Direct transformation of arylpropynes to acrylamides via a three-step tandem reaction

Article abstract of DOI:10.1039/c3ob42444h

A novel and metal-free acrylamides formation between arylpropynes and hydroxylamine hydrochloride through sp³ C-H and C-C bond cleavage has been achieved with DDQ as an oxidant. The mechanistic study shows that the acrylamides are formed through a three-step tandem sequence, including cross-dehydrogenative-coupling (CDC) reaction, aza-Meyer-Schuster rearrangement and Beckmann rearrangement. This journal is The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3ob42444h

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Direct transformation of arylpropynes to
acrylamides via a three-step tandem reaction†
Cite this: DOI: 10.1039/c3ob42444h
Jun Qiua,b and Ronghua Zhang*a,b
Received 6th December 2013,
Accepted 28th January 2014
DOI: 10.1039/c3ob42444h
www.rsc.org/obc
A novel and metal-free acrylamides formation between arylpro- reacted with azides into corresponding acrylamides via an oxi-
pynes and hydroxylamine hydrochloride through sp3 C–H and dative rearrangement was reported by Jiao et al.10
C–C bond cleavage has been achieved with DDQ as an oxidant. The
However, it is worth noting that a direct metal-free method
mechanistic study shows that the acrylamides are formed through for the preparation of acrylamides through direct C–H or C–C
a three-step tandem sequence, including cross-dehydrogenative- bond activation (cleavage) is still an extremely attractive yet
coupling (CDC) reaction, aza-Meyer–Schuster rearrangement and challenging task, and very few metal-free approaches to acryl-
Beckmann rearrangement.
amides have been reported. In a recent project, our group has
demonstrated an atom-efficient and transition metal-free reac-
tion between diarylpropenes and hydroxylamine hydrochloride
using DDQ as a promoter to generate corresponding acryl-
amides.11 In light of our recent success in this oxidative ami-
dation reaction of diarylpropenes, we turned our attention to
the much more challenging amidation reaction of arylpro-
pynes. Herein, we demonstrate an efficient and direct metal-
free transformation of arylpropynes into corresponding acryl-
amides via a three-step tandem reaction of a CDC reaction,
aza-Meyer–Schuster rearrangement and Beckmann rearrange-
ment in the presence of hydroxylamine hydrochloride and
DDQ (Scheme 1).
An initial study was carried out using 1-phenyl-3-(4-chloro-
phenyl)-propyne 1a and hydroxylamine hydrochloride as the
substrates, DDQ was used as the oxidant to examine suitable
reaction conditions, and the results are summarized in
Table 1. Several solvents including DCE, 1,4-dioxane, DMF,
CH3NO2, CH3CN, CH3CN–HOAc, CH3CN–HCOOH were
Various acrylamide derivatives have been studied to have many
different biological activities such as anticancer, antimitotic,
anti-oxidant, and seed-germination inhibitory effects.1
Additionally, acrylamides and their derivatives are employed in
a wide range of organic reactions, which include nucleophilic
additions, cycloaddition reactions, and cyclization reactions,
to name just a few.2 They are also extensively used in the syn-
thesis of polymeric materials.3 Accordingly, establishing
methods to form acrylamide derivatives is of long-standing
interest. The most prevalent strategy for acrylamide derivative
formation relies heavily on the interconverison of activated
acrylacid derivatives with an amine in the presence of a coup-
ling reagent.4
Recently, the direct transition-metal-catalyzed transform-
ation of hydrocarbon molecules into corresponding acryl-
amides has attracted considerable attention and has been the
focus of a significant number of studies, owing to not only its
fundamental scientific appeal but also its potential utility in
organic synthesis.5 Substituted acrylamides were directly syn-
thesized via palladium-catalyzed aminocarbonylation of a
variety of alkylamines with alkyl alkynes and a strong acidic
medium6 or in the presence of organic iodides,7 p-TsOH, H2
8
or ionic liquid [bmim][Tf2N].9 An alternative method for
an iron-catalyzed direct transformation of 1,3-diarylpropenes
aDepartment of Chemistry, Tongji University, Shanghai 200092, P. R. China
bKey Laboratory of Yangtze River Water Environment, Ministry of Education,
Siping Road 1239, Shanghai, 200092, P. R. China. E-mail: rhzhang@tongji.edu.cn
†Electronic supplementary information (ESI) available: Experiment procedure
and NMR data. See DOI: 10.1039/c3ob42444h
Scheme 1 DDQ-promoted transformation of arylpropynes into
acrylamides.
