Probing the Reactivity of 2,4-Dichlorofuro[3,4-d ]pyrimidin-7-one: A Versatile and Underexploited Scaffold to Generate Substituted or Fused Pyrimidine Derivatives

Article abstract of DOI:10.1055/s-0039-1690205

Herein, we describe the results of our investigation on the chemical reactivity and versatility of a poorly explored scaffold: 2,4-dichlorofuro[3,4-d ]pyrimidin-7-one (3). Highly functionalized pyrimidines can be obtained with a divergent approach by reacting the key intermediate 3 with different amine nucleophiles under carefully controlled reaction conditions. The set-up of a microwave-Assisted one-pot, two-or three-step protocol to rapidly generate 2,4,5,6-Tetrasubstituted or fused pyrimidines is also reported.

Full text of DOI:10.1055/s-0039-1690205

SYNLETT
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1
4
1
4
3
7
-
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9
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
P. Vincetti et al.
Letter
Synlett
Probing the Reactivity of 2,4-Dichlorofuro[3,4-d]pyrimidin-7-one:
A Versatile and Underexploited Scaffold to Generate Substituted
or Fused Pyrimidine Derivatives
R1
Paolo Vincetti
NH
Gabriele Costantino
Maria Grazia Martina
Marco Radi*
CH2OR7
O
N
R1
N
R1
N
NH
R4
NH
N
N
R5
N
NHR6
N
R6
O
R4
N
N
Cl
O
R5
O
Dipartimento di Scienze degli Alimenti e del Farmaco,
Università degli Studi di Parma, Viale delle Scienze,
27/A, 43124 Parma, Italy
Cl
R1
N
R1
O
NH
NH
N
O
CH2OH
NR2R3
Marco.radi@unipr.it
HN
N
Cl
N
O
R4
R1
O
O
N
H
1
COOH
N
R5
N
3
N
N
In memory of Prof. Maurizio Botta, inspiring mentor,
friend, and strong believer in chemistry-based drug
discovery
H
2,4-dichlorofuro[3,4-d]
pyrimidin-7-one
O
O
Orotic Acid
R1
N
R1
N
NH
N
NH
N
CH2OH
R1
O
NH
N
R4
NHR1
N
Cl
CH2OH
NR2R3
N
O
R5
O
Cl
O
Received: 14.08.2019
Accepted after revision: 10.09.2019
Published online: 24.09.2019
highly functionalized new chemical entities (NCEs) rep-
resents an essential input to feed PDD campaigns that may
lead to new first-in-class medicines. To increase the chanc-
es of identifying promising drug candidates, PDD can be
coupled with privileged diversity-oriented synthesis
(pDOS), which explore the chemical space around privi-
leged (drug-like) scaffolds by increasing their molecular di-
versity.6 Among the many privileged scaffolds identified so
far, the pyrimidine skeleton exhibits a wide range of biolog-
ical activities depending on its decoration and is one of the
most frequent nitrogen heterocycles in FDA-approved mol-
ecules.7,8 Drugs containing a pyrimidine ring are in clinical
use for the treatment of allergic rhinitis (Thonzylamine), di-
abetes (Lobeglitazone), HIV (Rilpivirine), erectile dysfunc-
tion (Avanafil), toxoplasmosis and cystoisosporiasis (pyri-
methamine), inflammation (Epirizole), hypertension (Mon-
oxidine), cardiovascular diseases (Rosuvastatin) and so on
(Figure 1).9
A number of convergent strategies for the synthesis of
pyrimidine derivatives have been reported and are mainly
based on the construction of the functionalized pyrimidine
core by assembling separate fragments.10,11 Other conver-
gent approaches to substituted pyrimidines are based on
metal-catalyzed cross-coupling reactions of halogenated
pyrimidines (Suzuki, Stille, Negishi reactions)12 or direct C–
H functionalization of pyrimidine derivatives.13 As part of
our continuous efforts in the development of new proce-
dures for the synthesis of functionalized pyridines with po-
tential biological application,14–16 we describe herein the
exploration of the chemical reactivity of the 2,4-dichloro-
furo[3,4-d]pyrimidin-7-one scaffold as a versatile key inter-
DOI: 10.1055/s-0039-1690205; Art ID: st-2019-k0426-l
Abstract Herein, we describe the results of our investigation on the
chemical reactivity and versatility of a poorly explored scaffold: 2,4-di-
chlorofuro[3,4-d]pyrimidin-7-one (3). Highly functionalized pyrimidines
can be obtained with a divergent approach by reacting the key interme-
diate 3 with different amine nucleophiles under carefully controlled re-
action conditions. The set-up of a microwave-assisted one-pot, two- or
three-step protocol to rapidly generate 2,4,5,6-tetrasubstituted or
fused pyrimidines is also reported.
