One-pot three-step synthesis of pyrazinothienopyrimidines using tandem aza-wittig/electrocyclic ring closure

Article abstract of DOI:10.1055/s-0028-1083318

A facile and efficient one-pot procedure for the preparation of pyrazino[3'′,2'′:4,5]thieno[3,2-d]pyrimidines following a tandem aza-Wittig/electrocyclic ring closure strategy is described. The one-pot, three-step reaction between 3-amino-2-formylthieno[2

Full text of DOI:10.1055/s-0028-1083318

438
PAPER
One-Pot Three-Step Synthesis of Pyrazinothienopyrimidines Using Tandem
Aza-Wittig/Electrocyclic Ring Closure
One-Pot
T
hree-Ste
e
p
Synthesis
r
of Pyr
a
a
zinothienop
r
yrimidin
d
es o Blanco, Antonio Fernández-Mato, José M. Quintela,* Carlos Peinador*
Departamento de Química Fundamental, Facultad de Ciencias, Universidad de A Coruña, 15071 A Coruña, Spain
Fax +34(981)167000; E-mail: jqqoqf@udc.es; capeveqo@udc.es
Received 7 July 2008; revised 23 September 2008
than in the stepwise process. The advantages of the
Abstract: A facile and efficient one-pot procedure for the prepara-
tion of pyrazino[3¢,2¢:4,5]thieno[3,2-d]pyrimidines following a tan-
dem aza-Wittig/electrocyclic ring closure strategy is described. The
one-pot, three-step reaction between 3-amino-2-formylthieno[2,3-
present method are easily accessible starting materials,
experimental simplicity of the one-pot procedure, and
good yields. We also wish to report the preparation of the
b]pyrazine, primary amines, dichlorotriphenylphosphine and het- pyrazinothienopyrimidine core directly by using a one-
erocumulenes, proceeded effectively and the yields of the products
pot, two-step methodology.
were higher than in the stepwise process. The products can also be
prepared directly by a one-pot, two-step reaction using the same al-
Our efforts were directed towards the development of a
one-pot, three-step reaction, which affords products in
good yield in order to confirm the effectiveness of the
one-pot process. The desired products 6 were prepared as
shown in Scheme 1. Thus, a one-pot, three-step procedure
involving sequential addition of aminoaldehyde 1, prima-
ry amines, dichlorotriphenylphosphine and heterocumu-
lenes such as isocyanates, carbon disulfide or carbon
dioxide, could allow access to pyrazinothienopyrimidino-
nes 6. The starting material for all of the following chem-
istry was 7-amino-6-formylthieno[2,3-b]pyrazine (1),
which was prepared by reduction of previously reported
3-amino-2-cyanothieno[2,3-b]pyrazine with diisobutyl-
aluminium hydride. The synthesis of 3-phenyl-2-phenyl-
imino-2,3-dihydropyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidine
(6a) was selected for establishing the effectiveness of the
one-pot, three-step reaction. First, aminoaldehyde 1,
aniline, and a catalytic amount of piperidine were mixed
in ethanol and heated at reflux for approximately one
hour. The solvent was evaporated to dryness under re-
duced pressure then toluene was added followed by tri-
phenylphosphine, hexachloroethane, and triethylamine
and the reaction mixture was heated at 100 °C. After re-
moving the solvent, a toluene solution containing the phe-
nyl isocyanate was added, the reaction flask sealed, and
the reaction mixture heated at 120 °C for approximately
eight hours. The material obtained by this thermal treat-
ment was purified by chromatography to give the pure
pyrazinothienopyrimidine 6a in 73% yield.
dehyde, dichlorotriphenylphosphine and isocyanates. The advan-
tages of the present method are easily accessible starting materials,
experimental simplicity of the one-pot procedure, and good yields.
Key words: heterocycles, Wittig reaction, electrocyclic reactions,
phosphazenes, cyclizations
Heterocyclic compounds occur very widely in nature and
are essential to life and their synthesis has been subject of
great interest due to their wide applicability.1 These struc-
tures represent a class of molecules that act as ligands for
various biological receptors with a high degree of binding
affinity. In this context, an increasingly important area of
ligand design involves the synthesis and study of new
bridging ligands and, in the recent years, new ring con-
struction processes have appeared that involves the prep-
aration of new fused nitrogen and sulfur heterocycles and
their use as chelating ligands.2 Among these heterocyclic
compounds, thienopyrimidines3 and substituted pyrazine4
motifs are of special significance.
The tandem aza-Wittig/electrocyclic ring closure of phos-
phazenes with heterocumulenic compounds has been
widely used for the synthesis of many types of five- and
six-membered N-heterocycles.5 This approach has also
been used by us for the preparation of triheterocyclic sys-
tems bearing various substituents in the pyridine ring.6
We have previously reported on the synthesis of novel tri-
and tetracyclic ring systems with anti-inflammatory, anti-
histaminic and antiprotozoal activity.7 In the frame of a
development of novel synthetic methodology for the prep-
aration of biologically active N-heterocyclic fused struc-
tures, we report here an efficient, one-pot procedure for
the preparation of pyrazino[3¢,2¢:4,5]thieno[3,2-d]pyrim-
idines following a tandem aza-Wittig/electrocyclic ring
closure strategy. The one-pot, three-step reaction proceed-
ed effectively, and the yields of the products were higher
We found that the yield obtained using the one-pot, three-
step synthesis was higher than that obtained from the step-
wise process. Thus, treatment of aldehyde 1 with aniline
in the presence of a catalytic amount of piperidine in re-
fluxing ethanol for one hour (reaction monitored by TLC)
led to the corresponding aldimine 2a in 72% yield. The
key intermediate phosphazene 3a was obtained from 2 as
an orange solid in 65% yield by treatment with the triphe-
nylphosphine, triethylamine, hexachloroethane system8 in
anhydrous toluene. Reaction of phosphazene 3a with phe-
nyl isocyanate at 120 °C in a sealed tube for approximate-
ly eight hours resulted in the formation of
SYNTHESIS 2009, No. 3, pp 0438–0444
x
x
.
