Catalytic Ynamide Oxidation Strategy for the Preparation of α-Functionalized Amides

Article abstract of DOI:10.1021/acscatal.6b01599

A Lewis acid-catalyzed alkyne oxidation strategy has been developed to produce diverse α-functionalized amides from readily and generally available ynamides. An efficient zinc(II)-catalyzed oxidative azidation and thiocyanation has been achieved, providing facile access to synthetically useful α-azido amides and α-thiocyanate amides, respectively. This chemistry can also be extended to oxidative halogenations by employing the 2-halopyridine N-oxide as both the oxidant and the halogen source, and its mechanistic rationale is also supported by density functional theory calculations. Moreover, NaBARF has been demonstrated to catalyze such an alkyne oxidation effectively, thus further excluding the metal carbene pathway in this cascade reaction.

Full text of DOI:10.1021/acscatal.6b01599

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Article
Catalytic Ynamide Oxidation Strategy for
the Preparation of #-Functionalized Amides
Fei Pan, Xin-Ling Li, Xiu-Mei Chen, Chao Shu, Peng-Peng Ruan, Cang-Hai Shen, Xin Lu, and Long-Wu Ye
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01599 • Publication Date (Web): 02 Aug 2016
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Catalytic Ynamide Oxidation Strategy for the Preparation of α‐
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Functionalized Amides
Fei Pan,†,# Xin‐Ling Li,†,# Xiu‐Mei Chen,‡ Chao Shu,† Peng‐Peng Ruan,† Cang‐Hai Shen,† Xin
Lu,*, ‡ and Long‐Wu Ye*,†,§
†State Key Laboratory of Physical Chemistry of Solid Surfaces & The Key Laboratory for Chemical Biology of Fujian
Province, Department of Chemistry, Xiamen University, Xiamen 361005, China.
‡State Key Laboratory of Physical Chemistry of Solid Surfaces & Center for Theoretical Chemistry, Department of
Chemistry, Xiamen University, Xiamen 361005, China.
§State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China.
ABSTRACT: Lewis acid‐catalyzed alkyne oxidation strategy has been developed to produce diverse α‐functionalized
amides from readily and generally available ynamides. An efficient zinc(II)‐catalyzed oxidative azidation and
thiocyanation has been achieved, providing a facile access to synthetically useful α‐azido amides and α‐thiocyanate
amides, respectively. This chemistry can also be extended to oxidative halogenations by employing the 2‐halo pyridine N‐
oxide as both the oxidant and the halogen source, and its mechanistic rationale is also supported by DFT calculations.
Moreover, NaBARF has been demonstrated to catalyze such an alkyne oxidation effectively, thus further excluding the
metal carbene pathway in this cascade reaction.
KEYWORDS: alkyne, oxidation, azidation, halogenation, homogeneous catalysis, synthetic methods
INTRODUCTION
accessible and potentially explosive α‐diazo carbonyls in
accessing α‐oxo metal carbenes.5 As a result, this strategy
has evolved into a robust and reliable methodology for
the C−C and C−X bond formation, especially in a highly
stereoselective manner.6 Albeit great achievements have
been reached, examples of intermolecular alkyne oxida‐
tions with external nucleophiles are still very scarce7
mainly due to the competing background reaction of ex‐
ternal nucleophiles with the activated alkynes and the
overoxidation of the highly electrophilic carbene center
by the same oxidant,8 thus generating the unwanted ole‐
fin and diketone byproducts, respectively (Scheme 1a). In
other words, if external nucleophiles are stronger nucleo‐
philes than N‐oxides, the external nucleophiles would
attack the alkynes directly to form olefin byproducts,
while diketone byproducts would be obtained in case that
N‐oxides are stronger nucleophiles than external nucleo‐
philes. Therefore, the ideal reaction pathway is that oxide
attacks the alkyne first, followed by reaction with the ex‐
ternal nucleophile rather than the second oxide. However,
to realize this cascade reaction in such an orderly manner
is highly challenging. In addition, it should be specially
mentioned that no success has been achieved for external
nucleophiles bearing strong coordinating groups (N3, NCS,
Br, Cl) in the gold‐catalyzed intermolecular alkyne oxida‐
The synthesis of α‐functionalized carbonyl compounds
always attracts considerable attention, because they are
versatile building blocks and pivotal intermediates for the
construction of a variety of biologically active natural
products and medicinal compounds. In spite of the my‐
riad methods available, most focus on the α‐
functionalization of carbonyl compounds1‐3 such as transi‐
tion metal‐catalyzed reaction of α‐diazo carbonyl com‐
pounds1 and hypervalent iodine participated α‐
functionalization of carbonyls,2 which often suffer from
multistep synthesis, limited substrate scope and inaccess‐
ible starting materials. In particular, compared to the
preparation of α‐functionalized ketones and esters, suc‐
cessful examples of α‐functionalized amide synthesis have
been relatively scarce. Consequently, the development of
novel methods for the construction of these skeletons is
highly desirable, especially those based on assembling
structures directly from readily available and easily diver‐
sified building blocks.
Recently, gold‐catalyzed intermolecular oxidation of
alkynes by an N‐O bond oxidant via a presumable α‐oxo
gold carbene4 pathway has attracted significant research
attention, as this protocol renders readily available and
safer alkynes as the replacement of hazardous, not easily
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tion probably due to the fact that these nucleophiles are
able to deactivate the noble catalyst.
tion, the high value‐added α‐azido carbonyls can serve as
direct precursors of α‐amino carbonyls14 and β‐azido alco‐
hols,15 both of which are important building blocks and
widely exist in pharmaceuticals or naturally occurring
compounds.16 It is surprising, however, that only a few
preparative methods have been reported on their synthe‐
sis. Among those, the most widely used method is the
nucleophilic substitution of the α‐substituted carbonyls
bearing a good leaving group such as a halide or a sulfo‐
nyloxy unit (Scheme 2a).12c Notable is that this methodol‐
ogy generally suffers from drawbacks such as multistep
synthesis, limited substrate scope, and low efficiency. In
addition, α‐diazo carbonyls have also been used to pre‐
pare the corresponding α‐azido carbonyls, but relying on
the stoichiometric use of CeCl3 (Scheme 2b).17 Therefore,
novel catalytic approaches are still highly demanded for
its construction, especially from readily and generally
available precursors. We envisioned that using the above‐
mentioned zinc‐catalyzed oxidative approach,11 the prepa‐
ration of α‐azido amides might be achieved directly from
the Lewis acid‐catalyzed oxidative reaction of ynamides
with TMSN3 (Scheme 2c).