Key words orotic acid, pyrimidines, multicomponent reactions,
microwave
Today, despite decades of efforts in target-based drug-
discovery (TBDD), the time and costs required to develop a
new drug are longer and more expensive than ever.1 The
number of new first-in-class drugs brought to the market
after huge investments in hypothesis-driven TBDD is also
lower than expectations, with classical phenotypic drug-
discovery (PDD) approaches providing better performance
in the discovery of new drugs with innovative mechanism
of action.2,3 The ‘one-drug, one-target, one-disease’ para-
digm is therefore being questioned4 and a polypharmacolo-
gy view based on the ‘one-drug, multiple-targets’ concept
may better explain the success of PDD since: (1) candidates
are evaluated in a more reliable cellular context; (2) novel
targets or modes of action can be identified; and (3) candi-
dates may display an additive effect by interacting with
multiple targets (polypharmacology).5 In this scenario, the
availability of versatile chemical approaches to generate
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
P. Vincetti et al.
Letter
Synlett
selective antagonism for the P2X3 purinergic receptor. Only
one other paper on the synthesis and functionalization of
compound 3 was reported in the literature, by Britikova et
al. in 1966, although doubts on the published structures
were reported by the same authors.21 Fascinated by the po-
tential versatility of compound 3, we decided to investigate
its tricky chemical reactivity for the generation of substi-
tuted pyrimidine derivatives.
O
S
N
NH
O
O
HN
N
N
N
N
N
O
HN
N
Thonzylamine
N
Rilpivirine
N
This scaffold presents, in fact, three electrophilic sites
that are characterized by different reactivity: the C2 and C4
positions on the pyrimidine ring and the lactone fused with
the pyrimidine ring. According to the published literature,20
substitution on C4 with a nucleophilic amine should pro-
ceed smoothly at room temperature. Treatment of 3 with
two equivalents of aniline or benzylamine gave the C4 sub-
stituted derivatives 4 and 5 in high yields after stirring for
two hours at room temperature (Scheme 2). Running the
same reaction with a large excess of benzylamine (6 equiva-
lents) compound 6 was obtained instead, which resulted
from a preliminary substitution on C4 followed by opening
of the lactone with an excess of the amine.
N
O
O
O
Lobeglitazone
N
Cl
Cl
N
NH
O
H2N
N
NH2
N
N
HO
N
N
H
Pyrimethamine
N
N
Avanafil
OH OH OH
O
N
NH
O
N
O
N
NH
Cl
N
N
O
N
S
O
N
O
N
N
F
N
Ph
Rosuvastatin
Moxonidine
Epirizole
HN
Figure 1 Representative drugs based on substituted pyrimidine scaffolds
N
PhNH2 (2 equiv)
O
nBuOH
r.t., 2 h
88%
Cl
N
4
O
Bn
mediate for the divergent synthesis of highly substituted
pyrimidines.
HN
Cl
N
N
BnNH2 (2 equiv)
O
O
Looking for a suitable starting point for the synthesis of
biologically active pyrimidine derivatives, we focused our
attention on the naturally occurring 4-pyrimidinecarboxyl-
ic acid (orotic acid, OA, 1; Scheme 1). This is a well-known
precursor in the biosynthesis of pyrimidines, which are
commonly upregulated in neoplastic diseases and promot-
ed by different viruses to sustain their replication. Non-nat-
ural analogues of OA should therefore represent promising
NCEs in antiviral and anticancer research. Surprisingly, only
a few papers on the chemical functionalization of OA to de-
velop new derivatives with potential biological activity
have been published to date.17–19 Intrigued by the lack of in-
formation on the chemical reactivity of OA and its ana-
logues, we planned to use 1 as a starting point for the gen-
eration of highly functionalized pyrimidine derivatives. To
do so, 1 was initially converted into the key intermediate
2,4-dichlorofuro[3,4-d]pyrimidin-7-one (3) by following
the synthetic protocol reported by Cantin et al. (Scheme
1).20 These authors used 3 for the synthesis, in low yields, of
2,4-disubstituted pyrrolo-pyrimidinones characterized by
nBuOH
r.t., 2 h
92%
Cl
N
5
Cl
N
O
O
3
Bn
HN
CH2OH
H
N
BnNH2 (6 equiv)
N
nBuOH
r.t., 2 h
96%
Cl
N
6
Bn
O
Scheme 2 Nucleophilic substitution at C4
We then tried the C4 substitution with the less nucleo-
philic sulfanilamide (2 equivalents) but, at room tempera-
ture, no reaction occurred and no trace of the desired prod-
uct 7 was recovered from the reaction mixture (Scheme 3).
