Arylation of diversely substituted hydrazines by tri- and pentavalent organobismuth reagents

Article abstract of DOI:10.1016/j.tet.2004.07.020

Various hydrazine derivatives were studied with respect to arylation by triarylbismuthane and triarylbismuth diacetate reagents with emphasis on scope and limitations. Among these reagents, a few contained bulky substituents in their aromatic rings. The a

Full text of DOI:10.1016/j.tet.2004.07.020

Tetrahedron 60 (2004) 8363–8373
Arylation of diversely substituted hydrazines by tri- and
pentavalent organobismuth reagents
a
Olga T sˇ ubrik, Uno M a¨ eorg, Rannar Sillard and Ulf Ragnarsson
a,*
b
c,*
a
Institute of Organic and Bioorganic Chemistry, University of Tartu, Tartu, 51014 Jakobi 2, Estonia
Department of Medical Biochemistry and Biophysics, Karolinska Institutet SE-171 77 Stockholm, Sweden
b
c
Department of Biochemistry, Biomedical Center, University of Uppsala, PO Box 576, SE-751 23 Uppsala, Sweden
Received 24 February 2004; revised 16 June 2004; accepted 8 July 2004
Available online 3 August 2004
Abstract—Various hydrazine derivatives were studied with respect to arylation by triarylbismuthane and triarylbismuth diacetate reagents
with emphasis on scope and limitations. Among these reagents, a few contained bulky substituents in their aromatic rings. The applied
substrates spanned a range from simple hydrazides to triply protected hydrazines and included a large number of intermediates of principal
synthetic interest. In the case of mono- and disubstituted hydrazines the results demonstrate apparent advantages of pentavalent over trivalent
reagents, exemplified by fast, highly chemoselective monoarylation of acylhydrazines at the terminal nitrogen. In contrast, trisubstituted
hydrazines are more efficiently substituted by trivalent reagents. With these substrates, a strong influence of steric factors was occasionally
observed, as reflected in lower yields and even complete reaction inhibition. The introduction of two different aromatic substituents into
disubstituted hydrazines using step-by-step or one-pot procedures was accomplished.
q 2004 Elsevier Ltd. All rights reserved.
4
AcOH. Chan introduced a useful modification of Barton’s
1. Introduction
method, involving employment of a promoter (Et N or
3
5
The problems associated with arylation of organic com-
pounds have for a long time attracted many synthetic
chemists and continue to do so. Along with such
modification at carbon and oxygen, NH arylation is
particularly challenging because it reveals new pathways
to compounds of pharmaceutical and technical importance
and has the potential to simplify their selective synthesis.
pyridine) in work with amides.
Hydrazine derivatives play important roles in the agro-
chemical and dye-stuff industries, as well as in a number of
pharmaceuticals. Thus an increasing interest in arylsubsti-
6
tuted hydrazines can presently be recognized.
For the synthesis of hydrazine derivatives a large number of
7
specialized procedures have been developed. More
From the earlier days of copper catalysis, initiated by
Ullmann, great progress on NH arylation has been made.
1
recently, a number of protected reagents have emerged
and been applied to make such derivatives in a stepwise
During the last decade, these efforts were crowned by
prominent work by Buchwald and Hartwig based on
application of palladium catalysis. Even earlier, around
8
–11
fashion.
After initial substitution, by alternating clea-
2
vages and substitutions, an ideal reagent of this type with
three orthogonal protecting groups would allow any
required hydrazine derivative to be formed. Protecting
groups such as alkoxycarbonyl, arylsulfonyl, phthaloyl and
triphenylphosphonium were exploited in these reagents, by
use of which alkylation and acylation have been
1
980, another approach was developed by Barton and
3
Finet, who applied tri- and pentavalent organobismuth
compounds, in the presence of Cu salts as catalysts, for this
purpose. Trivalent bismuth reagents Ar Bi, triarylbis-
3
muthanes, are synthesized from the corresponding aryl-
magnesium halides and BiCl . Triarylbismuth diacetates
4
3
are the most common pentavalent bismuth reagents and are
readily obtained from Ar Bi by oxidation using NaBO /
3
3
Keywords: Hydrazines; Arylation; Organobismuth reagents; Protecting
groups; Chemoselectivity.
*
Corresponding authors. Tel.: C372-7-375243; fax: C372-7-375245
U.M.); e-mail: uno@chem.ut.ee
Figure 1. Protected precursors for substituted hydrazines employed in this
work.
(
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.020

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O. T sˇ ubrik et al. / Tetrahedron 60 (2004) 8363–8373
accomplished and optimized, resulting in hydrazine deriva-
tives with up to four different substituents.
2. Results and discussion
2
.1. Arylation of monoacylhydrazines
To insert aryl groups into hydrazines by the organobismuth
approach is attractive because of its practical convenience
and mild reaction conditions. Recently we used simple
triarylbismuthanes to arylate precursors 1 and 2 (Fig. 1) in
Successful arylation of monoacylhydrazines by arylhalides
under Cu or Pd catalysis has been reported recently.
Steric factors were found to determine the outcome of the
reactions. The presence of a substituent in the ortho-position
of the arylhalide resulted in the predominant formation
6
a–c
1
2
essentially quantitative yields. Due to the oxidation of
BocNHNHR by stoichiometric amount of Cu(II), these
reagents were unsuitable but could be replaced by
triarylbismuth diacetates. A number of model compounds
of RCONHNHAr, while otherwise RCOArNNH was
2
6
a,b
obtained.
reactions require hours to go to completion.
All these procedures require heating and the
1
3
BocNHNArR were isolated in 74–95% yields. In view of
the fact that pentavalent organobismuth reagents are
1
4
Sorenson recently succeeded in arylating difunctional
substrates, containing amide and primary amine functions,
using triarylbismuthanes. Analogously, it should be
themselves oxidizing agents, these results might at first
seem contradictory but can be understood in the light of the
fact that only a catalytic amount (5%) of Cu(II) was required
in these experiments. Obviously a more scrupulous study of
the scope of these two types of bismuth reagents with
respect to arylation of different kinds of substituted
hydrazines is required.
1
6
possible and desirable to substitute RCONHNH chemo-
2
selectively (Scheme 1). Up to now there are no examples
of using organobismuth reagents for the substitution of
monoacylhydrazines in the literature.
When we tried to arylate compounds RCONHNH (RCOZ
2
As exemplified by Finet et al., steric hindrance occasionally
plays an important role in arylation by organobismuth
reagents. Therefore, we decided to include a few bulky
reagents in this study.
5
Boc, Troc, Cbz, Ph) using the standard Chan procedure (rt,
Ph Bi/Cu(OAc) /Et N/CH Cl ), our first efforts failed. The
3
1
5
2
3
2
2
starting material decomposed with violent gas evolution.
Considering the facile oxidation of hydrazides by copper
compounds, known to take place under quantitative
Whereas on one hand the idea behind the design of
triprotected precursors like 1 and 2 was to provide a
uniform site, at which substitution could be driven to
completion under tolerable conditions, 3 on the other hand
requires a high degree of regioselectivity to be practically
useful. This has also been demonstrated in several instances,
furnishing a considerable number of di- and trisubstituted
17
expulsion of nitrogen, an alternative procedure was sought
which required only a substoichiometric amount of copper
salt.
Pentavalent organobismuth reagents Ar Bi(OAc) are
3
2
usually considered to be more reactive than trivalent ones
and require only a catalytic amount of Cu salt. Their
reactivity was explored as shown above in Table 1, in most
1
3
hydrazines. These compounds, together with 1 and 2 and a
few simple monoacylhydrazines have been used as
substrates in the present work.
cases with tri(p-tolyl)bismuth diacetate and BocNHNH as
2
model compounds. The reactions occur extremely rapidly at
rt, producing a considerable amount of by-product, detected
by TLC. As disubstituted hydrazines can readily be oxidized
1
to the corresponding azo compounds and the H NMR
spectrum of crude 4a revealed two singlets at 1.64 and
2.41 ppm, the by-product was identified as p-TolN]NBoc.
When pure 4a was exposed to Cu(OAc)2 the same
compound was formed as detected by TLC. An analogous
Scheme 1. Selective arylation of monoacylhydrazines.
a
3 2
Table 1. Optimizing experiments with monoacylhydrazine and Ar Bi(OAc)
Entry
Compound
RCO
Ar
Cu(OAc)
2
, mol%
t, 8C
Yield, %
b
1
4a
4a
4a
4a
4a
4a
4a
4a
4b
4e
4c
4d
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Troc
Ac
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
o-Tol
o-Tol
5
5
2
2
20
2
2
2
2
2
rt
45
51
61
75
27
74
91
56
80
91
72
72
2
3
4
5
6
K84
K10
K50
K50
K91
K60
rt
K60
K60
K60
K60
c
7
c
8
c
9
c
10
11
12
c
c
d
1-Np
e
An
2
2
Cbz
a
Acylhydrazine (carbazate)/Ar Bi(OAc)
3
2
2 2 2
(1 equiv)/Cu(OAc) (as indicated)/CH Cl .
b
3 2
All (p-Tol) Bi(OAc) was added in one batch. In the other experiments, the solution of organobismuth reagent was added dropwise during 20–50 min.
