Direct and Efficient Synthesis of Dimethylformamidrazones Using Bentriazole Vilsmeier Reagent

Full text of DOI:10.1021/jo991807g

2246
J . Org. Chem. 2000, 65, 2246-2248
Sch em e 1
Dir ect a n d Efficien t Syn th esis of
Dim eth ylfor m a m id r a zon es Usin g
Ben tr ia zole Vilsm eier Rea gen t
Alan R. Katritzky,* Tian-Bao Huang, and
Michael V. Voronkov
Department of Chemistry, Center for Heterocyclic
Compounds, University of Florida,
Gainesville, Florida 32611-7200
Received November 22, 1999
Dimethylformamidrazones 1 are versatile synthetic
intermediates and are widely used as HN-NCH+ syn-
thons (Scheme 1). Thus, 1 has been used (i) for the
construction of various heterocycles including benzotri-
azepinones 2,1a,b triazoloquinolines 3 and their salts,2
tetrazines 4,3a,b triazolopyrimidines,4 triazoles,5 and oxa-
diazoles 56 and (ii) for the preparation of formamidra-
zones 6,7 hydrazines 7,3b,8 isocyanides 8,9 and cyanamides
9.9
Sch em e 2a
Further uses of 1 include synthesis of nucleosides,10
precursors for ureas, and other utilities.11a,b
Several different preparative methods for dimethyl-
formamidrazones 1 have been used previously (Scheme
2). Among these, the treatment of the corresponding
hydrazine 10 with POCl3 and DMF in benzene affords 1
in yields ranging from 63% to 71% and allows both alkyl
and aryl substituents R1 and R2.12a,b Similarly, a mixture
of DMF and (Me)2NSO2Cl was employed for preparation
of 1 with electron-deficient substituents (R1 ) H, R2 )
SO2Ar, NO2C6H4, (NO2)2C6H3, etc.) in yields of 71% to
88%. However, no synthesis of 1 with electron-rich
substituents using such methods was reported.4,13a,b
Other approaches are less straightforward. For example,
decarboxylation of arylazochloroacetic acids 1114 affords
1 in 41-79% yield but requires a multistep preparation
of the precursor that may have its own limitations on
the generality of the overall approach. Similar problems
arise in other examples such as a reaction of hydrazines
a
Key: (i)DMF,(Me)2NSO2Cl;(ii)DMF,POCl3;(iii)Me2N+CHClCl-.
Bt )benzotriazole;(iv)(Me)2N+CHSCH3Cl-;(v)(Me)2NCH(CN)OCH3;
(vi) (Me)2N+CHBtCl-.
with tert-butylaminal esters15 or dimethylformamide
diethyl acetal6 with amidrazines, which afford the se-
lected 1 in 64-82% yield. Finally, reaction of hydrazines
with dimethylaminoalkoxyacetonitrile16 produces toxic
byproducts.
We now report a direct and general method for the
preparation of dimethylformamidrazones 1 starting from
corresponding hydrazines 10 (R1, R2 ) Ar, COAr, Alk,
H) in 66-99% yields. For the preparation of 1, we utilized
the novel versatile reagent 1217 as a stable Vilsmeier
reagent analogue. Previously, 12 was used in the syn-
thesis of quinolines,18a pyridines,18b and pyrazoles18c
(Scheme 3).
Typically, to prepare compounds 1 (R1 ) H, Alk, Ar
and R2 ) H, Alk, Ar), 4 mmol of hydrazine 10 was reacted
with 4 mmol of reagent 12 in 30 mL of THF under reflux
to form the product 1 as a white precipitate. The desired
product 1 is separated into its pure form by simple
filtration. This procedure is applicable to hydrazines with
a wide variety of substitutions (Table 1). For example,
novel, or not readily available by other procedures,
(1) (a) Scheiner, P.; Frank, L.; Giusti, I.; Arwin, S.; Pearson, S. A.;
Excellent, F.; Harper, A. P. J . Heterocycl. Chem. 1984, 21, 1817. (b)
Leiby, R. W. J . Heterocycl. Chem. 1984, 21, 1825.
