Preparation of 9-substituted pyridine-stretched adenines and hypoxanthines

Article abstract of DOI:10.1055/s-0028-1088028

9-Methylsulfanyl pyridine-stretched adenine and hypoxanthine derivatives have been prepared via regioselective reaction of a 5-aminoimidazole with 2-(bis-methylsulfanylmethylene)malononitrile [(NC)₂C=C(SMe) ₂]. The 9-methylsulfanyl substituent can be replaced by sequential oxidation and substitution by nucleophiles including amines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1088028

PAPER
1271
Preparation of 9-Substituted Pyridine-Stretched Adenines and Hypoxanthines
a
b
a
9
J
-Substitu
u
ted Pyridine
l
i
ed Ade
a
nines and
H
ypox
A
anthines . Crawford, William Fraser, Christopher A. Ramsden*
a
Lennard-Jones Laboratories, School of Physical and Geographical Sciences, Keele University, Keele, Staffordshire, ST5 5BG, UK
Fax +44(1782)712378; E-mail: c.a.ramsden@chem.keele.ac.uk
School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, UK
b
Received 27 November 2008
NH2
NH2
Abstract: 9-Methylsulfanyl pyridine-stretched adenine and hypo-
xanthine derivatives have been prepared via regioselective reaction
of a 5-aminoimidazole with 2-(bis-methylsulfanylmethylene)mal-
ononitrile [(NC) C=C(SMe) ]. The 9-methylsulfanyl substituent
can be replaced by sequential oxidation and substitution by nucleo-
philes including amines.
N
N
N
N
N
N
2
2
X
X
N
N
HO
HO
O
O
Key words: 5-aminoimidazoles, lin-pyridoadenines, soft electro-
philes, tricyclic heterocycles, pyridine-stretched purines
HO OH
HO
1
2
(X = CH)
(X = N)
3 (X = CH)
4 (X = N)
NH2
O
Several groups have investigated the modification of pu-
rine nucleosides by insertion of a third ring between the
imidazole and pyrimidine fragments. The earliest investi-
gation was undertaken by Leonard and co-workers who
described the synthesis of the benzene-stretched adenos-
R3
R3
N
HN
N
N
N
N
R2
R2
N
N
N
N
R1
1
–4
R1
ine analogue 1 (Figure 1). Later, the 2¢-deoxy-deriva-
5
6
5
tive 3 was prepared. Subsequently, other groups have
6
–8
Figure 1
prepared tricyclic analogues and aspects of this work
9
have been reviewed. We have been interested in prepar-
ing pyridine-stretched purine derivatives for some time,
4
N
and have previously described the adenosine analogue 2
5
NC
SMe
Z
Y2N
R2
1
0
and the corresponding inosine analogue. More recently,
N
NC
we prepared the 2¢-deoxy analogues of adenosine 4 and
R1
1
1
inosine, which have been incorporated into oligonucle-
otides and their duplex-forming properties investigated.12
With the objective of providing access to a wider range of
pyridine-stretched purine derivatives, we have investigat-
7 (Y = O)
8 (Y = H)
9
Z = SMe
10 Z = NHPr
1
1 Z = NHPh
Figure 2
ed the preparation of 9-substituted derivatives of the gen-
3
eral types 5 and 6 (R ≠ H) and now report the results of tuted analogue of EMMN that reacts selectively at the
these studies.
C-4 position of 5-aminoimidazoles 8.
1
3,14
Two features of pyridine-stretched nucleosides may be In an earlier study,
we showed that 5-amino-
1
5
advantageous: (i) the presence of the nitrogen atom in imidazoles can react as either N- or C-nucleophiles and
position 4 may enhance the stability of triplex-forming demonstrated a correlation between the position of the re-
oligonucleotides (TFOs) targeted to DNA; (ii) their prep- action and the softness of the electrophile, measured by
aration via addition-elimination reactions of 5-aminoimi- the AM1 calculated LUMO energy. Thus, EMMN
dazoles may make them more easily accessible than the (LUMO –0.62 eV) gives exclusively C-adducts, where-
corresponding benzene-stretched derivatives. The 9- as diethyl ethoxymethylenemalonate
[EMME;
unsubstituted derivatives 2 and 4 were prepared via reac- (EtO C) C=CHOEt] (LUMO –0.27 eV) gives exclusively
2
2
tion of ethoxymethylene malononitrile [EMMN; N-adducts. The general conclusion of our studies on a
NC) C=CHOEt] with the appropriate 5-aminoimidazoles range of electrophiles was that reagents with a calculated
(
8
2
, which were obtained by reduction of the 5-nitroimida- (AM1) LUMO energy <–0.5 eV react predominantly at
1
0,11
14
zoles 7 (Figure 2).
The preparation of the 9-substituted the C-4 position of 5-aminoimidazoles. A C-substituted
3
derivatives 5 and 6 (R ≠ H) therefore requires a C-substi- analogue of EMMN with a LUMO energy <–0.5 eV was
therefore required in order to produce precursors of the 9-
substituted derivatives 5 and 6. Table 1 shows the AM1
calculated frontier orbital energies of selected electro-
philes.
SYNTHESIS 2009, No. 8, pp 1271–1278
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x
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x
x
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Advanced online publication: 25.03.2009
DOI: 10.1055/s-0028-1088028; Art ID: P13408SS
Georg Thieme Verlag Stuttgart · New York
©

1
272
J. A. Crawford et al.
PAPER
From Table 1 it is clear that introduction of a second
ethoxy substituent into EMME (entries 2 and 4) will in-
crease the LUMO energy and probably favour N-adduct
formation. However, replacement of the ethoxy group by
a methylsulfanyl substituent (entries 4 and 7) significantly
reduces the LUMO energy, whilst the introduction of a
second methylsulfanyl group (entry 8) leads to an
electrophile with an exceptionally low energy LUMO. We
therefore anticipated that 2-(bis-methylsulfanylmethyl-
ene)malononitrile [9; (NC) C=C(SMe) ] would give C-
SMe
N
NC
NC
N
a
H2N
Me
N
H2N
N
Me
Me
Me
13
b
12
SMe
SMe
NC
H2N
EtO NC
N
c
N
N
2
2
N
N
Me
Me
N
adducts with 5-aminoimidazoles and thus provide access
to 9-methylsulfanyl derivatives that can be further manip-
ulated. Although we have not previously worked with the
reagent 9, it is readily prepared in good yield by reaction
of malononitrile with carbon disulfide and methyl iodide
N
Me
Me
1
4
15
d
O
NH2
SMe
1
6
SMe
in the presence of potassium fluoride. The LUMO ener-
gy-lowering effect of an alkylsulfanyl substituent appears
to be general: a similar effect is observed for the corre-
sponding diesters (entries 1 and 3).
HN
N
N
e
N
N
N
N
Me
N
Me
N
N
Me
Me
1
7
Table 1 AM1 Calculated Frontier Orbital Energies of Electrophiles
16
Scheme 1 Reagents and conditions: (a) 9, THF, 50 °C, 12 h (47%
Entry Electrophile
LUMO (eV) HOMO (eV)
for 2 steps); (b) MeOH/H O, NaOH, 60 °C (87%); (c) CH(OEt) , PT-
2
3
1
2
3
4
5
6
7
8
(EtO C) C=CHOEt
–0.27
–0.29
–0.60
–0.62
–0.71
–0.90
–0.95
–1.31
–10.15
–9.53
–9.05
–10.05
–8.93
–8.87
–9.11
–8.91
SA·H
2
O, 150 °C, 4 h (86%); (d) NH
3
, EtOH, r.t., 1 h then reflux 12 h
2
2
(
85%); (e) 2M HCl, reflux, 2 h (74%).
