Synthesis of N-(protected)aminophthalimides: Application to the synthesis of singly labelled isoniazid

Article abstract of DOI:10.1039/a807230b

The synthesis of a series of N-(protected)aminophthalimides and the removal of their phthaloyl group leading to N-(protected) or N,N-bis(protected)hydrazines is described. As illustrated by the synthesis of monolabelled isoniazid 3b*, this strategy can be utilized for the preparation of monolabelled substituted hydrazines.

Full text of DOI:10.1039/a807230b

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Synthesis of N-(protected)aminophthalimides: application to the
synthesis of singly labelled isoniazid
Nicolas Brosse, Maria-Fatima Pinto and Brigitte Jamart-Grégoire*
MAEM UMR mixte CNRS-UHP no 7567, Faculté des Sciences, Université H. Poincaré
Nancy I, Bld des aiguillettes BP 239 F-54506 Vandoeuvre-lès-Nancy cedex France
E-mail: jamart@scbim.u-nancy.fr
Received (in Cambridge) 16th September 1998, Accepted 5th October 1998
The synthesis of a series of N-(protected)aminophthalimides and the removal of their phthaloyl group leading to
N-(protected) or N,N-bis(protected)hydrazines is described. As illustrated by the synthesis of monolabelled isoniazid
3b*, this strategy can be utilized for the preparation of monolabelled substituted hydrazines.
N-(Substituted)- or N,N-bis(substituted)hydrazines play an
O
O
NO2
ONH2
important role in organic chemistry because of their broad
range of synthetic applications which include the preparation
of azapeptides1 and heterocyclic2 and α-hydrazino acid com-
pounds.3 Several methods have been described in the literature
for the preparation of these substituted hydrazines which
usually require hydrazine or other commercially available sub-
stituted hydrazines as starting materials. One possible altern-
ative starting material is N-aminophthalimide 1. This com-
pound contains a protected nitrogen atom within the phthalide
moiety and a second nitrogen atom, capable of reacting with
electrophilic reagents which should lead to regiospecific
functionalization of 1. However, there are certain synthetic
limitations associated with 1 as well. For example, although
benzylation is possible via formation and hydrogenation of the
corresponding hydrazone,4 direct alkylation has not been
observed. In addition, acylation of 1 appears to be difficult to
perform. Studies described in the literature indicated that 1 is
inert towards even very reactive esters under conditions which
normally allow acylation of simple hydrazines. Furthermore,
when acyl chlorides are used this results in a mixture of
products.5
Perhaps the best result was obtained by M. J. Hearn and
Prisch who succeeded in acylating 1 under extreme conditions
by warming the neat compound in an excess of liquid acid
anhydrides at 120 ЊC.5 It is also worth noting that 1 undergoes
skeletal rearrangement to yield phthalohydrazide under acidic
or basic conditions.6 Thus, the degree of this conversion must
be taken into account when critically assessing the value of any
synthesis based on 1.
As part of our research dealing with the elucidation of the
mechanism of action of isoniazid (INH), a front-line antituber-
culosis drug,7 we showed for the first time that 1 can be easily
acylated, under mild conditions without rearrangement and in
good yield, with isonicotinic acid via a coupling reaction gener-
ally used for peptidic syntheses. Moreover, when N-amino[15N]-
phthalimide 1* was used as a starting material (obtained via
electrophilic amination of the commercially available potas-
sium [15N]phthalimide) we were able to synthesize N-iso-
nicotinamido[15N]phthalimide 2* which was subsequently
used as an intermediate in the preparation of singly labelled
isoniazid 3a*(14N, 15N)8 (Scheme 1).
i)
*
*
N-K+
N
NH2
+
NO2
O
O
1 N*= 14
1* N*= 15N
N
*
O
CONHNH2
iii)
ii)
*
N
NNHCO
N
3 N*= 14N
3a*(14N, 15N) N*=15
O
2 N*= 14N
N
2* N*= 15
N
Scheme 1 Reagents and conditions: i) DMF, rt, 1 h, 88%; ii) 4-C6H4N-
COOH, CO(Im)2, THF, reflux, 60 h, 78%; iii) N2H4, H2O, 15 min, rt,
70%.
imides 4 and the removal of their phthaloyl group leading to
N-(acyl)-, N-(alkyl)- and N,N-bis(alkoxycarbonyl)hydrazines 5
(Scheme 2).