On the other hand, increasing the reaction temperature to
80 °C in the presence of triethylamine led to a complex mix-
ture containing the desired compound 7 together with the
side products 8 and 9 in a 4:2:1 ratio.
To obtain 7 with higher yields and reduce the formation
of side products 8 and 9, different reaction conditions were
attempted: changing temperature, solvent, reaction time,
base and heating mode (Table 1). The best reaction condi-
tions were those using conventional heating at 80 °C for 2
hours in n-BuOH as solvent, with portionwise addition of 3
(0.5 equiv + 0.5 equiv), sulfanilamide (0.25 equiv each time
up to 2 equiv) and Et3N (0.25 equiv each time up to 2 equiv).
Frequent TLC monitoring allowed the reaction to be
O
O
(CH2O)n
Cl
POCl3,DIPEA
HCl conc.
HN
HN
N
O
O
reflux, 6 h
95%
20 h, 95 °C
70%
O
N
H
COOH
O
N
H
Cl
N
O
O
1
3
2
Scheme 1 Synthesis of the key intermediate 3
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

C
P. Vincetti et al.
Letter
Synlett
Table 1 Optimizing C4 Substitution on 3 with the Less Nucleophilic
SO2NH2
Sulfanilamide (2 equiv)
4-SO2NH2-PhNH2
HN
(2 equiv)
SO2NH2
N
O
Cl
N
nBuOH, r.t., 2 h
Cl
Cl
N
SO2NH2
HN
O
7
O
N
N
O
O
N
HN
Cl
N
4-SO2NH2-PhNH2
(2 equiv)
O
Cl
Cl
N
3
N
O
O
3
O
7
7
nBuOH, Et3N
(28%)
nBu
O
N
8
(7%)
80 °C, 2 h
O
Solvent
Temp (°C) Time (min) Base
Heating mode
Yield (%)a
SO2NH2
DCM
rt
80
85
80
80
120
120
rt
120
3
DIPEA
conventional
W
5
11
18
10
15
16
25
15
22
14
16
30
50b
HN
n-BuOH
n-BuOH
n-BuOH
n-BuOH
n-BuOH
n-BuOH
n-BuOH
n-BuOH
n-BuOH
THF
DIPEA
H2NO2S
N
O
12
3
–
W
N
N
9
(17%)
H
O
–
W
5
–
W
Scheme 3 Nucleophilic substitution at C4 with a poorly nucleophilic
9
–
W
amine
90
–
conventional
conventional
conventional
conventional
conventional
conventional
conventional
4 days
2 days
240
2 days
120
120
–
stopped as soon as starting material 3 was completely con-
sumed (2 h). The desired compound 7 was thus obtained in
an acceptable 50% yield and used as a starting point to set
up the C2 nucleophilic substitution. As we previously not-
ed, reaction of compound 3 with a large excess of primary
amine (6 equiv of benzylamine) led to the opening of the
lactone ring after C4 substitution, both at room tempera-
ture (see compound 6) and at high temperature (data not
shown). A nucleophilic substitution in C2 with benzyl-
amine did not occur under these reaction conditions. For
this reason we tried to accomplish the C2 substitution on 7
with the more nucleophilic morpholine: running the reac-
tion at room temperature only the lactone opening product
10 was obtained, whereas heating at 80 °C (or at 120 °C un-
der microwaves), a 1:1 mixture of 10 and the desired C2
substituted derivative 11 was obtained (Scheme 4).
rt–40
–
50
–
rt–40
80
–
n-BuOH
n-BuOH
a Isolated yield.