(NC) C=C(OEt)
2
2
(EtO C) C=CH.SMe
2
2
Treatment of a methanol solution of the C-adduct 13 with
aqueous sodium hydroxide at 60 °C resulted in cyclisation
to the imidazo[4,5-b]pyridine 14 (mp 300 °C; 86%). Sub-
sequent treatment with hot triethyl orthoformate gave the
ethyl imidate 15 (mp 197–200 °C; 87%), which, upon re-
action with hot ethanolic ammonia, gave the tricyclic
amine 16 (mp 252–255 °C; 85%). The properties of the
amine 16 were fully in accord with the proposed structure.
(NC) C=CHOEt
2
(NC) C=C(SMe)NHPr
2
(NC) C=C(SMe)NHPh
2
(NC) C=CHSMe
2
(NC) C=C(SMe)
2
2
1
The H NMR spectrum showed C–CH , S–CH and N–
3
3
CH singlets (d = 2.66, 2.94 and 3.75 ppm, respectively),
3
In these studies we have used 5-amino-1,2-dimethylimi-
dazole (12) as a model compound. A solution of the amine
together with a broad NH signal (d = 8.32 ppm) and a sin-
2
gle ring proton (d = 8.40 ppm). The mass spectrum
showed a strong molecular ion (m/z = 260). Compound 16
is an example of a 9-substituted pyridine-stretched ade-
nine derivative, so the route shown in Scheme 1, employ-
ing the soft bis-methylsulfanyl electrophile 9, therefore
establishes a viable route to derivatives of this type. Treat-
ment of compound 16 with hot 2 M HCl for two hours,
gave the pyridine-stretched hypoxanthine derivative 17
1
2 in tetrahydrofuran was generated by catalytic reduction
1
(
H /Pd/C) of 1,2-dimethyl-5-nitroimidazole (7; R =
2
2
R = Me). The amine solution was filtered through Celite
into a flask containing a five-fold excess of 2-(bis-methyl-
sulfanylmethylene)malononitrile (9) and the mixture was
stirred at 50 °C overnight. Workup gave a yellow-orange
solid that, in accord with prediction, was identified as the
C-adduct 13 (Scheme 1). The yield was 47%, based on the
nitroimidazole starting material, and no other products
(
mp >350 °C; 74%), which was fully characterised.
were identified in the reaction mixture. An analytically Reaction of the ethyl imidate 15 with n-propylamine un-
pure sample (mp 197–198 °C) was prepared by flash der various conditions gave only the amidine 18 and not
chromatography and recrystallisation (EtOAc–MeOH). the anticipated tricyclic N-(n-propyl)-derivative 19
The structure of compound 13 was fully supported by its (Figure 3). All attempts at cyclisation were unsuccessful,
1
spectroscopic properties. In particular, the H NMR spec- although similar cyclisations of 9-unsubstituted deriva-
trum showed a broad singlet (d = 7.05 ppm) correspond- tives have been reported.15
ing to the NH group and the absence of an imidazole ring
proton, which would be characteristic of the isomeric N-
2
Inspection of Table 1 reveals that amino-substituted elec-
trophiles (entries 5 and 6) also have a low-energy LUMO
and might be expected to react selectively to give C-ad-
ducts. In principle these reagents could provide a direct
route to 9-amino derivatives, for example, 5 and 6
adduct. The constitution C H N S was confirmed by
1
0
11
5
mass spectrometry and elemental analysis.
Synthesis 2009, No. 8, 1271–1278 © Thieme Stuttgart · New York

PAPER
9-Substituted Pyridine-Stretched Adenines and Hypoxanthines
1273
NH
tained an ethyl substituent (d = 1.67 and 5.34 ppm) and the
absence of a methyl sulfone signal (d = ~3.9 ppm). Excel-
lent yields of substitution products were obtained, without
chromatography, when the sulfone 25 was reacted with
alkylamines (Scheme 2). With n-propylamine in dichlo-
romethane at room temperature (2 h), a 98% yield of the
secondary amine 27 [mp 218 °C (decomp.)] was obtained.
A similar procedure gave the n-butyl derivative 28 [mp
SMe
SMe
NC
PrN
PrNH
N
N
N
N
N
Me
N
Me
N
N
Me
Me
18
19
Figure 3
2
20 °C (decomp.)] in 93% yield. The use of 9-sulfones,
for example 25, therefore provides access to 8,9-diamino
derivatives in the pyridine-stretched purine series.
3
(
R = NHR). We therefore investigated the reactions of
the reagents 10 and 11 with the aminoimidazole 12, how-
ever, in neither case was any reaction detected under a va-
riety of conditions. As might be expected, the nitrogen
lone pair appears to reduce the reactivity of the electro-
phile and, although the LUMO energy is an indicator of
regioselectivity, it is not a measure of reactivity. In order
to prepare 9-amino derivatives we next investigated meth-
ods of modifying the 9-methylsulfanyl substituent.
R1
R1
R2
SMe
R2
SOMe
N
N
N
N
a
N
N
N
N
N
N
Me
Me
N
N
Me
0 (R = R = Ac)
1 (R = H, R = t-Boc)
Me
1
2
1
2
2
2
22 (R = R = Ac)
Reaction of compound 16 with n-propylamine did not re-
sult in substitution of the thiomethyl group by the amine.
It was therefore decided to oxidise the thioether to the me-
thyl sulfone, which is a better leaving group. To avoid ox-
idation of the 8-amino group, N-protected derivatives
were prepared. Reaction with either acetic anhydride or
acetic anhydride/pyridine under various conditions gave
the N,N-diacetyl derivative 20 (mp 178–183 °C). In one
experiment, a very low yield of material (mp 218–220 °C)
that appeared to be the mono-acetyl derivative was ob-
tained, but attempts to repeat this by variation of method
or work-up were unsuccessful. Attempts to remove one
acetyl group using calcium carbonate in aqueous
1
2
1
2
23 (R = H, R = t-Boc)
b
R1
R2
N
R1
R2
N
OEt
N
SO2Me
N
c
N
N
N
N
N
Me
N
N
Me
N
Me
Me
1
2
1
2
2
4 (R = R = Ac)
25 (R = H, R = t-Boc)
26 (R = H, R = t-Boc)
1
2
e
d
R1
R1
R2
N
R2
N
9
methanol resulted in removal of both acetyl groups. We
NHPr
NHBu
N
therefore decided to carry out further work on the diacetyl
derivative 20. The 8-amino group was also protected as
the tert-butoxycarbonyl (t-Boc) derivative 21 [mp 167 °C
N
N
N
N
N
N
N
Me
Me
N
N
(
decomp.); 83%] by reaction with di-tert-butyl dicarbon-
ate in 1,4-dioxane for six hours at 120 °C.
