A practical and highly efficient hydroacylation reaction of azodicarboxylates with aldehydes in water

Article abstract of DOI:10.1055/s-0030-1258056

The very efficient hydroacylation reaction of azodicarboxylates, with various aldehydes, was carried successfully out at room temperature in water without the use of a catalyst to obtain a variety of hydrazine imide products in high yields. A wide range o

Full text of DOI:10.1055/s-0030-1258056

LETTER
2453
A Practical and Highly Efficient Hydroacylation Reaction of
Azodicarboxylates with Aldehydes in Water
H
ydroacylation Re
i
action
a
of Azodic
a
n
rboxylates
w
y
ith
A
ldehyde
i
s
in
W
n
ater g Zhang,1 Erica Parker,1 Allan D. Headley,* Bukuo Ni*
Department of Chemistry, Texas A&M University-Commerce, Commerce, TX 75429-3011, USA
Fax +1(903)4686020; E-mail: allan_headley@tamu-commerce.edu; E-mail: bukuo_ni@tamu-commerce.edu
Received 10 May 2010
tion at the a-position of amine and ethers (Scheme 1, path
c),7 and the ene-type reaction with olefins (Scheme 1, path
d).8 The direct hydroacylation reaction, which involves al-
dehydes has not been studied extensively (Scheme 1, path
Abstract: The very efficient hydroacylation reaction of azodicar-
boxylates, with various aldehydes, was carried successfully out at
room temperature in water without the use of a catalyst to obtain a
variety of hydrazine imide products in high yields. A wide range of
aldehydes, including aliphatic and aromatic compounds, was con- e),9 and is the focus of this report.
sidered, and the reaction is believed to proceed via a radical mech-
anism, in which water plays an integral role in stabilizing the radical
intermediate.
O
R3
R2
CO2R1
Key words: azo compounds, green chemistry, hydroacylation, al-
dehydes
N
R1O2C
N
R2
X
H
CO2R1
Ph3P
R2 = H, alkoxyl
3 = alkyl, cabonyl
N
CO2R1
R1O2C
N
H
N
N
R
R1O2C
The toxic and volatile nature of many organic solvents
that are widely used in organic synthesis pose a serious
hazard to the environment. Efforts aimed at replacing
such organic solvents with environmentally friendly ones
as reaction media have been actively pursued in recent
years.2 Carrying out reactions in aqueous media has re-
ceived considerable attention because water is a safe, eco-
nomical, nontoxic, and environmentally benign solvent,
compared to typical organic solvents.3 Moreover, when a
reaction is carried out in water, the water-insoluble prod-
ucts can be isolated easily by simple separation. As a re-
sult, research into organic reactions, which can be carried
out effectively in water, has become an active area of re-
search.
X = OR, NR2
zwitterionic intermediate
path a
path b
path c
CO2R1
N
N
R1O2C
path e
path d
O
H
N
R2
R2
N
CO2R1
CO2R1
N
CO2R1
R1O2C
N
H
One of the most important reactions in organic synthesis
is the formation of new carbon–nitrogen bonds from sim-
ple and easily available starting materials.4 There are var-
ious reactions, including those that use various polar
substrates, radicals, and transition-metal catalysts that
have been reported to construct such bonds.4 Of these re-
actions, the reaction that involves the use of azodicarbox-
ylates as electrophiles is a very efficient reaction for the
formation of C–N bonds. One of the reasons for the suc-
cess of this reaction is that azodicarboxylates contain a
strong electron-withdrawing group and a vacant orbital,
which also serves as good nucleophilic acceptors; these
features contribute to making this a favorable reaction.4a,b
There are many types of reactions involving azodicarbox-
ylates that have been studied extensively for the formation
of C–N bond, these include the zwitterion-mediated reac-
tions (Scheme 1, path a),5 electrophilic a-amination of
carbonyl compounds (Scheme 1, path b),6 the C–H activa-
Scheme 1 Reactions involving azodicarboxylates
Hydroacylation reaction with direct functionalization of
the aldehydic C–H to form a variety of hydrazine imides
is a highly efficient synthetic methodology to form a car-
bon–nitrogen bond. The compounds that result are versa-
tile building blocks for the synthesis of macrocyclic
enamide.10b Under photolytic or thermal conditions, the
yields have been low and only a narrow scope of sub-
strates can be utilized. The transition-metal catalyst, rhod-
ium acetate, has proven to be an effective catalyst for the
hydroacylation reaction involving aliphatic saturated or
unsaturated aldehydes with azodicarboxylates under mild
conditions to provide the hydrazine imides.10 A major
drawback with this method, however, is that the reaction
results in relatively low yields when aromatic aldehydes
are used as the substrates. In addition, very costly precious
metals are used. Therefore, the development of simple and
efficient reaction conditions, while increasing the scope of
the substrates without the use of expensive metal catalyst,
have become a challenging and very important task.
SYNLETT 2010, No. 16, pp 2453–2456
x
x
.x
x
.2
0
1
0
Advanced online publication: 19.08.2010
DOI: 10.1055/s-0030-1258056; Art ID: S12510ST
© Georg Thieme Verlag Stuttgart · New York