(2) Batori, S.; Sandor, P.; Messmer, A. Heterocycles 1990, 31, 289.
(3) (a) Langdon, S. P.; Simmonds, R. J .; Stevens, M. F. G. J . Chem.
Soc., Perkin Trans. 1 1984, 993. (b) Zelenin, K. N.; Khrustalev, V. A.;
Sergutina, V. P. Zh. Org. Khim. 1980, 16, 276.
(4) Guillot, N.; Viehe, H. G.; Tinant, B.; Declercq, J . P. Tetrahedron
1990, 46, 3897.
(5) J ones, S. D.; Kennewell, P. D.; Tulley, W. R.; Westwood, R.;
Sammes, P. G. J . Chem. Soc., Perkin Trans. 1 1990, 447.
(6) Eilingsfeld, H. Chem. Ber. 1965, 98, 1308.
(7) Khrustalev, V. A.; Zelenin, K. N.; Sergutina, V. P. Zh. Org. Khim.
1979, 15, 2288.
(8) Hempel, U.; Lippmann, E.; Tenor, E. Z. Chem. 1990, 30, 320.
(9) Zelenin, K. N.; Bazylevich, N. I.; Khrustalev, V. A. Zh. Org. Khim.
1977, 13, 2064.
(15) Kantlehner, W.; Kapassakalidis, J . J .; Maier, T. Liebigs Ann.
Chem. 1980, 1448.
(16) Bredereck, H.; Simchen, G.; Kantlehner, W. Chem. Ber. 1971,
104, 932.
(10) Tutonda, M. G.; Fain, H. D.; Buckheit, R. W. J r.; Broom, A. D.
Nucleosides Nucleotides 1997, 16, 173.
(11) (a) Becker, H. G. O.; Gwan, K. M. J . Prakt. Chem. 1992, 334,
231. (b) Kohn, H.; Olofson, R. A. J . Org. Chem. 1972, 37, 3504.
(12) (a) Sergutina, V. P.; Zelenin, K. N.; Khrustalev, V. A. Zh. Org.
Khim. 1978, 14, 622. (b) Bredereck, H.; Gompper, R.; Klemm, K.;
Rempfer, H. Chem. Ber. 1959, 92, 837.
(13) (a) Scott, F. L.; Barry, J . A. Tetrahedron Lett. 1968, 20, 2457.
(b) Hunig, S.; Muller, F. Liebigs Ann. Chem. 1962, 651, 89.
(14) Lozinskii, M. O.; Pel′kis, P. S. Zh. Obsh. Khim. 1962, 32, 526.
(17) Katritzky, A. R.; Cheng, D.; Leeming, P.; Chiviriga, I.; Hart-
shorn, C. M.; Steel, P. J . J . Heterocycl. Chem. 1996, 33, 1935.
(18) (a) Katritzky, A. R.; Arend, M. J . Org. Chem. 1998, 63, 9989.
(b) Katritzky, A. R.; Denisenko, A.; Arend, M. J . Org. Chem. 1999, 64,
6076. (c) Katritzky, A. R.; Denisenko, A.; Arend, M.; Denisenko, S. N.
Unpublished work.
(19) Winberg, H. E. US Patent 3,121,084, 1964; Chem. Abstr. 1964,
60, 13197d.
(20) Bartlett, R. K.; Humphrey, I. R. J . Chem. Soc. C 1967, 1664.
(21) Taylor, E. C.; Morrison, R. W., J r. J . Org. Chem. 1967, 32, 2379.
10.1021/jo991807g CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/02/2000

Notes
J . Org. Chem., Vol. 65, No. 7, 2000 2247
benzophenone under nitrogen immediately prior to use. All
reactions with air-sensitive compounds were carried out under
an argon atmosphere. Column chromatography was conducted
on silica gel 230-400 mesh.
