An efficient Darzens reaction promoted by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)

Article abstract of DOI:10.1016/j.tetlet.2019.06.034

An efficient DBU promoted Darzens reaction utilising α-haloketones containing an enolizable α′-hydrogen is reported. This method diastereoselectively afforded the corresponding α,β-epoxy ketones good to excellent yields in an one-pot reaction without using any transition metals or additives. Furthermore, haloketones without an α′-hydrogen are also applicable in this reaction.

Full text of DOI:10.1016/j.tetlet.2019.06.034

Accepted Manuscript
An Efficient Darzens Reaction Promoted by 1,8-Diazabicyclo[5.4.0]undec-7-
ene (DBU)
Juan Luo, Lanfang Hu, Minghao Zhang, Qiang Tang
PII:
S0040-4039(19)30587-8
https://doi.org/10.1016/j.tetlet.2019.06.034
TETL 50875
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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12 June 2019
18 June 2019
Please cite this article as: Luo, J., Hu, L., Zhang, M., Tang, Q., An Efficient Darzens Reaction Promoted by 1,8-
Diazabicyclo[5.4.0]undec-7-ene (DBU), Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.
2019.06.034
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Tetrahedron Letters
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An Efficient Darzens Reaction Promoted by 1,8-Diazabicyclo[5.4.0]undec-7-ene
(DBU)
Juan Luo,a Lanfang Hu,a Minghao Zhang,a Qiang Tang*a
aCollege of Pharmacy, Center for Lab Teaching and Management, Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University,
No.1 Yixueyuan Road, Chongqing 400016, P. R. China
Corresponding author.Tel.:+86 02368485161; e-mail address: tangqiang@cqmu.edu.cn (Q. Tang).
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient DBU promoted Darzens reaction utilising α-haloketones containing an enolizable
α’-hydrogen is reported. This method diastereoselectively afforded the corresponding α,β-epoxy
ketones good to excellent yields in an one-pot reaction without using any transition metals or
additives. Furthermore, haloketones without an α’-hydrogen are also applicable in this reaction.
Available online
Keywords:
DBU
2019 Published by Elsevier Ltd.
Darzens reaction
α,β-Epoxy ketone
α-Haloketone
Epoxide moieties are key structures which are present in
various bioactive compounds such as natural products,1
pharmaceuticals2 and agrochemicals.3 Furthermore, they are
versatile synthetic intermediates that can be converted into a wide
range of polyfunctional compounds.4 Hence, various methods
for the synthesis of epoxides have been reported.5 Among them,
the Darzens reaction is one of the most widely used
methodologies due to its ability to tolerate oxidation-sensitive
functionalities.6
to undergo α’-hydrogen abstraction and subsequent nucleophilic
substitution of the halide followed by nucleophilic addition at the
carbonyl group to afford carboxylic acids (Scheme 1, b).12 On the
basis of the competing rearrangement, neutral conditions might
be beneficial for the Darzens reaction. Thus, Sn(OTf)2,13
Zr(OtBu4),14 and stannyl carbamate15 have been employed as
enolate-generating agents to produce α,β-epoxy ketones in one or
two steps (Scheme 1, c). However, these methods are not
convenient because they require transition metals, some of which
are not prepared easily, and additives, such as HMPA or KF-
dicyclohexyl-18-crown-6.
1,8-Diazabicyclo[5.4.0]undec-7-ene
(DBU),
normally
regarded as a hindered and weak nucleophile,16 has been
efficiently utilised in a variety of base-mediated organic
transformations
including
elimination,
isomerization,
esterification, and halogenation.17 On the basis of this
background, we proposed that DBU might be an
effective promoter for the selective Darzens reaction of α-
haloketones bearing an enolizable α’-hydrogen.
Based on a primary screening of solvents (not shown),
dichloromethane was recognized as the
most suitable solvent.
Next, we investigated the influence of different bases on the
model Darzens reaction between aldehyde 1a and haloketone 2a
(Table 1). Unfortunately, the reaction in the presence of a weak
inorganic base (Na2CO3), afforded a poor yield of the desired
product 3a at room temperature (Entry 1). In contrast, a strong
base, such as NaOH, NaOMe, and NaOEt, accelerated the
reaction. However, the Favorskii rearrangement of haloketone 2a
occurred with other side reactions and resulted in the low yield of
3a (Entry 2). Use of a secondary amine, pyrrolidine, initially
Figure 1. Reactions of α-haloketones under basic conditions.
Generally, the Darzens reaction involves the condensation of
aldehydes with α-halo carbonyl compounds lacking an α’-
hydrogen in the presence of a base for the construction of α,β-
epoxy ketones,7 epoxy esters,8 epoxy amides,9 epoxy nitriles,10 or
epoxy sulfoxides11 (Scheme 1, a). Under strongly basic
conditions, α-halo ketones containing an α’-hydrogen are likely

