate group
linked to the 8-position of the purine base via a 3-atom lin-
ker.2 In early work to test this concept, we attempted to
prepare 8-(c-bromoalkyl)-purines with the expectation that
the desired phosphonate analogs could be synthesized via
an Arbuzov reaction. Since intramolecular cyclization of
5-(N-acyl)amino-6-aminopyrimidines is often used to pre-
pare various 8-substituted purines,3 we chose an analogous
approach to prepare our required adenine analogs (Scheme
1). Surprisingly, attempted cyclization of 5-(N-4-bromo-
butanoyl)aminopyrimidine 2 under standard conditions
did not give the desired 8-[(3-bromo)propyl]purine 1, but
rather gave the corresponding 8-[(3-hydroxy)propyl]purine
3 (Scheme 1). Herein, we describe the optimization of this
cyclization reaction and propose a potential reaction
mechanism.
Cl
H
N
(CH2)3Br
N
N
N
N
(CH2)3Br
Ph
O
N
N
NH
1
2
Ph
Cl
N
N
N
(CH2)3OH
Ph
N
3
Scheme 1.
Pyrimidine 2 was readily prepared in two steps.
Substitution of 5-amino-4,6-dichloropyrimidine with
phenethylamine (Et3N, n-BuOH, 100 °C, 12 h, 95%) gave
5-amino-6-chloro-4-phenethylaminopyrimidine,
which
was subsequently acylated with 4-bromobutanoyl chloride
(pyridine, CH2Cl2, 25 °C, 16 h, 93%) to give 2. Acyl pyr-
imidines have been cyclized to purines under basic reaction
conditions such as liquid ammonia in methanol4 and
aqueous sodium hydroxide5 but these types of reaction
conditions were deemed not suitable for compound 2 due
*
Corresponding author. Tel.: +1 858 622 5517; fax: +1 858 622 5573.
E-mail address: dang@mbasis.com (Q. Dang).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.095

2144
Q. Dang et al. / Tetrahedron Letters 49 (2008) 2143–2145
to the presence of a reactive primary bromide group.
Reaction conditions such as aqueous sulfuric acid,6 poly-
phosphoric acid,7 phosphorus oxychloride,8 and p-toluene-
sulfonic acid9 have also been reported for the conversion of
acyl pyrimidines to purines. Thus, compound 2 was sub-
jected to these acidic reaction conditions, but no desired
product was detected; only decomposition of the starting
material 2 was observed. Acyl 1,2-phenylenediamines are
often converted into benzimidazoles under various intra-
molecular cyclization reaction conditions, and these reac-
tions were also explored for conversion of pyrimidine 2
to purine 1. However, treatment of 2 with either phospho-
rus oxychloride in DMF10 or neat phosphorus oxychloride
in the presence of lutidine did not give desired product 1.
Subsequent treatment of 2 with lutidine hydrogen chloride
in N,N-dimethylacetamide (DMAc) at 140 °C11 surpris-
ingly gave a new purine derivative, which was identified
Another observation seems to rule out direct purine ring
formation when 4-chloro-5-(N-acetoxyacetyl)amino-6-
phenethylaminopyrimidine (4) was subjected to the current
reaction conditions, and even after one week no cyclization
was observed; only starting material was recovered (Eq. 1).
An alternative mechanism is proposed (Scheme 2), in
which intramolecular displacement of the bromide by the
amide oxygen gives intermediate A; this is followed by
intramolecular addition of the neighboring amino group
to the cyclic imidate, affording spiro-tetrahydrofuran B,
which spontaneously ring-opens to give compound 3.
2
3
˚
Cl
as compound 3 (Table 1, entry 1). Addition of 4 A mole-
Cl
H
cular sieves resulted in doubling of the yield (entries 2
and 3). To study the dehydration effect of molecular sieves,
magnesium sulfate was used in place of molecular sieves;
this change resulted in a lower yield of 3 (35%; entry 4).
It was subsequently discovered that a similar yield was
obtained in the absence of magnesium sulfate (entry 5).
These results suggest that the function of the molecular
sieves is not simply to promote dehydration, but may also
involve scavenging of HBr.12 Further optimization of this
reaction with regard to solvent and temperature resulted
in excellent conversion of 2 to 3 (Table 1, entries 6–8).13
N
N
N
N
O
O
N
N
N
NH
B
Ph
A
Ph
Scheme 2.