Et3N
Et3N
80
b Portionwise addition of 3, solfanilamide and Et3N.
These data suggested that C2 substitution on compound
7 occur under thermodynamic control whereas lactone
opening can be conducted under kinetic control. In fact,
dropwise addition of morpholine to a pre-heated solution
of 7 (at 110 °C), allowed the desired thermodynamic com-
pound 11 to be obtained in 98% yield. Compound 11 was
then used to investigate the reactivity of the lactone ring to-
wards a third amine nucleophile. Reacting 11 with benzyl-
amine (6 equiv) at room temperature never afforded the
open lactone derivative 12, whereas refluxing a pentanol
suspension of 11 in the presence of benzylamine (2.5 equiv)
and stoichiometric TFA gave the unexpected compound 13
in 43% yield (Scheme 5). The latter compound was the re-
sult of a tandem reaction in which TFA catalyzed first the
opening of the lactone by benzylamine and then the ether
formation with the high-boiling solvent. On the other hand,
when the same reaction was conducted in a sealed micro-
wave tube at 170 °C, compound 11 was converted into the
corresponding lactam 14 after 10 minutes in 53% yield.
Overall, it was clear that the reactivity of the lactone ring
depends on the reaction temperature, heating mode and
functionalization of the fused pyrimidine heterocycle: the
2,4-dichlorofuro[3,4-d]pyrimidin-7-one 3 and the 4-amino-
2-chlorofuro[3,4-d]pyrimidin-7(5H)-one derivatives (e.g., 5
and 7) react with primary and secondary amines at room
temperature (Scheme 2 and Scheme 4), whereas the 2,4-di-
SO2NH2
HN
CH2OH
morpholine (1 equiv)
N
O
nBuOH, r.t., 2 h
Cl
N
10
SO2NH2
75%
N
O
SO2NH2
HN
morpholine (1 equiv)
HN
N
nBuOH
O
10
+
N
80 °C, 2 h
or
(38%)
O
Cl
N
O
N
N
7
μW, 120 °C, 10 min
O
O
11
(40%)
a) nBuOH, 110 °C
11
b) morpholine (1 equiv)
110 °C, 2 h
98%
Scheme 4 Nucleophilic substitution in C2
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

D
P. Vincetti et al.
Letter
Synlett
amino-substituted furo[3,4-d]pyrimidin-7(5H)-one 11 may
react with a primary amine only at high temperatures, with
or without microwave irradiation (Scheme 5).
(3 equiv) was then added and the mixture was irradiated at
100 °C for 10 minutes, then TFA was added and the reaction
was heated at 170 °C for 10 minutes. Compound 14 was
thus obtained after 45 minutes in 23% yield (over three
steps), which is higher than that previously obtained in a
standard multistep protocol for similar compounds.20 In ad-
dition, the same one-pot protocol can be stopped after the
C2 substitution with morpholine to isolate the 2,4,5,6-tet-
rasubstituted pyrimidine 12 in 52% yield after a one-pot,
two-step sequence. The latter compound, suspended in
pentanol, can also be quantitatively converted into the cor-
responding pentyl ether 13 by acid-catalyzed etherification
under microwave irradiation at 100 °C for 10 minutes.
While high-boiling pentanol was initially used to allow the
lactone opening in compound 11 under conventional heat-
ing, a different solvent could also be used in the one-pot,
two- or three-step protocol.
The same reaction sequence reported in Scheme 6 was
thus conducted in dimethoxyethane (DME), which reached
the required high temperatures by using a sealed micro-
wave tube. Compounds 12 and 14 were thus obtained in yields
comparable to those previously obtained with pentanol.
In summary, we have reported a thorough investigation
on the chemical reactivity and versatility of the 2,4-dichlo-
rofuro[3,4-d]pyrimidin-7-one scaffold 3. This key interme-
diate, easily prepared from commercially available orotic
acid, provides access to highly functionalized pyrimidine
derivatives by reaction with amine nucleophiles under
carefully controlled reaction conditions. In addition, a 4-
amino substituted derivative of 3 (compound 7) has been
used as starting point to set up a microwave-assisted one-
pot, two- or three-step protocol that allows 2,4,5,6-tetra-
substituted or fused pyrimidines to be quickly generat-
ed.23,24 The know-how developed with this work has re-
cently been exploited for the generation of broad-spectrum
antiviral molecules.22 Further investigation on the versatili-
ty of the 2,4-dichlorofuro[3,4-d]pyrimidin-7-one scaffold
are ongoing and will be published in due course.
