An efficient synthesis of substituted hydrazides

Article abstract of DOI:10.1055/s-2005-869858

Routes for the selective synthesis of 1-, or 2-substituted hydrazides, and 1,2-disubstituted hydrazides are reported. These routes proceed via cyanoborohydride reduction of stable acyl hydrazone intermediates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869858

LETTER
1571
An Efficient Synthesis of Substituted Hydrazides
S
ubstituted Hydraz
a
ide Synthe
v
sis id J. Benstead,a Alison N. Hulme,*a Hamish McNab,*a Paul Wightb
a
School of Chemistry, The University of Edinburgh, Kings Buildings, West Mains Road, Edinburgh, EH9 3JJ, UK
Fax +44(131)6504743; E-mail: Alison.Hulme@ed.ac.uk; E-mail: H.McNab@ed.ac.uk
Avecia, PO Box 42, Hexagon House, Manchester, M9 8ZS, UK
b
Received 3 February 2005
predominantly the 2-substituted hydrazide 2 (Scheme 1).
The regioselectivity of synthesis of 1- or 2-substituted
hydrazides from simple hydrazines has been rationalized
in terms of a difference in the mechanisms.3c
Abstract: Routes for the selective synthesis of 1-, or 2-substituted
hydrazides, and 1,2-disubstituted hydrazides are reported. These
routes proceed via cyanoborohydride reduction of stable acyl
hydrazone intermediates.
Key words: aminations, reductions, hydrazones, condensation, In following these reaction conditions with a range of
regioselectivity
aroyl chlorides a number of problems were encountered.
Rapid reaction of the aroyl chloride even under slow
addition at 0 °C meant that a number of side-products was
produced, including the related diacyl hydrazines.3c Fur-
Substituted hydrazides have recently found use in applica-
thermore, the resultant mixtures of 1- and 2-substituted
hydrazides proved to be very difficult to separate, and on
a larger scale these frequently required careful distillation
which drastically lowered the yields of the reaction.
Finally, when we attempted to extend the reported pre-
paration of 2-substituted hydrazides3b to include the
reaction of a wider range of aroyl esters, no reaction was
observed even after extended reaction times of up to two
weeks. These problems, combined with an additional
need for a synthetic route for the preparation of 1,2-
dimethylhydrazides avoiding the use of the highly carci-
nogenic 1,2-dimethylhydrazine, prompted us to investi-
gate further the regioselective synthesis of substituted
hydrazides.
tions as diverse as: traceless linkers for solid-phase syn-
thesis;1a the synthesis of fluorobutenoic acid hydrazide
pesticides;1b the synthesis of new androstane steroid
derivatives;1c and as intermediates in the synthesis of
antimycobacterials.1d The synthesis and applications of
di- and tri-substituted hydrazides have been reviewed.2
Simple methods for the regioselective synthesis of 1- and
2-mono-substituted hydrazides were first reported in the
1950s and were refined in the 1970s (Scheme 1).3 More
recently, the palladium-catalyzed hydrazinocarbonylation
reaction has been shown to be an effective alternative for
the synthesis of some 1-methylhydrazides,1c whilst a cop-
per-catalyzed coupling of ortho-substituted aryl iodides
with benzoic acid hydrazides gives rise to moderate yields
of the corresponding 2-arylhydrazides.4a The Mitsunobu
reaction of N-acylaminophthalimides may be used to
prepare a range of 1-methyl and 1-benzylhydrazides.4b
Finally, an amination reaction of amides using chloramine
has also been shown to produce a limited number of
1-substituted methyl-, phenyl- and benzylhydrazides.4c
In order to control the reaction rate of the acid chloride
and prevent the formation of the diacyl hydrazine, the
reaction protocol reported by Condon was modified.3c
Dilution of the acid chloride with the reaction solvent to
give a 1.5 M solution in dichloromethane, and inversion
of the addition protocol (i.e. adding the acid chloride
solution to a solution of methyl hydrazine and not vice
versa), whilst increasing the number of equivalents of
methyl hydrazine employed, resulted in a significant
reduction in by-products. Under these new conditions
only the 1-methylhydrazide was observed in the crude
H
O
O
Me
N
Me
N
MeCO2R
b
MeCOCl
a
N
Me
N
H
Me
N
H
H
H2N
H
Me
1
2
1
material by H NMR spectroscopic and HPLC analysis.