O
1 N*= 14
N
i)
*
N
*
ii)
H2N-NPP'
5 N*= 14
5* N*= 15
NPP'
or
1* N*= 15
N
N
N
4 N*= 14
4* N*= 15N
N
O
Scheme 2 Reagents and conditions: i) see conditions and yields in
Table 1; ii) H2NNH2, H2O, EtOH, rt, 15 min, see footnotes and yields in
Table 1.
A synthetic application of this strategy is illustrated by the
preparation of the singly labelled N,N-bis(protected)hydrazine
5g*, required for the synthesis of isonicotinoyl[15N, 14NЈ]hydra-
zine 3b*(15N, 14N), the isotopic isomer of 3a*(14N, 15N).
Results and discussion
The results obtained are summarized in Table 1 and in Scheme
2.
Preparation of N-(protected)aminophthalimide 4
As a result, we postulated that this pathway could also pro-
vide a convenient means for preparing N-(protected) or N,N-
bis(protected)hydrazines and the corresponding singly labelled
compounds. In this paper, we now report conditions which
allow the synthesis of a series of N-(protected)aminophthal-
Based upon our previous studies, we first performed acylation
of 1 by acetic, benzoic and pyvaloic acid using 1,1Ј-carbonyl-
diimidazole [CO(Im)2] as an activating agent. These reactions
allowed the formation of the corresponding N-(acyl)amino-
J. Chem. Soc., Perkin Trans. 1, 1998, 3685–3688
3685

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Table 1
Compounds
obtained
Yield of
Yield of
Item
P
PЈ
Conditions
t/h
4 (%)a
5 (%)b
1
2
3
4
5
6
7
CH3CO
C6H5CO
tBuCO
F3CCO
Cl3CCO
(C6H5)3C
Boc
H
H
H
H
H
H
Boc
CH3COOH, CO(Im)2, THF, reflux
C6H5COOH, CO(Im)2, THF, reflux
tBuCOOH, CO(Im)2, THF, reflux
(F3CCO)2O, neat, 0 ЊC
Cl3CCOCl, pyridine, CH2Cl2, rt
(C6H5)3CCl, DMAP, Et3N, DMF, rt
Boc2O, DMAP, Et3N, THF, rt
20
96
96
2
4
20
2
4a
4b
4c
4d
4e
4f
82
65
72
87
90
34
65
5a, 75
5b, 68
5c, 55
5d, 70c
0
5f, 100
4g
5g, 87d
a Isolated yield calculated from 1. b Isolated yield calculated from the corresponding compound 4. c C6H5NHNH2 was used instead of hydrazine
hydrate. d Hydrazinolysis was performed at Ϫ20 ЊC during 2 hours.
phthalimides 4a, 4b and 4c in good to excellent yields (items 1, 2
and 3). Unfortunately, using trihalogenoacetic acids under the
same conditions led to the degradation of the reaction mixture.
However, we did succeed in obtaining N-(trifluoromethyl-
carbonyl)aminophthalimide 4d using neat trifluoroacetic acid
anhydride (item 4). N-(Trichloromethylcarbonyl)aminophthal-
imide 4e was also synthesized using trichloroacetyl chloride and
pyridine in CH2Cl2 (item 5). In addition, monoalkylation of 1
by a triphenylmethyl group was achieved, although in poor
yield, using triphenylmethyl chloride, DMAP as a catalyst and
Et3N in DMF at room temperature (item 6).
methylhydrazine) we were unable to isolate the corresponding
protected hydrazine as degradation of the reaction mixture
occurred. The triphenylmethylhydrazine 5f was obtained quan-
titatively but unfortunately this compound was unstable and so
we only succeeded in performing its 13C NMR spectrum. The
hydrazinolysis of 4g led to the formation of the new and inter-
esting compound 1,1-bis(tert-butoxycarbonyl)hydrazine 5g
which has, to the best of our knowledge, not been described in
the literature until now. Curiously, this reaction was impeded by
the formation of the N-(tert-butoxycarbonyl)hydrazine 7 which
can be explained by a nucleophilic attack of the hydrazine on
one of the two Boc groups as illustrated in Scheme 4. Based
upon this mechanism it appears that the hydrazine moiety of 7
arises equally from 4g and hydrazine hydrate (Scheme 4).
As carbamates are extensively used as protective groups for
amines, we attempted to obtain suitable conditions for the
introduction of a Boc or Z group to 1. Unreported results
obtained from our group showed that the use of BocCl,9
10
BocN3 and ZCl11 led to a slow degradation of the reaction
O
mixture. Furthermore, when using PhCH2OCOCCl3 in
acetonitrile12 only compound 4e was obtained resulting from
the splitting of the C–O bond of the starting ester.
