Efficient and library-friendly synthesis of furo- and thieno[2,3-d] pyrimidin-4-amine derivatives by microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2009.11.071

A new, divergent, efficient, and selective synthesis of furo- and thieno[2,3-d]pyrimidin-4-amine derivatives by microwave irradiation has been developed starting from readily available amines and substituted 2-aminofuran-3-carbonitrile or 2-aminothiophene-3-carbonitrile, which are converted into corresponding formamidines in DMF using benzenesulfonyl chloride.

Full text of DOI:10.1016/j.tetlet.2009.11.071

Tetrahedron Letters 51 (2010) 629–632
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Tetrahedron Letters
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Efficient and library-friendly synthesis of furo- and thieno[2,3-d]
pyrimidin-4-amine derivatives by microwave irradiation
a
b
a
b
Ying Han a, , Katalin Ebinger , Lauren E. Vandevier , Jennifer W. Maloney , David S. Nirschl ,
*
Harold N. Weller b
a Bristol-Myers Squibb Company R&D, 5 Research Parkway, Wallingford, CT 06492, United States
b Bristol-Myers Squibb Company R&D, Route 206 and Provinceline Road, Princeton, NJ 08543, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A new, divergent, efficient, and selective synthesis of furo- and thieno[2,3-d]pyrimidin-4-amine deriva-
tives by microwave irradiation has been developed starting from readily available amines and substituted
2-aminofuran-3-carbonitrile or 2-aminothiophene-3-carbonitrile, which are converted into correspond-
ing formamidines in DMF using benzenesulfonyl chloride.
Received 8 September 2009
Revised 16 November 2009
Accepted 17 November 2009
Available online 20 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Furo- and thieno[2,3-d]pyrimidin-4-amine derivatives have
been the focus of great interest because of their remarkable biolog-
ical properties in drug discovery (e.g., VEGFR2, GSK-3, DHFR, and
TS).1–14 In our efforts to pursue hit to lead and lead optimization,
we have focused on developing expedient parallel synthetic meth-
ods for a straightforward library synthesis route to furo-, thieno-,
and pyrrolo[2,3-d]pyrimidin-4-amine derivatives.
The traditional preparation of furo- and thieno[2,3-d]-pyrimi-
din-4-amine derivatives 4 involves the reaction of aminofurans
or aminothiophenes 5 (Scheme 1) with in situ-generated acetic for-
mic anhydride, which provides the N-formyl derivatives 6.10–15
Thermal cyclization, chlorination with phosphorus oxychloride,
and finally displacement with an amine provide the target com-
pounds. Overall, this four-step synthetic route is fairly labor inten-
sive, requires several intermediate purifications, as well as a
relatively high temperature reaction. In our view, access to the tar-
get compounds would require an alternate synthetic route to be
effectively accessed via library synthesis.
R1
O
N
R1
CN
R1
CN
NHCHO
220 oC
10min
HCO2COMe
85 o
NH2
NH
R2
C
R2
R2
X
X
X
5
6
7
X = O, S
Cl
N
R1
NHR
R1
RNH2,MeOH
Heat
POCl3
N
N
N
R2
R2
X
X
4
8
Scheme 1. Multi-step synthesis of compound 4.
R3HN
R1
N
CN
N
NMe2
CH3CN/HOAc
N
R1
R3NH2
+
uW,160 oC
10min
R2
R2
9
2
69-97% 10
Recently, a new methodology for the preparation of 4-amino-
quinazolines 10 has been reported in high yields from reactions
of amines 2 and the corresponding N0-(2-cyano-phenyl)-N,N-dim-
ethylformamidine 9 via microwave irradiation (Scheme 2).16 The
procedure is very efficient and straightforward, providing both ring
cyclization and incorporation of an anilino group at position 4 in a
single step. We envisioned that this process could be extended to
synthesize furo- and thieno [2.3-d]pyrimidin-4-amine derivatives
4 effectively.
Scheme 2. Synthesis of 4-aminoquinazoline derivatives.16
NH
p-MeO-C6H4
N
p-MeO-C6 H4
O
N
N
p-MeOC6 H4
p-MeOC6H4
3a
NH2
In an initial study (Scheme 3), we exposed formamidine 1a to
benzyl amine 2a under the same conditions described previously
(microwave, 160 °C, CH3CN/HOAc = 1:3, 10 min).16 Rather than iso-
+
O
NMe2
N
HN
p-MeO-C6H4
p-MeO-C6H4
lating
only
the
expected
N-benzyl-5,6-bis(4-methoxy-
N
1a
2a
O
N
* Corresponding author. Tel.: +1 203 677 3694; fax: +1 203 677 6900.