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Table 1 Screening of reaction conditionsa
Table 2 Direct transformation of 1,3-diarylpropynes 1 into the acryl-
amides 2a
Entry
Acid
Solvent
Oxidant
Yieldb (%)
Entry R1, R2
Product
Yieldb (%)
1
2
3
4
5
6
7
8
PPA
PPA
PPA
PPA
PPA
PPA
PPA
DCE
1,4-Dioxane
CH3NO2
DMF
MeCN
MeCN–HOAc
MeCN–HCOOH
MeCN–HCOOH
MeCN–HCOOH
MeCN–HCOOH
MeCN–HCOOH
MeCN–HCOOH
MeCN–HCOOH
MeCN–HCOOH
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
BQ
52
40
63
13
72
75
81
76
21
77
45
27
n.d.
n.d.
1
2
3
4
5
6
7
8
9
4-Cl, H 1a
4-F, H 1b
2a
2b
2c
2d
2e
2f
2g
2h
2i
81
83
77
72
78
85
82
52
16
4-Br, H 1c
2-Cl, H 1d
3-F, H 1e
2,4-Cl, H 1f
2,6-Cl, H 1g
4-CH3, H 1h
4-CH3O, H 1i
p-TSA
H2SO4
MsOH
9
10
11
12
13
14
c
10
11
12
13
14
15
4-F, 4-Cl 1j
4-Cl, 2,6-Cl 1k
4-Br, 4-Br 1l
4-CH3, 4-CH3 1m
4-Cl, 4-CH3 1n
4-CH3, 4-Cl 1o
2j
2k
2l
2m 31
2n
2o
88
86
83
—
PPA
PPA
PPA
TBHP
PhI(OAc)2
72
61
a Reaction conditions: 1a (1 mmol), NH2OH·HCl (0.5 mmol),
DDQ (0.75 mmol), acid (0.15 mmol), solvent (1.5 mL), co-solvent
(1.5 mL), stirred at 80 °C over 12 h. b Isolated yield. c No addition of
acid. PPA = polyphosphoric acid. DDQ = 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone. TBHP = tert-butyl hydroperoxide (70% aqueous
solution).
16
17
18
19
H, 4-Br 1p
H, 4-Cl 1q
H, 4-CH3 1r
H, H 1s
2p
2q
2r
75
77
67
72
2s
a Reaction conditions: 1 (1 mmol), NH2OH·HCl (0.5 mmol), DDQ
(0.75 mmol), PPA (0.15 mmol), HCOOH (1.5 mL), MeCN (1.5 mL)
stirred at 80 °C for 12 h. b Yield of the isolated product.
screened in the presence of PPA at 80 °C (Table 1, entries 1–7).
Moderate yields of the desired product 2a were obtained using
CH3NO2, DCE and 1,4-dioxane as a solvent (Table 1, entries
1–3). Considerable amounts of undesired products were to 88%). It is noteworthy that various electron-withdrawing
formed and resulted in lower yield using DMF (Table 1, entry substituents on the aromatic rings were compatible with the
4). It should be noted that a good yield of the desired product process and did not affect the efficiency of the reaction
2a was obtained using CH3CN and CH3CN–HOAc (Table 1, (Table 2, entries 1–7, 10–12 and 16–18). Fluoride, chloride,
entries 5 and 6). Fortunately, when CH3CN–HCOOH instead of and bromide substituents reacted well, thus leading to the
CH3CN and CH3CN–HOAc were used as the solvent, 2a was corresponding acrylamides in high yields (72–88%); especially
obtained in the highest yield of 81% (Table 1, entry 7). To excellent yields were obtained when the two phenyl rings of
establish the reaction conditions that improve the reactivity, the substrate had electron-withdrawing groups respectively
several acids such as p-TSA, H2SO4, MsOH, and PPA were (Table 2, entries 10–12). In comparison, when 1,3-diarylpro-
tested in CH3CN–HCOOH (1 : 1) at 80 °C (Table 1, entries pynes bearing electron-donating substituents like the methyl
7–10); the target acrylamide product 2a could be obtained in group on the aromatic ring were used, considerable amounts
21%–81% yields. Only 45% desired product was isolated in the of unwanted by-products were formed and the reaction
absence of other acids (Table 1, entry 11). It was found that resulted in lower yields (31–67%) (Table 2, entries 8, 13 and
PPA as the acid showed relatively higher efficiency compared 18). Furthermore, when the substrates bearing para-methoxyl
with other acids and thus was chosen as the acid for further groups on the aromatic ring were employed, only 16% acryl-
optimization. Furthermore, BQ, TBHP and PhI(OAc)2 were amide product were detected (Table 2, entry 9). Surprisingly,
screened as the oxidant. However, large amounts of undesired no regioisomeric acrylamides were detected when a variety of
by-products were observed and the yields were remarkably mono- or asymmetrically disubstituted 1,3-diarylpropynes were
diminished when BQ was used as the oxidant (Table 1, entry employed, the clearest example was the formation of 2n and
12). Both TBHP and PhI(OAc)2 used as the oxidant instead of 2o; it was found that there was no trace of 2o in the isolated 2n
DDQ demonstrated very poor activity and no desired product according to the experimental data, and vice versa (see NMR
was detected (Table 1, entries 13 and 14).