Dephthaloylation
*
N-NHBoc
H2N-NHBoc +
Nucleophilic
attack
Successful introduction of Boc groups was eventually
achieved using Boc2O with DMAP as a catalyst and Et3N in
THF. Surprisingly under these conditions the unexpected
N,N-bis(tert-butoxycarbonyl)aminophthalimide 4g was iso-
lated. It is important to note that we never observed the
formation of the corresponding N-(tert-butoxycarbonyl)-
aminophthalimide 6 even when one equivalent of Boc2O was
used. Furthermore, we observed from monitoring the progres-
sion of the reaction by TLC that yield of 4g generally improved
as the amount of Boc2O was increased (from one to eight
equivalents). However, the best yield of 4g was obtained when
six equivalents of Boc2O were used as greater values tended to
make subsequent purification of the product troublesome.
Finally, it was possible to synthesize compound 6 in 65% yield
from 4g by using 1.5 equivalents of trifluoroacetic acid in
CH2Cl2 (Scheme 3).
7
6
O
4*g + H4N2
H2N-NHBoc
Dephthaloylation
*
Nucleophilic
attack
*
H2N-N(Boc)2
5*g
+ H2N-NHBoc
7 and 7*
Scheme 4
With regard to the 15N labelled synthesis of isonicotin-
oyl[15N,14NЈ]hydrazine 3b*(15N, 14N), it is necessary to min-
imise the nucleophilic attack of hydrazine on the Boc group in
order to avoid a decrease in the isotopic yield. From an earlier
systematic study we determined that an optimal yield of 5g
could be obtained by using 1.5 equivalents of hydrazine hydrate
in ethanol at Ϫ20 ЊC. It is also interesting to note that com-
pound 7 may be produced in 90% yield by treating 5g with a
catalytic amount of Mg(ClO4)2.14 As shown in Scheme 5, this
O
CF3COOH
*
Mg(ClO4 )2 cat.
*
N-NHBoc
4g
5g
H2N-NHBoc
CH2Cl2, rt, 48 h, 65%
CH3CN, rt, 90%
N* =14N 7
O
6 N*=14
N
Scheme 5
Scheme 3
condition could thus be used in the labelled series to selectively
synthesize 7*.
Preparation of protected hydrazines 5
In most cases removal of the phthaloyl group from compounds
4 was performed using hydrazine hydrate as a nucleophilic
agent and gave the corresponding protected hydrazines 5 in
good yields. However, dephthaloylation of compound 4d neces-
sitated the use of phenylhydrazine instead of hydrazine hydrate.
This avoided the formation of a complex between the phthalo-
hydrazide by-product and the protected hydrazine 4d, described
previously,13 which would have complicated the purification
(item 4). With regard to compound 4e we observed that regard-
less of the reactant used (hydrazine hydrate, phenylhydrazine or
Synthesis of isonicotinoyl[15N, 14NЈ]hydrazine 3b*(15N, 14N)
Based upon our strategy to obtain protected hydrazines, the
singly labelled N,N-bis(tert-butoxycarbonyl)hydrazine 5*g was
obtained using commercially avalaible potassium [15N]phthal-
imide as starting material. Acylation with isonicotinic acid
was performed using 1,1Ј-carbonyldiimidazole as a coupling
reagent to produce compound 8* in good yield. Deprotection
of the amino group was easily performed using 3 M HCl and
resulted in the formation of singly labelled isoniazid 3b*(15N,
3686
J. Chem. Soc., Perkin Trans. 1, 1998, 3685–3688

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*
N-(tert-Butylcarbonylamino)phthalimide 4c
*
CONHN(Boc)2
CONHNH2
The procedure previously described for the preparation of 4a
was employed using 4 equivalents of pivalic acid and 4 equiv-
alents of CO(Im)2 (72%), mp 118–120 ЊC; 1H NMR (400 MHz,
CDCl3) δ 1.30 (s, 9H, CH3), 7.55–7.67 (m, 2H, arom.), 7.79–
7.84 (m, 2H, arom.), 10.40–10.45 (m, 1H, NH); 13C NMR
(CDCl3) δ 27.7 (CH3), 38.9 (CMe3), 124.1 (arom. CH), 130.5
i)
ii)
5*g
•2HCl
N
N
3b* (15N,14N)•2HCl
8*
Scheme 6 Reagents and conditions: i) 4-C6H4N-COOH, CO(Im)2,
THF, reflux, 72 h, 75%; ii) 3 M HCl, AcOEt, quantitative yield.