E-mail address: ying.han@bms.com (Y. Han).
4a
Scheme 3. Synthesis of compounds 3a and 4a.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.071

630
Y. Han et al. / Tetrahedron Letters 51 (2010) 629–632
Table 1
phenyl)furo[2,3-d]pyrimidin-4-amine 4a, we observed a signifi-
cant amount of the imine 3a, presumably a kinetic product—
known as Dimroth reaction.17 Also, there were some unidentified
impurities detected by LC–MS. Then we tested the same reaction
in acetic acid only and found that the reaction was much cleaner.
However, it still produced both 3a and 4a as a mixture.
By using acetic acid only, we were able to significantly alter the
product ratios simply by altering the reaction temperature as
shown in Table 1.
Optimization of reaction condition—the ratio of 3a and 4a affected by temperaturea
Entry
Temperature (°C)
Conversion of 1a
Ratio
Yield
to productsb (%)
(3a/4a)c
(3a or 4a)d
1
2
3
4
5
100
110
140
160
180
53
78
100
100
100
>99:1
>99:1
61/39
33/67
<1:99
45% (3a)
69% (3a)
n/a
n/a
88% (4a)
a
Reaction conditions: 1a (1.0 equiv), 2a (1.5 equiv), HOAc (0.8 mL) microwave
Further studies focused on the effects of reaction time and stoi-
chiometric ratios of 1a and 2a, the results of which are summarized
in Table 2. As the number of equivalents of 2a was increased from
1.0 to 3.0 in 25-min runs, the ratio of 3a/4a decreased from 9/91 to
0/100 (entries 1, 2, 4, and 5). Heating the same reaction for addi-
tional 10 min (35 min in total) showed a decrease in the ratio of
3a/4a from 9/91 to 2/98 (entry 1) and 3/97 to <1/99 (entry 2). Fur-
thermore, the reaction concentration was also important. As
shown in entries 2 and 3, the ratio of 3a/4a increased from 3/97
to 11/89, when the concentration was decreased from 0.2 mmol/
0.8 mL to 0.2 mmol/1.2 mL in 25-min runs.
To prepare thieno[2,3-d]pyrimidin-4-amine derivatives, we
next investigated the reaction of compound 1c with compound
2d (Scheme 4) applying our results from the studies of furo [2,3-
d]pyrimidin-4-amine derivative. Not surprising, the regioselectivi-
ty was controlled by temperature. As demonstrated in Table 3,
temperatures below or at 90 °C led to the formation of imine 3q
only, with significant unreacted starting material 1c, while at
180 °C amine 4q was the only product. Between 120 °C and
160 °C, a mixture of compounds 3q and 4q was formed, with an
increasing amount of 4q as the temperature was increased. Com-
pound 3q was transformed to compound 4q under microwaving
at 180 °C for 10 min.
Interestingly, when pyrrole 1d reacted with 2d at 90–140 °C for
35 min by microwave irradiation, 3s (86% isolated yield) was the
only product (Scheme 5). Unlike 1a and 1c, microwave heating of
1d and 2d at 180 °C and 210 °C gave 3s as the major product.
The microwave conditions depicted in Schemes 3–5 and Tables
1–3 were used to identify the preferred reaction conditions for the
synthesis of structurally diverse furo- and thieno [2,3-d] pyrimi-
din-4-amine derivatives: 180 °C, 1 equiv of formamidine, and
1.5 equiv of amine in HOAc (0.8 mL) for 35 min. Optimum condi-
tions were similarly identified for the preparation of furo-, thie-
no-, and pyrrolo[2,3-d]pyrimidin-4-imine derivatives: below
110 °C or at 140 °C, 1 equiv of formamidine and 1.5 equiv of amine,
and 25–35 min. Table 4 summarizes library synthesis of a variety
of compounds by these conditions. Benzylamines (2a, 2b, 2e, 2f,
and 2g), an aliphatic amine (2d), and an electron-rich aniline (2c)
were effective nucleophiles and offered good yields of desired
products.18,19
irradiation at the power of 25–40 W at target temperature for 35 min.
b
Determined by HPLC.
c
Determined by HPLC.
