Synthesis of acrylonitriles through an FeCl3-catalyzed domino propargylic substitution/aza-Meyer-Schuster rearrangement sequence

Article abstract of DOI:10.1002/chem.201200763

Nontoxic cyanide source: An unprecedented route to acrylonitriles by employing propargylic alcohols and para-tolylsulfonohydrazide as a combined cyano source has been developed (see scheme). This efficient and practical cyanation reaction proceeds through an FeCl₃-catalyzed domino propargylic substitution/aza-Meyer-Schuster rearrangement sequence, the rearrangement process of which is reported for the first time. Copyright

Full text of DOI:10.1002/chem.201200763

COMMUNICATION
DOI: 10.1002/chem.201200763
Synthesis of Acrylonitriles through an FeCl3-Catalyzed Domino Propargylic
Substitution/Aza-Meyer–Schuster Rearrangement Sequence
Lu Hao,[a] Feng Wu,[b] Zong-Cang Ding,[a] Su-Xia Xu,[a] Yan-Li Ma,[a] Li Chen,[a] and
Zhuang-Ping Zhan*[a, b]
Nitrile and acrylonitrile scaffolds constitute a key compo-
nent of numerous compounds, including dyes, natural prod-
ucts, agrochemicals, and pharmaceuticals.[1] The cyano group
may also be transformed into a variety of functional groups
consisting of amines, aldehydes, amidines, and amides. Ac-
cordingly, considerable effort has been invested in their syn-
theses. The cyano group is generally constructed from sour-
ces containing whole cyano units, such as metal cyanides
(CuCN, KCN, NaCN, Zn(CN)2, K3[Fe(CN)6], TMSCN) and
cyano-containing organic compounds,[2] and yet this type of
cyanation method suffers from the high toxicity of cyano
sources. Alternatively, this group may be formed by the de-
hydration of precursors, including primary amides and al-
doximes.[3] Very recently, a new strategy for generating
a cyano group by direct transformation of one precursor or
a combined cyano source has been revealed by the groups
of Jiao, Chang, Schmalz, Cheng, and Mizuno.[4] By these
methods, cyanation can be achieved through cyano genera-
tion from simple reagents, such as DMF, ammonia, and
azides (Scheme 1). Despite these pioneering methodologies,
the further development of new cyano sources generated in
situ from simple, low-toxicity, readily available reagents is
still an extremely attractive, yet challenging task.
During recent years, the transition-metal-catalyzed trans-
formation of propargylic alcohols has received considerable
attention.[5] Particularly intriguing is the reactivity of these
easily accessible compounds in the context of iron cataly-
sis,[6] which has been reflected in the development of a varie-
ty of diverse and elegant transformations leading to an array
of complex organic molecules. Herein, we wish to report an
unprecedented FeCl3-catalyzed synthesis of acrylonitriles by
Scheme 1. Various cyano sources for cyanation reactions (TMS=trime-
thylsilyl; Ts=tosyl).
employing propargylic alcohols and para-tolylsulfonohydra-
zide as a combined cyano source through a domino propar-
gylic substitution/aza-Meyer–Schuster rearrangement route.
In the field of propargylic alcohol chemistry, the classical
acid-catalyzed Meyer–Schuster rearrangement plays a very
important role[7] because a wide range of a,b-unsaturated
carbonyl compounds can be easily synthesized by this
named reaction. In addition, the rearrangement may serve
as a strategy for double-bond construction. It is generally
proposed that the propargylic alcohols rearrange to the cor-
responding a,b-unsaturated carbonyl compounds through
a formal [1,3] shift of the hydroxyl moiety (Scheme 2a).[8]
[a] L. Hao, Z.-C. Ding, S.-X. Xu, Y.-L. Ma, Prof. Dr. L. Chen,
Prof. Dr. Z.-P. Zhan
Department of Chemistry
College of Chemistry and Chemical Engineering
Xiamen University, Xiamen 361005, Fujian (P.R. China)
Fax : (+86)592-2180318
Scheme 2. The Meyer–Schuster rearrangement and its aza analogue.
E-mail: zpzhan@xmu.edu.cn
However, to the best of our knowledge, an aza-Meyer–
Schuster rearrangement in which the nitrogen atom migrates
has not yet been disclosed (Scheme 2b).
[b] F. Wu, Prof. Dr. Z.-P. Zhan
School of Pharmaceutical Sciences
Xiamen University, Xiamen 361005, Fujian (P.R. China)
Fax : (+86)592-2180318
In the course of our studies on propargylic substitution,[9]
we became interested in the employment of readily avail-
able and inexpensive reagents, such as para-tolylsulfonohy-
drazide (2a). When we carried out the reaction between 1,1-
E-mail: zpzhan@xmu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200763.
