Acid-Promoted One-Pot Synthesis of Substituted Furan and 6-Methylpyrazin-2(1 H)-one Derivatives via Allene Intermediate Formed in Situ

Article abstract of DOI:10.1021/acscombsci.8b00005

Under the acidic conditions, substituted furans were constructed from γ-alkynyl ketones through corresponding allene intermediates in one-pot. The methodology was also tailored to a series of the Ugi reaction products for the synthesis of 6-methylpyrazin-2(1H)-one derivatives. The current method offered significant advantages for the combinatorial applications of these chemical scaffolds.

Full text of DOI:10.1021/acscombsci.8b00005

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Acid-promoted one-pot synthesis of substituted furan and 6-
methylpyrazin-2(1H)-one derivatives via allene intermediate formed in situ
Jie Lei, Zhi-Gang Xu, Dianyong Tang, Yong Li, Jia Xu, Hong-yu Li, Jin Zhu, and Zhong-Zhu Chen
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.8b00005 • Publication Date (Web): 05 Apr 2018
Downloaded from http://pubs.acs.org on April 6, 2018
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Acidꢀpromoted oneꢀpot synthesis of substituted
furan and 6ꢀmethylpyrazinꢀ2(1H)ꢀone derivatives via
allene intermediate formed in situ
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∗
Jie Lei,†, ‡, # ZhiꢀGang Xu,# DianꢀYong Tang,# Yong Li,# Jia Xu,# Hongꢀyu Li,ǁ Jin Zhu#, Zhongꢀ
∗
Zhu Chen,#,
†Key Laboratory for Asymmetric Synthesis and Chiral Technology of Sichuan Province,
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences. Chengdu, 610041 China
‡University of Chinese Academy of Sciences, Beijing 100049, China
#Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key
Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts
and Sciences, 319 Honghe Ave., Yongchuan, Chongqing, 402160 China
ǁDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for
Medical Sciences, Little Rock, Arkansas 72205 United States
KEYWORDS Allene; Multicomponent reaction (MCR); Ugi reaction; 6ꢀmethylpyrazinꢀ2(1H)ꢀ
one; Substituted furans
ABSTRACT Under the acidic conditions, substituted furans were constructed from γꢀalkynyl
ketones through corresponding allene intermediates in oneꢀpot. The methodolgy was also
tailored to a series of the Ugi reaction products for the synthesis of 6ꢀmethylpyrazinꢀ2(1H)ꢀone
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derivatives. The current method offered significant advantages for the combinatorial applications
of these chemcial scaffolds.
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INTRODUCTION
Allenes are versatile structural motifs in organic transformations,1 which possess inherent
advantages for the construction of hetereocycles and have received considerable attentions for
the synthesis of biologically active compounds.2,3 In view of the high convertability of alkyne to
allene, the construction of alkyne derivatives has recently become a key focus to build the
complex heterocycles.4
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Furan and piperazinone play a significant role in medicinal chemistry. Numerous biologically
active molecules, pharmaceuticals, and natural products bear the core structures of these two
heterocycles.5 During the past decades, the carbeneꢀtransfer reaction with conjugated enynones
as the carbine precursors have been extensively reported by using medal catalysts such as Rh6,
Zn7, Cu8, Pd9 or Lewis acid Bi(OTf)310ꢀ11 Notebally, the γꢀalkynyl ketones could be converted to
the furanꢀcarbine precursors in situ and had been widely used in the carbeneꢀtransfer reactions.6ꢀ
11 Similary, the alkyne can be also efficiently converted to the corresponding allene intermediate
under a medal catalyst, or even under a basic condition, which led the syntheis of various
hetercycles including dihydropyrazinones.10ꢀ14 However, all cases reported, a two or more step
optional process or hazardous solvent MeNO2 were required. The synthesis of substituted furans
or piperazinones via the allene intermediate in one pot with an easy workꢀup would be
significantly combinatorial applicationꢀfriendly and costꢀeffcient.
