Preparation of Multiply Protected Alkylhydrazine Derivatives by Mitsunobu and PTC Approaches

Article abstract of DOI:10.1002/ejoc.200300445

Alkylation reactions of hydrazine derivatives by Mitsunobu or PTC approaches are described. It has been shown that aminophthalimide derivatives are better acidic partners than their aminoimidodicarbonate (NBoc₂) analogues, the presence of the phthaloyl group increasing the acidity of the sole proton and concomitantly reducing steric hindrance. Moreover, N-aminophthalimide derivatives can be efficiently converted into the corresponding N-amino-imidodicarbonates by a three-stage, one-flask procedure under very mild conditions. These procedures can also be efficiently used for the preparation of orthogonally N^α,N^β -diprotected α-hydrazino esters. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).

Full text of DOI:10.1002/ejoc.200300445

FULL PAPER
Preparation of Multiply Protected Alkylhydrazine Derivatives by Mitsunobu
and PTC Approaches
[a]
[a]
[a]
´
Nicolas Brosse, Maria-Fatima Pinto, and Brigitte Jamart-Gregoire*
Keywords: Hydrazine derivatives / Phase-transfer catalysis / Mitsunobu reaction / α-Hydrazino acids / Protecting groups
Alkylation reactions of hydrazine derivatives by Mitsunobu
or PTC approaches are described. It has been shown that
aminophthalimide derivatives are better acidic partners than
their aminoimidodicarbonate (NBoc2) analogues, the pres-
ence of the phthaloyl group increasing the acidity of the sole
proton and concomitantly reducing steric hindrance. More-
over, N-aminophthalimide derivatives can be efficiently con-
verted into the corresponding N-amino-imidodicarbonates
by a three-stage, one-flask procedure under very mild condi-
tions. These procedures can also be efficiently used for the
preparation of orthogonally Nα,Nβ-diprotected α-hydrazino
esters.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
nobu reaction, with our work showing that Nβ,Nβ,-disubsti-
tuted hydrazines could be efficiently prepared after removal
Phase-Transfer Catalysis (PTC) and the Mitsunobu reac- of the protecting groups.[4a] In that study, both primary
tion are the processes par excellence for the alkylation of and, more interestingly, secondary alkyl groups, as well as
various nucleophiles under mild reaction conditions. The functionalized groups, were introducible with good overall
Mitsunobu reaction is applicable for a wide range of pri- yields.[4] It is important, however, to recognize that the use
mary and secondary alcohols and results in stereospecific of the phthaloyl group can sometimes be regarded as a
alkylation.[1] However, there are disadvantages associated drawback as it is often difficult to remove this protecting
with the use of this procedure on a large scale. In particular, group under mild conditions. In order to address this po-
the by-products, triphenylphosphane oxide and dialkylhyd- tential problem, in the studies presented here we have also
razinedicarboxylates, are of considerable mass, making the examined the possibility of using iminodicarbonate deriva-
procedure far from ideal with regard to atom economy.[2] tives (NBoc2) 5 as acidic partners in alkylation processes.
For this reason, phase-transfer catalysis alkylation is often Finally, we demonstrate that the phthaloyl group can be
preferred when non-chiral starting materials are used.[3] converted into Boc protection in a ‘‘one-flask’’ reaction
Ragnarsson and colleagues, for example, have recently procedure.[5]
shown that PTC and the Mitsunobu conditions constitute
efficient synthetic routes for the preparation of substituted
Results and Discussion
hydrazines. They demonstrated that multiply substituted
hydrazines can be obtained from triprotected hydrazines by
a PTC alkylation method.[3] However, although primary
and benzylic groups can be easily introduced, hydrazines
substituted with secondary alkyl group cannot be obtained
in this way.
In order to investigate the utility of PTC and Mitsunobu
methods for the alkylation of hydrazine derivatives further,
we have compared them for the preparation of the N-acyl
and N-(alkyloxycarbonyl)aminophthalimides 2. As part of
an effort to develop new synthetic approaches for the prep-
aration of protected hydrazines, we had previously demon-
strated that N-acyl and N-[(alkyloxycarbonyl)amino]-
phthalimides can be used as acidic partners in the Mitsu-
Synthesis of Starting Materials
The results for the preparation of compounds 2 and 5,
reported in Scheme 1, show that the range of compounds
prepared by the PTC and Mitsunobu methods can be ex-
panded and that the strategies selected can be optimized in
relation to what we had previously described.[4a,6] Com-
pounds 2 were obtained by condensation of the commer-
cially available carbamates (1: R ϭ OtBu or OCH2Ph) or
hydrazides [1: R ϭ CH3, C6H5, CH3(CH2)6, ZNHCH2,
ZNHCH(CH3)] with phthalic anhydride in toluene at re-
flux. The compounds 5 were prepared in good yields in
three steps, involving: a) protection of the NH group of 2
R ϭ OtBu with Boc2O/DMAP, b) a dephthaloylation reac-
tion resulting in the formation of Nβ,Nβ-bis(tert-butoxycar-
bonyl)hydrazine (4), and c) acylation of 4 with carbonyldii-
midazole as a coupling reagent.[6]
[a]
´
Laboratoire de Chimie-Physique Macromoleculaire (LCPM),
UMR CNRS-INPL 7568, ENSIC, BP 451, 54001 Nancy
Cedex, France
Fax: (internat.) ϩ 33-383-379977
Eur. J. Org. Chem. 2003, 4757Ϫ4764
DOI: 10.1002/ejoc.200300445
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4757

´
N. Brosse, M.-F. Pinto, B. Jamart-Gregoire
FULL PAPER
nitrile at 50 °C in the presence of potassium carbonate as
base and an ammonium salt (BnEt3NCl) as catalyst accord-
ing to a procedure described in the literature.[3a] A system-
atic study, not reported in this paper, showed that the nature
of the ammonium salt has very little effect on the yield of
the reaction but a significant effect on the reaction time
(from 20 h for BnEt3NCl to 100 h for Bu4NI).
Alkylation with Primary Alkyl Groups
When starting from compounds 2, primary alkyl groups
can be introduced by use either of Mitsunobu (method A)
or PTC (method B) conditions to give compounds 6 in
good to excellent yields.
However, the alkylation of the compounds 5a and 5b (for
which R ϭ alkyl) by the Mitsunobu approach failed. It is
interesting, though, to note that this kind of alkylation did
become possible when acidic partners 5d and 5e, containing
electron-withdrawing groups, were used. This led us to pos-
tulate that electronic effects are an important factor govern-
ing the reaction. No such effects were observed when PTC
conditions were used: incorporation of primary alkyl
groups could be performed in good to excellent yields re-
gardless of the nature of the starting materials.
Alkylation with Secondary Alkyl Groups
In contrast with the PTC alkylation of triprotected hy-
drazines previously described in the literature,[3] PTC alky-
lation of N-aminopththalimide derivatives 2 with secondary
alkyl groups can be performed in good yields, so alkylation
of 2b in comparable yields can be achieved under either
Mitsunobu or PTC conditions. When applied to the more
hindered N-[(tert-butoxycarbonyl)amino]phthalimide (2a),
PTC conditions gave yields of the corresponding com-
pounds 6 20 % lower than had been obtained by the Mitsu-
nobu procedure. As suggested before,[4a] the success of these
reactions depends mainly on the presence of the phthaloyl
moiety, in which two acyl groups are incorporated into a
ring, which reduces steric hindrance. In fact, all attempts to
alkylate the sterically hindered imidodicarbonate derivatives
(compounds 5) with secondary alkyl groups failed either by
method A or by method B (unreported results).
Scheme 1
Alkylation Reactions
Scheme 2 and the associated Table 1 show the results ob-
tained by the Mitsunobu approach (Method A) and under
PTC conditions (Method B).
Moreover, the introduction of secondary alkyl groups
onto the acidic partner, particularly onto 2a, gives better
yields when the Mitsunobu approach is involved, suggesting
that PTC alkylation is more sensitive to steric hindrance
than the Mitsunobu reaction. In the synthesis of chiral hy-
drazine derivatives, we have previously demonstrated that
the conversion of chiral α-hydroxy esters into hydrazine de-
rivatives by the Mitsunobu reaction occurred with a com-
plete inversion of the configuration and was accompanied
Scheme 2
Mitsunobu Conditions (Method A): We employed the con- with a negligible loss of the enantiomeric purity (deter-
ditions previously described, with the use of a slight excess mined by HPLC after conversion into amino acid and deri-
of alcohol (RЈOH), triphenylphosphane and DIAD in THF vatisation).[4b] In contrast, this study showed that, when
at room temperature.[4a]
starting from (S)-bromopropanoate derivatives, the use of
Phase-Transfer Catalyst Conditions (Method B): Acidic PTC conditions afforded the corresponding α-hydrazino es-
partners 2 or 5 were alkylated with alkyl bromide RЈBr or ters 6q or 6t with total loss of optical purity ([α]D ϭ 0).