Me
Me
1
2
1
2
2
7 (R = H, R = t-Boc)
28 (R = H, R = t-Boc)
Oxidation of the N,N-diacetyl derivative 20 with one
equivalent of 3-chloroperoxybenzoic acid (MCPBA) in Scheme 2 Reagents and conditions: (a) MCPBA (1 equiv), CH
dichloromethane at 0 °C gave a poor yield (11%) of the
sulfoxide 22. A similar procedure gave a better yield
Cl
,
2
2
0
0
(
°C, 1.5 h (11% for 22, 63% for 23); (b) MCPBA (2 equiv), CH Cl ,
°C, 4 h (67% for 24, 65% for 25); (c) NaOEt, EtOH, r.t., 30 min
24%); (d) n-PrNH , CH Cl , r.t., 2 h (98%); (d) n-BuNH , CH Cl ,
r.t., 2 h (93%).
2
2
2 2 2 2 2 2
(
63%) of the sulfoxide 23. Both sulfoxides were fully
characterized and showed the expected spectroscopic
properties. Oxidation using two equivalents of MCPBA
gave the sulfones 24 (mp 185–186 °C; 67%) and 25 [mp
The application of this methodology to the synthesis of
2
2
¢-deoxyribonucleotide analogues requires the reaction of
-(bis-methylsulfanylmethylene)malononitrile (9) with 5-
1
00 °C (decomp.); 65%], respectively (Scheme 2). Fur-
ther studies were carried out using the t-Boc-protected
sulfone 25, which was obtained in greater overall yield
from the amine 16.
aminoimidazole 29, to give the C-adduct 30 (Scheme 3).
We have therefore made a preliminary investigation: reac-
tion of the amine 2911 with electrophile 9 gave a single
product which, after chromatography, was identified as
the desired adduct 30 (mp 98–100 °C; 15%), which was
fully characterised. The yield was low and requires opti-
misation, but the regioselectivity of the reaction demon-
strates that this is a potential route to 9-substituted
derivatives.
In order to demonstrate nucleophilic substitution of the
methyl sulfonyl substituent, we initially reacted com-
pound 25 with sodium ethoxide in ethanol at room tem-
perature (Scheme 2). A single product was formed and,
after chromatographic isolation in 24% yield, was identi-
fied as the 9-ethoxy derivative 26 [mp 204 °C (decomp.)].
1
H NMR spectroscopy clearly showed the product con-
Synthesis 2009, No. 8, 1271–1278 © Thieme Stuttgart · New York

1
274
J. A. Crawford et al.
PAPER
Anal. Calcd for C H N S: C, 53.01; H, 6.12; N, 23.18. Found: C,
NC
NC
SMe
N
8
11
3
5
2.93; H, 6.17; N, 23.05.
N
H2N
H2N
O
2-[(5-Amino-1,2-dimethyl-1H-imidazol-4-yl)methylsulfanyl-
p-TolO
N
p-TolO
N
a
methylene]malononitrile (13)
O
1
2
1
,2-Dimethyl-5-nitroimidazole (7; R = R = Me; 1.58 g, 11.2
mmol) and 5% Pd/C catalyst (1.20 g) were placed in a flask with an-
hydrous THF (125 mL). The resulting mixture was hydrogenated at
r.t. under atmospheric pressure, with vigorous stirring, over 2 h. The
p-TolO
p-TolO
29
30
reaction was monitored by TLC (Et O), which showed complete
2
Scheme 3 Reagents and conditions: (a) 9, THF, 50 °C, 12 h (15%).
consumption of all starting material. The product mixture was fil-
tered through dry Celite, in an enclosed system under argon, into a
flask containing 2-(bis-methylsulfanylmethylene)malononitrile (9;
9.64 g, 56.5 mmol). The reaction was stirred at 50 °C, under argon,
overnight to give an orange-brown solution. The solvent was re-
moved under reduced pressure at r.t. and the residue was treated
with liquid nitrogen-chilled EtOAc (100 mL). The solution was
then filtered to give a yellow-orange solid. The crude product 13
was used without further purification (yield over two stages 47%).
IR spectra were obtained using a Thermo-Nicolet Avatar 370 FT-IR
spectrometer. Mass spectra were obtained at the EPSRC National
Mass Spectrometry Centre, University of Wales, Swansea, and
were performed using either low-resolution electron impact (EI/
LR), low-resolution electrospray (ES/LR) or high-resolution elec-
trospray (ES/HR) ionisation techniques. Melting points were mea-
sured on a Stuart Scientific SMP3 melting point apparatus. NMR
spectra were recorded on a Bruker Avance DPX300 NMR spec-
trometer in either CDCl or DMSO-d . Chemical shifts (d) are quot-
An analytical sample was prepared by dissolving the solid in a min-
imum amount of MeOH followed by flash column chromatography
3
6
(EtOAc, 100%). The relevant fractions were combined and the sol-
ed as ppm relative to TMS as internal standard. Solvents were dried
as follows: THF was heated under reflux over, and then distilled
from, sodium wire and benzophenone; DMF was dried by distilla-
tion, and then standing over 4 Å molecular sieves; pyridine was re-
fluxed over KOH and allowed to stand over 4 Å molecular sieves;
vent removed by rotary evaporation to give a yellow solid that was
recrystallised (EtOAc–MeOH, 5:3) to give the product 13.
Yield: 0.70 g (27%); brilliant yellow crystals; mp 197–198 °C.
–
1
IR (KBr): 1313, 1489, 1603, 2213, 2251, 3469 cm .
1
,4-dioxane was refluxed over sodium and benzophenone, distilled
1
H NMR (DMSO-d ): d = 2.23 (s, 3 H, SCH ), 2.49 (s, 3 H, CCH ),
6
3
3
off and stored over molecular sieves under a nitrogen atmosphere.
Petroleum ether (PE), where used, had a boiling range of 60–80 °C.
TLC was carried out on aluminium-backed 0.2 mm silica gel plates
and visualised with 254 nm fluorescent indicator. Microanalyses
were conducted through the Elemental Analysis Service at London
3
.34 (s, 3 H, NCH ), 7.05 (br s, 2 H, NH ).
3
2
13C NMR (DMSO-d
(NCH
CN), 143.52 (imidazole-C4), 147.64 (imidazole-C2), 164.26 (meth-
ylene-C2).
): d = 13.22 (CCH
), 17.81 (SCH
), 29.38
6
3
3
), 60.64 (methylene-C1), 113.70 (imidazole-C5), 116.85 (2 ×
3
1
7
Metropolitan University. AM1 calculations were performed using
the MOPAC programme in CS Chem3D (CambridgeSoft Corpora-
tion). Calculated frontier orbital energies vary with configuration
but variations in the values recorded in Table 1 do not change the
conclusions.
+
MS (EI/LR): m/z (%) = 233 (100) [M ], 218 (8), 200 (22), 187 (21),
1
61 (17), 123 (4), 104 (10), 84 (22), 56 (63), 49 (29), 42 (24).
Anal. Calcd for C H N S: C, 51.48; H, 4.75; N, 30.02. Found: C,
10 11
5
5
1.53; H, 4.86; N, 29.84.
2
-(Bis-methylsulfanylmethylene)malononitrile (9)16 and 2-(meth-
1
8
ylsulfanyl-phenylaminomethylene) malononitrile (11) were pre-
5
-Amino-2,3-dimethyl-7-methylsulfanyl-3H-imidazo[4,5-b]py-
pared by literature methods.
ridine-6-carbonitrile (14)
2
-[(5-Amino-1,2-dimethyl-1H-imidazol-4-yl)methylsulfanylmeth-
2
2
-(Methylsulfanyl-propylaminomethylene)malononitrile (10)
-(Bis-methylsulfanylmethylene)malononitrile (9; 4.00 g, 23.5
ylene]malononitrile (13; 0.20 g, 0.86 mmol) was placed in a flask
with MeOH (50 mL) and heated to 60 °C. NaOH (0.18 g) in H O (2
mL) was added to the reaction mixture. The reaction was followed
by TLC (EtOAc–MeOH, 10:1) which, after 20 min, showed one
fluorescent spot (R = 0.67). The mixture was cooled to r.t. and the
precipitate was collected, recrystallised from DMF and identified as
the product 14.