x
x
.2
0
0
9
Advanced online publication: 09.01.2009
DOI: 10.1055/s-0028-1083318; Art ID: T11008SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Three-Step Synthesis of Pyrazinothienopyrimidines
439
PPh3
CHO
N
R1NH2, piperidine, R2N=C=O, toluene, 120 °C
60–94%
N
N
S
4
55%
Cl2PPh3
NH2
X
C
N
R1NH2,piperidine, Cl2PPh3,
X=C=Z (Z = O, S), toluene, 120 °C
X
NR1
N
N
N
N
N
N
CHO
N
R1
65–80%
S
N
S
S
1
5
6a–n
X = NR2, S, O
R1, R2 = aryl, alkyl
Cl2PPh3, PhNCO
75%
PhNH2,
piperidine
PhNCO
75%
72%
toluene, 120 °C
NH2
PPh3
N
N
N
NPh
N
N
NPh
Cl2PPh3
65%
S
S
2a
3a
Scheme 1 One-pot and stepwise syntheses of pyrazinothienopyrimidines 6a–n
triphenylphosphine oxide and the desired triheterocyclic
compound 6a as a yellow solid in 75% yield. We also car-
ried out the direct reaction of aldimines 2a with dichlo-
rodiphenylphosphine prepared in situ (using C2Cl6/PPh3/
Et3N), and phenylisocyanate, which afforded 6a in 75%
yield. Nevertheless, the total yield of the desired tricyclic
compound 6a using phosphorane 4, obtained by reaction
of 1 with dichlorotriphenylphosphine, aniline and phenyl-
isocyanate was comparable to the protocol described
above, but was lower than that in the one-pot, three-step
synthesis (Scheme 1).
Table 1 Pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidines 6a–q
Compd X
R1
Yield Mp (°C)
(%)
1 6a
PhN
Ph
Ph
73
65
80
66
71
67
76
77
77
79
70a
80
60
58
160–161
2 6b
3 6c
4-MeC6H4N
135–137 (dec.)
247–248
4-O2NC6H4N Ph
4 6d
5 6e
BuN
Ph
Ph
Bu
Bu
140–141 (dec.)
110–111 (dec.)
234–236
i-PrN
These preliminary experiments allowed us to design a
general one-pot procedure for the preparation of the
pyrazinothienopyrimidine core. The scope of the method
was established by synthesizing fourteen compounds
6a–n varying the primary amine and the heterocumulene
utilized. To this end, the one-pot, three-step reaction se-
quence between aminoaldehyde 1, aromatic and aliphatic
primary amines, dichlorotriphenylphosphine, and isocy-
6 6f
PhN
7 6g
4-MeC6H4N
249–250
8 6h
9 6i
4-O2NC6H4N Bu
265–267
BuN
i-PrN
S
Bu
Bu
Ph
Bu
Ph
Bu
111–113 (dec.)
140–142
10 6j
11 6k
12 6l
13 6m
14 6n
15 6o
16 6p
anates
provided
the
disubstituted
6a–j
pyrazi-
in
–
no[2¢,3¢:4,5]thieno[3,2-d]pyrimidines
a
S
142–143
straightforward manner (Table 1, entries 1–10). Trihet-
erocyclic compounds 6a–j were obtained in good overall
yields (65–80%) for the conversion 1→6, involving three
reaction steps in a one-pot process.
O
225–226
O
233–235
O
4-MeC6H4 93
4-O2NC6H4 70
260–262 (dec.)
>300
Having established an efficient preparation with isocyan-
ates, the potential application of the one-pot procedure us-
ing other heterocumulenes was explored. In this context,
O
the application of the procedure employing carbon disul- 17 6q
O
i-Pr
68
241–243 (dec.)
fide or carbon dioxide instead of isocyanates gave rise to
a Yield determined by 1H NMR analysis of reaction mixture.
the fused pyrimidines 6k–n in good yields (entries 11–14,
Table 1). The formation of these compounds can also be
understood to occur by aza-Wittig reaction between the
initially formed phosphazenes 3 and carbon dioxide or
carbon disulfide to give the corresponding isocyanate as
intermediates.9 Heating this intermediate in anhydrous
toluene at 120 °C causes it to cyclize spontaneously to the
corresponding fused pyrimidinone compounds 6k–n. It is
worth mentioning that the isolation of pure cyclic pyrazi-
nothienopyrimidine 6k was not possible because of diffi-
Synthesis 2009, No. 3, 438–444 © Thieme Stuttgart · New York

440
G. Blanco et al.
PAPER
R1
N
culties in separating the product from triphenylphosphine
oxide, the inevitable byproduct of the aza-Wittig reaction.
R1
N
N
N
PPh3
NR1
N
On the other hand, in one-pot processes, the sequential
treatment of aminoaldehyde 1 with dichlorotriphe-
nylphosphine (prepared in situ in the same reaction flask)
and isocyanates in anhydrous toluene at reflux, led to the
corresponding pyrazinothienopyrimidines 6o–q directly
in good yields, confirming the effectiveness of these one-
pot, two-step reactions (Scheme 2 and Table 1, entries
13–17). We also carried out the reaction of phosphazene
4 with isocyanates, affording pyrido[2¢,3¢:4,5]thieno[2,3-
d] in good to excellent yields (65–93%). The yield in the
one-pot, two-step synthesis was higher than those ob-
tained using the step-wise process. Presumably, the
1→6m–q conversion involves initial aza-Wittig reactions
between the generated phosphazene 4 (from reaction of
aminoaldehyde 2 with dichlorotriphenylphosphine) and
isocyanates, to afford carbodiimides 7. By heating in tol-
uene at reflux, these highly reactive intermediates under-
went a 6p-electrocyclization involving their conjugated
hexatriene fragment to give an unstable 1,3-oxazine-2-
imine 8 which, by a Dimroth-type rearrangement of the
lactone–lactam, underwent ring opening and closure to fi-
nally yield the pyrazinothienopyrimidines 6m–q.
i
N
N
N
N
S
S
S
9
N
N
N
N
O
O
N
N
PPh3
CHO
N
ii
N
N
N
N
N
10
N
S
S
S
N
N
Scheme 3 Attempted synthesis of bis(pyrazinothienopyrimidines) 9
and 10. Reagents and conditions: (i) C6H4(NCO)2, toluene, 120 °C;
(ii) C6H4(NCO)2, piperidine, toluene, 120 °C.
two doublets at d = 8.58 and 8.67 ppm (J = 2.3 Hz) due to
the pyrazine ring, and two triplets at d = 1.02 ppm (J = 7.3
Hz) and d = 4.09 ppm (J = 7.3 Hz) due to the CH3 and
NCH2 protons, respectively. The 13C NMR spectroscopic
data for 6f showed signals arising from the C=O (d =
162.4 ppm) and CH2 carbons (d = 13.8, 19.9, 29.9 and
53.8 ppm). The FAB spectrum of 6f showed a strong mo-
lecular ion peak (m/z = 336) with 100% abundance. The
structure of 6f was independently confirmed by X-ray
crystal structure analysis (Figure 1). In the crystal struc-
ture of 6f the pyrazinothienopyrimidine ring is planar. The
dihedral angle between the mean planes defined by the
pyrazinothienopyrimidine nucleus and the phenyl ring is
65°.
