Simple preparation of monoalkylhydrazines

Article abstract of DOI:10.1055/s-2004-831336

Alkylation of t-butyl isopropylidene carbazate with alkyl bromides occurs under phase-transfer conditions. Acid hydrolysis of the product completes a simple two-step synthesis of monoalkylhydrazines.

Full text of DOI:10.1055/s-2004-831336

LETTER
2355
Simple Preparation of Monoalkylhydrazines
S
imple Preparation
e
of Monoa
v
lkylhydrazine
i
s
n G. Meyer*
Dow AgroSciences LLC, 9330 Zionsville Road, Indianapolis, IN 46268, USA
Fax +1(317)3373215; E-mail: kgmeyer@dow.com
Received 9 March 2004
(Table 1, 2e), which could not be used under previous
conditions.5 Work-up consists only of washing the reac-
tion mixture with water until a neutral pH is obtained, fol-
lowed by removal of the toluene in vacuo. The reaction
does not require anhydrous conditions and has been suc-
cessfully used on a multi-gram scale.7 The reaction is lim-
ited to the use of primary alkyl bromides as the alkylating
agent, although activated (i.e. allyl, benzyl, etc.) alkyl
chlorides have also been used successfully.8
Abstract: Alkylation of t-butyl isopropylidene carbazate with alkyl
bromides occurs under phase-transfer conditions. Acid hydrolysis
of the product completes a simple two-step synthesis of monoalkyl-
hydrazines.
Key words: t-butyl carbazate, hydrazine, phase-transfer, alkyla-
tion, acid hydrolysis
tert-Butyl carbazate is a popular reagent for the prepara-
tion of substituted hydrazines. Protocols for the synthesis
of aryl1 and di- and tri-substituted2 hydrazines from tert-
butyl carbazate have recently appeared in the literature.
Procedures for the formation of monoalkylhydrazines,
important compounds in the synthesis of heterocycles
containing an N-N bond,3 from tert-butyl carbazate are
also present in the literature, but are limited in scope. Ven-
ton et al.4 reported formation of monoalkylhydrazines via
Table 1 Alkylation of t-Butyl Carbazate Acetone Hydrazone
Product
R
Yield (%)a
condensation of tert-butyl carbazate with ketones or alde- 2a
CH2CH2CH3
CH2CH2F
84
83
81
77
93
93
hydes followed by reduction with borane. This highly use-
ful method provides access to hydrazines with secondary
2b
alkyl groups, but is limited to saturated ketones and alde-
hydes. Also, the alkyl group itself is derived from a ketone
or aldehyde, limiting the hydrazines that can be prepared
from commercially available reagents.
2c
CH2(c-C3H5)
CH2CH2OCH2CH3
CH2CCH
2d
2e
Alkylative methods have also been reported for the syn-
thesis of monoalkylhydrazines. Zwierzak et al. have de-
scribed phase-transfer conditions5,6 for the alkylation of
acetone N-(diethoxyphosphoryl)hydrazone with alkyl
bromides, but the procedure requires large amounts of
base, limiting the type of hydrazine that can be prepared,
and often requires a multi-step synthesis of the hydrazone
itself. In a recent report by Zwierzak et al.,2a alkylations of
tert-butyl isopropylidene carbazate (1) with alkyl bro-
mides are performed under anhydrous conditions with so-
dium hydride as the base. While high yields are obtained
under these conditions, a milder, non-anhydrous proce-
dure would enable the use of acid sensitive alkyl bromides
and provide a safer alternative to sodium hydride for the
large-scale preparation of monoalkylhydrazines.
2f
CH2(C6H5)
a Isolated yield.
b Determined by GC analysis.
Table 2 Hydrolysis of BOC Protected Hydrazones 2
Product
3a
R
Yield (%)a
CH2CH2CH3
CH2CH2F
73
89
89
95
95
99
3b
It has been discovered that 1 can be alkylated under phase-
transfer conditions using only a small excess of potassium
hydroxide as base (Table 1). Despite the use of elevated
temperatures (80 °C), the reaction conditions allow the
use of base sensitive halides such as propargyl bromide
3c
CH2(c-C3H5)
CH2CH2OCH2CH3
CH2CCH
3d
3e
3f
CH2(C6H5)
SYNLETT 2004, No. 13, pp 2355–2356
Advanced online publication: 01.09.2004
0
3
.1
1
.2
0
0
4
a Isolated yield prior to dilution and storage in EtOH.
DOI: 10.1055/s-2004-831336; Art ID: S02504ST
© Georg Thieme Verlag Stuttgart · New York