2
mmol) was dissolved in EtOH (25 mL) with stirring. n-PrNH (1
2
mL, 11.8 mmol) was added dropwise over 1 h and the mixture was
stirred overnight. The solvent was then removed under reduced
pressure and the solid product was purified by column chromatog-
raphy (CH Cl , 100% then MeOH–CH Cl , 5%) to give the product
f
2
2
2
2
1
0.
Yield: 0.17 g (86%); off-white crystals; mp 300 °C.
Yield: 1.66 g (78%); pale-pink solid; mp 119–122 °C.
IR (KBr): 517, 639, 899, 1370, 1425, 1488, 1560, 1585, 1648, 2202,
2
IR (KBr): 632, 864, 920, 1153, 1248, 1290, 1302, 1364, 1419, 1442,
1
–1
931, 3338, 3412 cm .
–
1
467, 1500, 1548, 2187, 2206, 2877, 2935, 2964, 3306 cm .
1
H NMR (DMSO-d ): d = 2.45 (s, 3 H, CCH ), 3.03 (s, 3 H, SCH ),
6
3
3
1
H NMR (CDCl ): d = 0.99 (t, J = 7.0 Hz, 3 H, NHCH CH CH ),
3
2
2
3
3.54 (s, 3 H, NCH ), 6.54 (br s, 2 H, NH ).
3
2
1
3
.67 (sext, J = 7.0 Hz, 2 H, NHCH CH CH ), 2.68 (s, 3 H, SCH ),
2 2 3 3
1
3
C NMR (DMSO-d ): d = 14.38 (CCH ), 16.74 (SCH ), 28.64
.53 (q, J = 7.0 Hz, 2 H, NHCH CH CH ), 6.31 (br s, 1 H, NH).
6
3
3
2
2
3
(NCH ), 83.63 (C-6), 117.20 (CN), 126.01 (C-1a), 144.52 (C-3a),
3
1
3
C NMR (CDCl ): d = 11.00 (NHCH CH CH ), 17.55 (SCH ),
3
2
2
3
3
149.82 (C-2), 151.59 (C-7), 157.94 (C-5).
2
1
3.31 (NHCH CH CH ), 48.33 (NHCH CH CH ), 52.22 [C(CN) ],
2 2 3 2 2 3 2
+
MS (EI/LR): m/z (%) = 233 (100) [M ], 232 (24), 218 (9), 206 (11),
2
1
15.35 (CN), 115.64 (CN), 174.69 [C=C(CN)2].
00 (25), 188 (12), 187 (27), 186 (15), 145 (13), 123 (12), 117 (12),
09 (18), 105 (23), 104 (44), 95 (21), 91 (45), 82 (44), 77 (56), 69
+
MS (EI/LR): m/z (%) = 181 (38) [M ], 166 (9), 152 (18), 140 (13),
1
27 (15), 109 (12), 108 (19), 92 (58), 79 (15), 74 (22), 68 (22), 61
(
34), 67 (43).
(
63), 48 (25), 47 (33), 45 (40), 43 (75), 41 (100).
Anal. Calcd for C H N S: C, 51.48; H, 4.75; N, 30.02. Found: C,
1
0
11
5
5
1.33; H, 4.67; N, 29.90.
Synthesis 2009, No. 8, 1271–1278 © Thieme Stuttgart · New York

PAPER
9-Substituted Pyridine-Stretched Adenines and Hypoxanthines
1275
1
3
N-(6-Cyano-2,3-dimethyl-7-methylsulfanyl-3H-imidazo[4,5-
b]pyridin-5-yl)formimidic Acid Ethyl Ester (15)
C NMR (TFA): d = 14.74 (CCH ), 20.18 (SCH ), 33.08 (NCH ),
3
3
3
126.42 (C-8a), 149.03 (C-1a), 151.31 (C-3a), 154.42 (C-9), 155.07
(C-2), 161.66 (C-6), 161.99 (C-4a), 166.41 (C-8).
5
-Amino-2,3-dimethyl-7-methylsulfanyl-3H-imidazo[4,5-b]pyri-
dine-6-carbonitrile (14; 5.96 g, 25.5 mmol), CH(OEt) (500 mL)
+
3
MS (EI): m/z (%) = 261 (31) [M ], 228 (15), 187 (9), 105 (10), 91
and PTSA·H O (0.81 g, 4.3 mmol) were placed in a flask fitted with
2
(
17), 77 (9), 56 (12), 44 (100).
a Claisen head and condenser. The mixture was heated to 150 °C for
Anal. Calcd for C H N SO: C, 50.56; H, 4.24; N, 26.80. Found:
4
h, then activated carbon was then added and the hot mixture was
11 11
5
C, 50.54; H, 4.06; N, 26.65.
filtered. The precipitate, which appeared on cooling, was collected
and washed with a little Et O to give the product 15.
2
N-(6-Cyano-2,3-dimethyl-7-methylsulfanyl-3H-imidazo[4,5-
b]pyridin-5-yl)-N¢-propyl-formamidine (18)
N-(6-Cyano-2,3-dimethyl-7-methylsulfanyl-3H-imidazo[4,5-b]py-
ridin-5-yl)formimidic acid ethyl ester (15; 0.50 g, 1.7 mmol) and n-
Yield: 6.43 g (87%); fine colourless crystals; mp 197–200 °C.
–
1
IR (KBr): 1196, 1226, 1559, 1580, 1627, 2214, 2935 cm .
1
H NMR (DMSO-d ): d = 1.36 (t, J = 7.0 Hz, 3 H, CH CH ), 2.56
6
3
2
PrNH (0.70 mL, 8.5 mmol) in EtOH (25 mL) were allowed to stand
2
(
s, 3 H, CCH ), 3.11 (s, 3 H, SCH ), 3.69 (s, 3 H, NCH ), 4.37 (q,
3 3 3
at r.t. for 18 h. The solvent and excess amine were removed under
reduced pressure. The solid residue was recrystallised (EtOAc–PE)
and identified as the product 18.
J = 7.0 Hz, 2 H, CH CH ), 8.56 (s, 1 H, CHOEt).
3
2
1
3
C NMR (DMSO-d ): d = 13.84 (CCH ), 13.98 (CH CH ), 16.28
6
3
3
2
(
SCH ), 28.35 (NCH ), 63.34 (CH CH ), 94.81 (C-6), 115.78 (CN),
3 3 3 2
Yield: 0.31 g (58%); off-white crystals; mp 147–149 °C.
1
30.10 (C-1a), 144.19 (C-3a), 147.75 (C-2), 153.98 (C-7), 156.10
(
EtOC=N), 160.45 (C-5).
MS (EI): m/z (%) = 289 (21) [M ], 260 (100), 244 (46), 232 (15),
86 (12), 171 (10), 145 (12), 135 (12), 104 (19), 91 (15), 77 (13), 56
57), 46 (12), 42 (18).