In continuation of our work on ynamide chemistry,9,10
we recently disclosed that zinc could also effectively cata‐
lyze such an intermolecular alkyne oxidation and, impor‐
tantly, the unwanted overoxidation could be completely
suppressed in this oxidative zinc catalysis.11 Of note, me‐
chanistic studies revealed that the reaction presumably
proceeds by a Lewis acid‐catalyzed Friedel‐Crafts‐type
pathway (SN2 pathway), and that metal carbenes are not
involved as reaction intermediates. Inspired by these re‐
sults, we envisioned that the synthesis of α‐functionalized
amides might be accessed directly through such a Lewis
acid‐catalyzed reaction of ynamides with TMSX (Scheme
1b). Herein, we describe the realization of zinc‐catalyzed
oxidative azidation and thiocyanation, which constitutes
a very practical approach to the generation of synthetical‐
ly useful α‐azido amides and α‐thiocyanate amides, re‐
spectively. In addition, the challenging catalytic oxidative
halogenation has also been achieved through such an
alkyne oxidation by employing oxidant as a source of ha‐
logen. Moreover, NaBARF has been shown for the first
time to be highly effective catalyst to promote this cas‐
cade reaction.
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Scheme 2. Initial Design.
a) Most frequent used method for the synthesis of -azido carbonyls
Scheme 1. Catalytic Alkyne Oxidation.
O
O
O
R2
R2
R2
R1
R1
R1
N3
LG
(LG = Cl, Br, I, OTs, OMs)
b) Transformation of -diazo carbonyls into -azido carbonyls
NaN3
O
O
CeX3 (stoichiometric)
N2
N3
R
(X = Cl, OTf)
R
c) Zinc-catalyzed tandem alkyne oxidation/azidation (this work)
TMSN3
[LA]/N-oxide
O
PG
PG
R2
N
R2
N
R1
R1 N3
1
2
Our initial investigation focused on the reaction of
ynamide substrate 1a with TMSN3 by the use of 8‐
o
ethylquinoline N‐oxide 3b as oxidant in DCE at 60 C in
the presence of different Lewis acids (10 mol %). To our
delight, these Lewis acids could catalyze the oxidative
azidation smoothly to afford the desired α‐azido amide 2a
in 59‐72% yields (Table 1, entries 1−7) and Zn(OTf)2 gave
the best result (Table 1, entry 1). Of note, although dike‐
tone byproduct 2aa could be formed in a significant
amount in such an intermolecular cascade reaction, no
olefin byproduct formation via the direct reaction of
TMSN3 with ynamide 1a was observed in all these cases.18
Somewhat surprisingly, NaBARF (10 mol %) alone could
promote this oxidative azidation to give the correspond‐
ing 2a in 64% yield (Table 1, entry 8). Instead, Brønsted
acids such as MsOH and TfOH were not effective in pro‐
moting this reaction,19 and only hydration byproduct 2ab
was obtained (Table 1, entries 9‐10). In addition, the
RESULTS AND DISCUSSION
1. Zn(OTf)2‐Catalyzed Tandem Alkyne Oxida‐
tion/Azidation. Organoazides are highly valuable and
interesting compounds, and have been widely employed
in organic and pharmaceutical synthesis, including as
amine precursors, potential sources of nitrenes, valuable
dipoles in 1,3‐dipolar cycloaddition and starting materials
of iminophosphoranes utilized in aza‐Wittig reactions to
construct various heterocycles.12 Particularly, compared
with the simple alkyl or aryl azides, α‐azido carbonyls are
ubiquitous structural motifs in organic molecules.12c Fea‐
turing of high potential chemical reactivity, these com‐
pounds demonstrate particular synthetic utility.13 In addi‐
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screening of other N‐oxides failed to improve the yield
entries 1−9). Notably, the reaction was tolerant of various
(Table 1, entries 11‐14). Delightedly, it was found that the
use of 1.2 equiv of oxidant 3b minimized the formation of
diketone 2aa and 78% yield of 2a could be achieved (Ta‐
ble 1, entry 15). Finally, it should be mentioned that only
diketone 2aa was formed (>90% yield) if catalyzed by
typical gold catalysts such as IPrAuNTf2, Ph3PAuNTf2, Cy‐
JohnPhosAuNTf2 and XPhosAuNTf2, and no 2a formation
was observed in the absence of the catalyst (>95% of 1a
remained unreacted).
functional groups, including a C‐C double bond (Table 2,
entry 4), cyclopropyl (Table 2, entry 5) and protected OH
groups (Table 2, entries 7−8). In case of various aryl‐
substituted (R2 = aryl) ynamides, the reaction also led to
the effective formation of the desired products 2j−2p in
66−87% yields (Table 2, entries 9−16). Then, 3‐en‐1‐
ynamide 1q was investigated and the reaction proceeded
well to deliver α, β‐unsaturated imide 2q as a single iso‐
mer in 64% yield (Table 2, entry 17). In addition, yna‐
mides with different protecting groups could give the
desired 2r−2t in moderate to good yields (Table 2, entries
18−20). Our attempts to extend the reaction to aliphatic‐
substituted ynamides only resulted in the formation of
α,β‐unsaturated amides.20 Finally, it should be noted that
in some cases slightly improved yields could be achieved
by using 2,6‐dibromopyridine N‐oxide 3d as the oxidant
(Table 2, entry 9 and entry 20). To test the practicality of
the newly developed methodology, a gram‐scale reaction
of 1a and TMSN3 was carried out, and the desired 2a was
obtained in 70% yield (Table 2, entry 1). Thus, this Zn‐
catalyzed tandem alkyne oxidation/azidation provides a
direct and practical route for the construction of the syn‐
thetically useful α‐azido amides.
