Synthesis of novel N-pyridylcantharidinimides by using high pressure

Article abstract of DOI:10.1002/jccs.200100009

The recently described pressure reaction in the presence of trithylamine with subsequent thermal (200°C) cyclization provided 13N-pyridylcantharidinimides 4a-4m from aminopyridines and cantharidin in yields of 15-83%. 2-Amino-3,5-dichloropyridine failed t

Full text of DOI:10.1002/jccs.200100009

JournaloftheChineseChemicalSociety, 2001, 48, 49-53
49
Syn the sis of Novel N-Pyridylcantharidinimides by Using High Pres sure
Pen-Yuan Lin* (
), Sheng-Jie Shi ( 施勝傑 ), Lun-Huei Lin ( 林倫輝 ),
林本元
Hsue-Fen Chen (
) and Feng-Lin Hsu* (
)
陳雪芬
徐鳳麟
SchoolofPharmacy, TaipeiMedicalUniversity, Taipei, Taiwan250, R.O.C.
Therecentlydescribedpressurereactioninthepresenceoftrithylaminewithsubsequentther mal (200oC)
cyclization pro vided 13N-pyridylcantharidinimides 4a-4m from aminopyridines and cantharidin in yields of
15-83%. 2-Amino-3,5-dichloropyridine failed to yield4n.
INTRODUCTION
RESULTS AND DISCUSSION
Someofusdescribedrecentlyanimprovedsynthesisof
cantharidinimides.1 The usual heating to 200 oC of can-
tharidin 1 with the pri mary amines2,3,4 was per formed with
Neglecting steric shielding of the NH2 group, this
nucleophilicity should closely be re lated to the ther mo dy-
namicbasicity. Onemaythereforeexpectthatformationof2
thesolventtolueneinasealedtubepreventinganevaporation (Scheme I) and hence also that one of the re spec tive can-
of cantharidin as well as of the amine, if this is vol a tile. Ad di-
tion of triethylamine (TEA) coun tered the protonation of the
pri mary amine by the monoamide monocarboxylic acid 2 that
arises in the first step of the syn the sis (Scheme I). Po ten tial
bioactivity2,3,4,5 stim u lated re search on cantharidinimides and
re lated im ides. The pres ent in ves ti ga tion ex tended the im-
proved synthesis in order to obtain a novel type of can-
tharidinimides in us able yields and to si mul ta neously study
the scope of this syn the sis. The first mech a nis tic step, the at-
tack of the pri mary amine on a car bonyl car bon of 1, is very
dif fi cult for steric rea sons. It re quires heat and de pends nec-
es sar ily on the nucleophilicity of the pri mary amine.
tharidinimidewillbecomemoredifficultwhentheamineba-
sicity decreases, e.g., in aromatic amines. N-Phenylcan-
tharidini mide has pre vi ously been pre pared from 1 and an i-
line but this re port did not men tion the yield.2 We ob tained
now63%ofthiscompoundusingpressuresynthesis.Thisen-
couragedustoextendthepressuresynthesistoreactionsof1
with aminopyridines that should pro vide hith erto un known
N-pyridylcantharidinimides. The NH2 ba sic ity of amino-
pyridines is un known but will be slightly less than that one of
thecorrespondinganilinesduetotheelectrondeficiencyof
the pyridine ring. Of course, theringnitrogen basicitymaybe
rather high in - and -aminopyridines where both ni tro gen
Scheme I
O
O
O
O
O
H2N
O
NHR
COOH
+
R
2
1
1
O
N
O
X
X
H2N
Y
O
Y
+
N
N
3 a-n
X = H, CH3, Cl, Br, OH, OCH3, NO2
Y = H, CH3, Cl
4 a-n

50 J. Chin. Chem. Soc., Vol. 48, No. 1, 2001
Lin et al.
Table 1. Preparation of N-Pyridylcantharidinimides 4a-4n
Entry
Amine
Product Yield (%)a Entry
Amine
Product Yield (%)a
N
NH2
CH3
1
3a
3b
NH2
N
4a
4b
62
29
8
3h
3i
4h
37
CH3
N
N
NH2
2
NH2
9
4i
72
CH3
N
N
NH2
NH2
NH2
NH2
Cl
3
4
5
3c
3d
3e
4c
4d
4e
39
15
83
10
11
12
3j
3k
3l
4j
4k
4l
50
28
35
N
NH2
Cl
NO2
N
N
N
NH2
Br
OCH3
CH3
N
NH2
NH2
6
3f
4f
57
13
14
3m
4m
79
N
N
OH
N
CH3
NH2
Cl
7
3g
4g
47
3n
4n
0
NH2
Cl
a Yields obtained after purification by Chromatograph on silica gel.
