Pd-catalyzed regioselective allylation of Mono- and disubstituted hydrazines

Article abstract of DOI:10.1021/ol4014798

Palladium-catalyzed allylation of hydrazines using allyl alcohols is reported. This highly efficient protocol furnishes monoallylated hydrazines selectively, in 27-99% yields. Following an optimization of the reaction conditions and of the Pd-ligands, the allylations of both mono- and disubstituted hydrazines were investigated, as well as the effects of C2-substitution on the allylating agent. Of particular interest, a novel method for the selective monoallylation of monosubstituted hydrazines is demonstrated.

Full text of DOI:10.1021/ol4014798

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Pd-Catalyzed Regioselective Allylation
of Mono- and Disubstituted Hydrazines
ꢀ
Svetlana Tsupova and Uno Maeorg*
€
Dept of Chemistry, Tartu University, Ravila 14a, Tartu, 50411, Estonia
Uno@chem.ut.ee
Received May 25, 2013
ABSTRACT
Palladium-catalyzed allylation of hydrazines using allyl alcohols is reported. This highly efficient protocol furnishes monoallylated hydrazines
selectively, in 27À99% yields. Following an optimization of the reaction conditions and of the Pd-ligands, the allylations of both mono- and
disubstituted hydrazines were investigated, as well as the effects of C2-substitution on the allylating agent. Of particular interest, a novel method
for the selective monoallylation of monosubstituted hydrazines is demonstrated.
Hydrazine compounds are of particular interest due to
their applicability: many of them show remarkable biolo-
gical activity.1 In addition, hydrazine derivatives are used
as dyes and building blocks in organic synthesis.2 How-
ever, the alkylation of hydrazines, and allylation in parti-
culararenot easytasks, asselectivityand overallylationare
endemic problems. Several methods of direct selective
alkylation of mono- and disubstituted hydrazines exist;3
however, selective monoalkylation of monosubstituted
hydrazines is still challenging because of competitive
dialkylation.
The synthesis of 1,2-disubstituted hydrazines bearing
one or more alkyl groups is generally achieved by the
condensation of monosubstituted hydrazines with alde-
hydes or ketones and the subsequent reduction of the
obtained hydrazones.4 There are few literature reports on
the addition of Grignard reagents to monosubstituted azo-
compounds5 orofelectrophilic amination.6 Anorthogonal
protective group strategy could be applied as well, but
would involve numerous additional protection/deprotec-
tion steps.7 To the best of our knowledge, only two reports
of catalytic allylation of monosubstituted hydrazines exist.
Sterically encumbered allyl carbonates or dienes are used
in Ir or Pd catalysis to obtain 1,2-disubstituted or trisub-
stituted hydrazines.8
Inspired by amine allylation by alcohols,9 it was decided
to develop a new method to perform similar allylation
on hydrazines. Transition metal catalyzed reactions with
hydrazines remain widely unexplored, hence the novelty
of this approach. Additionally, this allylation method does
not require derivatization of the allyl alcohols prior to
allylation, which makes it highly atom efficient. In this
study, the use of different ligands on palladium, allyl
(1) (a) Zhang, R.; Durkin, J. P.; Windsor, W. T. Bioorg. Med. Chem.
Lett. 2002, 12, 1005–1008. (b) Raja, A.; Lebbos, J.; Kirkpatrick, P. Nat.
Rev. Drug Discovery 2003, 1, 857–858.
(5) Ternon, M.; Outurquin, F.; Paulmier, C. Tetrahedron 2001, 57,
10259–10270.
(6) Baburaj, T.; Thambidurai, S. Synlett 2011, 1993–1996.
(2) Ragnarsson, U. Chem. Soc. Rev. 2001, 30, 205–211.
€
(3) (a) Bredihhin, A.; Groth, U. M.; Maeorg, U. Org. Lett. 2007, 9,
~
(7) (a) Barluenga, J.; Isabel Merino, I.; Vina, S.; Palacios, F. Synth-
€
1097–1099. (b) Bredihhin, A.; Maeorg, U. Org. Lett. 2007, 9, 4975–4977.
esis 1990, 398–400. (b) Zhang, Y.; Tang, Q.; Luo, M. Org. Biomol. Chem.
€
(c) Bredihhin, A.; Maeorg, U. Tetrahedron 2008, 64, 6788–6793.
€
2011, 9, 4977–4982. (c) Maeorg, U.; Ragnarsson, U. Tetrahedron Lett.
ꢁ
(4) (a) Bonnet, D.; Margathe, J.-F.; Radford, S.; Pflimlin, E.; Riche,
S.; Doman, P.; Hibert, M.; Ganesan, A. Comb. Sci. 2012, 14, 323–334.
(b) Roveda, J.-G.; Clavette, C.; Hunt, A. D.; Gorelsky, S.; Whipp, C. J.;
Beauchemin, A. M. J. Am. Chem. Soc. 2009, 131, 8740–8741. (c) Sund,
€
1998, 39, 681–684. (d) Maeorg, U.; Grehn, L.; Ragnarsson, U. Angew.
ꢀ
€
Chem., Int. Ed. 1996, 108, 2626–2627. (e) Tsubrik, O.; Maeorg, U. Org.
Lett. 2001, 15, 2297–2299.
(8) Matunas, R.; Amy J. Lai, A. J.; Lee, C. Tetrahedron 2005, 61,
6298–6308. (b) Johns, A. M.; Liu, Z.; Hartwig, J. F. Angew. Chem., Int.
Ed. 2007, 46, 7259–7261.
C.; Belda, O.; Borkakoti, N.; Lindberg, J.; Derbyshire, D.; Vrang, L.;
˚
Hamelink, E.; Ahgren, C.; Woestenenk, E.; Wikstrom, K.; Eneroth, A.;
€
€
Lindstrom, E.; Kalayanov, G. Bioorg. Med. Chem. Lett. 2012, 22, 6721–
6727.
(9) Sawadjoon, S.; Samec J. Org. Biomol. Chem. 2011, 9, 2548–2554.
r
10.1021/ol4014798
XXXX American Chemical Society