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Table 1. Optimization of Reaction Conditionsa
entry
1
catalyst
oxidant (R)
NMR yield (%)b
2a 2aa 2ab
Zn(OTf)2
Yb(OTf)3
3b (Et)
3b (Et)
3b (Et)
3b (Et)
3b (Et)
3b (Et)
3b (Et)
3b (Et)
3b (Et)
3b (Et)
72 15 <1
2
3
4
5
6
66 25 <1
62 27 <1
63 28 <1
61 33 <1
59 34 <1
71 10 <1
64 35 <1
<1 <1 45
<1 <1 48
68 16 <1
Fe(OTf)2
In(OTf)3
Sm(OTf)2
Y(OTf)3
Table 2. Reaction Scope for the Formation of α‐Azido
Amides 2a
7c
8
Zn(OTf)2/NaBARF
NaBARF
MsOH
9d
10d
11
12
13
14
15e
TfOH
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
3a (Me)
i
66 18
6
3c
( Pr)
3d (2,6-Br2)
3e
35 <1 10
10 <1 45
78 <2 <2
(2,6-Cl2)
3b (Et)
aThe reaction was carried out with 1a (0.1 mmol), TMSN3 (0.3
mmol), 3 (0.2 mmol), catalyst (10 mol %) in DCE (2 mL) at 60
b
1
oC. Measured by H NMR using diethyl phthalate as the in‐
ternal standard. c20 mol % NaBARF was used. d45% of 1a
remained unreacted. 1.2 equiv. of 3b was used. NaBARF =
e
sodium tetrakis[3,5‐bis(trifluoromethyl)phenyl] borate.
With the optimized reaction conditions in hand, the
scope of this Zn‐catalyzed oxidative azidation was then
examined. A variety of different R1‐substituted (R1 = alkyl
or aryl) ynamides that were evaluated in this study
reacted well with TMSN3, affording the corresponding α‐
azido amides 2a−2i in moderate to good yields (Table 2,
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aReactions were run in vials; isolated yields are reported. b5.0
mmol scale. c2,6‐dibromopyridine N‐oxide 3d was used as
the oxidant.
8
9
The synthetic utility of this protocol was demonstrated
by the transformation of the above α‐azido amide 2a, as
outlined in Scheme 3. For instance, the amide 2a could be
readily transformed into the corresponding α‐amino
amide 2ac in 78% yield under the catalysis of Pd/C. In
addition, the amide 2a could also undergo facile click
reaction and subsequent reduction of amide group, pro‐
ducing the final triazole‐substituted alcohol 2ad (72%
two‐step overall yield).
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Scheme 3. Transformation of the α‐Azido Amide.
Figure 1. Crystal structure of compound 4n.
Table 3. Reaction Scope for the Formation of α–
Thiocyanate Amides 4a
2. Zn(OTf)2‐Catalyzed Tandem Alkyne Oxida‐
tion/Thiocyanation. Although attempts to expand this
chemistry to tandem oxidation/cyanation have remained
unsuccessful so far, the relevant tandem oxida‐
tion/thiocyanation could be achieved by employing tri‐
methylsilylisothiocyanate (TMSNCS) as the thiocyanation
reagent.21 Notably, the reaction of cyanate salts, such as
NaSCN, KSCN, and NH4SCN, also afforded the desired
product, but with low yields (<20%). Under the optimized
reaction conditions (for details, see the Supporting In‐
formation), ynamides 1 underwent oxidative thiocyana‐
tion smoothly to deliver the desired α‐thiocyanate amides
4a‐4p in generally good to excellent yields, whereas nei‐
ther diketone nor olefin byproduct formation could be
observed in all cases (Table 3). The molecular structure of
4n was further confirmed by an X‐ray crystallographic
study (Figure 1). Thus, this protocol provides a highly effi‐
cient and practical way for the preparation of α‐
thiocyanate carbonyls, which have gained considerable
importance in various areas of organosulfur chemistry,22
especially as a precursor for sulfur‐containing heterocyclic
compounds, such as thiazolidine, cyclic thioureas, and
thiazoles.23 And importantly, they are conventionally pre‐
pared from α‐halocarbonyl compounds or α‐
tosyloxycarbonyls, which typically suffers from narrow
substrate scope, rather harsh reaction conditions, and low
yields.24
O
O
O
O
Ts
Ph
SCN
(4) 4d, 90%
Ts
Ph
SCN
Ts
Ph
SCN
Ts
Ph
N
N
N
N
nBu SCN
(1) 4a, 80%
(2) 4b, 62%
(3) 4c, 79%
Cl
F
O
O
O
O
Ts
Ph
Ts
Ph
Ts
Ts
N
N
N
N
PMB SCN
Ph SCN
Ph
SCN
Ph SCN
(5) 4e, 63%
(6) 4f, 83%
(7) 4g, 71%
(8) 4h, 75%
Cl
Br
OMe
Ts
O
O
O
O
Ts
Ts
Ts
N
N
N
N
Ph SCN
Ph SCN
Ph SCN
Ph SCN
(9) 4i, 65%
(10) 4j, 76%
(11) 4k, 78%
(12) 4l, 72%
O
O
O
O
Ms
Ph
N
MBS
Ph
SCN
PhO2S
Ph
SCN
Ns
N
Ph
N
N
Ph
Ph
Ph
SCN
SCN
(13) 4m, 81%
(14) 4n, 85%
(15) 4o, 86%
(16) 4p, 74%
aReactions run in vials; isolated yields are reported.