O
NH2
Cl2PPh3, R1N=C=O,
toluene, 120 ºC
N
N
N
N
O
H
N
R1
N
65–93%
S
S
6m–q
1
58%
N
Cl2PPh3
55%
NPh
N
O
PPh3
CHO
N
N
S
N
N
8
S
NPh
C
4
N
120 ºC
toluene
PhNCO
N
N
CHO
S
7
Scheme 2 One-pot and stepwise preparations of pyrazinothienopy-
rimidines 6m–q
We reasoned that by thermal treatment with diisocyan-
ates, the phosphazenes 3 and 4 could transform into
pyrazinothienopyrimidines 9 and 10, respectively, follow-
ing a similar mechanistic sequence to that involved in the
conversions 3→6 and 4→6 (Scheme 3). Unfortunately,
when toluene solutions of compounds 3 and 4 and diiso-
cyanates (1,3- an 1,4-phenylene diisocyanate), were heat-
ed at 120 °C for one hour in a sealed tube, only very
complex reaction mixtures were obtained.
Figure 1 Crystal structure of 6f. Solvent molecules and hydrogen
atoms have been omitted for clarity. Color labeling scheme is as fol-
lows: S (yellow), N (blue), C (gray).
In summary, we have presented herein a novel and effi-
cient methodology for the synthesis of disubstituted
pyrazinothienopyrimidines through processes which in-
volve tandem aza-Wittig/electrocyclic ring closure of
phosphazenes with heterocumulenic compounds. These
Structural elucidation of compounds 6 was accomplished
from their analytical and spectral data. For example, the
IR spectrum of 6f exhibited a strong band at n = 1627 cm–1
due to the imino group. Their 1H NMR spectrum showed
Synthesis 2009, No. 3, 438–444 © Thieme Stuttgart · New York

PAPER
One-Pot Three-Step Synthesis of Pyrazinothienopyrimidines
441
appeared (~1.5 h, monitored by TLC). After cooling, the precipitat-
ed solid was filtered off and recrystallized (EtOH) to yield 2a.
structures are assembled from readily available starting
materials in a simple one-pot procedure in high yields, un-
der mild reaction conditions. This procedure presents all Yield: 0.51 g (72%); red crystals; mp 184–186 °C (dec.).
IR (KBr): 3434 (NH2), 1540, 1481, 1465, 1359 cm–1.
the advantages associated with one-step domino process-
es, such as reduction of reaction time, molecular diversity,
no need for purification of intermediates and minimiza-
tion of costs and waste production.
1H NMR (CDCl3, 300 MHz): d = 6.73 (br s, 2 H), 7.20–7.28 (m,
3 H), 7.36–7.45 (m, 2 H), 8.56 (d, J = 2.3 Hz, 1 H), 8.27 (s, 1 H),
8.60 (d, J = 2.3 Hz, 1 H).
13C NMR (CDCl3, 125 MHz): d = 109.5, 120.9, 126.0, 129.2, 140.9,
141.0, 142.1, 142.6, 151.5, 154.2, 156.4.
All reagents were commercial grade chemicals from freshly opened
containers. Merck 60 F254 foils were used for thin layer chromatog-
raphy and Merck 60 (230–400 mesh) silica gel was used for flash
MS (FAB): m/z (%) = 255 (100).
Anal. Calcd for C13H10N4S: C, 61.40; H, 3.96; N, 22.03; S, 12.61.
Found: C, 61.07; H, 4.37; N, 22.18; S, 12.35.
1
chromatography. H and 13C NMR spectra were obtained using a
Bruker Avance 300 (300 MHz and 75 MHz for 1H and 13C, respec-
tively) or a Bruker Avance 500 (500 MHz and 125 MHz for 1H and
13C, respectively) in CDCl3 as solvent, and the chemical shifts are
6-[(N-Phenylimino)methyl]-7-[(triphenylphosphoranyl-
idene)amino]thieno[2,3-b]pyrazine (3a)
1
expressed in ppm relative to TMS (d = 0.00 ppm) for H and to
To a mixture of 2a (0.25 g, 0.98 mmol), Ph3P (0.39 g, 1.47 mmol)
and hexachloroethane (0.35 g, 1.47 mmol) in anhydrous toluene (10
mL), Et3N (0.34 mL, 2.46 mmol) was added dropwise. The reaction
mixture was heated at 100 °C with stirring in a sealed tube for ap-
proximately 2 h (monitored by TLC). After cooling, the resulting
solid was filtered off and recrystallized (EtOAc) to give 3a.
CDCl3 (d = 77.1 ppm) for 13C. 31P NMR spectra were obtained us-
ing a Bruker Avance 300 with 85% phosphoric acid as standard. IR
spectra were recorded as KBr disks on a Bruker VECTOR 22 spec-
trophotometer. Mass spectrometry experiments were carried out us-
ing a Thermo MAT 95 XP spectrometer. Melting points were
measured using Stuart Scientific SMP3 apparatus and are uncor-
rected. Microanalyses were performed by the elemental analyses
general service of the University of A Coruña on a Carlo Erba EA-
1108 instrument.
Yield: 0.33 g (65%); orange solid; mp 205–207 °C (dec.).
IR (KBr): 1550, 1462, 1410 cm–1.
1H NMR (CDCl3, 300 MHz): d = 7.10–7.55 (m, 14 H), 7.65–7.90
(m, 6 H), 7.97 (d, J = 2.3 Hz, 1 H), 8.23 (d, J = 2.3 Hz, 1 H), 9.32
(s, 1 H).
3-Amino-2-cyanothieno[2,3-b]pyrazine was prepared starting from
commercial 3-cyanopyrazine according to a literature procedure.10
The crystal and molecular structure of 6f was determined by X-ray
diffraction studies.11 Crystals were mounted on glass fiber and
transferred to the cold gas stream of the diffractometer (Bruker
Smart APEX). Data were recorded with Mo-Ka radiation
(l = 0.71073 Å) in w-scan mode. The structures were solved by di-
rect methods and refined anisotropically12 on F2. Methyl groups
were refined using rigid groups and other hydrogens were refined
using a riding method.
