Base-promoted amide synthesis from aliphatic amines and ynones as acylation agents through C-C bond cleavage

Article abstract of DOI:10.1039/c7cc09310a

A new protocol for the synthesis of amides via base-promoted cleavage of the C(sp)-C(CO) bond of ynones with aliphatic primary and secondary amines under transition-metal-, ligand-, and oxidant-free conditions has been developed. This method exhibits a wide substrate scope, high functional group tolerance and exclusive chemoselectivity, as well as mild reaction conditions.

Full text of DOI:10.1039/c7cc09310a

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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Base-Promoted Amide Synthesis from Aliphatic Amines and
Ynones as Acylation Agents through C–C Bond Cleavage
Received 00th January 20xx,
Accepted 00th January 20xx
Guolin Cheng,*a Weiwei Lv,a Changsheng Kuai,a Si Wena and Shangyun Xiaoa
DOI: 10.1039/x0xx00000x
www.rsc.org/
A new protocol for the synthesis of amides via base-promoted
cleavage of the C(sp)–C(CO) bond of ynones with aliphatic primary
and secondary amines under transition-metal-, ligand-, and
oxidant-free conditions has been developed. This method exhibits
a wide substrate scope, high functional group tolerance and
exclusive chemoselectivity, as well as mild reaction conditions.
a, Rh-catalyzed cleavage of C(sp)-C(CO) bond of ynones
O
[Rh(COD)Cl]2, Xantphos
R1
+
CO
R
R
150 oC, 48 h
R1
described by Dong, ref. 5a
b, Cu/Fe-catalyzed cleavage of C-C triple bond of ynones
O
O
O
O
Cu(acac)2/FeCl3
P(OnBu)2
The selective cleavage of C−C bonds has aꢀracted great
attentions owing to its potential utility in organic synthesis and
fundamental scientific interest.1 In recent times, transition-
metal (TM)-catalyzed C−C bond cleavage has been studied
extensively using strained molecules bearing three- or four-
membered rings2 and molecules with an auxiliary directing
group.3 Compared with TM-catalyzed C–C bond cleavage
reactions, the selective cleavage of C–C bonds in TM-free
reactions represents a fascinating topic in organic synthesis for
significant potential environmental and economic benefits.4
However, the cleavage of unstrained C−C bonds under TM-free
conditions still remains a major challenge due to its inherent
inert nature and uncontrollable selectivity. Ynones are
abundant structural motifs in a wide range of natural products,
and can be used as versatile building blocks for rapid
construction of sophisticated synthetic targets.5 In 2015, Dong
H
+
P(OnBu)2
Ph
Ph
DIPEA, DCE, 90 oC
R
described by Song, ref. 5b
c, Acid-mediated cleavage of C-C triple bond of ynones
O
O
O
TFA
NH2
NH
PhCO2H
+
+
Ph
90 oC
NH2
R
N
R
described by our goup, ref. 5c
d, base-promoted cleavage of C(sp)-C(CO) bond of ynones
NaOH
toluene reflux
O
Me
Me
R
+
R
O
HO
Me Me
I
R1
R2
II
HO
N
Alkyl
Alkyl
O
Alkyl
Alkyl
base
rt
R2
R1
disclosed
a
Rh-catalyzed disubstituted alkynes synthesis
Alkyl
+
+
N H
N
Alkyl
R1
R2
through cleavage of the C(sp)–C(CO) bond of ynones (Scheme
1a).6 Later on, a Cu/Fe-catalyzed oxidative C−C triple bond
cleavage of ynones with H-phosphonates, followed by the
formation of a new C−P bond was developed by Song’s group
(Scheme 1b).7 Recently, our group uncovered a TM-free C−C
triple bond cleavage reaction of ynones with 2-
aminobenzamides for the synthesis of 4(3H)-quinazolinones
(Scheme 1c).4c Despite the significant progress offered by the
abovementioned reactions, there are still certain limitations
This work
Scheme 1 Cleavage of C–C bond of ynones.
including long reaction time and elevated temperatures. Thus,
it continues to be an area of intense interest to improve upon
the harsh reaction conditions and develop a TM-free synthetic
method for the selective cleavage of C−C bond of ynones.