2454
Q. Zhang et al.
LETTER
Recently, we have demonstrated that the hydroacylation
reaction can be carried out successfully in the presence of
the ionic liquid, 1-n-butyl-3-methylimidazolium bis(tri-
fluoromethane sulfonyl)imide without a catalyst.11 Carry-
ing out the above reaction in water would be of
tremendous benefit, from a green chemistry perspective,
and in this communication, we wish to report the hydro-
acylation reaction of azodicarboxylates with aldehydes
without the use of a catalyst. The reaction in this study is
conducted under mild reaction conditions in the presence
of water.
Table 2 Hydroacylation Reaction of Aldehydes with Azobicarbox-
ylatesa
CO2R2
O
O
H
N
H2O, r.t.
+
N
N
R1
H
R1
N
CO2R2
R2O2C
CO2R2
1
2
3
Entry R1
R2
Time Product15 Yield
(h)
(%)b
97
92
97
92
98
98
96
70
42
80
60
59
90
87
1
2
n-Bu
n-C8H17
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
10 3b
20 3c
Initially, the hydroacylation reaction with propionalde-
hyde and diisopropyl azodicarboxylate in various solvents
was examined at room temperature in the absence of a cat-
alyst.12 As shown from the results summarized in Table 1,
the reaction proceeded smoothly and gave the best yield in
water after only 10 hours (Table 1, entry 1). The reaction
yield in MeOH, which is a polar protic solvent and similar
to water, is extremely low (Table 1, entry 2). Poor yields
were also obtained when acetonitrile or ethyl acetate was
used as a solvent (Table 1, entries 3 and 4). When THF
and CH2Cl2 were used as solvents, the desired hydroacy-
lation product 3a was obtained in low yields, 35% and
20%, respectively (Table 1, entries 5 and 6).
3
Me2CHCH2
Me2CH
6
3d
4
36 3e
5
cyclohexyl
cyclopentyl
PhCH2CH2
8
8
3f
6
3g
7
25 3h
96 3i
168 3j
76 3k
168 3l
360 3m
8
(cis) n-C5H11CH=CH(CH2)2 i-Pr
9
CH2=CHCH2Me2C
Ph
i-Pr
10
11
12
13
14
i-Pr
4-ClC6H4
i-Pr
Table 1 Optimization Reaction of Propionaldehyde 1a with Diiso-
propyl Azodicarboxylate 2aa
4-MeOC6H4
cyclohexyl
cyclohexyl
i-Pr
solvent
r.t., 10 h
O
H
N
O
CO2i-Pr
2b Et
2c Bn
3
5
3n
3o
+
N
N
N
CO2i-Pr
H
i-PrO2C
CO2i-Pr
1a
2a
3a
a Reaction were performed with a 2:1 ratio of 1 and 2 on a 0.5 mmol
scale in 0.5 mL of H2O.
Entry
Solvent
H2O
Yield (%)b
b Isolated yields of pure product.
1
2
3
4
5
6
97
<5
<5
<5
35
20
Next, we investigated a wide range of this hydroacylation
reaction involving various aldehydes and azodicarboxy-
lates. As revealed in Table 2, these reactions proceeded
smoothly to give the hydroacylation products 3b–c. These
results show that not only the linear saturated aldehydes
1b–c, but also branched aldehydes 1e–h can be employed
successfully as nucleophiles to afford the desired products
3b–h in excellent yields (Table 2, entries 1–7). The hy-
droacylation reactions with other aliphatic aldehydes 1i–j
with unsaturation either at the terminal or internal position
also provided the desired products 3i and 3j, respectively,
but in low to moderate yields (Table 2, entries 8 and 9).
The reason for the relatively low yields in these two cases
is probably due to the ene-type reaction to generate the
bisazodicarboxylates,13 which was also observed by Lee’s
research group using rhodium acetate as catalyst.10a The
aromatic benzaldehyde is also a good substrate for this re-
action and afforded the hydroacylation product 3k in 76
hours with 80% yield (Table 2, entry 10). This result is su-
perior to that obtained by Lee and Otte, in which rhodium
acetate catalyst is used (120 h, yield 46%).10a However,
the reaction rates for the reactions involving aromatic al-
dehydes with the electron-withdrawing group Cl (1l). and
the electron-donating group OMe (1m) were very low and
MeOH
MeCN
EtOAc
THF
CH2Cl2
a Reaction were performed with a 2:1 ratio of 1a and 2a on a 0.5 mmol
scale in 0.5 mL of H2O.
b Isolated yields of pure product.
The large-scale hydroacylation reaction was carried out,
in which 10 mmol of diisopropyl azodicarboxylate 2a was
allowed to react with propionaldehyde 1a under standard
reaction conditions. After the reaction was completed, the
reaction mixture was separated into two phases. The aque-
ous phase was removed by simple separation, and the or-
ganic phase was purified by flash chromatography on
silica gel to give the hydroacylation product 3a in 95%.
Notably, the procedure is green and practical, and no or-
ganic solvent is required for the workup step.
Synlett 2010, No. 16, 2453–2456 © Thieme Stuttgart · New York