CH3I under phase-transfer catalysis conditions in aceto- This racemization could be explained by an enolisation of
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Eur. J. Org. Chem. 2003, 4757Ϫ4764

Preparation of Multiply Protected Alkylhydrazine Derivatives
FULL PAPER
Table 1. Preparation of the alkylhydrazine derivatives 6, 7, 10
2 or 5
R
RЈ
2 Ǟ 6 or 5 Ǟ 7
6 Ǟ 7
7 Ǟ 10
Method A
Method B
% Yield[a]
% Yield[a]
% yield[a]
% yield[a] (time)
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2c
2c
2d
2d
5a
5a
5b
5b
5c
5c
5d
5d
5e
5e
2a
2a
2a
2b
2b
2b
2e
2e
2f
OtBu
OtBu
OtBu
OtBu
OtBu
OBzl
OBzl
OBzl
OBzl
OBzl
CH3
CH3
C6H5
C6H5
CH3
CH3
CH3
CH2Ph
(CH2)5CH3
CH2CHϭCH2
CH2COOCH3
CH3
6a
6b
6c
6d
6e
6f
6g
6h
6i
97[b]
83[b]
86[b]
67[b]
70
71[c] (12 h)
96 (2 h)
7k: 82
7l: 91
10k: 96
10l: 84
91 (24 h)
85 (18 h)
86 (2 h)
94[b]
84[b]
80
94[c] (12 h)
92 (2 h)
7o: 76
7p: 80
10o: 98
10p: 96
CH2Ph
(CH2)5CH3
CH2CHϭCH2
CH2COOCH3
CH3
CH2Ph
CH3
CH2Ph
CH3
CH2Ph
CH3
CH2Ph
CH3
CH2Ph
CH3
CH2Ph
CH3
CH2Ph
CH(CH3)2
Cyclopentyl
(S)CH(CH3)COOMe
CH(CH3)2
Cyclopentyl
(S)CH(CH3)COOEt
CH3
CH2Ph
CH3
CH2Ph
CH3
87 (3 h)
82 (1 h)
78 (4 h)
89 (24 h)
82 (5 h)
92 (15 h)
86 (16 h)
58 (48 h)
81 (48 h)
43 (48 h)
92 (48 h)
69 (24 h)
54 (2 h)
70 (24 h)
83 (2 h)
68 (24 h)
84 (2 h)
86
6j
6k
6l
81[d]
85
7a: 90
7b: 94
7e: 75
7f: 80
10a: 85
10b: 81
10e: 86
10f: 85
80
90
85
0
0
0
0
42
60
77
40
50
6m
6n
7a
7b
7c
7d
7e
7f
(CH2)6CH3
(CH2)6CH3
Ph
Ph
ZNHCH2
ZNHCH2
ZNHCH(Me)
ZNHCH(Me)
OtBu
OtBu
OtBu
OBzl
OBzl
OBzl
(CH2)6CH3
(CH2)6CH3
ZNHCH2
ZNHCH2
ZNHCH(Me)
ZNHCH(Me)
7g
7h
7i
7j
35
6o
6p
6q
6r
6s
6t
77[b]
85[b]
82[d]
61
46[d](150 h)
49 (15 h)
70 (30 h)
75[d](150 h)
71 (10 h)
93 (2 h)
7m: 92
7n: 84
10m: 95
10n: 97
83
7q: 76
7r: 90
7c: 86
7d: 72
7g: 84
7h: 78
7i:[e] 94
7j: 81
10q: 91
10r: 90
10c: 86
10d: 83
10g: 91
10h: 91
10i: 93
10j: 77
90[d]
74
6u
6v
6w
6x
6y
6z
79
88
2f
82
2g
2g
93[b]
97[b]
CH2Ph
[a]
[b]
Yield of isolated compounds. See reference.[4a] [c] For volatile reagents, reactions were performed at room temperature with 4 equiv.
of alkyl halides. See reference.[4b] [e] Including 29 % of compound 7iЈ BocZNCH(CH3)CONMeNBoc2.
[d]
the alkyl halide prior to the substitution reaction in the me-
dium.
To summarise, compounds 2 can be efficiently alkylated
Transprotection Reaction
In preliminary studies[5] we showed that the use of meth-
by primary or secondary alkyl groups either by the PTC or ylamine, described in the literature for the dephthaloylation
by the Mitsunobu approach and are better acidic partners of some protected amines,[7] was not efficient for removal
than imidodicarbonate analogues 5. These results can be of the phthaloyl group in compounds 6. These conditions
explained by the presence of the phthaloyl group, which actually resulted in the formation of compounds 8, prod-
contributes to an increase in the acidity of the sole proton ucts of opening of the phthaloyl ring. From this obser-
and concomitantly to a reduction in the steric hindrance. vation, we deduced that the attachment of an electron-with-
Unfortunately, as other authors have reported, we were con- drawing group onto the acidic nitrogen atom of the hydra-
fronted with the difficulty involved in finding general mild zide function might help the dephthaloylation step by fav-
conditions for removal of the phthaloyl group. In some ouring the splitting of the COϪN bond of the hydrazide
cases this drawback contributed to the detriment of this group.[8] This strategy has been reported in the literature
new strategy of hydrazine derivatives synthesis. In order to previously, since amides can be activated towards hydrolysis
find mild efficient conditions to remove the phthaloyl group by prior conversion into the N-Boc imide derivatives. As a
and to obtain Boc protection of our hydrazine derivatives, result, we were able to show that the removal of the
we developed a strategy to transform a phthaloyl moiety phthaloyl group of 8 can be achieved very efficiently by the
into a Boc group.
use of (Boc)2O in the presence of a catalytic amount of
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´
N. Brosse, M.-F. Pinto, B. Jamart-Gregoire
FULL PAPER
DMAP. In fact, use of these conditions resulted in the direct
formation of the corresponding Nβ,Nβ-bis(tert-butoxycar-
bonyl)hydrazides or carbazates 7. Systematic assays per-
formed on compound 6g demonstrated that the reaction
was better achieved with 3 equivalents of (Boc)2O, since the
use of one equivalent of reagent resulted in the formation
of a mixture of compounds 7p and 10p (in 25 % and 55 %
yields, respectively). To improve our technique, we carried
out investigations to perform the conversion of
phthaloylhydrazides or carbazates 6 into the corresponding
compounds 7 in a one-flask fashion that might potentially
find use in the combinatorial synthesis of Boc-protected hy-
drazides or carbazates. The results reported in the Table 1
(6 Ǟ 7) show that the conversions of 6 into 7 occurred in
very good yields, regardless of the nature of R or RЈ (RЈ
can also be a secondary group). Moreover, we also demon-
strated on a few examples that this strategy can be applied
for the preparation of orthogonal Nα,Nβ-triprotected α-hy-
drazino esters (see compounds 7gϪ7j). A proposed mecha-
nism of formation of 7 is given in Scheme 3.
Scheme 4
Conclusion
Protected alkylhydrazines can be obtained by alkylation
of the phthalimide derivatives 2. Thanks to the particular
structural features pertaining when the two acyl groups are
incorporated into a ring, these compounds have been shown
to be better acid partners than imidodicarbonate analogues
5 in Mitsunobu and PTC procedures, allowing their alky-
lation by either primary or secondary groups. The obtained
N-aminophthalimide derivatives 6 can be efficiently con-
verted into the corresponding N-(amino)imidodicarbonates
7 under very mild conditions by use of a three-stage, one-
flask method. Selective removal of one Boc group of com-
pounds 7 resulted in the formation of N-(tert-butoxycar-
bonyl)hydrazine derivatives 10. This strategy can also be ap-
plied for the preparation of orthogonally Nα,Nβ-diprotected
α-hydrazino esters.
Experimental Section
Scheme 3
General: Melting points were obtained on a hot-stage apparatus
and were uncorrected. NMR spectra were recorded with spec-
trometers operating at 400 MHz or 250 MHz. Mass spectra were
performed by the ULIRS Mass Spectrometry Facility (the School
of Pharmacy, London). Tetrahydrofuran were dried by distillation
over sodium-benzophenone.
As described above, the action of the methylamine on 6
gave the corresponding compound 8, which can be isolated.
