hexane to give 4g (65%), mp 175 ЊC; 1H NMR (400 MHz,
CDCl3) δ 1.38 (s, 18H, CH3), 7.68–7.74 (m, 2H, arom.), 7.77–
7.87 (m, 2H, arom.); 13C NMR (CDCl3) δ 28.1 (CH3), 85.5
(CMe3), 124.3 (arom. CH), 130.2 (arom. C), 135.2 (arom. CH),
dryness in vacuo to give 3bؒ2HCl (quantitative yield), mp 225–
235 ЊC; 1H NMR (400 MHz, D2O) δ 8.28 (d, J = 6.7 Hz,
arom.), 8.85 (d, J = 6.7 Hz, arom.); 13C NMR (D2O) δ 126.5
(arom. CH), 143.2 (arom. CH), 146.8 (arom. C), 163.7 (CO).
These data were found to be identical to the dihydrochlor-
ide salt of isoniazid prepared from commercially available
isoniazid.
149.1 (COOtBu), 164.2 (O᎐C-Pht); IR (KBr) νmax/cmϪ1 1751,
᎐
1778, 1801 (C᎐O), 3320 (NH ). HRMS Calcd. for C H N O
᎐
2
18 23
2
6
[M ϩ H]ϩ m/z 363.1556, found 363.1548.
Dephthaloylation of compounds 4
Spectroscopic data of 15N labelled compounds
To a suspension of compound 4 in EtOH (10 ml) was added at
0 ЊC (or in one case at Ϫ20 ЊC, see Table 1) 1.5 equivalents of
H2NNH2, H2O (or in one case PhNHNH2, see Table 1) via
syringe. The solution was then allowed to warm to room tem-
perature. After 15 min a white precipitate was filtered off. The
filtrate was then evaporated to give a solid which was recrystal-
lized from EtOH to give pure compoud 5. Acetic hydrazide 5a
(75%, mp 66–68 ЊC) and benzoic hydrazide 5b (68%, mp 113–
117 ЊC) were found to be identical to authentic samples com-
mercially available (Lancaster). Pyruvic hydrazide 5c (55%), mp
58–60 ЊC (lit.,15 56–57 ЊC); 1H NMR (400 MHz, CDCl3) δ 1.10
(s, 9H, CH3), 4.00–4.30 (m, 3H, NH); 13C NMR (CDCl3) δ 27.6
(CH3), 38.8 (CMe3), 179.3 (COtBu); IR (KBr) νmax/cmϪ1 1637
4g*. 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 18H, CH3), 7.72–
7.79 (m, 2H, arom.), 7.83–7.90 (m, 2H, arom.); 13C NMR
(CDCl3) δ 28.3 (CH3), 85.5 (CMe3), 124.4 (arom. CH), 130.2 (d,
15
JCN = 10.3 Hz, arom. C), 135.2 (arom. CH), 149.1 (COOtBu),
15
164.2 (d, JCN = 13.3 Hz O᎐C-Pht).
᎐
6*. 1H NMR (400 MHz, D2O) δ 1.46 (s, CH3, 18H), 7.13 (d,
JHH = 5.9 Hz, 2H, arom.), 8.59 (d, JHH = 5.9 Hz, 2H, arom.),
10.07 (d, JHN = 102.8 Hz, 1H, NH); 13C NMR (CDCl3) δ 28.2
15
15
(CH3), 84.6 (CMe3), 121.9 (arom. CH), 139.9 (d, JCN = 11.6
Hz, arom. C), 150.5 (arom. CH), 150.9 (COOtBu), 164.5 (d,
JCN = 14.9 Hz, Pyr-CO-); HRMS Calcd. for C16H24N215NO5
15
m/z 339.1686, found 339.1681.
(C᎐O), 3300 (NH). Trifluoroacetic hydrazide 5d (70%), mp
᎐
114 ЊC (lit.,16 110–113 ЊC). Triphenylmethylhydrazine 5f (100%)
(this compound being unstable, we only succeeded in perform-
ing its 13C NMR spectrum) 13C NMR (CDCl3) δ 74.8 (CPh3),
127.3, 128.6, 129.3 (arom. CH), 144.5 (arom. C).