13C NMR (CDCl3, 125 MHz): d = 121.4, 125.2, 128.2, 128.4, 129.0,
131.5, 132.6, 132.9, 138.8, 141.4, 145.8, 145.9, 141.7, 152.6, 153.6,
156.5.
31P NMR (CDCl3, 121.5 MHz): d = 8.06.
MS (FAB): m/z (%) = 515 (90).
Anal. Calcd for C31H23N4PS: C, 72.36; H, 4.51; N, 10.89; S, 6.23.
Found: C, 71.96; H, 4.78; N, 11.07; S, 5.96.
7-Amino-6-formylthieno[2,3-b]pyrazine (1)
6-Formyl-7-[(triphenylphosphoranylidene)amino]thieno[2,3-
b]pyrazine (4)
To a solution of 3-amino-2-cyanothieno[2,3-b]pyrazine (2 g, 11
mmol) in anhydrous THF (150 mL) cooled to –15 °C, DIBAL-H
(1.5 M in toluene, 15.1 mL, 22.7 mmol) was added dropwise, and
the reaction mixture was stirred at the same temperature for 2 h.
MeOH (5 mL) was added and the reaction mixture was stirred for 5
min and then poured into ice-cooled HCl (1 M, 90 mL) and stirred
for 30 min. The THF was removed under reduced pressure and the
aqueous solution was extracted with Et2O (15 × 50 mL). The organ-
ic layers were dried over MgSO4, the solvent was removed under re-
duced pressure, and the resulting material was purified by column
chromatography on silica gel (hexanes–EtOAc, 70:30) to give 1.
To a mixture of aldehyde 1 (0.3 g, 1.67 mmol), Ph3P (0.66 g, 2.51
mmol) and hexachloroethane (0.59 g, 2.51 mmol) in anhydrous tol-
uene (15 mL), Et3N (0.42 mL, 4.19 mmol) was added dropwise. The
reaction mixture was heated at 100 °C in a sealed tube for 1.5 h
(monitored by TLC). After cooling, the solvent was removed under
reduced pressure and the residue was subjected to chromatography
on silica gel (CH2Cl2) to give 4.
Yield: 0.40 g (55%); yellow solid; mp 230–232 °C (dec.).
IR (KBr): 1622 (C=O), 1494, 1468, 1430, 1348 cm–1.
Yield: 1.0 g (50%); orange solid; mp 185–187 °C.
1H NMR (CDCl3, 300 MHz): d = 7.40–7.46 (m, 6 H), 7.49–7.54 (m,
3 H), 7.77–7.83 (m, 6 H), 7.99 (d, J = 2.3 Hz, 1 H), 8.31 (d, J = 2.3
Hz, 1 H), 10.74 (s, 1 H).
IR (KBr): 3331 (NH2), 1621 (C=O), 1606, 1566, 1530, 1487, 1350
cm–1.
1H NMR (CDCl3, 500 MHz): d = 6.80 (s, 2 H, NH2), 8.63 (d, J = 2.3
Hz, 1 H), 8.67 (d, J = 2.3 Hz, 1 H), 9.81 (s, 1 H, CHO).
13C NMR (CDCl3, 125 MHz): d = 128.5, 128.6, 131.0, 131.8, 131.9,
131.9, 132.6, 132.6, 139.2, 143.4, 157.9, 184.3.
13C NMR (CDCl3, 125 MHz): d = 109.6, 140.9, 141.4, 145.1, 145.5,
31P NMR (CDCl3, 121.5 MHz): d = 9.67.
157.7, 185.2.
MS (FAB): m/z (%) = 440 (100).
MS (EI): m/z (%) = 179 (100) [M+].
Anal. Calcd for C25H18N3OPS: C, 68.33; H, 4.13; N, 9.56; S, 7.30.
Found: C, 68.56; H, 3.98; N, 9.69; S, 7.06.
Anal. Calcd for C7H5N3S: C, 46.92; H, 2.81; N, 23.45; S, 17.89.
Found: C, 46.74; H, 3.00; N, 23.28; S, 17.75.
One-Pot Synthesis of Pyrazinothienopyrimidines 6a–n; General
Procedure
A mixture of aminoaldehyde 1 (0.1 g, 0.56 mmol), the appropriate
amine (benzylamine or aniline) (0.67 mmol) and a catalytic amount
of piperidine in EtOH (10 mL) was refluxed for 1–2 h (monitored
7-Amino-6-[(N-phenylimino)methyl]thieno[2,3-b]pyrazine (2a)
A mixture of 3-aminothieno[2,3-b]pyrazine-2-carbaldehyde (1; 0.5
g, 2.8 mmol), aniline (0.33 mL, 3.6 mmol) and a catalytic amount
of piperidine in EtOH (20 mL) was refluxed until the aldehyde dis-
Synthesis 2009, No. 3, 438–444 © Thieme Stuttgart · New York

442
G. Blanco et al.
PAPER
by TLC). After cooling, the solvent was removed to dryness under
reduced pressure, a solution of Ph3P (0.22 g, 0.84 mmol) and
hexachloroethane (0.20 g, 0.84 mmol) in anhydrous toluene (10
mL) was added, then Et3N (0.19 mL, 1.40 mmol) was added drop-
wise. The reaction flask was sealed and the mixture was heated at
100 °C for 1–2 h (monitored by TLC). After cooling to r.t., the sol-
vent was removed under reduced pressure and a solution of the ap-
propriate heterocumulene (isocyanate, CS2 or CO2; 0.67 mmol) in
anhydrous toluene (5 mL) was added in the same reaction flask. The
flask was sealed and the reaction mixture containing the phosp-
hazene and heterocumulene was heated at 120 °C for ~8 h until the
phosphazene had disappeared (monitored by TLC). After cooling to
r.t., the solvent was removed under reduced pressure, Et2O (5 mL)
was added, and the mixture was stirred at r.t. for 1–3 h. The result-
ing material formed was filtered off and purified by column chro-
matography on silica gel (EtOAc–CH2Cl2, 30→40%).
2-n-Butylimino-3-phenyl-2,3-dihydropyrazino[2¢,3¢:4,5]thi-
eno[3,2-d]pyrimidine (6d)
Yield: 66%; green crystals; mp 140–141 °C (dec.).