Scheme 1 Reagents and conditions: (a) MeCOCl (0.33 equiv),
CH2Cl2, 0 °C to r.t.;3a (b) MeCO2R (1 equiv), EtOH (aq), reflux
(R = Me,3b R = Et3c).
Analytically pure hydrazides 3 were isolated by pouring
the reaction mixture onto a saturated solution of sodium
carbonate and extracting the hydrazide into dichloro-
methane. In this manner, tedious distillation procedures
were avoided and the yields of the 1-substituted
hydrazides 3 were greatly increased as shown in Table 1.5
The reaction of methylhydrazine with an acyl chloride,3a
or anhydride,3b,c has been reported to give the 1-sub-
stituted hydrazide 1 with high selectivity. Conversely, the
reaction of methylhydrazine with the corresponding
methyl,3b or ethyl ester3c has been reported to give
With a reliable synthesis of the 1-substituted hydrazides 3
in hand, we then attempted to synthesize the 1,2-disub-
stituted hydrazides 5. By analogy with the preparation of
N-substituted hydrazines,6a and simple 1,2-disubstituted
acetylhydrazides,6b we predicted that this should be
readily achieved using a reductive amination protocol
(Scheme 2).7 To this end, we were able to exploit the well-
SYNLETT 2005, No. 10, pp 1571–1574
1
7
.0
6
.2
0
0
5
Advanced online publication: 07.06.2005
DOI: 10.1055/s-2005-869858; Art ID: D03305ST
© Georg Thieme Verlag Stuttgart · New York

1572
D. J. Benstead et al.
LETTER
Table 1 Synthesis of 1-Substituted Arylhydrazides 3
Using this reductive amination protocol 1,2-disubstituted
hydrazides 5, could be produced in excellent yields (83–
97%) as shown in Table 2. This method is applicable to
both electron-rich and electron-poor aromatic acyl hydra-
zones 4 and is particularly attractive as it negates the need
for the use of dimethylhydrazine in the synthesis of 1,2-
dimethylhydrazides 5.
Method A
O
H
N
H
N
O
or
Method B
H
Cl
+
N
H
Ar
N
H
Me
Me
R
3
Arylhydrazide 3 (R)
3a (H)
Method Aa (%)c
Method Bb (%)c
69
68
66
65
61
90
92
93
92
79
Table 2 Synthesis of 1,2-Disubstituted Arylhydrazides 5
Arylhydrazide 3 (R) Acyl hydrazone 4 (%)a,b Hydrazide 5 (%)a,c
3b (OMe)
3c (Me)
3a (H)
4a (96)
4b (95)
4c (96)
4d (93)
4e (89)
5a (95)
5b (97)
5c (92)
5d (97)
5e (83)
3d (Cl)
3b (OMe)
3c (CH3)
3d (Cl)
3e (NO2)
a Method A: MeNHNH2 (6.5 M in CH2Cl2, 3 equiv), ArCOCl (neat,
slow addition), 0 °C, 3 h.
b Method B: MeNHNH2 (1.5 M in CH2Cl2, 10 equiv), ArCOCl (0.15
M in CH2Cl2, slow addition), 0 °C, 3 h.
