New Synthesis of 1,1-Substituted Hydrazines by Alkylation of N-Acyl- or N-alkyloxycarbonylaminophthalimide Using the Mitsunobu Protocol

Article abstract of DOI:10.1021/jo000225s

N-acyl- and N-alkoxycarbonylaminophthalimides are prepared using a convenient reaction and are efficiently used as acid partners in Mitsunobu reaction. This reaction allows them to be alkylated by primary, secondary or benzyl groups. Comparison of the reactivities and pK_a values of these N-substituted aminophthalimides suggest that the success of the Mitsunobu reaction in this case seems to be governed more by steric than by electronic effects. A final dephthaloylation step results in an efficient method for the preparation of 1,1-substituted hydrazines.

Full text of DOI:10.1021/jo000225s

4370
J . Org. Chem. 2000, 65, 4370-4374
New Syn th esis of 1,1-Su bstitu ted Hyd r a zin es by Alk yla tion of
N-Acyl- or N-a lk yloxyca r bon yla m in op h th a lim id e Usin g th e
Mitsu n obu P r otocol
Nicolas Brosse, Maria-Fatima Pinto, and Brigitte J amart-Gre´goire*
MAEM UMR mixte CNRS-UHP no. 7567, Faculte´ des Sciences, Universite´ H. Poincare´ Nancy I,
Bld. des Aiguillettes BP 239 F-54506 Vandoeuvre-le`s-Nancy France
Brigitte.J amart@maem.uhp-nancy.fr
Received February 17, 2000
N-acyl- and N-alkoxycarbonylaminophthalimides are prepared using a convenient reaction and
are efficiently used as acid partners in Mitsunobu reaction. This reaction allows them to be alkylated
by primary, secondary or benzyl groups. Comparison of the reactivities and pKa values of these
N-substituted aminophthalimides suggest that the success of the Mitsunobu reaction in this case
seems to be governed more by steric than by electronic effects. A final dephthaloylation step results
in an efficient method for the preparation of 1,1-substituted hydrazines.
Sch em e 1
In tr od u ction
The search for an efficient synthetic route for the
preparation of substituted hydrazines is currently an
area under active investigation as recent literature
suggests.1 For example Ragnarsson and colleagues1h,i
have shown that multisubstituted hydrazines can be
obtained from triprotected hydrazines by a stepwise
synthesis that utilizes phase transfer catalysis (PTC) as
an alkylation method. Specifically, primary and benzylic
groups could be introduced easily using their method but
fail when secondary halides are used. The corresponding
substituted hydrazines are obtained via the formation of
a hydrazone which must then be followed by a reduction
step. The availability of a more general method for the
production of substituted hydrazines is of great interest
in this context.
direct influence on their reactivities. In particular, com-
pounds 2 contain three electron-withdrawing groups
including two incorporated into the phthaloyl moiety,
which increases the acidity of the sole proton and,
concomitantly reduces steric hindrance. This structural
arrangement has subsequently enabled us to develop, for
the first time, a protocol for the synthesis of alkylated
hydrazines3 using compound 2 (R ) OtBu) in a Mitsunobu
reaction.4
As part of our research effort aimed at developing
synthetic protocols for the preparation of protected hy-
drazines we have demonstrated that the direct acylation
of the N-aminophthalimide is possible, without skeletal
rearrangement, to yield compounds 2 (Scheme 1).2 We
have also shown that N-tert-butoxycarbonylaminophthal-
imide 2 R ) OtBu can be efficiently obtained in two steps
using N-aminophthalimide as a starting material. The
compounds obtained from that study can thus be con-
sidered as one of two types which are the triacylhydrazine
derivatives and the diacylcarbazates (arising from BOC
protection). The structure of these compounds has a
In this paper, we aim to show the scope and limitations
of our current studies regarding the application of the
Mitsunobu reaction to the synthesis of a greater range
of substituted hydrazines 5 and 6. We will demonstrate
that, by using the Mitsunobu reaction step, a large
variety of alkyl groups can be introduced and we will
highlight the main factors that influence the successful
use of this reaction for hydrazine substitution. In addi-
tion, we will present a new efficient method for the
preparation of N-acyl- and N-alkyloxycarbonylamino-
phthalimides 2.
Resu lts a n d Discu ssion
* To whom correspondence should be addressed.
(1) (a) Cheguillaume, A.; Lehardy, F.; Bouget, K.; Baudy-Floc′h, M.;
Le Grel, P. J . Org. Chem. 1999, 64, 2924-2927. (b) Ghali, N. I.; Venton,
D. L. J . Org. Chem. 1981, 46, 5413-5414. (c) Gray, C. J .; Quibell, M.;
J iang, K. L.; Bagett, N. Synthesis 1991, 141-146. (d) Hoffman, R. V.;
Kim, H. O. Tetrahedron Lett. 1990, 31, 2953-2956. (e) Hoffman, R.
V.; Navyar, N. K. J . Org. Chem. 1995, 60, 7043-7046. (f) Vanderesse,
R.; David, L.; Grand, V.; Marraud, M. Tetrahedron Lett. 1997, 38,
2669-2672. (g) Wang, Z.; Skerlji, R. T.; Bridger, G. J . Tetrahedron
Lett. 1999, 40, 3543-3546. (h) Grehn, L.; Ragnarsson, U. Tetrahedron
1999, 55, 4843-4852. Ma¨eorg, U.; Ragnarsson, U. Tetrahedron Lett.
1998, 39, 681-684. Grehn, L.; Nyasse, B.; Ragnarsson, U. Synthesis
1997, 1429-1432. (i) Ma¨eorg, U.; Grehn, L.; Ragnarsson, U. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2626-2627.
Syn th esis of N-Acyl- or N-Alk yloxyca r bon yla m i-
n op h th a lim id e 2. We have recently shown that the
(3) (a) Brosse, N.; Pinto, M. F.; J amart-Gre´goire, B. Tetrahedron Lett.
2000, 41, 205-207. (b) One example of intramolecular Mitsunobu
reaction from a substituted hydrazine has been previously reported:
Iwagami, H.; Yasuda, N. Heterocycles 1990, 31, 529-536.