O
Y
O
N
O
X
N
X = H, CH3, Cl, Br, OH, OCH3, NO2
Y = H, CH3, Cl

SynthesisofN-Pyridylcantharidinimides
J. Chin. Chem. Soc., Vol. 48, No. 1, 2001 51
at oms are part of an amidine struc ture or of an vinylogous
amidine.
heated to 200 oC for 2 h un der stir ring in the sealed tube. Af ter
cool ing to room tem per a ture, to lu ene and TEA were evap o-
rated. The res i due was heated to 200 oC for an other 1 h and
was subsequently subjected to column chromatography
(silical gel, CHCl3 : MeOH = 9 : 1). The prod uct was recrys-
tallizedfrommethanol.
As shown by Ta ble 1, the N-pyridylcantharidinimides
4a-4m couldbepreparedbymeansofpressuresynthesis. The
yield(aftercrystallizationfrommethanol)varyfrom15%to
83%andshowa trendcom pat i ble withthe expectedba sic ity
in flu ence of3. The high est yields were ob tained from meth-
oxypyridine 3e and hydroxypyridine 3m. The pKa val ues 6 of
thetwoanilines,orratyeraniliniumions,correspondingto3e
and 3m are 5.3-5.4 and ca. 4.8, i.e. slightly higher than ca. 4.6
fortheparentanilinewhosepyridinecounterpartsare3a-3c.
The vari a tion in yields of 4a-4c may per haps re flect the in-
duc tive elec tron with drawal by the ring ni tro gen, since an in-
duc tive ef fect will in versely in crease with the dis tance be-
tweenthetwonitrogenatoms. However, oneshouldnotover-
stressthiswholetopicsincetheyieldobtainedbypreparative
tech niques will also be in flu enced by other fac tors that can
causeastrongvariation. Theresultsobtainedwith3d and3n,
how ever, strongly con firm the in flu ence of amine nucleo-
philicityandbasicity.Pkaoftheanilinecounterpartisca.1.0
for 3d and 2.0-2.6 for 3n. The fail ure to ob tain 4n can be ex-
plained by the com bined in flu ence of low ba sic ity and steric
hindrance.Thelattermustbeextremelyeffectiveinthereac-
tion with the sterically shielded car bonyl of 1.
N-Phenylcantharidinimide
Cantharidin (197 mg, 1.0 mmole), amine (110 mg, 1.2
mmole), TEA (3 mL), Toluene (3 mL), 62% yield; m.p.
123-124 oC (MeOH) (lit.2 120-122 oC); 1H NMR (CDCl3, 400
MHz) 1.24 (s, 6H), 1.72-1.86 (m, 4H), 4.69 (t, 2H, J = 2.6
Hz), 7.26 (d, 2H,J = 8.0 Hz, Phenyl H-3, H-5), 7.45 (dd, 2H,J
= 7.2 Hz, 8.4 Hz, phenyl H-2, H-6); IR (KBr), 1710, 1766
(imide) cm-1; MS m/z (rel. int. %), 272 (M+, 10), 202 (70), 96
(100).
N-(4-Pyridyl)cantharidinimide (4a)
Cantharidin (197 mg, 1.0 mmole), amine (105 mg, 1.1
mmole), TEA (1 mL), Toluene (3 mL), 61% yield; m.p.
135-136 oC (MeOH); 1H NMR (CDCl3, 300 MHz), 1.26 (s,
6H), 1.73-1.91 (m, 4H), 4.69 (t, 2H, J = 2.6 Hz), 7.43 (dd-
like, 2H, J = 1.2, 6.0 Hz, pyridyl H-2, H-6), 8.71 (d, 2H, J =
4.1, pyridyl H-3, H-5); IR (KBr), 1717, 1772 (imide) cm-1;
MS m/z (rel. int. %), 272 (M+, 20), 204 (100), 96 (45); HRMS
(EI) calcd. for C15H16O3N2 272.1161, found: 272.1158.
EXPERIMENTALSECTION
N-(3-Pyridyl)cantharidinimide (4b)
General Methods
Cantharidin (197 mg, 1.0 mmole), amine (129 mg, 1.4
mmole), TEA (2 mL), Toluene (3 mL), 29% yield; m.p.