3. NaBARF or Zn(OTf)2‐Catalyzed Tandem Alkyne
Oxidation/Halogenation. Halo carbonyls are highly
useful and valuable compounds that can be found in vari‐
ous natural products and bioactive molecules.25 In addi‐
tion, they can also serve as versatile intermediates for a
wide range of synthetic transformations.26 As a result, a
number of halogenation reactions have been developed
for the preparation of these compounds. The classical
methods involve the halogenation of the carbonyls with
halogenation agents such as X2, HX and NXS. However,
such methods have several crucial limitations, including
low selectivity of the products, use of hazardous and toxic
chemicals, low yields, and tedious workup procedures. In
our previous work, ZnX2 has been demonstrated to pro‐
mote the oxidative halogenation, but the use of stoichi‐
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ometric amounts of metal was required.11 Therefore, sub‐
stantial challenges remain in this area especially for the
transformations involved with transition metal catalysis
as the halogen is capable of coordinating and deactivating
the metal catalyst.
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Inspired by the above oxidative zinc catalysis, we envi‐
sioned that the tandem alkyne oxidation/halogenation
might be achieved by using TMSX (X = Br, Cl) as the ha‐
logen source, thus allowing the facile synthesis of valuable
α‐halo amide compounds. To our disappointment, the
treatment of ynamide 1a with 3 equiv of TMSBr in the
presence of 10 mol % Zn(OTf)2 and 2 equiv of 8‐
ethylquinoline N‐oxide 3b only led to the formation of
vinyl bromide 5a (eq 1).27
NMR yield (%)b
entry
metal catalyst
T
5a 2aa 2ab
60 oC
60 oC
60 oC
60 oC
60 oC
1
2
3
4
5
6
7
Zn(OTf)2
Yb(OTf)3
63 <3 <3
52 <5 <5
66 <3 <3
58 <5 <5
48 <5 <5
75 <3 <3
76 <3 <3
44 <5 11
In(OTf)3
Sm(OTf)3
Y(OTf)3
60 o
60 o
60 o
60 o
C
C
C
C
Zn(OTf)2/NaBARF
NaBARF
8
9
BF3 Et2O
(C6F5)3B
We then turned to investigate other halogen sources to
achieve such an oxidative halogenation. In the screening
of the oxidant for the oxidative azidation, we noticed the
formation of significant amounts of α–bromo amide 5a
when 2‐bromopyridine N‐oxide 3f was employed as the
oxidant. Of note, the bromo was not transferred if 2,6‐
dibromo pyridine N‐oxide 3d was used as an oxidant. As
shown in Table 4, the reaction of ynamide 1a with 2 equiv
of TMSN3 and of 2 equiv of oxidant 3f at 60 oC by employ‐
ing Zn(OTf)2 as catalyst could afford the α–bromo amide
5a in 63% yield (Table 4, entry 1). This result demonstrat‐
ed that oxidant 3f plays dual roles both as the oxidant and
a source of halogen, and greatly motivated us to further
optimize the reaction by examining a variety of different
catalysts (Table 4, entries 2‐10). Eventually, we discovered
that the desired 5a could be furnished in 76% yield in the
presence of 10 mol % NaBARF (Table 4, entry 7). In addi‐
tion, it was found that other Lewis acids, especially the
commercially available electron‐deficient (C6F5)3B,28‐29
could also catalyze such an oxidative bromination effec‐
tively (Table 4, entries 8‐9), further supporting our pre‐
viously proposed Lewis acid‐catalyzed SN2 pathway but
not the metal carbene pathway involved in such a catalyt‐
ic alkyne oxidation.30 Notably, other sodium salts such as
NaBPh4 and NaBF4 could not catalyze this oxidative bro‐
mination (>95% of 1a remained unreacted), indicating
that the potential role of sodium cation as a Lewis acid is
less likely. Once again, diketone 2aa was obtained as the
main product when the gold catalyst was used (Table 4,
entry 10). Finally, a temperature screening revealed that
65 <5
<5 73
6
7
10c
11
12
Ph3PAuNTf2
NaBARF
60 oC
80 oC
71 <5 <3
82 <1 <1
40 o
C
NaBARF
aThe reaction was carried out with 1a (0.1 mmol), TMSN3 (0.2
mmol), 3f (0.2 mmol), catalyst (10 mol %) in DCE (2 mL) at
o
b
1
40‐80 C. Measured by H NMR using diethyl phthalate as
the internal standard. c5 mol % gold catalyst was used.
Table 5. Reaction Scope for the Formation of α‐
Bromo Amides 5a
O
O
O
O
Ts
Ph
Ts
Ph
Ts
Ph
Ts
Ph
N
N
N
N
Br
Br
nBu Br
Bn Br
(1) 5a, 81%
(2) 5b, 82%
(3) 5c, 70%
(4) 5d, 76%
O
Cl
O
O
O
Ts
Ph
Ts
N
Ph
Ts
Ph
N
N
Ts
Ph
N
Br
BocO
Br
Ph Br
Br
(5) 5e, 92%
(6) 5f, 75%
(7) 5g, 78%
(8) 5h, 90%
Br
O
O
O
O
Ms
N
Bs
N
Ph
Ts
Ts
N
N
Br
Br
Br
Br
o
this transformation worked best at 40 C, and the desired
(9) 5i, 85%
(10) 5j, 83%
(11) 5k, 81%
(12) 5l, 78%
5a could be obtained in 82% yield (Table 4, entry 12).
Table 4. Optimization of Reaction Conditionsa
O
O
O
O
MBS
PhO2S
Ph
N
Ns
Ph
Ph
Ts
n-hexyl
N
N
N
Br
(13) 5m, 70%
Br
Br
Br
(16) 5p, 55%
(14) 5n, 84%
(15) 5o, 56%
aReactions run in vials; isolated yields are reported.
