Water-promoted synthesis of enaminones: Mechanism investigation and application in multicomponent reactions

Article abstract of DOI:10.1080/00397911.2012.715712

Highly stereoselective synthesis of Z-enaminones bearing reactive secondary amino group has been successfully performed in water using tertiary amino group functionalized enaminones under ambient conditions. An interesting promotion effect of water on the

Full text of DOI:10.1080/00397911.2012.715712

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Water Promoted Synthesis of Enaminones, Mechanism
Investigation and Application in Multicomponent
Reactions
Yunyun Liu a , Rihui Zhou a & Jie-Ping Wan a
a College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, P.R.
China
Accepted author version posted online: 26 Mar 2013.
To cite this article: Yunyun Liu , Rihui Zhou & Jie-Ping Wan (2013): Water Promoted Synthesis of Enaminones, Mechanism
Investigation and Application in Multicomponent Reactions, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, DOI:10.1080/00397911.2012.715712
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Water Promoted Synthesis of Enaminones, Mechanism Investigation and
Application in Multicomponent Reactions
Yunyun Liu1, Rihui Zhou1, Jie-Ping Wan1
1College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang,
P.R. China
Corresponding author College of Chemistry and Chemical Engineering, Jiangxi Normal
University, Nanchang 330022, P.R. China Tel.: +86 791 88120380; fax: +86 791
88120380 Email: wanjieping@gmail.com
Abstract
Highly stereoselective synthesis of Z-enaminones bearing reactive secondary amino
group has been successfully performed in water using tertiary amino group functionalized
enaminones under ambient conditions. An interesting promotion effect of water on the
reaction via hydrolysis-dehydration condensation has been observed through designed
isotope labeling experiment.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications® to view the free supplemental file.
O
OH(D)
N
H(D)
O
O
Ar1
Ar1
Ar2 NH2
Ar2
H(D)
O
Ar3
NH
O
Ar1
Ar1
N
O HN
FeCl3/water/rt
water promotion
H2O or D2O
Ar1
MCRs
N
H
S
Ar2 NH2
H(D)
H2O or HOD
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KEYWORDS: Enaminone; Green synthesis; Mechanism; Water promotion;
Multicomponent.
INTRODUCTION
Enaminones are also known as β-enamino ketones, are a class of useful building blocks
in synthetic organic chemistry.[1–3] In known results, enaminones have been found as
particularly versatile starting materials for the synthesis of heterocyclic compounds.[4–6]
In addition, enaminone itself is also a substructure that frequently occurred in natural
products and biologically functional compounds.[7–9] During the past decades, the
chemistry of enaminones has won enormous interests from chemical community due to
their excellent and broad reactivities for a vast number of different organic synthesis.[10,11]
Therefore, it is not surprising that the research on enaminone synthesis has also become a
topic of broad attention. Presently, there are several different approaches available for
synthesizing different enaminones. The prominent and straightforward one may be the
condensation of carbonyl compounds with amines, which was able to afford various
enaminones functionalized with sutituent R1 (R1 ≠ H) (Eq 1, Scheme 1).[12–15] Another
widely employed approach was using active methylene substrates to react with
N-dialkoxyl-N,N-dialkylamines such as N,N-dimethylforamide dimethyl acetal
(DMF-DMA) to provide N,N-dialkyl masked enaminones (Eq 2, Scheme 1).[16] In
addition, the addition reactions of amines to electron deficient terminal alkynes have also
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been found useful for the preparation of some useful enamiones (Eq 3, Scheme 1).[6, 17–19]
In rare cases, novel methodology had also been devised for the synthesis of interesting
enaminone scaffolds.[20]
During our research on the methodology of enaminone-based heterocycle synthesis,[21–23]
we were interested in developing facile and efficient synthetic methods towards
enaminones. One of the methods we have employed for enaminone synthesis was the
reactions between readily available (E)-N,N-disubstituted enaminones and primary
amines (Eq 4, Scheme 1).[24] Interestingly, during detailed optimization on this approach,
we discovered that excellent yield has been afforded by this transformation by
performing the reactions in water. Being aware of the importance of green synthesis and
that no water mediated synthesis of enaminone via this transformation is presently
available, we then further explored this synthetic method in detail by invetigating the
application scope of the protocol as well as the reaction mechanism. The experiments of
isotope labeling indicated that water accelerated the reaction via an interesting
hydrolysis-dehydrative condensation process in the reaction, suggested bifunction of
water in the reaction by serving as medium and promoter. We report herein our results on
the green synthesis of NH functionalized Z-enaminones 3 using E-N,N-dimethyl amino
functionalized enaminones 1 and primary amines 2, the investigation on the reaction
mechanism as well as the application of enaminones 3 in multicomponent reactions.