SO2NH2
HN
PhNH2 (6 equiv)
CH2OH
N
H
N
nBuOH
r.t., 24 h
N
N
N
N
12
Bn
SO2NH2
O
O
O
O
SO2NH2
HN
BnNH2 (2.5 equiv)
TFA
HN
N
O
CH2O(CH2)4CH3
n-pentanol
12 h, reflux
43%
N
N
N
H
N
O
O
11
N
13
Bn
O
SO2NH2
BnNH2 (2.5 equiv)
TFA
HN
n-pentanol
μW, 10 min, 170 °C
N
N
Bn
53%
N
O
14
Scheme 5 Reaction of the fused-lactone 11 with a nucleophilic amine
Based on the collected information on the reactivity of
the 2,4-dichlorofuro[3,4-d]pyrimidin-7-one scaffold and its
derivatives towards amine nucleophiles, we decided to de-
velop a microwave-assisted one-pot multistep approach
that may be used to quickly generate highly functionalized
pyrimidine derivatives. The 4-substituted 2-chlorofuro[3,4-
d]pyrimidin-7(5H)-one derivative 7 was considered as the
preferred starting point for the following reaction se-
quence: (1) opening of the lactone ring with a primary
amine at 80 °C; (2) C2 substitution with a secondary amine;
(3) TFA promoted condensation to generate the pyrrolo[3,4-
d]pyrimidin-7-one core. After a number of test reactions,
the optimized conditions for the one-pot, three-step proto-
col are those reported in Scheme 6. In a microwave tube, in-
termediate 7 and benzylamine (5 equiv) were suspended in
n-pentanol and heated at 80 °C for 15 minutes, morpholine
SO2NH2
SO2NH2
SO2NH2
SO2NH2
BnNH2 (5 equiv)
n-pentanol
or DME
morpholine (3 equiv)
n-pentanol
TFA
n-pentanol
or DME
HN
HN
HN
HN
CH2OH
CH2OH
or DME
N
N
N
N
O
N
Bn
μW, 80 °C
15 min
μW, 100 °C
μW, 170 °C
10 min
23%
(over 3 steps)
O
O
Cl
N
Cl
N
N
N
N
N
10 min
O
O
NHBn
NHBn
O
O
7
52%
12
14
15
(over 2 steps)
SO2NH2
HN
TFA
n-pentanol
CH2O(CH2)4CH3
N
H
μW, 100 °C, 10 min
N
N
N
Bn
98%
O
O
13
Scheme 6 One-pot multistep protocol
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

E
P. Vincetti et al.
Letter
Synlett
Funding Information
(21) Britikova, N. E.; Chkhikvadze, K. A.; Magidson, O. Y. Khim. Get-
erotsikl. Soedin. 1966, 5, 783.
Work in MR laboratory was supported by the University of Parma
(Università degli Studi di Parma; FIL 2016) and by the Ministero
dell'Istruzione, dell'Università della Ricerca Italiano (MIUR), PRIN
2017 project ‘ORIGINALE CHEMIAE in Antiviral Strategy - Origin and
Modernization of Multi-Component Chemistry as a Source of Innova-
(22) Vincetti, P.; Kaptein, S. J. F.; Costantino, G.; Neyts, J.; Radi, M.
ACS Med. Chem. Lett. 2019, 10, 558. Published during the prepa-
ration of the present manuscript.
(23) General Procedure for the One-Pot, Two-Step Synthesis of N-
Benzyl-5-(hydroxymethyl)-2-morpholino-6-[(4-sulfamoyl-
phenyl)amino]pyrimidine-4-carboxamide (12)
tive Broad Spectrum Antiviral Strategy’, cod. 2017BMK8JR_002.
