Highly selective arylation of disubstituted hydrazines by pentavalent organobismuth reagents

Article abstract of DOI:10.1016/S0040-4039(02)01327-8

The scope of a set of recently reported hydrazine reagents has been explored with respect to arylation. Compounds of type R¹NHNHCOR² can be selectively arylated under very mild conditions using triarylbismuth diacetates.

Full text of DOI:10.1016/S0040-4039(02)01327-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6213–6215
Highly selective arylation of disubstituted hydrazines by
pentavalent organobismuth reagents
Olga Tsˇubrik,a Uno Ma¨eorga,* and Ulf Ragnarssonb
aInstitute of Organic and Bioorganic Chemistry, University of Tartu, Tartu, 51014 Jakobi 2, Estonia
bDepartment of Biochemistry, Biomedical Center, University of Uppsala, PO Box 576, SE-751 23 Uppsala, Sweden
Received 30 April 2002; revised 7 June 2002; accepted 28 June 2002
Abstract—The scope of a set of recently reported hydrazine reagents has been explored with respect to arylation. Compounds of
type R1NHNHCOR2 can be selectively arylated under very mild conditions using triarylbismuth diacetates. © 2002 Published by
Elsevier Science Ltd.
The intensive development within the hydrazine field
has stimulated, during the last few years, the design of
several triprotected reagents for the stepwise synthesis
of multisubstituted derivatives.1,2 Recently we also
prior separation. Initial arylation attempts using triva-
lent bismuth compounds and stoichiometric Cu(OAc)2
catalysis were carried out, but instead of arylation we
observed slow oxidation to hydrazones Boc-
NHNꢀCHR. Therefore, the effect of the promoter
Et3N was examined as previously described by Chan.8
Under these conditions both the oxidation and the
N-arylation of the resulting hydrazone were signifi-
cantly accelerated. Thus after 1 h, 55% of the hydra-
reported
a very convenient diprotected hydrazine
reagent 1 and demonstrated that various alkyl and acyl
substituents could be introduced selectively.3 The aryla-
tion of nitrogen compounds is nowadays of great sig-
nificance. Two main pathways are known to fulfil this,
namely halides under palladium catalysis as developed
by the groups of Buchwald and Hartwig4 and
organobismuth compounds as applied by Barton and
Finet.5 In this context arylation of hydrazines has also
recently attracted attention in the literature.6 Triarylbis-
muthanes were successfully used in our group to arylate
triprotected hydrazine precursors.7 Up to now there are
no reports on the selective arylation of disubstituted
hydrazines with similar reagents which induced us to
investigate compounds derived from 1 from this
perspective.
zone
and
27%
of
its
were
arylated
formed
product,
Boc(Ph)NNꢀCHCOOEt,
(R1=
CH2COOEt, 1.5 equiv. of Ph3Bi, 2 equiv. of Et3N, rt)
as shown by NMR. Analogous products were detected
with two other substrates (R1=PhCH2 and CH2=
CHCH2) as well.
The utilization of pentavalent bismuth compounds
instead of triarylbismuthanes furnished a route to the
successful arylation of 3 and similar substrates. With
9
Ar3Bi(OAc)2 in the presence of 5% Cu(OAc)2 for a
range of compounds the reactions turned out to be
remarkably fast and were complete in 5–10 min at
room temperature, giving the desired compounds 4 in
good to high yields over the two steps starting from the
phosphonium salts 2 (Table 1, compounds 4a–e).10 In
A number of compounds 3, required as starting materi-
als in the arylation experiments below, were obtained as
outlined in Scheme 1.3 Step c afforded an equimolar
mixture of 3 and Ph3PO, which was reacted without
Boc
R1
Ar
Boc
R1
c
d
a, b
BocNHNHR1
BocNHNHP+Ph3 Br-
N N
N N
H
H
P+Ph3X-
3
4
1
2
Scheme 1. Reagents and conditions: (a) BuLi, THF; (b) R1X; (c) 1 M NaOH/CH2Cl2; (d) arylation with organobismuth
compounds.
* Corresponding author. Tel.: 3727 375243; fax: 3727 375245; e-mail: uno@chem.ut.ee
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01327-8