Experiments 5 and 7–12 were carried out under argon.
% of BHT (2,6-di-tert-butyl-4-methyl-phenol; butylated hydroxytoluene) was added.
NpZ1-Naphthyl.
AnZ4-Anisyl.
c
d
e
3

O. T sˇ ubrik et al. / Tetrahedron 60 (2004) 8363–8373
8365
by-product was also isolated in the synthesis of 4d, for
which the structure p-CH OC H N]NCOOCH Ph was
Table 2. Arylation of 1-acyl-2-alkylhydrazines 7, prepared in situ from 6,
by Ar Bi(OAc)
3
2
3
6
4
2
1
13
a
Yield, %
confirmed by H and C NMR spectroscopy and elemental
analysis. Reducing the temperature and amount of Cu gave
somewhat better results (entries 2 and 4), but 4a isolated by
column chromatography still contained w10% of azo
compound. The situation changed drastically, when we
added the antioxidant BHT (entry 7). Still, in entry 12, 14%
of azo compound was isolated together with 4d. All
remaining arylation experiments went smoothly and only
traces of azo compounds could be detected by TLC. The
reactions were complete immediately after addition of the
reagents and column chromatography furnished products in
good to high yields, completely pure by TLC and NMR
spectroscopy.
Compound
Product
BocNHNBzlPh
BocNHNBuPh
BocNHNMeNp
8
8
a
b
95
86
87
93
74
86
89
92
48
82
80
8c
8
8
8
8
d
e
f
BocNHN(CH
BocNHN(CH
2
C^CH)(p-Tol)
COOEt)(p-Tol)
2
BocNHNMe(o-Tol)
BocNHNBu(p-Tol)
BocNHNBuAn
BocNHNBu(2-MeO-4-MeC
CbzNHNMe(p-Tol)
AcNHNMe(Np)
g
8h
8
9
1
i
6 3
H )
0
a
Yield over two steps from 6.
This is the first demonstration of mild, fast and highly
selective monoarylation of RCONHNH at the terminal
2
nitrogen. Although the reasons are not understood, it seems
that the combined effect of low temperature and addition of
an antioxidant results in a useful decrease in substrate
oxidation, allowing the intended reaction to take place.
No difference in selectivity was noticed with the more bulky
o-tolyl and 1-naphthyl bismuth reagents, in contrast to
6
a,b
earlier findings involving methods quoted below.
Scheme 3. Synthesis of compounds 8. (a) BuLi, THF; (b) RX; (c) 1 M
NaOH/CH Cl ; (d) arylation with organobismuth compounds.
2
.2. Arylation of disubstituted hydrazines
2
2
Hydrazines with two electron-withdrawing groups can be
smoothly arylated by organobismuth reagents in the
presence of promoter Et N and Cu(OAc) . Symmetrical
substrates, such as BocNHNHBoc, give monoarylated
products (Scheme 2). Phenyl (5a) was introduced more
from 6. Table 2 also includes 9 and 10, with Cbz and Ac
instead of Boc groups. It should be noted that some more
bulky substituents were successfully introduced in these
experiments (8c, 8f, 8i), although the yield was significantly
lower for the last compound, in which case the formation of
a considerable amount of by-product, probably hydrazone,
was also detected by TLC.
3
2
efficiently when Ar Bi was used (2 h, 100%) instead of
3
1
Ar Bi(OAc) (4 h, 86%) and we experienced no diffi-
3
3
2
culties with the more bulky 1-naphthyl (5b) using Np Bi
3
(
(
3 h, 93%). Unsymmetrically substituted hydrazines
CbzNHNHBoc, CbzNHNHTs, CbzNHNHTroc) and
Ar Bi yield mixtures of both possible monoaryl derivatives,
3
2.3. Arylation of trisubstituted hydrazines
as determined by NMR spectra. Reactions are complete in
0
This section deals with the arylation of the triprotected
precursors 1 and 2 (Scheme 4) and the trisubstituted
hydrazines 8 and 13 (Scheme 5) by organobismuth reagents.
Since all substrates are BocNH-acids and electronic effects
of substituents on the second nitrogen are expected to be of
minor importance, their acidity should be quite similar. In
related work with less reactive NH compounds an effect of
.5–4 h.
Scheme 2. Arylation of 1,2-di-Boc-hydrazine.
5
their basicity has been invoked.
Substituted substrates with one electron-withdrawing and
one electron-donating group are more challenging, due to
regioselective arylation. Indeed such a reaction could be
1
3
realized recently for a small set of substrates, but this has
now been expanded with further examples (8f, 8g, 8h, 8i) as
seen in Table 2. Compounds 7, generated in situ from the
phosphonium salts 6, were obtained as illustrated in Scheme
3
. Like acylhydrazines they cannot be arylated by Chan’s
5
method, because of rapid oxidation. With only 1 equiv of
Ar Bi(OAc) and 5% of Cu(OAc) , however, clean
transformation could be carried out in 5–10 min, furnishing
3
2
2
1
3
products in good to high yields, calculated over two steps
Scheme 4. Arylation of precursors 1 and 2.

8366
O. T sˇ ubrik et al. / Tetrahedron 60 (2004) 8363–8373
column chromatography from the reaction mixture (struc-
ture confirmed by NMR spectroscopy), indicating a gradual
decomposition of the bismuth reagent. By carrying out the
1
5
experiments in refluxing CH Cl , however, both 1 and 2
2
2
could be brought to react and as shown the corresponding
products (11b, 11c, 12b and 12c) isolated in high yields,
provided the decomposition of Ar Bi was compensated for
3
by additional amounts of fresh reagents. Precursor 2 showed
somewhat better reactivity than 1 in this context. Also, the
bulky (2-MeO-4-MeC H ) Bi reagent reacted correspond-
6
3 3
ingly and only the highly hindered Mes Bi failed to react
3
completely, even at reflux.
2
Scheme 5. Aryl derivatives originating from precursor 3. (a) Ac O;
(
b, d) arylation; (c) Ar
3
Bi(OAc) , Cu(OAc)
2
2
, CH
2
Cl
2
.
Cleavage of one Boc group from 11c by magnesium
perchlorate in acetonitrile furnished 5b in quantitative
yield with NMR spectra identical with those measured
earlier in the direct synthesis of 5b from BocNHNHBoc
(Section 2.2).
1
8
2.3.1. Precursors 1 and 2. Quantitative arylation of 1 and 2
by a few trivalent bismuth reagents was previously
reported, but in that context no examples involving
sterically hindered aryl groups were presented and are
therefore included in this work. ortho-Substituted arylating
1
2
2
.3.2. Trisubstituted hydrazines with the general for-
1
5
reagents have been observed occasionally to react poorly
mula BocNHNAcR. With reference to the results in the
preceding paragraph, the next step was to study two less
hindered substrates, derived from precursor 3. These
compounds, 13a (RZBzl) and 13b (RZMe) described
and this tendency might be reinforced with these substrates,
as they are quite bulky. Initially, we also wanted to find out
whether pentavalent bismuth reagents offer some advantage
over trivalent ones in these cases. Hence, 1 and 2 were
reacted with Ph Bi(OAc) to afford products 11a and 12a in
11
previously, were obtained as outlined in Scheme 5 and the
corresponding results are shown below in Table 4.
3
2
7
4 and 86% yields, respectively. The high reactivity of this
reagent toward amino functions, that could be exploited
above with mono- and disubstituted hydrazines, was not
verified in these experiments, when much longer reaction
times were required. Longer reaction times and lower yields
All transformations in this table were conducted at rt, in
most cases without supplying additional amounts of
reagents during the reaction. With compound 13a as a
substrate, using the corresponding tri- and pentavalent
provide evidence in favour of Ar Bi.
3
reagents, firstly phenylation was compared and again Ph Bi
3
was found to be more efficient than Ph Bi(OAc) as judged
3
by reaction time and especially the yield.
2
All new results related to the arylation of 1 and 2 are
presented in Table 3. First we tried to introduce o-tolyl and
1
-naphthyl substituents by the standard protocol at rt but
only very little 11b was obtained and neither 1 nor 2 reacted
Secondly, the compounds 13a and 13b were compared as
substrates by reacting them with Np Bi. Although they only
differ by one of the substituents on the not directly involved
3
with Np Bi. Instead, naphthyl acetate was isolated by
3
Table 3. Arylation of trisubstituted reagents 1 and 2 by sterically hindered bismuth reagents
a
Compound
Arylating agent
t, 8C
Reaction time
Yield, %
11a
12a
11b
11b
12b
11c
11c
12c
11d
12d
11e
Ph
Ph
o-Tol
o-Tol
o-Tol
3
Bi(OAc)
Bi(OAc)
2
rt
rt
rt
5 days
32 h
96 h
72 h
54 h
5 days
96 h
96 h
40 h
40 h
74
86
26
100
98
—
83
73
85
97
—
3
2
3
3
3
Bi
Bi
Bi
Reflux
Reflux
rt
Reflux
Reflux
Reflux
Reflux
Reflux
Np
3
Np
3
Np
3
Bi
Bi
Bi
(2-OMe-4-MeC
(2-OMe-4-MeC
6
H
H
3
)
)
3
3
Bi
Bi
6
3
Mes Bi
3
3 days
a
Ar
3 2
Bi(OAc) R1.2 equiv/Cu(OAc)
2
R1.2 equiv/Et
3
NR1.2 equiv/CH
2
Cl
2
; Ar
3
BiR1.5 equiv/Cu(OAc)
2
R1.5 equiv/Et
3
NR1.5 equiv/CH
2
Cl
2
.