U
n
i
v
ersità
d
e
g
l
iStu
d
idiParm
a
(F
I
L
2
0
1
6)M
i
n
i
stero
d
el'
I
stru
z
i
o
n
e
,
d
e
l
l'
U
n
i
v
ersità
e
d
el
a
R
i
c
erc
a
(2
0
1
7
B
M
K
8
J
R
_
0
0
2)
In a microwave tube, intermediate 7 (100 mg, 0.36 mmol) and
benzylamine (198 L, 1.80 mmol) were suspended in 2 mL of n-
pentanol (or DME) and heated at 80 °C for 15 minutes (max W
power input: 250 W; ramp time: 1 minute; reaction time: 15
minutes; power max: off; maximum pressure: 250 psi). At the
end of the irradiation, morpholine (93.1 L, 1.08 mmol) was
added and the reaction was submitted to a second irradiation
cycle at 100 °C for 10 minutes (max W power input: 250 W;
ramp time: 1 minute; reaction time: 10 minutes; power max:
off; maximum pressure: 250 psi). At the end of irradiation the
reaction mixture was evaporated under vacuum and the crude
material was purified by flash chromatography (CHCl3/i-PrOH,
98:2) to obtain 12 in 55% yield. MS (ESI): m/z = 497.5 [M – H]–.
1H NMR (400 MHz, DMSO-d6):  = 3.70 (m, 8 H), 4.46 (d, J =
8 Hz, 2 H), 4.83 (s, 2 H), 5.39 (br s, 1 H), 7.24 (br s, 3 H), 7.34 (s,
4 H), 7.80 (m, 4 H), 9.09 (m, 1 H), 9.17 (s, 1 H). 13C NMR (DMSO-
d6, 100 MHz):  = 42.64, 44.63, 55.33, 66.52, 107.19, 120.40,
127.02, 127.23, 127.56, 128.77, 137.78, 139.82, 143.00, 156.89,
159.66, 160.89, 166.45.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690205.
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References and Notes
(1) Pretorius, S. Drug Discovery Today 2018, 23, 1319.
(2) Swinney, D. C. Clin. Pharmacol. Ther. 2013, 93, 299.
(3) Zheng, W.; Thorne, N.; McKew, J. C. Drug Discovery Today 2013,
18, 1067.
(4) Hopkins, A. L. Nat. Chem. Biol. 2008, 4, 682.
(5) Csermely, P.; Agoston, V.; Pongor, S. Trends Pharmacol. Sci.
2005, 26, 178.
(6) Kim, J.; Kim, H.; Park, S. B. J. Am. Chem. Soc. 2014, 136, 14629.
(7) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57,
10257.
(24) General Procedure for the One-Pot, Three-Step Synthesis of
4-[(6-Benzyl-2-morpholino-7-oxo-6,7-dihydro-5H-pyr-
rolo[3,4-d]pyrimidin-4-yl)amino]benzenesulfonamide (14)
In a microwave tube, intermediate 7 (100 mg, 0.36 mmol) and
benzylamine (198 L, 1.80 mmol) were suspended in 2 mL of n-
pentanol (or DME) and heated at 80 °C for 15 minutes (max W
power input: 250 W; ramp time: 1 minute; reaction time: 15
minutes; power max: off; maximum pressure: 250 psi). At the
end of the irradiation, morpholine (93.1 L, 1.08 mmol) was
added and the reaction was submitted to a second irradiation
cycle at 100 °C for 10 minutes (max W power input: 250 W;
ramp time: 1 minute; reaction time: 10 minutes; power max:
off; maximum pressure: 250 psi). TFA (13.78 L, 0.18 mmol)
was then added and the reaction was heated in the microwave
at 170 °C for 10 minutes (max W power input: 300 W; ramp
time: 1 minute; reaction time: 10 minutes; power max: off;
maximum pressure: 250 psi). The resulting mixture was evapo-
rated under vacuum and the crude material was purified by
flash chromatography using DCM/EtOH abs/HCOOH 80% aq
(9.4:03:03) to give 14 in 23% yield. MS (ESI): m/z = 479.1 [M –
H]–. 1H NMR (400 MHz, DMSO-d6):  = 3.7 (m, 8 H), 4.42 (s, 2 H),
4.74 (s, 2 H), 7.34 (m, 5 H), 7.21 (s, 2 H), 7.77 (dd, J = 8.76 Hz,
2 H), 7.86 (dd, J = 8.76 Hz, 2 H), 9.48 (s, 1 H). 13C NMR (DMSO-d6,
100 MHz):  = 44.99, 46.08, 46.27, 66.47, 109.65, 120.15,
127.02, 128.01, 128.28, 129.26, 137.58, 137.87, 142.95, 155.96,
158.23, 162.91, 166.14.
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