Selective propargylation of AZO compounds with barium reagents

Article abstract of DOI:10.1055/s-0029-1219944

A Barbier-type propargylation of azo compounds with γ- trialkylsilylated propargylic bromides has been achieved using reactive barium as a low-valent metal in THF. Corresponding propargylated hydrazines (α-adducts) were exclusively formed not only from azobenzenes (diaryldiazenes) but also from dialkyl azodicarboxylates. This method is also applicable to -alkylated or γ-phenylated propargylic bromides, providing the desired propargylated products only. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219944

LETTER
1515
Selective Propargylation of Azo Compounds with Barium Reagents
S
elective Propargy
k
lation of
A
zo
i
C
om
p
r
ounds a Yanagisawa,* Takanori Koide, Kazuhiro Yoshida
Department of Chemistry, Graduate School of Science, Chiba University, Inage, Chiba 263-8522, Japan
Fax +81(43)2902789; E-mail: ayanagi@faculty.chiba-u.jp
Received 10 March 2010
The addition of a propargylic or an allenylic metal reagent
to azo compounds is a convenient method for the prepara-
tion of propargylic hydrazines.5,6 First, we examined the
utility of diethyl azodicarboxylate (DEAD) as an azo
Abstract: A Barbier-type propargylation of azo compounds with g-
trialkylsilylated propargylic bromides has been achieved using re-
active barium as a low-valent metal in THF. Corresponding propar-
gylated hydrazines (a-adducts) were exclusively formed not only
from azobenzenes (diaryldiazenes) but also from dialkyl azodicar- compound in the barium-promoted reaction. When a mix-
boxylates. This method is also applicable to g-alkylated or g-pheny-
lated propargylic bromides, providing the desired propargylated
products only.
ture of DEAD (1 equiv) and (3-bromoprop-1-ynyl)trime-
thylsilane (2 equiv) was treated with reactive barium (2.2
equiv) in THF at –78 °C for two hours, the anticipated
propargylic hydrazine (a-adduct) was furnished in 55%
yield. In contrast, the corresponding allenylic hydrazine
(g-adduct) was not detected at all (Scheme 2). Thus, ex-
clusive a-selectivity was also observed for the propargy-
lation of azo compounds with barium reagents.
Key words: azo compounds, barium, hydrazine, propargylation,
propargylic bromides
Allylic and propargylic/allenylic barium reagents are
known to show regioselectivity and/or stereoselectivity
characteristics that markedly differ from those of other
group 2 metal reagents.1 We have previously reported that
a trimethylsilylated propargyl bromide reacts with alde-
hydes and ketones in the presence of reactive Rieke
barium1,2 to afford homopropargylic alcohols almost ex-
clusively.3 The corresponding regioisomers, allenylic al-
cohols, can be observed in the Barbier-type reaction
promoted by other reactive alkaline-earth metals (Ca and
Sr) and reactive magnesium. In particular, in the case of a
Grignard reagent, an allenylic alcohol is formed as the
major product. Reactive barium has been further found to
promote the selective propargylation of imines with trim-
ethylsilylated propargylic bromides, resulting in the pre-
dominant formation of homopropargylic amines.4 We
report herein a reactive-barium-promoted Barbier-type
reaction of azo compounds with propargylic halides
(Scheme 1).