Isolated yields and characterized by 1H NMR, 13C NMR, LC–MS, and HRMS.
d
Table 2
Optimization of reaction condition—the ratio of 3a and 4a affected by concentration,
equivalence of amine, and reaction timesa
Entry
Eqs. of amine (2a) (equiv)
HOAc (mL)
Ratio (3a/4a)b
1
2
3
4
5
1
0.8
0.8
1.2
0.8
0.8
9/91 (2/98)c
1.5
1.5
2.0
3.0
3/97 (<1/99)c
11/89 (<1/99)c
1/99 (<1/99)c
0/100 (0/100)c
a
b
c
All reactions were run at 180 °C for 25 min.
Determined by HPLC.
The data in parentheses are from additional 10-min runs to the same sample.
NH
oC
S
90
O
N
N
N
NH2
25min.
3q
HOAc
uW
180 oC
10min.
+
S
N
NMe2
O
180 oC
35min.
H
N
O
S
1c
2d
N
4q
N
Scheme 4. Synthesis of thieno[2,3-d]pyrimidin-4-amine derivatives (3q and 4q).
Table 3
Optimization of reaction condition—the ratio of 3q and 4q affected by temperature
Entry Temperature
Conversion of 1c to
Ratio (3q/
4q)b
Yieldc
(°C)
productsa (%)
1
2
70
90
46d
59e
>99/1
>99/1
n/a
47%
(3q)
n/a
n/a
n/a
3
4
5
6
120
140
160
180
100
100
100
100
35/65
17/83
2/98
<1:99
87%
(4q)
a,b
Determined by HPLC.
The proposed reaction mechanism via Dimroth rearrangement
is shown in Scheme 6. First, the nitrogen of amine 2 attacked the
carbon of formamidine to give species 11. Then the intramolecular
c
Isolated yields characterized by 1H NMR, 13C NMR, LC–MS, and HRMS.
54% of 1c remained.
d
e
41% of 1c remained.
O
O
HN
N
Me
N
NH
Me
N
Me
Me
Cl
Me
Cl
N
N
N
Me
HOAc
N
Cl
+
N
O
N
H2N
+
NMe2
uW
35min.
Cl
Cl
major
minor
Cl
1d
2d
3s
4s
90-140 o
,
3s:4s
3s:4s
3s:4s
C
> 99:1
= 96:4
= 82:18
180 o
210 o
C
C
,
,
Scheme 5. Selective synthesis of 3H-pyrrolo[2,3-d]pyrimidin-4(7H)-imine derivative (3s).

Y. Han et al. / Tetrahedron Letters 51 (2010) 629–632
631
Table 4
reaction of 11 and ring closing took place to form species 12 fol-
lowed by eliminating HNMe2, to yield product 3 (imino-product
3 is a kinetic product). Second, water as a nucleophile attacked
the pyrimidine ring, and opened the ring to afford a ring-opened
species 13, which could undergo a 180° turn to its tautomeric form
14. Third, a subsequent electrocyclization to 15 and elimination of
water yielded the thermodynamic stable product 4 (favored at high
temperature). Even when pyrrole 1d was used as starting material
this tendency was also observed (Scheme 5).
For comparison, entry 5 in Table 1 was conducted using an oil
bath under otherwise identical conditions (concentration, reaction
vessel, and temperature). After capping tightly, the microwave vial
was immersed in an oil bath at 180 °C for 35 min. The reaction was
then cooled to room temperature. LC–MS analysis gave the ratio of
20/80 of 3a/4a in 100% conversion versus <1/99 in 100% conversion
with microwave conditions. It is demonstrated that microwave
irradiation conditions are superior.
In summary, we have developed library friendly and highly
selective methods for the synthesis of furo- and thieno [2,3-d] pyr-
imidin-4-amine derivatives. Also, we provided a method for the
preparation of furo-, thieno-, and pyrrolo-[2,3-d]pyrimidin-4-
imine derivatives. The advantages of our methods are: (1) a short
synthetic route; (2) a high selectivity for amine and imine deriva-
tives by simply changing the reaction temperature; and (3) a pro-
tocol suitable for library synthesis. Further studies and applications
of this new methodology will be reported in due course.