IR (KBr): 1627, 1599, 1577, 1503, 1471, 1422, 1365, 1346 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.02 (t, J = 7.3 Hz, 3 H), 1.40–
1.54 (m, 2 H), 1.86–2.00 (m, 2 H), 4.09 (t, J = 7.3 Hz, 2 H), 6.94–
7.04 (m, 1 H), 7.27–7.38 (m, 4 H), 7.88 (s, 1 H), 8.58 (d, J = 2.3 Hz,
1 H, H-7), 8.67 (d, J = 2.3 Hz, 1 H, H-8).
13C NMR (CDCl3, 75 MHz): d = 13.8, 19.9, 29.9, 53.8, 107.9, 122.0,
123.0, 128.6, 142.5, 143.2, 143.7, 146.0, 148.8, 149.0, 160.9, 162.5.
MS (FAB): m/z (%) = 336 (60) [MH]+.
Anal. Calcd for C18H17N5S: C, 64.45; H, 5.11; N, 20.88; S, 9.56.
Found: C, 64.32; H, 4.92; N, 20.53; S, 9.40.
2-Isopropylimino-3-phenyl-2,3-dihydropyrazino[2¢,3¢:4,5]thi-
eno[3,2-d]pyrimidine (6e)
Yield: 71%; yellow solid; mp 110–111 °C (dec.).
3-Phenyl-2-phenylimino-2,3-dihydropyrazino[2¢,3¢:4,5]thi-
eno[3,2-d]pyrimidine (6a)
Yield: 73%; yellow crystals; mp 160–161 °C.
IR (KBr): 1631, 1575, 1549, 1486, 1438 cm–1.
IR (KBr): 1670, 1624, 1599, 1549, 1539, 1498, 1430, 1339, 1280
cm–1.
1H NMR (CDCl3, 500 MHz): d = 7.10–7.18 (m, 1 H), 7.31–7.43 (m,
4 H), 7.48–7.59 (m, 5 H), 8.36 (s, 1 H), 8.74 (d, J = 2.3 Hz, 1 H, H-
7), 8.86 (d, J = 2.3 Hz, 1 H, H-8).
13C NMR (CDCl3, 125 MHz): d = 112.7, 121.6, 126.2, 129.3, 129.3,
129.7, 129.8, 140.6, 143.4, 144.3, 147.0, 150.2, 152.5, 154.8, 162.8,
165.0.
1H NMR (CDCl3, 500 MHz): d = 1.52 (d, J = 6.8 Hz, 6 H), 5.30
(sept, J = 6.8 Hz, 1 H), 7.39–7.46 (m, 5 H), 8.35 (s, 1 H), 8.70 (d,
J = 2.3 Hz, 1 H, H-7), 8.83 (d, J = 2.3 Hz, 1 H, H-8).
13C NMR (CDCl3, 125 MHz): d = 21.8, 51.2, 112.6, 121.7, 123.1,
125.1, 140.4, 143.2, 146.6, 151.2, 154.5, 157.1, 160.2, 167.8.
MS (FAB): m/z (%) = 322 (40) [MH]+.
Anal. Calcd for C17H15N5S: C, 63.53; H, 4.70; N, 21.79; S, 9.98.
Found: C, 63.37; H, 4.58; N, 22.01; S, 9.89.
MS (EI): m/z (%) = 278 (20) [M+ – C6H5].
3-n-Butyl-2-phenylimino-2,3-dihydropyrazino[2¢,3¢:4,5]thi-
eno[3,2-d]pyrimidine (6f)
Anal. Calcd for C20H13N5S: C, 67.59; H, 3.69; N, 19.70; S, 9.02.
Found: C, 67.36; H, 3.79; N, 19.52; S, 9.19.
Yield: 67%; purple crystals; mp 234–236 °C.
3-Phenyl-2-(4-methylphenyl)imino-2,3-dihydro-
pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidine (6b)
Yield: 65%; yellow crystals; mp 135–137 °C (dec.).
IR (KBr): 1627, 1590, 1490, 1452, 1349, 1322, 1305 cm–1.
1H NMR (CDCl3, 500 MHz): d = 2.43 (s, 3 H), 7.13–7.18 (m, 4 H),
7.32–7.36 (m, 5 H), 8.35 (s, 1 H), 8.73 (d, J = 2.3 Hz, 1 H, H-7),
8.85 (d, J = 2.3 Hz, 1 H, H-8).
13C NMR (CDCl3, 125 MHz): d = 21.3, 112.6, 125.9, 128.5, 128.5,
129.5, 130.3, 139.2, 140.1, 143.3, 144.5, 146.9, 152.1, 154.9, 155.8,
162.7, 164.7.
IR (KBr): 1627, 1577, 1503, 1471, 1422, 1365, 1346 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.02 (t, J = 7.3 Hz, 3 H), 1.40–
1.54 (m, 2 H), 1.86–2.00 (m, 2 H), 4.09 (t, J = 7.3 Hz, 2 H), 6.96–
7.04 (m, 1 H), 7.28–7.36 (m, 4 H), 7.88 (s, 1 H), 8.58 (d, J = 2.3 Hz,
1 H), 8.67 (d, J = 2.3 Hz, 1 H).
13C NMR (CDCl3, 75 MHz): d = 13.8, 19.9, 29.9, 53.8, 107.9, 122.0,
123.0, 128.6, 142.5, 143.2, 143.7, 146.0, 148.7, 149.0, 161.0, 162.4.
MS (FAB): m/z (%) = 336 (100) [MH]+.
Anal. Calcd for C18H17N5S: C, 64.45; H, 5.11; N, 20.88; S, 9.56.
Found: C, 64.14; H, 5.29; N, 20.78; S, 9.32.
MS (FAB): m/z (%) = 370 (20) [MH]+.
3-n-Butyl-2-(4-methylphenyl)imino-2,3-dihydro-
pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidine (6g)
Yield: 76%; purple crystals; mp 249–250 °C.
Anal. Calcd for C21H15N5S: C, 68.27; H, 4.09; N, 18.96; S, 8.68.
Found: C, 68.45; H, 3.87; N, 18.72; S, 8.49.
3-Phenyl-2-(4-nitrophenyl)imino-2,3-dihydro-
pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidine (6c)
Yield: 80%; yellow crystals; mp 247–248 °C.
IR (KBr): 1628, 1551, 1504, 1453 cm–1.
1H NMR (CDCl3, 500 MHz): d = 7.46–7.52 (m, 5 H), 7.73–7.77 (m,
2 H), 8.24–8.28 (m, 2 H), 8.42 (s, 1 H), 8.78 (d, J = 2.3 Hz, 1 H, H-
7), 8.88 (d, J = 2.3 Hz, 1 H, H-8).
13C NMR (CDCl3, 125 MHz): d = 113.4, 125.1, 125.3, 126.2, 127.5,
129.6, 130.4, 131.5, 142.2, 142.6, 144.1, 145.6, 147.3, 151.2, 162.4,
163.3.