Table 4. Arylation of trisubstituted hydrazines 13
a
Starting material
Arylating agent
Ph Bi
Ph Bi(OAc)
Product
Reaction time, h
Yield, %
13a
13a
13a
13b
13b
13b
3
14a
14a
14b
14c
14d
14e
9
93
73
51
100
100
56
3
2
12
46
14
6
Np
Np
An
3
Bi
3
Bi
3
Bi
Mes Bi
3
20
a
See Scheme 5.

O. T sˇ ubrik et al. / Tetrahedron 60 (2004) 8363–8373
8367
Table 5. Arylation of trisubstituted hydrazines 8
a
Starting material
Arylating agent
(p-Tol) Bi
Product
Reaction time, h
Yield, %
8
8
8
8
a
e
g
h
3
15a
15b
15c
15d
26
44
45
46
92
80
96
100
Ph Bi
(p-An) Bi
(p-Tol) Bi
3
3
3
a
See Table 2.
nitrogens, the results indicate that the latter substrate
provides significantly less hindrance for the approaching
reagent. When 13b was arylated by three different Ar Bi
reagents with gradually increasing bulkiness from p-anisyl
to mesityl, the experiments demonstrated a clear depen-
dence of bismuthane reactivity upon steric factors. It is
dichloromethane. The analogous preparation, detailed in
Section 4, furnished 15e in 83% yield. The Ph PO initially
formed was readily removed in the final chromatographic
purification of the products.
3
3
noteworthy that 14e could be made in this way as Mes Bi
3
3. Conclusions
did not react with 1 which underlines the effect of the
substituents on the neighbouring nitrogen.
Based on experiments with a large number of model
hydrazine substrates, it appears that tri- and pentavalent
organobismuth reagents complement each other with
respect to arylation on nitrogen. As pentavalent reagents
exhibit high chemoselectivity for amino over amide
functions and require only a catalytic amount of copper,
they are especially useful for monoacylated free and 2-alkyl
substituted substrates which are sensitive, the former indeed
hypersensitive, to oxidation. Arylation of carbazates is
further improved by cooling and addition of antioxidant.
2
.3.3. Trisubstituted hydrazines with the general for-
1
mula BocNHNAr R. The trisubstituted hydrazines 8,
described in Section 2.2, could be used as substrates in
order to explore the synthesis of derivatives with two
different aryl substituents by means of triarylbismuthanes.
Considering the fact that such substituents on the second
nitrogen can be quite bulky, it follows from above that they
could impede the further reaction. A set of four compounds
1
Arylation of amidic NH in disubstituted RCONHNHCOR
8
was examined with respect to arylation by simple
triarylbismuthanes and the related data is shown in Table
. The reactions were monitored by TLC and they
or BocNH in trisubstituted hydrazines can be performed by
both types of reagents. In most cases, trivalent reagents in
the presence of a stoichiometric amount of Cu salt faster
afforded the products. More bulky substituents, such as
o-tolyl, 1-naphthyl and 2-methoxy-4-methylphenyl, were
introduced into trisubstituted precursors 1 and 2 under
standard conditions (Ar Bi/Cu(OAc) /Et N) except that
5
occasionally required small amounts of bismuthane in
excess of 1.5 equiv to go to completion within one to two
days, whereupon the products were purified by column
chromatography to afford pure products in satisfactory
yields. It should again be pointed out that argon had a
negative effect on the reaction rates in these experiments. As
3
2
3
refluxing dichloromethane was required. For another
trisubstituted substrate, 1-acetyl-1-methyl-2-Boc-hydra-
zine, a dependence of the reactivity on the bulkiness of
the reagent was demonstrated. A bulky substituent on the
non-reacting nitrogen can also influence arylation reactivity.
A few tetrasubstituted hydrazines with two different aryl
groups were also obtained.
a comparison, when 8a was reacted with p-Tol Bi under
3
argon, the reaction was not complete after three days and
several by-products were formed and the same observations
were made in the case of 8e.
Based on the data in Table 5 it is concluded that a phenyl
ring as such on the neighbouring nitrogen does not block
access of a simple triarylbismuthane to the reactive site but
in a fifth experiment (p-Tol) Bi failed to react with 8i. AM1
3
4. Experimental
quantum chemical calculations on this compound (using
Spartan Pro 1.08 software) afforded a Boc-N-o-MeO
˚
distance of 2.273 A, which indicates that a strong hydrogen
4.1. General methods
bonding is present. As a result the molecule is presumably
locked in a rigid conformation that no longer allows reaction
to take place.
All melting points were measured on a Gallenkamp melting
point apparatus. TLC analyses were carried out on 0.25 mm
thick precoated silica plates (Merck DC-Fertigplatten
Kieselgel 60 F254). TLC spots were visualized under UV
light or by alcoholic phosphomolybdic acid with subsequent
heating (blue spots). Column chromatography was carried
1
Compound 15a together with 15e (RZn-Bu, Ar ZPh,
2
Ar Zp-Tol) was also obtained by a three-stage one-pot
1
procedure 6/7/8/15 (Schemes 3 and 5). After
cleavage of the phosphonium protecting group, exploiting
out on Merck Kieselgel (70–230 mesh). H NMR were
recorded at 200 MHz and C NMR spectra at 50 MHz on a
1
3
1
the high reactivity of Ar Bi(OAc) the substituent Ar
could be inserted in 10 min as described previously
1
Bruker AC 200P spectrometer in CDCl solution. Chemical
3
3
2
shifts are given in ppm using TMS as reference and coupling
constants in Hz. Chemical shifts of conformers are given in
decreasing order of intensity and separated by slashes.
Positive-ion mass spectra were recorded on an Ettan
ESI-ToF electrospray time-of-flight mass spectrometer
(Amersham Biosciences, Uppsala, Sweden) at capillary
1
monitored by TLC). This was directly followed by
3
(
reaction with Ar Bi and auxiliary reagents (Ar Bi/Et N/
2
2
3
3
3
1
2
Cu(OAc)2 1.5:1.5:1.5 equiv).
Compound 15a was
obtained in 85 and 69% overall yields, after final reaction
for nearly 2 days at rt, alternatively 1.5 days in boiling

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O. T sˇ ubrik et al. / Tetrahedron 60 (2004) 8363–8373
exit voltages 80–150 V and capillary temperature 170 8C.
Electrospray tuning mix (Agilent, USA) was used for
calibration of the instrument. Samples were dissolved in
HPLC grade acetonitrile or methanol (Sigma-Aldrich,
Germany) and infused at 10–50 mL/min via ESI source
89.5–91 8C (lit. 85.5–86.5 8C), spectroscopic data identical
19
to literature.
4.3.2. 1-tert-Butoxycarbonyl-2-(o-tolyl)-hydrazine (4b).
The mixtures EtOAc–hexane 1:20 and 1:3 were used for
chromatography, furnishing the yellow solid (80%), pure by
TLC and NMR. Analytical sample was prepared by
using a syringe pump. Cu(OAc) was dried at 90 8C in vacuo
2
(1 mm Hg). All remaining reagents and solvents were used
as supplied without prior purification.
crystallization from hexane/CHCl . Yellowish needles, mp
3
89–91 8C (lit. 77 8C), spectroscopic data identical to
literature.
6b
4
.2. Synthesis of organobismuth reagents
4
.3.3. 1-Acetyl-2-(1-naphthyl)-hydrazine (4c). The mix-
ture EtOH–CHCl 1:7 was used to monitor the arylation.
Typical preparations of Ar Bi and Ar Bi(OAc) were
3
3
2
4
,15
described elsewhere.
Similar procedures were used for
3
0.8 g of silica was added to the reaction mixture and the
solvent was evaporated in vacuo. The remaining material
the synthesis tris(2-methoxy-4-methylphenyl)bismuthane
and tris(2-methoxy-4-methylphenyl)bismuth diacetate.
was placed on the top of a chromatography column (18!
1
.5 cm) and eluted with EtOH–CHCl 1:9. Product was
3
4
2
.2.1. Tris(2-methoxy-4-methylphenyl)bismuthane.
.951 g were obtained in 93% crude yield (essentially
obtained in 72% yield, pure by TLC and NMR. Analytical
sample was prepared by crystallization from hexane/CHCl3.