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RESULTS AND DISCUSSION
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As part of our continued efforts to develop cascade reactions based on MCRs for the
combinatorial applications, we hypothesized that an acid catalyst could potenttially transfer
γꢀalkynyl ketones to the furanꢀcarbine precursors and the acid catalyst could also promote a
sequential cyclization in oneꢀpot. To test the hypothesis, compound 1{1} was selected as a
model substrate to evaluate the feasibility for the synthesis of substituted furans. To our delight,
two sequential reactions occurred in oneꢀpot at the first attempt with pꢀTsOH (pꢀtoluenesulfonic
acid) at 70 °C for 5 h in toluene, although the isolated yield was low at 45% (entry 1). We then
investigated a variety of different Brønsted acids, catalyst loadings, temperature, reaction times
and solvents to optimize yields (Table 1). Higher reaction temperatures afforded higher yields
(78ꢀ87%, entries 2ꢀ3). Unfortunately, decreasing the loading of pꢀTsOH from 20% to 10%
resulted in a sharp reduction of the yield from 87% to 53% (entry 4). Interestingly, when pꢀTsOH
was combined with a Lewis acid catalyst, the starting material was transformed to the
corresponding product just in 1 h (entry 5 and 6). To confirm the superiority of pꢀTsOH in this
reaction, more acids were tested. However, none of other acids (entries 7ꢀ9) were better. When
solvents such as DMSO, CH3CN, CH3OH and DMF were explored, lower yields were obtained
(Table 1, entries 10ꢀ13). Most importantly, with DCE (1,2ꢀdichloroethane) as the solvent and 20
mol% pꢀTsOH as the catalyst the reaction yielded the desired product in an excellent yield (92%,
entry 14). As expected, DCM (dichloromethane) and CHCl3 (chloroform), the twins of DCE,
gave the desired product in good yields (80% and 81%, resepctively entries 15 and 16). In a
sharp contrast, the reaction without pꢀTsOH did not yield the product (entry 17). Hence, the
optimized reaction condition is summaried here: the reaction was stirred with the acid catalyst pꢀ
TsOH (20 mol%) in the solvent of DCE (2.0 mL) at 110 oC for 3 h (entry 14).
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Table 1. Optimization for synthesizing compound fruan 2{1}.a
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8
O
O
O
acid, additive
O
solvent, temp., time
O
9
O
{1}
1
2
{1}
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Temp. Time Yield
Entry
Acid
Additive Solvent
(oC)
70
(h)
3
3
3
3
1
1
3
3
3
3
3
3
3
3
3
3
3
(%)b
45
1
2
3
pꢀTsOH
pꢀTsOH
pꢀTsOH
pꢀTsOH
pꢀTsOH ZnCl2 toluene
pꢀTsOH ZnBr2 toluene
TFA
AcOH
PPOA
pꢀTsOH
pꢀTsOH
pꢀTsOH
pꢀTsOH
pꢀTsOH
pꢀTsOH
pꢀTsOH
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
toluene
toluene
toluene
toluene
90
78
87
53
89
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
4c
5d
6d
7
88
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
toluene
toluene
toluene
DMSO
CH3CN
CH3OH
DMF
DCE
DCM
CHCl3
DCE
NR
NR
15
NR
35
27
NR
92
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9
10
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12
13
14
15
16
17e
80
81
NR
a Reaction conditions: compound 1{1} (1.0 mmol), acid (20 mol%), solvent (2.0 mL).
b Yield (%) based on the integral of the LC/MS peaks detected at 254nm.
c The acid loading was increased to 10 mol%.
d Lewis acid (20 mol%).
eThe reaction was carried out in the absence of acid.
With the optimized reaction conditions, the scope of this transformation was subsequently
explored. As shown in Scheme 1, various starting materials were successfully transformed into
corresponding products in moderate to good yields. Morover, the thiophen substrate 2{9} could
be well tolerated with the yield of 72%.
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Scheme 1. Synthesis of furan 2{1-15}.
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Isolated yield (%) in parentheses.
Based on our aforementioned acidꢀcatalyzed two sequnetial transformation for the synthesis
of furan analogues in oneꢀpot, we envisoned that an acid catalyst could be also useful for
converting the Ugi 4ꢀCR/propargyl products to the 6ꢀmethylꢀ3,4ꢀdihydropyrazinone derivatives
(Scheme 2). We first selected the Ugiꢀproduct 7{1,1,1} as the model substrate which was
obtained by mixing benzaldehyde 3{1}, 2ꢀpropynylamine 4, 2ꢀnitrobenzoic acid 5{1}, and
benzyl isocyanide 6{1} with a standard Ugi reaction condition. The Ugi adduct 7{1,1,1} was
then treated with the aforementioned acidic condition. Unfortunately, the desired prodcut
9{1,1,1} was not detected in the reaction mixture by the LC/MS determination and also not
found after workꢀup and column purification. Instead, compound 10{1,1,1} was isolated as the
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only reaction product. It was found that the dehydrogenation and hydrolysis reactions were took
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place for intermediate 9{1,1,1} to afford 10{1,1,1}. The chemcial structure of compound
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10{1,1,1} was determined by the combination of H NMR, C NMR, LC/MS, and HRMS. It
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was further confirmed by the Xꢀray crystal structure analysis (Figure 2).15
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Scheme 2. Synthetic route of 6ꢀmethylpyrazinꢀ2(1H)ꢀone 10{1,1,1}.