The mechanism then predicts a selective reaction between
(Boc)2O and the nitrogen of the hydrazide group of 8, af-
fording the non-isolable compound 9. The cleavage of the
CϪN bond in the hydrazide moiety can be explained in
terms of an intramolecular attack of the nitrogen atom of
the amide group. The isolation and the identification of the
methylphthalimide as a by-product of the reaction is in
agreement with the proposed reaction mechanism. The for-
mation of compound 7 would be the result of the reaction
of a second equivalent of (Boc)2O. On one example we
demonstrated that the replacement of the methylamine in
step i) by a secondary amine allowed the isolation of com-
pound 11 from 6n; the conversion of 11 to 10f then required
General Procedure for the Preparation of N-Acyl- and N-[(Alkyloxy-
carbonyl)amino]phthalimides 2: Hydrazide or carbazate (0.1 mol)
was added to a suspension of phthalic anhydride (0.1 mol, 14.8 g)
in toluene (200 mL) and the resulting mixture was heated to reflux,
the water formed in the reaction being trapped in a DeanϪStark
receiver. After 3 h, the solution was cooled to 0 °C; after filtration,
the solid obtained by precipitation was recrystallised from EtOAc/
hexane (or CHCl3/CCl4 for 2b). Spectroscopic data of compounds
2aϪd were previously described.[4a]
Nα-[(Heptanoyl)amino]phthalimide (2e): M.p. 103 °C. IR (KBr): ν˜ ϭ
3273, 1799, 1750, 1665 cmϪ1. 1H NMR (CDCl3): δ ϭ 8.64 (s, 1
H), 7.86Ϫ7.62 (m, 4 H), 2.45Ϫ2.25 (m, 2 H), 1.74Ϫ1.49 (m, 2 H),
1.40Ϫ1.11 (m, 8 H), 0.95Ϫ0.72 (m, 3 H) ppm. 13C NMR: δ ϭ
the use of another nucleophile Ϫ methylamine Ϫ in step ii) 173.0, 165.7, 135.0, 130.3, 124.2, 34.1, 32.0, 29.4, 25.7, 23.0, 14.4
ppm.
(Scheme 4). This result is in agreement with the proposed
reaction mechanism.
Finally, we showed that the presence of a catalytic
amount of Mg(ClO4)2 in CH3CN[9] promoted mild, selec-
tive monodeprotection of imidodicarbonates 7 to yield
compounds 10 (Scheme 3, Table 1, 7 Ǟ 10).
NЈ-(Benzyloxycarbonyl)-Nβ-phthaloylglycinehydrazide (2f): M.p. 155
°C. IR (KBr): ν˜ ϭ 3346, 3197, 1794, 1764, 1741, 1700 cmϪ1 1H
.
NMR (CDCl3): δ ϭ 12.00 and 11.02 (m, 1 H), 10.11Ϫ9.92 (m, 1
H), 8.32Ϫ7.74 (m, 4 H), 7.56Ϫ7.01 (m, 5 H), 5.04 (s, 2 H), 3.82 (d,
J ϭ 7.2 Hz, 2 H) ppm. 13C NMR: δ ϭ 168.8, 164.3, 157.3, 137.8,
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Preparation of Multiply Protected Alkylhydrazine Derivatives
133.4, 129.2, 128.6, 128.5, 125.9, 66.4, 42.8 ppm. C18H15N3O5 (S)-NЈ-(Benzyloxycarbonyl)-Nβ,Nβ-bis(tert-butyloxycarbonyl)-
FULL PAPER
(353.3): calcd. C 61.19, H 4.28, N 11.89; found C 61.21, H 4.34,
N 11.88.
alaninehydrazide (5e): Yield 86 %; m.p. 138Ϫ140 °C. IR (KBr): ν˜ ϭ
3264, 1763, 1703 cmϪ1. 1H NMR (CDCl3): δ ϭ 9.25 and 9.18 (2 s,
1 H), 7.32Ϫ7.21 (m, 5 H), 6.06 and 6.02 (2 d, 1 H), 5.06Ϫ4.98 (m,
2 H), 4.46Ϫ4.35 (m, 1 H), 1.52Ϫ1.34 (m with s at 1.45, 21 H) ppm.
13C NMR: δ ϭ 171.0, 156.5, 150.7, 136.4, 128.9, 128.6, 128.4, 84.3,
67.4, 49.2, 28.3, 18.6 ppm. C21H31N3O7 (437.5): calcd. C 57.65,
H 7.14, N 9.60; found C 57.57, H 7.15, N 9.77.
Procedure for the Preparation of Nβ,Nβ-Bis(tert-butoxycarbonyl)-
hydrazine (4): A solution of N-[(tert-butoxycarbonyl)amino]phthal-
imide (2) R ϭ OtBu (20 mmol, 5.2 g), Et3N (5 mL) and a catalytic
amount of DMAP in THF (150 mL) was stirred and cooled in
an ice-water bath. Di-(tert-butyl) dicarbonate (6.5 g, 30 mmol) was
added and stirring was continued at room temperature for 15 min.
The solution was concentrated in vacuo. Water and diethyl ether
were added, and the aqueous layer was separated and extracted
General Procedure for the Alkylation with Alcohols (Mitsunobu’s
Procedure. Method A): DIAD (7.5 mmol, 1.5 g) was added in one
portion with stirring under nitrogen at 0Ϫ5 °C to a solution of 2
twice with diethyl ether. The organic layer was washed with diluted or 5 (5 mmol), PPh3 (7.5 mmol, 2 g) and alcohol (R-OH, 7.5 mmol)
HCl and dried with MgSO4, and the solvents were evaporated to
dryness. The residue was chromatographed through silica gel with
EtOAc/hexane to give Nβ,Nβ-[bis(tert-butoxycarbonyl)amino]ph-
in dry THF. The resulting solution was stirred at room temperature
for 0.5 h (monitored by TLC until completion) and concentrated
in vacuo. The residue was evaporated and the residue was chroma-
thalimide (3) (80 %). H2NϪNH2·H2O (1.5 equivalents, 0.750 mL) tographed on silica gel (with a mixture of hexane and EtOAc as elu-
was then added by syringe at Ϫ20 °C to a suspension of 3
(10 mmol, 3.62 g) in EtOH (100 mL). The solution was warmed to
room temperature, and after 15 min a white precipitate was filtered
off. The filtrate was evaporated to give a solid, which was chroma-
tographed through silica gel with EtOAc/hexane to give pure com-
pound 4 (87 %).
ent).
General Procedure for the Alkylation with Alkyl Halides (PTC Pro-
cedure, Method B): Dry K2CO3 (7.6 mmol, 4 equiv.) and BnEt3NCl
(0.2 equiv.) were added to a solution of 2 or 5 (1.9 mmol) in MeCN
(8 mL). The alkyl halide (CH3I or RЈBr, 1.25 or 4 equiv.; see
Table 1) was added dropwise (over 5 min) under nitrogen and the
resulting mixture was vigorously stirred at the temperature and for
General Procedure for the Preparation of Nβ,Nβ-Bis(tert-butyloxy-
carbonyl)hydrazines 5: 1,1Ј-Carbonyldiimidazole (10 mmol, 1.62 g) the time indicated in the Table 1 (monitored by TLC until com-
was added to a solution of carboxylic acid (10 mmol) in THF. The
mixture was heated at reflux for 10 min (corresponding to the end
of CO2 evolution), and Nβ,Nβ-bis(tert-butyloxycarbonyl)hydrazine
(4) (5 mmol, 1.16 g) was then added. Heating at reflux was con-
tinued for 20Ϫ96 h (monitored by TLC until completion). The me-
dium was concentrated in vacuo and the residue was partitioned
between water and diethyl ether. The water layer was extracted
twice with diethyl ether, the organic layer was dried with MgSO4
and concentrated in vacuo, and the residue was chromatographed
on silica gel.
pletion). Water (50 mL) was added and the mixture was extracted
three times with diethyl ether. The combined organic phases were
dried with MgSO4 and concentrated in vacuo. The residue was
chromatographed on silica gel (with a mixture of hexane and
EtOAc as eluent). Spectroscopic data of compounds 6aϪg, jϪq, t,
y, z were previously described.[4a]
N-[(Benzyloxycarbonyl)(hexyl)amino]phthalimide (6h): IR (NaCl):
ν˜max. ϭ 1796, 1746 cmϪ1 1H NMR (400 MHz, CDCl3): δ ϭ
.
7.90Ϫ7.68 (m, 4 H), 7.41Ϫ7.09 (m, 5 H), 5.23 and 5.10 (2 s, 2 H),
3.80Ϫ3.69 (m, 2 H), 1.67Ϫ1.17 (m, 8 H), 0.85 (t, 3 H) ppm. 13C
NMR (CDCl3): δ ϭ 165.8, 165.5, 154.9, 154.7, 136.1, 135.9, 135.2,
Nα-Acetyl-Nβ,Nβ-bis(tert-butyloxycarbonyl)hydrazine (5a): Yield 90
1
%; m.p. 109 °C. IR (KBr): ν˜ ϭ 3302, 1759, 1675 cmϪ1. H NMR 135.1, 130.2, 130.1, 128.9, 128.7, 128.4, 128.3, 127.5, 124.2, 69.0,
(CDCl3): δ ϭ 8.47 (s, 1 H), 1.98 (s, 3 H), 1.47, 1.43 (2 s, 18 H)
68.4, 51.1, 50.4, 31.8, 28.4, 28.0, 26.5, 22.9, 14.4 ppm. HRMS
ppm. 13C NMR: 169.2, 151.1, 84.1, 28.2, 20.8 ppm. calcd. for C22H24N2O4 [Mϩ] m/z ϭ 380.1736 found 380.1723.