We then investigated the reaction of various azo com-
pounds with a trimethylsilyl-substituted a-methylated
propargylic barium reagent and the results are summa-
rized in Table 1. We initially tested the reactivity of
azobenzene. An equimolar mixture of the azo compound
and (3-bromobut-1-ynyl)trimethylsilane was treated with
reactive barium (1.1 equiv) under standard reaction condi-
tions; however, the reaction proceeded sluggishly and a
low yield (16%) of the propargylated product was ob-
tained even after 12 hours (entry 1). The chemical yield
was improved when the amount of the propargylic bro-
mide was increased, exceeding 80% when three or more
equivalents of the propargylation reagent were used (en-
tries 4 and 5). Employment of the corresponding propar-
gylic chloride resulted in a remarkable decrease in yield
(compare entry 3 with entry 4). The effect of azobenzene
substituents on the chemical yield was also examined and
as a result, electron-donating groups reduced the reactivi-
ty of azobenzene (entries 6 and 7), while an electron-with-
drawing group enhanced the reaction rate (entry 8). We
then attempted the propargylation of diethyl azodicarbox-
ylate. In order to acquire a satisfactory yield of the DEAD
adduct, at least two equivalents of the azo compound were
necessary (entries 9–11). Sterically bulky azodicarboxy-
late esters also furnished the desired propargylated prod-
ucts (entries 12 and 13). The propargylation according to
R1
R1
NH
N
R2
X
N
N
Ba*
R2
+
R1
R1
THF
R3
R3
Scheme 1 Barbier-type reaction of propargylic halides with azo
compounds promoted by reactive barium
EtO2C
CO2Et
NH
N
SiMe3
Br
N
N
γ
Ba* (2.2 equiv)
α
+
α
Me3Si
EtO2C
THF, –78 °C, 2 h
EtO2C
(2 equiv)
55% (α/γ = >99:1)
Scheme 2 Regioselective propargylation of diethyl azodicarboxylate with a g-trimethylsilylated propargylic barium reagent
SYNLETT 2010, No. 10, pp 1515–1518
x
x
.x
x
.2
0
1
0
Advanced online publication: 25.05.2010
DOI: 10.1055/s-0029-1219944; Art ID: U01510ST
© Georg Thieme Verlag Stuttgart · New York

1516
A. Yanagisawa et al.
LETTER
the Barbier-type technique was superior to the one using trialkylsilyl-substituted propargylic bromides except a tri-
a preformed propargylic/allenylic barium reagent in terms isopropylsilylated substrate (entries 4–6). In addition to g-
of isolated yield (entries 4 and 10).
trialkylsilyl-substituted propargylic bromides, g-alkyl- or
g-phenyl-substituted propargylic bromides could be em-
ployed as propargylation reagents (entries 7–10). Note-
worthy was the fact that even 3-bromo-1-phenylbut-1-
yne, which afforded a mixture of a- and g-adduct in its re-
action with an imine,4 exhibited exclusive a-selectivity
(entry 10).
Subsequently, we studied the propargylation of DEAD
with various propargylic halides under the optimized re-
action conditions (Table 2). Propargylic bromides showed
superior reactivity to propargylic chlorides (compare en-
tries 1 and 10 with entries 2 and 11, respectively). The in-
troduction of a long alkyl substituent to the a-position of
the trimethylsilyl-substituted propargylic bromide did not To investigate the electronic effect on the site selectivity
affect the regioselectivity and in fact, the targeted propar- of the two nitrogen atoms, we carried out the propargyla-
gylated product was gained exclusively in 77% yield (en- tion of an asymmetric azobenzene derivative possessing
try 3). Remarkable reactivity was also seen for bulky an electron-donating group on one benzene ring and an
electron-withdrawing group on another benzene ring and
Table 1 Reactive-Barium-Promoted Selective Propargylation of
as a consequence, an almost 1:1 mixture of the two regio-
isomers was obtained as the product (Scheme 3). Thus,
the difference in electron density between the two nitro-
gen atoms was found to be small in this case.
Various Azo Compounds with (3-Bromobut-1-ynyl)trimethylsilanea
R1
R1
R1
+
Br
NH
N
SiMe3
γ
Ba* (1.1xn equiv)
THF, –78 °C, 2 h
α
N
N
Me3Si
α
R1
A plausible reaction mechanism is indicated in Scheme 4.
Two pathways are suggested for propargylic hydrazines
(a-adducts). A barium reagent generated from a trimeth-
ylsilyl-substituted propargylic bromide is considered to
exist in equilibrium between allenic isomer A and acety-
lenic isomer B.7 Thus, propargylic hydrazines can be
formed from both isomers A and B by their reaction with
an azo compound via transition state structure C or D.
However, transition state D is more probable because of
its minimal steric repulsion. In contrast, allenylic hydra-
zines (g-adducts) are obtainable from B via its SE2¢-type
reaction with the azo compound through six-membered
cyclic transition state E, which is, however, destabilized
by the trimethylsilyl group.
(n equiv)
R1
Entry
1c
2
n
1
2
3
3
4
3
3
3
1
2
3
2
2
Yield (%)b
16d
Ph
Ph
50d
3e
4
Ph
59d
Ph
82d (76)d
87d
5
Ph
6
4-MeC6H4
4-MeOC6H4
4-FC6H4
EtO2C
73d
7
52d
8
92d
In summary, we have achieved a Barbier-type propargy-
lation of azo compounds with propargylic halides, which
is promoted by reactive barium. This method is syntheti-
cally useful with regard to regioselectivity and gives di-
verse propargylic hydrazines in moderate to high yields. It
is worthy of note that the ester moieties of dialkyl azodi-
carboxylates are unaffected by barium reagents. Further
studies of related reactions promoted by barium reagents
are in progress.