Br
CHO
CHO Cl
CHO Br
CHO
3{1}
3{2}
3{3}
3{4}
Br
Cl
CHO O2N
CHO
Cl
CHO
3{5}
3{6}
3{7}
O
CHO
O
CHO
CHO
O
3{8}
3{9}
3{10}
NO2
COOH
O
O
COOH
COOH
COOH
OH
N
5{1}
5{2}
5{3}
5{4}
5{5}
N
C
N C
N
C
N
C
6{1}
6{2}
6{3}
6{4}
Figure 1. Building blocks for Ugi reaction.
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Table 2. Optimization of cyclization step for compound 10{1,1,1}.
Entry
1
Cat.
Solvent
DCE
Condition
110 oC, 3 h
110 oC, 12 h
Yield (%)a
pꢀTsOH
pꢀTsOH
10
2
DCE
21
3
10% TFA/DCE
10% TFA/DCE
10% HCl/AcOH
50% HCl/AcOH
50% HCl/AcOH
50% HCl/AcOH
50% HCl/AcOH
50% HCl/AcOH
50% HCl/AcOH
50% HCl/AcOH
MW 110 oC, 10 min.
MW 120 oC, 10 min.
MW 110 oC, 10 min.
MW 110 oC, 10 min.
MW 120 oC, 10 min.
MW 130 oC, 10 min.
MW 120 oC, 10 min.
MW 120 oC, 10 min.
MW 120 oC, 10 min.
MW 120 oC, 10 min.
trace
trace
trace
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75
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59
9b
10c
11d
12e
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71
75
70
a Isolated yield (%) after column chromatography. MW = microwave.
b 2ꢀNitrobenzoic acid 5{1} was replaced by benzoic acid 5{2} as acid sources in Ugi reaction.
c 2ꢀNitrobenzoic acid 5{1} was replaced by acetic acid as acid 5{3} sources in Ugi reaction.
d 2ꢀNitrobenzoic acid 5{1} was replaced by 2ꢀfuroic acid 5{4} as acid sources in Ugi reaction.
e 2ꢀNitrobenzoic acid 5{1} was replaced by nicotinic acid 5{5} as acid sources in Ugi reaction.
To understand the mechanism of action for producing compound 10{1,1,1}, rather than
9{1,1,1} with the Ugi product 7{1,1,1} which was derived from 2ꢀnitrobenzoic acid 5{1}, we
replaced 2ꢀnitrobenzoic acid 5{1} with much less eletron withdrawing benzoic acid 5{2}, acetic
acid 5{3}, 2ꢀfuroic acid 5{4}, and nicotinic acid 5{5} as shown in Figure 1. The reaction yields
(Table 2, entries 9ꢀ12) were compriable for all different Ugi products, indicating that the nitroꢀ
functionality doesn’t plays a role in the reaction. Obviously, the dehydrogenation of the
dihydropyrazinone ring occurred first and then the hydrolysis was followed as shown in Scheme
2.
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Scheme 3. Synthetic route and structures of 6ꢀmethylpyrazinꢀ2(1H)ꢀones 10{1-10,1-5,1-3}.
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Isolated yield (%) in parentheses
The literatures search revealed that the previous synthesis of 6ꢀmethylpyrazinꢀ2(1H)ꢀones was
complex and required 5 step protocols.16 Oneꢀpot synthesis would offer a quick entry of 6ꢀ
methylpyrazinꢀ2(1H)ꢀone analogues for the combinatiorail applications. We therefore conducted
the optimization of the reaction conditions in Table 2. Among the acids tested, 50% HCl/AcOH
at 120 oC for 10 min gave the best yield (75%) (entry 7). The increase of the temperature to 130
oC lowed the yield to 59% (entry 8).
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Figure 2. Xꢀray analysis of compound 10{9,1,1}.
With the optimized reaction conditions, the scope of this reaction were explored and
representative final products were presented in scheme 2. For this reaction, aldehydes with
electroꢀdrawing, electronꢀdonating, and heterocyclic substituents all afforded good yields. A
diverse collection of isocyanides including benzyl isocyanide 6{1}, 2ꢀphenylethanꢀ1ꢀisocyanide
6{2}, 2,6ꢀdimethylphenyl isocyanide 6{3} and cyclohexyl isocyanide 6{4} were converted to
the corresponding products in moderate (65%) to good yields (78%). In contrast, the previous
methdology (citation) was restricted to the 2,6ꢀdimethylphenyl isocyanide and required multiple
workꢀup procedrues. It is worth to mention that, in addition to classical carboxylic acids, carbolic
acid, a phenol analogue {1ꢀ5} also demonstrated a robust reactivity in the reaction to afford
compound 10{1ꢀ10,1ꢀ5,1ꢀ3} in a good yield (see SI for detailed information).
