A novel and convenient synthesis of 'reversed' diamidino 2,5-aryl- and 2,5-azaheterocycle-substituted furans

Article abstract of DOI:10.1055/s-0029-1216817

A novel and convenient two-step synthesis of 'reversed' diamidino 2,5-aryl- and 2,5-azaheterocycle-substituted furans is described. The key step, a Stille cross-coupling reaction between N-(bromoaryl)arenecarboxamidines and 2,5-bis(tri-n-butylstannyl)fura

Full text of DOI:10.1055/s-0029-1216817

SHORT PAPER
2143
A Novel and Convenient Synthesis of ‘Reversed’ Diamidino 2,5-Aryl- and
2,5-Azaheterocycle-Substituted Furans
S
ynthesis of ‘R
e
a
versed’
D
i
i
a
midin
x
o 2, 5-Substit
i
ute
d
Fu
n
rans g Hu, David W. Boykin*
Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA
Fax +1(404)4135505; E-mail: dboykin@gsu.edu
Received 12 January 2009; revised 9 March 2009
amines gave good yields (60–80%) of the desired reversed
amidines 1 as long as the diamines were relatively elec-
tron-rich (either phenyls or phenyls substituted with elec-
tron donors).1 However, the thioimidate reactions failed
when the phenyl ring was substituted with the electron-
withdrawing trifluoromethyl group or replaced with elec-
tron-deficient rings including pyridyl, pyrazinyl, or pyri-
midinyl systems. Therefore, it is highly desirable to
develop a new methodology for the synthesis of diarylfu-
ran reversed amidines that is more direct and accommo-
dates a broad structural range. This report describes the
novel and convenient synthesis of reversed diamidino 2,5-
aryl- and 2,5-azaheterocycle-substituted furans.
Abstract: A novel and convenient two-step synthesis of ‘reversed’
diamidino 2,5-aryl- and 2,5-azaheterocycle-substituted furans is de-
scribed. The key step, a Stille cross-coupling reaction between N-
(bromoaryl)arenecarboxamidines and 2,5-bis(tri-n-butylstannyl)fu-
ran, is reported for the first time.
Key words: reversed amidines, thioimidates, Stille cross-coupling
reaction, furans, N-heterocycles
‘Reversed’ amidines refer to a series of potentially di-
cationic compounds that have the imino group attached to
an ‘anilino’ nitrogen in contrast to the original amidines in
which the imino group is directly attached to the aryl ring.
We first reported a series of 2,5-diarylfuran reversed di-
amidines that showed strong DNA binding properties and
antimicrobial activities against Candida albicans and
Mycobacterium tuberculosis.1 Recently, ‘reversed’
amidines have been of much interest, since a series of 2,5-
R1
a
Bu3Sn
SnBu3
Br
NO2
+
O
2
3
R1
R1
bis(4-{[imino(2-pyridyl)methyl]amino}phenyl)furans
1
b
(Figure 1) were found to be quite effective against Trypa-
nosoma cruzi, Leishmania donovani, and Leishmania in-
fantum, which infect millions of people in large parts of
the world.2,3
O
H2N
NH2
4
R1
R1
NH
NH
R1
R1
O
N
H
N
H
NH
NH
R2
R2
1
N
N
O
N
H
N
H
R2
R2
N
N
Scheme 1 Reagents and conditions: (a) 1. Pd(PPh3)4, 1,4-dioxane;
2. H2, Pd/C, EtOAc, EtOH; (b) 1. S-(2-naphthylmethyl)-2-pyridyl-
thioimidate hydrobromide, MeCN, EtOH; 2. 1 N aq NaOH; 3.
HCl(g), EtOH.