3b*(15N, 14N). 1H NMR (400 MHz, D2O) δ 8.28 (d, JHH = 6.5
Hz, 2H, arom.), 8.87 (d, JHH = 6.5 Hz, 2H, arom.); 13C NMR
(D2O) δ 126.1 (arom. CH), 143.2 (arom. C), 146.8 (arom. CH),
15
163.6 (d, JCN = 13.3 Hz, Pyr-CO-). HRMS Calcd. for
C6H7N215NO m/z 138.0560, found 138.0563.
1,1-Bis(tert-butoxycarbonyl)hydrazine 5g. (87%), mp 102–
104 ЊC; 1H NMR (400 MHz, CDCl3) δ 1.45 (s, CH3, 18H), 4.36
(s, 2H, NH2); 13C NMR (CDCl3) δ 28.1 (CH3), 83.6 (CMe3),
Acknowledgements
Financial support from the European Communities
Commission under contract BMH4-CT96-1492 is gratefully
acknowledged.
150.3 (COOtBu); IR (KBr) νmax/cmϪ1 1741 (C᎐O), 3353 (NH).
᎐
HRMS Calcd. for C10H21N2O4 m/z 233.1501, found 233.1503.
N-(tert-Butoxycarbonyl)aminophthalimide 6
To a solution of 4g (500 mg) in CH2Cl2 was added 1.5 equiv-
alents of trifluoroacetic acid and the solution was stirred during
36 h. After removing the solvent in vacuo, the crude product
References
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1
was chromatographed to give 6 (65%), H NMR (400 MHz,
CDCl3–DMSO) δ 1.50 (s, 9H, CH3), 7.88–7.96 (m, 4H, arom.),
9.60 (s, 1H, NH); 13C NMR (CDCl3) δ 28.7 (CH3), 81.9 (CMe3),
124.1 (arom. CH), 130.4 (arom. C), 135.3 (arom. CH), 154.8
(COOtBu), 166.0 (O᎐C-Pht); IR (KBr) νmax/cmϪ1 1706, 1740,
᎐
1783 (C᎐O), 3395 (NH). HRMS Calcd. for C H N O
᎐
13 14
2
4
[MϩH]ϩ m/z 263.1032, found 263.1034.
NЈ,NЈ-Bis(tert-butoxycarbonyl)isonicotinohydrazide 8†
The typical conditions previously described for the preparation
of 4a were used starting from 5g (180 mg, 0.8 mmol), CO(Im)2
(420 mg, 2.6 mmol) and isonicotinic acid (pyridine-4-carboxylic
acid) (320 mg, 2.6 mmol) in THF at reflux during 72 hours
(75%), 1H NMR (400 MHz, CDCl3) δ 1.46 (s, CH3, 18H), 7.13
(d, J = 5.9 Hz, 2H, arom.), 8.59 (d, J = 5.9 Hz, 2H, arom.), 9.90
(s, 1H, NH); 13C NMR (CDCl3) δ 28.2 (CH3), 84.7 (CMe3),
121.8 (arom. CH), 139.9 (arom. C), 150.6 (arom. CH), 150.9
(COOtBu), 164.5 (Pyr-CO); IR (KBr) νmax/cmϪ1 1698, 1756
(C᎐O). HRMS Calcd. for C H N O m/z 338.1715, found
᎐
16 24
3
5
338.1708.
Deprotection of INH
The N,N-bis(tert-butoxycarbonyl)isonicotinic hydrazide 8 † (7.4
mmol) was dissolved in 1.5 ml of 3 M HCl and left to stand at
room temperature for one hour. The solution was evaporated to
14 J. A. Stafford, M. F. Brackeen, D. S. Karanewsky and N. L. Valvano,
Tetrahedron Lett., 1993, 34, 7873.
15 A. Bühler and B. Fierz-David, Helv. Chim. Acta, 1943, 26, 2131.
16 W. Ried and G. Franz, Liebigs Ann. Chem., 1961, 644, 141.
† IUPAC name: NЈ,NЈ-bis(tert-butoxycarbonyl)pyridine-4-carbo-
hydrazide.
Paper 8/07230B
3688
J. Chem. Soc., Perkin Trans. 1, 1998, 3685–3688