alcohols, and hydrazines was studied along with an opti-
mization of the reaction conditions.
electron-poor tris(2,4,6-trimethoxyphenyl) phosphane
(entry 9). It can be expected thatan increaseof thebulkiness
of the ligands may lead to an improvement in selectivity
toward the monoallylated product; therefore, more steri-
cally hindered ligands were screened. Though no starting
material was observed after employing XPhos in the reac-
tion, a significant amount of the diallylated product was
detected. When using XPhos, the overall yield was slightly
lower than with Pd[P(OPh)3]4 (entries 10À12). A parent
ligand, BrettPhos, gave a better mono-/diallylated ratio,
but at the expense of a slower rate of the reaction (entry 13).
Finally dppf was screened both alone and in combination
with triphenyl phosphite. Two dppf ligands resulted in only
trace amounts of product, presumably due to strong co-
ordination of the ligand and saturation of the Pd coordina-
tion sphere (entry 14). For a single equivalent of dppf, the
catalyst was unstable and black palladium quickly pre-
cipitated from the reaction mixture, hence the poor yield
(entry 15). However, a combination of 1 equiv of the
selective dppf with 2 equiv of P(OPh)3 (which gave the
fastest turnover) resulted in a 71% yield.
A test reaction was initially set up with a 1,2-disubsti-
tuted hydrazine (BocNHNHPh), allyl alcohol (10 equiv),
and Pd[P(OPh)3]4 (5 mol %) in toluene at 80 °C, which
resulted in the monoallylation of the phenyl-bearing nitro-
gen. This indicates that the presence of a carbamate-type
protecting group prevents the allylation of the protected
nitrogen due to the steric hindrance and the electron-
withdrawing character of that group. Therefore, the num-
ber of possible products of the allylation reaction of
BocNHNH2 is theoretically limited to two: BocNHNHAll
and BocNHN(All)2. As such, the study was focused on
allylation of monosubstituted hydrazines. Tert-butyl car-
bazate and unsubstituted allyl alcohol were chosen as
model substrates, as they are cheap, nontoxic, and easily
accessible.
Table 1. Optimization of Reaction Conditions and Catalytic
System
Table 2. Allylation of Mono- and Disubstituted Hydrazines
ligand,
hydrazine
(equiv)
temp
time
yield
(%)a
entry
equiv to Pd
(°C)
(days)
entrya
compd
hydrazine
yield (%)b
1
P(OPh)3, 4
P(OPh)3, 4
P(OPh)3, 4
P(OPh)3, 4
P(OPh)3, 4
P(OPh)3, 4
P(OPh)3, 4
PPh3, 4b
1
80
80
80
80
55
55
23
55
55
55
55
23
55
55
55
55
1
1
1
1
1
1
1
1
1
2
1
1
2
2
1
1
34
45
49
57
44
50
-
2
1.2
1.5
2
1
2
1a
2
BocNHNH2
CbzNHNH2
PhNHNH2
71
64
53c
3
4
3
3
5
1.2
1.5
2
d
4
À
À
À
4
FmocNHNH2
TsNHNH2
À
6
d
5
À
7
d
6
PhthNNH2
À
8
2
-
7
Boc2NNH2
71
9
P(Ph(OMe)3)3, 4
XPhos, 2c
XPhos, 2c
XPhos, 2c
BrettPhos, 2c
dppf, 2
2
trace
40
47
-
8
5
PhNHNHBoc
EtNHNHBoc
FmocNHNHi-Pr
99e
77e
27e
10
11
12
13
14
15
16
1.5
2
9
6
10
7
2
2
52
trace
29
71
a Reaction conditions: 2% of Pd(dba)2, 2% of dppf, 4% of P(OPh)3,
2 equiv of hydrazine. b Isolated yields. c Yield of the corresponding
hydrazone. d Hydrazine was insoluble in toluene under reaction conditions.
e Pd(dba)2 and 4 equiv P(OPh)3 were used as catalysts.
2
dppf, 1
2
P(OPh)3, 2;
dppf, 1
2
a Isolated yields. b Pd(PPh3)4 was used as catalyst. c Pd(OAc)2 was
used.
With the optimized reaction conditions and the catalytic
system in hand, a library of substituted hydrazines were
used to test the scope of this method (Table 2). Boc proved
to be the optimal protecting group and Cbz, with its similar
size, provided a similar yield (entry 2). Phenyl monosub-
stitution made for a poorer substrate, likely due to the
rapid and unselective oxidation of the generated product in
air, to form 1-allylidene-2-phenylhydrazine. Decomposi-
tion of the hydrazone in an NMR tube was suppressed by
employing d8-THF under argon which allowed the con-
firmation of its structure. Entries 4À6 gave no conversion
as the starting hydrazines were insoluble in the reaction
media. An attempt to conduct the reaction in refluxing
CH2Cl2 was made, but it afforded an unstable catalytic
system and no product was formed.
As can be seen in Table 1, the reaction showed some
degree of sensitivity to the equivalents of hydrazine em-
ployed, with the yield increasing from 34 to 57% (entries
1À4) by doubling its amount in relation to the allylating
partner. In comparison to the reaction at 80 °C, a decrease
of the temperature to 55 °C had no effect on the yields
(entries 2,3 and 5,6); however, room temperature proved
insufficient for the reaction to proceed (entry 7).
Having found optimal reaction conditions, a library of
phosphine ligands were screened against the test com-
pounds. The highly electron-donating triphenylphosphine
failed to offer any conversion (entry 8), as well as the
B
Org. Lett., Vol. XX, No. XX, XXXX