δ
ϭ
C12H22N2O5 (274.3): calcd. C 52.54, H 8.08, N 10.21; found C
52.06, H 7.84, N 10.34.
N-[(Allyl)(benzyloxycarbonyl)amino]phthalimide (6i): IR (NaCl):
ν˜max ϭ 1796, 1740 cmϪ1 1H NMR (400 MHz, CDCl3): δ ϭ
.
Nβ,Nβ-Bis(tert-butyloxycarbonyl)-Nα-heptanoylhydrazine (5b): Yield 7.89Ϫ7.65 (m, 4 H), 7.43Ϫ7.02 (m, 5 H), 6.00Ϫ5.80 (m, 1 H),
85 %; m.p. 78 °C. IR (KBr): ν˜ ϭ 3310, 1774, 1677 cmϪ1. 1H NMR
(CDCl3): δ ϭ 8.54 (s, 1 H), 2.16 (t, J ϭ 7.5 Hz, 2 H), 1.62Ϫ1.50
5.23Ϫ5.03 (m, 2 H), 4.31Ϫ4.19 (m, 2 H). 13C NMR (CDCl3): δ ϭ
165.0 and 164.7, 154.1, 135.5 and 135.4, 134.8, 131.8 and 131.7,
(m, 2 H), 1.37 (s, 18 H), 1.28Ϫ1.10 (m, 8 H), 0.76 (t, J ϭ 7.5 Hz, 129.5 and 129.4, 128.5, 128.3, 127.9, 127.1, 123.7, 119.8, 68.6, 68.1,
3 H) ppm. 13C NMR: δ ϭ 172.0, 150.9, 83.6, 34.1, 31.9, 29.5, 23.3, 53.3, 52.3 ppm. HRMS calcd. for C19H16N2O4 [Mϩ] m/z ϭ
28.1, 25.6, 22.8, 14.3 ppm. C18H26N2O5: calcd. C 60.31, H 9.56,
N 7.81; found C 60.28, H 9.46, N 7.90.
336.1742 found 336.1743.
N-[(Benzyloxycarbonyl)(isopropyl)amino]phthalimide
(6r):
IR
Nα-Benzoyl-Nβ,Nβ-bis(tert-butyloxycarbonyl)hydrazine (5c): Yield
(NaCl): ν˜max. ϭ 1794, 1745 cmϪ1 1H NMR (400 MHz, CDCl3):
.
95 %; m.p. 172 °C. IR (KBr): ν˜ ϭ 3313, 1766, 1692 cmϪ1. 1H NMR δ ϭ 7.95Ϫ7.88 (m, 4 H), 7.45Ϫ7.07 (m, 5 H), 5.25 and 5.11 (2 s, 2
(DMSO): δ ϭ 10.86 (s, 1 H), 7.86 (s, 2 H), 7.59Ϫ7.41 (m, 3 H),
H), 4.71 and 4.58 (2 hept., 1 H), 1.26 (d, J ϭ 6.5 Hz, 6 H) ppm.
1.41 (s, 18 H) ppm. 13C NMR: δ ϭ 165.4, 150.5, 132.3, 132.0, 13C NMR (CDCl3): δ ϭ 166.9, 166.5, 153.9, 136.2, 136.0, 135.2,
128.6, 127.5, 82.8, 27.7 ppm. C17H24N5O2 (330.4): calcd. C 60.70,
H 7.19, N 8.33; found C 60.62, H 7.19, N 8.42.
130.4, 130.2, 129.0, 128.7, 128.5, 128.4, 128.3, 127.4, 124.3, 69.0,
68.2, 60.7, 52.2, 51.5, 21.2, 20.8, 14.6 ppm. HRMS calcd. for
C19H22N3O4 [M ϩ NH4ϩ] m/z ϭ 356.1610 found 356.1610.
NЈ-(Benzyloxycarbonyl)-Nβ,Nβ-bis(tert-butyloxycarbonyl)glycine-
hydrazide (5d): Yield 96 %. IR (neat): ν˜ ϭ 3299 1760, 1718 cmϪ1
.
N-[(Benzyloxycarbonyl)(cyclopentyl)amino]phthalimide (6s): IR
1H NMR (CDCl3): δ ϭ 9.15 (s, 1 H), 7.29Ϫ7.17 (m, 5 H),
(NaCl): ν˜max ϭ 1796, 1740 cmϪ1 1H NMR (400 MHz, CDCl3):
.
6.18Ϫ6.11 (pt, 1 H), 5.01 (m, 2 H), 3.91 (d, J ϭ 5 Hz,2 H,), 1.45, δ ϭ 7.85Ϫ7.82, 7.72Ϫ7.66 (m, 4 H), 7.37Ϫ7.02 (m, 5 H), 5.19 and
1.40 (2s, 18 H) ppm. 13C NMR: δ ϭ 168.6, 157.2, 150.8, 136.6, 5.06 (2 s, 2 H), 4.81Ϫ4.59 (m, 1 H), 2.06Ϫ1.93 (m, 4 H), 1.74Ϫ1.42
128.8, 128.4, 128.3, 84.2, 67.3, 28.2 ppm. HRMS calcd. for
(m, 4 H) ppm. 13C NMR (CDCl3): δ ϭ 166.6, 166.3, 154.3, 136.1,
135.3, 130.1, 128.9, 128.7, 128.2, 127.3, 124.3, 69.0, 68.3, 61.3, 60.8,
C20H33N4O7 [M ϩ NH4ϩ] m/z ϭ 441.2349 found 441.2339.
Eur. J. Org. Chem. 2003, 4757Ϫ4764
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4761

´
N. Brosse, M.-F. Pinto, B. Jamart-Gregoire
FULL PAPER
30.6, 30.0, 23.6 ppm. HRMS calcd. for C21H24N3O4 [M ϩ NH4
m/z ϭ 382.1767 found 383.1772.
ϩ
]
Nβ,Nβ-Bis(tert-butyloxycarbonyl)-Nα-heptanoyl-Nα-methylhydrazine
(7c): IR (neat): ν˜ ϭ 1802, 1764, 1724, 1666 cmϪ1 1H NMR
.
(CDCl3): δ ϭ 3.01 (s, 3 H), 2.25 and 2.07 (2 t, J ϭ 7.3 Hz, 2 H),
1.65Ϫ1.11 (m with s at 1.14, 28 H), 0.84Ϫ0.74 (m, 3 H) ppm. 13C
NMR: δ ϭ 174.7, 150.1, 84.7, 34.9, 32.0, 31.6, 29.7, 29.3, 28.2,
24.8, 22.9, 14.3 ppm. HRMS calcd. for C19H37N2O5 [M ϩ Hϩ]
m/z ϭ 373.2702, found 373.2694.
N-[(Methyl)(heptanoyl)amino]phthalimide (6u): M.p. 68 °C. IR
(KBr): ν˜ ϭ 1795, 1736, 1623 cmϪ1 1H NMR (CDCl3): δ ϭ
.
7.97Ϫ7.65 (m, 4 H), 3.40 and 3.18 (2 s, 3 H), 2.47 and 2.04 (2 t, 2
H, J ϭ 7.5 Hz), 1.69Ϫ1.44 (m, 2 H), 1.37Ϫ1.04 (m, 8 H), 0.83Ϫ0.69
(m, 3 H) ppm. 13C NMR: δ ϭ 174.6, 171.9, 165.4, 164.9, 135.6,
134.9, 130.4, 130.0, 124.5, 124.2, 38.9, 35.4, 33.1, 32.0, 31.9, 31.7,
29.4, 29.3, 29.2, 24.9, 24.6, 22.9, 22.8, 14.3 ppm. C17H22N2O3
(302.4): calcd. C 67.53, H 7.33, N 9.26; found C 67.42, H 7.30, N
9.30.
Nα-Benzyl-Nβ,Nβ-bis(tert-butyloxycarbonyl)-Nα-heptanoylhydrazine
(7d): IR (neat): ν˜ ϭ 3088, 3064, 3030, 1801, 1765, 1731, 1686 cmϪ1
.