(4) For a review, see: Mitsunobu, O. Synthesis 1981, 1-28. For
recent applications of the Mitsunobu reaction see Dodd, D. S.;
Kozikowski, A. P. Tetrahedron Lett. 1994, 35, 977-980. Kim, T. H;
Lee G. J .; Cha, M. H Synth. Commun. 1999, 29, 2753-2758. Nikam,
S. S.; Kornberg, B. E.; Rafferty, M. F. J . Org. Chem. 1997, 62, 3754-
3757. Lochead, A.; Galli, F.; J egham, S.; Nedelec, A.; George, P. Synth.
Commun. 1999, 29, 799-802.
(2) Brosse, N.; Pinto, M. F.; J amart-Gre´goire, B. J . Chem. Soc.,
Perkin Trans. 1 1998, 3685-3688.
10.1021/jo000225s CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/09/2000

Synthesis of 1,1-Substituted Hydrazines
J . Org. Chem., Vol. 65, No. 14, 2000 4371
Ta ble 1
2, yield (%)
Mitsunobu reaction
dephthaloylation
R
method A
87
method B
52a
R′
5
yield (%)
Z/E or E/Z
time (h)
6
yield (%)
CF3
CH3
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
90
85
85
80b
84
97
83
77
86
67
85
72
84
85f
80
90
85
85f
80
93
77
20/80
20/80
13/87
c
70
70
70
70
70
70
15
7
24
15
24
0.5
1
0.5
20
0.5
20
20
20
20
20
6a
6b
6c
6d
6e
6
6g
6h
6i
0
0
0
0
0
CH2CH3
CH2Ph
CH(CH3)2
(CH2)5CH3
CH3
c
O-tBu
75d
82
40/60
40/60
40/60
c
65
65
63
81
89
85
94
90
82
73
40
92
40g
42
90
85
CH2Ph
CH(CH3)2
(CH2)5CH3
CH2CHdCH2
cyclopentyl
CH3
40/60
40/60
45/55
45/55
20/80
15/85
0/100
0/100
0/100
0/100
20/80
c
6j
6k
6l
O-CH2Ph
CH3
0
82
65
78
72
97
80
85
80
78
CH2-Ph
6m
6n
6o
6p
6q
6r
6s
6t
e
CH3
CH2-Ph
C6H5
CH3
CH2-Ph
e
C5H4N
CH3
CH2Ph
CH3
CH2Ph
5s
5t
5u
CH(CH3)NHZ
6u
a
b
d
2 equiv of phthalic anhydride and reflux conditions was used. Reaction time: 1 h. c Not able to be determined. Formation of di-
tert-butoxycarbonylaminophthalimide which can be converted into 2 R ) OtBu by reacting with CF3COOH; see ref 2. e Tsunoda conditions
were used.9 f Reaction time: 3 h. 5 equiv of MeNH-NH2 was used.
g
Sch em e 2
formation of some N-acylaminophthalimides can be
achieved with good yields directly from N-aminophthal-
imide (see Table 1, method A).2 This procedure applied
to singly labeled N-aminophthalimides constitutes a very
convenient way to obtain 15N singly labeled N-acylamino-
phthalimides.2 The direct substitution of N-aminophthal-
imide has, however, subsequently proved to be limited
owing to the particular behavior of this compound.5 For
example, despite considerable efforts, we were unable to
obtain direct substitution of 1 by a benzyloxycarbonyl
group.2 In addition, when BOC2O was allowed to react
with 1, a disubstituted compound was always obtained
regardless of the quantities of reactants used. Another
the literature7 for performing the cyclization of phtha-
drawback was that these reactions required the use of
lamic acid derivatives into isophthalimides, we chose
DCC. The addition of DCC to the reaction mixture upon
the completion of the first step allowed the cyclization of
compounds 3 into the corresponding isophthalimides 4.
The final step in method B is the isomerization of
compounds 4 into the corresponding N-substituted ami-
nophthalimides 2. Good results were obtained when,
following a rapid filtration to remove any dicyclohexyl-
urea, the filtrate was then allowed to reflux in the
presence of two equivalents of triethylammonium acetate.7c
For the preparation of most substituted hydrazines,
Method B gave better results than Method A with the
exception of compound 2, R ) CF3. This clean method
was thus used to prepare N- acyl, aroyl and trifluoroacyl
aminophthalimides 2 in good to very good yields and
required a total reaction time of only about 2 h. Notably,
method B also enabled the synthesis, for the first time,
of the N-(tert-butoxycarbonyl)- and N-(benzyloxycarbo-
nyl)- aminophthalimides (2, R ) OtBu8 and 2, R ) OCH2-
Ph respectively), from commercially avalaible correspond-
ing carbazates.
expensive starting materials. Others have reported the
synthesis of N-substituted aminophthalimides using
phthalic anhydride and substituted hydrazines as start-
ing materials;6 however, all these methods required
multistep procedures for the synthesis of specific com-
pounds and, in most cases, used extreme reaction condi-
tions. Taking all these factors into account, we were
motivated to find alternative synthetic routes which
would enable the preparation of a variety of N-substi-
tuted aminophthalimides.
Shown in Scheme 2 and in Table 1 are the results
obtained using method B, which conveniently permits the
general preparation of N-substituted aminophthalimides
2 using commercially avalaible hydrazides or carbazates.
Method B involves the formation of two intermediates,
compounds 3 and 4, which (for R ) OtBu) were isolated
and identified as described in the experimental part. In
the first step, the reaction of phthalic anhydride with
substituted hydrazines at room temperature in THF
yielded corresponding N-substituted-o-carboxybenzoyl-
hydrazines 3. Among the range of reagents described in
Mitsu n obu Rea ction : F or m a tion of 5. As a prelimi-
nary study,3 we showed that N-tert-butyloxycarbonylami-
(5) (a) Hearn, M. J .; Lucero, E. R. J . Heterocycl. Chem. 1982, 19,
1537-1539. (b) Hearn, M. J .; Prisch, S. B. Org. Prep. Proced. Int. 1981,
421-424. (c) Drew, H. D. K.; Hatt, H. H. J . Chem. Soc. 1937, 16-26.