Yellow solid, mp 137.5–139.5 8C, lit. 143 8C from etha-
pure by TLC and NMR), further crystallized from CHCl3/
EtOH in 54% yield (1.740 g). White shiny plates, which
tend to darken on storage. mp 145–147 8C. IR (KBr):
2
0
K1 1
nol. IR (KBr): 3283, 3241, 1646 cm ; H NMR: dZ
K1
1
2.04/2.06 (s, 3H, CH ), 6.4–6.9 (m, 2H, 2!NH), 7.2–7.9
3
1
226 cm ; H NMR: dZ2.13 (s, 3H, CH ), 3.71 (s, 3H,
3
13
13
(m, 7H, 1-Np); C NMR: dZ20.9/19.0 (CH ), 106.2,
3
CH O), 6.9–7.3 (m, 3H, Ar); C NMR: dZ20.6 (CH3),
5
Anal. calcd for C H BiO : C, 50.46; H, 4.75; found C,
3
1
07.8, 119.4, 120.4, 121.5, 121.8, 125.5, 125.7, 125.9,
26.1, 126.3, 128.6, 128.9, 134.3, 142.6 (1-Np), 169.8 (CO,
5.8 (CH O), 109.8, 129.5, 132.9, 139.6, 142.9, 160.4 (Ar).
3
1
Boc).
2
4
27
3
5
0.34; H, 4.62.
4.3.4. 1-Benzyloxycarbonyl-2-(p-anisyl)-hydrazine (4d).
CbzNHNH2 was dissolved in 3 mL of CH Cl . Eluent
4
.2.2. Tris(2-methoxy-4-methylphenyl)bismuth diace-
tate. A crude product was obtained by evaporating most
2
2
mixtures EtOAc–hexane 1:5 and EtOAc–hexane 1:1 was
used to elute azo compound (14%) and the bright yellow
solid product (72%), both pure by TLC and NMR.
Analytical samples of azo-compound was prepared by
crystallization from hexane and very pure 4d was obtained
from hexane/CHCl3.
of acetic acid (reaction medium) and chloroform (extractive
agent) in vacuo. It was then recrystallized from Et O–
hexane in 52% yield, furnishing 863 mg of the acetic acid
solvate, pure by TLC and NMR. Yellow crystals, mp 148–
1
in chloroform–ethanol mixture and evaporating the solvents
2
50 8C. The unsolvated product was obtained by dissolving
K1
1
in vacuo. IR (KBr): 1756, 1719, 1253 cm ; H NMR: dZ
.79 (s, 12H, CH CO and CH COOH), 2.37 (s, 9H,
CH C H ), 3.85 (s, 9H, CH O), 7.0–7.3 (m, 6H, Ar), 8.0–
p-CH OC H N]NCOOCH Ph, orange-red crystals, mp
3
6
4
2
1
K1 1
7–48 8C. IR (KBr): 1730, 1232, 1137 cm ; H NMR:
3
3
4
3
6
3
3
dZ3.90 (s, 3H, CH O), 5.46 (s, 2H, CH ), 6.99 (d, JHHZ
1
3
3
2
8
.1 (m, 3H, Ar); C NMR: dZ21.0 (CH C H ), 21.8
3 6 3
9
2
1
Hz, 2H, C H ), 7.3–7.5 (m, 5H, Ph), 7.96 (d, JHHZ9 Hz,
6 4
13
(
1
CH CO), 56.3 (CH O), 112.8, 132.3, 132.6, 133.9, 150.9,
56.3, 175.9. Anal. calcd for C H BiO !2AcOH
28 33 7
3
3
H, C H ); C NMR: dZ55.8 (CH O), 69.7 (CH ), 114.6,
6
4
3
2
26.5, 128.7, 128.8, 134.9, 146.3, 162.2 (Ar), 164.8 (CO,
(
C H BiO ): C, 47.41; H, 5.10; found C, 46.87; H, 4.79.
32 41 11
Cbz). Anal. calcd for C H N O : C, 66.66; H, 5.22; N,
5 14 2 3
1
1
0.36; found C, 66.82; H, 5.26; N, 10.03.
4
4
.3. Synthesis of 1-acyl-2-arylhydrazines (compounds 4)
Compound 4d, slightly yellowish plates, mp 110–111 8C. IR
K1
1
.3.1. 1-tert-Butoxycarbonyl-2-(p-tolyl)-hydrazine (4a).
(KBr): 3325, 3225, 1703, 1232, 1163 cm ; H NMR: dZ
3.73 (s, 3H, CH O), 5.13 (s, 2H, CH ), 5.66 (br s, 1H,
ArNH), 6.7–7.3 (m, together 10H, Ar and BocNH);
NMR: dZ55.7 (CH O), 67.5 (CH ), 114.8, 114.9, 128.2,
128.4, 128.6, 136.0, 141.8, 154.7 (Ar), 157.2 (CO, Cbz).
Anal. calcd for C15 : C, 66.16; H, 5.92; N, 10.29;
tert-Butyl carbazate (77 mg, 0.583 mmol) was dissolved in
dichloromethane (2 mL) and BHT (3 mg, 0.03 equiv) was
added to the solution. The mixture was cooled to K60 8C
and Cu(OAc)2 (2 mg, 0.02 equiv) was added. Under
stirring, a solution of (p-Tol) Bi(OAc) (350 mg, 1 equiv)
3
2
1
3
C
3
2
H N O
16 2 3
3
2
in dichloromethane (2 mL) was added dropwise during
0 min. The reaction was monitored by TLC (EtOAc–
found C, 66.18; H, 5.87; N, 10.25.
3
hexane 1:1 and 1:4) and the starting material was consumed
just after the reagent was added. The reaction mixture was
let to warm to the rt. 0.8 g of silica was added and the
solvent evaporated in vacuo. The remaining material was
placed on top of a short silica column and eluted first with
EtOAc–hexane 1:20 to remove unpolar components, then
with EtOAc–light petroleum 1:4 to isolate yellow solid 4a in
4.3.5. 1-(2,2,2-Trichloroethoxycarbonyl)-2-(o-tolyl)-
hydrazine (4e). The mixtures EtOAc–hexane 1:20 and 1:3
were used for chromatography, furnishing the yellow solid
(91%), pure by TLC and NMR. Analytical sample was
prepared by crystallization from hexane/CHCl . White
3
needles, mp 104.5–106 8C. IR (KBr): 3356, 3277, 1719,
K1
1
1237, 1169 cm ; H NMR: dZ2.16 (s, 3H, CH C H ),
3
6 4
91% yield, pure by TLC and NMR. Analytical sample was
prepared by crystallization from hexane. White needles, mp
4.77 (s, 2H, CH ), 5.74 (s, 1H, ArNH), 6.8–6.9 (m, 2H,
C H ), 6.95 (br s, 1H, BocNH), 7.0–7.2 (s, 2H, C H );
2
1
3
C
6
4
6 4

O. T sˇ ubrik et al. / Tetrahedron 60 (2004) 8363–8373
8369
NMR: dZ16.8 (CH C H ), 74.9 (CH ), 95.1 (CCl ), 111.8,
43.0 (CH N), 80.4 (C ), 117.8, 123.7, 126.1, 131.4, 131.8,
3 q
3
6
4
2
3
121.1, 122.7, 127.0, 130.6, 145.1 (Ar), 155.3 (CO, Troc).
Anal. calcd for C H Cl N O : C, 40.36; H, 3.73; N, 9.41;
found C, 40.56; H, 3.65; N, 9.34.
149.1 (C H ), 154.7 (CO, Boc). Anal. calcd for
6 4
C H N O : C, 66.07; H, 8.53; N, 11.85; found C, 66.10;
13 20 2 2
H, 8.55; N, 11.80.
1
0
11
3
2
2
4
4
.4. Synthesis of compounds 5 RCONArNHCOR
4.5.2. 1-(tert-Butoxycarbonyl)-2-(n-butyl)-2-(p-tolyl)-
hydrazine (8g). Slightly yellowish crystals, mp 41–42 8C
(
K1
from hexane). IR (film): 3298, 1704, 1247, 1163 cm ; H
1
.4.1. 1,2-Bis(tert-butoxycarbonyl)-1-phenylhydrazine
1
3
(
5a). To the solution of BocNHNHBoc (69.7 mg,
.300 mmol) in CH Cl (2 mL) Et N (84 mL, 2 equiv),
Cu(OAc) (14 mg, 0.25 equiv) were added, followed by
NMR: dZ0.95 (t, 3H, JHHZ7 Hz, CH of n-Bu), 1.2–1.7
3
0
2
2
3
(overlapped s and m, together 14H, CH CH CH CH
and Boc), 2.25 (s, 3H, CH C H ), 3.40 (br m, 2H,
3 6 4
2
2
2
3
2
Ph Bi(OAc) (335 mg, 2 equiv). The reaction was moni-
3
2
CH CH CH CH ), 6.32/6.09 (br s, 1H, NH), 6.73 (d,
2 2 2 3
tored by TLC, using EtOAc–light petroleum 1:5 as eluent.
After 30 min 0.5 equiv Ph Bi(OAc) and 1 equiv of Et N
J
Z8.4 Hz, 2H, C H ), 7.04 (d, J Z8.4 Hz, 2H, C H );
HH
3
6 4 HH 6 4
1
3
2
3
C NMR: dZ14.0 (CH3 of n-Bu), 20.3 (overlapped
CH CH CH CH and CH C H ), 28.4 (CH , Boc), 28.9
were added to accelerate the process. Most of the starting
material reacted in 3 h and some minimal traces were
detected even after 4 h. Then 0.8 g of silica was added to the
reaction mixture and the solvent was evaporated in vacuo.