2356
K. G. Meyer
LETTER
(4) Ghali, N. I.; Venton, D. L.; Hung, S. C.; Le Breton, G. C.
J. Org. Chem. 1981, 46, 5413.
Hydrolysis of the hydrazone and removal of the BOC pro-
tecting group with two equivalents of aqueous HCl effec-
tively liberate the monoalkylhydrazine (Table 2). After
three hours the reaction is concentrated in vacuo and dried
via azeotropic removal of water with toluene. The result-
ing salts were dissolved in ethanol and stored as stock
solutions.9
(5) Zawadski, S.; Osowska-Pacewicka, K.; Zwierzak, A. Synth.
Commun. 1987, 485.
(6) The alkylation conditions described in ref.5 have also been
used for N-alkylation of N-substitued carboxamides. See:
Koziara, A.; Zawadzki, S.; Zwierzak, A. Synth. Commun.
1979, 527.
(7) Hydrazine 3c was prepared on 1 mol scale (68% overall
yield) without any modification of the experimental
procedure. In addition, a differential scanning calorimetry
(DSC) test established compound 1 to be chemically stable
in the temperature range described in the reaction conditions.
(8) Alkylations with allyl and benzyl chlorides were performed
under identical conditions as those described for alkyl
bromides with comparable yields and purities.
In conclusion, a simple, robust procedure for the synthesis
of monoalkylhydrazines has been described. The reaction
is performed under non-anhydrous conditions using inex-
pensive, readily accessible reagents. The utilization of po-
tassium hydroxide as the base presents a much safer
alternative to sodium hydride. These benefits make this
procedure the ideal method for both small- and large-scale
production of monoalkylhydrazines and add to the
breadth of synthetic methods of hydrazine preparation.
(9) The stock solutions of hydrazines have been stored in amber
vials at room temperature for up to 1 year with no noticeable
loss of molarity.
(10) Experimental Procedure for the Preparation of t-Butyl
Isopropylidene Carbazate (1): Added MgSO4 (ca. 2 g) and
5 drops of HOAc to a solution of tert-butyl carbazate (10 g,
75.6 mmol) in acetone (75 mL). The mixture was heated to
reflux for 1 h then cooled, filtered and concd in vacuo to give
12.58 g (97%) of a white solid. Mp 85–87 °C.; lit. mp2a 85–
87 °C. 1H NMR (300 MHz, CDCl3): d = 7.46 (br s, 1 H), 1.97
(s, 3 H), 1.77 (s, 3 H), 1.45 (s, 9 H). 13C NMR (300 MHz,
CDCl3): d = 16.1, 25.5, 28.4, 81.0, 150.0, 153.1.
General Preparation of Alkylated Hydrazones (2): Solid KOH
(powdered, 218 mg, 3.9 mmol) and tetrabutylammonium hydrogen
sulfate (100 mg, 0.3 mmol) were added to a solution of tert-butyl
isopropylidene carbazate (1)10 (516 mg, 3.0 mmol) in toluene (10
mL). The mixture was stirred vigorously and heated to 50 °C where-
upon neat alkyl bromide (3.6 mmol) was added slowly. The temper-
ature was increased to 80 °C and maintained until the reaction was
complete as indicated by GC-MS analysis (1–3 h). The mixture was
cooled and washed with H2O until the aqueous extract had a neutral
pH. The organic layer was dried (MgSO4) and concd in vacuo to
give lightly colored oils (2),11 which were used without further pu-
rification.
(11) 2a (R = n-propyl): 1H NMR (300 MHz, CDCl3): d = 3.45 (t,
J = 7.4 Hz, 2 H), 2.06 (s, 3 H), 1.86 (s, 3 H), 1.48 (m, 2 H),
1.44 (s, 9 H), 0.88 (t, J = 7.4 Hz, 3 H). 2b (R = 2-fluoro-