(6) (a) El Sadek, M. M.; El Essawi, M. M.; Abdel Baky, S. A. J . Chem.
Eng. Data 1989, 34, 257-259. (b) El Sadek, M. M.; Soccary, N. N.
Carbohydr. Res. 1991, 222, 267-269.
(7) (a) Pyriadi, T. M. J . Org. Chem. 1972, 37, 4184-4186. (b)
Roderick, W. R. J . Org. Chem. 1964, 29, 745-747. (c) Cotter, R. J .;
Sauers, C. K.; Whelan, J . M. J . Org. Chem. 1961, 26, 10-21. (d)
Kukolja, S.; Lammert, S. R. J . Am. Chem. Soc. 1975, 97, 5582-5583.

4372 J . Org. Chem., Vol. 65, No. 14, 2000
Brosse et al.
Sch em e 3a
Deph th aloylation : Syn th esis of 1-Alkylh ydr azides
a n d 1-Alk ylca r ba za tes 6. We previously demonstrated
that dephthaloylation of N-substituted aminophthalim-
ides was better achieved using methylhydrazine, result-
ing in a very clean reaction, compared to hydrazine
hydrate which gave poor results.2,3 Methylhydrazine is
known to disfavor formation of a complex with the free
amine7d and its use in dephthaloylation for most of the
compounds 5 resulted in the formation of the correspond-
ing compounds 6 with very good yields. Curiously though,
when compounds 5 were substituted by a pyridyl group,
the yield decreased to 40%, even when a large excess of
methylhydrazine was present. In addition, we were not
able to obtain suitable conditions for dephthaloylation of
trifluoroacyl forms of compounds 5. In this case the use
of methylhydrazine, as well as hydrazine hydrate, re-
sulted in the degradation of the reaction mixture. How-
ever, using phenylhydrazine, which we had employed
previously for the difficult dephthaloylation of N-trifluoro-
acylaminophthalimide,2 the N-benzylaminophthalimide5a
was obtained from compound 5c instead of the desired
compound. To circumvent this problem we thus at-
tempted to enhance the reactivity of the imido group by
converting it to isoimide as suggested in the literature.7d,13
The corresponding isophthalimide was easily prepared;
however, the subsequent use of methylhydrazine in the
dephthaloylation of this compound resulted in some
degradation of the reaction mixture. Finally, when
performed onto starting materials 5t and 5u , dephthal-
oylation led to compounds 6t and 6u which could be
useful in pseudopeptide synthesis.
a
Key: method A, see conditions in ref 2; method B, see
conditions in Scheme 2.
nophthalimide 2, R ) OtBu, could be efficiently used in
the synthesis of substituted hydrazines and/or carbazates
using the Mitsunobu protocol. The results reported in
Scheme 3 and Table 1 show that the range of compounds
2 used as acid partners in this reaction can be expanded
compared to what we previously described. The corre-
sponding compounds 5 were obtained with very good
yield. It is interesting to note that secondary alkyl groups
can also be introduced using this protocol as attested by
the synthesis of compounds 5d , 5h , and 5k . To circum-
vent any problem of purification, the synthesis of com-
pounds 5n and 5r was performed by using the Tsunoda
conditions9 instead of the Mitsunobu protocol. The suc-
cess of this reaction depends, however, on the presence
of the phthaloyl group. It followed that all attemps to
alkylate tri-tert-butoxycarbonylhydrazine1i using the Mit-
sunobu protocol failed. The similarity of the pKa value
for tri-tert-butoxycarbonylhydrazine (11.3) with those for
compounds 2, R ) OtBu, CH3 (10.9 and 11.8, respec-
tively)10 in water suggests that the poor reactivity of tri-
tert-butoxylcarbonylhydrazine is not due to an electronic
effect. Furthermore, previous studies11 indicate that pKa
of approximately 9 in water is generally required for the
acid partner in the Mitsunobu reaction to achieve a
satisfactory result. Surprisingly, in spite of their high pKa
values, alkylation of compounds 2 using the Mitsunobu
protocol was successful. This result, including the dif-
ferential reactivities of compounds, led us to postulate
that steric hindrance was possibly the main factor
governing the reaction. The observation of two sets of
resonance for some groups in 1H and 13C NMR spectra
(see experimental part) suggested that compounds 5 were
present as two isomers. This phenomenon has been
described elsewhere for amide and hydrazide derivatives
resulting from hindered rotation about the nitrogen to
carbonyl bond thus permitting to distinguish between Z
and E forms.12 Complementary studies are under active
investigation to assign resonance signals.
Con clu sion
We have shown that N-acyl and N-alkoxycarbonylami-
nophthalimides 2 can be prepared using a convenient
reaction. Owing to the particular structural features
where two acyl groups are incorporated into a ring, these
compounds 2 have been shown to be very good acid
partners in a Mitsunobu protocol thus allowing them to
be alkylated with primary, secondary or benzyl groups.
Comparison of the reactivities and pKa values of com-
pounds 2 with that of tri-tert-butoxycarbonylhydrazine
suggested that the successful use of the Mitsunobu
protocol in this case is governed more by steric than
electronic effects. The subsequent use of a dephthaloyl-
ation step thus results in an efficient method for the
preparation of 1,1-substituted hydrazines.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were obtained on a hot-
stage apparatus and were uncorrected. NMR spectra were
recorded on spectometers operating at 400 and 250 MHz. Mass
spectra were performed by the ULIRS Mass Specrtroscopy
Facility (the School of Farmacy, London).
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Acyl- or
N-Alk yloxyca r bon yla m in op h th a lim id e 2 (Meth od B).