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Table 2. Screening of different substituted hydrazines.[a]
diphenyl-3-(trimethylsilyl)propargylic alcohol (1a) and 2a,
in addition to the main substitution product 3a, the acryloni-
trile compound 4a was obtained as a byproduct in 27%
yield (Table 1, entry 1). To obtain 4a selectively, different
Table 1. Screening of reaction parameters.[a]
Entry
2
Yield 3/4a
Recovered 1a
[%][b]
[%][b]
1
2
3
4
5
6
2a: TsNHNH2
0:99
0:0
0:0
0:0
0:0
0:0
0
98
93
98
96
95
2b: BocNHNH2
2c: PhCONHNH2
2d: PhNHNH2
2e: AcNHNH2
2 f: tBuCONHNH2
Entry
Catalyst
(10 mol%)
Solvent
T
[8C]
t
Yield 3a/4a
G
[h]
[%][b]
[a] Reaction conditions: 1a (0.5 mmol), 2 (0.75 mmol), FeCl3 (10 mol%)
in CH3NO2 (3 mL) at 608C for 2 h in air (Boc=tert-butoxycarbonyl).
[b] Isolated yields.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20[g]
21
22[h]
FeCl3
FeCl3
BiCl3
CH3CN
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
PhCH3
THF
CH3NO2
CH3NO2
1,4-dioxane
CH2Cl2
DMF
CH3NO2
CH3NO2
CH3NO2
60
60
60
60
RT
60
60
60
60
60
5
1
2
2
2
2
2
2
2
2
2
2
2
2
2
4
2
1
5
2
2
2
68:27
0:93
0:42
InCl3
0:76
AuCl3
ZnCl2
ZnBr2
AgOTf
18:0[c]
0:25
conditions gave neither substitution products 3 nor acryloni-
trile 4a (Table 2, entries 2–6). We reasoned that the catalytic
activity of FeCl3 was suppressed by the stronger alkalinity of
the alternative substituted hydrazines.
0:23
42:40
0:57
In
A
Cu
A
0:82
Next, we probed the substrate scope of this FeCl3-cata-
lyzed synthesis of acrylonitriles under the optimized condi-
tions (Table 3). Moderate to excellent yields were obtained
in most cases examined, and a range of functionalities could
be tolerated. We began our investigation by examining the
cyanation of symmetrical propargylic alcohols (R1 =R2).
Substrates with both electron-rich and -poor substituents re-
acted very well, providing compounds 4 in good to excellent
yields (Table 3, examples 4a–4d and 4n). The asymmetric
p-TSA·H2O
TfOH
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
-
60
60
60
60
5:0[d]
0:88
0:68
85:0
0:99
60
RT
100
40
100
60
99:0[e]
complex mixture
0:90
0:0[f]
9:89
0:0
0:99
60
60
propargylic alcohols (R1 ¼
6
R2) investigated also gave good
FeCl3
yields. It should be noted that a single isomer was observed
in the cases of 4 f, 4g, 4k, 4l, 4m, and 4o. In comparison
with the similar compounds 4k and 4l, a lower yield was ob-
tained for 4p.[10] Although a wide range of propargylic alco-
hols could be employed, dialkyl-substituted and monoaryl-
substituted propargylic alcohols proved to be uniquely chal-
lenging partners and none of the desired products were de-
tected (Table 3, examples 4s and 4t).
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), catalyst
(10 mol%) in solvent (3 mL) in air (DCE=dichloroethane; Tf=triflyl;
p-TSA=para-toluenesulfonic acid). [b] Isolated yields. [c] 72% of 1a was
recovered. [d] 77% of 1a was recovered. [e] After being heated at 608C
for 2 h, 3a transformed into 4a in nearly quantitative yield. [f] 96% of
1a was recovered. [g] 5 mol% FeCl3 was used. [h] Run on a 5 g scale.
parameters were carefully screened and the optimal reaction
conditions were determined to be FeCl3 (10 mol%) in nitro-
methane at 608C for an appropriate time (Table 1, entry 15).
In contrast, reactions performed in THF at reflux or in ni-
tromethane at room temperature exclusively led to the sub-
stitution product 3a (Table 1, entries 14 and 16), and the
latter gave a nearly quantitative yield. Decreasing the cata-
lyst loading made the reaction sluggish (Table 1, entry 20),
and performing the reaction without using the catalyst gave
neither products (Table 1, entry 21). We also examined the
potential of scaling up this novel cyanation; the reaction of
1a and 2a was run on a 5 g scale in air, and a remarkably
clean cyanation reaction was observed, producing 4a in
99% isolated yield (Table 1, entry 22).
To probe the mechanism of this reaction, we first isolated
the substitution product 3a under the reaction conditions
shown in Table 1, entry 16. Then, by using 3a as the sub-
strate, two reactions were carried out (Scheme 3). Under
the optimized reaction conditions, the desired 3,3-diphenyl-
AHCTUNGTREGaNNUN crylonitrile 4a was obtained in 99% isolated yield
(Scheme 3). However, it was found that 3a did not react at
all without the added FeCl3 catalyst (Scheme 3).
Very interestingly, the examination into the use of differ-
ent substituted hydrazines showed that only para-tolylsulfo-
nohydrazide (2a) worked in the cyanation reaction. Reac-
tions with other substituted hydrazines under the standard
Scheme 3. Direct cyanation of substitution product 3a.