ethyl): 1H NMR (300 MHz, CDCl3): d = 4.56 (t, J = 5.1 Hz,
1 H), 4.40 (t, J = 5.1 Hz, 1 H), 3.86 (t, J = 5.1 Hz, 1 H), 3.78
(t, J = 5.1 Hz, 1 H), 2.07 (s, 3 H), 1.90 (s, 3 H), 1.46 (s, 9 H).
2c (R = cyclopropylmethyl): 1H NMR (300 MHz, CDCl3):
d = 3.36 (d, J = 6.9 Hz, 2 H), 2.08 (s, 3 H), 1.91 (s, 3 H), 1.45
(s, 9 H), 0.96 (m, 1 H), 0.43 (m, 2 H), 0.20 (m, 2 H). 2d
(R = 2-ethoxyethyl): 1H NMR (300 MHz, CDCl3): d = 3.69
(t, J = 6.3 Hz, 2 H), 3.48 (m, 4 H), 2.06 (s, 3 H), 1.88 (s, 3
H), 1.45 (s, 9 H), 1.16 (t, J = 7.1 Hz, 3 H). 2e (R = 3-
propynyl): 1H NMR (300 MHz, CDCl3): d = 4.24 (d, J = 2.3
Hz, 2 H), 2.18 (t, J = 2.3 Hz, 1 H), 2.10 (s, 3 H), 1.92 (s, 3
H), 1.46 (s, 9 H). 2f (R = benzyl): 1H NMR (300 MHz,
CDCl3): d = 7.29 (m, 5 H), 4.68 (s, 2 H), 2.03 (s, 3 H), 1.70
(s, 3 H), 1.45 (s, 9 H).
Monoalkylhydrazines (3): 2 N HCl (2 acid equiv) was added to a
solution of 2 in THF (0.5 M) and heated for 3 h at reflux. The mix-
ture was cooled and concd in vacuo. The residues were brought to
complete dryness by addition and in vacuo removal of toluene (3 ×)
and the yield was calculated. The resulting dihydrochloride salts12
were diluted with EtOH, filtered through a filter disc (0.2 mm) to re-
move fine particles, and stored at ambient temperature in amber vi-
als.
Acknowledgment
The author wishes to thank Dr. Kim Arndt for his successful efforts
to verify the reaction conditions on large scale. The author also wis-
hes to thank Dr. Mezzie Ash and the Global Reactive Chemicals Re-
source Center of The Dow Chemical Company for their analytical
support.
(12) 3a (R = n-propyl): 1H NMR (300 MHz, d6-DMSO): d =
2.84 (t, J = 7.7 Hz, 2 H), 1.57 (m, 2 H), 0.88 (t, J = 7.5 Hz, 3
H). 13C NMR (300 MHz, d6-DMSO): d = 11.1, 18.1, 52.2. 3b
(R = 2-fluoroethyl): 1H NMR (300 MHz, d6-DMSO): d =
4.60 (dt, J = 47.2, 4.7 Hz, 2 H), 3.19 (dt, J = 28.0, 4.7 Hz, 2
H). 13C NMR (300 MHz, d6-DMSO): d = 49.6 (d, J = 20 Hz),
80.5 (d, J = 166 Hz). 3c (R = cyclopropylmethyl): 1H NMR
(300 MHz, d6-DMSO): d = 2.78 (d, J = 7.5 Hz, 2 H), 1.01
(m, 1 H), 0.52 (m, 2 H), 0.31 (m, 2 H). 13C NMR (300 MHz,
d6-DMSO): d = 3.7, 6.4, 55.3. 3d (R = 2-ethoxyethyl): 1H
NMR (300 MHz, d6-DMSO): d = 3.56 (t, J = 5.5 Hz, 2 H),
3.45 (q, J = 7.0 Hz, 2 H), 3.05 (t, J = 5.5 Hz, 2 H), 1.12 (t,
J = 7.0 Hz, 3 H). 13C NMR (300 MHz, d6-DMSO): d = 15.0,
49.6, 65.7. 3e (R = 3-propynyl): 1H NMR (300 MHz, d6-
DMSO): d = 3.68 (d, J = 2.4 Hz, 2 H), 3.40 (t, J = 2.4 Hz, 1
H). 13C NMR (300 MHz, d6-DMSO): d = 39.1, 77.6, 78.8. 3f
(R = benzyl): 1H NMR (300 MHz, d6-DMSO): d = 7.45–
7.30 (m, 5 H), 4.06 (s, 2 H). 13C NMR (300 MHz, d6-
DMSO): d = 54.3, 128.8, 129.1, 130.1, 134.6.
References
(1) Kabalka, G. W.; Guchhait, S. K. Org. Lett. 2003, 5, 4129.
(2) (a) Zawadzki, S.; Zwierzak, A. Polish J. Chem. 2003, 77,
315. (b) Tšubrik, O.; Mäeorg, U.; Ragnarsson, U.
Tetrahedron Lett. 2002, 6213. (c) Tšubrik, O.; Mäeorg, U.
Org. Lett. 2001, 3, 2297.
(3) (a) Smith, P. A. S. The Chemistry of Open Chain Nitrogen
Compounds, Vol. 2; W. A. Benjamin: New York, 1966,
Chap. 9. (b) Sidgwick, N. V. Organic Chemistry of
Nitrogen, 3rd ed.; Oxford University Press: London, 1966,
Chap. 15. (c) Timberlake, J. W.; Stowell, J. C. In Chemistry
of Hydrazo-, Azo-, and Azoxy Groups; Patai, S., Ed.; Wiley:
New York, 1975, Chap. 4.
Synlett 2004, No. 13, 2355–2356 © Thieme Stuttgart · New York