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We next studied the scope and generality of this oxida‐
found that besides the α–bromo amide product 5a, 0.27
tive bromination reaction under the above optimized
reaction conditions, as outlined in Table 5. The reaction
worked well for various ynamides 1, leading to the effi‐
cient formation of the corresponding α–bromo amides 5a‐
5p in generally good to excellent yields. Of note, the
transformation could also be applied to an alkyl‐
substituted ynamide to give the desired 5p, albeit less
efficiently, and no α, β‐unsaturated imide product was
formed (Table 5, entry 16). Significantly, neither overoxi‐
dation product nor background α‐azido amide was de‐
tected in such a tandem alkyne oxidation/bromination.
6
7
8
9
mmol of 2‐bromopyridine 3f, 0.19 mmol of 2‐
azidoopyridine 3h, 0.28 mmol of 2‐bromopyridine N‐
oxide 3f, and 0.23 mmol of 2‐azidopyridine N‐oxide 3h
were isolated, respectively. In addition, no reaction oc‐
curred when 3f or 3f was treated with TMSN3 (eqs 3‐4).
Moreover, the reaction of 3f with 3h under the relevant
reaction conditions also failed to give the corresponding
3f and 3h (eq 5). Several conclusions can be drawn from
these studies: (a) The bromide is indeed from the original
oxide as the pyridine azide and its oxide total to 0.42
mmol, which exceeds 0.4 mmol of the product. (b) The
bromide is presumably exchanged after the oxygen of 3f is
alkylated. (c) The oxygen in 5a can be delivered by both
pyridine N‐oxides 3f and 3h, and 3h is probably generated
from the vinyl borate intermediate.
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Facile transformation of the as‐synthesized α–bromo
amide was also explored (Scheme 4). Treatment of amide
5a with BnNH2 afforded the corresponding α–amino
amide, which could be readily transformed into syntheti‐
cally useful α–amino ester 5aa (75% two‐step overall
yield). 5a was additionally functionalized to form α–
benzoyloxy carboxylic acid 5ab31 by reaction with benzoic
acid and subsequent hydrolysis (65% two‐step overall
yield). These transformations thus further strengthen the
synthetic impact of this protocol for the preparation of α‐
functionalized carbonyls.
To rationalize the formation of 5a via NaBARF‐
catalyzed oxidative bromination, a plausible mechanism
(Scheme 5) is proposed in accordance to experimental
observation and preliminary density functional theory
(DFT) computations.32 Presumably NaBARF dissociates to
release triarylborane33‐34 that serves as a Lewis acid to ac‐
tivate the ynamide 1a to form A and to facilitate the sub‐
sequent nucleophilic attack of N‐oxide 3f with a moderate
free‐energy barrier of 11.0 kcal/mol. The as‐formed inter‐
mediate B, when treated with TMSN3, exothermically
generates intermediate C and TMSBr. The in situ pro‐
duced TMSBr then serves as nucleophilic bromination
agent to react with the carbocationic intermediate D and
to afford sequentially intermediates E and F and the final
product 5a. The overall transformation is highly exother‐
mic with free energy release of 89.5 kcal/mol. It is worth
noting that the formation of 2‐azidopyridine N‐oxide 3h
is the reverse process of A to C, which has slightly higher
energy barrier of 5.9 kcal/mol than the forward reaction.32
To cleave nitrogen‐oxygen bond of the intermediate B to
form 3f demands relatively low activation free energy of 7.4
kcal/mol.32 This data shows that the process of changing
intermediate B to intermediate D is favored.
Scheme 4. Transformation of the α‐Bromo Amide.
1) PhCO2H (1.5 equiv)
K2CO3 (1.5 equiv)
DMF, rt, 10 h
1) BnNH2 (1.1 equiv)
TBAI (0.2 equiv)
NEt3, THF, rt, 5 h
O
O
Ph
Ph
HO
5a
MeO
2) MeONa (2.0 equiv)
MeOH, 60 oC, 4 h
75% yield (2 steps)
2) LiOH (1.0 equiv)
THF/H2O, rt, 10 h
65% yield (2 steps)
O2CPh
NHBn
5ab
5aa
Scheme 5. M06(SMD, DCE)/6‐31G(d) Free Energies for
the Conversion of 1a to the Final Product 5a.
To probe the reaction mechanism, several control expe‐
riments were conducted. First, the reaction was per‐
formed in a 0.5 mmol scale. As shown in eq 2, it was
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O
N
GDCE (298 K, in kcal/mol)
Ar = Ph
N3
3h
TSC-A
18.7
Ts
Ts
O
N
BAr3
Ph
N
BAr3
Ph
N
Br
O
N
O
N
11
12
13
14
TMSN3
TMSBr
BAr3
Ph
Br
Ts
N3
3f
N
TSB
11.0
Ts
A
B
4.7
0.0
C
-5.9
Ts
N
Ph
15
16
17
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19
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TSB-D
N
O
Ph
Br
N
N3
1a
12.1
TSD
2.6
Br
N
TMS
F
-68.8
3h'
H2O
3f'
aReactions run in vials; isolated yields are reported.
O
N
S
Ts
TMSOH
O
Ph
Br
N
O
BAr3
O
Ar3B
TMS
CONCLUSIONS
O
Ts
N
Ph
Br
TMSBr
5a
-89.5
E
D
-67.0
In summary, an efficient and practical Lewis acid‐
catalyzed cascade reaction towards versatile α‐
functionalized amides from easily accessible ynamides
has been developed, constituting a powerful process for
C‐X bond formation. This method provides an efficient
protocol for the preparation of synthetically useful α‐
azido amides and α‐thiocyanate amides via oxidative azi‐
dation and thiocyanation, respectively. Of particular in‐
terest, the challenging catalytic oxidative halogenation
has also been achieved by the use of the 2‐halo pyridine
N‐oxide serving as both the oxidant and the halogen
source, and its mechanistic rationale is also well sup‐
ported by DFT calculations. In addition, NaBARF was
demonstrated for the first time to be highly effective cata‐
lyst to promote such an alkyne oxidation. Of note, Na‐
BARF has previously been used in organic and organome‐
tallic chemistry as a loosely coordinating counter ion, but,
to our best knowledge, there are no studies investigating
NaBARF directly as a catalyst. Importantly, this Lewis
acid‐catalyzed alkyne oxidation strategy has proven to be
a general solution to the problem of over‐oxidation,
which frequently occurs in intermolecular alkyne oxida‐
tion with external nucleophiles. Moreover, this study
strongly support that this non‐noble promoted oxidative
catalysis presumably proceeds by a Lewis acid‐catalyzed
SN2 pathway, which is distinctively different from the
related oxidative gold catalysis where the gold carbene
intermediate is presumably proposed. Further research on
this Lewis acid‐promoted oxidative catalysis is ongoing in
our laboratories.