1
Figure 1 2,5-Diarylfuran reversed diamidines
Our initial preparation of the ‘reversed’ amidines 1 was
achieved in three steps1,2 beginning with a Stille coupling
reaction between 2,5-bis(tri-n-butylstannyl)furan (2) and
4-bromonitrobenzenes 3 to form 2,5-bis(4-nitrophe-
nyl)furans,4 which were reduced to form the correspond-
ing 2,5-bis(4-aminophenyl)furans 4 (Scheme 1). The
‘reversed’ amidines 1 were obtained by reaction of di-
amines 4 with S-(2-naphthylmethyl)thioimidates. It is
necessary to prepare the thioimidates in two steps from
arylnitriles via the corresponding arylthioamides, which
were allowed to react with 2-(bromomethyl)naphtha-
lene.5,6 The reaction between the thioimidates and the
The synthesis of N-(substituted phenyl)pyridine-2-car-
boxamidines by condensation of substituted anilines with
2-cyanopyridine in the presence of aluminum(III) chlo-
ride in moderate yields has previously been reported.7
However, low solubility of some amidine products in or-
ganic solvents and the presence of aluminum salts led to
emulsion formation during the reaction workup, which re-
sulted in difficulty of isolation of pure amidines.8,9 The
synthesis of arylbenzamidines by reaction of substituted
benzonitriles with anilines catalyzed by various bases was
reported recently.9 Best results were obtained when the
amidine formation was carried out in tetrahydrofuran with
sodium hexamethyldisilazide as a strong non-nucleophilic
base.9 We first attempted to react 2,5-bis(4-aminophe-
nyl)furan directly with 2-cyanopyridine using sodium
hexamethyldisilazide in tetrahydrofuran as previously de-
SYNTHESIS 2009, No. 13, pp 2143–2145
x
x.
x
x
.
2
0
0
9
Advanced online publication: 14.05.2009
DOI: 10.1055/s-0029-1216817; Art ID: M00409SS
© Georg Thieme Verlag Stuttgart · New York

2144
L. Hu, D. W. Boykin
SHORT PAPER
scribed,9,10 but the ‘reversed’ amidines could not be isolat- (Scheme 3). Interestingly, the yields were higher than that
ed from the complex reaction mixture. These unfortunate for the parent product 7 (Scheme 2). It appears that the
results may be due, in part, to the low solubility of the pu- electron-deficient azahetaryl bromides are beneficial for
tative monoamidine intermediate. We explored an alter- this Stille cross-coupling reaction.
native approach (Scheme 2), in which the bromoaryl
reversed amidine 6 is first prepared in good yield by reac-
In conclusion, we have developed a novel and convenient
two-step process for the synthesis of ‘reversed’ diamidino
2,5-aryl- and 2,5-azaheterocycle-substituted furans,
tion of 4-bromoaniline (5) with 2-cyanopyridine by the re-
ported Khanna method.9,10 Direct Stille cross-coupling
which includes straight-forward product isolation. The
between 2,5-bis(tri-n-butylstannyl)furan and N-(bromoar-
Stille cross-coupling reaction of N-(bromoaryl)arenecar-
yl)arenecarboxamidine 6 gave the desired bis-‘reversed’
boxamidines with 2,5-bis(tri-n-butylstannyl)furan is re-
ported for the first time.
amidine 7 in reasonable yield. To our knowledge, Stille
coupling using unprotected N-(bromoaryl)arenecarbox-
amidines as substrates has not been reported.
All commercial reagents were used without purification. Melting
points were determined on a Mel-Temp 3.0 melting-point appara-
tus, and are uncorrected. TLC analysis was carried out on silica gel
NH
a
b
60 F254 precoated aluminum sheets, and UV light was used for de-
Br
NH2
Br
N
H
1
tection. H and 13C NMR spectra were recorded on a Bruker 400-
N
6
5
MHz spectrometer. Mass spectra were obtained from the Georgia
State University Mass Spectrometry Laboratory, Atlanta, GA,
USA. Elemental analysis were performed by Atlantic Microlab Inc.,
Norcross, GA, USA.
NH
NH
O
N
H
N
H
7
N
N
N-(Bromoaryl)pyridine-2-carboxamidines 6 and 9a–c; General
Procedure
Scheme
2
Reagents and conditions: (a) 2-cyanopyridine,
NaHMDS, THF, 85%; (b) 2, Pd(PPh3)4, xylene, 120 °C, 43%.
A soln of 5 or one of 8a–c (10.0 mmol) in anhyd THF (30 mL) was
added dropwise to 1 M NaHMDS in THF (10.5 mL) while the reac-
tion mixture was magnetically stirred under N2 at ice-bath tempera-
ture. After completed addition, the mixture was stirred for 30 min,
and 2-cyanopyridine (1.07 g, 10 mmol) was added in one portion.