108-109 oC (MeOH); 1H NMR (CDCl3, 300 MHz), 1.27 (s,
6H), 1.73-1.91 (m, 4H), 4.69 (t, 2H,J = 2.6 Hz), 7.43 (dd, 2H,
J = 4.8, 8.1 Hz, pyridyl H-4), 7.73 (dt, 1H,J = 1.7, 4.5, 8.1 Hz,
pyridyl H-5), 8.62 (dd, 1H, J = 7.6, 5.3 Hz, pyridyl H-6), 8.63
(d, 1H, J = 1.8 Hz, pyridyl H-2); IR (KBr), 1713, 1767
(imide) cm-1; MSm/z (rel. int. %) 272 (M+, 20), 204 (100), 96
(47); HRMS (EI) calcd. for C15H16O3N2 272.1161, found:
272.1154.
Melting points were de ter mined with a melt ing point
microscope (Yanaco ap pa ra tus) and Büchi melt ing point
B-545. Sil ica gel (0.063-0.200 mm, 70-230 mm mesh if not
oth er wise stated, else 0.040-0.063 mm, 230-400 mesh) sup-
plied by Merck was used for col umn chro ma tog ra phy. In fra-
red spec tra were re corded on a Perkin Elmer Model 882 and a
Nicolet 510 PFT-IR spectrophotometer. Mass spec tra were
ob tained on a Joel JMSHX 110 FABMS and Joel JMS-HX
110 for high resolution spectrometers. 1H NMR spectra
(CDCl3 un less oth er wise stated) were re corded at 200 MHz
and at 300 MHz on Bruker AC spectrometers. Chemical
shifts are shown in val ues (ppm) with tetramethylsilane
(TMS)asaninternalreference.
N-(2-Pyridyl)cantharidinimide (4c)
Cantharidin (196 mg, 1.0 mmole), amine (95 mg, 1.0
mmole), TEA (2 mL), Toluene (5 mL), 39% yield; m.p.
154-155 oC (MeOH); 1H NMR (CDCl3, 300 MHz), 1.27 (s,
6H), 1.73-1.90 (m, 4H), 4.72 (t, 2H,J = 2.6 Hz), 7.35 (dd, 2H,
J = 2.4, 8.0 Hz, pyridyl H-3, H-5), 7.87 (dt, 1H, J = 1.9, 5.0,
7.9 Hz, pyridyl H-4), 8.65 (d, 1H,J = 5.4 Hz, pyridyl H-6); IR
(KBr) 1711, 1772 (imide) cm-1; MS m/z (rel. int. %), 272 (M+,
20), 96 (30), 203 (100); HRMS (EI) calcd. for C15H16O3N2
General Procedure
Gen eral Pro ce dure for the Re ac tion of Can th ar idini-
mides. The syn the sis both fol lowed the gen eral method and
used the sealed tube de scribed in Ref. 1. Amine (1 mmol of 3
oraniline),1 (1 mmol), TEA (2 mL) and to lu ene (3 mL) were

52 J. Chin. Chem. Soc., Vol. 48, No. 1, 2001
Lin et al.
1
272.1161, found: 272.1184.
189-190 oC (MeOH); H NMR (CDCl3, 300 MHz) 1.26 (s,
6H), 1.73-1.89 (m, 4H), 2.38 (s, 3H, pyridyl 5-CH3), 4.72 (d,
2H, J = 2.2 Hz), 7.22 (d, 1H, J = 8.1 Hz, pyridyl H-4), 7.65 (d,
1H, J = 8.1 Hz, pyridyl H-3), 8.46 (s, 1H, pyridyl H-6); IR
(KBr) 1711, 1775 (imide) cm-1; MS m/z, (rel. int. %), 286
(M+, 7), 217 (100), 96 (25); HRMS (EI), calcd. for
C16H18O3N2 286.1317, found: 286.1366.
N-(5-Nitropyridyl-2)cantharidinimide (4d)
Cantharidin (196 mg, 1.0 mmole), amine (139 mg, 1.0
mmole), TEA (3 mL),Toluene (3 mL), 15% yield; m.p.