Driven by the ability of 2-(2-hydroxylpropyl)-alkynes
I to
generate acetone and terminal alkynes at basic conditions
(Scheme 1d, top),8 we questioned whether the tertiary alcohol
intermediate II could be formed from 1,2-addition of amines to
ynones, thus generating amides and terminal alkynes via
C(sp)–C(CO) bond cleavage (Scheme 1d, bottom). As our
a.College of Materials Science & Engineering, Huaqiao University, Xiamen 361021,
China. E-mail: glcheng@hqu.edu.cn
†Electronic
DOI: 10.1039/x0xx00000x
Supplementary
Information
(ESI)
available:
See
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ongoing interest in ynones chemistry,9 we report herein an (0.2 mmol), 2a (1.2 equiv), LiOtBu (1.2 equiv), DCM (1 mL), at
unprecedented base-promoted chemoselective cleavage of
room temperature, under air atmosphere.
With the optimized conditions in hand, we examined the
substrate scope for the C−C bond cleavage reacꢁon of ynones
Table 1. Screen of the Reaction Conditions.a
Entry
1
R
Ph
Base
NaOH
KOtBu
NaOtBu
LiOtBu
Li2CO3
Et3N
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCM
Yieldb
<5%
9%
2
Ph
3
Ph
16%
45%
0%
4
Ph
5
Ph
6
Ph
0%
7
Ph
DBU
0%
8
Ph
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
83%
7%
9
Ph
CH3CN
THF
10
11
12c
13d
14c
15c
16c
17c
18e
Ph
0%
Ph
DMF
0%
Ph
DCM
82%
65%
79%
72%
0%
Ph
DCM
MeOC6H4
4-FC6H4
nBu
tBu
Ph
DCM
DCM
DCM
DCM
14%
83%
DCM
a
Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), base (2.0 equiv), solvent (1
mL), room temperature for 12 h.bIsolated yield based on 1a. 1.2 equiv of LiOtBu
was used.d1.0 equiv of LiOtBu was used. eUnder N2, DMF
c
= N,N-
dimethylformamide.
Scheme 2 Reactions of various ynones 2a–l with benzylamine 1a.a
C(sp)–C(CO) single bond of ynones with alkyl amines, and
subsequent formation of
temperature.10,11
a new C–N bond at room
2a−l with benzylamine 1a (scheme 2). In general, the base-
We began our study to examine the model reaction of
benzylamine 1a with 1,3-diphenylprop-2-yn-1-one 2a in the
presence of 2.0 equiv of NaOH as the base in toluene at room
temperature (Table 1). Gratifyingly, we observed the desired
product, albeit in low yield (entry 1). Excitedly, we obtained a
moderated result (45% isolated yield, entry 4) after screening
of a series of bases (entries 1−7). In our subsequent screening
of other solvents, we discovered that DCM was a highly
effective solvent to promote the desired reaction, affording
product 3a in a satisfying 83% yield (entry 8). Then, the base
equivalency was reevaluated, and we found that a little excess
of base is required for good yields (entries 12 and 13). We then
examined the influence that the substituents exert on the
reactivity of ynones. Notably, 3-aryl-substituted ynones
furnished the expected product 3a in relatively good yields
(entries 14 and 15) whereas 3-alkyl-substituted ynones proved
to be essentially unreactive under identical conditions (entries
16 and 17). 83% yield was obtained when the reaction was
performed under N2 atmosphere, which indicated that O2 may
not be involved in this reaction process (entry 18). Finally, the
optimized reaction conditions were identified as follows: 1a
promoted reaction occurred relatively smoothly with various
aryl-substituted ynones bearing either electron-donating
moieties 2e
furnishing the desired amides (3e
ortho-substituted ynones were examined, the yields were only
modest (3b ). Other ynone bearing a hetero aromatic
−
h
or electron-withdrawing moieties 2i and 2
j,
−j
) in good yields. When the
−d
substituent was also suitable substrate for the C−C bond
cleavage reaction (3k).However, the use of 1-alkyl-substituted
ynone led to a low yield (3l).