CONCLUSION
We have developed an efficient protocol for the acidꢀcatalyzed (pꢀTsOH) synthesis of allene
intermediates from alkynes in situ. The allene intermediates were sequntially transferred to
polysubstituted furans in oneꢀpot. The combination of HCl and ACOH in a ratio of 1/1 was
tailored to the Ugi 4ꢀCR/propargyl products for the construction of 6ꢀmethylpyrazinꢀ2(1H)ꢀone
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derivatives. With the concise synthesis of diverse furan and pyrazinone derivatives
combinatorially, this oneꢀpot protocol of the acidꢀcatalyzed conversion of alkynes to allene
intermediates could provide a new tool for the diversification of complex heterocycles in an
expeditious manner. The biological tests are undergoing for these furans and pyrazinone
derivatives. The results will be reported in due course.
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EXPERIMENTAL SECTION
a) General procedures for γꢀalkynyl ketones 2{1-15}.10
To a solution of ketone starting material (1.0 mmol) in DCE (10 mL), pꢀTsOH (0.20 mmol)
was added and the mixture was heated to 110 oC for 3 h. The reaction mixture was monitored by
TLC. When no starting material was left, the reaction mixture was diluted with EtOAc (15.0
mL), washed with sat. Na2CO3 and brine. The organic layer was dried over MgSO4 and
concentrated. The residue was purified by silica gel column chromatography using a gradient of
ethyl acetate/hexane (10ꢀ60%) to afford the relative targeted products 2{1ꢀ15}.
b) General procedures for compounds 10{1-10,1-5,1-3}.
A solution of propargylamine (1.0 mmol), benzyl isonitriles (1.0 mmol), 2ꢀnitrobenzoic acid
(1.0 mmol) and benzaldehyde (1.0 mmol) in MeOH (2.0 mL) was stirred overnight at room
temperature. The reaction mixture was monitored by TLC. When no isonitrile was left, the
solvent was removed under nitrogen blowing and the crude residue was dissolved in 50%
o
HCl/AcOH solution in microwave at 120 C for 10 min. After the microwave vial was cooled to
room temperature, the reaction mixture was diluted with EtOAc (15.0 mL), washed with sat.
Na2CO3 and brine. The organic layer was dried over MgSO4 and concentrated. The residue was
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purified by silica gel column chromatography using a gradient of ethyl acetate/hexane (10ꢀ100%)
to afford the relative targeted product 10{1ꢀ10,1ꢀ5,1ꢀ3}.
ASSOCIATED CONTENT
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Supporting Information
The supporting information is available free of charge on the ACS Publications website at
DOI:XXX
Full analytical data of compounds for intermediates and final products, along with the copies of
1H NMR, 13C NMR and Xꢀray of compound 10{9,1,1} spectra of all the synthesized compounds,
and complete description of the studies for the reactions (PDF).
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: jinzhu@cioc.ac.cn, 188837138277@163.com
ORCID
Jin Zhu: 0000ꢀ0001ꢀ6453ꢀ4958
ZhongꢀZhu Chen: 0000ꢀ0001ꢀ9555ꢀ6738
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
Funding Sources
This work was supported by the Chongqing Research Program of Basic Research and Frontier
Technology (cstc2015jcyjA1328, cstc2015zdcyꢀztzx120003 and cstc2015zdcyꢀztzx0191),
Chongqing Education commission Project of China (KJZH17129) and the Scientific Research
Foundation of Chongqing University of Arts and Sciences (Grant Nos. R2013XY01 and
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R2013XY02). HL was supported by the grants (NIH 1R01CA194094ꢀ010 and 1R01CA197178ꢀ
01A1).
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Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We would also like to thank Ms H.Z. Liu for obtaining the LC/MS and NMR data.
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Graphical abstract
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Acid-promoted one-pot synthesis of substituted furan and
6-methylpyrazin-2(1H)-one derivatives via allene
intermediate formed in situ
Jie Lei, Zhi-Gang Xu, Dian-Yong Tang, Yong Li, Jia Xu, Hong-yu Li, Jin Zhu and
Zhong-Zhu Chen
The construction of substituted furans from allene intermediates was successfully
applied to Ugi products for the synthesis of 6-methylpyrazin-2(1H)-one derivatives.
R'
R''
EWG
O
R'
OH
p-TsOH
EWG
15 samples, 72-85% yield
R''
R2
R2
O
O
H
50% HCl/AcOH
MW, 120 o
N
N
R1
N
R3
N
O
R1
C, 10 min
Three Steps, One-pot protocol
12 samples, 69-78% yield
Ugi-4CR
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