LETTER
Hydroacylation Reaction of Azodicarboxylates with Aldehydes in Water
2455
Guzei, I. A.; Lee, D. Org. Lett. 2005, 7, 495. (d) Nair, V.;
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Lett. 2005, 7, 2121. (e) Nair, V.; Biju, A. T.; Vinod, A. U.;
Suresh, E. Org. Lett. 2005, 7, 5139.
gave hydroacylation products 3l–m in moderate yield
(Table 2, entries 11 and 12). To broaden the scope of the
reaction, a wide range of azodicarboxylates 2b,c, were
used in the reaction with cyclohexanecarboxaldehyde also
gave the desired products 3n,o in high yields (87–90%,
Table 2, entries 13 and 14).
(6) For selected a-amination of carbonyl compounds, see:
(a) Zhu, R.; Zhang, D.; Wu, J.; Liu, C. Tetrahedron:
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19, 2131. (g) Abarca, B.; Ballesteros, R.; Gonzalez, E.;
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31, 1811. (h) Reliquet, A.; Besbes, R.; Reliquet, F.; Meslin,
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The mechanism for the hydroacylation reaction is still not
clear, but we assume that when this reaction is carried out
in water, it proceeds via a radical mechanism, which was
described in previous studies.9,10a,14 The hydrogen of wa-
ter plays an important role in stabilizing the radical transi-
tion state through hydrogen bonding and facilitating the
addition of the acyl radical intermediate to azodicarboxy-
late to form the hydroacylation product.
In summary, we have developed an efficient hydroacyla-
tion reaction involving aldehydes and azodicarboxylates
to give the hydrazine imide products in water. For these
reactions, moderate to excellent yields are obtained under
convenient conditions without the use of metal catalysts.
The synthetic procedure presented is simple, practical,
and environmentally benign. Further study on the reaction
mechanism and the exploration of the scope of the reac-
tion substrates are under way in our laboratory.
Acknowledgment
We are grateful to the Robert A. Welch Foundation (T-1460) for fi-
nancial support of this research.
References and notes
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(1) These authors contributed equally to this work.
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(12) The reaction of hexanal and diisopropyl azodicarboxylate
without catalyst under neat conditions was described by Lee
et al.10a and afforded the addition product with 14 days at r.t.
(13) Due to the many byproducts observed in the reaction
mixture, the bisazodicarboxylates could not be isolated.10a
(14) Chudasama, V.; Fitzmaurice, R. J.; Caddick, S. Nature
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(15) Typical Procedure for the Hydroacylation Reaction in
H2O
To a stirred solution of aldehyde 1 (1.0 mmol) in H2O (0.5
mL) was added azodicarboxylate 2 (0.5 mmol). The reaction
was stirred at r.t. for the time as indicated in Tables 1 and 2.
The reaction mixture was extracted with Et2O for two times
Synlett 2010, No. 16, 2453–2456 © Thieme Stuttgart · New York