Phthalic anhydride (2.96 g, 20 mmol) and carbazate or
hydrazide (20 mmol) were dissolved in THF (100 mL) at room
temperature under stirring. After 5 min, DCC (4.95 g, 24
mmol) is added, and the mixture is stirred for 1 h. The white
precipitate of DCU is removed by filtration, acetic acid (2.4 g,
40 mmol) and Et3N (4.05 g, 40 mmol) are added and the
(8) Some authors have mentionned the preparation in one step of 2
RdOtBu by reacting phthalic anhydride with tert-butylcarbazate in
refluxed CHCl3. In our hand this reaction which did not use cyclization
reagent led to the formation of compound 3 RdOtBu instead of the
desired product. Krause, J . G.; Kwon, S.; George, B. J . Org. Chem.
1972, 37, 2040-2042.
(9) Tsunoda, T.; Yamamiya, Y.; Itoˆ, S. Tetrahedron Lett. 1993, 34,
1639-1942.
(10) The pKa of compounds 2 was measured in aqueous solution at
25 °C by potentiometric titration of their potassium salt with hydro-
chloric acid. Koppel, L. K.; Koppel, J .; Leito, I.; Pihl, V.; Grehn, L.;
Ragnarsson, U. J . Chem. Res. (S) 1994, 212-213. J . Chem. Res. (M)
1994, 1173-1186.
(11) Wada, M.; Mitsunobu, O. Tetrahedron Lett 1972, 1279-1282.
Koppel, I.; Koppel, J .; Degerbeck, F.; Pihl, V.; Grehn, L.; Ragnarsson,
U. J . Org. Chem. 1991, 56, 7172-7174. Berre´e, F.; Michelot, G.; Le
Corre, M. Tetrahedron Lett. 1998, 39, 8275-8276.
(12) Lewin, A. H.; Frucht, M. Org. Magn. Res. 1975, 7, 202-225.
Chakrabarty, M.; Khasnobis, S. Synth. Commun. 1998, 28, 1361-1368.
(13) Stocksdale, M. G.; Ramurthy, S.; Miller, M. J . J . Org. Chem.
1998, 63, 1221-1225.

Synthesis of 1,1-Substituted Hydrazines
J . Org. Chem., Vol. 65, No. 14, 2000 4373
solution is refluxed for 1 h. The mixture was poured into water,
the organic layer was separated and the aqueous layer was
extracted with Et2O. The combined organic layers were dried
over MgSO4. The solid resulting from evaporation was washed
several times with EtOAc-hexane.
N -H e xy l-N -t r iflu o r o m e t h ylc a r b on y la m in o p h t h a l-
im id e 5e: 84%; IR (NaCl) νmax/cm-1 1802, 1742, 1729; 1H NMR
(400 MHz, CDCl3) δ 8.03-7.82 (m, 4H), 3.89-3.75 (m, 2H),
1.78-1.18 (m, 8H), 0.96-0.75 (m, 3H); 13C NMR (CDCl3) δ
164.3, 158.0 (q, J ) 25 Hz), 135.8 and 135.5, 130.0 and 129.5,
124.8 and 124.6, 115.8 (q, J ) 278 Hz), 51.0, 31.6, 30.0, 28.0,
27.1, 26.4, 22.7, 14.1.
N-Ben zyloxyca r b on yla m in op h t h a lim id e 2,
R
)
OCH2P h : 97%; mp 140 °C; IR (NaCl) νmax/cm-1 3284, 3031,
1797, 1741; 1H NMR (400 MHz, CDCl3) δ 10.24 (s, 1H), 7.88-
7.77 (m, 4H), 7.43-7.29 (m, 5H), 5.19 (s, 2H); 13C NMR (CDCl3)
δ 165.8, 155.9, 136.4, 135.6, 130.2, 129.1, 128.9, 128.8, 124.3,
68.0; HRMS calcd for C16H12N2O4 m/z 296.0797, found 296.0790.
L-N′-Ben zyloxyca r bon yla la n in e p h th a loylh yd r a zid e 2,
R ) Z-Ala : 78%; mp 164 °C; [R]D ) -1.5 (c 1.6, CH3COCH3);
IR (NaCl) νmax/cm-1 1795, 1739, 1679; 1H NMR (250 MHz,
CDCl3) δ 11.00-10.40 (m, 1H), 8.15-7.80 (m, 4H), 7.46-7.20,
(2 m, 5H), 5.11 (s, 2H), 4.50 (pt, 1H), 3.70-3.10 (m, 1H), 1.46
(d, J ) 7 Hz, 3H); 13C NMR (CDCl3) δ 171.2, 164.4, 163.9,
154.9, 135.8, 133.8, 128.9, 127.3, 126.8, 122.5, 65.0, 48.0, 17.6;
HRMS calcd for C19H17N3O5 [M + NH4+] m/z 385.1525, found
385.1522.
N -Me t h yl-N -t er t -b u t yloxyca r b on yla m in op h t h a lim -
1
id e 5f: 97%; mp 123 °C; IR (NaCl) νmax/cm-1 1793, 1731; H
NMR (250 MHz, CDCl3) δ 7.98-7.73 (m, 4H), 3.34 and 3.31
(2 s, 3H), 1.52 and 1.35 (2 s, 9H); 13C NMR (CDCl3) δ 165.5,
165.2, 154.1, 135.1 and 135.0, 130.3 and 130.2, 124.1, 83.1 and
82.4, 38.3 and 36.8, 28.4 and 28.2; HRMS calcd for C15H20N3O4
[M + NH4+] 294.1454, found 294.1448.
N -Be n zyl-N -t er t -b u t yloxyca r b on yla m in op h t h a lim -
1
id e 5g: 83%; mp 108 °C; IR (NaCl) νmax/cm-1 1796, 1737; H
NMR (400 MHz, CDCl3) δ 7.85-7.66 (m, 4H), 7.50-7.22 (m,
5H), 4.78 and 4.81 (2 s, 2H), 1.47and 1.45 (2 s, 9H); 13C NMR
(CDCl3) δ 165.8 and 165.4, 153.9 and 153.7, 136.1 and 135.6,
135.1, 130.2 and 130.0, 129.4, 128.9, 128.7, 128.3, 124.1, 83.6
and 82.8, 55.0, 53.0, 28.4 and 28.3; HRMS calcd for C20H21N2O4
[M + H+] 353.1501, found 353.1510.