IR (KBr): 1628, 1582, 1493, 1470, 1421, 1362 cm–1.
1H NMR (CDCl3, 500 MHz): d = 1.00 (t, J = 7.3 Hz, 3 H), 1.40–
1.50 (m, 2 H), 1.87–1.96 (m, 2 H), 2.31 (s, 3 H), 4.06 (t, J = 7.3 Hz,
2 H), 7.08–7.13 (m, 2 H), 7.17–7.21 (m, 2 H), 7.85 (s, 1 H), 8.56 (d,
J = 2.3 Hz, 1 H, H-7), 8.66 (d, J = 2.3 Hz, 1 H, H-8).
13C NMR (CDCl3, 125 MHz): d = 13.9, 20.0, 21.0, 30.0, 53.8, 107.6,
122.8, 129.3, 131.2, 142.5, 143.3, 143.7, 146.1, 149.0, 152.0, 160.9,
162.5.
MS (FAB): m/z (%) = 350 (100) [MH]+.
Anal. Calcd for C19H19N5S: C, 65.30; H, 5.48; N, 20.04; S, 9.18.
Found: C, 64.97; H, 5.26; N, 20.17; S, 9.01.
MS (FAB): m/z (%) = 401 (30) [MH]+.
Anal. Calcd for C20H12N6O2S: C, 59.99; H, 3.02; N, 20.99; S, 8.01.
Found: C, 59.83; H, 2.91; N, 20.73; S, 7.80.
3-(n-Butyl)-2-(4-nitrophenyl)imino-2,3-dihydro-
pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidine (6h)
Yield: 77%; brown solid; mp 265–267 °C.
Synthesis 2009, No. 3, 438–444 © Thieme Stuttgart · New York

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One-Pot Three-Step Synthesis of Pyrazinothienopyrimidines
443
IR (KBr): 1624, 1523, 1480, 1417, 1363, 1320 cm–1.
13C NMR (CDCl3, 125 MHz): d = 112.6, 126.3, 129.7, 129.8, 140.6,
143.4, 144.3, 147.0, 154.7, 162.8, 165.0.
1H NMR (CDCl3, 500 MHz): d = 1.04 (t, J = 7.3 Hz, 3 H), 1.45–
1.54 (m, 2 H), 1.91–1.99 (m, 2 H), 4.19 (t, J = 7.3 Hz, 2 H), 7.40–
7.45 (m, 2 H), 8.07 (s, 1 H), 8.17–8.21 (m, 2 H), 8.67 (d, J = 2.3 Hz,
1 H, H-7), 8.77 (d, J = 2.3 Hz, 1 H, H-8).
13C NMR (CDCl3, 125 MHz): d = 13.8, 20.0, 30.2, 54.5, 110.6,
123.3, 125.0, 141.9, 142.7, 143.1, 143.8, 146.7, 150.4, 156.0, 161.2,
162.6.
MS (FAB): m/z (%) = 281 (15) [MH]+.
Anal. Calcd for C14H8N4OS: C, 59.99; H, 2.88; N, 19.99; S, 11.44.
Found: C, 60.34; H, 3.09; N, 19.63; S, 10.95.
3-n-Butyl-2-oxo-pyrazino[2¢,3¢:4,5]thieno[3,2-d]pyrimidine
(6n)
Yield: 58%; yellow solid; mp 233–235 °C.
IR (KBr): 1639 (C=O), 1499, 1470, 1445, 1417, 1359 cm–1.
1H NMR (CDCl3, 500 MHz): d = 0.99 (t, J = 7.4 Hz, 3 H), 1.40–
1.50 (m, 2 H), 1.86–1.94 (m, 2 H), 4.14 (t, J = 7.5 Hz, 2 H), 8.30 (s,
1 H), 8.71 (d, J = 2.3 Hz, 1 H, H-7), 8.84 (d, J = 2.3 Hz, 1 H, H-8).
13C NMR (CDCl3, 125 MHz): d = 13.6, 19.9, 31.0, 53.3, 112.1,
142.6, 143.1, 144.0, 146.6, 155.0, 162.1, 163.7.
MS (FAB): m/z (%) = 261 (50) [MH]+.
MS (FAB): m/z (%) = 381 (30) [MH]+.
Anal. Calcd for C18H16N6O2S: C, 56.83; H, 4.24; N, 22.09; S, 8.43.
Found: C, 56.67; H, 4.18; N, 22.15; S, 8.49.
3-n-Butyl-2-n-butylimino-2,3-dihydropyrazino[2¢,3¢:4,5]thi-
eno[3,2-d]pyrimidine (6i)
Yield: 77%; yellow solid; mp 111–113 °C (dec.).
IR (KBr): 1662, 1635, 1541, 1466, 1411, 1377, 1337 cm–1.
1H NMR (CDCl3, 500 MHz): d = 1.00 (t, J = 7.3 Hz, 6 H), 1.39–
1.52 (m, 4 H), 1.86–1.94 (m, 4 H), 4.12–4.16 (m, 4 H), 8.27 (s,
1 H), 8.71 (d, J = 2.3 Hz, 1 H, H-7), 8.85 (d, J = 2.3 Hz, 1 H, H-8).
Anal. Calcd for C12H12N4OS: C, 55.37; H, 4.65; N, 21.52; S, 12.32.
Found: C, 55.11; H, 4.17; N, 21.41; S, 11.88.
13C NMR (CDCl3, 125 MHz): d = 13.7, 26.5, 31.0, 53.4, 112.2,
143.2, 144.0, 146.7, 154.1, 155.1, 162.2, 163.8.
Preparation of Pyrazinothienopyrimidines 6m–q; Typical Pro-
cedure
A solution of aminoaldehyde 1 (0.1 g, 0.56 mmol), Ph3P (0.22 g,
0.84 mmol), hexachloroethane (0.20 g, 0.84 mmol), and Et3N (0.19
mL, 1.40 mmol) in anhydrous toluene (10 mL) was heated at 100 °C
for 1–2 h (monitored by TLC) in a sealed reaction flask. After cool-
ing to r.t., the solvent was removed under reduced pressure and a so-
lution of the appropriate isocyanate (0.67 mmol) in anhydrous
toluene (5 mL) was added in the same reaction flask. The flask was
sealed and the reaction mixture containing the phosphazene and het-
erocumulene was heated at 120 °C for ~8 h until the phosphazene
had disappeared (monitored by TLC). After cooling to r.t., the sol-
vent was removed under reduced pressure, Et2O (5 mL) was added,
and the mixture was stirred at r.t. for 1–3 h. The resulting material
formed was filtered off and purified by column chromatography on
silica gel (EtOAc–CH2Cl2, 50→100%) to give 6m (71% yield), 6n
(65% yield), and 6o–q as pure compounds.