Furthermore, we explored the scope of amines (Scheme 3).
Both electron-rich and electron-deficient benzylamines could
be applied in this reaction, giving the corresponding amides in
good yields (4a–g).It is especially noteworthy that the aniline
NH2 were well tolerated, and delivering the desired product 4d
in good yield, showing good chemoselectivity of aliphatic NH2
over aniline NH2. Other primary amines with 1-naphthyl (4h),
heteroaryl (4i, 4j), as well as allyl substituents (4m) were
proved to be well tolerated under the standard reaction
conditions. Notably, secondary amines were also compatible
substrates, affording the corresponding products in moderated
yields (4s
,
4t). However, the reactions were not compatible
2 | J. Name., 2012, 00, 1-3
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with the use of sterically hindered primary amine (4r) and
secondary amine (4u).
To further understand the reaction mechanism, catalytic
amount of CuI was introduced in the reaction system, 1,3-
The synthetic versatility of this chemistry was demonstrated diyne
6 could be isolated in 76% yield, suggesting that the
through a large-scale reaction. The reaction of 1a with 2a on a putative phenylacetylene cleaved from ynone 2a was further
20 mmol scale completed within 4 h, producing 3.55 g of the involved in the Glaser–Hay coupling reaction (eq.3).12 On the
corresponding product 3a in 84% yield (eq. 1). As aniline NH2 basis of the above result, we proposed that the reaction would
could be tolerated in this reaction system, we then employed a proceed as discussed in the introduction (Scheme 1d). Namely,
the tertiary alcohol intermediate II was formed via 1,2-addition
of amines to ynones, followed by base-promoted C(sp)–C(CO)
bond cleavage, thus generating the desired amides and
terminal alkynes.
In conclusion，we have developed a base-promoted highly
chemoselective C(sp)–C(CO) bond cleavage of ynones with
aliphatic amines for the synthesis of valuable amide
derivatives. Free arylamines, alkenes, as well as halogens were
tolerated, suggesting a promising substrate scope. This novel
and fundamental reactivity disclosed in this work is expected
to open a door to new avenues for developing transition-
metal-free unstrained C−C bonds cleavage reactions.
This work was supported by NSF of China (21672075),
Program for New Century Excellent Talents in Fujian Province
University. Outstanding Youth Scientific Research Cultivation
Plan of Colleges and Universities of Fujian Province (JA14012).
Conflicts of interest
There are no conflicts to declare.
Notes and references
1
2
3
4
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Billett, T. Tsukamoto and G. Dong, Acs Catal., 2017,
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P. Liu and G. Dong, Nature, 2016, 539, 546 (c) H. Li, Y.
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Chem. Soc., 2011, 133, 15244; (d) A. M. Dreis and C. J.
Douglas, J. Am. Chem. Soc., 2009, 131, 412.
7
,
Scheme 3 Reactions of various amines with 3-diphenylprop-2-yn-1-one 2aa
straightforward one-pot strategy to synthesize the di-amide
5
directly from the di-amines substrate 1b and ynone2a, without
isolating the mono-amide intermediate (eq. 2). To our delight,
the di-amide 5a and 5b containing one benzamide and one
Boc-amide or Ac-amine scaffold could be generated from 1b
and 2a in 86% and 84% yields, respectively.
For selected examples: (a) A. Verma and S. Kumar, Org.
Lett., 2016, 18, 4388; (b) X. Yang, G. Cheng, J. Shen, C.
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Lian, M. Liu, J. Yuan, G. Yin and A. Wu, J. Org. Chem.,
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2012, 77, 9865; (e) B. Tiwari, J. Zhang and Y. R. Chi,
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4 | J. Name., 2012, 00, 1-3
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The synthesis of amides via base-promoted cleavage of the C(sp)–C(CO) bond
of ynones with aliphatic primary and secondary amines is reported.