Bronsted acid mediated nitrogenation of propargylic alcohols: An efficient approach to alkenyl nitriles

Article abstract of DOI:10.1039/c4ob00888j

A novel and efficient approach to alkenyl nitriles from readily available propargylic alcohols has been developed. This nitrogenation reaction is transition-metal-free and could be conducted under air at ambient temperature, which makes this protocol promising and practical. Moreover, NH₄Br is disclosed as an efficient additive to promote the stereoselectivity of this reaction. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00888j

Organic &
Biomolecular Chemistry
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Brønsted acid mediated nitrogenation of
propargylic alcohols: an efficient approach to
alkenyl nitriles†
Xiaoqiang Huanga and Ning Jiao*a,b
Cite this: Org. Biomol. Chem., 2014,
12, 4324
Received 1st May 2014,
Accepted 2nd May 2014
DOI: 10.1039/c4ob00888j
www.rsc.org/obc
A novel and efficient approach to alkenyl nitriles from readily avail-
able propargylic alcohols has been developed. This nitrogenation
reaction is transition-metal-free and could be conducted under air
at ambient temperature, which makes this protocol promising and
practical. Moreover, NH4Br is disclosed as an efficient additive to
promote the stereoselectivity of this reaction.
Propargylic alcohols, which are readily available by practical
and vigorous strategic bond-forming reactions, are very useful
building blocks and have been widely used in organic syn-
thesis.1 The Meyer–Schuster rearrangement represents a sig-
nificant transformation of propargylic alcohols and provides
an efficient, highly selective and atom-economic protocol to
enones,2 which are definitely one of the most versatile bifunc-
tional building blocks as well as core components of many bio-
active natural products, pharmaceuticals and materials.3 The
exploration of novel transformations of propargylic alcohols
and the broadening of the utility of the Meyer–Schuster
rearrangement have attracted considerable attention.4 Enlight-
ened by the mechanism, the capture of allenol, which is the
key intermediate in this named reaction, opens up a fertile
world for chemists to develop new reactions. Recently, some
elegant studies for the synthesis of complex enones from pro-
pargylic alcohols directly have been carried out by the groups
of Zhang,5a Trost,5b,c Gaunt,5d Tan and Liu5e respectively
(Scheme 1, a). In these cases, the electrophilic interception of
the allenoate type intermediate has been designed to replace
the protonation step and represents a fascinating strategy for
modification of the Meyer–Schuster rearrangement. To enable
these novel processes, transition-metal catalyst systems were
Scheme 1 Nitrogenation of propargylic alcohols.
employed to promote the desired rearrangement over many
side reactions of propargylic alcohols.2a
Inspired by the above work and in the course of our studies
on using azides as the nitrogen source to construct nitrogen-
containing compounds,6 we hypothesized that if a highly reac-
tive allenyl azide7 could be generated in situ during the
rearrangement of propargylic alcohols in the presence of an
azido nucleophile, a new type of reaction with N-containing
products would be discovered. Herein, we report a novel
Brønsted acid mediated nitrogenation of propargylic alcohols
for the efficient synthesis of alkenyl nitriles (Scheme 1, b).
The significance and advantages of the present protocol
can be summarized as follows: (1) this is a novel metal-free
transformation of simple propargylic alcohols to alkenyl
nitriles which is an important class of α,β-unsaturated carbo-
nyl compounds due to their significance in chemistry and
biology,8 through a direct N-incorporation strategy. Although
various methods have been developed,9 the preparation of
alkenyl nitriles from a wide range of readily available sub-
strates via an efficient and practical way is still extremely attrac-
tive. (2) This process is transition-metal-free and could be
conducted under air at ambient temperature, which makes
this protocol promising and practical.
aState Key Laboratory of Natural and Biomimetic Drugs, Peking University, School of
Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191,
China. E-mail: jiaoning@bjmu.edu.cn; Fax: (+86)-010-8280-5297;
Tel: (+86)-01082805297
bState Key Laboratory of Elemento-organic Chemistry, Nankai University,
94 Weijin Road, Tianjin 300071, China
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ob00888j
Commercially available propargylic alcohol 1-phenylprop-
2-yn-1-ol (1a) was chosen to evaluate our hypothesis of inter-
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Table 1 Optimization of the nitrogenation reactiona
the methyl group did not affect the efficiency (Table 2, entries
2, 8 and 9). It is noteworthy that the cinnamonitriles (2a–2g,
2i–2j) were obtained with high stereoselectivity regardless of
the substituents at the phenyl ring of the corresponding pro-
pargylic alcohols. Moreover, naphthyl and thienyl groups were
tolerated under these conditions, though in lower yields
(Table 2, entries 12 and 13). Intriguingly, 1-(ferrocenyl)prop-
2-yn-1-ol performed well, generating E-2n in 23% yield
(Table 2, entry 14).