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RESULTS AND DISCUSSION
Initially, the reaction of dimethyl masked enaminone 1a with aniline (2a) was selected as
model reaction for the examination on the effect of related reaction conditions. As shown
by the results given in Table 1, by employing water as medium, different Lewis as well as
Brønted acid catalysts such as FeCl3, AlCl3, AcOH etc. have been found to be capable of
catalyzing this reactions with good results at room temperature. The yields from different
entries indicate that FeCl3 was the best catalyst among the screened candidates (entries
2-7, Table 1) when used in 50 mol- % loading. On the other hand, the entries with
catalyst free condition or using L-proline as catalyst gave no desired product (entries 1
and 8, Table 1). Further optimization disclosed that 20 mol- % catalyst was ideal loading
(entries 9-12, Table 1).
Subsequently, we examined the application scope of this water mediated protocol by
subjecting a class of different starting materials 1 and 2. According to the obtained results
(Table 2), excellent functional group tolerance were displayed when aromatic amines
were utilized. All entries with the aromatic amines as starting materials provided
corresponding products in good to excellent yields in despite of the presence of electronic
withdrawing as well as electronic donating substitution (entries 1-3, 5-9), while slight
influence of an ortho-substituent on the aromatic amines was implied as slightly lower
yield of products were obtained (entries 4 and 15). On the other hand, the variation of the
substituent in the reactants 1 was also allowed in broad diversity without making evident
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difference in product yield. It is worthy of noting that the presence of some sensitive
functional groups such as hydroxyl, amino etc. were also well tolerated (entries 13 and
14). Nevertheless, it was not successful when aliphatic amines such as benzylamine,
cyclohexylamine were subjected for the same transformation under present conditions
(entry 17-18). Structures of all products have been unambiguously identified with 1H
NMR, HRMS as well as comparison with typical known data in literature.
As for the synthetic application of enaminone products 3, some examples have been
previously reported by us and others,6, 22 in order to further explore the synthetic
application of 3, we performed the multicomponent reaction of 3a, benzaldehyde and
thiourea, expecting that tetrahehydropyrimidinthiones (THPMS) would be provided in
the system of CAN/TMSCl/EtOH following analogous pathway found in our previous
reported four-component reactions,[23] however, the expected product 4 was not observed.
Instead, by modifying reaction conditions as heating in DMF in the presence of TMSCl,
dihydropyrimidinthione (DHPM) 5a was formed in good yield.[21] Primary investigation
implied that different aromatic aldehydes were tolerated well to this three-component
reaction by giving good results (Scheme 2).
During our survey on literature regarding this kind of enaminone synthesis, we noticed
that no any study had ever been conducted to explore the mechanism of this reaction.
Even though this transformation is formally simple, we suspected that water had
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promoted the reactions someway because of the truly excellent yields of most products
acquired from these reactions in water. Therefore, we decided to probe the possible
reaction mechanism as this is important not only for elucidating the function of water in
the synthesis of 3, but also for explaining the good results provided by more complex
domino reactions involving the formation of 3 as intermediates in aqueous media.22 After
analyzing possible processes of the reaction, we adopted the isotope labeling using
deuterium oxide as solvent in hope of acquiring direct information on whether and how
did water participated the reaction process. To our delight, the hypothesis has been
validated by the designed experiment. Under standard catalyst conditions, we observed
the formation of deuterium labeled product 3a-d1 and unlabeled product 3a in the ratio of
9 : 1 (Eq 1 in Scheme 3, and see the Supplementary Materials, available online, for the 1H
NMR of D-labeled product) which was resulted from the release of 1:9 DNMe2/HNMe2.