The remaining product was placed on the top of chroma-
tography column (18!1.5 cm). For purification the mixture
EtOAc–light petroleum 1:5 was used as eluent, yielding
3
2
2
2
3
6
4
3
(CH CH CH CH ), 52.7 (CH N), 80.7 (C ), 113.2, 128.4,
3 2 2 2 2 q
129.6, 147.4 (C H ), 155.1 (CO, Boc). Anal. calcd for
C H N O : C, 69.03; H, 9.41; N, 10.06; found C, 69.00;
H, 9.45; N, 9.95.
6 4
1
6 26 2 2
4.5.3. 1-(tert-Butoxycarbonyl)-2-(n-butyl)-2-(p-anisyl)-
hydrazine (8h). Colourless viscous oil. IR (film): 3298,
79.2 mg (86%) of 5a as yellowish solid, pure by TLC and
NMR. The H and C NMR spectra were identical with
previously published data.
1
13
K1 1
1
3
1
714, 1242, 1163 cm ; H NMR: dZ0.94 (t, JHHZ7.2 Hz,
1
2
H, CH of n-Bu), 1.3–1.6 (overlapped s and m, together
4H, CH CH CH CH and Boc), 3.34 (m, 2H, CH N), 3.72
3
2
2
2
3
2
4
.4.2. 1,2-Bis(tert-butoxycarbonyl)-1-(1-naphthyl)hydra-
zine (5b). To the solution of BocNHNHBoc (80 mg,
.344 mmol) in CH Cl (1 mL) Et N (72 mL, 1.5 equiv),
(
s, 3H, CH O), 6.50/6.36 (br s, 1H, NH), 6.79 (s, 4H, C H );
3 6 4
13
C NMR: dZ14.0 (CH of n-Bu), 20.3 (CH CH CH CH ),
3
3
2
2
2
0
2
2
3
2
5
1
9
8.4 (CH , Boc), 29.0 (CH CH CH CH ), 53.1 (CH N),
5.7 (CH O), 80.5 (C ), 114.6, 115.0, 144.1, 153.5 (C H ),
3 3 2 2 2 2
Cu(OAc)2 (94 mg, 1.5 equiv) were added, followed by
Np Bi (305 mg, 1.5 equiv). The reaction was monitored by
3
q
6 4
3
55.2 (CO, Boc). Anal. calcd for C H N O : C, 66.20; H,
1
6 26 2 3
TLC, using EtOAc–light petroleum 1:3 as eluent. Most of
the starting material reacted in 2 h and the reaction was
complete in 3 h. Then 0.8 g of silica was added to the
reaction mixture and the solvent was evaporated in vacuo.
The remaining product was placed on the top of short
chromatography column. At first EtOAc–light petroleum
.15; N, 9.08; found C, 62.00; H, 9.18; N, 8.98.
4
4
3
.5.4. 1-(tert-Butoxycarbonyl)-2-(n-butyl)-2-(2-methoxy-
-methyl)-hydrazine (8i). Colourless viscous oil. IR (film):
K1
1
293, 1698, 1242, 1163 cm ; H NMR: dZ0.95 (t, 3H,
JHHZ6.8 Hz, CH of n-Bu), 1.3–1.6 (overlapped s and m,
together 14H, CH CH CH CH and Boc), 2.29 (s, 3H,
CH C H ), 3.28 (t, J Z7.2 Hz, 2H, CH N), 3.84 (s, 3H,
CH O), 6.7–7.2 (overlapped br s and m, together 4H, NH
3
and C H ); C NMR: dZ14.0 (CH3 of n-Bu), 20.2
3
1
:20 was used to elute most of unpolar components. The
2
2
2
3
elution was continued using mixture EtOAc–light petro-
leum 1:4, yielding 114 mg (93%) of 1,2-bis(tert-butoxy-
carbonyl)-1-(1-naphthyl)hydrazine, pure by TLC and NMR.
Analytical sample was obtained by crystallization from
3
6
3
HH
2
1
3
6
3
(
CH C H ), 20.6 (CH CH CH CH ), 28.4 (CH , Boc),
3 6 3 3 2 2 2 3
hexane–CHCl , mp 142.5–143.5 8C. IR (KBr): 3288, 1746,
3
K1
1
29.8 (CH CH CH CH ), 55.6 (CH N), 55.8 (CH O), 79.8
3 2 2 2 2 3
(C ), 112.3, 123.8, 125.1, 130.1, 139.0, 151.5 (C H ), 155.8
q 6 3
1
overlapped, 18H, 2!Boc), 7.2–8.0 (m, 7H, 1-Np);
688, 1247, 1153 cm ; H NMR: dZ1.33, 1.46 (two s
13
C
(CO, Boc). Anal. calcd for C H N O : C, 65.28; H, 8.90;
17 28 2 3
NMR: dZ28.1, 28.3 (two s overlapped, 2!Boc), 81.4, 81.9
N, 9.52; found C, 65.29; H, 8.94; N, 9.30.
.6. Synthesis of 1,1,2-tris(tert-butoxycarbonyl)-2-
arylhydrazines (11) and 1,2-bis(tert-butoxycarbonyl)-1-
(
C ), 123.0, 125.5, 126.0, 126.4, 128.2, 130.3, 134.4, 138.8
q
(1-Np), 154.8, 155.5 (CO, Boc). Anal. calcd for
C H N O : C, 67.02; H, 7.31; N, 7.82; found C, 66.97;
H, 7.34; N, 7.71.
4
2
0 26 2 4
benzyloxycarbonyl-2-arylhydrazines (12)
4.5. Synthesis of 1-tert-butoxycarbonyl-2-alkyl-2-
arylhydrazines (compounds 8)
4.6.1. 1,1,2-Tris(tert-butoxycarbonyl)-2-phenylhydra-
zine (11a) and 1,2-bis(tert-butoxycarbonyl)-1-(benzoxy-
carbonyl)-2-phenylhydrazine (12a). Compounds 11a and
12a were synthesized analogously with preparation of
1,2-bis(tert-butoxycarbonyl)-1-phenylhydrazine (5a) as
described above (Section 4.4.1). Products were pure by
TLC and NMR spectra were fully consistent with
1
3
Substances 8a–8e, 9 and 10 were synthesized before.
Compounds 8f–8i were prepared using the same procedure,
pure by TLC and NMR.
4.5.1. 1-(tert-Butoxycarbonyl)-2-methyl-2-(o-tolyl)-
hydrazine (8f). Slightly yellowish crystals, mp 49.5–
1
2
experimental data published previously.
5
1
0.5 8C (from hexane). IR (KBr): 3225, 1709, 1274,
1
K1
179 cm ; H NMR: dZ1.42 (s, 9H, Boc), 2.32 (s, 3H,
In the synthesis of 11a, 0.7 equiv of each reagent
(Ph Bi(OAc) , Et N and Cu(OAc) ) were added after 24 h
in order to bring the reaction to completion (48 h).
CH C H ), 3.04 (CH N), 6.17 (s, 1H, NH), 6.9–7.2 (m, 4H,
C H ); C NMR: dZ18.7 (CH C H ), 28.4 (CH , Boc),
3
6
4
3
3
2
3
2
1
3
6
4
3
6
4
3

8370
O. T sˇ ubrik et al. / Tetrahedron 60 (2004) 8363–8373
4
.6.2. 1,1,2-Tris(tert-Butoxycarbonyl)-2-(o-tolyl)hydra-
zine (11b). To the solution of BocNHNHBoc (116 mg,
.349 mmol) in CH Cl (1.5 mL) Et N (73 mL, 1.5 equiv),
4.6.5. 1,2-Bis(tert-butoxycarbonyl)-1-(benzyloxycarbo-
nyl)-2-(1-naphthyl)hydrazine (12c). Compound 12c was
prepared analogously with 11b. During the 96 h of reaction,
additional amounts of reagents were added (in all 2.5 equiv
of Et N, 1.5 equiv of Np Bi and 0.9 equiv of Cu(OAc) ).