2456
Q. Zhang et al.
LETTER
(4 × 5 mL). The Et2O solution was combined, concentrated,
and purified by flash chromatography on silica gel (hexane–
EtOAc = 4:1) to afford the product 3.
Hz, 2 H), 3.44–3.34 (m, 1 H), 2.00–1.60 (m, 6 H), 1.52–1.17
(m, 10 H) ppm. 13C NMR (100 MHz, CDCl3): d = 177.1,
155.6, 153.1, 63.7, 62.4, 62.2, 43.9, 29.3, 28.9, 28.8, 25.7,
25.6, 25.5, 25.3, 14.3, 14.1 ppm. Anal. Calcd for
Data for the new hydroacylation products: Compound 3b:
1H NMR (400 MHz, CDCl3): d = 6.57 (br, 1 H), 5.10–4.90
(m, 2 H), 2.94–2.84 (m, 2 H), 1.72–1.58 (m, 4 H), 1.40–1.15
(m, 20 H), 0.88 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (100
MHz, CDCl3): d = 173.9, 155.1, 152.6, 72.1, 70.4, 37.0,
31.8, 29.3, 29.2, 29.1, 24.7, 24.6, 22.6, 21.9, 21.7, 14.1 ppm.
Anal. Calcd for C16H32N2O5Na [M + Na]+: 367.2209; found:
367.2207. Compound 3n: 1H NMR (400 MHz, CDCl3):
d = 6.68 (br, 1 H), 4.30 (q, J = 7.2 Hz, 2 H), 4.21 (q, J = 7.2
C13H22N2O5Na [M + Na]+: 309.1421; found: 309.1421.
Compound 3o: 1H NMR (400 MHz, CDCl3): d = 7.34 (br, 10
H), 6.76 (br, 1 H), 5.24 (s, 2 H), 5.17 (s, 2 H), 3.46–3.26 (m,
1 H), 2.00–1.14 (m, 10 H) ppm. 13C NMR (100 MHz,
CDCl3): d = 176.8, 155.4, 153.0, 135.3, 134.7, 128.6, 128.5,
128.4, 128.1, 69.1, 68.0, 43.9, 29.3, 28.8, 25.7, 25.5, 25.3
ppm. Anal. Calcd for C23H26N2O5Na [M + Na]+: 433.1734;
found: 433.1738.
Synlett 2010, No. 16, 2453–2456 © Thieme Stuttgart · New York