1-ter t-Bu tyloxyca r bon yl-2-(2′-ca r boxyben zoyl)-h yd r a -
zin e 3, R ) OtBu : 100%; mp 186 °C; IR (KBr) νmax/cm-1 3600-
2600;1H NMR (400 MHz, CDCl3) δ 9.80-9.70 (m, 1H), 7.77
(d, J ) 7.5 Hz, 1H), 7.56-7.38 (m, 3H), 1.42 (s, 9H); 13C NMR
(CDCl3) δ 168.5, 156.2, 136.8, 131.7, 131.6, 130.3, 80.3, 28.6.
N-ter t-Bu tyloxyca r bon yla m in oisop h th a lim id e 4, R )
OtBu : 82%; mp 177-179 °C (lit.14 mp 179.5-180.5 °C); IR
(KBr) νmax/cm-1 1795, 1720; 1H NMR (400 MHz, CDCl3) δ
8.90-8.82 (m, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.58 (t, 2H), 1.44
(s, 9H); 13C NMR (CDCl3) δ 163.3, 152.5, 135.7, 135.0, 132.2,
126.4, 126.0, 122.4, 82.2, 28.5. Compounds 2, R ) OtBu, CH3,
N-Isop r op yl-N-ter t-bu tyloxyca r bon yla m in op h th a lim -
id e 5h : 77%; mp 140-143 °C; IR (NaCl) νmax/cm-1 1797, 1734,
1715; 1H NMR (400 MHz, CDCl3) δ 7.99-7.77 (m, 4H), 4.66-
4.50 and 4.44-4.34 (m, 1H), 1.55-1.16 (m, 15H, with 2 s at
1.53 and 1.28); 13C NMR (CDCl3) δ 167.2, 166.9, 152.7, 135.1,
135.0, 130.5, 130.3, 124.1, 82.9, 82.0, 51.90, 50.10, 28.6, 28.3,
21.2, 20.8; HRMS calcd for C16H24N3O4 [M + NH4+] 322.1767,
found 322.1761.
N-Hexyl-N-ter t-bu tyloxycar bon ylam in oph th alim ide 5i:
86%; IR (NaCl) νmax/cm-1 1796, 1733; 1H NMR (400 MHz,
CDCl3) δ 8.00-7.73 (m, 4H), 3.71-3.60 (m, 2H), 1.69-1.22 (m
with 2 s at 1.51 and 1.32, 17H), 0.93-0.83 (m, 3H); 13C NMR
(CDCl3) δ 165.9, 153.6, 135.1 and 135.0, 130.5 and 130.3, 124.2,
83.0 and 82.3, 51.1 and 49.6, 31.9, 28.6 and 28.3, 28.1, 26.6,
22.9, 14.4; HRMS calcd for C19H30N3O4 [M + NH4+] 364.2236,
found 364.2238.
t
C6H5, C5H4N, Bu, CCl3, CF3 were previously described.2
Gen er a l P r oced u r e for th e Alk yla tion of N-Acyl- or
N-Alkoxyca r bon yla m in oph th a lim id e with Alcoh ols (Mit-
su n obu P r otocol). To a solution of 2 (5 mmol), PPh3 (2 g,
7.5 mmol), and alcohol (R′OH, 7.5 mmol) in dry THF (70 mL)
and under Nitrogen was added in one portion DEAD (1.3 g,
7.5 mmol) with stirring at 0-5 °C. The resulting solution was
stirred for 0.5 h (monitored by TLC until completion) or 1 h
N-Allyl-N-ter t-bu tyloxyca r bon yla m in op h th a lim id e 5j:
1
67%; mp 76-78 °C; IR (NaCl) νmax/cm-1 1796, 1730; H NMR
i
in the special case of R ) CF3, R′ ) Pr and concentrated in
(400 MHz, CDCl3) δ 7.70-7.50 (m, 4H), 6.00-5.80 (m, 1H),
5.23-5.04 (m, 2H), 4.31-4.20 (m, 2H), 1.47, 1.28 (2 s, 9H);
13C NMR (CDCl3) δ 165.8, 165.7, 153.4, 135.1, 134.9, 132.7,
132.5, 130.3, 130.1, 124.2, 120.0, 119.6, 83.4, 82.7, 53.9, 52.0,
28.5, 28.2; HRMS calcd for C16H22N3O4 [M + NH4+] 320.1610,
found 320.1617.
vacuo. The residue was triturated in EtOAc, and most of the
triphenylphosphine oxide and diethylhydrazinedicarboxylate
was removed by filtration. The filtrate was evaporated and
the residue was chromatographed on silica gel.
N -Me t h yl-N -t r iflu or om e t h ylca r b on yla m in op h t h a l-
im id e 5a : 90%; mp 134 °C; IR (NaCl) νmax/cm-1 1802, 1756;
1H NMR (400 MHz, CDCl3) δ 8.00-7.79 (m, 4H), 3.56 and 3.35
(2 s, 3H); 13C NMR (CDCl3) δ 163.9, 158.2 (q, J ) 28 Hz), 135.9
and 135.5, 130.2 and 129.8, 124.9 and 124.6, 115.7 (q, J ) 280
Hz), 39.5 and 37.0; HRMS calcd for C11H7F3N2O3 m/z 272.0409,
found 272.0406.
N-Cyclop en tyl-N-ter t-bu tyloxyca r bon yla m in op h th a l-
im id e 5k : 85%; mp 131 °C; IR (NaCl) νmax/cm-1 1796, 1738,
1709; 1H NMR (400 MHz, CDCl3) δ 7.96-7.74 (m, 4H), 4.80-
4.46 (m, 1H), 3.06-1.16 (m, 17H); 13C NMR (CDCl3) δ 166.8,
153.2, 135.1, 130.3, 124.2, 82.1, 61.3, 59.6, 30.7, 30.0, 28.6, 28.3,
23.9, 23.6; HRMS calcd for C18H26N3O4 [M + NH4+] 348.1923,
found 348.1924.