2
Tetrahedron
gave epoxide 3a, but other products were formed when the
reaction time was increased (Entry 3). When tertiary amines,
such as Et3N, 1,4-diazabicyclo[2.2.2]octane (DABCO), N,N-
dimethylpyridin-4-amine
(DMPA),
and
hexamethylphosphoramide (HMPA) were screened, low reaction
rates and poor yields were observed (Entry 4).
Entry
Haloketone
Epoxide
Time
[h]
Yield
[%]b,c
1
8
74
To
our
delight,
when
DBU
or
DBN
(1,5-
diazabicyclo[4.3.0]non-5-ene) was used as a base, the Darzens
reaction proceeded quickly with only small amounts of byproduct
4a (Entries 5-6). The reaction afforded better yields of epoxide
3a when conducted at a lower temperature (Entry 7). Notably, the
reaction did not proceed to completion when a substoichiometric
amount of DBU and an excess amount of other bases, such as
Na2CO3, Et3N, and DABCO were employed.
2
3
8
8
93
94
4
5
20
20
80
71
Table 1. Model reaction optimization. a
6
12
82
Entry
1
Base
oC
25
Time
3a [%] b,c
4a [%]b,c
Na2CO3
>48 h
14
-- d
7
8
12
12
73
75
2
3
4
5
6
7
8
Strong base e
pyrrolidine
25
25
4 h
24 h
>48 h
4 h
31 f
complex
10-30
63
trace
-- d
-- d
9
Tertiary amine g
DBN
25
25
a
Reagents and conditions: 1a (0.5 mmol), 2 (0.55 mmol), DBU (0.6 mmol),
CH2Cl2 (2 mL); Isolated yield; The configuration was determined by
comparison with literature data.
b
c
DBU
25
4 h
71
8
DBU
-20
-20
8 h
84
trace
-- d
DBU/base h
>48 h
30-50
Table 3. Reaction of 2-chlorocyclohexanone 2a with various aldehydes a..
a
Reagents and conditions: 1a (0.5 mmol), 2a (0.55 mmol), base (0.6
b
c
mmol), CH2Cl2 (2 mL); Isolated yield; The configuration was
determined by comparison with literature data; d Not detected; e Strong
f
g
base: NaOH, NaOMe, NaOEt; Accompanied by other by-products;
Tertiary amine: Et3N, DABCO, DMPA, HMPA; h DBU (0.1 mmol),
base (0.6 mmol: Na2CO3, Et3N, DABCO).
Entry
Aldehyde
Epoxide
Time
[h]
Yield
[%]b,c
We then explored the reaction scope of α-haloketones with
benzaldehyde 1a using DBU as the base at -20 C. When cyclic
o
1
α-haloketones were employed (Table 2, entries 1-3), the ring size
strongly affected the reaction yields and cyclic haloketones with
larger rings resulted in excellent yields (Entries 2-3). On the other
hand, the reactions of acyclic α-haloketones resulted in moderate
to good yields with longer reaction times compared to cyclic
haloketones (Entries 4-7). The reactions of α-bromoketones 2g-h
were faster than those of α-chloroketones 2e-f. Additionally,
these reaction conditions were applicable for aromatic α-
bromoketone 2i lacking α’-hydrogens (Entry 8).
8
8
8
8
84
94
90
93
2
3
4
To further explore the reaction scope, we examined the
Darzens reaction of 2-chlorocyclohexanone 2a with different
aromatic aldehydes (Table 3). The reaction with benzaldehydes
possessing electron donating groups (Entries 2-4) led to the
corresponding epoxy ketones (3j-l) in excellent yields, while the
use of benzaldehydes containing electron withdrawing groups
(Entries 5-8) gave lower yields. Notably, the reaction with
unsaturated aliphatic aldehydes such as cinnamaldehyde (Entry
9), gave 3q while the reaction was complex using saturated
aliphatic aldehydes.
5
4
4
4
85
77
81
6
7
Table 2. Reaction of benzaldehyde 1a with various α-haloketones bearing
enolizable α’-hydrogens.a