Synthesis of substituted furo, thieno[2,3-d] pyrimidin-4-amines, and substituted 3H-
pyrrolo[2,3-d]pyrimidin-4(7H)-imine derivatives by microwave irradiationa
R3
HN
R2
NH
R2
X
R2
X
N
N
R3
+
HOAc
uW
R1
+
H2N
N
R1
R1
R3
X
N
NMe2
N
N
3
4
1a-d
2
Me
N
N
N
N
N
N
Me
Cl
p-MeOC6 H4
p-MeOC6H4
N
NMe2
N
N
NMe2
NMe2
S
C6 H5
NMe2
O
O
Cl
1d
1a
1b
1c
Entry
1
2
Product (yield)b
1
2
1a
4a (88%)
3a (69%)c
1a
1a
2a
3
4b (87%)
4
5
1a
1a
4c (53%)
4d (91%)
6
1a
4e (62%)
7
8
9
1b
1b
1b
1b
2a
2b
2c
2e
4f (72%)
4g (60%)
4h (51%)
4i (80%)
10
Acknowledgments
11
1b
4j (68%)
12
13
14
1c
1c
1c
2b
2f
2e
4k (86%)
4l (68%)
4m (77%)
We thank Drs. Louis Chupak and Tao Wang for discussion of this
chemistry.
References and notes
15
1c
4n (81%)
16
17
18
19
1d
1d
1d
1d
2a
2b
2c
2f
3t (79%)d
3u (81%)d
3v (69%)d
3w (54%)d
1. Modica, M.; Romeo, G.; Materia, L.; Russo, F.; Cagnotto, A.; Mennini, T.; Gaspar,
R.; Falkay, G.; Fulopd, F. Bioorg. Med. Chem. 2004, 12, 3891–3901.
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2005, 15, 2203–2207.
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L.; Buckner, W. H.; Cheng, A.; Faust, T.; Hsieh, F.; Huang, X.; Lee, J. H.; Marshall,
T. L.; Martin, M. W.; McGowan, D. C.; Schneider, S.; Turci, S. M.; Whitea, R.; Zhu,
X. Bioorg. Med. Chem. Lett. 2007, 17, 2305–2309.
a
Reaction conditions: 0.2 mmol of formamidine, 0.3 mmol of amine in HOAc
(0.8 mL) at 180 °C for 35 min with Biotage Initiator, and 1a–d were prepared from
the corresponding 2-amino-3-carbonitrile starting materials in DMF in the presence
of benzenesulfonyl chloride.
Isolated yields and all products were characterized by 1H NMR, 13C NMR, HPLC,
b
and HRMS.
c
Reaction was run at 110 °C.
Reactions were run at 140 °C.
5. Maeda, Y.; Nakano, M.; Sato, H.; Miyazaki, Y.; Schweiker, S. L.; Smith, J. L.;
Truesdale, A. T. Bioorg. Med. Chem. Lett. 2004, 14, 3907–3911.
6. Aleem Gangjee, A.; Zeng, Y.; McGuire, J. J.; Kisliuk, R. L. J. Med. Chem. 2005, 48,
5329–5336.
d
7. Gangjee, A.; Zeng, Y.; Lind, M. I.; Warnke, A.; Green, D. W.; Kisliuk, R. L.; Lin, F.
Bioorg. Med. Chem. 2005, 13, 5475–5491.
8. Yasushi Miyazaki, Y.; Tang, J.; Maeda, Y.; Nakano, M.; Wang, L.; Nolte, R. T.;
Sato, H.; Sugai, M.; Okamoto, Y.; Truesdale, A. T.; Hassler, D. F.; Nartey, E. N.;
Patrick, D. R.; Hoc, M. L.; Ozawa, K. Bioorg. Med. Chem. Lett. 2007, 17, 1773–
1778.
9. Miyazaki, Y.; Maeda, Y.; Sato, H.; Nakano, M.; Mellor, G. W. Bioorg. Med. Chem.
Lett. 2008, 18, 1967–1971.
10. Gangjee, A.; Yang, J.; McGuire, J. J.; Kisliuk, R. L. Bioorg. Med. Chem. 2006, 14,
8590–8598.
11. Wan, Z.; Wacharasindhu, S.; Levins, C. G.; Lin, M.; Tabei, K.; Mansour, T. S. J. Org.
Chem. 2007, 72, 10194–10210.
N
R1
N
R1
NHR3
HOAc
+
NH2R3
R2
N
H
NMe2
X
R2
N
X
2
11
1
NMe2
R3
NH
R1
NH
R1
NR3
N
-NHMe2 R2
R
2
X
N
H
NMe2
R3
X
N
3
12. Manisha, S.; Phoujdar, M. S.; Kathiravan, M. K.; Bariwal, J. B.; Shah, A. K.; Jain, K.
S. Tetrahedron Lett. 2008, 49, 1269–1273.
12
H2O
N
13. Joseph, T.; Kim, J. T.; Hamilton, A. D.; Bailey, C. M.; Domoal, R. A.; Wang, L.;
Anderson, K. S.; Jorgensen, W. L. J. Am. Chem. Soc. 2006, 128, 15372–15373.
