Metal-free synthesis of alkynyl imines using an oxophosphonium-mediated approach at ambient temperatures

Article abstract of DOI:10.1016/j.tetlet.2008.01.024

A metal-free approach was developed for the mild synthesis of N-aryl α-alkynyl imines from corresponding amide precursors for the first time. The electronic effects of substrates and the reaction mechanisms were investigated and discussed. This newly deve

Full text of DOI:10.1016/j.tetlet.2008.01.024

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1636–1640
Metal-free synthesis of alkynyl imines using an
oxophosphonium-mediated approach at ambient temperatures
Qing-Li Dong a,b, Guan-Sai Liu a,c, Hai-Bin Zhou a, Lin Chen b,*, Zhu-Jun Yao a,c,
*
a State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
b Department of Chemistry, Yunnan Nationalities University, Kunming, Yunnan 650031, China
c Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
Received 13 November 2007; revised 25 December 2007; accepted 8 January 2008
Available online 11 January 2008
Abstract
A metal-free approach was developed for the mild synthesis of N-aryl a-alkynyl imines from corresponding amide precursors for the
first time. The electronic effects of substrates and the reaction mechanisms were investigated and discussed. This newly developed oxo-
phosphonium-triggered one-pot multiple-step method presents the advantages of mild conditions, ease of operation and satisfactory
efficiency.
Ó 2008 Elsevier Ltd. All rights reserved.
R3
Quinolines have been found as substructures in many
natural products, drugs and drug leads, as well as func-
tional polymers.1 Some recent syntheses of quinolines have
been reported using the multiple-step protocols,2,3 amongst
which N-aryl a-alkynyl imines were frequently regarded as
the suitable precursors (Scheme 1, Eq. 1).4–7 Due to the
weak acidity of a-proton of imines, most known methods
for the preparation of N-aryl a-alkynyl imines require the
use of reactive and sensitive organometallic reagents. Diffi-
cult operations and high costs make these methods less
impractical in the laboratory, especially for those cases to
raise materials in a larger scale. Therefore, development
of milder, more efficient and easily operative procedures
for N-aryl a-alkynyl imines is of great value.
R3
conditions
eq.1
eq.2
R1
R1
R2
N
R2
N
N
-aryl α-alkynyl imines
quinolines
R3
R3
oxophosphonium
O
R1
R1
+
N
R2
N
H
R2
R
N
-aryl amides
N-aryl α-alkynyl imines
R=H or TMS
Scheme 1.
diene) at ambient temperatures and triggered the intramo-
lecular Diels–Alder reaction and the following cascade
sequence. The above mechanism suggests that an intermo-
lecular version of this reaction might provide a new mild
access to the quinolines via N-aryl a-alkynyl imines with-
out using those sensitive organometallic reagents (Scheme
1, Eq. 2). The Use of a metal-free method in preparation
of a-alkynyl imines and/or quinolines will broaden the
applications of these compounds as intermediates in
organic synthesis, especially in those sensitive to the
Very recently, we developed a generally efficient strategy
for the total syntheses of camptothecin-family alkaloids.8
In this mild cascade reaction, an oxophosphonium salt
(Hendrickson reagent)9 was used to the convert the stable
aniline amides to corresponding imidates (part of the active
*
Corresponding authors. Tel.: +86 21 54925133; fax: +86 21 64166128
(Z.-J.Y.).
E-mail address: yaoz@mail.sioc.ac.cn (Z.-J. Yao).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.024