The resulting mixture was stirred overnight at r.t. The precipitate
that had formed was collected by filtration, or the reaction mixture
was concentrated in vacuo to form a precipitate, which was collect-
We explored using this methodology to prepare the re-
versed diamidino 2,5-azaheterocycle-substituted furans,
as shown in Scheme 3. The N-(bromoaryl)pyridine-2-car-
boxamidines 9a and 9b were smoothly prepared in good
yields (79–83%) from commercially available 5-bro- ed by filtration; washing of the precipitate with H2O and Et2O and
drying in vacuo gave 6 and 9a–c.
mopyridin-2-amine (8a) and 5-bromopyrazin-2-amine
(8b) when sodium hexamethyldisilazide was used
(Scheme 3). The reaction of 5-bromopyrimidin-2-amine
(8c) with 2-cyanopyridine did not furnish product 9c as
easily under the same conditions. The starting material 5-
bromopyrimidin-2-amine (8c) was less soluble in tetrahy-
drofuran and thus apparently reacts slowly, yielding a
mixture which required recrystallization to provide the
product 9c (65%).
N-(4-Bromophenyl)pyridine-2-carboxamidine (6)
Yield: 85%; mp 85–86 °C (Lit.7 85–86 °C).
1H NMR (400 MHz, DMSO-d6): d = 6.68 (s, 2 H), 6.88 (d, J = 8.0
Hz, 2 H), 7.46 (d, J = 8.0 Hz, 2 H), 7.55 (m, 1 H), 7.94 (m, 1 H),
8.28 (d, J = 8.0 Hz, 1 H), 8.62 (d, J = 4.4 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 114.1, 121.3, 123.9, 125.5,
131.9, 137.1, 148.0, 149.8, 151.3, 152.0.
N-(5-Bromo-2-pyridyl)pyridine-2-carboxamidine (9a)
Yield: 83%; mp 127–129 °C.
1H NMR (400 MHz, DMSO-d6): d = 7.12 (d, J = 8.4 Hz, 1 H), 7.57
(m, 1 H), 7.92 (dd, J = 7.2, 2.0 Hz, 1 H), 7.97 (m, 1 H), 8.42 (d,
J = 8.0 Hz, 1 H), 8.47 (s, 1 H), 8.47 (d, J = 1.2 Hz, 1 H), 8.67 (d,
J = 4.8 Hz, 1 H), 9.65 (s, 1 H).
The Stille cross-coupling reaction of N-(bromoaryl)pyri-
dine-2-carboxamidines 9a–c with 2,5-bis(tri-n-butylstan-
nyl)furan gave the desired reversed amidines 10a–c
NH
Z
Y
Z
Y
X
a
b
Br
NH2
Br
N
H
13C NMR (100 MHz, DMSO-d6): d = 112.4, 121.8, 123.6, 125.8,
X
N
137.3, 140.2, 147.0, 148.3, 151.4, 155.2, 161.3.
9a–c
8a–c
NH
Anal. Calcd for C11H9BrN4: C, 47.68; H, 3.27; N, 20.22. Found: C,
47.70; H, 3.25; N, 20.09.
Z
Z
NH
Y
Y
O
N
H
N
H
X
X
N-(5-Bromopyrazin-2-yl)pyridine-2-carboxamidine (9b)
Yield: 79%; mp 165–167 °C.
N
N
10a–c
1H NMR (400 MHz, DMSO-d6): d = 7.60 (m, 1 H), 8.00 (m, 1 H),
8.28 (d, J = 1.2 Hz, 1 H), 8.43 (d, J = 8.0 Hz, 1 H), 8.53 (d, J = 1.2
Hz, 1 H), 8.69 (d, J = 4.4 Hz, 1 H), 9.02 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 122.1, 126.2, 130.4, 137.5,
142.6, 144.2, 148.5, 150.8, 156.9, 157.3.
a X = N, Y = C, Z = C
b X = N, Y = C, Z = N
c X = N, Y = N, Z = C
Scheme
3
Reagents and conditions: (a) 2-cyanopyridine,
NaHMDS, THF, 65–83%; (b) 1. 2, Pd(PPh3)4, xylene, 120 °C; 2.