Anal. Calcd for C H N OS: C, 53.92; H, 5.22; N, 24.29. Found:
IR (KBr): 938, 959, 1151, 1195, 1250, 1349, 1373, 1423, 1475,
–
1
+
1574, 1615, 2212, 2873, 2929, 2958, 3243 cm .
1H NMR (DMSO-d6):
0.97 (t, J = 7.5 Hz, 3 H,
NHCH CH CH ), 1.64 (m, 2 H, NHCH CH CH ), 3.05 (s, 3 H,
1
(
d =
2
2
3
2
2
3
CCH3), 3.34 (s, 3 H, SCH3), 3.38 (q, J = 6.5 Hz, 2 H,
NHCH CH CH ), 3.62 (s, 3 H, NCH ), 8.09 (d, J = 4.5 Hz, 1 H,
13
15
5
2
2
3
3
C, 53.75; H, 5.00; N, 24.07.
CH), 8.52 (d, J = 4.5 Hz, 1 H, NH).
1
3
2
,3-Dimethyl-9-methylsulfanyl-3H-1,3,4,5,7-pentaaza-cyclo-
C NMR (DMSO-d ): d = 11.44 (NHCH CH CH ), 13.89 (CCH ),
6
2
2
3
3
penta[b]naphthalen-8-ylamine (16)
16.17 (SCH ), 21.49 (NHCH CH CH ), 28.07 (NCH ), 42.16
3 2 2 3 3
N-(6-Cyano-2,3-dimethyl-7-methylsulfanyl-3H-imidazo[4,5-b]py-
ridin-5-yl)formimidic acid ethylester (15; 3.03 g, 10.5 mmol) was
(NHCH CH CH ), 94.16 (C-6), 116.89 (CN), 128.27 (C-1a),
2 2 3
143.56 (C-3a), 148.16 (C-2), 152.30 (C-7), 153.21 (N=CN), 160.11
(C-5).
added to EtOH (300 mL) saturated with NH . The mixture was
3
stirred at r.t. for 1 h and then heated under reflux overnight. The
mixture was cooled in a freezer and the precipitate was collected
and identified as the product 16. An analytical sample was recrys-
tallised from i-PrOH.
+
MS (EI): m/z (%) = 302 (26) [M ], 287 (10), 269 (12), 244 (9), 200
(13), 187 (22), 56 (14).
Anal. Calcd for C H N S: C, 55.61; H, 6.00; N, 27.79. Found: C,
14 18
6
5
5.64; H, 5.79; N, 27.61.
Yield: 2.31 g (85%); fine colourless crystals; mp 252–255 °C.
IR (KBr): 1346, 1401, 1429, 1455, 1500, 1521, 1551, 1576, 1638,
N-Acetyl-N-(2,3-dimethyl-9-methylsulfanyl-3H-1,3,4,5,7-pen-
taaza-cyclopenta[b]naphthalen-8-yl)acetamide (20)
–
1
2
360, 2937, 3075, 3282, 3434 cm .
1
To a suspension of 2,3-dimethyl-9-methylsulfanyl-3H-1,3,4,5,7-
pentaaza-cyclopenta[b]naphthalen-8-ylamine (16; 2.00 g, 7.7
H NMR (DMSO-d ): d = 2.66 (s, 3 H, CCH ), 2.94 (s, 3 H, SCH ),
6
3
3
3
1
.75 (s, 3 H, NCH ), 8.32 (br s, 2 H, NH ), 8.40 (s, 1 H, CH).
3 2
mmol) in pyridine (27 mL), was added Ac O (20 mL). The mixture
2
3
C NMR (DMSO-d ): d = 14.45 (CCH ), 19.48 (SCH ), 28.27
6
3
3
was heated under reflux for 2 h, then poured onto ice water (50 mL).
(
1
NCH ), 105.43 (C8a), 133.47 (C-1a), 135.41 (C-3a), 150.56 (C-9),
3
The product was extracted into CH Cl (2 × 50mL), dried (MgSO )
2
2
4
55.78 (C-2), 155.90 (C-6), 157.88 (C-4a), 163.70 (C-8).
and the solvent volume reduced by half (~20 mL). Et O (20 mL)
2
+
was added and the solution was left to cool overnight. The precipi-
tate was collected, dried under high vacuum at 100 °C, and identi-
fied as the product 20.
MS (EI): m/z (%) = 260 (88) [M ], 254 (13), 245 (21), 234 (12), 233
(
(
53), 227 (75), 218 (16), 214 (22), 212 (44), 210 (68), 204 (71), 197
100), 187 (85), 179 (59), 169 (62).
Yield: 2.01 g (76%); fine yellow crystals; mp 178–183 °C.
Anal. Calcd for C H N S: C, 50.75; H, 4.65; N, 32.28. Found: C,
1
1
12
6
5
0.60; H, 4.44; N, 32.28.
IR (KBr): 1163, 1219, 1296, 1353, 1404, 1479, 1539, 1574, 1608,
–
1
1
731, 2341, 2359, 2930, 3007 cm .
2
,3-Dimethyl-9-methylsulfanyl-3,7-dihydro-1,3,4,5,7-pentaaza-
1
H NMR (CDCl ): d = 2.30 [s, 6 H, NC(O)CH ], 2.66 (s, 3 H,
3
3
cyclopenta[b]naphthalen-8-one (17)
CCH ), 3.17 (s, 3 H, SCH ), 3.86 (s, 3 H, NCH ), 9.29 (s, 1 H, CH).
3
3
3
2
,3-Dimethyl-9-methylsulfanyl-3H-1,3,4,5,7-pentaaza-cyclopen-
1
3
ta[b]naphthalen-8-ylamine (16; 1.00 g, 3.8 mmol) in 2 M HCl (100
mL) was heated under reflux for 2 h. The solution was cooled in an
ice bath and basified with aq NH . The resulting precipitate was col-
C NMR (CDCl ): d = 15.01 (CCH ), 20.11 (SCH ), 27.10
3
3
3
[2 × NC(O)CH ] 28.93 (NCH ), 115.15 (C-8a), 136.06 (C-1a),
138.28 (C-3a), 152.94 (C-9), 155.70 (C-2), 157.79 (C-6), 157.85
3
3
3
lected, washed with H O (15 mL), EtOH (15 mL) and Et O (25 mL)
to give the product 17.
(C-4a), 160.60 (C-8), 171.67 [2 × NC(O)CH ].
2
2
3
+
MS (EI): m/z (%) = 344 (3) [M ], 301 (3), 269 (12), 255 (19), 245
Yield: 0.74 g (74%); colourless solid; mp >350 °C.
(12), 227 (3), 171 (6), 135 (2), 94 (6), 82 (3), 56 (12), 43 (100).
IR (KBr): 956, 1242, 1314, 1324, 1351, 1373, 1423, 1472, 1548,
Anal. Calcd for C H N O S: C, 52.31; H, 4.68; N, 24.40. Found:
C, 52.43; H, 4.36; N, 24.19.
1
5
16
6
2
–
1
1
575, 1615, 1668, 2629, 2910, 3046 cm .
1
H NMR (TFA): d = 3.12 (s, 3 H, CCH ), 3.15 (s, 3 H, SCH ), 4.17
3
3
(
s, 3 H, NCH ), 9.56 (s, 1 H, CH).