Meanwhile, the effects of additives, electronic nature and
steric hindrance on the stereoselectivity of products were
studied. Therefore, a series of tertiary propargylic alcohols
were investigated under optimized conditions. The reactions
of tertiary propargylic alcohols worked well affording the
desired alkenyl nitriles in moderate to good yields (Table 2,
entries 15–23). Interestingly, NH4Br played a dual role in both
improving the yield and affecting the stereoselectivity dramati-
cally (compare entries 1 and 6 of Table 1, entries 16 and 17 of
Table 2). In contrast, the electronic nature of propargylic alco-
hols did not affect the stereoselectivity remarkably (entries 16,
18–21 of Table 2). Notably, the selectivity decreased with the
increase of the steric hindrance of substrates (compare entries
1, 16, 22, 23 of Table 2; compare entries 1, 11 of Table 2;
and compare entries 2, 8, 9 of Table 2). It is interesting
that Z-4-methyl-3-phenylpent-2-enenitrile (2v) was mainly
obtained. In other words, the cyano group preferred to be
trans to the larger substituent in the presence of NH4Br as
an additive. In conclusion, bromide ion and the steric
hindrance played an important role in the control of
stereoselectivity.
Entry
Acid (1 equiv.)
Additive
Solvent
Yieldb (%)
E/Zc
1
2
3
4
5
6
7
8
conc. H2SO4
conc. HCl
TsOH·H2O
Cu(OTf)2
—
—
—
—
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
71
66 : 34
—
71 : 29
—
0
35
0
0
FeCl3
—
—
conc. H2SO4
conc. H2SO4
conc. H2SO4
conc. H2SO4
conc. H2SO4
conc. H2SO4
conc. H2SO4
conc. H2SO4
NH4Br
NH4Cl
TBAB
NH4Br
NH4Br
NH4Br
NH4Br
NH4Br
82 (79)d
E only
93 : 7
95 : 5
E only
—
—
96 : 4
—
81
73
82
0
9e
10f
11
12
13
0
Toluene
DMF
65
0
a Reaction conditions: 1a (0.5 mmol), TMSN3 (1.5 equiv.), acid (1.0
equiv.), additive (0.1 equiv.) and solvent (2.0 mL), stirred at ambient
temperature under air for 12 hours. b Determined by 1H NMR yield
using 1,1,2,2-tetrachloroethane as the internal standard. c Determined
by 1H NMR measurement of the crude mixture. d The number
in parenthesis is the isolated yield. e The reaction was run under Ar.
f NaN3 (1.5 equiv.) instead of TMSN3 was employed. TBAB
tetrabutylammonium bromide.
=
ception of allenyl azides using proton as an electrophile. To
our delight, the expected product cinnamonitrile (2a) was
obtained in 71% yield although in low stereoselectivity, when
1a was treated with azido trimethylsilane (TMSN3) and 1.0
equiv. of concentrated sulfuric acid (conc. H2SO4)10 under air
at ambient temperature (Table 1, entry 1). After failing in
using a catalytic amount of acid (see ESI†), other stoichio-
metric Lewis acids and Brønsted acids were tested for this
transformation (entries 2–5). The results indicate that conc.
H2SO4 is the best choice in this present ionization of pro-
pargylic alcohols. Then we turned our attention to improve the
stereoselectivity by screening a wide range of additives (entries
6–8, also see ESI†).11 Gratifyingly, the E-selectivity was dramati-
cally achieved in the presence of only 0.1 equiv. of NH4Br as an
additive with also a slight improvement in yield (entry 6). No
product was obtained when NaN3 was employed instead of
TMSN3 (entry 10). Further screening of the solvent showed that
MeCN was the best one (entries 11–13).
With the optimized conditions in hand, we next investi-
gated the substrate scope of this transformation. Secondary
propargylic alcohols were proved to be efficient to afford the
corresponding alkenyl nitriles in moderate to excellent yields
with high stereoselectivity (Table 2, entries 1–10). Generally,
substrates bearing an electron donating group performed
better than that containing an electron withdrawing group.