3e (NO2)
a Isolated yields.
c Isolated yields.
b HCHO, PhCH3, reflux, 18 h.
c NaCNBH3, AcOH, MeOH, r.t., 18 h.
known, but unexpected stability of methylene hydra-
zones. Although few examples of acyl hydrazones such as
4 are known, they were readily produced by condensation
of the 1-substituted hydrazides 3 with formaldehyde in
toluene under Dean–Stark reflux conditions. The use of
paraformaldehyde allowed the accurate introduction of
the one equivalent of formaldehyde required for
monoalkylation, negating the need for purification of the
It was anticipated that the application of this simple two-
step procedure to unsubstituted arylhydrazides would
result in the regioselective synthesis of 2-substituted
hydrazides (Scheme 3). A range of unsubstituted hydra-
zides 6 is commercially available, making an attractive
starting point for the attempted condensation with formal-
dehyde. However, in the absence of the methyl group in
the 1-position the intermediate unsubstituted acyl hydra-
zone is not stable to isolation and rapid formation of cyclic
dimers and trimers occurs, in agreement with the results of
Fox et al. on a related condensation with formaldehyde.11
1
intermediate acyl hydrazones 4. H NMR spectroscopic
analysis of acyl hydrazones 4 in CDCl3 showed two char-
acteristic doublets corresponding to the methylene pro-
tons, typically at d = 6.45 and 6.25 ppm, with a geminal
coupling of 2JHH = 10.6 Hz.8 This unusually high coupling
constant has been reported in related systems;6b,9 and this
assignment was confirmed by COSY analysis of com-
pound 4b.
H
N
O
O
O
a
b
N
N
Ar
N
H
Ar
N
Ar
N
H
H
H
H
6
7
8
H
N
O
O
O
Me
N
a
b or c
N
Scheme 3 Reagents and conditions: (a) (CH3)2C=O, Na2SO4, r.t.,
Ar
N
H
Ar
N
Ar
N
H
18 h; (b) NaCNBH3, AcOH, MeOH, r.t., 18 h.
Me
Me
Me
3
4
5
In contrast, the same condensation reaction conducted
with acetone in place of formaldehyde gives stable acyl
hydrazones 7. These are characterized by two singlets in
Scheme 2 Reagents and conditions: (a) HCHO, PhCH3, reflux, 18
h; (b) Pd(OH)2, H2 (20 bar), EtOAc, 50 °C, 18 h; (c) NaCNBH3,
AcOH, MeOH, r.t., 18 h.
1
the H NMR spectrum in CDCl3,6b typically at d = 2.12
and 1.93 ppm.12 Reduction with NaCNBH3/AcOH, gives
the isopropyl-substituted hydrazides 8 as shown in
Table 3. Again, the efficiency of the cyanoborohydride
reduction was independent of the electron-donating/elec-
tron-withdrawing nature of the para substituent on the
acyl hydrazone intermediate 7.13
Different reduction conditions were investigated for the
conversion of acyl hydrazones 4 to 1,2-disubstituted
hydrazides 5. Literature methods for the catalytic hydro-
genation of hydrazones tend not to specify either the
hydrogen pressure and/or reaction temperature em-
ployed.10 A high pressure (20 atm) reduction protocol
using Pearlman’s catalyst [Pd(OH)2/C] in ethyl acetate
was shown to reduce acyl hydrazone intermediate 4c in a
In conclusion, we have developed an efficient synthesis of
1-methylhydrazides (3), 1,2-dimethylhydrazides (5), and
moderate yield (53%). However, the effectiveness of this 2-isopropylhydrazides (8). The methodology has been
method was by no means universal.
shown to be applicable to hydrazide precursors with a
range of electron-donating and electron-withdrawing
substituents. The route to the 1,2-dimethylhydrazides is
In contrast, the use of NaCNBH3 in the presence of acetic
acid was found to be particularly effective (Scheme 2).7
Synlett 2005, No. 10, 1571–1574 © Thieme Stuttgart · New York

LETTER
Substituted Hydrazide Synthesis
1573
Table 3 Synthesis of 2-Substituted Arylhydrazides 8
Acknowledgment
We thank the EPSRC (DTA award to DJB) and Avecia for funding.