1H NMR (CDCl3): δ ϭ 7.31Ϫ7.21 (m, 5 H), 4.66 (s, 2 H), 2.42 and
2.14 (2 t, J ϭ 7.3 Hz, 2 H), 1.60 and 1.57 (m, 2 H), 1.41Ϫ1.17 (m
with s at 1.30, 26 H), 0.87Ϫ0.79 (m, 3 H) ppm. 13C NMR: δ ϭ
174.6, 150.0, 135.4, 130.6, 128.5, 128.0, 84.1, 51.4, 31.8, 31.7, 29.5,
29.2, 27.9, 24.5, 22.7, 14.2 ppm. HRMS calcd. for C25H40N2O5
m/z ϭ 448.2937, found 448.2935.
N-[(Benzyl)(heptanoyl)amino]phthalimide (6v): M.p. 72 °C. IR
(KBr): ν˜ ϭ 1815, 1735, 1690 cmϪ1 1H NMR (CDCl3): δ ϭ
.
7.92Ϫ7.67 (m, 4 H), 7.55Ϫ7.13 (m, 5 H), 4.98 and 4.94 (2 s, 2 H),
2.58 and 2.16 (2 t, J ϭ 7.5 Hz, 2 H), 1.78Ϫ1.57 (m, 2 H), 1.43Ϫ1.15
(m, 8 H), 0.91Ϫ0.80 (m, 3 H) ppm. 13C NMR: δ ϭ 174.6, 165.1,
135.4, 134.9, 134.7, 130.0, 129.6, 129.1, 128.7, 128.6, 128.5, 128.3,
124.4, 124.2, 55.1, 51.4, 32.4, 32.0, 29.4, 24.7, 22.9, 14.4 ppm.
C23H26N2O3 (378.5): calcd. C 72.99, H 6.93, N 7.40; found C 72.67,
H 7.06, N 7.40.
Nα-Benzoyl-Nβ,Nβ-bis(tert-butyloxycarbonyl)-Nα-methylhydrazine
(7e): M.p. 58Ϫ60 °C. IR (KBr): ν˜ ϭ 1754, 1717, 1677 cmϪ1 1H
.
NMR (CDCl3): δ ϭ 7.32Ϫ7.10 (m, 5 H), 3.06 (s, 3 H), 1.36 and
1.25 (2 s, 18 H) ppm. 13C NMR: δ ϭ 172.7, 149.9, 134.8, 130.7,
128.2, 126.8, 84.6, 35.5, 28.1 ppm.
Nα-Benzoyl-Nα-benzyl-Nβ,Nβ-bis(tert-butyloxycarbonyl)hydrazine
(7f): M.p. 99 °C. IR (KBr): ν˜ ϭ 1798, 1661 ppm. 1H NMR
(CDCl3): δ ϭ 7.57Ϫ7.22 (m, 10 H), 4.89 (s, 2 H), 1.43 and 1.29 (2s,
18 H) ppm. 13C NMR: δ ϭ 172.8, 135.2, 135.1, 131.1, 130.7, 128.8,
128.6, 128.3, 128.2, 84.7, 52.6, 28.2 ppm. C24H30N2O5 (426.5):
calcd. C 67.59, H 7.09, N 6.57; found C 67.79, H 7.14, N 6.71.
NЈ-(Benzyloxycarbonyl)-Nα-methyl-Nβ-(phthaloyl)glycinehydrazide
(6w): M.p. 149 °C. IR (KBr): ν˜ ϭ 3328, 1792, 1747, 1684 cmϪ1
.
1H NMR (CDCl3): δ ϭ 7.97Ϫ7.76 (m, 4 H), 7.36Ϫ7.26 (m, 5 H),
5.72Ϫ5.62 (m, 1 H), 5.12 and 5.05 (2 s, 2 H), 4.29 and 3.89 (2 d,
J ϭ 4.5 Hz, 2 H), 3.41 and 3.29 (2 s, 3 H) ppm. 13C NMR: δ ϭ
170.2, 164.6, 156.3, 136.7, 135.8, 135.3, 130.0, 128.9, 128.5, 128.4,
124.8, 124.5, 67.4, 42.3, 35.8 ppm. C19H17N5O3 (363.4): calcd. C
62.12, H 4.66, N 11.44; found C 62.03, H 4.70, N 11.52.
NЈ-(Benzyloxycarbonyl)-Nβ,Nβ-bis(tert-butyloxycarbonyl)-Nα-
methylglycinehydrazide (7g): IR (KBr): ν˜ ϭ 1802, 1765, 1724, 1702
1
cmϪ1. H NMR (CDCl3): δ ϭ 7.38Ϫ7.27 (m, 5 H), 5.60Ϫ5.54 (m,
N-Benzyl-NЈ-(benzyloxycarbonyl)-Nβ-(phthaloyl)glycinehydrazide
(6x): M.p. 132 °C. IR (KBr): ν˜ ϭ 3364, 1796, 1735, 1713, 1686
1 H), 5.11 (s, 2 H), 3.89 (d, J ϭ 4.6 Hz, 2 H), 3.13 (s, 3 H), 1.53
(s, 18 H) ppm. 13C NMR: δ ϭ 170.4, 156.5, 149.7, 136.8, 128.6,
128.2, 85.3, 66.9, 42.1, 35.0, 28.0 ppm. HRMS calcd. for
C21H32N3O7 [M ϩ Hϩ] m/z ϭ 438.2240 found 438.2256.
1
cmϪ1. H NMR (CDCl3): δ ϭ 7.92Ϫ7.70 (m, 4 H), 7.49Ϫ7.11 (m,
10 H), 5.77Ϫ5.62 (m, 1 H), 5.20Ϫ4.84 (m, 4 H), 4.05Ϫ3.82 (m, 2
H) ppm. 13C NMR: δ ϭ 170.2, 164.7, 156.4, 136.7, 135.6, 133.6,
130.2, 129.5, 129.2, 128.9, 128.7, 128.5, 128.4, 124.6, 124.4, 67.4,
52.0, 42.8 ppm. C25H21N3O5 (443.5): calcd. C 67.71, H 4.77,
N 9.47; found C 67.47, H 4.80, N 9.49.
Nα-Benzyl-NЈ-(benzyloxycarbonyl)-Nβ,Nβ-bis(tert-butyloxy-
carbonyl)glycinehydrazide (7h): M.p. 82 °C. IR (KBr): ν˜ ϭ 1772,
1
1731, 1715, 1682 cmϪ1. H NMR (CDCl3): δ ϭ 7.45Ϫ7.20, (m, 10
H), 5.66Ϫ5.56 (m, 1 H), 5.19Ϫ5.08 (m, 2 H), 4.79Ϫ4.69 (m, 2 H),
4.01Ϫ3.88 (m, 2 H), 1.38 (s, 18 H) ppm. 13C NMR: δ ϭ 170.2,
164.7, 156.4, 136.7, 135.6, 135.2, 133.6, 130.2, 129.2, 128.9, 128.7,
128.5, 128.4, 124.6, 67.4, 52.0, 42.8 ppm. C27H35N7O3 (505.6):
calcd. C 63.14, H 6.87, N 8.18; found C 63.13, H 6.78, N 8.20.
General Procedure for the Transprotection Reaction: A solution of
methylamine (4.5 mM, 2  in MeOH) was added at room tempera-
ture to a solution of compound 6 (3 mM) in THF (20 mL). The
mixture was stirred at room temperature until completion (1 to 4 h,
monitored by TLC). The solvent and the excess of methylamine
were removed in vacuo. The residue was dissolved in THF (20 mL),
and Boc2O (9 mM, 2 g) and a catalytic amount of DMAP were
added. The mixture was stirred at room temperature until com-
pletion (1 to 4 h, monitored by TLC). The solvent was removed in
vacuo and the residue was separated by column chromatography.
(S)-NЈ-(Benzyloxycarbonyl)-Nβ,Nβ-bis(tert-butyloxycarbonyl)-Nα-
methylalaninehydrazide (7i): IR (KBr): ν˜ ϭ 3327, 1802, 1770, 1728,
1
1685cmϪ1. H NMR (CDCl3): δ ϭ 7.33Ϫ7.22 (m, 5 H), 5.81 and
5.62 (2d, J ϭ 8.5 Hz, 1 H), 5.09Ϫ5.00 (m, 2 H), 4.70Ϫ4.53 (m, 1
H), 3.26 and 3.08 (2 s, 3 H), 1.51 and 1.43 (2 s, 18 H), 1.35 and
1.23 (2 d, J ϭ 6.5 Hz) ppm. 13C NMR: δ ϭ 175, 155.9, 155.5,
150.2, 149.7, 136.9, 128.8, 128.4, 128.2, 85.6.85.4, 84.2, 67.1, 47.3,
46.8, 38.2, 35.5, 28.2, 28.0, 19.4, 18.6 ppm. HRMS calcd. for
C22H34N3O7 [M ϩ Hϩ] 452.2397 m/z, found 452.2397.