HCl(g), EtOH, 72–78%.
Synthesis 2009, No. 13, 2143–2145 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of ‘Reversed’ Diamidino 2,5-Substituted Furans
2145
Anal. Calcd for C10H8BrN5: C, 43.19; H, 2.90; N, 25.18. Found: C,
42.81; H, 2.86; N, 24.80.
HRMS: m/z calcd for C24H19N10O: 463.1743; found: 463.1735.
Anal. Calcd for C24H18N10O·3HCl·1.4H2O: C, 48.27; H, 4.02; N,
23.46. Found: C, 48.25; H, 3.87; N, 23.47.
N-(5-Bromopyrimidin-2-yl)pyridine-2-carboxamidine (9c)
Yield: 65%; mp 150–152 °C (THF).
2,5-Bis(2-{[imino(2-pyridyl)methyl]amino}pyrimidin-5-yl)fu-
ran Hydrochloride (10c)
Yield: 78%; mp 262–264 °C (dec.).
1H NMR (400 MHz, DMSO-d6): d = 7.58 (s, 2 H), 7.87 (m, 2 H),
8.23 (m, 2 H), 8.47 (d, J = 8.4 Hz, 2 H), 8.91 (d, J = 3.6 Hz, 2 H),
9.47 (s, 4 H), 11.36 (s, 2 H), 11.64 (s, 2 H).
1H NMR (400 MHz, DMSO-d6): d = 7.64 (m, 1 H), 8.04 (m, 1 H),
8.44 (d, J = 8.0 Hz, 1 H), 8.72 (d, J = 2.0 Hz, 1 H), 8.84 (s, 2 H),
9.08 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 111.3, 122.1, 126.2, 137.5,
148.4, 151.0, 157.5, 158.0, 164.8.
Anal. Calcd for C10H8BrN5: C, 43.19; H, 2.90; N, 25.18. Found: C,
42.97; H, 2.88; N, 24.99.
13C NMR (100 MHz, CD3OD): d = 112.7, 123.6, 125.3, 130.5,
140.0, 145.2, 150.3, 151.8, 155.0, 157.3, 161.6.
HRMS: m/z calcd for C24H19N10O: 463.1743; found: 463.1738.
2,5-Diarylfurans 7 and 10a–c
Anal. Calcd for C24H18N10O·2HCl·H2O: C, 52.09; H, 4.01; N, 25.31.
Found: C, 52.11; H, 3.75; N, 25.25.
2,5-Bis(tri-n-butylstannyl)furan (2; 0.65 g, 1.0 mmol) was added to
a soln of 6 or one of 9a–c (2.0 mmol) and Pd(PPh3)4 (0.24 g, 0.2
mmol) in anhyd xylene (20 mL) while the reaction mixture was
magnetically stirred under N2. The mixture was subsequently heat-
ed overnight at 120 °C. The resulting mixture was cooled and the
precipitate that had formed was collected by filtration, washed with
xylene, acetone, and Et2O, and dried in vacuo; this gave free bases
7 and 10a–c.
Acknowledgment
This work was supported by NIH grant AI46365 and by the Bill and
Melinda Gates Foundation.
To prepare the hydrochloride salt, the free base (one of 10a–c) was
suspended in EtOH (30 mL) and treated with anhyd HCl gas for 5–
10 min at ice-bath temperature, and the mixture was stirred for an-
other 4 h. The resulting soln was concentrated in vacuo and the pre-
cipitate that had formed was collected by filtration, washed with
Et2O, and dried in vacuo; this gave hydrochloride salts 10a–c.
References
(1) Stephens, C. E.; Tanious, F.; Kim, S.; Wilson, W. D.; Schell,
W. A.; Perfect, J. R.; Franzblau, S. G.; Boykin, D. W.
J. Med. Chem. 2001, 44, 1741.
(2) Stephens, C. E.; Brun, R.; Salem, M. M.; Werbovetz, K. A.;
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C.; Hall, J. E.; Bakunova, S.; Patrik, D. A.; Bakunov, S.;
Stephens, C. E.; Kumar, A.; Boykin, D. W.; Tidwell, R. R.
Vet. Parasitol. 2007, 145, 207.