Sch em e 3
Gen er a l P r oced u r e for th e P r ep a r a tion of 1a -l. A
mixture of 4 mmol (0.85 g) of N-(1H-1,2,3-benzotriazol-1-yl-
methylene)-N-methylmethanamium and 4 mmol of the corre-
sponding hydrazine in 30 mL of dry THF was refluxed for 4 h
under dry nitrogen. The solution was cooled to room tempera-
ture, and the resulting white precipitate was quickly filtrated
off and was washed once with 10 mL of dry THF to give 1 as a
hydrochloride salt.
Ta ble 1. P r ep a r a tion of Dim eth ylfor m a m id r a zon e
Hyd r och lor id es 1
N,N-Dim et h yl-N′-p h en ylh yd r a zon ofor m a m id e h yd r o-
ch lor id e (1a ): 98% yield; white solid; mp 185-186 °C; 1H NMR
δ 3.08 (s, 3H), 3.18 (s, 3H), 6.88 (d, 2H, J ) 8.0 Hz), 6.97 (t, 1H,
J ) 7.5 Hz), 7.28 (t, 2H, J ) 8.13 Hz), 8.03 (s, 1H); 13C NMR δ
38.3, 44.7, 115.3, 123.7, 131.0, 147.9, 160.4. Anal. Calcd for
C9H14ClN3: C, 54.13; H, 7.07; N, 21.04. Found: C, 53.67; H, 7.22;
N, 21.07.
yield
(%)
published
yield (%)
entry
R1
R2
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
C6H5
4-BrC6H4
4-NO2C6H4
H
H
H
H
H
H
CH3
H
H
99
84
98
98
75
98
88a
73b
79
69a
98c
91
89
87
90
98d
74
91
8113a
7113a
2,4-(NO2)2C6H3
N ′-(4-Br om op h e n yl)-N ,N -d im e t h ylh yd r a zon ofor m a -
m id e h yd r och lor id e (1b): 84% yield; pale yellow solid; mp
215-216 °C; 1H NMR δ 3.19 (br. s, 6H), 6.85 (d, 2H, J ) 8.8
Hz), 7.38 (d, 2H, J ) 8.8 Hz), 8.47 (s, 1H); 13C NMR δ 38.8, 39.9,
114.4, 115.2, 131.2, 146.9, 159.2. Anal. Calcd for C9H13BrClN2:
C, 38.80; H, 4.70; N, 15.08. Found: C, 38.66; H, 4.64; N, 14.83.
N,N-Dim eth yl-N′-4-n itr oph en ylh ydr azon ofor m am ide h y-
4-CH3C6H4
C6F5
CH3
8216
4-(N-oxide-pyridinyl)-CO
4-CH3C6H4SO2
not given19
not given20
8020
H
H
H
H
1
-CHdN-NdCH-
d r och lor id e (1c): 98% yield; yellow solid; mp 241-242 °C; H
C6H5SO2
H
88e,13b
66e,21
NMR δ 3.19 (br.s, 6H), 6.90 (d, 2H, J ) 8.0 Hz), 8.04-8.18 (m,
2H), 8.90 (s, 1H); 13C NMR δ 42.0, 43.0, 113.7, 127.6, 142.2,
154.2, 160.8. Anal. Calcd for C9H13ClN4O2: C, 44.18; H, 5.36;
N, 22.90. Found: C, 43.94; H, 5.61; N, 22.76.