charts in ESI†). Regioisomers were generally obtained when
With the optimized reaction conditions established, various unsymmetric 1,3-diarylpropenes reacted with various nucleo-
substrates were subjected to the reaction and representative philic reagents.11,12 Additionally, it was found that the “R1”
results are summarized in Table 2. To our delight, a variety of substituent on the benzene ring exerts more influence on the
substituted 1,3-diarylpropynes could easily be converted into reaction in comparison with the “R2” substituent (Table 2,
the corresponding acrylamides in moderate to good yields (up entries 1, 3, 8 and 16–18).
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Encouraged by the above results, we further investigated (Table 3, entries 2–4), while considerable amounts of un-
the reactions between 1,3,3-triarylpropynes and hydroxylamine desired by-products were formed and no target product was
hydrochloride under the standard reaction conditions. To our obtained with the methyl group on the aromatic ring (Table 3,
delight, several triarylpropynes could successfully afford the entry 5). Unfortunately, when 3-isopropyl-1,3-diphenylpropyne
corresponding acrylamides in moderate to good yields. As indi- was used as the substrate, no acrylamide products were gener-
cated in Table 3, good yields in the acrylamides products 4b, ated and the enyne 4f was detected (Table 3, entry 6). We
4c, 4d were obtained when 1,3,3-triarylpropynes bearing elec- speculated that the enyne may be generated by dehydrogena-
tron-withdrawing substituents were employed as the substrates tion with DDQ.13
Additional mechanistic studies with possible key intermedi-
ates have been investigated (Scheme 2). One possible pathway
Table 3 Direct transformation of 1,3,3-triarylpropynes 3 into the acryl-
amides 4a
for this transformation is likely to be an oxidation of diarylpro-
pyne to chalcone with a subsequent Beckmann rearrangement.
However, when 1a was tested in the absence of hydroxylamine
hydrochloride under the standard reaction conditions, no
chalcone 5a was observed (eqn (1)). In addition, when the reac-
tion of ketoxime 6a was carried out under the standard reac-
tion conditions, the target acrylamide 2a was produced in 89%
yield (eqn (2)). These results suggest that the reaction does not
undergo oxidation of diarylpropyne to chalcone with a sub-
sequent Beckmann rearrangement. To further probe the mecha-
nism of this novel transformation, propargylic hydroxylamine
7a was synthesized from propargylic alcohols and could also
successfully afford the target acrylamide 2a in 84% yield under
the standard reaction conditions (eqn (3)).14 All these results
indicate that the ketoxime 6a and propargylic hydroxylamine
7a may be involved as the key intermediates in this transformation.
Although the mechanism is not completely clear yet, a
plausible mechanism for our methodology is hypothesized on
the basis of the literature9–13,15 and the above mechanistic
studies (Scheme 3). Initially, the reaction is a single-electron
Entry
1
Product
Yieldb (%)
65
2
3
71
75
4
80
5
6
Trace
Scheme 2 Investigation of the possible key intermediates.
31
a Reaction conditions: 1 (1 mmol), NH2OH·HCl (0.5 mmol), DDQ
(0.75 mmol), PPA (0.15 mmol), HCOOH (1.5 mL), MeCN (1.5 mL)
stirred at 80 °C for 12 h. b Yield of the isolated product.
Scheme 3 Plausible mechanism for the formation of 2.
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transfer (SET) process between substrates 1 and DDQ to form
the propargyl cation B. The cation B with a hydroxylamine
hydrochloride gave rise to the C–N bond coupling product C
by a subsequent CDC reaction process. Subsequently, C under-
goes a [1,3] shift of the –NH-OH group to the transition state
D, which further generates allene E through the aza-Meyer–
Schuster rearrangement in the presence of an acid. Then rapid
tautomerization of allene E would lead to the ketoxime F. Sub-
sequently the target acrylamide 2 could be generated from the
ketoxime F through the Beckmann rearrangement in the pres-
ence of an acid.
In summary, we have demonstrated a novel and metal-free
method for the direct transformation of arylpropynes into
corresponding acrylamides by one C(sp3)–H, and one N–H,
one C–C bond cleavages. The mechanistic study shows that the
acrylamides are formed through a three-step cascade sequence
involving a hetero-CDC reaction with a subsequent tandem aza-
Meyer–Schuster rearrangement and Beckmann rearrangement.
To the best of our knowledge, this is the first direct transform-
ation of arylpropynes to acrylamides without a metal catalyst.
This method provides a new and unique strategy to function-
alize simple and readily available hydrocarbon molecules by a
CDC reaction with subsequent tandem rearrangements. Further
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