The results clearly demonstrated the participation of water to the reactions. In oder to
further confirm the process, we also conducted the control experiement by subjecting 1a
in the mxiture of D2O and MeOD at room temperature without adding catalyst and
aniline, the entry provided no deuterium labeled product 1a-d1 at all (Eq 2 in Scheme 3).
This result further illustrated that the labeling process took place during the catalysis
cycle. Based on the clues obtained in these experiments, we proposed the mechanism of
as outlined in Scheme 4. Generally, the reactions were intiated in the presence of water
and iron catalyst by the hydrolysis 1 to give β-ketoaldehyde 7 as intermediate via 6, the
tandem dehydration condensation and tautomerization transformation of 7 with primary
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amines 2 then furnished enaminone products 3 while simultaneously released water
molecule. FeCl3 served as Lewis acid to activate and stabilize intermediates 6, 7 and 8.
During the whole process, water molecule was involved in the key hydrolysis and
dehydration conversions to promote the reaction.
CONCLUSION
In conclusion, we have developed a very green and efficient synthetic approach for the
preparation of enaminones bearing free NH group. Water has been found playing the
roles of both medium and promoting agent in the reactions. Whilst having provided the
first water mediated synthesis of useful enaminone scaffolds, we have also elucidated the
possible reaction mechanism of this kind of transformation for the first time by
employing isotope labeling approach. The promoting effect of water on this kind of
reactions has been clearly indicated. These results are not only meaningful in explaining
the reaction process, but also useful for guiding the design of more complex and green
reactions involving the formation of enaminones 3 as intermediates.
EXPERIMENTAL
General Procedure For Water Mediated Synthesis Of Enaminones 3
In a 25 mL round bottom flask located with 0.3 mmol 1 and 0.3 mmol 2, 20 mol % FeCl3
as well as 1.5 mL water were added. The flask was then sealed and stirred at romm
temperature for 2 h, upon completion (TLC), 5 mL more water was added and the
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mixture were extracted with ethyl acetate (3 × 8 mL). The organic layers were combined
and dried overnight in anhydrous Na2SO4. Removal of organic solvent in vaccum gave
target products 3 in generally analytical purity. And washing by 2 mL mixed EtOH and
water (1 : 4) on the products was performed when necessary.
(Z)-3-(4-Methoxyphenylamino)-1-Phenylprop-2-En-1-One (3b)
Deep green solid; m.p. 145-147 oC; 1H NMR (CDCl3, 400 Mz) δ 12.15 (d, 1 H, J = 12.0
Hz), 7.93 (d, 2 H, J = 6.8 Hz), 7.47 (t, 4 H, J = 8.0 Hz), 7.06 (d, 2 H, J = 8.0 Hz), 6.90 (d,
2 H, J = 8.0 Hz), 5.98 (d, 1 H, J = 8.0 Hz); HRMS Calcd for [M+H]+ C16H16NO2:
254.1176; Found: 254.1180. Lit.[6] m.p. 145-147 oC 1H NMR (400 MHz, CDCl3, Me4Si)
δ 3.75 (s, 3H), 5.94 (d, J = 8.0 Hz, 1H), 6.83-6.87(m, 2H), 7.00-7.04 (m, 2H), 7.37-7.49
(m, 4H), 7.90-7.93 (m, 2H), 12.21 (d, J = 12.0 Hz, 1H); 13C NMR (100 MHz, CDCl3,
Me4Si) δ 55.40, 92.76, 114.85, 117.74, 127.10, 128.28, 131.26, 133.60, 139.18, 145.74,
156.20, 190.35. HRMS (EI) calcd for C16H15NO2: 253.1103, found 253.1106.