-77.0
We then wondered whether the above strategy is appli‐
cable to the relevant oxidative chlorination. To our de‐
light, the use of 2‐chloropyridine N‐oxide 3g instead of 2‐
bromopyridine N‐oxide 3f afforded the desired α–chloro
amide whereas the use of TMSCl as halogen source only
delivered the vinyl chloride 6a (eq 6).As depicted in Ta‐
ble 6, the treatment of ynamides 1 with 2 equiv of TMSN3
o
and of 2 equiv of oxidant 3g at 60 C in the presence of 10
mol % Zn(OTf)2 (for details about the reaction conditions
optimization, see the Supporting Information) could lead
to the formation of the desired α–chloro amides 6a−6l in
moderate to good yields. It is worthwhile to point out that
neither diketone nor α‐azido amide was detected in such
a cascade reaction, highlighting the power of this metho‐
dology. Thus, this new strategy provides a very efficient
and practical alternative route to synthetically useful α–
chloro amides.
Table 6. Reaction Scope for the Formation of α‐
Chloro Amides 6a
ASSOCIATED CONTENT
Supporting Information. The experimental procedure,
1
characterization data, and copies of H and 13C NMR spectra.
The Supporting Information is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*longwuye@xmu.edu.cn
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Int. Ed. 2014, 53, 3715−3719. (i) Wang, T.; Huang, L.; Shi, S.; Ru‐
*xinlu@xmu.edu.cn
dolph, M.; Hashmi, A. S. K. Chem. Eur. J. 2014, 20, 14868−14871. (j)
Wang, T.; Shi, S.; Rudolph, M.; Hashmi, A. S. K. Adv. Synth. Catal.
2014, 356, 2337−2342. (k) Shu, C.; Li, L.; Xiao, X.‐Y.; Yu, Y.‐F.;
Ping, Y.‐F.; Zhou, J.‐M.; Ye, L.‐W. Chem. Commun. 2014, 50,
8689−8692. (l) Shu, C.; Li, L.; Yu, Y.‐F.; Jiang, S; Ye, L.‐W. Chem.
Commun. 2014, 50, 2522−2525. (m) Wu, G.; Zheng, R.; Nelson, J.;
Zhang, L. Adv. Synth. Catal. 2014, 356, 1229−1234. (n) Ji, K.; Zhang,
L. Org. Chem. Front. 2014, 1, 34−38.
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Zhang, L. J. Am. Chem. Soc. 2012, 134, 17412−17415. For other ex‐
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Org. Lett. 2015, 17, 3502−3505. (e) Santos, M. D.; Davies, P. W.
Chem. Commun. 2014, 50, 6001−6004. (f) He, W.; Li, C.; Zhang, L.
J. Am. Chem. Soc. 2011, 133, 8482−8485.
(8) (a) Nösel, P.; dos Santos Comprido, L. N.; Lauterbach, T.;
Rudolph, M.; Rominger, F.; Hashmi, A. S. K. J. Am. Chem. Soc.
2013, 135, 15662−15666. (b) Wang, K.‐B.; Ran, R.‐Q.; Xiu, S.‐D.; Li,
C.‐Y. Org. Lett. 2013, 15, 2374−2377. (c) Yang, L.‐Q.; Wang, K.‐B.;
Li, C.‐Y. Eur. J. Org. Chem. 2013, 2775−2779. (d) Dateer, R. B.;
Pati, K.; Liu, R.‐S. Chem. Commun. 2012, 48, 7200−7202. (e)
Mukherjee, A.; Dateer, R. B.; Chaudhuri, R.; Bhunia, S.; Karad, S.
N.; Liu, R.‐S. J. Am. Chem. Soc. 2011, 133, 15372−15375. (f) Vasu, D.;
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G.; Theunissen, C.; Lecomte, M. Aldrichim. Acta 2015, 48, 59−70.
(b) Wang, X.‐N.; Yeom, H.‐S.; Fang, L.‐C.; He, S.; Ma, Z.‐X.; Ke‐
drowski, B. L.; Hsung, R. P. Acc. Chem. Res. 2014, 47, 560−578. (c)
DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang,
Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064−5106. (d) Evano, G.;
Coste, A.; Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840−2859.
(10) For our recent study on the gold‐catalyzed tandem reac‐
tions based on ynamides, see: (a) Shu, C.; Wang, Y.‐H.; Zhou, B.;
Li, X.‐L.; Ping, Y.‐F.; Lu, X.; Ye, L.‐W. J. Am. Chem. Soc. 2015, 137,
9567−9570. (b) Zhou, A.‐H.; He, Q.; Shu, C.; Yu, Y.‐F.; Liu, S.;
Zhao, T.; Zhang, W.; Lu, X.; Ye, L.‐W. Chem. Sci. 2015, 6,
1265−1271. (c) Li, L.; Shu, C.; Zhou, B.; Yu, Y.‐F.; Xiao, X.‐Y.; Ye,
L.‐W. Chem. Sci. 2014, 5, 4057−4064. (d) Pan, F.; Liu, S.; Shu, C.;
Lin, R.‐K.; Yu, Y.‐F.; Zhou, J.‐M.; Ye, L.‐W. Chem. Commun. 2014,
50, 10726−10729. (e) Shen, C.‐H.; Li, L.; Zhang, W.; Liu, S.; Shu, C.;
Xie, Y.‐E.; Yu, Y.‐F.; Ye, L.‐W. J. Org. Chem. 2014, 79, 9313−9318.