3
Synthesis 2009, No. 8, 1271–1278 © Thieme Stuttgart · New York

1
276
J. A. Crawford et al.
PAPER
tert-Butyl (2,3-Dimethyl-9-methanesulfanyl-3H-1,3,4,5,7-pen-
taaza-cyclopenta[b]naphthalen-8-yl)carbamate (21)
IR (KBr): 749, 812, 839, 879, 927, 958, 1022, 1074, 1146, 1225,
1252, 1307, 1373, 1429, 1493, 1527, 1588, 1752, 2728, 2927, 2978,
3494 cm .
–
1
2
,3-Dimethyl-9-methylsulfanyl-3H-1,3,4,5,7-pentaaza-cyclopen-
ta[b]naphthalen-8-ylamine (16; 1.00 g, 3.8 mmol) was suspended in
anhydrous 1,4-dioxane (100 mL) and heated to 120 °C. When all
1
H NMR (CDCl ): d = 1.59 [s, 9 H, C(CH ) ], 2.79 (s, 3 H, CCH ),
3
3
3
3
3
(
.12 (s, 3 H, SOCH ), 3.95 (s, 3 H, NCH ), 9.22 (s, 1 H, CH), 12.28
3
3
the starting material had dissolved, Boc O (4.19 g, 19.2 mmol) was
2
br s, 1 H, NH).
added and the solution was stirred for 5 h, after which time TLC
1
3
C NMR (CDCl ): d = 15.56 (CCH ), 28.66 [OC(CH ) ], 29.57
(MeOH) showed that all starting material had reacted. The solvent
3
3
3 3
(
(
9
NCH ), 39.84 (SOCH ), 82.18 [(Me) CO], 107.99 (C-8a), 134.44
was removed by evaporation and the resulting solid was treated
3 3 3
C-3a), 136.30 (C-1a), 151.54 (C-2), 153.33 (HNCOO), 157.30 (C-
), 158.27 (C-6), 158.81 (C-4a), 162.37 (C-8).
with Et O (50 mL). The solid was collected, washed with further
2
Et O (2 × 25 mL) and identified as the product 21.
2
Yield: 1.15 g (83%); yellow solid; mp 167 °C (decomp.).
N-Acetyl-N-(9-methanesulfonyl-2,3-dimethyl-3H-1,3,4,5,7-pen-
taaza-cyclopenta[b]naphthalen-8-yl)acetamide (24)
IR (KBr): 1060, 1152, 1248, 1305, 1353, 1372, 1426, 1505, 1580,
–
1
1
697, 1758, 2923, 2976, 3422 cm .
N-Acetyl-N-(2,3-dimethyl-9-methylsulfanyl-3H-1,3,4,5,7-penta-
aza-cyclopenta[b]naphthalen-8-yl)acetamide (20; 2.00 g, 5.8
mmol) was dissolved in CH Cl (50 mL) and cooled to 0 °C. MCP-
1
H NMR (CDCl ): d = 1.61 [s, 9 H, C(CH ) ], 2.77 (s, 3 H, CCH ),
3
3 3
3
2
2
2
.87 (s, 3 H, SCH ), 3.91 (s, 3 H, NCH ), 9.10 (s, 1 H, CH), 11.49
3
3
BA (50–55%, 4.00 g, 11.6 mmol) was added and the mixture was
stirred for 4 h. The organic layer was diluted with a further portion
of CH Cl (50 mL), washed with H O (2 × 100 mL) and dried
(
br s, 1 H, NH).
1
3
C NMR (CDCl ): d = 15.08 (CCH ), 20.74 (SCH ), 28.25
3
3
3
2
2
2
[
O(CH ) ], 28.97 (NCH ), 82.21 [(Me) CO], 108.08 (C-8a), 131.27
3 3 3 3
(MgSO ). After the solvent had been removed under reduced pres-
4
(
2
C-1a), 138.25 (C-3a), 149.79 (C-9), 151.74 (HNCOO), 156.09 (C-
), 156.46 (C-6), 158.64 (C-4a), 159.72 (C-8).
sure, the crude solid was recrystallised from EtOAc and identified
as the product 24.
Anal. Calcd for C H N O S: C, 53.32; H, 5.59; N, 23.32. Found:
C, 53.03; H, 5.43; N, 23.57.
1
6
20
6
2
Yield: 1.51 g (67%); orange crystals; mp 185–186 °C.
IR (KBr): 537, 579, 640, 755, 933, 1009, 1038, 1122, 1152, 1211,
1
1
1
236, 1259, 1310, 1353, 1366, 1404, 1426, 1485, 1517, 1561, 1577,
623, 1706, 1733, 2924, 3016 cm .
N-Acetyl-N-(9-methanesulfinyl-2,3-dimethyl-3H-1,3,4,5,7-pen-
taaza-cyclopenta[b]naphthalen-8-yl)acetamide (22)
–
1
N-Acetyl-N-(2,3-dimethyl-9-methylsulfanyl-3H-1,3,4,5,7-penta-
aza-cyclopenta[b]naphthalen-8-yl)acetamide (20; 194 mg, 0.56
mmol) was dissolved in CH Cl (20 mL) and cooled to 0 °C. MCP-
H NMR (CDCl ): d = 2.48 (s, 6 H, COCH ), 2.81 (s, 3 H, CCH ),
3 3 3
3.83 (s, 3 H, SO CH ), 3.98 (s, 3 H, NCH ), 9.42 (s, 1 H, CH).
13
2
3
3
2
2
C NMR (CDCl ): d = 15.44 (CCH ), 27.89 [C(O)CH ], 29.36
3
3
3
BA (50–55%, 194 mg, 0.56 mmol) was added and the mixture was
stirred for 1.5 h. The organic layer was then washed with sat. aq
NaHCO (2 × 20 mL) and H O (2 × 20 mL). The organic layer was
(NCH ), 48.90 (SCH ), 112.17 (C-8a), 132.79 (C-3a), 132.83 (C-
3
3
1
1
a), 143.21 (C-2), 155.55 (C-9), 155.86 (C-6), 160.25 (C-4a),
63.78 (C-8), 173.18 [C(O)CH3].
3
2
dried (MgSO ) and the solvent removed under reduced pressure.
4
+
MS (EI): m/z (%) = 377 (2) [M + H ], 299 (4), 255 (35), 215 (4), 200
The crude material was dissolved in EtOAc and the solvent volume
was reduced until crystallisation began. After cooling, the solid was
collected and identified as the product 22.
(
6
7), 177 (4), 163 (4), 140 (4), 119 (9), 111 (18), 97 (24), 77 (100),
0 (12).
Anal. Calcd for C H N O S: C, 49.87; H, 4.28; N, 22.33. Found:
C, 47.69; H, 4.05; N, 22.11.
Yield: 22 mg (11%); yellow crystals; mp 191–192 °C.
15 16
6
4
IR (KBr): 568, 599, 640, 685, 926, 867, 1006, 1040, 1067, 1157,
1
3
1
230, 1301, 1369, 1423, 1475, 1514, 1577, 1616, 1698, 1720, 2922,
006 cm .
tert-Butyl (9-Methanesulfonyl-2,3-dimethyl-3H-1,3,4,5,7-pen-
taaza-cyclopenta[b]naphthalen-8-yl)carbamate (25)
Using the procedure described for the synthesis of compound 24,
compound 25 was obtained from tert-butyl (2,3-dimethyl-9-meth-
anesulfanyl-3H-1,3,4,5,7-pentaaza-cyclopenta[b]naphthalen-8-
yl)carbamate (21; 2.00 g, 5.5 mmol).