Unsubstituted hydrazide
(R)
Acyl hydrazone 7 Hydrazide 8
(%)a,b
(%)a,c
References
6a (H)
7a (97)
7b (98)
7c (95)
7d (95)
7e (91)
8a (93)
8b (89)
8c (92)
8d (91)
8e (79)
(1) (a) Stieber, F.; Grether, U.; Waldmann, H. Chem.–Eur. J.
2003, 9, 3270. (b) Kraatz, U.; Kraemer, W.; Adersch, W.;
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Horváth, J.; Tuba, Z. J. Org. Chem. 1999, 64, 2134.
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Eur. J. Med. Chem. 1999, 34, 1093.
(2) Licandro, E.; Perdicchia, D. Eur. J. Org. Chem. 2004, 665.
(3) (a) Peet, N. P.; Sunder, S.; Cregge, R. J. J. Org. Chem. 1976,
41, 2733. (b) Hinman, R. L.; Fulton, D. J. Am. Chem. Soc.
1958, 80, 1895. (c) Condon, F. E. J. Org. Chem. 1972, 37,
3608.
6b (OMe)
6c (CH3)
6d (Cl)
6e (NO2)
a Isolated yields.
b (CH3)2C=O, Na2SO4, r.t., 18 h.
c NaCNBH3, AcOH, MeOH, r.t., 18 h.
particularly attractive as it avoids the use of 1,2-dimethyl-
hydrazine. The synthesis of 2-isopropylhydrazides opens
up a previously uninvestigated class of pharmacophore
which will provide an important bridge between 2-meth-
yl- and 2-tert-butylhydrazides.14 Now that a range of
unsubstituted hydrazides is readily available through the
use of an efficient carbodiimide/HOBt-mediated coupling
of carboxylic acids with hydrazine,15 facile extension of
this methodology to a diverse array of 2-substituted
hydrazides is envisaged.
(4) (a) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001,
3, 3803. (b) Brosse, N.; Pinto, M.-F.; Jamart-Grégoire, B. J.
Org. Chem. 2000, 63, 4370. (c) Khatib, A. A.; Sisler, H. H.
Inorg. Chem. 1990, 29, 309.
(5) All compounds gave spectroscopic data in agreement with
the assigned structures.
(6) (a) Perdicchia, D.; Licandro, E.; Maiorana, S.; Baldolib, C.;
Giannini, C. Tetrahedron 2003, 59, 7733. (b) Condon, F. E.
J. Org. Chem. 1972, 37, 3615.
(7) (a) Gomez, S.; Peters, J. A.; Maschmeyer, T. Adv. Synth.
Catal. 2002, 344, 1037. (b) Kobayashi, S.; Ishitani, H.
Chem. Rev. 1999, 99, 1069. (c) Gribble, G. W. Chem. Soc.
Rev. 1998, 27, 395.
(8) Data for acyl hydrazone 4c: 1H NMR (250 MHz, CDCl3):
d = 7.55 (2 H, d, J = 8.0 Hz, ArH), 7.25 (2 H, d, J = 8.0 Hz,
ArH), 6.45 (1 H, d, J = 10.6 Hz, N=CHaHb), 6.25 (1 H, d,
J = 10.6 Hz, N=CHaHb), 3.41 [3 H, s, (CO)NCH3], 2.39 (3 H,
s, ArCH3). 13C NMR (63 MHz, CDCl3): d = 171.29, 140.45,
131.81, 129.34 (2 C), 128.92, 128.07 (2 C), 27.53, 21.31.
MS (ESI+): m/z = 177 [M + H]+.
(9) (a) Pomerantz, M.; Bittner, S.; Khader, S. B. J. Org. Chem.
1982, 47, 2217. (b) Diel, P. J.; Maier, L. Phosphorus Sulfur
Relat. Elem. 1988, 36, 85.