(11) Li, L.; Zhou, B.; Wang, Y.‐H.; Shu, C.; Pan, Y.‐F.; Lu, X.; Ye,
L.‐W. Angew. Chem., Int. Ed. 2015, 54, 8245−8249.
6
7
8
9
Author Contributions
F.P. and X.-L.L. contributed equally.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful for financial support from the National Natu‐
ral Science Foundation of China (21272191, 21273177, and
21572186), the Natural Science Foundation of Fujian Province
for Distinguished Young Scholars (No. 2015J06003), the Pres‐
ident Research Funds from Xiamen University (No.
20720150045), NFFTBS (No. J1310024) and the Program for
Changjiang Scholars and Innovative Research Team in Uni‐
versity (PCSIRT). We also thank Professor Dr. Yuanzhi Tan
for assistance with X‐ray crystallographic analysis.
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Am. Chem. Soc. 2015, 137, 15469−15477. (g) Wilkins, L. C.; Wie‐
neke, P.; Newman, P. D.; Kariuki, B. M.; Rominger, F.; Hashmi, A.
S. K.; Hansmann, M. M.; Melen, R. L. Organometallics 2015, 34,
5298‐5309. (h) Melen, R. L.; Wilkins, L. C.; Kariuki, B. M.; Wa‐
depohl, H.; Gade, L. H.; Hashmi, A. S. K.; Stephan, D. W.; Hans‐
mann, M. M. Organometallics 2015, 34, 4127‐4137. (i) Hansmann,
M. M.; Melen, R. L.; Rominger, F.; Hashmi, A. S. K.; Stephan, D.
W. J. Am. Chem. Soc. 2014, 136, 777−782. (j) Hansmann, M. M.;
Melen, R. L.; Rominger, F.; Hashmi, A. S. K.; Stephan, D. W.
Chem. Commun. 2014, 50, 7243−7245. (k) Hansmann, M. M.;
Rominger, F.; Boone, M. P.; Stephan, D. W.; Hashmi, A. S. K.
Organometallics 2014, 33, 4461–4470. (l) Chen, C.; Harhausen, M.;
Liedtke, R.; Bussmann, K.; Fukazawa, A.; Yamaguchi, S.; Petersen,
(14) For recent selected examples, see: (a) Deng, Q.‐H.; Bleith,
T.; Wadepohl, H.; Gade, L. H. J. Am. Chem. Soc. 2013, 135,
5356−5359. (b) Shibatomi, K.; Soga, Y.; Narayama, A.; Fujisawa, I.;
Iwasa, S. J. Am. Chem. Soc. 2012, 134, 9836−9839. (c) Guerrini, G.;
Ponticelli, F. Eur. J. Org. Chem. 2010, 3919−3926.
(15) For recent selected examples, see: (a) Craig, W.; Chen, J.;
Richardson, D.; Thorpe, R.; Yuan, Y. Org. Lett. 2015, 17,
4620−4623. (b) Bisogno, F. R.; Lavandera, I.; Kroutil, W.; Gotor,
V. J. Org. Chem. 2009, 74, 1730−1732. (c) Ankati, H.; Yang, Y.; Zhu,
D.; Biehl, E. R.; Hua, L. J. Org. Chem. 2008, 73, 6433−6436. (d)
Brenelli, E. C. S.; Brenelli, J. A.; Pinto, R. C. L. Tetrahedron Lett.
2005, 46, 4531−4533. (e) Watanabe, M.; Murata, K.; Ikariya, T. J.
Org. Chem. 2002, 67, 1712−1715.
(16) For recent selected examples, see: (a) Sun, X.; Li, X.; Song,
S.; Zhu, Y.; Liang, Y.‐F.; Jiao, N. J. Am. Chem. Soc. 2015, 137,
6059−6066. (b) Prasad, P. K.; Reddi, R. N.; Sudalai, A. Chem.
Commun. 2015, 51, 10276−10279. (c) Al‐Lakkis‐Wehbe, M.; Chail‐
lou, B.; Defoin, A.; Albrecht, S.; Tarnus, C. Bioorg. Med. Chem.
2013, 21, 6447−6455. (d) Sulake, R. S.; Chen, C.; Lin, H.‐R.; Lua,
A.‐C. Bioorg. Med. Chem. Lett. 2011, 21, 5719−5721. (e) Tidgewell,
K.; Groer, C. E.; Harding, W. W.; Lozama, A.; Schmidt, M.;
Marquam, A.; Hiemstra, J.; Partilla, J. S.; Dersch, C. M.; Rothman,
R. B.; Bohn, L. M.; Prisinzano, T. E. J. Med. Chem. 2008, 51,
2421−2431.
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(17) Yadav, J. S.; Reddy, B. V. S.; Srinivas, M. Chem. Lett. 2004,
33, 882−883.
(18) For Au‐ or Ag‐catalyzed reactions of alkynes with TMSN3,
see: (a) Qin, C.; Su, Y.; Shen, T.; Shi, X.; Jiao, N. Angew. Chem.,
Int. Ed. 2016, 55, 350−354. (b) Liu, Z.; Liu, J.; Zhang, L.; Liao, P.;
Song, J.; Bi, X. Angew. Chem., Int. Ed. 2014, 53, 5305−5309. (c) Liu,
Z.; Liao, P.; Bi, X. Org. Lett. 2014, 16, 3668−3671. (d) Qin, C.; Feng,
P.; Ou, Y.; Shen, T.; Wang, T.; Jiao, N. Angew. Chem., Int. Ed.