MS (FAB): m/z (%) = 316 (100) [MH]+.
Anal. Calcd for C16H21N5S: C, 60.92; H, 6.71; N, 22.20; S, 10.17.
Found: C, 60.85; H, 6.58; N, 22.12; S, 10.34.
3-n-Butyl-2-isopropylimino-2,3-dihydropyrazino[2¢,3¢:4,5]thi-
eno[3,2-d]pyrimidine (6j)
Yield: 79%; brown solid; mp 140–142 °C.
IR (KBr): 1659, 1632, 1522, 1464, 1334 cm–1.
1H NMR (CDCl3, 500 MHz): d = 1.01 (t, J = 7.3 Hz, 3 H, CH3),
1.38–1.41 (m, 2 H, CH2), 1.53 (d, J = 6.8 Hz, 6 H, CH3), 1.78–1.84
(m, 2 H), 3.88 (t, J = 7.3 Hz, 2 H), 4.62–4.69 (sept, J = 6.8 Hz, 1 H),
8.41 (s, 1 H), 8.69 (d, J = 2.3 Hz, 1 H, H-7), 8.94 (d, J = 2.3 Hz,
1 H, H-8).
13C NMR (CDCl3, 125 MHz): d = 13.8, 19.5, 23.4, 29.9, 43.9, 46.8,
116.6, 143.5, 143.7, 144.3, 151.5, 157.8, 160.7, 163.4.
3-(4-Methylphenyl)-2-oxo-2,3-dihydropyrazino[2¢,3¢:4,5]thi-
eno[3,2-d]pyrimidine (6o)
Yield: 93%; yellow solid; mp 260–262 °C (dec.).
IR (KBr): 1671 (C=O), 1623, 1526, 1428, 1350, 1278 cm–1.
1H NMR (CDCl3, 300 MHz): d = 2.42 (s, 3 H), 7.29–7.35 (m, 2 H),
7.37–7.42 (m, 2 H), 8.39 (s, 1 H), 8.72 (d, J = 2.3 Hz, 1 H, H-7),
8.84 (d, J = 2.3 Hz, 1 H, H-8).
MS (FAB): m/z (%) = 302 (100) [MH]+.
Anal. Calcd for C15H19N5S: C, 59.77; H, 6.35; N, 23.24; S, 10.64.
Found: C, 59.64; H, 6.29; N, 23.38; S, 10.51.
3-n-Butyl-2-thioxo-2,3-dihydropyrazino[2¢,3¢:4,5]thieno[3,2-
d]pyrimidine (6l)
Yield: 80%; orange solid; mp 142–143 °C.
IR (KBr): 1598, 1492, 1438, 1374 cm–1.
13C NMR (CDCl3, 75 MHz): d = 29.6, 112.4, 125.8, 130.1, 138.0,
139.7, 143.2, 144.5, 146.8, 154.7, 162.6, 164.6, 171.1.
1H NMR (CDCl3, 500 MHz): d = 1.03 (t, J = 7.3 Hz, 3 H), 1.45–
1.54 (m, 2 H), 1.98–2.05 (m, 2 H), 4.64 (t, J = 7.3 Hz, 2 H), 8.45 (s,
1 H), 8.73 (d, J = 2.3 Hz, 1 H, H-7), 8.89 (d, J = 2.3 Hz, 1 H, H-8).
13C NMR (CDCl3, 125 MHz): d = 13.7, 20.0, 30.1, 59.4, 118.0,
142.0, 143.8, 144.0, 146.9, 157.6, 162.2, 180.1.
MS (FAB): m/z (%) = 295 (40) [MH]+.
Anal. Calcd for C15H10N4OS: C, 61.21; H, 3.42; N, 19.04; S, 10.89.
Found: C, 61.52; H, 3.25; N, 19.15; S, 10.28.
3-(4-Nitrophenyl)-2-oxo-2,3-dihydropyrazino[2¢,3¢:4,5]thi-
eno[3,2-d]pyrimidine (6p)
Yield: 70%; yellow solid; mp >300 °C.
MS (FAB): m/z (%) = 277 (20) [MH]+.
Anal. Calcd for C12H12N4S2: C, 52.15; H, 4.38; N, 20.27; S, 23.20.
Found: C, 52.22; H, 4.25; N, 20.09; S, 22.98.
IR (KBr): 1657 (C=O), 1614, 1521, 1494, 1465, 1416, 1348, 1317
cm–1.
1H NMR (DMSO-d6, 500 MHz): d = 7.76–7.80 (m, 2 H), 8.34 (s,
1 H), 8.42–8.46 (m, 2 H), 8.76 (d, J = 2.3 Hz, 1 H, H-7), 8.90 (d,
J = 2.3 Hz, 1 H, H-8).
2-Oxo-3-phenyl-2,3-dihydropyrazino[2¢,3¢:4,5]thieno[3,2-d]py-
rimidine (6m)
Yield: 60%; pale-yellow solid; mp 225–226 °C.
IR (KBr): 1676 (C=O), 1454, 1376 cm–1.
1H NMR (CDCl3, 500 MHz): d = 7.52–7.65 (m, 5 H), 8.42 (s, 1 H),
8.80 (d, J = 2.3 Hz, 1 H, H-7), 8.93 (d, J = 2.3 Hz, 1 H, H-8).
13C NMR (DMSO-d6, 125 MHz): d = 111.9, 124.5, 128.3, 141.7,
143.6, 145.9, 147.2, 147.3, 147.6, 153.9, 162.3, 164.2.
MS (FAB): m/z (%) = 281 (25) [MH+ – NO2].
Synthesis 2009, No. 3, 438–444 © Thieme Stuttgart · New York

444
G. Blanco et al.
PAPER
Anal. Calcd for C14H7N5O3S: C, 51.69; H, 2.17; N, 21.53; S, 9.86.
Found: C, 51.06; H, 2.47; N, 21.02; S, 9.97.
(2) (a) Steel, P. J. Acc. Chem. Res. 2005, 38, 243.
(b) Encyclopedia of Supramolecular Chemistry; Atwood, J.
L.; Steed, J. W., Eds.; Marcel Dekker: New York, 2004.
(c) Steed, J. W.; Atwood, J. L. Supramolecular Chemistry;
John Wiley & Sons: New York, 2000. (d) Lehn, J.-M.