14. Foloppe, N.; Fisher, L. M.; Howes, P.; Kierstan, P.; Potter, A.; Alan, G. S.;
Robertson, A. G. S.; Surgenor, A. E. J. Am. Chem. Soc. 2006, 128, 15372–15373.
15. Foloppe, N.; Fisher, L. M.; Howes, P.; Kierstan, P.; Potter, A.; Alan, G. S.;
Robertson, A. G. S.; Surgenor, A. E. J. Med. Chem. 2005, 48, 4332–4345.
16. Yoon, D. S.; Han, Y.; Stark, T. M.; Haber, J. C.; Gregg, B. T.; Stankovich, S. B. Org.
Lett. 2004, 6, 4775–4778.
17. (a) Dimroth, O. Ann. 1909, 183; (b) Kanth, S. R.; Reddy, G. V.; Kishore, K. H.; Rao,
P. S.; Narsaiah, B.; Murthy, U. S. N. Eur. J. Med. Chem. 2006, 41, 1011–1016.
18. Typical procedure for the preparation of 1a–d: (E)-N0-(3-cyano-4,5-bis(4-
methoxyphenyl)furan-2-yl)-N,N-dimethylformamidine 1a: To a 100 mL flask
R1
NH2
R
1
NH2
R3
O
R1
N
R1
X
N
H
O
X
N
H
14
13
R3
N
HN
R3
R1
HN
N
R1
-H 2O
R1
N
R1
X
N
H 15
OH
X
4
equipped with
a magnetic stir bar were added DMF (20 mL) and
Scheme 6. Proposed mechanism of the Dimroth rearrangement to 3 and 4.

632
Y. Han et al. / Tetrahedron Letters 51 (2010) 629–632
benzenesulfonyl chloride (2.1 g, 12 mmol). The solution was stirred for 20 min
yield): The procedure for the preparation of 3a is similar to that for 4a while
the reaction temperature was 110 °C. Compound 3a was obtained as a solid. 1H
NMR (500 MHz, DMSO-d6) d ppm 8.33 (s, 1H), 7.23–7.47 (m, 9H), 7.09 (d,
J = 8.55 Hz, 2H), 6.90 (d, J = 8.85 Hz, 2H), 5.17 (s, 2H), 3.83 (s, 3H), 3.74 (s, 3H).
13C NMR (126 MHz, DMSO-d6) d ppm 171.79, 159.30, 159.11, 157.96, 154.05,
149.33, 145.63, 137.02, 130.84, 128.32, 127.60, 127.28, 126.84, 123.10, 121.77,
116.59, 114.76, 114.23, 105.29, 55.14, 48.72, 20.93. HRMS calcd for
C27H23N3O3: 437.1739, found 437.1720.
and the color of the solution turned to light yellow. Then 2-amino-4,5-bis(4-
methoxyphenyl)furan-3-carbonitrile (2 g, 6.2 mmol) was added as solid and
the mixture was stirred for 30 min at room temperature. A solid was formed
and diethyl ether (70 mL) was added. After filtration, the solid was neutralized
with 2 N NaOH, extracted with ethyl acetate, washed with water and brine,
and dried with Na2SO4. After removal of the solvents, the pure product was
obtained as a colorless solid, 2.2 g, 94% yield. 1H NMR (500 MHz, DMSO-d6) d
ppm 3.05 (s, 3H), 3.18 (s, 3H), 3.74 (s, 3H), 3.81 (s, 3H), 6.88 (d, J = 8.55 Hz, 2H),
7.03 (d, J = 8.55 Hz, 2H), 7.31 (d, J = 8.55 Hz, 2H), 7.34 (d, J = 8.85 Hz, 2H), 8.45
(s, 1H); 13C NMR (126 MHz, DMSO-d6) d ppm 34.27, 55.08,80.55, 114.01,
114.37, 115.57, 119.84, 122.12, 123.16, 126.47, 130.05, 139.83, 155.05, 158.53,
158.98, 162.94; HRMS calcd for C22H21N3O3: 375.1583, found 375.1571.