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Synthesis of Acrylonitriles
COMMUNICATION
Table 3. FeCl3-catalyzed syntheses of acrylonitriles.[a]
2 h, 99%
2 h, 99%
3 h, 92%
2 h, 88%
Scheme 4. Plausible mechanism for the cyanation reaction.
2 h, 99%[b]
3 h, 91%[c]
3 h, 81%[c]
2 h, 99%[b]
Consequently, we propose the following plausible mecha-
nism for this cyanation reaction (Scheme 4). First, propar-
gylic alcohol 1 reacted under iron catalysis to yield propar-
gylic cation 5. Next, the propargylic substitution occurs re-
gioselectively by attack of the terminal nitrogen atom
(-NH2) of 2a, resulting in the substitution product 3. Then,
compound 3 experiences an FeCl3-mediated [1,3] shift of the
-NHNHTs group to generate allene intermediate 7 via tran-
sition states 6 (aza-Meyer–Schuster rearrangement, an olefi-
nation process). Finally, allene 7 transforms into the final
product 4 through rapid tautomerization and subsequent
elimination of TsNHTMS (cyanation process). To further
clarify the mechanism, we performed the reactions of 1,1,3-
triphenylprop-2-yn-1-ol (9a) and 1,1-diphenylhept-2-yn-1-ol
(9b) with para-tolylsulfonohydrazide (Scheme 5). The two
analogues 8 (8a and 8b) were observed and isolated in ex-
cellent yields.
2 h, 99%[b]
3 h, 94%[b]
2 h, 87%[c]
24 h, 73%[c]
2 h, 88%[c]
3 h, 63%
2 h, 96%[c]
20 h, 53%[d]
2 h, 97%[d]
3 h, 92%[d]
24 h, 0%
24 h, 0%
2 h, 85%[d]
2 h, 82%[d]
[a] Reaction conditions: 1 (0.5 mmol), 2a (0.75 mmol), FeCl3 (10 mol%)
in CH3NO2 (3 mL) in air for an appropriate time. Isolated yields based
on 1. The isomeric ratio of 4 was determined by 1H NMR spectroscopy.
[b] A 1:1 ratio of olefin isomers. [c] A single olefin isomer was observed
and the double-bond geometry was determined by NOE experiment.
[d] The olefin isomer ratios of 4p, 4q, 4r, 4u, and 4v are 55:45, 75:25,
89:11, 62:38, and 57:43, respectively.
Scheme 5. Isolation of analogues 8.
In summary, we have developed a highly efficient and
practical FeCl3-catalyzed domino synthesis of acrylonitriles
by using propargylic alcohols and para-tolylsulfonohydra-
zide as a combined cyano source, which avoids the use of
highly toxic metal cyanides. This novel cyanation reaction
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ACHTUNGTRENNUNGaction for practical and large-scale applications. Further
studies are currently in progress in our laboratory.
Experimental Section
General procedure for the syntheses of acrylonitriles 4: Propargylic alco-
hol 1 (0.5 mmol, 1.0 equiv), para-tolylsulfonohydrazide 2a (0.75 mmol,
1.5 equiv), and nitromethane (3 mL) were successively added to a flame-
dried flask (10 mL) equipped with a magnetic stirring bar. The mixture
was stirred until 2a was completely dissolved. Subsequently, FeCl3
(10 mol%, 0.05 mmol) was added. The reaction mixture was stirred at
room temperature in air for about 15 min, that is, until the reaction
system became homogeneous. Then, the mixture was put in an oil bath
(608C) for an appropriate time, and monitored periodically by thin-layer
chromatography. Upon completion of the reaction, the solvent was re-
moved under reduced pressure, and the residue was purified by column
chromatography on silica gel to afford the acrylonitrile.
Acknowledgements
We thank the NSFC (No. 21072159), the 973 Projects (No.
2011CB935901), the NFFTBS (No. J1030415), and the Science & Tech-
nology Bureau of Xiamen (No. 3502Z20093007) for financial support of
this project.
Keywords: acrylonitriles · cyanides · domino reactions ·
iron · propargylic substitution · rearrangement
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Received: March 7, 2012
Published online: && &&, 0000
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Synthesis of Acrylonitriles
COMMUNICATION
Cyanation
L. Hao, F. Wu, Z.-C. Ding, S.-X. Xu,
Y.-L. Ma, L. Chen,
Z.-P. Zhan* ................... &&&& — &&&&
Nontoxic cyanide source: An unprece-
dented route to acrylonitriles by
employing propargylic alcohols and
para-tolylsulfonohydrazide as a com-
bined cyano source has been devel-
oped (see scheme). This efficient and
practical cyanation reaction proceeds
through an FeCl3-catalyzed domino
propargylic substitution/aza-Meyer–
Schuster rearrangement sequence, the
rearrangement process of which is
reported for the first time.
Synthesis of Acrylonitriles through an
FeCl3-Catalyzed Domino Propargylic
Substitution/Aza-Meyer–Schuster
Rearrangement Sequence
Chem. Eur. J. 2012, 00, 0 – 0
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These are not the final page numbers!