SCHEME 3. Thermal Removal of Boc-group
General Procedure for Dialkylation, Synthesis of Di-tert-butyl
,2-Dibenzylhydrazine-1,2-dicarboxylate 5a: To a solution of di-
1
tert-butyl hydrazine-1,2-dicarboxylate (500 mg, 2.15 mmol) in DMF
10 mL) was added cesium carbonate (2.10 g, 6.45 mmol) and
(
benzyl bromide (809 mg, 4.73 mmol). The mixture was stirred at
room temperature for 7 h. The crude product was diluted with water
(
20 mL) and extracted with ethyl acetate (3 × 20 mL). The
combined organic phases were washed with brine (3 × 20 mL),
dried over magnesium sulfate, and concentrated in vacuo. Flash
chromatography (ethyl acetate/hexane 1/20) yielded 91% of 5a as
SCHEME 4. Alkylation of 7
1
a white solid. H NMR (600 MHz, CDCl
(
MHz, CDCl , 50 °C) δ 28.8, 53.6, 81.7, 128.3, 129.1, 130.5, 137.8,
3
3
, 50 °C) δ 1.32-1.45
m, 18H), 4.18-4.93 (m, 4H), 7.08-7.27 (m, 10H). 13C NMR (600
+
+
1
55.8. MS (ESI-TOF): calcd for C24
32 2 4
H N O Na (MNa ), 435.2254;
found, 435.2260. Mp 104.5-105.4 °C.
General Procedure Unsymmetrically Disubstituted Deriva-
tives, Synthesis of Di-tert-butyl 1-Allyl-2-(prop-2-ynyl)hydrazine-
1,2-dicarboxylate 6b: To a solution of 4d (300 mg, 1.11 mmol)
Removal of the Boc-group from all the aforementioned
products under standard conditions gives rise to the mono-, di-,
and trisubstituted hydrazines.
in DMF (6 mL) were added cesium carbonate (398 mg, 1.22 mmol)
and allyl bromide (201 mg, 1.66 mmol). The reaction mixture was
stirred for 16 h at room temperature. The reaction was diluted with
water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The
combined organic phases were washed with brine (3 × 20 mL),
dried over magnesium sulfate, and concentrated in vacuo. Flash
In summary we have investigated the use of di-tert-butyl
hydrazine-1,2-dicarboxylate 3 as a precursor for the synthesis
of certain mono-, di-, and trisubstituted hydrazines. The ease
with which the degree of substitution can be controlled makes
this commercially available protected hydrazine a practical and
useful precursor for the synthesis of substituted hydrazines and
adds to the already existing synthetic methods for achieving
substituted hydrazines. Furthermore, we have shown that
compounds such as 5a-e upon heating loose one of the two
Boc-groups and that the resulting monoprotected hydrazine can
be alkylated to yield trisubstituted hydrazines.
chromatography (ethyl acetate/hexane 1/20) yielded 75% of 6b as
1
a colorless liquid. H NMR (600 MHz, CDCl
3
, 50 °C) δ 1.46 (s,
1
8H), 2.22 (s, 1H), 4.00-4.59 (m, 4H), 5.12-5.22 (m, 2H), 5.96-
.97 (m, 1H). C NMR (600 MHz, CDCl , 50 °C) δ 29.0, 29.1,
3
13
5
40.0, 40.1, 42.1, 53.7, 55.9, 73.0, 73.5, 78.0, 79.3, 82.0, 82.4, 118.0,
118.9, 134.2, 134.9, 155.2. MS (ESI-TOF): calcd for C16
26 2 4
H N O -
+
+
Na (MNa ), 333.1785; found, 333.1784.
Synthesis of tert-Butyl 1,2-Di(prop-2-ynyl)hydrazinecarboxy-
late 7: A solution of 5d (400 mg, 1.30 mmol) in diphenyl ether
(10 mL) was heated to 185 °C for 1.5 h. The crude mixture was
subjected to flash chromatography using hexane (250 mL) and then
Experimental Section
ethyl acetate/hexane 1/16, compound 7 was isolated in 71% as a
1
General Procedure for Monoalkylation, Method A, Synthesis
of Di-tert-butyl 1-Benzylhydrazine-1,2-dicarboxylate 4a: To a
solution of di-tert-butyl hydrazine-1,2-dicarboxylate (500 mg, 2.15
mmol) in DMF (10 mL) was added cesium carbonate (1.40 g, 4.30
mmol) and benzyl bromide (405 mg, 2.37 mmol). The mixture was
stirred at room temperature for 2 h. The reaction mixture was diluted
with water (20 mL) and extracted with ethyl acetate (3 × 20 mL).