N-Meth yl-N-ben zyloxyca r bon yla m in op h th a lim id e 5l:
72%; mp 113 °C; IR (NaCl) νmax/cm-1 1795, 1738; 1H NMR (250
MHz, CDCl3) δ 7.92-7.72 (m, 4H), 7.45-7.10 (m, 5H), 5.25
and 5.14 (2 s, 2H), 3.41 and 3.37 (2 s, 3H); 13C NMR (CDCl3)
δ 165.3 and 164.9, 155.1 and 155.0, 136.0, 135.2, 130.3, 130.2,
129.0, 128.8, 128.7, 128.5, 128.4, 127.6, 124.3, 69.2 and 68.6,
38.4 and 37.5; HRMS calcd for C17H14N2O4 m/z 310.0953, found
310.0947.
N -E t h y l-N -t r iflu o r o m e t h y lc a r b o n y la m in o p h t h a l-
im id e 5b: 85%; mp 122-124 °C; IR (NaCl) νmax/cm-1 1804,
1
1751, 1724; H NMR (400 MHz, CDCl3) δ 8.00-7.81 (m, 4H),
3.96-3.85 (2 q, J ) 7.5 Hz, 2H), 1.32 and 1.24 (2 t, J ) 7.5
Hz, 3H); 13C NMR (CDCl3) δ 164.4, 158.4 (q, J ) 30 Hz), 135.8
and 135.5, 129.5, 124.9 and 124.6, 115.8 (q, J ) 285 Hz), 46.8
and 46.2, 13.1 and 12.2; HRMS calcd for C12H10N2F3O3 [M +
H+] 287.0651, found 287.0644.
N -Be n zyl-N -t r iflu or om e t h ylca r b on yla m in op h t h a l-
im id e 5c: 85%; mp 86 °C; IR (NaCl) νmax/cm-1 1802, 1752; 1H
NMR (400 MHz, CDCl3) δ 8.00-7.77 (m, 4H), 7.47-7.23 (m,
5H), 5.10 and 5.10 (2 s, 2H); 13C NMR (CDCl3) 164.0, 158.4 (q,
J ) 28 Hz), 135.6 and 135.4, 131.9 and 130.7, 129.4, 129.3,
129.1, 124.7, 124.5, 115.8 (q, J ) 286 Hz), 53.9; HRMS calcd
for C17H12N2F3O3 [M + H+] 349.0788, found 349.0800.
N-Isop r op yl-N-tr iflu or om eth ylca r bon yla m in op h th a l-
im id e 5d : 80%; 1H NMR (400 MHz, CDCl3) δ 7.90-7.83, 7.80-
7.73 (m, 4H), 5.43 (sept, J ) 6 Hz, 1H), 1.50 (d, J ) 6 Hz, 6H);
13C NMR (CDCl3) δ 163.9, 159.9 (q, J ) 30 Hz), 135.7, 135.4,
131.1, 124.8, 123.9, 115.8 (q, J ) 282 Hz), 76.1, 21.1; HRMS
calcd for C13H12N2F3O3 [M + H+] 301.0787, found 301.0800.
N-Ben zyl-N-ben zyloxyca r bon yla m in op h th a lim id e 5m :
84%; mp 87 °C; IR (NaCl) νmax/cm-1 3089, 3033, 1796, 1737;
1H NMR (250 MHz, CDCl3) δ 7.89-7.59 (m, 4H), 7.48-7.11
(m, 10H), 5.28 and 5.18 (2 s, 2H), 4.96 and 4.92 (2 s, 2H); 13C
NMR (CDCl3) δ 165.0, 155.0, 136.0, 135.0, 129.9, 129.6, 129.1,
129.0, 128.8, 128.5, 128.4, 127.6, 124.2, 69.4 and 68.8, 54.8
and 53.8; HRMS calcd for
404.1610, found 404.1617.
C
23H22N3O4 [M + NH4+] m/z
N-Meth yl-N-a cetyla m in op h th a lim id e 5n : 85%; mp 202
°C; IR (NaCl) νmax/cm-1 1795, 1740, 1710; 1H NMR (250 MHz,
CDCl3) δ 7.97-7.76 (m, 4H), 3.49 and 3.25 (2 s, 3H), 2.30 and
1.97 (2 s, 3H); 13C NMR (CDCl3) δ 171.9, 164.7, 135.5, 135.0,
130.3, 129.8, 124.5, 124.1, 39.4, 35.2, 21.1, 20.1; HRMS calcd
for C22H30N3O3 [M + NH4+] m/z 374.1505, found 374.1505.
(14) Carpino, L. A. J . Am. Chem. Soc. 1957, 79, 98-101.

4374 J . Org. Chem., Vol. 65, No. 14, 2000
Brosse et al.
N-Ben zyl-N-a cetyla m in op h th a lim id e 5o: 80%; mp 102
°C;1H NMR (250 MHz, CDCl3) δ 7.78-7.62 and 7.31-7.09 (2
m, 9H), 4.90 and 4.87 (2 s, 2H), 2.31 and 2.00 (2 s, 3H); 13C
NMR (CDCl3) δ 171.9, 164.8, 135.4, 134.9, 134.5, 129.9, 129.5,
129.0, 128.6, 128.5, 128.2, 124.4, 124.1, 55.6, 51.2, 21.4 and
20.8; HRMS calcd for C17H14N2O3 m/z 294.1004, found 294.1001.
N-Meth yl-N-ben zoyla m in op h th a lim id e 5p : 90%; mp 155
°C; IR (NaCl) νmax/cm-1 1793, 1737, 1671; 1H NMR (400 MHz,
CDCl3) δ 7.12-7.81 (m, 9H), 3.37 (s, 3H); 13C NMR (CDCl3) δ
173.1, 164.7, 135.4, 134.1, 130.9, 129.6, 128.5, 126.8, 124.4,
36.3; HRMS calcd for C16H12N2O3 m/z 280.0848, found 280.0842.
N-Ben zyl-N-ben zoyla m in op h th a lim id e 5q: 85%; mp 133
0.70 (t, J ) 7 Hz, 3H); 13C NMR (CDCl3) δ 157.2, 80.1, 50.5,
31.7, 28.6, 27.7, 26.5, 22.8, 14.2; HRMS calcd for C11H25N2O2
[M + H+] 217.1616, found 217.1614.