the unsubstituted allyl alcohol (entry 1) and for all the
alkyl substituted alcohols regardless of sterics (entries
2À4). Greater differences in yields were obtained be-
tween the aromatic compounds. Generally the reactions
with aromatic alcohols proceeded more slowly than with
aliphatic alcohols; therefore, a higher catalytic loading
was necessary. On the other hand, the same level of
selectivity was achieved with fewer equivalents of hydra-
zine. The electron-donating para-methoxyphenyl substi-
tuent on allyl alcohol afforded the product in the highest
yield (78%) owing to its high selectivity (entry 5). The
other aromatic allyl alcohols gave slightly lower yields
(entries 6, 8). However using 2 equiv of hydrazine instead
of 1.5 equiv resulted in a significant yield increase
(entry 7).
In conclusion, a new method for the selective mono-
allylation of monosubstituted hydrazines has been devel-
oped. Its scope was tested for different hydrazines and allyl
alcohols. Up to a 99% yield was obtained when allylating
the substituted hydrazines. The limitations of the method
were tested, and the solubility of the starting material
seems to be its current main impediment.
Table 3. Allylation with Substituted Alcohols
Pd
(%)a
BocNHNH2
(equiv)
yield
(%)b
entry
compd
R
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
2
2
2
2
5
5
5
5
2
H
71
71
72
70
78
52
74
60
2
Bn
2
n-Pe
i-Pr
2
1.5
1.5
2
4-anisyl
Ph
1f
Ph
1g
1.5
4-tolyl
a Pd(dba)2/dppf/P(OPh)3 1:1:2. b Isolated yield.
The best result (99% yield) was obtained for entry 8,
since diallylation was unlikely to proceed (in accordance
with the initial test results). This shows the versatility of
this methodology which allows the allylation of both
mono- and disubstituted hydrazines. It is known from
previous experience10 that EtNHNHBoc is more reactive
and more likely to give rise to byproducts. Indeed, some
side products were observed by TLC, which explains the
decrease of the yield to 77% (entry 9). Finally, much as in
the case of its parent compound (entry 4), poor solubility
prevented the azo-Valine precursor from reaching a high
yield (entry 10). The aforementioned cases show that the
general course of the reaction is strongly influenced by the
solubility of the starting hydrazine.
Acknowledgment. This work was supported by the
Estonian Science Foundation (Grant No. 8794), European
Regional Development Fund (Center of Excellence
‘‘Mesosystems: Theory and Applications’’, TK114), and
Estonian Science Targeted Project No. SF0180032s12. We
would like to thank Oleg Lebedev (University of Tartu,
Estonia) and Alban Cadu (Uppsala University, Sweden)
for proofreading the manuscript and giving valuable
comments and Kristjan Tomson (University of Tartu,
Estonia) for his help with the synthesis of the starting
material.
The scope of the reaction was further studied by probing
the effect of substitution on the allyl alcohol.
As can be seen in Table 3, the reaction proceeded
efficiently and resulted in very similar yields to that of
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
ꢀ
(10) Lebedev, O.; Bredihhin, A.; Tsupova, S.; Maeorg, U. Tetrahedron
€
2009, 65, 5438–5442.
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
C