–
1
H NMR (CDCl ): d = 2.12 (s, 3 H, COCH ), 2.65 (s, 3 H, COCH ),
3
3
3
2
9
.88 (s, 3 H, CCH ), 3.45 (s, 3 H, SOCH ), 4.01 (s, 3 H, NCH ),
3
3
3
.46 (s, 1 H, CH).
1
3
C NMR (CDCl ): d = 15.97 (CCH ), 26.76 [NC(O)CH ], 28.15
3
3
3
[NC(O)CH ], 29.69 (NCH ), 40.86 (SOCH ), 113.77 (C-8a),
Yield: 1.42 g (65%); dark-gold, crystalline solid; mp 100 °C (de-
comp.).
3
3
3
1
36.33 (C-3a), 138.37 (C-1a), 156.00 (C-9), 156.36 (C-2), 156.82
(
[
C-6), 160.42 (C-4a), 164.18 (C-8), 170.72 [NC(O)CH ], 174.51
NC(O)CH3].
3
IR (KBr): 774, 840, 1145, 1218, 1245, 1297, 1353, 1375, 1414,
–1
1
509, 1578, 1752, 2925, 2976, 3422 cm .
+
MS (EI): m/z (%) = 361 (3) [M + H ], 345 (9), 303 (6), 277 (4), 255
(
1
H NMR (CDCl ): d = 1.59 [s, 9 H, C(CH ) ], 2.79 (s, 3 H, CCH ),
3
3
3
3
85), 246 (6), 200 (6), 120 (26), 119 (54), 111 (8), 97 (12), 77 (100).
3
.92 (s, 3 H, SO CH ), 3.95 (s, 3 H, NCH ), 9.16 (s, 1 H, CH), 10.03
2 3 3
Anal. Calcd for C H N O S: C, 49.99; H, 4.47; N, 23.32. Found:
(br s, 1 H, NH).
1
5
16
6
3
C, 49.73; H, 4.52; N, 23.06.
13
C NMR (CDCl ): d = 15.69 (CCH ), 28.53 [OC(CH ) ], 29.56
3
3
3 3
(NCH ), 48.26 (SO CH ), 82.44 [(Me) CO], 104.32 (C-8a), 132.17
3 2 3 3
tert-Butyl (9-Methanesulfinyl-2,3-dimethyl-3H-1,3,4,5,7-pen-
taaza-cyclopenta[b]naphthalen-8-yl)carbamate (23)
Using the procedure described for the synthesis of compound 22,
compound 23 was obtained from tert-butyl (2,3-dimethyl-9-meth-
anesulfanyl-3H-1,3,4,5,7-pentaaza-cyclopenta[b]naphthalen-8-
yl)carbamate (21; 1.00 g, 2.8 mmol).
(
9
C-3a), 133.95 (C-1a), 150.91 (HNCOO), 154.93 (C-2), 155.97 (C-
), 156.83 (C-6), 157.16 (C-4a), 163.16 (C-8).
tert-Butyl (9-Ethoxy-2,3-dimethyl-3H-1,3,4,5,7-pentaaza-cyclo-
penta[b]naphthalen-8-yl)carbamate (26)
tert-Butyl (9-methanesulfonyl-2,3-dimethyl-3H-1,3,4,5,7-penta-
aza-cyclopenta[b]naphthalen-8-yl)carbamate (25; 0.50 g, 1.3
mmol) was dissolved in EtOH (50 mL) with stirring. Sodium metal
Yield: 0.66 g (63%); pale-yellow, crystalline solid; mp 172 °C (de-
comp.).
(
3
0.10 g, 2.5 mmol) was then added and the mixture was stirred for
0 min, at which point TLC (EtOAc–MeOH, 5:1) showed the dis-
Synthesis 2009, No. 8, 1271–1278 © Thieme Stuttgart · New York

PAPER
9-Substituted Pyridine-Stretched Adenines and Hypoxanthines
1277
appearance of the starting material and a new, slower running spot
Rf = 0.38). The EtOH was removed under reduced pressure and the
residue was re-dissolved in CH Cl (50 mL). The organic layer was
CCH3), 3.72 (s, 3 H, NCH3), 4.21 (q, J = 6.0 Hz, 2 H,
NHCH CH CH CH ), 8.04 (s, 1 H, CH), 11.58 (br s, 1 H,
(
2
2
2
3
NHCH CH CH CH ), 13.62 (br s, 1 H, Boc-NH).
2
2
2
2
2
3
washed with H O (2 × 50 mL), dried (MgSO ) and the solvent re-
13
2
4
C NMR (CDCl ): d = 14.40 (NHCH CH CH CH ), 14.68 (CCH ),
3
2
2
2
3
3
moved. The solid product was then purified by column chromatog-
raphy (EtOAc–MeOH, 3:1) and the relevant fractions were
combined to give compound 26.
2
3
0.29 (NHCH CH CH CH ), 28.60 [OC(CH ) ], 29.00 (NCH ),
2.28 (NHCH CH CH CH ), 45.54 (NHCH CH CH CH ), 80.22
2 2 2 3 3 3 3
2
2
2
3
2
2
2
3
[
(CH ) CO], 98.02 (C-8a), 120.13 (C-1a), 143.00 (C-3a), 148.91
3 3
Yield: 0.11 g (24%); colourless solid; mp 204 °C (decomp.).
(C-2), 149.20 (C-9), 151.77 (C-4a), 156.50 (C-6), 160.74
HNCOO), 163.68 (C-8).
(
IR (KBr): 815, 949, 1016, 1060, 1109, 1143, 1241, 1356, 1369,
–
1
1
380, 1466, 1507, 1555, 1597, 1624, 1663, 1751, 2973, 3342 cm .
5
-Amino-4-(1-methylsulfanyl-2,2-dicyanovinyl)-1-(2¢-deoxy-
1
H NMR (CDCl ): d = 1.58 [s, 9 H, C(CH ) ], 1.67 (t, J = 7.0 Hz,
3
3
3
3¢,5¢-di-O-p-toluoyl-b-D-ribofuranosyl)imidazole (30)
3
H, OCH CH ), 2.65 (s, 3 H, CCH ), 3.86 (s, 3 H, NCH ), 5.34 (q,
2 3 3 3
1-(2¢-Deoxy-3¢,5¢-di-O-p-toluoyl-b-D-erythro-pentofuranosyl)-5-
J = 7.0 Hz, 2 H, OCH CH ), 9.01 (s, 1 H, CH), 10.40 (br s, 1 H,
11
2
3
nitroimidazole (29; 3.00 g, 6.4 mmol), and 5% Pd/C catalyst (3.00
NH).
g) were placed in anhydrous THF (120 mL) and the mixture was hy-
drogenated at r.t. and atmospheric pressure, with vigorous stirring
for 2 h. The solution was filtered through dry Celite, under argon,
into a flask containing 2-(bis-methylsulfanylmethylene)malononi-
trile (9; 5.50 g, 32.3 mmol). The Celite was washed with a further
portion of THF (120 mL). The reaction was stirred at 50 °C, under
argon, overnight giving a dark-brown solution. The mixture was
evaporated to dryness and the residue was treated with liquid nitro-
gen-chilled EtOAc (200 mL). The solution was then filtered to give
the crude product, which was purified by column chromatography
(CH Cl , 100% then MeOH–CH Cl , 1%). The relevant fractions
1
3
C NMR (CDCl ): d = 15.02 (OCH CH ), 15.75 (CCH ), 28.54
3
2
3
3
[
OC(CH ) ], 29.26 (NCH ), 72.23 (OCH CH ), 82.10 [(CH ) CO],
3 3 3 2 3 3 3
1
1
00.20 (C-8a), 122.51 (C-1a), 149.85 (C-3a), 152.39 (HNCOO),
55.45 (C-2), 155.63 (C-6), 157.21 (C-4a), 157.42 (C-8), 158.92
(
C-9).