Supramolecular Chemistry: Concepts and Perspectives;
VCH: Weinheim, 1995.
3-Isopropyl-2-oxo-2,3-dihydropyrazino[2¢,3¢:4,5]thieno[3,2-
d]pyrimidine (6q)
Yield: 68%; yellow solid; mp 241–243 °C (dec.).
IR (KBr): 1647 (C=O), 1524, 1503, 1466, 1374, 1349, 1272 cm–1.
1H NMR (CDCl3, 500 MHz): d = 1.53 (d, J = 6.8 Hz, 6 H), 5.30
(sept, J = 6.8 Hz, 1 H), 8.34 (s, 1 H), 8.70 (d, J = 2.3 Hz, 1 H, H-7),
8.83 (d, J = 2.3 Hz, 1 H, H-8).
13C NMR (CDCl3, 125 MHz): d = 22.1, 51.2, 112.6, 140.3, 142.8,
143.2, 146.6, 154.9, 162.2, 162.8.
(3) For reviews on the synthesis and biological activity of
thienopyridines, see: (a) Litvinov, V. P.; Dotsenko, V. V.;
Krivokolysko, S. G. Russ. Chem. Bull. Int. Ed. 2005, 54,
864. (b) Bakhite, E. A.-G. Phosphorus, Sulfur, Silicon Relat.
Elem. 2003, 178, 929.
(4) (a) Pawar, V. G.; De Borggraeve, W. H. Synthesis 2006,
2799. (b) Burns, C. J.; Wilks, A. F.; Bu, X.
MS (FAB): m/z (%) = 247 (90) [MH]+.
WO2005054230, 2005; Chem. Abstr. 2005, 143, 60004o.
(c) Chill, L.; Aknin, M.; Kashman, Y. Org. Lett. 2003, 5,
2433. (d) Baker, D. C.; Hand, E. S.; Plowman, J.; Rampal, J.
B.; Safavy, A.; Haugwitz, R. D.; Narayanan, V. L. Anti-
Cancer Drug Des. 1987, 2, 297.
Anal. Calcd for C11H10N4OS: C, 53.64; H, 4.09; N, 22.75; S, 13.02.
Found: C, 53.98; H, 4.38; N, 23.05; S, 13.19.
2-Oxo-3-phenyl-2,3-dihydropyrazino[2¢,3¢:4,5]thieno[3,2-d]py-
rimidine (6m)
(5) See for example: (a) Palacios, F.; Alonso, C.; Aparicio, D.;
Rubiales, G.; de los Santos, J. M. Tetrahedron 2007, 63,
523. (b) Fresneda, P. M.; Molina, P. Synlett 2004, 1.
(c) Molina, P.; Fresneda, P. M.; Delgado, S. Synthesis 1999,
326. (d) Molina, P.; Alcántara, J.; López-Leonardo, C.
Tetrahedron 1997, 53, 3281. (e) Chavignon, O.; Teulade, J.
C.; Roche, D.; Madesclaire, M.; Blache, Y.; Gueiffier, A.;
Chabard, J. L.; Dauphin, G. J. Org. Chem. 1994, 59, 6413.
(f) Molina, P.; Vilaplana, M. J. Synthesis 1994, 1197.
(6) (a) Álvarez-Sarandés, R.; Peinador, C.; Quintela, J. M.
Tetrahedron 2001, 57, 5413. (b) Quintela, J. M.; Álvarez-
Sarandés, R.; Peinador, C. Tetrahedron 1998, 54, 8107.
(7) See for example: (a) Martínez-Poveda, B.; Múñoz-Chápuli,
R.; Rodríguez-Nieto, S.; Quintela, J. M.; Fernández, A.;
Medina, M.; Rodríguez-Quesada, A. Mol. Cancer Ther.
2007, 6, 2675. (b) Quintela, J. M.; Peinador, C.; González,
L.; Devesa, I.; Ferrándiz, M. L.; Alcaraz, M. J.; Riguera, R.
Bioorg. Med. Chem. 2003, 11, 863. (c) Rioja, I.; Ubeda, A.;
Terencio, M. C.; Guillén, I.; Riguera, R.; Quintela, J. M.;
Peinador, C.; González, L.; Alcaraz, M. J. Eur. J.
Pharmacol. 2000, 397, 207. (d) Quintela, J. M.; Peinador,
C.; González, L. M.; Rioja, I.; Terencio, M. C.; Ubeda, A.;
Alcaraz, M. J.; Riguera, R. J. Med. Chem. 1999, 42, 4720.
(8) Okawa, T.; Eguchi, S. Synlett 1994, 555.
To a solution of phosphazene 4 (0.1 g, 0.23 mmol) in anhydrous
THF (5 mL) was added phenyl isocyanate (0.27 mmol). The reac-
tion mixture was heated at 120 °C in a sealed tube for ~8 h until the
phosphazene had disappeared (monitored by TLC). The solution
was concentrated to dryness, and the residual material was purified
by column chromatography on silica gel (EtOAc–CH2Cl2,
50→100%) to give 6m (58% yield), whose properties were identi-
cal to those of the compound obtained by the one-pot procedure.
X-ray Crystallographic Data for Compound 6f
Suitable crystals for an X-ray diffraction analysis were grown from
EtOH. Formula weight: 668.86; Crystal system: monoclinic; Space
group: P2(1)/c; Unit cell dimensions: a = 10.7553(3) Å,
b = 13.6974(4) Å, c = 12.3887(4) Å, a = 90°, b = 115.752(2)°,
g = 90°; V = 1643.84(8) Å3; Z = 2; D (calcd) = 1.351 mg m–3;
F(000) = 700; T = 100 (2) K.
Acknowledgment
This work was supported by the Xunta de Galicia and MCyT
(Spain) and FEDER (projects and PGIDIT06PXIB103224PR and
CTQ2007-63839). G.B. and A.F.-M. acknowledge predoctoral fel-
lowships from the Xunta de Galicia and the University of A Coruña.
(9) Molina, P.; Arqués, A.; Vinader, M. V.; Becher, J.;
Brondum, K. J. Org. Chem. 1988, 53, 4654.
(10) Johnston, D. B. R. U.S. Patent 4,442,095, 1984.
(11) Crystallographic data (excluding structure factors) for 6f has
been deposited with the Cambridge Crystallographic Data
Center as supplementary publication number CCDC
692136. Copies of the data may be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge, CB2
1EZ, UK [fax: +44(1223)33603 or e-mail:
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