0
2
2
3
Cu(OAc)2 (95 mg, 1.5 equiv) were added, followed by
o-Tol) Bi (252 mg, 1.5 equiv). The resulting mixture was
(
3
3
3
2
heated under reflux (w45 8C). The reaction was monitored
by TLC, using EtOAc–light petroleum 1:5 as eluent and
EtOAc–light petroleum 1:30 was used to monitor the
The product was obtained in 73% as slightly yellow viscous
oil, pure by TLC. IR (film): 1803, 1767, 1730, 1247,
K1
1
1153 cm ; H NMR: dZ1.24, 1.46/1.54 (s, 18H, Boc),
1
3
consumption of (o-Tol) Bi. In order to accelerate the
3
5.1–5.3 (m, 2H, CH ), 7.2–7.8 (m, 12H, 1-Np and Ph);
C
2
reaction and due to the disappearance of bismuth
compound, during the 72 h additional amounts of reagents
were added (in all 4.5 equiv of Et N, 1.5 equiv of (o-Tol) Bi
NMR: dZ28.0/27.8/28.1 (Boc), 69.2/69.3 (CH ), 82.4,
2
84.6/84.7 (C ), 122.6, 123.4, 124.8, 125.2, 125.3, 125.4,
q
125.8, 125.9, 126.0, 127.7, 127.9, 128.2, 128.4, 128.5,
128.6, 128.7, 130.1, 130.3, 134.1, 134.3, 135.0, 137.8, 138.2
(1-Np and Ph), 151.0/150.9, 152.8/152.7 (CO, Boc and
Cbz). Anal. calcd for C H N O : C, 68.28; H, 6.55; N,
3
3
and 1.7 equiv of Cu(OAc) ). Then 0.8 g of silica was added
2
to the reaction mixture and the solvent was evaporated in
vacuo. The remaining product was placed on the top of short
chromatography column. At first EtOAc–light petroleum
2
8 32 2 6
5.69; found C, 68.57; H, 6.44; N, 5.40.
1
:20 was used to elute most of non-polar components. The
elution was continued using mixture EtOAc–light pet-
roleum 1:7, yielding 150 mg (100%) of 1,1,2-tris(tert-
butoxycarbonyl)-1-(o-tolyl)hydrazine as colourless viscous
oil, pure by TLC. IR (film): 1798, 1761, 1730, 1253,
4.6.6. 1,1,2-Tris(tert-butoxycarbonyl)-2-(2-methoxy-4-
methylphenyl)hydrazine (11d). Compound 11d was pre-
pared analogously with 11b. The reaction was monitored by
TLC, using toluene–EtOAc 4:1 as eluent. For the isolation
K1
1
1
2
142 cm ; H NMR: dZ1.54/1.52/1.44 (s, 27H, Boc),
of product, at first hexane–CHCl 1:2 was used to elute most
3
1
3
.35/2.40 (s, 3H, CH C H ), 7.1–7.5 (m, 4H, C H );
C
of non-polar components. The elution was continued using
mixture EtOAc–light petroleum 1:4, yielding 118 mg (85%)
of 11d as colourless viscous oil, pure by TLC. The
chromatography also afforded 27 mg of 11d, slightly
contaminated by another component probably due to the
3
6
4
6 4
NMR: dZ18.8 (CH C H ), 28.1/28.2 (Boc), 81.7/82.0,
3
6 4
8
3.9/83.8 (C ), 124.6, 125.2, 126.2, 127.1, 130.7, 130.9,
q
1
35.7, 135.8, 139.5, 140.2 (C H ), 151.2/151.3, 152.0/152.5
6
4
(CO, Boc). Anal. calcd for C H N O : C, 62.54; H, 8.11;
23 32 2 3
N, 6.63; found C, 62.29; H, 8.15; N, 6.21.
1
partial Boc group removal. H NMR: dZ1.52/1.48 (br s,
2
3
7H, Boc), 2.25/2.29/2.27 (s, 3H, CH C H ), 3.76/3.78 (s,
3 6 3
1
3
H, CH O), 6.7–7.2 (m, 3H, C H ). C NMR: dZ20.4
3
6 3
4
.6.3. 1,2-Bis(tert-butoxycarbonyl)-1-(benzyloxycarbo-
(
CH C H ), 28.0/28.2 (Boc), 55.8 (br s, CH O), 81.4, 83.1
3 6 4 3
nyl)-2-(o-tolyl)hydrazine (12b). Compound 12b was pre-
pared analogous to 11b. During the 54 h of reaction,
additional amounts of reagents were added (in all 2.5 equiv
of Et N, 0.2 equiv of (o-Tol) Bi and 0.2 equiv of
(C ), 111.4, 112.6, 123.4, 127.1, 127.9, 128.2, 129.3 (C H ),
q 6 3
151.0, 152.5 (CO, Boc). HRESIMS m/z 475.2454 [MC
Na] ; calcd for C H N NaO 475.2420.
C
2
3
36
2
7
3
3
Cu(OAc) ). The chromatography was carried out the same
2
4
.6.7. 1,2-Bis(tert-butoxycarbonyl)-1-(benzyloxycarbo-
way as above, only using EtOAc–light petroleum 1:5 to
elute the product in 98% as colourless viscous oil, pure by
TLC. IR (film): 1803, 1767, 1730, 1253, 1153 cm ; H
nyl)-2-(2-methoxy-4-methylphenyl)hydrazine (12d).
Compound 12d was prepared analogously with 11b. The
reaction was monitored by TLC, using EtOAc–hexane 1:4
as eluent. For the isolation of product, at first hexane–CHCl3
1:2 was used to elute most of non-polar components. The
elution was continued using mixture EtOAc–light petro-
K1
1
NMR: dZ1.28/1.27, 1.40/1.38 (s, 18H, Boc), 2.12/2.13 (s,
3
H, CH C H ), 5.2–5.3 (m, 2H, CH ), 7.0–7.3 (m, 9H, Ph
3 6 4 2
1
3
and C H ); C NMR: dZ18.5 (CH C H ), 27.98/28.03/
6
4
3 6 4
2
8.10 (Boc), 69.1/69.2 (CH ), 82.0/82.3 (C ), 84.5/84.4
2 q
leum 1:3, yielding 97% of 12d as colourless viscous oil,
pure by TLC. IR (film): 1798, 1767, 1724, 1253, 1158 cm
(
C ), 124.6, 125.1, 126.2, 126.3, 127.3, 128.28, 128.34,
q
K1
;
1
1
28.5, 130.8, 131.0, 135.1, 135.9, 136.1, 139.2, 139.9 (Ar),
50.7, 151.6, 152.5/152.7 (CO, Boc and Cbz). Anal. calcd
1
H NMR: dZ1.40, 1.51 (s, 18H, Boc), 2.21/2.29/2.27 (s,
H, CH C H ), 3.63/3.57/3.78/3.81 (s, 3H, CH O), 5.1–5.4
3
3
6
3
3
for C H N O : C, 65.77; H, 7.07; N, 6.14; found C, 65.79;
2
13
6 34 2 7
(m, 2H, CH ), 6.6–7.4 (m, 8H, Ph and C H ); C NMR: dZ
2 6 3
H, 7.19; N, 5.87.
2
5
0.4 (CH C H ), 27.97, 28.04 (overlapped s, Boc), 55.7/
3 6 4
5.2 (CH ), 68.7 (CH O), 81.7, 83.7 (C ), 112.4, 127.1,
q
2
3
4
.6.4. 1,1,2-Tris(tert-butoxycarbonyl)-2-(1-naphthyl)-
128.4, 129.3, 135.4 (C
HRESIMS m/z 509.2243 [MCNa] ; calcd for
6
H
3
), 150.5, 152.5 (CO, Boc, Cbz);
C
hydrazine (11c). Compound 11c was prepared analogous
to 11b. During the 96 h of reaction, additional amounts of
reagents were added (in all 3.5 equiv of Et N, 1.4 equiv of
C
H
34
N
NaO
509.2264.
7
26
2
3
Np Bi and 0.4 equiv of Cu(OAc) ). The product was
2
4.6.8. Selective Boc-cleavage from 1,1,2-tris(tert-butoxy-
3
1
8
obtained in 83% as slightly yellow viscous oil, pure by
TLC. IR (film): 1798, 1761, 1730, 1247, 1153 cm ; H
carbonyl)-2-(1-naphthyl)hydrazine (11c). Compound
11c (77 mg, 0.168 mmol) was dissolved in acetonitrile
(1 mL) and the solution was rapidly heated to 50 8C under
argon and stirring. Mg(ClO4)2 (13 mg, 0.35 equiv) was
added and the reaction was monitored by TLC (EtOAc–
hexane 1:8). Almost all starting material was consumed
within 10 min when 0.2 equiv of Mg(ClO ) were added to
K1
1
NMR: dZ1.27, 1.54/1.57 (s, 27H, Boc), 7.4–7.9 (m, 7H, 1-
1
3
Np); C NMR: dZ28.1/27.9/28.2 (Boc), 82.1, 84.1 (Cq),
1
1
1
22.5, 123.3, 125.1, 125.3, 125.5, 125.8, 125.9, 127.7,
27.90, 127.95, 128.4, 130.1, 130.4, 134.1, 134.3, 138.1,
38.6 (1-Np), 151.43/151.39, 152.9/153.0 (CO, Boc);
4
2
C
HRESIMS m/z 481.2332 [MCNa] ; calcd for
C H N NaO 481.2315.
complete the reaction. After 30 min the reaction was
quenched with 0.2 M citric acid (3 mL), brine (2 mL) and
2
5
34
2
6

O. T sˇ ubrik et al. / Tetrahedron 60 (2004) 8363–8373
8371
ethyl ether (15 mL). The aq. phase was extracted with ethyl
ether (3!10 mL), the combined extracts washed with brine
to neutral (4!3 mL) and dried (Na SO ). After evaporation
28.1/28.3 (Boc), 82.9/81.8 (C ), 122.9, 123.0, 124.8, 125.5,
q
125.9, 126.2, 126.5, 128.3, 128.7, 128.8, 129.8, 134.4, 137.0
(1-Np). HRESIMS m/z 315.1726 [MCH] ; calcd for
C
2
4
in vacuo, a product was obtained in quantitative yield with
data in agreement with those of 5b from 1,2-bis(tert-
butoxycarbonyl)hydrazine.