+
MS (EI): m/z (%) = 359 (14) [M + H ], 259 (100), 244 (24), 222
(
(
67), 204 (24), 192 (22), 176 (22), 150 (30), 148 (42), 135 (53), 122
71), 100 (64), 98 (76), 84 (76), 72 (86).
+
HRMS (ES): m/z [M + H ] calcd for C H N O : 359.1826; found:
1
7
22
6
3
2
2
2
2
3
59.1825.
were combined and evaporated to dryness to give the amine 30.
Yield: 0.53 g (15%); brown crystalline solid; mp 98–100 °C.
IR (KBr): 752, 1102, 1178, 1209, 1270, 1311, 1377, 1449, 1486,
tert-Butyl (2,3-Dimethyl-9-propylamino-3H-1,3,4,5,7-pentaaza-
cyclopenta[b]naphthalen-8-yl)carbamate (27)
tert-Butyl (9-methanesulfonyl-2,3-dimethyl-3H-1,3,4,5,7-penta-
aza-cyclopenta[b]naphthalen-8-yl)carbamate (25; 0.86 g, 2.2
mmol) was dissolved in CH Cl (75 mL). To this solution was add-
–
1
1
508, 1544, 1578, 1611, 1720, 2209, 2923, 3035, 3329 cm .
1
H NMR (DMSO-d ): d = 2.30 (s, 3 H, SCH ), 2.39 (s, 3 H, ArCH ),
6
3
3
2
2
2.41 (s, 3 H, ArCH ), 2.70 (m, 1 H, 2¢-CH), 2.88 (m, 1 H, 2¢-CH),
3
ed n-PrNH (0.18 mL, 2.2 mmol) and stirring was maintained at r.t.
2
4.54 (m, 3 H, 5¢-CH and 4¢-CH), 5.63 (d, J = 4.0 Hz, 1 H, 3¢-CH),
2
for 2 h. The solvent was removed under reduced pressure and the re-
sulting solid was dried under high vacuum at 70 °C for 12 h, to give
the product 20.
6
2
.19 (m, 1 H, 1¢-CH), 7.18 (br s, 2 H, NH ), 7.34 (d, J = 8.0 Hz, 2 ×
2
H, ArH), 7.38 (d, J = 8.0 Hz, 2 H, 2 × ArH), 7.79 [s, 1 H, imida-
zole(2)-H], 7.88 (d, J = 8.0 Hz, 2 H, 2 × ArH), 7.97 (d, J = 8.0 Hz,
2
H, 2 × ArH).
Yield: 0.80 g (98%); dark-yellow solid; mp 218 °C (decomp.).
1
3
C NMR (DMSO-d ): d = 17.61 (SCH ), 21.09 (2 × ArCH ), 36.08
IR (KBr): 1003, 1071, 1114, 1157, 1218, 1253, 1384, 1439, 1528,
1
6
3
3
–
1
(C-2¢), 64.02 (C-5¢), 64.40 (C-3¢), 74.80 [C(CN) ], 81.59 (C-1¢),
586, 1652, 1700, 2862, 2965, 3408 cm .
2
8
(
2.73 (C-4¢), 114.16 (imidazole-C4), 126.41 (2 × CN), 129.22
2 × ArC), 129.30 (4 × ArC), 129.45 (4 × ArC), 132.29 (imidazole-
C2), 143.82 (CCH ), 144.04 (CCH ), 145.42 (imidazole-C5),
1
H NMR (CDCl ): d = 1.15 (t, J = 7.0 Hz, 3 H, NHCH CH CH ),
3
2
2
3
1
.53 [s, 9 H, C(CH ) ], 1.77 (m, 2 H, NHCH CH CH ), 2.55 (s, 3 H,
3 3 2 2 3
3
3
CCH3), 3.74 (s, 3 H, NCH3), 4.18 (q, J = 6.0 Hz, 2 H,
NHCH CH CH ), 8.05 (s, 1 H, CH), 11.63 (t, J = 6.0 Hz, 1 H,
NHCH CH CH ), 13.60 (br s, 1 H, Boc-NH).
1
65.08 (C=O), 165.38 (C=O), 167.13 [C=C(CN)2].
2
2
3
+
MS (EI): m/z (%) = 558 (5) [M + H ], 234 (52), 219 (10), 179 (13),
2
2
3
1
54 (43), 153 (15), 119 (27), 115 (58), 98 (100), 81 (85).
1
3
C NMR (CDCl ): d = 11.82 (NHCH CH CH ), 14.7 (CCH ),
3.49 (NHCH CH CH ), 28.57 [OC(CH ) ], 29.00 (NCH ), 47.57
3
2
2
3
3
Anal. Calcd for C H N O S: C, 62.47; H, 4.88; N, 12.56. Found:
2
29 27
5
5
2
2
3
3 3
3
C, 62.30; H, 4.65, N; 12.26.
(NHCH CH CH ), 80.24 [(CH ) CO], 98.04 (C-8a), 120.13 (C-1a),
2 2 3 3 3
1
42.97 (C-3a), 148.94 (C-2), 149.19 (C-9), 151.78 (C-4a), 156.50
(
C-6), 160.73 (HNCOO), 163.65 (C-8).
Acknowledgment
+
HRMS (ES): m/z [M + H ] calcd for C H O N : 372.2142; found:
1
8
26
2
7
3
72.2149.
We thank the EPSRC for a studentship (to J.A.C.) and the EPSRC
National Mass Spectrometry Service for mass spectra.
tert-Butyl (9-Butylamino-2,3-dimethyl-3H-1,3,4,5,7-pentaaza-
cyclopenta[b]naphthalen-8-yl)carbamate (28)
Using the procedure described for the synthesis of compound 27,
compound 28 was obtained from tert-butyl (9-methanesulfonyl-
References
(
(
(
(
1) Leonard, N. J.; Sprecker, M. A.; Morrice, A. G. J. Am.
2
,3-dimethyl-3H-1,3,4,5,7-pentaaza-cyclopenta[b]naphthalen-8-
Chem. Soc. 1976, 98, 3987.
2) Scopes, D. I.; Barrio, J. R.; Leonard, N. J. Science 1977, 195,
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Yield: 0.91 g (93%); dark-orange solid; mp 220 °C (decomp.).
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1979, 76, 4262.
–
1
2
867, 2924, 2964, 3439 cm .
1H NMR (CDCl3):
NHCH CH CH CH ), 1.52 [s, 9 H, C(CH ) ], 1.62–1.76 (m, 4 H,
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d
=
0.99 (t, J = 7.0 Hz, 3 H,
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1984, 23, 3868.
2
2
2
3
3 3
NHCH CH CH CH and NHCH CH CH CH ), 2.54 (s, 3 H,
2
2
2
3
2
2
2
3
Synthesis 2009, No. 8, 1271–1278 © Thieme Stuttgart · New York

1
278
J. A. Crawford et al.
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Synthesis 2009, No. 8, 1271–1278 © Thieme Stuttgart · New York