Experimental for the Formation of 1-Methylhydrazides 3
To a solution of methylhydrazine (1.5 M in CH2Cl2) at 0 °C was
added the aroyl chloride (0.15 M in CH2Cl2) slowly via syringe
pump under an atmosphere of nitrogen. After stirring at 0 °C for 1
h the reaction was warmed to r.t. and stirred for a further 2 h. The
reaction mixture was then poured onto sat. aq Na2CO3 and extracted
with CH2Cl2. The combined organics were dried (Na2SO4) and con-
centrated under reduced pressure to give the pure hydrazide 3.
Experimental for the Formation of 1,2-Dimethylhydrazides 5
To a stirred solution of 1-substituted hydrazide 3 (0.25 M in tolu-
ene) was added paraformaldehyde (1.0 equiv). The reaction mixture
was heated under reflux under Dean–Stark conditions for 18 h. The
toluene was removed under reduced pressure to yield the acyl
hydrazone intermediate 4. To a solution of hydrazone 4 (0.25 M in
MeOH) was added NaCNBH3 (1.1 equiv) and AcOH (1.1 equiv).
The reaction mixture was stirred at r.t. for 18 h before being poured
cautiously onto sat. aq Na2CO3 and extracted with CH2Cl2. The
combined organics were dried (Na2SO4) and concentrated under
reduced pressure to give the pure 1,2-disubstituted hydrazide 5.
(10) (a) Neighbours, D. W.; Foster, A. L.; Clark, S. M.; Miller, J.
E.; Bailey, J. R. J. Am. Chem. Soc. 1922, 44, 1557.
(b) Taipele, K.; Smirnow, I. Chem. Ber. 1923, 56, 1794.
(c) Nilsson, J. W.; Kvarnström, I.; Musil, D.; Nilsson, I.;
Samulesson, B. J. Med. Chem. 2003, 46, 3985. (d) Cavill, J.
L.; Peters, J.-U.; Tomkinson, N. C. O. Chem. Commun.
2003, 728.
(11) Fox, H. H. J. Org. Chem. 1958, 23, 468.
(12) Data for acyl hydrazone 7c: 1H NMR (250 MHz, CDCl3):
d = 8.79 [1 H, br s, C(O)NH], 7.65 (2 H, d, J = 8.1 Hz, ArH),
7.25 (2 H, d, J = 8.1 Hz, ArH), 2.35 (3 H, s, ArCH3), 2.12 (3
H, s, CCH3), 1.93 (3 H, s, CCH3). 13C NMR (63 MHz,
CDCl3): d = 163.6, 155.6, 142.0, 130.5, 129.0 (2 C), 127.0 (2
C), 25.3, 21.3, 16.4. MS (ESI+): m/z = 191 [M + H]+.
(13) Data for 2-isopropyl hydrazides:
Experimental for Formation of 2-Isopropylhydrazides 8
To a stirred solution of unsubstituted hydrazide 6 (0.25 M in ace-
tone) was added Na2SO4 (ca. 100 equiv). The reaction mixture was
stirred at r.t. for 18 h, then filtered and concentrated under reduced
pressure to yield the acyl hydrazone intermediate 7 as a colorless
crystalline solid. To a solution of acyl hydrazone 7 (0.25 M in
MeOH) was added NaCNBH3 (1.1 equiv) and AcOH (1.1 equiv).
The reaction was stirred at r.t. for 18 h before being poured cau-
tiously onto sat. aq Na2CO3 and extracted with CH2Cl2. The com-
bined organics were dried (Na2SO4) and concentrated under
reduced pressure to give the pure 2-substituted hydrazide 8.
Compound 8a: 1H NMR (250 MHz, CDCl3): d = 7.54 (5 H,
m, ArH), 3.26 [1 H, sept, J = 6.3 Hz, CH(CH3)2], 1.13 [6 H,
d, J = 6.3 Hz, CH(CH3)2]. 13C NMR (63 MHz, CDCl3): d =
167.3, 132.8, 131.7, 128.6 (2 C), 126.7 (2 C), 51.2, 20.7 (2
C). MS (ESI+): m/z = 179 [M + H]+.