9f
62
10
11
12f
13
EtO2C
80 (79)d
81
EtO2C
i-PrO2C
t-BuO2C
82
62
a Unless otherwise specified, the reaction was carried out using (3-
bromobut-1-ynyl)trimethylsilane (n equiv), azo compound (1 equiv),
and reactive barium (1.1 × n equiv) in anhyd THF at –78 °C for 2 h.
b Isolated yield. Values in parentheses are isolated yields of products
from a preformed propargylic/allenylic barium reagent.
c The reaction was performed for 12 h.
Typical Experimental Procedure for the Barbier-Type Propar-
gylation (Entry 10 in Table 1 and Entry 1 in Table 2)
An oven-dried, 20 mL Schlenk flask equipped with a Teflon®-coat-
ed magnetic stirring bar was flushed with argon. Freshly cut lithium
(16 mg, 2.2 mmol) and biphenyl (340 mg, 2.2 mmol) were put into
the apparatus and covered with anhyd THF (5 mL), and the mixture
was stirred for 1.5 h at r.t. (lithium was completely consumed). An-
d The yield was determined by 1H NMR.
e The reaction was performed using (3-chlorobut-1-ynyl)trimethyl-
silane.
f The reaction was performed for 3 h.
Ar2
Ar1
Ar1
Ar2
Ar2
Br
NH
N
SiMe3
NH
N
SiMe3
γ
Ba* (3.3 equiv)
N
N
α
+
Me3Si
+
α
α
THF, –78 °C, 2 h
Ar1
3 equiv
Ar1 = 4-MeC6H4
Ar2 = 4-FC6H4
73% (53:47 or 47:53)
Scheme 3 Reactive-barium-promoted selective propargylation of an asymmetric azo compound with (3-bromobut-1-ynyl)trimethylsilane
Synlett 2010, No. 10, 1515–1518 © Thieme Stuttgart · New York

LETTER
Selective Propargylation of Azo Compounds
1517
Table 2 Reactive-Barium-Promoted Selective Propargylation of Diethyl Azodicarboxylate with Various Propargylic Halidesa
EtO2C
EtO2C
CO2Et
NH
N
R2
N
N
X
γ
Ba* (2.2 equiv)
α
R2
α
+
THF, –78 °C, 2 h
EtO2C
R3
R3
2 equiv
Entry
R2
R3
X
Yield (%)b
1
2
Me3Si
Me3Si
Me3Si
Me
Me
Pr
Br
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Cl
80
74
77
59
85
84
69
75
77
75
45
3
4
(i-Pr)3Si
Ph3Si
(t-Bu)Me2Si
Me
Me
Me
Me
Me
Me
Me
Me
Me
5
6
7
8
c-Hex
t-Bu
9
10
11
Ph
Ph
a The reaction was carried out using propargylic halide (2 equiv), diethyl azodicarboxylate (1 equiv), and reactive barium (2.2 equiv) in anhyd
THF at –78 °C for 2 h.
b Isolated yield.
XBa
R1
γ
γ
α
α
·
Me3Si
Me3Si
R1
BaX
R2
A
B
R2
R2
N
N
N
N
N
N
R2
R2
R1
R2
R1
γ
R2
R2
R2
Me3Si
N
N
N
BaX
XBa
N
R2
Me3Si
N
N
R2
·
α
Ba
X
R2
α
Me3Si
R1
C
D
E
R2
R2
R2
Me3Si
HN
N
HN
N
γ
R1
·
α
R2
R1
Me3Si
allenylic hydrazines
propargylic hydrazines
Scheme 4 Plausible reaction pathways to propargylic hydrazines and allenylic hydrazines
hyd BaI2 (430 mg, 1.1 mmol) was placed in a separate oven-dried,
50 mL two-necked flask that was also equipped with a Teflon®-
coated magnetic stirring bar under argon atmosphere, and this was
covered with anhyd THF (5 mL) and stirred for 20 min at r.t. To the
solution of BaI2 in THF was added at r.t. a solution of lithium biphe-
nylide in THF under an argon stream. The reaction mixture was
stirred for 30 min at r.t. A solution of (3-bromobut-1-ynyl)trimeth-
ylsilane (191 mL, 1.0 mmol) and diethyl azodicarboxylate (2.2 M
toluene solution, 227 mL, 0.50 mmol) in anhyd THF (4 mL) was
added dropwise to the resulting dark brown suspension of reactive
barium (1.1 mmol) in THF (10 mL) at –78 °C. After being stirred
for 2 h at this temperature, the mixture was treated with sat. NH4Cl
aq solution (10 mL) at –78 °C, and the aqueous layer was extracted
three times with Et2O (10 mL each). The combined organic extracts
were washed with 1 N Na2S2O3 solution (20 mL), dried over anhyd
MgSO4, and concentrated in vacuo after filtration. The residual
crude product was purified by column chromatography on silica gel
to give the propargylic hydrazine (120.7 mg, 80% yield).