-COC6H4CO-
C6H5
CH3
71e,12b
-CH2CH2N(CH3)CH2CH2-
-CH2CH2OCH2CH2-
N ,N -Dim e t h yl-N ′-2,4-d in it r op h e n ylh yd r a zon ofor m a -
m id e h yd r och lor id e (1d ): 98% yield; yellow solid; mp 238-
239 °C; 1H NMR δ 3.22 (br.s, 6H), 7.64 (d, 1H, J ) 9.4 Hz), 8.38
(d, 1H, J ) 9.3 Hz), 8.53 (s, 1H), 8.9 (s, 1H), 10.96 (s, 1H); 13C
NMR δ 23.1, 38.6, 40.3, 116.0, 125.3, 129.8, 136.7, 145.7, 157.7.
Anal. Calcd for C9H12ClN5O4: C, 37.32; H, 4.18; N, 24.18.
Found: C, 37.09; H, 4.26; N, 23.88.
4-CH3OC6H4
H
a
b
Extremely hydroscopic, no mp was obtained. 9% of the
corresponding oxadiazole was isolated along with the product.
c Bisadduct was obtained when 2 equiv of 12 was used. Was
d
obtained as the bis hydrochloride salt. e The yield for the free
amidrazones.
N ′-(4-Me t h ylp h e n yl)-N ,N -d im e t h ylh yd r a zon ofor m a -
m id e h yd r och lor id e (1e): 75% yield; white solid; mp 212-213
°C; 1H NMR δ 2.21 (s, 3H), 3.21 (br. S, 6H), 6.78 (d, 2H, J ) 7.2
Hz), 7.04 (d, 2H, J ) 7.2 Hz), 8.44 (s, 1H); 13C NMR δ 19.9, 41.9,
113.4, 129.0, 129.1, 145.1, 159.1; HRMS calcd for C10H16N3 (M
+ 1) 178.1344, found 178.1347.
Sch em e 4
N′-(P en t a flu r op h en yl)-N,N-d im et h ylh yd r a zon ofor m a -
m id e h yd r och lor id e (1f): 98% yield; white solid; mp 202-204
1
°C; H NMR δ 3.13 (s, 6H), 8.38 (s, 1H); 13C NMR δ 38.7, 40.4,
116.2, 128.1, 137.0, 137.4, 137.6, 139.6, 140.7, 143.0, 160.1. Anal.
Calcd for C9H9ClF5N3: C, 37.32; H, 3.13; N, 14.51. Found: C,
36.87; H, 2.97; N, 14.01.
formamidrazones with both electron-deficient aromatic
substituents (entries 1c, 1d , and 1f) and more electron-
rich aromatic rings (entries 1a , 1e, 1o, and 1r ) were
prepared in 69-98% yields (Table 1). A number of novel
heterocyclic formamidrazones (entries 1h , 1l, 1p , and 1q)
are now available in 73-98% yields. In reactions of
acyclic 1,1-disubstituted hydrazines, the yields of the
corresponding compounds (entries 1g and 1o) were 88%
and 90%. Similarly, compounds 1j and 1k were prepared
from unsubstituted hydrazine giving 69% and 98% yields.
When we extended this procedure to hydrazides 13,
1,3,4-oxadiazoles 14 were obtained as pure compounds
in 95-98% yields (Scheme 4).
N,N,N′,N′-Tetr a m eth ylh yd r a zon ofor m a m id e h yd r och lo-
1
r id e (1g): 88% yield; colorless solid; mp 144-145 °C; H NMR
δ 2.62 (s, 3H). 2.67 (s, 3H), 3.00 (br, 6H), 7.94 (br.s, 1H); 13C
NMR δ 38.0, 44.0, 48.5, 157.5. Anal. Calcd for C5H14ClN3: C,
39.60; H, 9.37; N, 27.71. Found: C, 39.54; H, 9.77; N, 27.44.