Nα-Acetyl-Nβ,Nβ-bis(tert-butyloxycarbonyl)-Nα-methylhydrazine
(7a): M.p. 80 °C. IR (KBr): ν˜ ϭ 1754, 1710, 1699 cmϪ1. 1H NMR
(CDCl3): δ ϭ 3.06 (s, 3 H), 1.93 (s, 3 H), 1.50 (s, 18 H) ppm. 13C
NMR: δ ϭ 172.4, 150.0, 84.9, 34.9, 28.3, 20.2 ppm. C13H24N2O5
(288.3): calcd. C 54.15, H 8.39, N 9.71; found C 54.22, H 8.40, N
9.75.
(S)-NЈ-(Benzyloxycarbonyl)-Nβ,Nβ,NЈ-tris(tert-butyloxycarbonyl)-
Nα-methylalaninehydrazide (7iЈ): 1H NMR (CDCl3): δ ϭ 7.33Ϫ7.16
(m, 5 H), 5.19, 5.12 (2 s, 2 H), 4.91 (q, J ϭ 6.8 Hz, 1 H), 3.05, 2.99
(2 s, 3 H), 1.40, 1.38 (2 s, 27 H), 1.32 (d, J ϭ 6.8 Hz, 3 H) ppm.
13C NMR: δ ϭ 171.7, 153.2, 151.0, 150.2, 150.1, 135.5, 128.7,
128.6, 128.5, 84.9, 84.0, 68.9, 53.0, 35.9, 28.2, 16.2 ppm.
Nβ-(Acetyl)-Nα-benzyl-Nβ-bis(tert-butyloxycarbonyl)hydrazine (7b):
1
M.p. 70Ϫ75 °C. IR (KBr): ν˜ ϭ 1757, 1726, 1679 cmϪ1. H NMR
(CDCl3): δ ϭ 7.27Ϫ7.16 (m, 5 H), 4.61 (s, 2 H), 1.91 (s, 3 H), 1.27
(s, 18 H) ppm. 13C NMR: δ ϭ 172.6, 150.0, 135.3, 130.7, 128.7,
(S)-Nα-Benzyl-NЈ-(benzyloxycarbonyl)-Nβ,Nβ-bis(tert-butyloxy-
128.2, 54.6, 51.4, 28.1, 20.5 ppm. C19H28N2O5 (364.4): calcd. C carbonyl)alaninehydrazide (7j): IR (neat): ν˜ ϭ 1803, 1767, 1727,
1
62.62, H 7.74, N 7.69; found C 63.25, H 6.68, N 8.10.
1680 cmϪ1. H NMR (CDCl3): δ ϭ 7.40Ϫ7.27 (m, 10 H), 5.69 (d,
4762
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4757Ϫ4764

Preparation of Multiply Protected Alkylhydrazine Derivatives
FULL PAPER
J ϭ 8.4 Hz, 1 H), 5.15Ϫ4.92 (m, 3 H), 4.78Ϫ4.48 (m, 2 H), 1.47 added at room temperature to a solution of compound 11 (1 mM,
(s, 9 H), 1.32 (d, J ϭ 6.1 Hz, 3 H), 1.20 (s, 9 H) ppm. 13C NMR: 420 mg) in THF (10 mL). The mixture was stirred for 10 min at
δ ϭ 175.2, 155.4, 150.3, 149.6, 136.9, 134.7, 130.9, 128.8, 128.7,
128.6, 128.4, 128.3, 85.2, 66.9, 52.0, 47.3, 28.1, 27.9, 22.4, 19.7 ppm.
HRMS calcd. for C28H41N4O7 [M ϩ NH4ϩ] m/z ϭ 545.2975
found 545.2975.
room temperature (until completion, monitored by TLC). The sol-
vent and the excess methylamine were removed in vacuo. The sol-
vent was removed in vacuo and the residue was separated by col-
umn chromatography to give compound 10f in quantitative yield.
Nα,Nα,Nβ-Tris(tert-butyloxycarbonyl)-Nα-cyclopentylhydrazine
(7m): 1H NMR (CDCl3): δ 4.10 (quint, J ϭ 8 Hz, 1 H), 1.72Ϫ1.62
(m, 4 H), 1.49Ϫ1.22 (m, 33 H) ppm. 13C NMR: δ ϭ 153.6, 151.1
ppm.
General Procedure for the Deprotection of Compounds 7 with
Mg(ClO4)2: Mg(ClO4)2 (110 mg, 0.5 mM) was added to a stirring
solution of compound 7 (3 mM) in CH3CN (30 mL). The solution
was stirred at room temperature for 3 h (monitored by TLC until
completion) and then partitioned between water and diethyl ether.
The aqueous layer was extracted twice with diethyl ether, and the
combined organic layers were dried with MgSO4, filtered and con-
centrated in vacuo. The residue was chromatographed on silica gel
with a mixture of hexane and EtOAc as eluent.
(R)-N-(tert-Butyloxycarbonyl)-Nβ,Nβ-[bis(tert-butyloxycarbonyl)-
1
amino]alanine Methyl Ester (7n): H NMR (CDCl3): δ ϭ 4.48 (q,
J ϭ 7 Hz, 1 H), 3.68 (s, 3 H), 1.48, 1.47, 1.40 (3 s, 27 H), 1.28 (d,
J ϭ 7 Hz, 3 H) ppm. 13C NMR: δ ϭ 171.7, 153.8, 151.1, 83.9, 83.3,
82.1, 56.4, 52.2, 28.4, 28.2, 14.7 ppm. HRMS calcd. for
C19H35N2O8 [M ϩ Hϩ] m/z ϭ 419.2393, found 419.2393.
Nα-Acetyl-Nβ-(tert-butyloxycarbonyl)-Nα-methylhydrazine
(10a):
M.p. 80 °C. IR (KBr): ν˜ ϭ 1731, 1637 cmϪ1. H NMR (CDCl3):
δ ϭ 7.71 (s, 1 H), 3.05 (s, 3 H), 2.01 (s, 3 H), 1.12 (s, 9 H) ppm.
13C NMR: δ ϭ 174.3, 154.7, 82.0, 36.0, 28.5, 20.7 ppm. C8H16N2O3
(188.2): calcd. C 51.05, H 8.57, N 14.88; found C 51.62, H 8.53,
N 13.54.
1
Nα-(Benzyloxycarbonyl)-Nβ,Nβ-bis(tert-butyloxycarbonyl)-Nα-
methylhydrazine (7o): M.p. 92 °C. IR (KBr): ν˜ ϭ 1801, 1710 cmϪ1
.
1H NMR (CDCl3): δ ϭ 7.38Ϫ7.26 (m, 5 H), 5.19, 5.15 (2 s, 2 H),
3.15, 3.13 (2 s, 3 H), 1.47, 1.42 (2 s, 18 H) ppm. 13C NMR: δ ϭ
155.3, 150.2, 136.4, 128.8, 128.6, 128.3, 84.1, 68.4 and 68.1, 37.4
and 36.7, 28.2 ppm. C19H28N2O6 (380.4): calcd. C 59.98, H 7.42,
N 7.36; found C 60.06, H 7.51, N 7.44.
Nα-Acetyl-Nα-Benzyl-Nβ-(tert-butyloxycarbonyl)hydrazine
M.p. 62Ϫ65 °C. IR (KBr): ν˜ ϭ 1730, 1655 cmϪ1
(10b):
.
1H NMR
(CDCl3): δ ϭ 7.34Ϫ7.12 (m, 5 H), 5.36Ϫ4.27 (m, 2 H), 2.02 (s, 3
H), 1.37 (s, 9 H) ppm. 13C NMR: δ ϭ 174.0, 154.6, 136.2, 129.3,
129.1, 128.1, 81.9, 50.8, 28.4, 20.1 ppm. HRMS calcd. for
C14H21N2O3 [M ϩ Hϩ] 265.1552 m/z, found 265.1551.
Nα-Benzyl-Nα-(benzyloxycarbonyl)-Nβ,Nβ-bis(tert-butyloxy-
carbonyl)hydrazine (7p): M.p. 65 °C. IR (KBr): ν˜ ϭ 1798, 1712
1
cmϪ1. H NMR (CDCl3): δ ϭ 7.45Ϫ7.24 (m, 10 H), 5.20 (s, 2 H),
4.67 (s, 2 H), 1.36, 1.29 (2 s, 18 H) ppm. 13C NMR: δ ϭ 155.5,
150.3, 136.3, 135.4, 130.6, 130.2, 128.8, 128.7, 128.6, 128.4, 84.0,
68.7, 68.3, 54.9, 53.9, 28.1 ppm. C25H32N2O6 (456.5): calcd. C
67.77, H 7.06, N 6.13; found C 65.72, H 7.05, N 6.15.