1-Allyl-1-ter t-b u t oxyca r b on ylh yd r a zin e 6j: 89%; IR
(NaCl) νmax/cm-1 3335 cm-1, 1695; 1H NMR (400 MHz, CDCl3)
δ 5.81-5.69 (m, 1H), 5.13-5.02 (m, 2H), 3.99 (s, 2H), 3.89 (d,
2H, J ) 9 Hz), 1.38 (s, 9H); 13C NMR (CDCl3) δ 161.0, 133.8,
116.8, 80.8, 53.7, 28.6; HRMS calcd for C8H17N2O2 [M + H+]
173.1290, found 173.1290.
1-Cyclopen tyl-1-ter t-bu toxycar bon ylh ydr azin e 6k: 85%;
IR (NaCl) νmax/cm-1 3342, 1690; 1H NMR (400 MHz, CDCl3) δ
4.39 (quint, J ) 7.5 Hz, 1H), 4.00-3.34 (m, 1H), 1.80-1.61
(m, 6H), 1.56-1.41 (m with s at 1.47, 11H); 13C NMR (CDCl3)
157.0, 80.6, 58.5, 29.0, 28.9, 24.7; HRMS calcd for C10H21N2O2
[M + H+] 201.1603, found 201.1601.
1
°C; H NMR (400 MHz, CDCl3) δ 7.80-7.19 (m, 9H), 5.12 (s,
2H); 13C NMR (CDCl3) δ 157.4, 135.1, 128.8, 128.5, 124.2, 52.4;
HRMS calcd for C22H30N3O3 [M + NH4+] m/z 374.1505, found
374.1505.
1-Meth yl-1-ben zyloxyca r bon ylh yd r a zin e 6l: 94%; IR
(NaCl) νmax/cm-1 3330, 3025, 1697;1H NMR (400 MHz, CDCl3)
δ 7.42-7.20 (m, 5H), 5.06 (s, 2H), 4.40-3.80 (m, 2H), 3.02 (2
s, 3H); 13C NMR (CDCl3) δ 155.5, 136.9, 128.8, 128.4, 128.2,
67.8 and 67.6, 38.7; HRMS calcd for C9H12N2O2 [M + H+] m/z
181.0977, found 181.0976.
N-Meth yl-N-ison icotin oyla m in op h th a lim id e 5r : 85%;
mp 124-126 °C; IR (NaCl) νmax/cm-1 1794, 1738, 1684;1H NMR
(400 MHz, CDCl3) δ 8.57 (s, 2H), 7.34 (d, J ) 6 Hz, 2H), 7.91-
7.76 (m, 4H), 3.40 (s, 3H); 13C NMR (CDCl3) δ 170.7, 164.5,
150.4, 141.9, 135.6, 129.4, 124.5, 120.7, 36.1; HRMS calcd for
C15H11N3O3 m/z 281.0800, found 281.0795.
1-Ben zyl-1-ben zyloxyca r bon ylh yd r a zin e 6m : 90%; IR
(NaCl) νmax/cm-1 3336, 3031, 1698;1H NMR (400 MHz, CDCl3)
δ 7.32-7.18 (m, 10H), 5.19 (s, 2H), 4.59 (s, 2H), 4.18-3.70 (m,
2H); 13C NMR (CDCl3) δ 137.6, 128.9, 128.5, 128.4, 128.3,
127.8, 68.2, 54.8; HRMS calcd for C15H16N2O2 m/z 256.1211,
found 256.1202.
1-Meth yl-1-a cetylh yd r a zin e 6n : 82%; mp 17-20 °C (lit.15
mp 16 °C).
1-Ben zyl-1-a cetylh yd r a zin e 6o: 73%; mp 49-51 °C (lit.16
mp 50-51 °C).
N-Ben zyl-N-ison icot in oyla m in op h t h a lim id e 5s: 80%;
mp 96-98 °C; IR (KBr) νmax/cm-1 1794, 1740, 1683;1H NMR
(400 MHz, CDCl3) δ 8.53 (d, J ) 6 Hz, 2H) 7.74-7.21 (m, 4H),
7.40-7.15 (m, 7H), 5.04 (s, 2H); 13C NMR (CDCl3) δ 170.5,
164.5, 142.2, 135.5, 133.7, 130.3, 128.9, 124.4, 120.7, 52.3;
HRMS calcd for C21H15N3O3 [M + H+] m/z 358.1192, found
358.1197.
L-N′-Ben zyloxyca r bon yla la n in e-N-m eth ylp h th a loylh y-
d r a zid e 5t: 93%; mp 133 °C; IR (NaCl) νmax/cm-1 1795, 1740,
1686; 1H NMR (400 MHz, CDCl3) δ 8.00-7.76 (m, 4H), 7.40-
7.25 (m, 5H), 5.82-5.73 and 5.69-5.61 (2 pd, 1H), 5.07-4.83
(m, 2H), 4.45 and 4.12 (2 q, J ) 7 Hz, 1H), 3.49 and 3.28 (2 s,
3H), 1.49 and 1.28 (2 d, J ) 7 Hz, 3H); 13C NMR (CDCl3) δ
174.6, 164.9, 164.6, 155.6, 136.7, 135.6, 135.2, 130.3, 128.8,
128.5, 128.4, 124.4, 67.3, 47.6 and 47.0, 39.0 and 35.9, 19.5;
HRMS calcd for C20H19N3O5 m/z 381.1325, found 381.1323.
L-N′-Ben zyloxyca r bon yla la n in e-N-ben zylp h th a loylh y-
1-Meth yl-1-ben zoylh yd r a zin e 6p : 40%; mp 47-49 °C
(lit.17 mp 48-50 °C).
1-Ben zyl-1-ben zoylh yd r a zin e 6q: 92%; mp 68 °C (lit.18
mp 68-70 °C).
1-Meth yl-1-ison icotin oylh yd r a zin e 6r : 40%; mp 96-97
°C (lit.19 mp 95-96 °C).