General Procedure For The Synthesis Of Dhpms 5 Using Enaminones 3
0.3 mmol 3, 0.3 mmol adehyde and 0.4 mmol thiourea were located in a 25 mL round
bottom flask, and 1 eq mol TMSCl as well 1.5 mL DMF were added. The reaction
mixture was heated to 70 oC and stirred for 8 h (TLC). After cooling down to room
temperature, 5 mL water was added and the mixture was extracted with 3 × 8 mL ether
acetate. The combined organic layer was dried overnight with anhydrous Na2SO4. The
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solvent was removed in reduced pressure and the residue was subjected to silica gel
chromatography to provide pure products 5, the structures of products were assigned by
comparing their 1H NMR spectra with previously reported results.21
Phenyl(4-Phenyl-2-Thioxo-1,2,3,4-Tetrahydropyrimidin-5-Yl)Methanone (5a)
m.p. 278-280 oC; 1H NMR (DMSO-d6, 300 Mz) δ =
10.47 (δ, 1 Η, ϑ = 6.0 Ηζ), 9.80 (σ, 1 Η), 7.55−7.44 (µ, 5 Η), 7.41−7.28 (µ, 5 Η), 6.89 (δ,
1 Η, ϑ = 6.0 Ηζ), 5.44 (δ, 1 Η, ϑ = 3.0 Ηζ). Lit. [21] m. p. 277-280 oC; 1H NMR
(DMSO-d6, 500 MHz) δ = 10.46 (d, 1 H, J = 4.6 Hz), 9.79 (s, 1 H), 7.57-7.45 (m, 5 H),
7.40-7.29 (m, 5 H), 6.88 (d, 1 H, J = 5.8 Hz), 5.44 (d, 1 H, J =3.3 Hz); 13C NMR
(DMSO-d6, 125 MHz) δ = 193.0, 175.0, 144.0, 139.3, 138.7, 132.5, 129.9, 129.7, 129.3,
129.0, 127.8, 114.4, 54.7; IR (KBr, cm-1): 3323, 3155, 2960, 1652, 1625, 1565, 1470,
1205, 1133, 1031, 892; ESI-MS: m/z 295 ([M+H]+); ESI-HRMS: Calcd for
C17H14N2OSNa ([M+Na]+), 317.0719; Found, 317.0729.
ACKNOWLEDGEMENTS
Financial support from NSFC of China (no. 21102059) and NSF program of Jiangxi
Province (no. 20114BAB213005) as well as a Sponsored Program for Cultivating Youths
of Outstanding Ability in Jiangxi Normal University is gratefully acknowledged are
gratefully acknowledged.
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Table 1. Evaluation on different reaction conditions for the synthesis of enaminone 3aa
Entry Catalyst Cat. laoding (mol-%) Yield (%)b
1
No
-
0
2
FeCl3
AlCl3
FeSO4
CAN
TMSCl
AcOH
50
50
50
50
50
50
95
91
68
60
75
90
0
3
4
5
6
7
8
L-proline 50
9
FeCl3
FeCl3
FeCl3
FeCl3
20
10
5
95
92
70
62
10
11
12
3
aGeneral reaction conditions: 0.3 mmol 1a and 0.3 mmol aniline in 1.5 mL water, stirred
at rt for 2 h.
bIsolated yield.
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Table 2. Water mediated synthesis of enaminones with various functional groupsa
Entry R1
R2
Product Yield (%)b
1
Ph
Ph
95
94
86
83
91
93
96
89
88
90
88
84
92
81
77
85
3a
3b
3c
3d
3e
3f
2
Ph
4-MeOC6H4
4-ClC6H4
2-MeOC6H4
Ph
3
Ph
4
Ph
5
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-NO2C6H4
4-NO2C6H4
4-MeC6H4
2-OHC6H4
6
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-NO2C6H4
Ph
7
3g
3h
3i
8
9
10
11
12
13
14
15
16
3j
4-ClC6H4
Ph
3k
3l
Ph
3m
3n
3o
3p
4-Me2NC6H4 3-ClC6H4
4-CF3C6H4
4-BrC6H4
2-IC6H4
4-AcC6H4
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17
Ph
Benzyl
-
trace
18
Ph
Cyclohexyl
-
trace
aReaction conditions: 0.3 mmol 1 and 0.3 mol 2, 20 mol- % FeCl3 in 1.5 mL water, stirred
at rt for 2 h.
bIsolated yield.
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Scheme 1. Different routes for enaminone synthesis
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Scheme 2. Application of product 3a in heterocycle synthesis
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Scheme 3. Deuterium labeling experiments on model reaction
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Scheme 4. Proposed reaction mechanism based on water promoted enaminone synthesis
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