TLC: Rf = 0.26 (EtOAc–hexane = 1:4). IR (neat): 3301, 2985, 2902,
2175, 1760, 1715, 1519, 1472, 1415, 1384, 1314, 1251, 1228, 1112,
1
1063, 846 cm–1. H NMR (400 MHz, CDCl3): d = 0.16 (s, 9 H, 3
CH3), 1.26–1.31 (m, 6 H, 2 CH3), 1.41 (d, 3 H, J = 6.8 Hz, CH3),
4.15–4.28 (m, 4 H, 2 CH2), 5.11 (m, 1 H, CH), 6.19 (br s, 0.25 H,
NH), 6.40 (br s, 0.75 H, NH). 13C NMR (100 MHz, CDCl3): d =
–0.2 (3 C), 14.3 (2 C), 19.3, 47.0, 61.9, 62.7, 88.1, 103.4, 155.1,
Synlett 2010, No. 10, 1515–1518 © Thieme Stuttgart · New York

1518
A. Yanagisawa et al.
LETTER
(2) (a) Sell, M. S.; Rieke, R. D. Synth. Commun. 1995, 25,
4107. For reviews, see: (b) Rieke, R. D.; Sell, M. S.; Klein,
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(5) (a) An, D. K.; Hirakawa, K.; Okamoto, S.; Sato, F.
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156.2. The above-mentioned spectral data showed good agreement
with the reported data.5b
References and Notes
(1) For reactions of allylic barium reagents, see:
(a) Yanagisawa, A.; Habaue, S.; Yamamoto, H. J. Am.
Chem. Soc. 1991, 113, 8955. (b) Yanagisawa, A.; Habaue,
S.; Yasue, K.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116,
6130. For reviews, see: (c) Yanagisawa, A.; Yamamoto, H.
In Active Metals. Preparation, Characterization,
Applications; Fürstner, A., Ed.; VCH: Weinheim, 1996, 61.
(d) Yanagisawa, A. In Science of Synthesis, Vol. 7;
Yamamoto, H., Ed.; Thieme: Stuttgart, 2004, 695.
(e) Yanagisawa, A. In Main Group Metals in Organic
Synthesis, Vol. 1; Yamamoto, H.; Oshima, K., Eds.; Wiley-
VCH: Weinheim, 2004, 175. For related strontium reagents,
see: (f) Miyoshi, N.; Kamiura, K.; Oka, H.; Kita, A.;
Kuwata, R.; Ikehara, D.; Wada, M. Bull. Chem. Soc. Jpn.
2004, 77, 341. (g) Miyoshi, N.; Ikehara, D.; Kohno, T.;
Matsui, A.; Wada, M. Chem. Lett. 2005, 34, 760.
(7) For reviews, see: (a) Epsztein, R. In Comprehensive
Carbanion Chemistry, Chap. 3; Buncel, E.; Durst, T., Eds.;
Elsevier: New York, 1984, 107. (b) Yamamoto, H. In
Comprehensive Organic Synthesis, Vol. 2; Trost, B. M.;
Fleming, I.; Heathcock, C. H., Eds.; Pergamon: Oxford,
1991, 81.
(h) Miyoshi, N. In Science of Synthesis, Vol. 7; Yamamoto,
H., Ed.; Thieme: Stuttgart, 2004, 685. (i) Miyoshi, N.;
Ikehara, D.; Matsuo, T.; Kohno, T.; Matsui, A.; Wada, M.
J. Synth. Org. Chem. Jpn. 2006, 64, 845.
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