The combined organic phases were washed with brine (3 × 20
mL), dried over magnesium sulfate, and concentrated in vacuo.
white solid. H NMR (500 MHz, CDCl , rt) δ 1.46 (s, 9H), 2.19-
3
1
3
2.20 (m, 2H), 3.64 (m, 2H), 4.14 (s, 2H), 4.55 (bs, 1H). C NMR
(500 MHz, CDCl , rt) δ 28.2, 40.1, 71.2, 72.3, 79.5, 79.8, 81.8.
3
+
+
MS (ESI-TOF): calcd for C H N O Na (MNa ), 231.1104;
11
16
2
2
found, 231.1107. Mp 58.1-60.2 °C.
Synthesis of tert-Butyl 2-Methyl-1,2-di(prop-2-ynyl)hydrazi-
necarboxylate 8: To a solution of 7 (142 mg, 0.68 mmol) in DMF
(
8 mL) was added cesium carbonate (443 mg, 1.36 mmol) and
methyl iodide (484 mg, 3.41 mmol). The mixture was stirred at
room temperature for 3 days. The reaction mixture was diluted with
water (30 mL) and extracted with dichloromethane (3 × 25 mL).
The combined organic phases were washed with brine (3 × 25
mL), dried over magnesium sulfate, and concentrated in vacuo.
Flash chromatography (ethyl acetate/hexane 1/10) yielded 86% of
1
4
a as a white solid. H NMR (600 MHz, CDCl
3
, 50 °C) δ 1.43 (s,
9
H), 1.48 (s, 9H), 4.62 (bs, 2H), 6.2 (bs, 1H), 7.25-7.32 (m, 5H).
1
3
C NMR (500 MHz, CDCl
3
, rt) δ 28.4, 53.0, 54.6, 81.4, 127.6,
+
1
28.6, 137.4, 155.2. MS (ESI-TOF): calcd for C17H N O Na
26 2 4
Flash chromatography (ethyl acetate/hexane 1/30) yielded 50% of
+
(MNa ), 345.1785; found, 345.1791. Mp 103.1-105.2 °C.
1
8
as a colorless liquid. H NMR (500 MHz, CDCl
3
, rt) δ 1.46 (s,
General Procedure for Monoalkylation, Method B, Synthesis
9
H), 2.18-2.20 (m, 2H), 2.78 (s, 3H), 3.74 (bs, 2H), 4.09 (bs, 1H).
C NMR (500 MHz, CDCl
1.5. MS (ESI-TOF): calcd for C12H N O Na (MNa ), 245.1260;
of Di-tert-butyl 1-Allylhydrazine-1,2-dicarboxylate 4c: Di-tert-
butyl hydrazine-1,2-dicarboxylate (300 mg, 1.29 mmol) was
dissolved in a mixture of toluene (2 mL) and 5% aqueous sodium
hydroxide (2 mL). To the biphasic mixture were added tetrabutyl-
ammonium hydrogensulfate (10 mg, 0.03 mmol) and allyl bromide
13
3
, rt) δ 28.6, 45.8, 71.1, 72.3, 80.27,
+
+
8
18 2 2
found, 245.1257.
Acknowledgment. The author thanks Professor K. B.
Sharpless and Professor Valery V. Fokin for their advice.
Financial support from H. Lundbeck A/S and The Danish
Ministry of Science, Technology, and Innovation is highly
appreciated.
(
468 mg, 3.87 mmol). The reaction was stirred at room temperature
for 2.5 h. Water (20 mL) was added, and the mixture was extracted
with ethyl acetate (3 × 15 mL). The combined organic phases were
washed with brine (15 mL), dried over magnesium sulfate, and
concentrated in vacuo. Flash chromatography (ethyl acetate/hexane
1
1
/14) yielded 88% of 4c as a white solid. H NMR (600 MHz,
CDCl
1
2
3
, 50 °C) δ 1.43 (s, 9H), 1.48 (s, 9H), 4.62 (bs, 2H), 6.22 (bs,
H), 7.25-7.32 (m, 5H). 13C NMR (600 MHz, CDCl
, 50 °C) δ
8.4, 52.7, 53.3, 81.3, 81.4, 117.7, 133.4, 155.3. MS (ESI-TOF):
Supporting Information Available: Experimental procedures
and full spectroscopic details. This material is available free of
charge via the Internet at http://pubs.acs.org.
3
+
+
24 2 4
calcd for C13H N O Na (MNa ), 295.1628; found, 295.1633. Mp
74.0-74.4 °C.
JO0525783
J. Org. Chem, Vol. 71, No. 9, 2006 3629