(arom. C), 134.9 (arom. CH), 166.0 (O᎐C-Pht), 179.0 (COtBu);
᎐
᎐
IR (KBr) νmax/cmϪ1 1737, 1795 (C᎐O). HRMS Calcd. for
14N) as shown in Scheme 6 in an overall yield of 36% from
potassium [15N]phthalimide.
C10H5N2F3O3 m/z 246.1004, found 246.1004.
In conclusion, we have found appropriate conditions for the
acylation and alkylation of N-aminophthalimide without
N-(Trifluoromethylcarbonylamino)phthalimide 4d
N-Aminophthalimide 1 (18.5 mmol, 3 g) was dissolved with
stirring at 0 ЊC in 5 ml of trifluoroacetic anhydride. The solu-
tion was kept in an ice–water bath under stirring for 2 hours.
The excess of trifluoroacetic anhydride was removed in vacuo
and the remaining solid was washed with hexane to give 4d
allowing skeletal rearrangement to occur.
A subsequent
dephthaloylation leads to the formation of a series of 1-mono-
protected hydrazines and, for the first time, the formation of
N,N-bis(tert-butoxycarbonyl)hydrazine 5g. As illustrated by the
synthesis of compound 3b*(15N, 14N), we have demonstrated
that this strategy can be effectively utilized for the preparation
of hydrazine synthons which can then be used in other synthetic
schemes.
1
(90%), mp 122–124 ЊC; H NMR (400 MHz, CDCl3) δ 7.67–
8.11 (m, 4H, arom.), 9.69–10.11 (m, 1H, NH); 13C NMR
(CD3OD–DMSO) δ 90.6 (q, JCF = 288 Hz, CF3), 115.6 (arom.
CH), 124.1 (arom. CH), 129.9 (arom. C), 135.7 (arom. CH),
156.7 (q, JCF = 39 Hz, COCF ), 164.4 (O᎐C-Pht); IR (KBr)
᎐
3
Experimental
νmax/cmϪ1 1746, 1802 (C᎐O). HRMS Calcd. for C H N F O
᎐
10
5
2
3
3
Melting points were obtained on a Kofler hot-stage apparatus
and were uncorrected. The IR spectra were recorded on a FTIR
ATI MATTSON Genesis Series. Elemental analyses were per-
formed by the ‘service de Microanalyse du CNRS, Division de
Vernaison’. NMR spectra were recorded on a Bruker AM 400
MHz or 250 MHz. J Values are given in Hz. Mass spectra were
run on a micromass AutoSpec-Q spectrometer in the chemistry
department at Imperial College, London. Potassium [15N]-
phthalimide was purchased from Eurisotop CEA and N-amino-
phthalimide from Lancaster. Merck silica gel 60 was used for all
chromatographic separations and thin layer chromatographic
techniques used Merck silica gel 60 F254 TLC plates. Ether
refers to diethyl ether. Tetrahydrofuran and dichloromethane
were dried by distilling respectively over sodium–benzophenone
and P2O5.
m/z 258.0252, found 258.0255.
N-(Trichloromethylcarbonylamino)phthalimide 4e
To a cooled solution of N-aminophthalimide 1 (20 mmol, 3.24
g) and pyridine (30 mmol, 2.4 g) in CH2Cl2 (200 ml) was added
dropwise 1 equivalent of trichloroacetyl chloride (20 mmol).