Q.-L. Dong et al. / Tetrahedron Letters 49 (2008) 1636–1640
1637
organometallic reagents. To best of our knowledge, no
metal-free approach has been reported yet for the synthesis
of N-aryl a-alkynyl imines.
with trimethylsilyl acetylene afforded trace amount of N-
aryl a-alkynyl imines 3a only (entry 1). Electronic property
of an alkyne is thus mentioned to be critical for this multi-
ple-step reaction by stabilizing the active intermediates in
the reaction process.
As mentioned above, choose of proper acetylenes is crit-
ical to improve the yields of N-aryl a-alkynyl imines. The-
oretical inference suggests commercially available
bis(trimethylsilyl)acetylene would be a better electron
donor, in which the TMS group can play not only as a
good electron-donating group, but also a ‘super proton’10
for the final elimination to generate acetylene 3a (Fig. 2).
Using similar conditions, the reaction of N-(4-methoxy-
phenyl)benzamide (1a) with bis(trimethylsilyl)acetylene
gave N-aryl a-alkynyl imine 3a in 70–72% yield. Attempts
to use more equivalents of Hendrickson reagent could not
improve the chemical yields.
To explore the generality of this reaction, a variety of
aniline amides were then examined and the results are
shown in Table 2. The substrates bearing electron-donating
groups (entries 1, 2, 4 and 6) afforded the corresponding
products in better yields, and those having electron-with-
drawing groups (entries 3, 5, 10, 11 and 12) gave relatively
lower yields. Due to the strong acidity of TfOH generated
in this reaction, substrate 1m (bearing an N,N-dimethyl
Hendrickson reagent can be conveniently prepared
in situ by simply mixing Tf2O and 2 equiv of Ph3PO in
dichloromethane as an oxophosphonium salt at room tem-
perature. Due to the high affinity of phosphorous to oxy-
gen atom, conversion of an amide to the corresponding
imidate can be achieved in high efficiency by using Hend-
rickson reagent.8,9 To screen the reaction with alkynes in
the presence of Hendrickson reagent, N-(4-methoxy-
phenyl)benzamide (1a) was chosen as the amide substrate.
Three mono- or di-substituted aliphatic alkynes 2a–c were
examined as the first batch of reactants. These reactions
were performed and carried out in dichloromethane at
0 °C to room temperature (Table 1). The results showed
two reactions (entries 2 and 3) worked, producing quino-
line derivative and N-aryl a-alkynyl imine (entry 2) or its
equivalence (entry 3) in similar yields. This mentions that
at least two competitive pathways exist in this reaction
(Fig. 1). Quinolines were generated by a pathway of inter-
molecular Diels–Alder reaction followed by eliminative
aromatization, and the other cationic process provided
N-aryl a-alkynyl imine or its equivalence (which is not able
to cyclize under the same conditions). However, its reaction
Table 1
Reactions of amide 1a with aliphatic alkynes 2a–c
Tf2O (1.5 eq.)
Ph3PO (3 eq.)
DCM
Ph Ph
MeO
O
Ph
Ph
Ph
Ph
P
P
O
R1
R2
+
Products
N
H
OTf
OTf
0 oC, 10 min
then rt for 6 h
2a-c
Hendrickson reagent
N-(4-methoxyphenyl)benzamide
(1a)
Entry
2
Product(s)
Yields (%)
Trace
TMS
MeO
1
2a: R1 = H; R2 = TMS
3a
N
N
nC5H11
nC5H11
MeO
MeO
2b: R1 = H; R2 = n-C5H11
43 (4a)
32 (4b)
+
2
N
4a
4b
OTf
nC3H7
nC3H7
nC3H7
MeO
nC3H7
MeO
+
3a
2c: R1 = R2 = n-C3H7
42 (5)
37 (4c)
N
N
4c
5

1638
Q.-L. Dong et al. / Tetrahedron Letters 49 (2008) 1636–1640
MeO
PPh3
MeO
[Ph3P+OP+Ph3](OTf)2
O
O
OTf
OTf
N
R2
N
N
MeO
R1
H
1a
R1
R2
-Ph3PO
5
cationic
Diels-Alder
2
R1=nC3H7
R1
R1
R1
N
R1
R2
O
H
MeO
MeO
R2
R2
MeO
PPh3
OTf
R2
MeO
OTf
OTf
OTf
N
N
O
N
O
Ph3P
Ph3P
R1=H
-TfOH
-Ph3PO
-TfOH
R2
R1
MeO
MeO
R2
N
N
4a
4b/4c
Fig. 1. Proposed mechanism for the competitive pathways.
MeO
MeO
PPh3
O
O
[Ph3P+OP+Ph3](OTf)2
OTf
N
H
N
A
1a
TMS
MeO
TMS
O
-Ph3PO
PPh3
TMS
TMS
OTf
N
-TMSOTf
TMS
TMS
OTf
MeO
TMS
MeO
N
N
3a
B
Fig. 2. Proposed mechanism for the reaction of N-(4-methoxyphenyl)benzamide (1a) with bis(trimethylsilyl)-acetylene.
group) was in situ converted to the ammonium salt, an
electron-withdrawing group, and gave a lower yield (entry
13). In addition, the vinylogous amide (1n, entry 14) men-
tions that aryl ring B is not an essential for this reaction,
though only a medium yield of product 3n was achieved.
Improvement of competitive products distribution
(favoured to N-aryl a-alkynyl imine) was verified by the
reaction of 1b with 1-trimethylsilyl-1-octyne (2e). In this
reaction, the final cationic elimination of TMSOTf was
devised in replace of HOTf (Scheme 2). Under similar con-
ditions for the previous reaction with 1-heptyne (Table 1,
entry 2), both N-aryl a-alkynyl imine (3o, 53%, cationic
pathway) and quinoline derivative (4o, 24%, Diels–Alder
pathway) were afforded. However, N-aryl a-alkynyl imine
3o was improved to be a major product after such a treat-
ment by enhancing the driving force of final cationic elim-
ination of TMSOTf.
Reactions of amide 1a with phenylacetylene (2f) and 1-
phenyl-2-trimethylsilylacetylene (2g) were also examined
under the above conditions (Scheme 3). Similar to the pre-
vious observations, both N-aryl a-alkynyl imine (3p, 35%)
and quinoline derivative (4p, 28%) were produced in the
reaction of amide 1a and acetylene 2f. When a TMS
group-bearing acetylene 2g was used, the reaction afforded
a quinoline derivative (4q, 33%) and a lower yield of imine
(3p, 13%), as well as other unidentified byproducts. The
later results might be due to the spatial crowd in corre-
sponding intermediate (B, Fig. 2). Such a situation dramati-
cally decreased the rate to form a planar intermediate
structure which was required for the next elimination of

