Lewis base mediated halogenation/semipinacol rearrangement of diazo compounds: New access to α-halo-quaternary ketones

Article abstract of DOI:10.1039/c4cc04154b

A novel halogenation/semipinacol rearrangement of α-diazo alcohol catalyzed by Lewis base has been developed through a carbene-free mechanism. This semipinacol transposition, initiated by an electrophilic halogenation (X = Cl⁺, Br⁺, and I⁺) of diazo carbon event, furnished a convenient synthetic route for the efficient synthesis of α-halo-quaternary ketones under mild conditions. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc04154b

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Lewis base mediated halogenation/semipinacol
rearrangement of diazo compounds: new access
to a-halo-quaternary ketones†
Cite this: Chem. Commun., 2014,
50, 9773
Received 30th May 2014,
Accepted 3rd July 2014
Haibin Mao,a Zhongkai Tang,a Hongwen Hu,a Yixiang Cheng,a Wen-Hua Zhenga
and Chengjian Zhu*ab
DOI: 10.1039/c4cc04154b
www.rsc.org/chemcomm
A novel halogenation/semipinacol rearrangement of a-diazo alcohol
catalyzed by Lewis base has been developed through a carbene-free
mechanism. This semipinacol transposition, initiated by an electro-
philic halogenation (X = Cl+, Br+, and I+) of diazo carbon event,
furnished a convenient synthetic route for the efficient synthesis of
a-halo-quaternary ketones under mild conditions.
As metal carbene precursors, diazo compounds have been widely
applied in organic synthesis which participate in metal-catalyzed
rearrangements, cycloadditions, X–H (X = C, N, O, Si, S, etc.) bond
insertions, and ylide-forming reactions (Scheme 1A).1 On the
other hand, diazo group transformations can also be realized
through the carbene-free mechanism since diazo carbon is
electron-rich in nature,2 as evident from the resonance structure
II (Scheme 1B). Diazo carbon can react with the electron-deficient
species (E+ = H+,3 organoboron,4 carbonyl activated by Lewis
Scheme 1 Activation patterns of the diazo carbon.
acids,5 imine activated by Brønsted acids,6 etc.) to form a a novel asymmetric halogenation/semipinacol rearrangement8
procarbonium ion intermediate III, which is quenched by the reaction of allylic alcohols catalyzed by chiral Lewis bases for the
electron-rich species with concomitant expulsion of N2 synthesis of chiral a-quaternary b-haloketones (Scheme 2A).9
(Scheme 1B). It is observed that the long-standing interest in Furthermore, Murphy realized the gem-dihalogenation of diazo-
the diazo chemistry was based on the reactions of carbene, acetate derivatives using Lewis bases as catalysts.10 Inspired by
particularly in transition-metal catalysis. While in considera- this previous work, and also in conjunction with our ongoing
tion of environmental friendliness, convenient operation interest in the synthesis and applications of diazo compounds
and diversity of diazo transformation, the development of without a metal catalyst,11 we describe herein our results on the
efficient and elegant functionalization of diazo compounds Lewis base catalyzed halogenation/semipinacol rearrangement of
by the carbene-free mechanism is really of great signifi- diazo compounds (Scheme 2B). This strategy provides new access
cance for further application of diazo compounds in organic to a-halo-quaternary ketones via the carbon-chain extension or
synthesis.
ring expansion of ketones. These organohalo compounds
Very recently, chiral Lewis bases (LB) were used to catalyze the are a very important class of synthetic intermediates that are
asymmetric halogenation of alkenes.7,9 Especially, Tu developed useful for the construction of a-quaternary ketones.12 More-
over, we also make a preliminary effort to develop the catalytic,
a School of Chemistry and Chemical Engineering, State Key Laboratory of
Coordination Chemistry, Nanjing University, Nanjing, 210093, P. R. China.
E-mail: cjzhu@nju.edu.cn; Fax: +86-25-83594886
asymmetric version of this reaction, which led to moderate
enantioselectivity.
We began by testing the halogenation/semipinacol rearrange-
ment of a-diazo alcohols 2a, which could be easily prepared from
the commercially available benzophenone and ethyl diazoacetate.13
We observed that a combination of 2a and 1,3-dichloro-5,5-
dimethylhydantoin (DCDMH, 3a) in THF at room temperature
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Shanghai, 200032, P. R. China
† Electronic supplementary information (ESI) available: Complete experimental
procedures, characterization data and copies of NMR spectra of all the new
compounds. See DOI: 10.1039/c4cc04154b
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rearrangement (Table 2). Various a-diazo alcohols 2 derived
from symmetrical benzophenone derivatives with halogen or
electron-donating substituents were suitable substrates for the
chlorination (Table 2, entries 1–5) or bromination reaction
(Table 2, entries 11–14), leading to the desired products in
excellent yields (up to 93%). Generally, chlorination reaction gave
lower yields and lower reaction efficiency, while bromination