However, as to strong electron donating groups, alkenyl nitriles
(2c, 2n and 2o) were obtained in lower yields mainly because
of the unknown side reactions.2a The substituting position of
As mentioned above, alkenyl nitriles are among the most
versatile building blocks in organic synthesis due to their
bifunctional and dipolar nature. The product 2a could be
easily converted into diverse building blocks for further appli-
cations such as the primary allylic amine
3 (90%, a,
Scheme 2),12 a diphenylphosphine oxide addition product pro-
vided 4 (96%, b, Scheme 2),13 α,β-unsaturated amide 5 (99%, c,
Scheme 2),14 and tri-substituted alkenyl nitrile 6 (94%, d,
Scheme 2).15 Moreover, 2a could undergo some other interest-
ing reactions, creating a compound library including many
bioactive natural products, pharmaceuticals and materials
according to the literature.16
To demonstrate the mechanism of this transformation,
some control experiments were investigated. Although cinnam-
aldehyde 7 was converted into 2a under the optimal con-
ditions via a Schmidt reaction17 (eqn (1)), 1a was unable to
produce 7 through the Meyer–Schuster reaction (eqn (2)).
These results may exclude the possibility of a tandem process
involving the Meyer–Schuster reaction of propargylic alcohols
into α,β-unsaturated aldehydes and a subsequent Schmidt
reaction giving alkenyl nitriles.
ð1Þ
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Table 2 The scope of the propargylic alcoholsa
Entry
Product
R = H
(Yieldb, E/Zc)
Entry
14
Product
(Yieldb, E/Zc)
2n (24%, E only)
1
2a (79%, E only)
15
2o (39%, —)
2
3
4
5
R = p-Me
R = p-OMe
R = p-tBu
R = p-F
R = p-Cl
R = p-Br
2b (98%, E only)
2c (58%, E only)
2d (93%, E only)
2e (75%, E only)
2f (69%, E only)
2g (70%, E only)
16
17e
18
19
20
21
R = H
R = H
R = p-Me
R = p-F
R = p-Cl
R = p-Br
2p (92%, 78 : 22)
2p (58%, 32 : 68)
2q (65%, 76 : 24)
2r (87%, 84 : 16)
2s (82%, 77 : 23)
2t (85%, 78 : 22)
6
7d
8
R = o-Me
2h (87%, 96 : 4)
22
2u (66%, 54 : 46)
9
R = m-Me
2i (84%, E only)
23
2v (41%, 21 : 79)
10
11
R = 3,4-dimethyl
2j (83%, E only)
2k (44%, 93 : 7)
12
13
2l (51%, E only)
2m (42%, 98 : 2)
a Reaction conditions: see entry 6, Table 1. b Isolated yields. c Determined by 1H NMR measurement of the mixture. d The reaction was carried out
at 30 °C. e Without NH4Br.
Scheme 2 Further applications of the product.
Scheme 3 Proposed mechanism.
ð2Þ
intermediate A.2 When the reaction was executed in the pres-
−
ence of a catalytic amount of NH4Br as an additive, N3 shows
a weaker nucleophilicity than Br−,18 which preferentially
attacks the carbocationic intermediate A to generate the
On the basis of the above results and previous work, a
plausible mechanism is illustrated in Scheme 3. First of all,
the ionization of propargylic alcohol 1 forms the carbocationic
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allenic bromide intermediate B.19 Subsequently, regioselective
hydroazidation to the styryl double bond of the allene takes
place to form the intermediate C,20 which undergoes [3,3]-
sigmatropic rearrangement to produce E-terminal allylic azide
(E)-E via the chair-like transition state D.21 The elimination of
intermediate (E)-E generates species (E)-F and Br− to recycle
this process. Finally, the Schmidt type rearrangement of the
carbocation (E)-F occurs leading to (E)-2 and H+ to complete
this transformation6,17 (Scheme 3). Alternatively, when NH4Br
was not employed in this reaction, the reaction will undergo
the allenyl azide7 pathway (b, Scheme 1) followed by H+ elec-
trophilic addition leading to carbocations F for the subsequent
Schmidt type rearrangement.
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Conclusions
In summary, we developed a novel transformation to alkenyl
nitriles under mild and transition-metal-free conditions via
the direct incorporation of a nitrogen atom into readily
assembled propargylic alcohols. Moreover, NH4Br is disclosed
as an efficient additive to promote the stereoselectivity of this
reaction. This transformation would broaden the toolbox
of chemical reactions and provide a facile entry to alkenyl
nitriles. Further studies on the mechanism and the appli-
cations of this transformation are ongoing in our group.
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Acknowledgements
Financial support from the National Science Foundation of
China (no. 21325206, 21172006), the National Young Top-
notch Talent Support Program, and the Ph.D. Programs
Foundation of the Ministry of Education of China (no.
20120001110013) is greatly appreciated. We thank Xiaoyang
Wang in our group for reproducing the results of 2g and 2u.
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