6214
O. Tsˇubrik et al. / Tetrahedron Letters 43 (2002) 6213–6215
Table 1. Synthesis of compounds R1ArNNHCOR2 by arylation of R1NHNHCOR2
Compd
R1
R2CO
Ar
Yield%
Mp
1H NMR spectra
(°C)/hexane
4a12
4b
PhCH2
Boc
Boc
Ph
Ph
95
86
92.5–93.5
1.44 (s, 9H, Boc), 4.71 (br s, 2H, CH2), 6.41 (br s, 1H,
NH), 6.8–7.3 (m, 10H, Ph)
(94–9512
39–40
)
n-Bu
0.96 (t, 3H, CH3, 3JHH=7.2), 1.3–1.7 (m, 13H, 3×CH3,
2×CH2), 3.4–3.6 (br m, 2H, NCH2), 6.38/6.20 (two br s,
together 1H, NH), 6.8–7.3 (m, 5H, Ph)
1.44 (s, 9H, Boc), 3.16 (s, 3H, CH3), 6.26 (s, 1H, NH),
7.2–8.4 (m, 7H, 1-naphthyl)
4ca
CH3
Boc
1-Naphthyl
87
85–86
4d
HCꢁCCH2
EtOCOCH2
Boc
Boc
4-CH3C6H4
4-CH3C6H4
93
74
80.5–82
102–103.5
Ref. 10
1.25 (t, 3H, CH3
(s, 3H, CH3C6H4), 4.18 (q, 2H, CH3CH6 2,
4eb
6
CH2, 3JHH=7.2), 1.50 (s, 9H, Boc), 2.25
3JHH=7.2), 4.28
6
(br s, 2H, NCH2), 6.7–7.1 (m, 5H, NH, C6H4)
2.24 (s, 3H, CH3C6H4), 3.10 (s, 3H, NCH3), 5.14 (s, 2H,
CH2), 6.6–7.4 (m, 10H, Ar, NH)
2.15/1.84 (two s, together 3H, CH3CO), 3.08/3.16 (two s,
together 3H, NCH3), 7.2–8.3 (m, 7H, 1-naphthyl), 8.68
(s, NH)
5
6
CH3
CH3
Cbz
4-CH3C6H4
82
80
112.5–113
116–117
CH3CO 1-Naphthyl
7
Boc
Boc
Ph
86
106–107
Consistent with Ref. 7
(110–1117)
a Additional purification by chromatography was required.
b Subsequent purification by crystallization from hexane/CHCl3 mixture was required.
addition, regioselective substitution was possible using
1 equiv. of the pentavalent bismuth compound. Pheny-
lation of Ph2CꢀNNH2 with this type of reagent was first
reported by Barton et al.,11 but to the best of our
knowledge this is the first time such reagents have been
exploited to arylate substituted hydrazines.
Finally, as an example of a diacylated hydrazine, the
arylation of 1,2-di-Boc-hydrazine with Ar3Bi(OAc)2
was studied both in the presence and absence of
Cu(OAc)2 as catalyst. In the first case (Et3N was used
as a promoter) monoarylation required 4 h to go to
completion. Obviously the increased reaction time
needed in comparison with that for the monoacylated
hydrazines investigated above accounts for the
observed regioselectivity and explains why we did not
detect any side-products due to arylation at the carba-
mate nitrogens. In the absence of Cu(OAc)2 the only
product detected was BocNꢀNBoc which could be iso-
lated after reaction of 1,2-di-Boc-hydrazine for 48 h. Its
identity was proved by comparison (NMR and TLC)
with an authentic sample, prepared by oxidation of
BocNHNHBoc with the Br2/Py complex according to
the described protocol.14 The formation of oxidation
products in the reaction of some hydrazines with
Ph3BiCO3 has been reported earlier15 and obviously
occurs here as well due to the dual nature of the
pentavalent bismuth compounds, behaving as arylation
agents or oxidants. In the syntheses in Table 1 the first
process dominates to the extent that only traces of
hydrazones could be detected by TLC. Their formation
can be explained in terms of a well-known rapid
isomerization16 of azo compounds, which arise primar-
ily from oxidation of BocNHNHR1 by the bismuth
reagents.
It is worth noting that arylation can be accomplished
even without a copper catalyst. In this case the reaction
occasionally requires longer time or a larger excess of
Ar3Bi(OAc)2 to go to completion in the presence of air.
Nevertheless, 93% of 4a was obtained as a result of the
reaction with 1.3 equiv. of the pentavalent bismuth
reagent, after 10 min, under an inert gas atmosphere.
With R1=n-Bu and HCꢁCCH2 the corresponding
products 4b and 4d were also formed.
In order to study the scope of the reaction and to verify
the selectivity, we tested a few other hydrazines under
these arylation conditions (Table 1, compounds 5–7).
Initially CbzNHNHCH3 was synthesized by analogy
with Scheme 1 and arylation furnished 5, which could
subsequently be benzylated smoothly under standard
PTC conditions2a to give (4-CH3C6H4)CH3N-
N(CH2Ph)Cbz in 95% yield. The NMR spectrum was
identical with recently published data,7 which indicates
a similar selectivity in the arylation step as that for the
Boc-derivatives in Scheme 1. For comparison of
alkoxycarbonyl and acyl moieties, an acetylated hydra-
zine derivative was also included. Arylation of 1-acetyl-
2-methylhydrazine, prepared by Condon’s method,13
proceeded similarly to give 6. Thus it can be stated that
In conclusion, a convenient protocol for the arylation
of hydrazines is described. In contrast to triarylbis-
muthanes, pentavalent bismuth compounds can be
readily used for the smooth and selective arylation of
hydrazines bearing electron-donating or electron-with-
drawing substituents on either nitrogen.
on reaction with
1 equiv. of these pentavalent
organobismuth reagents all the monoacylated, 1,2-dis-
ubstituted hydrazines studied undergo highly selective
arylation of their non-acylated nitrogens.

O. Tsˇubrik et al. / Tetrahedron Letters 43 (2002) 6213–6215
6215
Acknowledgements
9. Combes, S.; Finet, J.-P. Synth. Commun. 1996, 26, 4569–
4575.
This work was supported by the Estonian Science
Foundation (Grant 5255). We are very grateful to
Professor P. Trapencieris and coworkers (Latvian Insti-
tute of Organic Synthesis) for microanalyses.
10. Typical procedure: To a solution of 0.579 mmol of
HCꢁCCH2NHNHBoc/Ph3PO mixture in dichloro-
methane (2 mL) 0.05 equiv. of Cu(OAc)2 was added,
followed by 1.1 equiv. of Tol3Bi(OAc)2. The reaction was
monitored by TLC (EtOAc–light petroleum 1:4). After
completion (10 min) silica (ꢀ0.8 g) was added, where-
upon the solvent was evaporated under reduced pressure.
The remaining material was placed on top of a short
silica column and eluted first with EtOAc–hexane 1:30 to
remove nonpolar components, then with EtOAc–light
petroleum 1:4 to isolate the product 4d. An analytical
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