1
d r a zid e 5u : 77%; mp 148 °C; H NMR (400 MHz, CDCl3) δ
1-Ben zyl-1-ison icotin oylh yd r a zin e 6s: 42%; mp 101 °C
(lit.19 mp 99-100 °C).
L-N′-Ben zyloxycar bon ylalan in e-Nr-m eth ylh ydr azide 6t:
7.90-7.73 (m, 4H), 7.51-7.15 (m, 10H), 5.80-5.68 (pd, 1H),
5.20-4.90 (m, 4H), 4.21-4.15 and 4.54-4.42 (2 m, 1H), 1.40
(d, 3H);13C NMR (CDCl3) δ 173.2, 165.2, 164.8, 155.9, 136.8,
136.5, 135.4, 134.0, 130.3, 130.0, 129.8, 129.1, 129.0, 128.9,
128.8, 128.7, 128.5, 128.3, 128.2, 127.2, 124.4, 67.1, 52.8, 52.2,
38.7; HRMS calcd for C26H23N3O5 [M + H+] m/z 458.1716,
found 458.1720.
90%; mp 118 °C; [R]D ) +15.75 (c 1.27, CHCl3); IR (NaCl) νmax
/
cm-1 3407, 3324, 3225, 1710, 1661; 1H NMR (400 MHz, CDCl3)
δ 7.40-7.24 (m, 5H), 5.80 (pd, 1H), 5.22-4.98 (m with s at
5.08, 3H), 3.87 (s, 2H), 3.13 (s, 3H), 1.31 (d, J ) 7 Hz);13C NMR
(CDCl3) δ 175.1, 155.9, 136.9, 128.7, 128.4, 128.2, 66.8, 47.3
and 47.0, 38.9, 19.2; HRMS calcd for C12H17N3O3 m/z 251.1270,
found 251.1264.
Gen er a l P r oced u r e for th e Dep h th a loyla tion Rea c-
tion s. To a solution of compound 5 (3 mmol) in THF (50 mL)
was added at 0 °C, MeNHNH2 (4.5 mmol, 225 mg). The
solution was then allowed to warm to room temperature,
stirred for the time indicated in Table 1, and then concentrated
in vacuo. EtOAc was added, and the white precipite of
phthalhydrazide was filtrated off. The filtrate was evaporated
and the residue was chromatographed on neutral alumina gel.
1-Meth yl-1-ter t-bu toxyca r bon ylh yd r a zin e 6f: 65%; IR
(NaCl) νmax/cm-1 3346, 1691; 1H NMR (400 MHz, CDCl3) δ
4.02-3.82 (m, 2H), 2.87 (s, 3H), 1.28 (s, 9H); 13C NMR (CDCl3)
δ 155.5, 80.4, 38.4, 28.8; HRMS calcd for C6H15N2O2 [M + H+]
147.1133, found 147.1135.
1-Ben zyl-1-ter t-bu toxyca r bon ylh yd r a zin e 6g: 65%; IR
(NaCl) νmax/cm-1 3333, 1696; 1H NMR (400 MHz, CDCl3) δ
7.36-7.22 (m, 5H), 4.55 (s, 2H), 4.20-3.80 (m, 2H), 1.48 (s,
9H); 13C NMR (CDCl3) 157.2, 138.4, 128.8, 128.2, 127.7, 81.0,
54.8, 28.8; HRMS calcd for C12H19N2O2 [M + H+] 223.1446,
found 223.1445.
L-N′-Ben zyloxyca r b on yla la n in e-Nr-b en zylh yd r a zid e
6u : 85%; mp 148 °C; [R]D ) +12.04 (c 1.27, CHCl3); IR (NaCl)
1
ν
max/cm-1 3405, 3325, 3220, 1715, 1657; H NMR (400 MHz,
CDCl3) δ 7.35-7.12 (m, 10H), 5.79 (d, J ) 8 Hz, 1H), 5.21 (m,
1H), 5.05 (s, 2H), 4.76 and 4.56 (2 d, J ) 15 Hz, 2H), 3.70-
3.52 (m, 1H), 1.38 (d, J ) 6.5 Hz, 3H); 13C NMR (CDCl3) δ
175.4, 156.1, 137.1, 135.5, 128.4, 128.5, 128.8, 129.4, 129.5,
67.0, 53.7, 47.7, 19.4; HRMS Calcd for C18H21N3O3 [M + H+]
m/z 328.1661, found 328.1665.
N-Ben zyla m in op h th a lim id e: 55%; mp 106 °C (lit.5a mp
108-110 °C).
Ack n ow led gm en t. We are grateful to the European
Community
for
financial
support
(contract
BMH4-CT96-1492).
1-Isop r op yl-1-ter t-bu toxyca r bon ylh yd r a zin e 6h : 63%;
IR (NaCl) νmax/cm-1 3341, 3227, 1797, 1738, 1686; 1H NMR
(400 MHz, CDCl3) δ 4.19-4.03 (m, 1H), 3.52 (s, 2H), 1.35 (s,
9H), 0.99 (d, 6H, J ) 6.5 Hz); 13C NMR (CDCl3) δ 80.2, 49.0,
28.7, 19.8; HRMS calcd for C8H19N2O2 [M + H+] 175.1446,
found 175.1447.
1-Hexyl-1-ter t-bu toxyca r bon ylh yd r a zin e 6i: 81%; IR
(NaCl) νmax/cm-1 3341, 1696; 1H NMR (400 MHz, CDCl3) δ 3.86
(s, 2H), 3.13 (t, J ) 7 Hz, 2H), 1.26 (s, 9H), 1.15-1.05 (m, 8H),
J O000225S
(15) Condon, F. E. J . Org. Chem. 1972, 37, 3608-3615.
(16) Ronco, K.; Erlenmeyer, H. Helvetica Chim. Acta 1956, 39, 124-
125.
(17) Bentley, T. W. J . Chem. Soc., Perkin Trans. 1 1973, 449-453.
(18) Nakajima, M.; Anselme, J .-P. J . Org. Chem. 1980, 45, 3673-
3676.
(19) Fox, H. H.; Gibas, J . T. J . Org. Chem. 1956, 21, 356-361.