Stirring was continued at room temperature for 4 hours. After
the mixture was poured into ice–water, the organic layer was
separated and aqueous layer was extracted with CH2Cl2. The
combinated organic layer was washed with diluted HCl, dried
over MgSO4 and evaporated in vacuo. The solid residue was
recrystallized with AcOEt–hexane to give pure 4e (87%), mp
170–172 ЊC; 1H NMR (400 MHz, CD3OD–DMSO) δ 7.77–8.12
(m, 4H, arom.), 10.89–12.41 (m, 1H, NH); 13C NMR (CD3OD–
DMSO) δ 90.6 (CCl3), 124.1 (arom. CH), 129.9 (arom. C),
135.6 (arom. CH), 161.7 (COCCl ), 164.4 (O᎐C-Pht); IR (KBr)
᎐
3
N-(Acetylamino)phthalimide 4a
νmax/cmϪ1 1723, 1747, 1807 (C᎐O). HRMS Calcd. for C H N -
᎐
10
5
2
To a solution of acetic acid (1.5 g, 24.6 mmol) in THF (20 ml)
was added 1,1Ј-carbonyldiimidazole (4 g, 24.6 mmol). The mix-
ture was refluxed for 10 min (corresponding to the end of CO2
evolution). N-Aminophthalimide 1 (2 g, 12.3 mmol) was then
added. The reflux was continued during the time indicated in
Table 1. The medium was concentrated in vacuo and the residue
was partitioned between ether and water; the water layer was
extracted twice with ether. The organic layer was dried over
MgSO4 and concentrated in vacuo. The solid obtained by pre-
cipitation into hexane was recrystallized from AcOEt–hexane
Cl3O3 m/z 305.9365, found 305.9363.
N-(Triphenylmethylamino)phthalimide 4f
A mixture of N-aminophthalimide 1 (6.2 mmol, 1 g), Et3N (1.5
ml), triphenylmethyl chloride (10.8 mmol, 3 g) and a catalytic
amount of DMAP in DMF (30 ml) was stirred during 20 hours
at room temperature. The mixture was poured into ice–water
and extracted with CH2Cl2. The combined organic layer was
washed with diluted HCl, dried over MgSO4 and evaporated in
vacuo. The crude product was purified by column chrom-
1
to give pure compound 4a (82%), mp 226–228 ЊC; H NMR
1
atography on silica gel to give 4f (34%), H NMR (250 MHz,
(400 MHz, CDCl3–DMSO) δ 2.15 (s, 3H, CH3), 7.78–7.92 (m,
4H, arom.), 10.37 (m, 1H, NH); 13C NMR (CDCl3–DMSO)
δ 21.0 (CH3), 124.4 (arom. CH), 130.4 (arom. C), 135.1 (arom.
CH), 165.7 (O᎐C-Pht), 169.6 (CH -CO); IR (KBr) νmax/cmϪ1
CDCl3) δ 7.16–7.64 (m, arom.); 13C NMR (CDCl3) δ 74.9
(CPh3), 122.8, 127.0, 127.4, 129.6 (arom. CH), 129.6 (arom. C),
133.7 (arom. CH), 143.6 (arom. C), 166.1 (O᎐C-Pht); IR (KBr)
᎐
᎐
3
νmax/cmϪ1 1725, 1783 (C᎐O), 3320 (NH ). Because of the
1672, 1745, 1798 (C᎐O). Calcd. for C H N O : C, 58.83; H,
᎐
2
᎐
10
8
2
3
instability of 4f, no mass spectrum was performed.
3.94; N, 13.71. Found: C, 58.80; H, 4.07; N, 13.49%.
N-(Benzoylamino)phthalimide 4b
N,N-Bis(tert-butoxycarbonyl)aminophthalimide 4g
The procedure previously described for the preparation of 4a
was employed using 4 equivalents of benzoic acid and 4 equiv-
alents of CO(Im)2 (65%), mp 204–206 ЊC; 1H NMR (400 MHz,
DMSO) δ 7.50–7.67 (m, 3H, arom.), 7.86–8.05 (m, 6H, arom.),
11.30–11.44 (m, 1H, NH); 13C NMR (DMSO) δ 124.7, 128.7,
129.7 (arom. CH), 130.4, 131.6 (arom. C), 133.7, 136.2 (arom.
CH), 166.2, 166.3 (2 CO); IR (KBr) νmax/cmϪ1 1664, 1750, 1799
A suspension of N-aminophthalimide 1 (2.5 g, 15.4 mmol),
Et3N (90 mmol) and a catalytic amount of DMAP in THF (100
ml) was stirred and cooled in an ice–water bath. Di-tert-butyl
dicarbonate (20 g, 90 mmol) was added and stirring was con-
tinued at room temperature for 2 hours. The solution was con-
centrated in vacuo. Water and ether were added, the aqueous
layer was separated and extracted twice with ether. The organic
layer was dried over MgSO4 and evaporated to dryness. The
residue was chromatographed through silica gel with AcOEt–
(C᎐O). Calcd. for C H N O : C, 67.67; H, 3.79; N, 10.52.
᎐
15 10
2
3
Found: C, 67.54; H, 3.94; N, 10.71%.
J. Chem. Soc., Perkin Trans. 1, 1998, 3685–3688
3687

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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