Nβ-(tert-Butyloxycarbonyl)-Nα-methyl-Nα-heptanoylhydrazine (10c):
M.p. Ͻ 50 °C. IR (KBr): ν˜ ϭ 1733, 1648 cmϪ1. 1H NMR (CDCl3):
δ ϭ 7.35Ϫ7.12 (m, 1 H), 3.08 (s, 3 H), 2.36Ϫ2.26 (m, 2 H),
1.61Ϫ1.50 (m, 2 H), 1.45 (s, 9 H), 1.31Ϫ1.18 (m, 8 H), 0.83 (t, J ϭ
6 Hz, 3 H) ppm. 13C NMR: δ ϭ 176.6, 154.7, 81.9, 32.4, 32.1, 29.7,
29.4, 28.5, 25.1, 23.0, 14.4 ppm. C13H27N2O3 (259.4): calcd. C
60.20, H 10.49, N 10.80; found C 60.70, H 10.21, N 10.17.
Nα-(Benzyloxycarbonyl)-Nβ,Nβ-bis(tert-butyloxycarbonyl)-Nα-cyclo-
pentylhydrazine (7q): IR (neat): ν˜ ϭ 3065, 3033, 1801, 1753, 1722
1
cmϪ1. H NMR (CDCl3): δ ϭ 7.38Ϫ7.21 (m, 5 H), 5.16Ϫ5.09 (m,
2 H), 4.37Ϫ4.18 (m, 1 H), 1.97Ϫ1.77 (m, 2 H), 1.72Ϫ1.29 (m, 24
H) ppm. 13C NMR: δ ϭ 154.9, 151.1, 136.5, 128.8, 128.4, 128.2,
83.9, 67.8, 61.4, 29.5, 28.3, 23.5 ppm. HRMS calcd. for
C23H38N3O6 [M ϩ NH4ϩ] 452.2761 m/z, found 452.2774.
Nα-Benzyl-Nβ-(tert-butyloxycarbonyl)-Nα-heptanoylhydrazine (10d):
M.p. 66 °C. IR (KBr): ν˜ ϭ 3261, 1729, 1642 cmϪ1 1H NMR
.
(CDCl3): δ ϭ 7.37Ϫ7.19 (m, 5 H), 6.68Ϫ6.60 (m, 1 H), 5.61Ϫ4.95,
4.38Ϫ3.90 (2 m, 2 H), 2.46Ϫ2.29 (m, 2 H), 1.72Ϫ1.18 (m with s at
1.43, 18 H), 0.88 (t, J ϭ 6.9 Hz, 3 H) ppm. 13C NMR: δ ϭ 176.2,
154.5, 136.4, 129.4, 129.1, 128.2, 82.1, 50.6, 32.7, 32.1, 29.7, 29.5,
28.5, 25.1, 23.0, 14.5 ppm. C19H31N2O3 (335.5): calcd. C 68.03,
H 9.31, N 8.35; found C 68.48, H 9.38, N 8.14.
(R)-Nα-(Benzyloxycarbonyl)-Nβ,Nβ-[bis(tert-butyloxycarbonyl)-
amino]alanine Ethyl Ester (7r): IR (neat): ν˜ ϭ 1800, 1764, 1734
1
cmϪ1. H NMR (CDCl3): δ ϭ 7.38Ϫ7.26 (m, 5 H), 5.29Ϫ5.17 (m,
2 H), 4.58 (q, J ϭ 7 Hz, 1 H), 4.20 (t, J ϭ 7 Hz, 3 H), 1.51, 1.47,
1.45, 1.40 (4 s, 18 H), 1.36 (d, J ϭ 7 Hz, 3 H), 1.26 (t, J ϭ 7 Hz,
3 H) ppm. 13C NMR: δ ϭ 155.5, 150.3, 136.3, 135.4, 130.6, 130.2,
128.8, 128.7, 128.6, 128.4, 84.0, 68.7, 68.3, 54.9, 53.9, 28.1 ppm.
HRMS calcd. for C23H38N3O8 [M ϩ NHϩ] 484.2659 m/z, found
484.2661.
Nα-Benzoyl-Nβ-(tert-butyloxycarbonyl)-Nα-methylhydrazine (10e):
M.p. 112Ϫ114 °C. IR (KBr): ν˜ ϭ 3440, 1702, 1663 cmϪ1. 1H NMR
(CDCl3): δ 7.44Ϫ7.22 (m, 5 H), 3.23 (s, 3 H), 1.35 (s, 9 H) ppm. 13
C
NMR: δ ϭ 134.9, 130.6, 128.3, 127.6, 82.0, 28.4 ppm. C13H18N2O3
(250.3): calcd. C 62.38, H 7.25, N 11.19; found C 62.53, H 7.26,
N 11.21.
Procedure for the Transprotection of Compound 6n with Pyrrolidine:
Pyrrolidine (2 mM, 100 mg) was added to a solution of compound
6n (1.5 mM, 540 mg) in THF (10 mL) at room temperature. The
mixture was stirred at room temperature for 72 h. Boc2O (3 mM,
650 mg) and a catalytic amount of DMAP were added. The mix-
ture was stirred at room temperature for 3 h. The solvent was re-
moved in vacuo and the residue was separated by column chroma-
Nα-Benzoyl-Nα-benzyl-Nβ-(tert-butyloxycarbonyl)hydrazine (10f):
M.p. 124 °C. IR (KBr): ν˜ ϭ 3223, 1726, 1645 cmϪ1 1H NMR
.
(CDCl3): ϭ δ 7.62Ϫ7.22 (m, 10 H), 6.75 (s, 1 H), 6.61Ϫ4.07 (m, 2
H), 1.31 (s, 9 H) ppm. 13C NMR: δ ϭ 154.4, 136.2, 135.3, 130.5,
129.1, 129.0, 128.3, 128.0, 127.7, 82.0, 28.6 ppm. C19H22N2O3
(326.4): calcd. C 69.92, H 6.79, N 8.58; found C 69.72, H 6.79,
N 8.72.
1
tography to give 11 (87 %). H NMR (CDCl3): δ ϭ 7.63Ϫ7.02 (m,
14 H), 5.43 (d, J ϭ 14 Hz, 1 H), 4.52 (d, J ϭ 14 Hz, 1 H),
3.63Ϫ3.43 (m, 2 H), 3.31Ϫ3.20 (m, 2 H), 0.82 s, 9 H) ppm. 13C
NЈ-(Benzyloxycarbonyl)-Nβ-(tert-butyloxycarbonyl)-Nα-methyl-
NMR: δ ϭ 173.3, 169.3, 168.2, 150.5, 131.0, 130.5, 129.7, 128.6, glycinehydrazide (10g): IR (neat): ν˜ ϭ 1720, 1670 cmϪ1. H NMR
1
128.5, 128.4, 128.1, 126.9, 126.1, 85.1, 52.6, 49.5, 46.2, 27.3, 26.5,
24.8 ppm. A solution of methylamine (1.5 mM, 2  in MeOH) was
(CDCl3): δ ϭ 9.57Ϫ9.48 (m, 1 H), 7.42Ϫ7.28 (m, 5 H), 5.04 (s, 2
H), 4.09Ϫ3.47 (m, 2 H), 2.97 (s, 3 H), 1.44 (s, 9 H) ppm. 13C NMR:
Eur. J. Org. Chem. 2003, 4757Ϫ4764
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4763

´
N. Brosse, M.-F. Pinto, B. Jamart-Gregoire
FULL PAPER
δ ϭ 171.7, 157.3, 155.2, 137.9, 129.2, 128.6, 128.5, 81.4, 66.2, 42.2,
Nα-Benzyl-Nα-(benzyloxycarbonyl)-Nβ-(tert-butyloxycarbonyl)-
1
36.0, 28.8 ppm. C16H23N3O5 (337.4): calcd. C 56.96, H 6.87, hydrazine (10p): M.p. 66 °C. IR (KBr): ν˜ ϭ 3265, 1709 cmϪ1. H
N 12.45; found C 56.75, H 6.90, N 12.48.
NMR (CDCl3): δ ϭ 7.57Ϫ7.06 (m, 10 H), 6.68Ϫ6.17 (m, 1 H),
5.23 (s, 2 H), 4.75 (s, 2 H), 1.44 (s, 9 H) ppm. 13C NMR: δ ϭ 156.7,
136.9, 136.4, 129.2, 129.0, 128.6, 128.3, 128.2, 128.1, 82.0, 68.6,
54.0, 28.5 ppm. C20H24N2O4: calcd. C 67.40, H 6.79, N 7.86; found
C 67.49, H 6.79, N 7.89.