N′-(4-N′′-oxid eison icot in oyl)-N,N-d im et h ylh yd r a zon o-
for m a m id e h yd r och lor id e (1h ): 73% yield; white solid; mp
155-156 °C; 1H NMR δ 3.20 (s, 3H), 3.22 (s, 3H), 7.89 (d, 2H, J
) 3.9 Hz), 8.27 (s, 1H), 8.77 (s, 2H); 13C NMR δ 42.3, 123.9, 141.8,
150.0, 160.0, 167.1; HRMS calcd for C9H12N4O2 208.0960, found
208.0963. Anal. Calcd for C9H13ClN4O2: N, 22.90. Found: N,
22.75.
N,N-Dim et h yl-N′-t olu en olsu lfon ylfor m a m id r a zon h y-
d r och lor id e (1i): 79% yield; white solid; mp 215-216 °C; 1H
NMR δ 2.32 (s, 3H). 2.90 (s, 3H), 3.17 (s, 3H), 7.37 (d, 2H, J )
8.0 Hz), 7.66 (d, 2H, J ) 8.0 Hz), 8.03 (s, 1H); 13C NMR δ 22.5.
38.8, 45.2, 129.6, 131.9, 133.2, 148.1, 160.6. Anal. Calcd for
C10H16ClN3O2S: C, 43.24; H, 5.81; N, 15.13. Found: C, 43.23;
H, 5.93; N, 15.15.
Con clu sion . A simple and efficient procedure of
preparation of dimethylformamidrazones was developed.
Eighteen examples were prepared in 69-99% yields.
N,N-Dim eth ylh yd r a zon ofor m a m id e h yd r och lor id e (1j):
69% yield; colorless crystals; mp 215-216 °C; 1H NMR δ 2.57
(s, 6H). 2.60 (s, 3H), 8.38 (s, 1H); 13C NMR δ 35.9, 145.9.
N,N-Dim eth ylh yd r a zon ofor m a m id in e (1k ): 98% yield;
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined with a
MEL-TEMP capillary melting point apparatus equipped with a
Fluka 51 digital thermometer. NMR spectra were taken in
DMSO-d6, D2O, and CDCl3 with tetramethylsilane as the
internal standard for 1H (300 MHz) or solvent as the internal
standard for 13C (75 MHz). THF was distilled from sodium/
1
colorless oil; H NMR δ 2.64 (s, 3H), 2.66 (s, 3H), 2.71 (s, 3H),
7.83 (s, 1H), 7.86 (s, 1H); 13C NMR δ 36.9, 39.9, 153.7, 163.2.
N,N-Dim eth yl-N′-1,2,4-tr ia zol-4-ylfor m a m id in e h yd r o-
ch lor id e (1l): 91% yield; white solid; mp 176-177 °C; 1H NMR

2248 J . Org. Chem., Vol. 65, No. 7, 2000
Notes
δ 38.4, 44.0, 44.8, 53.7, 54.5, 158.5. Anal. Calcd for C8 H20
Cl2N4: C, 39.51; H, 8.29; N, 23.04. Found: C, 39.12; H, 8.65; N,
22.71.
δ 2.81 (s, 3H), 2.94 (s, 3H), 7.99 (s, 1H), 9.06 (s, 2H); 13C NMR
δ 36.3, 42.6, 141.7, 163.1. Anal. Calcd for C5H10ClN5: N, 39.88.
Found: N, 40.07.
-
N,N-Dim eth yl-N′-(ph en ylsu lfon yl)h ydr azon ofor m ide h y-
d r och lor id e (1m ): 89% yield; white solid; mp 198-200 °C; H
NMR δ 2.87 (s, 3H), 3.15 (s, 3H), 7.54 (t, 2H, J ) 7.8 Hz), 7.66
(t, 1H, J ) 7.8 Hz), 7.80 (d, 2H, J ) 7.8 Hz), 8.03 (s, 1H); 13C
NMR δ 39.1, 45.6, 129.9, 131.8, 136.5, 137.0, 161.0. Anal. Calcd
for C9H14ClN3O2S: C, 40.99; H, 5.36; N, 15.94. Found: C, 40.87;
H, 5.58; N, 15.96.