C H N O 315.1709.
18 23 2 3
4.7.4. 1-(tert-Butoxycarbonyl)-1-(p-anisyl)-2-acetyl-2-
methylhydrazine (14d). Compound 14d was synthesized
analogously with 5b. The reaction was monitored by TLC
using EtOAc–hexane 1:2 as eluent. Mixtures EtOAc–
hexane 1:20 and 1:2 were used to isolate product by short
column chromatography, furnishing 14d as slightly yellow
viscous oil in quantitative yield, pure by TLC. It solidified
on standing for several months in the refrigerator, mp 67.5–
4
2
.7. Synthesis of 1-(tert-butoxycarbonyl)-1-aryl-2-acetyl-
-alkylhydrazines (14)
1-(tert-Butoxycarbonyl)-2-acetyl-2-benzylhydrazine (13a)
and 1-(tert-butoxycarbonyl)-2-acetyl-2-methylhydrazine
1
1
(
13b) were prepared as described elsewhere.
6
9.5 8C, but resisted further crystallization. IR (KBr): 1709,
K1
1
4
.7.1. 1-(tert-Butoxycarbonyl)-1-phenyl-2-acetyl-2-ben-
1672, 1252, 1163 cm ; H NMR: dZ1.53 (s, 9H, Boc),
2.10 (s, 3H, CH CO), 3.13 (m, 2H, CH ), 3.79 (s, 3H,
CH O), 6.89 (perturbed d, JHHZ9 Hz, 2H, C ), 7.32
(perturbed d, JHHZ9 Hz, 2H, C ); C NMR: dZ20.2
(CH CO), 28.3 (Boc), 34.0 (CH N), 55.5 (CH O), 82.9 (C ),
114.3, 123.2, 133.2, 152.5 (C ), 157.5 (CO, Boc), 173.4
(CH CO). HRESIMS m/z 317.1497 [MCNa] ; calcd for
NaO 317.1477.
zylhydrazine (14a). The synthesis was carried out using
.5 equiv of Ph Bi or 1.2 equiv of Ph Bi(OAc) as arylating
3
2
1
3
H
6 4
3
3
2
1
3
reagent (in analogy with procedures detailed in Sections
.4.2 or 4.4.1). The reaction was monitored by TLC, using
H
6 4
4
3
3
3
q
EtOAc–hexane 1:4 as eluent. Mixtures 1:20 and 1:4 were
used to isolate product by short column chromatography,
furnishing 93% and 73% of 14a depending on use of either
Ph Bi or Ph Bi(OAc) . Product was obtained as colourless
H
6 4
C
3
C
H
N
15
22
2
4
3
3
2
viscous oil, pure by TLC. IR (film): 1719, 1678, 1253,
1
4.7.5. 1-(tert-Butoxycarbonyl)-1-(2,4,6-trimethylphenyl)-
2-acetyl-2-methylhydrazine (14e). Compound 14e was
synthesized analogously with 5b. The reaction was
monitored by TLC using EtOAc–hexane 1:1 as eluent.
Mixtures EtOAc–hexane 1:8 and 1:1 were used to isolate
product by short column chromatography, furnishing 14d as
colourless oil in 56% yield, pure by TLC. It solidified on
standing in refrigerator and was recrystallized from hexane,
giving white crystals, mp 88–90.5 8C. IR (KBr): 1719, 1672,
K1
1
153 cm ; H NMR: dZ1.25 (s, 9H, Boc), 2.16 (s, 3H,
CH CO), 4.09 (d, 1H, CH , JZ14 Hz), 5.14 (d, 1H, CH ,
3
2
2
1
3
JZ14 Hz), 7.2–7.4 (m, 10H, Ph); C NMR: dZ20.5
(
CH CO), 27.9 (Boc), 49.9 (CH ), 82.9 (C ), 121.8, 125.3,
3 2 q
1
Boc), 173.2 (CH CO). Anal. calcd for C H N O : C,
27.8, 128.3, 128.9, 130.4, 135.6, 139.6 (Ph), 152.3 (CO,
3
20 24 2 3
7
0.57; H, 7.11; N, 8.23; found C, 70.60; H, 7.17; N, 8.27.
K1 1
4
.7.2. 1-(tert-Butoxycarbonyl)-1-(1-naphthyl)-2-acetyl-2-
1247, 1163 cm ; H NMR: dZ1.54/1.42/1.40/1.50 (s, 9H,
benzylhydrazine (14b). Compound 14b was synthesized
analogously with 5b. The reaction was monitored by TLC
using EtOAc–hexane 1:4 as eluent. During the process,
Boc), 2.1–2.3 (overlapped m, together 12H, CH
3
CO and
N), 6.9 (br s,
); C NMR: dZ18.7, 18.8, 18.9, 19.0, 19.2, 19.9,
CO and
), 28.3/28.2/30.9/30.7/29.7 (Boc), 36.1/36.0
N), 82.6/82.3/81.1/81.4 (C ), 128.9, 129.3, 129.7,
(CH
2H, C
)
C
H
H
), 2.92/2.91/3.05/3.08 (s, 3H, CH
3
3
6
2
1
3
3
6
2
0
.2 equiv of each reagent was added to accelerate the
20.0, 20.70, 20.75, 20.79, 20.85, 22.1, 22.3 (CH
3
reaction. Mixtures EtOAc–hexane 1:20 and 1:3 were used to
isolate product by short column chromatography, furnishing
(CH
(CH
3
)
3
C
6
H
2
3
q
1
4b as yellowish viscous oil in 51% yield, pure by TLC. IR
130.2, 130.3, 130.5, 130.7, 133.1, 133.6, 135.87, 135.94,
136.26, 136.29, 137.3, 137.7, 137.8, 138.0 (C ), 153.6/
154.7/152.5 (CO, Boc), 172.8/168.1/173.2 (CH CO). Anal.
calcd for C17 : C, 66.64; H, 9.14; N, 8.55; found C,
K1
1
(
film): 1719, 1678, 1258, 1158 cm ; H NMR: dZ1.28/
H
6 2
1
2
.20/1.26/1.46/1.22 (overlapped s, 9H, Boc), 2.44/2.00/
.19/2.22 (s, 3H, CH CO), 4.6–5.3 (m, 2H, CH ), 7.0–7.9
3
H N O
26 2 3
3
2
1
3
(
m, 12H, Ph and 1-Np). C NMR: dZ20.8/22.0 (CH CO),
66.83; H, 9.06; N, 8.68.
3
2
1
1
7.9/28.2/29.7 (Boc), 50.9 (CH ), 82.8/81.8 (C ), 122.4,
23.6, 125.3, 125.9, 126.2, 127.2, 127.8, 128.3, 128.5,
28.7, 129.3, 129.8, 134.4, 136.4 (Ph and 1-naphthyl), 153.0
2 q
4.8. Synthesis of 1-(tert-butoxycarbonyl)-1,2-diaryl-2-
alkylhydrazines (15)
(
CO, Boc), 173.0 (CH CO). Anal. calcd for C H N O : C,
3 24 26 2 3
7
3.82; H, 6.71; N, 7.17; found C, 73.62; H, 6.66; N, 6.86.
4.8.1. 1-(tert-Butoxycarbonyl)-1-(p-tolyl)-2-phenyl-2-
benzylhydrazine (15a). Compound 15a was synthesized
analogously with 5b. The reaction was monitored by TLC
using EtOAc–hexane 1:10 as eluent. During the process,
0.2 equiv of each reagent was added to the mixture in order
4
.7.3. 1-(tert-Butoxycarbonyl)-1-(1-naphthyl)-2-acetyl-2-
methylhydrazine (14c). Compound 14c was synthesized
analogously with 5b. The reaction was monitored by TLC
using EtOAc–hexane 1:1 and 1:4 as eluent. Mixtures
EtOAc–hexane 1:20 and 1:1 were used to isolate product
by short column chromatography, furnishing 14c as light-
brown viscous oil in quantitative yield, pure by TLC. It
solidified while standing in refrigerator and was recrystal-
lized from hexane, giving yellowish microcrystalline
product, mp 107–108.5 8C. IR (KBr): 1719, 1672, 1237,
to accelerate the reaction. Mixtures CHCl –hexane 1:2 and
3
CH Cl –hexane 1:1 were used to isolate product by column
2
2
chromatography, furnishing 15a as slightly yellow viscous
oil in 92% yield, pure by TLC. It solidified while standing in
refrigerator and was recrystallized from hexane, giving
yellowish solid, mp 75.5–76.5 8C. IR (KBr): 1709, 1253,
K1
1
1158 cm ; H NMR: dZ1.32 (s, 9H, Boc), 2.29/2.27/2.33
K1
1
1
2
7
158 cm ; H NMR: dZ1.27/1.54 (br s, 9H, Boc), 2.36/
(s, 3H, CH C H ), 4.59, 4.67, 4.79, 4.87 (AB , 2H, CH ),
3
6
4
q
2
1
3
.06/2.16 (s, 3H, CH CO), 3.19/3.33/3.30 (s, 3H, CH N),
6.8–7.3 (m, 14H, 2!Ph and C H ); C NMR: dZ20.8
3
3
6 4
1
3
.4–8.0 (m, 7H, 1-Np); C NMR: dZ20.7/21.9 (CH CO),
(CH C H ), 28.2 (Boc), 58.2 (CH N), 81.7 (C ), 113.0,
3 6 4 2 q
3

8372
O. T sˇ ubrik et al. / Tetrahedron 60 (2004) 8363–8373
1
1
19.6, 122.4, 127.2, 128.2, 128.3, 128.9, 129.1, 134.3,
37.2, 139.9, 149.7 (Ph and C H ), 153.9 (CO, Boc). Anal.