Nα-Benzyl-NЈ-(benzyloxycarbonyl)-Nβ-(tert-butyloxycarbonyl)-
glycinehydrazide (10h): M.p. 146 °C. IR (KBr): ν˜ ϭ 3460, 1724,
1634 cmϪ1 1H NMR (CDCl3): δ ϭ 7.42Ϫ7.21 (m, 10 H),
.
7.08Ϫ7.00 (m, 1 H), 5.79Ϫ5.67 (m, 1 H), 5.54Ϫ4.95 (m, 2 H),
4.47Ϫ3.80 (m, 3 H), 1.43 (s, 9 H) ppm. 13C NMR: δ ϭ 171.5, 156.8,
154.3, 136.8, 135.2, 129.5, 129.2, 128.9, 128.5, 128.4, 82.9, 67.3,
51.2, 42.9, 28.5 ppm.
Nα-(Benzyloxycarbonyl)-Nβ-(tert-butyloxycarbonyl)-Nα-cyclopentyl-
hydrazine (10q): 1H NMR (CDCl3): δ ϭ 7.40Ϫ7.24 (m, 5 H),
6.54Ϫ6.40 (m, 1 H), 5.30Ϫ4.97 (m, 2 H), 4.66Ϫ4.46 (m, 1 H),
1.94Ϫ1.23 (m, 18 H) ppm. 13C NMR: δ ϭ 156.2, 136.5, 128.8,
128.4, 128.3, 81.5, 68.2, 29.3, 24.1 ppm.
(S)-NЈ-(Benzyloxycarbonyl)-Nβ-(tert-butyloxycarbonyl)-Nα-methyl-
1
alaninehydrazide (10i): IR (KBr): ν˜ ϭ 1723, 1667 cmϪ1. H NMR
(R)-N-Benzyloxycarbonyl-N-[(tert-butyloxycarbonyl)amino]alanine
(CDCl3): δ ϭ 7.94Ϫ7.80 (m, 1 H), 7.38Ϫ7.22 (m, 5 H), 5.98Ϫ5.86
(m, 1 H), 5.13Ϫ4.72 (m, 2 H), 3.09 (s, 3 H), 1.45 (s, 9 H), 1.28 (d,
J ϭ 7 Hz, 3 H) ppm. 13C NMR: δ ϭ 175.8, 156.3, 154.7, 136.8,
128.8, 128.4, 128.3, 82.4, 67.1, 47.0, 36.0, 28.3, 18.5 ppm. HRMS
calcd. for C17H29N4O5 [M ϩ NH4ϩ] 369.2138 m/z, found 369.2134.
Ethyl Ester (10r): IR (neat): ν˜ ϭ 1737, 1718 cmϪ1 1H NMR
.
(CDCl3): δ ϭ 7.39Ϫ7.26 (m, 5 H), 6.69Ϫ6.52 (m, 1 H), 5.22 (‘‘d’’,
1 H), 5.10 (‘‘d’’, 1 H), 5.05Ϫ4.95, 4.85Ϫ4.73 (2 m, 1 H), 4.23Ϫ4.03
(m, 2 H), 1.47 (d, J ϭ 7 Hz, 3 H), 1.39, 1.35 (2 s, 9 H), 1.29Ϫ1.14
(m, 3 H) ppm. 13C NMR: δ ϭ 172.6, 156.4, 155.5, 136.1, 128.8,
128.5, 128.1, 81.6, 68.7, 61.8, 28.4, 14.5 ppm. HRMS calcd. for
C18H30N3O6 [M ϩ NH4ϩ] 384.2135 m/z, found 384.2126.
(S)-Nα-Benzyl-NЈ-(benzyloxycarbonyl)-Nβ-(tert-butyloxycarbonyl)-
alaninehydrazide (10j): IR (neat): ν˜ ϭ 3288, 1718, 1666 cmϪ1 1H
.
NMR (CDCl3): δ ϭ 7.42Ϫ7.09 (m, 10 H), 6.14Ϫ5.96 (m, 1 H),
5.19Ϫ4.69 (m, 4 H), 4.33Ϫ4.07 (m, 1 H), 1.43 (s, 9 H), 1.34 (d, J ϭ
6 Hz, 3 H) ppm. 13C NMR: δ ϭ 175.7, 156.4, 154.5, 136.7, 135.5,
129.4, 129.3, 129.1, 128.8, 128.4, 82.2, 67.1, 50.7, 47.3, 28.5, 24.2,
18.5 ppm. HRMS calcd. for C23H30N3O5 [M ϩ Hϩ] m/z ϭ
428.2185 found 428.2188.
[1]
For reviews see: O. Mitsunobu, Synthesis 1981, 1Ϫ28; D. L.
Hughes, Org. React. 1992, 42, 435.
[2]
For a review on atom economy see: B. M. Trost, Angew. Chem.
Int. Ed. Engl. 1995, 34, 259.
[3] [3a]
U. Ragnarsson, B. Fransson, L. Grehn, J. Chem. Soc., Per-
[3b]
kin Trans. 1 2000, 1405Ϫ1409.
U. Mäeorg, U. Ragnarsson,
Nα,Nβ-Bis(tert-butyloxycarbonyl)-Nα-(cyclopentyl)hydrazine (10m):
1H NMR (CDCl3): δ ϭ 6.25Ϫ5.99 (m, 5 H), 4.57Ϫ4.36 (m, 1 H),
1.86Ϫ1.37 (m with s at 1.46, 17 H) ppm. 13C NMR: δ ϭ 156.3,
155.4, 81.2, 59.5, 29.3, 28.5, 24.0 ppm. HRMS calcd. for
C15H28N2O4 300.2049 m/z, found 300.2045.
[3c]
Tetrahedron Lett. 1998, 39, 681Ϫ684.
L. Grehn, B. Nyasse,
U. Ragnarsson, Synthesis 1997, 1429Ϫ1432. [3d] U. Mäeorg, L.
Grehn, U. Ragnarsson, Angew. Chem. Int. Ed. Engl. 1996, 35,
2626Ϫ2627.
[4] [4a]
´
N. Brosse, M.-F. Pinto, B. Jamart-Gregoire, J. Org. Chem.
[4b]
2000, 65, 4370Ϫ4374.
N. Brosse, M.-F. Pinto, J. Bodiguel,
B. Jamart-Gregoire, J. Org. Chem. 2001, 66, 2869Ϫ2873.
M.-F. Pinto, N. Brosse, B. Jamart-Gregoire, Synthetic Commun.
(R)-Nα(tert-Butyloxycarbonyl)-Nβ-[(tert-butyloxycarbonyl)amino]-
´
[4c]
1
´
alanine Methyl Ester (10n): H NMR (CDCl3): δ ϭ 6.49Ϫ6.28 (m,
2002, 32, 3603Ϫ3610.
1 H), 4.98Ϫ4.85 (m, 1 H), 3.68 (s, 3 H), 1.60Ϫ1.26 (m, 21 H) ppm.
[5]
[6]
[7]
´
13C NMR:
δ ϭ 173.3, 155.4, 82.1, 52.6, 28.5, 14.7 ppm.
N. Brosse, B. Jamart-Gregoire, Tetrahedron Lett. 2002, 43,
249Ϫ251.
C14H26N2O6: calcd. C 52.81, H 8.23, N 8.80; found C 52.94,
H 8.15, N 8.82.
´
N. Brosse, M.-F. Pinto, B. Jamart-Gregoire, J. Chem. Soc., Per-
kin Trans. 1 1998, 3685Ϫ3688.
M. S. Motawia, J. Wengel, A. E.-S. Abdel-Medig, E. B. Peter-
son, Synthesis 1989, 384Ϫ387; S. E. Sen, S. L. Roach, Synthesis
1995, 756Ϫ758.
Nα-(Benzyloxycarbonyl)-Nβ-(tert-butyloxycarbonyl)-Nα-(methyl)-
1
hydrazine (10o): M.p. 63 °C. IR (KBr): ν˜ ϭ 3278, 1694. H NMR
(CDCl3): δ ϭ 7.39Ϫ7.24 (m, 5 H), 5.14 (s, 2 H), 3.17 (s, 3 H), 1.42
(s, 9 H) ppm. 13C NMR: δ ϭ 156.8, 136.5, 128.8, 128.5, 128.3, 81.8,
68.2, 38.3, 28.6 ppm. C14H20N2O4: calcd. C 59.98, H 7.19, N 9.99;
found C 59.90, H 7.24, N 10.04.
[8]
[9]
C. M. J. Burk, J. G. Allen, J. Org. Chem. 1997, 62, 7054Ϫ7057.
J. A. Stafford, M. F. Brackeen, D. S. Karanewsky, N. L. Val-
vano, Tetrahedron Lett. 1993, 34, 7873Ϫ7876.
Received July 17, 2003
4764
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4757Ϫ4764