Compound 8b: 1H NMR (250 MHz, CDCl3): d = 7.74 (2 H,
d, J = 8.8 Hz, ArH), 6.93 (2 H, d, J = 8.8 Hz, ArH), 3.85 (3
H, s, ArOCH3), 3.20 [1 H, sept, J = 6.3 Hz, CH(CH3)2], 1.11
[6 H, d, J = 6.3 Hz, CH(CH3)2]. 13C NMR (63 MHz, CDCl3):
d = 166.9, 162.3, 128.5 (2 C), 125.0, 113.7 (2 C), 55.3, 51.2,
20.7 (2 C). MS (ESI+): m/z = 231 [M + Na]+.
Synlett 2005, No. 10, 1571–1574 © Thieme Stuttgart · New York

1574
D. J. Benstead et al.
LETTER
Compound 8c: 1H NMR (250 MHz, CDCl3): d = 8.63 [1 H,
s, C(O)NH], 7.65 (2 H, d, J = 8.1 Hz, ArH), 7.21 (2 H, d,
J = 8.1 Hz, ArH), 4.83 (1 H, NHNH), 3.23 [1 H, sept, J = 6.4
Hz, CH(CH3)2], 2.37 (3 H, s, ArCH3), 1.08 [6 H, d, J = 6.4
Hz, CH(CH3)2]. 13C NMR (63 MHz, CDCl3): d = 167.3,
142.2, 129.9, 129.2 (2 C), 126.7 (2 C), 51.2, 21.3, 20.7 (2 C).
MS (ESI+): m/z = 193 [M + H]+.
H, sept, J = 6.3 Hz, CH(CH3)2], 1.11 [6 H, d, J = 6.3 Hz,
CH(CH3)2]. 13C NMR (90 MHz, CDCl3): d = 165.2, 149.6,
138.3, 128.0 (2 C), 123.8 (2 C), 51.4, 20.7 (2 C). MS (ESI+):
m/z = 224 [M + H]+.
(14) For recent examples of the use of the use of 2-tert-
butylhydrazides, see: (a) Wang, Q.; Li, Z.; Huang, R.;
Cheng, J. Heteroat. Chem. 2001, 12, 68. (b) Nakagawa, Y.;
Hattori, K.; Minakuchi, C.; Kugimiya, S.; Ueno, T. Steroids
2000, 65, 117. (c) Mohammed-Ali, A. M.; Chan, T.-H.;
Thomas, A. W.; Strunz, G. M.; Jewett, B. Can. J. Chem.
1995, 73, 550.
(15) Zhang, X.; Breslav, M.; Grimm, J.; Guan, K.; Huang, A.;
Liu, F.; Maryanoff, C. A.; Palmer, D.; Patel, M.; Qian, Y.;
Shaw, C.; Sorgi, K.; Stefanick, S.; Xu, D. J. Org. Chem.
2002, 67, 9471.
Compound 8d: 1H NMR (250 MHz, CDCl3): d = 7.64 (2 H,
d, J = 8.6 Hz, ArH), 7.36 (2 H, d, J = 8.6 Hz, ArH), 3.17 [1
H, sept, J = 6.3 Hz, CH(CH3)2], 1.05 [6 H, d, J = 6.3 Hz,
CH(CH3)2]. 13C NMR (63 MHz, CDCl3): d = 166.3, 137.9,
131.1, 128.8 (2 C), 128.2 (2 C), 51.2, 20.7 (2 C). MS (ESI+):
m/z = 213 [35M + H]+, 215 [37M + H]+.
Compound 8e: 1H NMR (360 MHz, CDCl3): d = 8.29 (2 H,
d, J = 8.9 Hz, ArH), 7.95 (2 H, d, J = 8.9 Hz, ArH), 3.25 [1
Synlett 2005, No. 10, 1571–1574 © Thieme Stuttgart · New York