reaction gave higher yields and higher reaction efficiency. Besides
the carbon-chain extension, this method could effectively achieve
the ring expansion of cyclic ketones (Table 2, entries 6 and 15).
Interestingly, the chlorination reaction proceeded well over sub-
strates derived from dissymmetrical alkyl aryl ketones, giving the
products chemoselectively in good yields. When employing the
chain alkyl aryl ketones as substrates, electron-rich phenyl ring
migration had priority in the selective formal C–C insertion
process (Table 2, entries 7–9). While when the diazo compound
2j derived from a-tetralone was used, alkyl migration is dominant
Table 2 Substrate scope studiesa
Scheme 2 Semipinacol rearrangement initiated by electrophilic halogenation.
afforded the corresponding product in 72% yield (Table 1, entry 1).
To further improve reaction efficiency, we examined a number of
Lewis bases (Table 1, entries 2–5). The addition of 10 mol% tri-
ethylamine prolonged the reaction time obviously compared with
the background reaction (Table 1, entry 3). Surprisingly, when
10 mol% of DABCO was used, the desired a-chloro-quaternary
ketone 4a was obtained in 78% isolated yield in 20 min (Table 1,
entry 4). Next, a variety of common organic solvents were
screened (Table 1, entries 4, 6–9). The experimental results
revealed that increased solvent polarity led to the increase of
reaction efficiency. However, this was associated with some
by-products, resulting in significantly reduced yields.
Entry Substrate
X
Product
Yieldb (%)
1
2
3
4
5
2a: R1 = R2 = Ph
3a:Cl 4a
78
80
71
81
85
2b: R1 = R2 = 4-F-C6H4
2c: R1 = R2 = 4-Cl-C6H4
2d: R1 = R2 = 4-Me-C6H4
Cl
Cl
Cl
4b
4c
4d
4e
2e: R1 = R2 = 4-OMe-C6H4 Cl
6
Cl
91
7
8
9
2g: R1 = Ph, R2 = Me
2h: R1 = Ph, R2 = Et
Cl
Cl
Cl
4g
4h
4i
76
73
78
2i: R1 = Ph, R2 = Pr
i
With the optimal reaction conditions in hand, we investi-
gated the substrate scope of this halogenation/semipinacol
10
Cl
61
Table 1 Optimization of the reaction conditionsa
11
12
13
14
2a: R1 = R2 = Ph
3b:Br 4k
92
93
82
91
2b: R1 = R2 = 4-F-C6H4
2c: R1 = R2 = 4-Cl-C6H4
2d: R1 = R2 = 4-Me-C6H4
Br
Br
Br
4l
4m
4n
Entry
Cat.
Solvent
t
Yieldb (%)
1
2
3
4
5
6
7
8
9
None
Py
Et3N
DABCO
DBU
DABCO
DABCO
DABCO
DABCO
THF
THF
THF
THF
2 h
40 min
12 h
20 min
1 h
1 h
10 min
10 min
1 min
72
72
71
78
68
76
72
68
67
15
Br
95
78
THF
16c
2a: R1 = R2 = Ph
NIS
Toluene
DCM
EA
a
The reaction was carried out using 0.20 mmol of 2, 0.25 mmol of 3,
MeCN
and 10 mol% of DABCO (0.02 mmol) in THF (2.0 mL) at room
a
b
c
Unless otherwise noted, the reaction was carried out using 0.20 mmol temperature. Yield of the isolated product. The reaction was carried
b
of 2a, 0.25 mmol of 3a, and 10 mol% of the catalyst (0.02 mmol). Yield out using 0.20 mmol of 2a and 0.25 mmol of NIS in THF (0.2 mL) under
of the isolated product.
an argon atmosphere at room temperature for 20 hours.
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Scheme 3 Catalytic asymmetric variant of this process.
(Table 2, entry 10; see the ESI† for possible reasons). In addition,
under the dry and oxygen-free argon atmosphere, a-iodo-quaternary
ketone could be synthesized efficiently by iodination/semipinacol
rearrangement (Table 2, entry 16). It is noteworthy that DABCO
would drastically reduce the efficiency of iodination reaction.
We also attempted to develop a catalytic asymmetric version
of this halogenation/semipinacol rearrangement for gaining
access to enantioenriched a-halo-quaternary ketones. After a
series of efforts (see the ESI† for further details), we discovered
that product 4o could be obtained in 86% yield with 72% ee
when employing 20 mol% cinchona alkaloid (DHQD)2PHAL as
a catalyst (Scheme 3).
In conclusion, we have developed a novel halogenation/
semipinacol rearrangement of a-diazo alcohol catalyzed by Lewis
base. This methodology greatly expands the synthetic applica-
tions of diazo compounds through the carbene-free mechanism.
The protocol provides a straightforward way to generate the
a-halo-quaternary ketones under mild conditions. We believe
that the resulting densely functionalized ketones bearing a-halo
quaternary carbon could be highly valuable and versatile inter-
mediates for further transformations. To further realize the
asymmetric version of this reaction, we examined a number of
chiral tertiary amines and various reaction parameters, which
led to moderate enantioselectivity. Efforts to realize the highly
enantioselective version of this reaction and further exploration
of the asymmetric reaction scope are ongoing in our laboratory.
We gratefully acknowledge the National Natural Science
Foundation of China (21372114, 21172106, 21074054), National
Science Fund for Talent Training in Basic Science (no. J1103310),
the National Basic Research Program of China (2010CB923303) and
the Research Fund for the Doctoral Program of Higher Education
of China (20120091110010) for their financial support.
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Chem. Commun., 2014, 50, 9773--9775 | 9775