N-(2-Methoxyethyl)thieno[2,3-d]pyrimidin-4-amine (4q, 87% yield): 1H NMR
(500 MHz, DMSO-d6) d ppm 3.32 (s, 1H), 3.54 (t, J = 5.65 Hz, 2H), 3.67 (q,
J = 5.60 Hz, 2H), 7.55 (d, J = 6.10 Hz, 1H), 7.64 (d, J = 5.80 Hz, 1H), 8.06 (t,
J = 5.04 Hz, 1H), 8.34 (s, 1H); 13C NMR (126 MHz, DMSO-d6) d ppm 40.14, 57.91,
70.27, 116.08, 119.31, 122.4, 153.59, 156.92, 165.47; HRMS calcd for
C9H11N3OS: 209.0623, found 209.0616.
19. Typical procedure for the preparation of 4: N-benzyl-5,6-bis(4-methoxyphenyl)
furo-[2,3-d]pyrimidin-4-amine 4a: To 0.5–2 mL Biotage microwave vial
equipped with magnetic stir bar were added acetic acid (0.8 mL),
a
3-(2-Methoxyethyl)thieno[2,3-d]-pyrimidin-4(3H)-imine 3q (47% yield): The
preparation of 3q was similar to that of 4q while the reaction temperature
was 90 °C, 25 min. 1H NMR (500 MHz, DMSO-d6) d ppm 3.26 (s, 4H), 3.61 (t,
J = 5.04 Hz, 3H), 4.14 (t, J = 5.04 Hz, 2H) 7.42 (d, J = 5.80 Hz, 1H), 7.60 (d,
J = 5.80 Hz, 1H), 7.92 (s, 1H); 13C NMR (126 MHz, DMSO-d6) d ppm 46.00, 58.04,
68.22, 122.18, 122.53, 148.41, 152.24, 157.37, 171.89; HRMS calcd for
C9H11N3OS: 209.0623, found 209.0621.
7-(2,6-Dichlorobenzyl)-3-(2-methoxyethyl)-5,6-dimethyl-3H-pyrrolo[2,3-
d]pyrimidin-4(7H)-imine (3s, 86% yield): 1H NMR (500 MHz, DMSO-d6) d ppm
7.72 (s, 1H), 7.44–7.51 (m, 2H), 7.30–7.41 (m, 1H), 5.48 (s, 2H), 4.13 (t,
J = 5.19 Hz, 2H), 3.59 (t, J = 5.19 Hz, 2H), 3.24 (s, 3H) 2.24 (s, 3H), 1.98 (s, 3H);
13C NMR (126 MHz, DMSO-d6) d ppm 172.06, 154.14, 145.32, 142.72, 135.36,
131.85, 130.27, 128.92, 127.02–127.40, 108.46, 102.85, 68.74, 58.03, 45.89,
41.76, 21.45, 10.29, 9.16; HRMS calcd for C18H20Cl2N4O: 378.1014 found
378.1006.
a
formimidamide 1a (0.2 mmol), and benzylamine 2a (0.3 mmol). The vial was
capped and heated in a Biotage Initiator at 180 °C for 35 min. The solution was
transferred into a 16 ꢀ 100 mm culture tube and dried with nitrogen in a
TurboVap evaporator at 40 °C overnight. Then the crude product was dissolved
in DMF (1.6 mL) and purified by HPLC. (4a, 88% yield). 1H NMR (500 MHz,
DMSO-d6) d ppm 8.30 (s, 1H), 7.44 (d, J = 8.55 Hz, 2H), 7.38 (d, J = 8.85 Hz, 2H),
7.30 (t, J = 7.32 Hz, 2H), 7.24 (d, J = 7.02 Hz, 1H), 7.20 (d, J = 7.02 Hz, 2H), 7.08
(d, J = 8.55 Hz, 2H), 6.94 (d, J = 8.85 Hz, 2H), 5.58 (t, J = 5.65 Hz, 1H), 4.62 (d,
J = 5.49 Hz, 2H), 3.81 (s, 3H), 3.75 (s, 3H); 13C NMR (126 MHz, DMSO-d6) d ppm
146.27, 159.40, 156.90, 153.35, 146.04, 138.83, 130.89, 128.25, 127.39, 126.72,
121.69, 115.03, 114.27, 113.16, 55.17, 55.1, 43.78; HRMS calcd for C27H23N3O3:
437.1739, found 437.1729.
3-Benzyl-5,6-bis(4-methoxyphenyl)furo[2,3-d]pyrimidin-4(3H)-imine 3a (69%