Q.-L. Dong et al. / Tetrahedron Letters 49 (2008) 1636–1640
1639
Table 2
Generality examination of amide substrates
nOe
TMS
R1
TMS
TMS
R1
MeO
+
H
MeO
O
nOe
2d
A
(1.2 mmol)
N
N
N
B
H
N
R2
Tf2O (1.5 eq.)
Ph3PO (3 eq.)
DCM
4p (28%)
3p (35%)
1a-1m
(1 mmol)
R2
3a-3m
0 oC, 10 min
then rt for 6 h
typical
conditions
2f
TMS
MeO
O
O
MeO
N
H
MeO
NH
N
1n
1a
3n
TMS
typical
conditions
Entry
Reactants
Products
Yields (%)
1a: R1 = OMe; R2 = H
1b: R1 = OMe; R2 = OMe
1c: R1 = OMe; R2 = Cl
1d: R1 = OMe; R2 = tBu
1e: R1 = OMe; R2 = NO2
1f: R1 = Me; R2 = OMe
1g: R1 = Cl; R2 = OMe
1h: R1 = H; R2 = OMe
1i: R1 = F; R2 = OMe
1j: R1 = NO2; R2 = OMe
1k: R1 = CN; R2 = OMe
1l: R1 = CO2Me; R2 = OMe
1m: R1 = NMe2; R2 = OMe
1n
3a
3b
3c
3d
3e
3f
71
86
44
81
28
80
69
65
59
50
57
65
50
45
2g
1
2a
3
4
5
6
7
8
9
nOe
TMS
MeO
+
3p (13%)
nOe
3g
3h
3i
N
4q (33%)
10
11
12
13
14
a
3j
Scheme 3.
3k
3l
3m
3n
nium-triggered one-pot multiple-step method presents
advantages of mild conditions, ease of operation, satisfac-
tory efficiency. Further, the improvement of this reaction
and the transformation of N-aryl a-alkynyl imines to the
functional quinolines are underway in our laboratory.
Product 3b was confirmed by the X-ray single crystal diffraction
method.
MeO
O
Acknowledgements
TMS
nC6H13
+
N
H
This project is financially supported by National
Natural Science Foundation (20425205, 20621062),
Chinese Academy of Sciences (KGCX2-SW-213, KJCX2-
YW-H08) and the Shanghai Municipal Committee of
Science and Technology (06QH14016, 04DZ14901 and
07DZ22001).
OMe
2e
(1.2 mmol)
1b
(1 mmol)
0 oC, 10 min
then rt for 6 h
Tf2O (1.5 eq.)
Ph3PO (3 eq.)
DCM
nC6H13
nOe
Supplementary data
nC6H13
TMS
MeO
MeO
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2008.01.024.
H
N
N
OMe
OMe
3o (53%)
4o (24%)
References and notes
Scheme 2.
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1640
Q.-L. Dong et al. / Tetrahedron Letters 49 (2008) 1636–1640
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