Our result of Eq. 1 is consistent with this proposed
mechanism since compound 4 cannot undergo the cyclic
imidate formation as compound 2. Other existing reports
also provide support to this proposed mechanism. For
example, Fishwick and co-workers reported the conversion
of bromoalkylacyl amines to cyclic imidates (similar to A)14
and these cyclic imidates can undergo cyclization reac-
tions.15 Upon treatment of 2 with silver tetrafluoroborate
under Fishwick’s conditions (AgBF4, TEA, acetone), 3
was indeed isolated (15% yield, not optimized) along with
two other products. Analysis by 1H NMR and mass
spectroscopy indicated that the two new products were
the Z- and E-isomer of A,16 providing strong support for
the proposed pathway.
Table 1
Formation of purine 3 via the cyclization of pyrimidine 2
Entry
Additives
Conditionsa
Yield (%)
1
2
3
4
5
6
7
8
a
Lutidine–HCl (1.2 equiv)
Lutidine–HCl (1.2 equiv)
Lutidine–HCl (1.2 equiv)
MgSO4 (10 equiv)
None
MS (10 equiv)
MS (4 equiv)
MS (4 equiv)
DMAc, 140 °C, 24 h
DMAc, 140 °C, 24 hc
DMAc, 140 °C, 24 hd
n-BuOH, 120 °C, 15 h
n-BuOH, 120 °C, 15 h
n-BuOH, 120 °C, 15 h
n-BuOH, 120 °C, 16 h
i-PrOH, 90 °C, 92 h
20b
43b
50
35
30b
66
76
92
The reaction was conducted under nitrogen atmosphere.
Some unreacted 2 was recovered.
Five equiv (based on weight) of 4 A molecular sieves (MS) was added.
Ten equiv of MS was added.
b
c
References and notes
˚
d
1. Erion, M. D.; Dang, Q.; Reddy, M. R.; Kasibhatla, S. R.; Huang, J.;
Lipscomb, W. N.; van Poelje, P. D. J. Am. Chem. Soc. 2007, 129,
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Danley, D. E.; Hageman, D. L.; Karam, G. A.; Mansour, M. N.;
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Plausible reaction pathways can be envisioned to explain
the conversion of 2 to 3. Cyclization of 2 to the correspond-
ing purine followed by the hydrolysis of the x-bromide to
the x-hydroxyl is one viable route. However, cyclization
followed by hydrolysis seems to be unlikely given the cur-
rent anhydrous reaction conditions.
Cl
Cl
H
4 eq MS
iPrOH, 90
N
°
OAc
C
N
N
N
OAc
N
ð1Þ
X
1 week
O
N
NH
N
4
Ph
Ph
5

Q. Dang et al. / Tetrahedron Letters 49 (2008) 2143–2145
2145
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13. General procedure: A solution of 2 (1.02 g, 2.56 mmol) in anhydrous
˚
2-propanol (50 mL) was treated with powder 4 A molecular sieves
(4.5 g), and the resulting mixture was heated to reflux under nitrogen
for 92 h. The cooled reaction mixture was filtered through a Celite
pad (washed with EtOAc, 3 ꢀ 20 mL), and the filtrate was evaporated
to give a yellow solid that was purified by flash chromatography
(SiO2, 3 ꢀ 17 cm, 60% EtOAc–hexane) to give 3 as a white solid. Mp
96–97 °C; 1H NMR (DMSO-d6, 200 MHz) d 8.68 (1H, s), 7.25–7.05
(5H, m), 5.58 (2H, t, J = 7.2 Hz), 4.48 (1H, t, J = 7.2 Hz, D2O
exchangeable), 3.48–3.33 (2H, m), 3.11 (2H, t, J = 7.2 Hz), 2.72 (2H,
t, J = 7.2 Hz), 1.86 (2H, p, J = 7.2 Hz); UV (MeOH) kmax 270
(1.43 ꢀ 10ꢁ3); HRMS calcd for C16H17N4OCl: 316.7900, found,
316.7900. Anal. Calcd for C16H17N4OCl: C, 60.66; H, 5.41; N,
17.69. Found: C, 60.38; H, 5.17; N, 17.69.
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16. Products were isolated via preparative TLC (SiO2, 50% EtOAc–
hexane). A (Z-isomer, 12% yield): 1H NMR (CDCl3, 200 MHz) d 8.18
(1H, s), 7.34–7.19 (5H, m), 5.21 (1H, br peak), 4.37 (2H, m), 3.72 (2H,
m), 2.91 (2H, t, J = 7 Hz), 2.76 (2H, t, J = 8 Hz), 2.21 (2H, m); MS:
317.3 and 319.3 (M+1). A (E-isomer, 2% yield): 1H NMR (CDCl3,
200 MHz) d 8.30 (1H, s), 7.36–7.19 (5H, m), 6.25 (1H, br peak), 4.47
(2H, t, J = 7 Hz), 3.78–3.63 (4H, m), 2.89 (2H, t, J = 7 Hz), 2.48 (2H,
m), 2.01 (2H, m); MS: 317.3 and 319.3 (M+1).
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