193-194 oC (MeOH); 1H NMR (CDCl3, 300 MHz), 1.29 (s,
6H), 1.76-1.90 (m, 4H), 4.75 (t, 2H,J = 2.4 Hz), 7.63 (d, 1H, J
= 8.7 Hz, pyridyl H-3), 8.63 (d, 1H, J = 8.8 Hz, pyridyl H-4),
9.45 (d, 1H, J = 2.6 Hz, pyridyl H-6); IR (KBr) 1714, 1780
(imide) cm-1; MS (rel. int. %), 318 (M+, 20), 274 (60), 248
(100); HRMS (EI) calcd. for C15H15O5N3 317.1012, found;
317.1002.
N-(4,6-Dimethylpyridyl-2)cantharidinimide (4i)
Cantharidin (205 mg, 1.05 mmole), amine (128 mg,
1.05 mmole), TEA (2 mL), To lu ene (10 mL), 72% yield; m.p.
181-183 oC (MeOH); 1H NMR (CDCl3, 200 MHz), 1.25 (s,
6H), 1.70-1.89 (m, 4H), 2.33 (s, 3H, pyridyl 4-CH3), 2.52 (s,
3H, pyridyl 6-CH3), 4.70 (t, 2H, J = 2.5 Hz), 6.89 (s, 1H,
pyridyl H-5), 7.02 (s, 1H, pyridyl H-3); IR (KBr) 1710, 1778
(imide) cm-1; MS m/z (rel. int. %) 300 (M+, 8), 217 (100), 96
(18); HRMS (EI) calcd. for C17H20O3N2 300.1473, found:
300.1480.
N-(6-Methoxypyridyl-3)cantharidinimide (4e)
Cantharidin (200 mg, 1.02 mmole), amine (126 mg,
1.02 mmole) TEA (2 mL), To lu ene (5 mL), 83% yield; m.p.
154-155 oC (MeOH);1H NMR (CDCl3, 300 MHz), 1.25 (s,
6H), 1.73-1.88 (m, 4H), 3.95 (s, 3H), 4.69 (t, 2H, J = 2.6 Hz),
6.81 (d, 1H, J = 8.8 Hz, pyridyl H-4), 7.52 (dd, 1H, J = 2.7,
8.8 Hz, pyridyl H-5), 8.13 (d, 1H,J = 2.6 Hz, pyridyl H-2); IR
(KBr) 1710, 1764 (imide) cm-1 ; MSm/z (rel. int. %), 302 (M+,
100), 233 (95), 96 (90); HRMS (EI) calcd. for C16H18O4N2
302.1267, found: 302.1275.
N-(5-Chloropyridyl-2)cantharidinimide (4j)
Cantharidin (196 mg, 1.0 mmole), amine (129 mg, 1.0
mmole), TEA (3 mL), Toluene (2 mL), 50% yield; m.p.
148-151 oC (MeOH); 1H NMR (CDCl3, 200 MHz), 1.27 (s,
6H), 1.74-1.89 (m, 4H), 4.71 (dd, 2H, J = 2.2, 4.5 Hz), 7.32
(d, 1H,J = 8.6 Hz, pyridyl H-3), 7.82 (dd, 1H, J = 2.9, 8.8 Hz,
pyridyl H-4), 8.59 (d, 1H, J = 2.6 Hz, pyridyl H-6); IR (KBr)
1171, 1778 (imide) cm-1; MS m/z (rel. int. %) 306 (M+, 20),
237 (100) 96 (90); HRMS (EI) calcd. for C15H15O3N2Cl
306.0771, found: 306.0793.
N-(4-Methylpyridyl-2)cantharidinimide (4f)
Cantharidin (197 mg, 1.0 mmole), amine (110 mg, 1.0
mmole), TEA (2 mL), Toluene (6 mL), 57% yield; m.p.
157-158 oC (MeOH);1H NMR (CDCl3, 300 MHz), 1.27 (s,
6H), 1.74-1.87 (m, 4H), 2.42 (s, 3H, pyridyl 3-CH3), 4.73 (t,
2H, J = 2.4 Hz), 7.16 (s, 1H, pyridyl H-3), 7.18 (d, 1H,J = 5.2
Hz, pyridyl H-5), 8.50 (d, 1H, J = 5.0 Hz, pyridyl H-6); IR
(KBr) 1713, 1772 (imide) cm-1 ; MSm/z (rel. int. %), 286 (M+,
10), 217 (100), 96 (20); HRMS (EI) calcd. for C16H18O3N2
286.1317, found: 286.1318.
N-(6-Chloropyridyl-3)cantharidinimide (4k)
Cantharidin (150 mg, 0.8 mmole), amine (100 mg, 0.8
mmole), TEA (4 mL), Toluene (5 mL), 28% yield; m.p.