N′-(1,3-Dioxo-1,3-d ih yd r o-2H-isoin d ol-2-yl)-N,N-d im eth -
ylim in ofor m a m id e h yd r och lor id e (1n ): 87% yield; white
solid; mp 247-248 °C; 1H NMR δ 3.18 (s, 3H), 3.27 (s, 3H), 7.77
(dd, 4H, J ) 8.0 Hz, 3.1 Hz), 8.20 (s, 1H); 13C NMR δ 39.0, 45.6,
125.0, 130.3, 137.3, 160.4, 167.1.
N,N-Dim et h yl-N′-m or p h olin oim in ofor m a m id e h yd r o-
ch lor id e (1q): 74% yield; white solid; mp 145-146 °C; 1H NMR
δ 2.92 (t, 2H, J ) 8.0 Hz), 2.96 (s, 3H), 3.17 (s, 3H), 3.72 (s, 3H),
8.07 (s, 1H); 13C NMR δ 38.2, 44.6, 57.1, 67.4, 157.9. Anal. Calcd
for C7H16ClN3O: N, 21.70. Found: N, 21.28.
N′-(4-Met h oxyp h en yl)-N,N-d im et h ylh yd r a zon ofor m a -
m id e h yd r och lor id e (1r ): 91% yield; white solid; mp 185-186
°C; 1H NMR δ 3.03 (s, 3H), 3.19 (s, 3H), 3.70 (s, 3H), 6.84-6.85
(br. s, 4H), 8.04 (s, 1H); 13C NMR δ 38.3, 44.8, 57.2, 116.5, 117.4,
141.8, 156.0, 160.2. Anal. Calcd for C10H16ClN3O: N, 18.29.
Found: N, 18.00.
2-P h en yl-1,3,4-oxa d ia zole (14a ): 89% yield; white solid; mp
34-36 °C; 1H NMR δ 7.75-7.90 (m, 3H), 8.20 (d, 2H, J ) 8.4
Hz), 9.57 (s, 1H); 13C NMR δ 123.2, 126.6, 129.3, 131.9, 154.4,
163.6.
2-(4-P yr id in yl)-1,3,4-oxa d ia zole (14b ): 95% yield; white
solid; mp 118 °C; 1H NMR δ 7.98 (d, 2H, J ) 6.1 Hz), 8.66 (s,
1H), 8.88 (d, 2H, J ) 6.1 Hz); 13C NMR δ 120.4, 130.6, 150.9,
153.3, 163.0. Anal. Calcd for C7H5N3O: C, 57.14; H, 3.43; N,
28.56. Found: C, 57.25; H, 3.44; N, 28.47.
1
N ′-Me t h yl-N ′-p h e n yl-N ,N -d im e t h ylh yd r a zon ofor m a -
m id e h yd r och lor id e (1o): 90% yield; white solid; mp 223-224
1
°C; H NMR δ 3.04 (s, 3H), 3.10 (s, 3H), 3.19 (s,3H), 6.91-7.02
(m, 3H), 7.29 (t, 2H, J ) 6.8 Hz), 8.10 (s, 1H); 13C NMR δ 38.5,
44.4, 44.9, 116.5, 123.7, 131.0, 150.7, 159.8. Anal. Calcd for
C10H15ClN3: C, 56.20; H, 7.56; N, 19.67. Found: C, 55.77; H,
8.03; N, 19.70.
N ,N -Dim e t h yl-N ′-(4-m e t h ylp ip e r a zin o)im in ofor m a -
m id e bish yd r och lor id e (1p ): 87% yield; white solid; mp 250-
251 °C; 1H NMR δ 2.79 (s, 3H), 2.93 (s, 3H), 3.13 (s, 3H), 3.22 (t,
4H, J ) 7.2 Hz), 3.40 (t, 4H, J ) 7.2 Hz), 8.08 (s, 1H); 13C NMR
J O991807G