2013, 52, 7850−7854. (e) Shen, T.; Wang, T.; Qin, C.; Jiao, N.
Angew. Chem., Int. Ed. 2013, 52, 6677−6680. (f) Gaydou, M.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2013, 52, 13468−13471.
For a Pd‐catalyzed reaction of ynamide with TMSN3, see: (g)
Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. Tetrahedron Lett. 2002,
43, 9707−9710.
(19) For acid‐promoted oxidative cyclizations, see: (a) Graf, K.;
Rühl, C. L.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Angew.
Chem., Int. Ed. 2013, 52, 12727−12731. (b) Chen, D.‐F.; Han, Z.‐Y.;
He, Y.‐P.; Yu, J.; Gong, L.‐Z. Angew. Chem., Int. Ed. 2012, 51,
12307−12310.
(20) Pan, F.; Shu, C.; Ping, Y.‐F.; Pan, Y.‐F.; Ruan, P.‐P.; Fei,
Q.‐R.; Ye, L.‐W. J. Org. Chem. 2015, 80, 10009−10015.
(21) For recent selected examples on the use of TMSNCS as the
thiocyanation reagent, see: (a) Liang, Z.; Wang, F.; Chen, P.; Liu,
G. Org. Lett. 2015, 17, 2438−2441. (b) Sun, N.; Che, L.; Mo, W.; Hu,
B.; Shen, Z.; Hu, X. Org. Biomol. Chem. 2015, 13, 691−696.
(22) For biologically active natural products containing thi‐
ocyanato motif, see: (a) Meshram, H. M.; Thakur, P. B.; Babu, B.
M.; Bangade, V. M. Tetrahedron Lett. 2012, 53, 1780−1785. (b)
Yasman, Y.; Edrada, R. A.; Wray, V.; Proksch, P. J. Nat. Prod.
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Dumdei, E. J. In Studies in Natural Products Chemistry; Atta‐ur‐
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Gerhaeusers, C.; Pezzuto, J. M.; Moon, R. C.; Moriarty, R. M.
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Chem., Int. Ed. 2013, 52, 5992−5996. (m) Melen, R. L.; Hansmann,
M. M.; Lough, A. J.; Hashmi, A. S. K.; Stephan, D. W. Chem. Eur.
J. 2013, 19, 11928−11938.
(29)
Our
attempts
to
prepare
tris(3,5‐
bis(trifluoromethyl)phenyl)borane in pure form always met with
difficulty.
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(30) For relevant gold‐catalyzed alkyne oxidations proposed
by an SN2 pathway, see: (a) Chen, M.; Chen, Y.; Sun, N.; Zhao, J.;
Liu, Y.; Li, Y. Angew. Chem., Int. Ed. 2015, 54, 1200−1204. (b) Qian,
D.; Hu, H.; Liu, F.; Tang, B.; Ye, W.; Wang, Y.; Zhang, J. Angew.
Chem., Int. Ed. 2014, 53, 13751−13755. (c) Henrion, G.; Chavas, T. E.
J.; Le Goff, X.; Gagosz, F. Angew. Chem., Int. Ed. 2013, 52,
6277−6282.
(31) Kumar, P. S.; Banerjee, A.; Baskaran, S. Angew. Chem., Int.
Ed. 2010, 49, 804−807.
(32) For details, please see the Supporting Information (SI).
(33) For relevant examples on the formation of triarylborane
from tetraarylborate anion, see: (a) Chisholm, M. H.; Gallucci, J.
C.; Yin, H. Dalton Trans. 2007, 4811−4821. (b) Kiviniemi, S.;
Nissinen, M.; Alaviuhkola, T.; Rissanen, K.; Pursiainen, J. J. Chem.
Soc., Perkin Trans. 2 2001, 2364−2369. (c) Meisters, M.; Vande‐
berg, J. T.; Cassaretto, F. P.; Posvic, H.; Moore, C. E. Anal. Chim.
Acta 1970, 49, 481−485.
1
(34) While NMR spectroscopic studies (including H and 11B
NMR spectroscopy) did not show significant shifting by mixing
the N‐oxide with NaBARF under various reaction conditions, we
suspect that N‐oxide should have some weak coordination with
NaBARF. As a result, the coordination may facilitate the dissoci‐
ation of trace triarylborane from NaBARF, which serve as a Lewis
acid to activate the CC triple bond. Studies to elucidate it will be
pursued further.
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unified approach to diverse -functionalized amides
O
O
R2
PG
R2
PG
N
N
readily available starting materials
mild reaction conditions
R1
Br
R1 N3
TMSN3
NaBARF (cat.)
Br
20 examples
63-87% yield
16 examples
55-92% yield
N
TMS
3
R2
Zn(OTf)2 (cat.)
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X
N-oxide (
=
)
N-oxide
N
O
X
TMSN3
Zn(OTf)2 (cat.)
Cl
NCS
Zn(OTf)2 (cat.)
TMS
N
R1
PG
X
N-oxide (
=
)
N-oxide
O
O
no overoxidation reaction
oxidant as a source of halogen
inexpensive catalyst and no required ligands
PG
R2
PG
R2
N
N
R1 SCN
R1 Cl
12 examples
56-75% yield
16 examples
62-90% yield
ABSTRACT: Lewis acid-catalyzed alkyne oxidation strategy has been developed to
produce diverse α-functionalized amides from readily and generally available
ynamides. An efficient zinc(II)-catalyzed oxidative azidation and thiocyanation has
been achieved, providing a facile access to synthetically useful α-azido amides and
α-thiocyanate amides, respectively. This chemistry can also be extended to oxidative
halogenations by employing the 2-halo pyridine N-oxide as both the oxidant and the
halogen source, and its mechanistic rationale is also supported by DFT calculations.
Moreover, NaBARF has been demonstrated for the first time to catalyze such an
alkyne oxidation effectively, thus further excluding the metal carbene pathway in this
cascade reaction.
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