110-112 oC (MeOH); 1H NMR (CDCl3, 200 MHz), 1.27 (s,
6H), 1.79-1.90 (m, 4H), 4.70 (t, 2H,J = 2.6 Hz), 7.43 (d, 1H,J
= 8.9 Hz, pyridyl H-3), 7.70 (dd, 1H, J = 2.8, 8.7 Hz, pyridyl
H-4), 8.44 (d, 1H, J = 3.1 Hz, pyridyl H-2); IR (KBr) 1707,
1770 (imide) cm-1; MS m/z (rel. int. %) 306 (M+, 35), 237
N-(6-Methylpyridyl-2)cantharidinimide (4g)
Cantharidin (206 mg, 1.06 mmole), amine (137 mg,
1.27 mmole), TEA (2 mL), To lu ene (5 mL), 47% yield; m.p.
196-197 oC (MeOH); 1H NMR (CDCl3, 300 MHz) 1.27 (s,
6H), 1.74-1.90 (m, 4H), 2.59 (s, 3H, pyridyl 6-CH3), 4.72 (t,
2H, J = 2.2 Hz), 7.09 (d, 1H,J = 7.8 Hz, pyridyl H-3), 7.21 (d,
1H, J = 7.6 Hz, pyridyl H-5), 7.72 (dd-like, 1H, J = 7.7, 7.8
Hz, pyridyl H-4); IR (KBr) 1711, 1774 (imide) cm-1; MS m/z
(rel. int. %) 286 (M+, 8), 217 (100), 96 (18); HRMS (EI),
calcd. for C16H18O3N2 286.1317, found: 286.1318.
(100), 96 (94); HRMS (EI), calcd. for C H15O3N2Cl
306.0771, found: 306.0768.
15
N-(5-Bromopyridyl-2)cantharidinimide (4l)
Cantharidin (113 mg, 0.6 mmole), amine (100 mg, 0.6
mmole), TEA (3 mL), Toluene (3 mL), 35% yield; m.p.
188-190 oC (MeOH); 1H NMR (CDCl3, 200 MHz), 1.28 (s,
6H), 1.74-1.90 (m, 4H), 4.69 (s, 2H), 7.28 (dd, 1H, J = 2.4,
7.4 Hz, pyridyl H-3), 8.00 (dd, 1H, J = 2.3, 10.2 Hz, pyridyl
H-4), 8.70 (s, 1H. pyridyl H-6); IR (KBr) 1710, 1776 (imide)
cm-1; MS m/z (rel. int. %) 351 (M+, 4) 352 (20), 353 (4), 281
N-(5-Methylpyridyl-2)cantharidinimide (4h)
Cantharidin (196 mg, 1.0 mmole), amine (108 mg, 1.0
mmole), TEA (3 mL), Toluene (5 mL), 37% yield; m.p.

SynthesisofN-Pyridylcantharidinimides
J. Chin. Chem. Soc., Vol. 48, No. 1, 2001 53
(100), 282 (98); HRMS (EI) calcd. for C H15O3N2Br
Received July 25, 2000.
15
351.0266, found: 351.0244.
Key Words
Cantharidinimide; Cantharidin; Aminopyridine.
N-(3-Hydroxypyridyl-2)cantharidinimide (4m)
Cantharidin (205 mg, 1.04 mmole), amine (120 mg,
1.09 mmole), TEA (2 mL), To lu ene (2 mL), 79% yield; m.p.
over 300 oC (MeOH); 1H NMR (CDCl3, 200 MHz), 1.27 (s,
6H), 1.71-1.96 (m, 4H), 2.70 (sb, OH), 4.96 (dd, 2H, J = 2.1,
2.8 Hz), 7.27 (dd, 1H, J = 4.7, 8.2 Hz, pyridyl H-5), 7.41 (dd,
1H, J = 1.5, 8.2 Hz, pyridyl H-4), 8.13 (dd, 1H, J = 1.5, 4.5
Hz, pyridyl H-6); IR (KBr) 1713, 1776 (imide) cm-1, 3737
(OH) cm-1; MS m/z (rel. int. %), 288 (M+, 30), 219 (100), 39
(60), 53 (45); HRMS (EI) calcd. for C15H16O4N2 288.1110,
found: 288.1169.
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ACKNOWLEDGMENT
This re search was sup ported by the Na tional Sci ence
Coun cil of the Re pub lic of China, Tai wan (NSC87- 2314-
B-038-011).