4.8.5. 1-(tert-Butoxycarbonyl)-1-(p-tolyl)-2-phenyl-2-(n-
butyl)hydrazine (15e) by a one pot reaction. 1-(tert-
Butoxycarbonyl)-2-(n-butyl)hydrazine (0.441 mmol) as
6
4
calcd for C H N O : C, 77.29; H, 7.21; N, 7.26; found C,
2
0 26 2 4
7
7.18; H, 7.35; N, 7.04.
equimolar mixture with Ph PO was prepared as described
3
1
1
previously. It was dissolved in dichloromethane (2 mL)
and Cu(OAc) (4 mg, 0.05 equiv) was added, followed by
Ph Bi(OAc) (246 mg, 1 equiv). The reaction was moni-
tored by TLC, using EtOAc–hexane 1:5 as eluent. It was
complete in 10 min and then Et N (92 mL, 1.5 equiv),
Cu(OAc) (120 mg, 1.5 equiv) and (p-Tol) Bi (319 mg,
4
(
.8.2. 1-(tert-Butoxycarbonyl)-1-(phenyl)-2-(p-tolyl)-2-
ethoxycarbonylmethyl)hydrazine (15b). Compound 15b
2
3
2
was synthesized analogously with 5b. The reaction was
monitored by TLC using EtOAc–hexane 1:1 and 1:4 as
eluent. During the process, 0.1 equiv of Cu(OAc)2 and
3
2
3
0
.2 equiv of Ph Bi were added to accelerate the reaction.
3
1.5 equiv) were added. The reaction mixture was heated
under reflux. After 22 h, the transformation was complete
(EtOAc–hexane 1:10). Then 0.8 g of silica was added to the
reaction mixture and the solvent was evaporated in vacuo.
The remaining product was placed on the top of chroma-
Mixtures EtOAc–hexane 1:30 and EtOAc–hexane 1:10
were used to isolate product by column chromatography,
furnishing 15b as colourless viscous oil in 80% yield, pure
by TLC. IR (film): 1756, 1719, 1253, 1153 cm ; H NMR:
dZ1.18 (t, 3H, JHHZ7.2 Hz, CH CH ), 1.32 (s, 9H, Boc),
K1 1
tography column and eluted with CHCl
obtained 129 mg (83%) of 15e as colourless oil, pure by
-hexane 1:2. It was
3
3
2
2
.26 (s, 3H, CH C H ), 4.0–4.5 (overlapped q and AB ,
3 6 4 q
together 4H, CH CH ), 6.6–7.7 (9H, Ph, C H ); C NMR:
1
3
K1 1
TLC. IR (film): 1714, 1253, 1163 cm ; H NMR: dZ0.86
(t, JHHZ7 Hz, 3H, CH CH CH CH ), 1.2–1.7 (overlapped
s and m, together 13H, Boc and CH
3H, CH ), 3.3–3.6 (m, 2H, CH
(m, 10H, Ph and C
CH ), 20.5, 20.7 (CH
Boc), 29.5 (CH CH CH CH ), 52.3 (CH N), 81.5, 81.7
3
2
6 4
dZ14.0 (CH CH ), 20.3 (CH C H ), 28.2 (Boc), 56.8
3
2
2
2
3
2
3 6 4
(
CH N), 61.1 (CH CH O), 82.2 (C ), 112.2, 121.0, 124.3,
3
CH
CH
2
2
CH
CH
2
2
CH
CH
2
2
), 2.30 (s,
), 6.7–7.6
2
3
2
q
128.5, 129.2, 129.7, 142.0, 146.1 (Ph and C H ), 153.9 (CO,
Boc), 169.6 (COOEt). Anal. calcd for C H N O : C,
6
3
C
6
H
4
3
6
4
1
3
H
); C NMR: dZ13.8 (CH
and CH CH CH CH
2
CH
), 28.1
CH
2 2
2
2 28 2 4
6
4
3
8.73; H, 7.34; N, 7.29; found C, 68.92; H, 7.35; N, 6.72.
2
3
C
6
H
4
3
2
2
(
3
2
2
2
2
4
(
.8.3. 1-(tert-Butoxycarbonyl)-1-(p-anisyl)-2-(p-tolyl)-2-
n-butyl)hydrazine (15c). Compound 15c was synthesized
(C
q
), 112.1, 118.8, 119.0, 121.1, 124.2, 128.4, 129.0, 129.1,
), 153.9 (CO, Boc). Anal.
: C, 74.54; H, 8.53; N, 7.90; found C,
133.7, 140.2, 149.4 (Ph and C
calcd for C22
74.56; H, 8.55; N, 7.71.
H
6 4
similarly with 5b. The reaction was monitored by TLC
using EtOAc–hexane 1:10 as eluent. Mixtures CHCl3–
hexane 1.5:1 and EtOAc–hexane 1:5 were used to isolate
product by column chromatography, furnishing 15c as
H N O
30 2 2
4.8.6. 1-(tert-Butoxycarbonyl)-1-(p-tolyl)-2-phenyl-2-
benzylhydrazine (15a). This synthesis was carried out in
a manner similar to that described in Section 4.8.2. Mixtures
CHCl –hexane 1:3 and CHCl –hexane 1:1 were used to
colourless viscous oil in 92% yield, pure by TLC. IR (film):
K1 1
1
3
714, 1247, 1158 cm ; H NMR: dZ0.85 (t, JHHZ7.4 Hz,
H, CH CH CH CH ), 1.2–1.6 (overlapped s and m,
3
2
2
2
3
3
together 13H, Boc and CH CH CH CH ), 2.26 (s, 3H,
3
isolate product by column chromatography, furnishing 15a
as slightly yellow viscous oil in 85% yield, pure by TLC.
The H and C NMR spectra were identical with data
obtained in the procedure 4.8.1.
2
2
2
CH C H ), 3.3–3.6 (m, 2H, CH CH CH CH ), 3.75 (s, 3H,
2
3
6
4
3
2
2
1
3
1
13
CH O), 6.6–7.4 (m, 8H, 2!C H ); C NMR: dZ13.9
3
6 4
(
CH CH CH CH ), 20.3, 20.5 (CH C H and CH CH
3 2 2 2 3 6 4 3 2
CH CH ), 28.2 (Boc), 29.6 (CH CH CH CH ), 52.3
2
2
3
2
2
2
(
CH N), 55.4 (CH O), 81.3 (C ), 112.3, 113.7, 123.0,
2 3 q
1
Boc). Anal. calcd for C H N O : C, 71.84; H, 8.39; N,
28.0, 129.6, 136.1, 147.3, 154.1 (2!C H ), 156.6 (CO,
6 4
Acknowledgements
2
3 32 2 3
7
.29; found C, 71.75; H, 8.43; N, 6.85.
This work was supported by Estonian Science Foundation
(Grant 5255). We are very grateful to Prof. P. Trapencieris
and Dr. Emma Sarule (Latvian Institute of Organic
Synthesis) for microanalyses. U. R. thanks Magn. Bergvall’s
stiftelse for support.
4
(
.8.4. 1-(tert-Butoxycarbonyl)-1-(p-tolyl)-2-(p-anisyl)-2-
n-butyl)hydrazine (15d). Compound 15d was synthesized
similarly with 5b. The reaction was monitored by TLC
using EtOAc–hexane 1:10 as eluent. Mixtures CHCl3–
hexane 1:1 and EtOAc–hexane 1:5 were used to isolate
product by column chromatography, furnishing 15d as
colourless viscous oil in quantitative yield, pure by TLC. It
solidified on standing for several months in the refrigerator
References and notes
and was recrystallized from hexane/CHCl , mp 67–69 8C.
3
K1
1
IR (film): 1704, 1242, 1153 cm ; H NMR: dZ0.85 (t,
JHHZ7.2 Hz, 3H, CH CH CH CH ), 1.2–1.6 (overlapped s
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3
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3 6 4 3 2 2 2
1
3
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2
2
3
2
2
2
(
CH N), 55.7 (CH O), 81.4 (C ), 113.6, 114.7, 121.3,
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6 4
2
3 32 2 3
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