2,5-Bis(4-{[imino(2-pyridyl)methyl]amino}phenyl)furan (7)
Yield: 43%; mp 221–223 °C (Lit.1 221–223 °C).
1H NMR (400 MHz, DMSO-d6): d = 6.63 (s, 4 H), 6.94 (s, 2 H), 7.01
(d, J = 8.4 Hz, 4 H), 7.57 (m, 2 H), 7.77 (d, J = 8.4 Hz, 4 H), 7.95
(m, 2 H), 8.32 (d, J = 8.0 Hz, 2 H), 8.64 (d, J = 4.4 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 106.5, 121.3, 122.2, 124.4,
124.7, 125.4, 137.1, 148.0, 149.7, 151.4, 151.8, 152.5.
2,5-Bis(6-{[imino(2-pyridyl)methyl]amino}-3-pyridyl)furan
Hydrochloride (10a)
Yield: 72%; mp 226–228 °C (dec.).
1H NMR (400 MHz, DMSO-d6): d = 7.39 (s, 2 H), 7.87 (m, 2 H),
7.97 (d, J = 8.8 Hz, 2 H), 8.25 (m, 2 H), 7.51 (dd, J = 8.4, 2.4 Hz, 2
H), 8.59 (d, J = 8.0 Hz, 2 H), 8.93 (d, J = 4.8 Hz, 2 H), 9.03 (d,
J = 2.0 Hz, 2 H), 11.28 (s, 2 H), 11.84 (s, 2 H), 12.48 (s, 2 H).
(4) Kumar, A.; Stephens, C. E.; Boykin, D. W. Heterocycl.
Commun. 1999, 5, 301.
(5) Shearer, B. G.; Oplinger, J. A.; Lee, S. Tetrahedron Lett.
1997, 38, 179.
(6) Taylor, E. C.; Zoltewicz, J. A. J. Am. Chem. Soc. 1960, 82,
2656.
13C NMR (100 MHz, CD3OD): d = 111.6, 117.5, 124.9, 126.1,
130.2, 135.8, 139.9, 143.5, 145.3, 151.7, 152.0, 152.2, 160.5.
(7) Hisano, T.; Tasaki, M.; Tsumoto, K.; Matsuoka, T.;
Ichikawa, M. Chem. Pharm. Bull. 1983, 31, 2484.
(8) Khanna, I. K.; Weier, R. M.; Yu, Y.; Xu, X. D.; Koszyk, F.
J.; Collins, P. W.; Koboldt, C. M.; Veenhuizen, A. W.;
Perkins, W. E.; Casler, J. J.; Masferrer, J. L.; Zhang, Y. Y.;
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1997, 40, 1634.
HRMS: m/z calcd for C26H21N8O: 461.1838; found: 461.1854.
Anal. Calcd for C26H20N8O·2HCl·2.5H2O: C, 53.99; H, 4.70; N,
19.37. Found: C, 54.01; H, 4.35; N, 19.32.
(9) Khanna, I. K.; Yu, Y.; Huff, R. M.; Weier, R. M.; Xu, X.;
Koszyk, F. J.; Collins, P. W.; Cogburn, J. N.; Isakson, P. C.;
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C.; Adolfs, T. J. P.; McCreary, A. C.; Keizer, H. G.; Wals,
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2,5-Bis(5-{[imino(2-pyridyl)methyl]amino}pyrazin-2-yl)furan
Hydrochloride (10b)
Yield: 76%; mp 267–269 °C (dec.).
1H NMR (400 MHz, DMSO-d6): d = 7.52 (s, 2 H), 7.88 (m, 2 H),
8.25 (m, 2 H), 8.57 (d, J = 8.0 Hz, 2 H), 8.93 (d, J = 4.4 Hz, 2 H),
9.08 (d, J = 0.9 Hz, 2 H), 9.12 (d, J = 0.9 Hz, 2 H), 11.28 (s, 4 H).
13C NMR (100 MHz, DMSO-d6): d = 113.2, 124.6, 128.7, 136.1,
138.3, 139.2, 139.8, 144.6, 147.4, 149.7, 151.7, 158.8.
Synthesis 2009, No. 13, 2143–2145 © Thieme Stuttgart · New York