8
9
4
8
65
78
3. Matsumoto, E.; Kawanaka, Y.; Yun, S.-J.; Oyaizu, H., Appl. Microbiol. Biotechnol.
2009, 84, 205-216.
4. (a) Shen, J.; Yang, Y.; Hou, X.; Zeng, W.; Yu, A.; Zhao, X.; Meng, X., Organic &
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Cussó, O.; Serrano-Plana, J.; Costas, M., ACS Catalysis 2017, 7, 5046-5053; (d)
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a
Reagents and conditions: 1 (0.5 mmol), 2a (0.55 mmol), DBU (0.6 mmol),
CH2Cl2 (2 mL); Isolated yield; The configuration was determined by
comparison with literature data.
b
c
6. (a) Li, Z.; Jangra, H.; Chen, Q.; Mayer, P.; Ofial, A. R.; Zipse, H.; Mayr, H., J. Am.
Chem. Soc. 2018, 140, 5500-5515; (b) de los Santos, J. M.; Ochoa de Retana, A. M.;
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(e) Watanabe, S.-i.; Hasebe, R.; Ouchi, J.; Nagasawa, H.; Kataoka, T., Tetrahedron
Lett. 2010, 51, 5778-5780.
In summary, we have developed an efficient DBU promoted
Darzens reaction of acyclic and cyclic α-haloketones bearing an
enolizable α’-hydrogen. Moreover, the reaction is also applicable
for haloketones without an α’-hydrogen. Further research for the
asymmetric catalysis of this reaction is being pursued in our lab.
7. Ashokkumar, V.; Siva, A.; Ramaswamy Chidambaram, R., Chem. Commun. 2017, 53,
10926-10929.
8. Tanaka, K.; Kobayashi, K.; Takatori, K.; Kogen, H. Tetrahedron 2017, 73, 2062-
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2109-2115.
Acknowledgments
We appreciate financial support from the Fundamental and Advanced
Research Projects of Chongqing City (No. cstc2018jcyjA0150), and
Chongqing Science and Technology Commission (cstc2015zdcy-ztzx120003).
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Supplementary Material
Detailed experimental procedures, characterisation data, and copies of 1H
and 13C NMR spectra of products can be found online at
https://doi.org/10.1016/
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4
Tetrahedron

 Darzens reaction with the α-haloketones
containing an enolizable α’-hydrogen as
starting materials.
 The
reaction proceeds with high
diasteroselectivity.
 Without using any transition metals or
additives.

Graphical Abstract
DBU promoted Darzens reaction with the α-haloketones
containing an enolizable α’-hydrogen as starting materials.
An Efficient Darzens Reaction Promoted by
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)
Leave this area blank for abstract info.
Juan Luo, Lanfang Hu, Minghao Zhang, Qiang Tang