Reduction of 2,2,2-trichloro-1-arylethanones by RMgX: Mechanistic investigation and the synthesis of substituted α,α-dichloroketones

Article abstract of DOI:10.1039/c3cc39147g

2,2,2-Trichloro-1-arylethanones undergo high yielding reductions to the corresponding 2,2-dichloro-1-arylethanones in the presence of RMgX. A single electron transfer mechanism for the reaction is proposed based on trapping experiments. Reaction of the intermediate enolates with a range of electrophiles is described, providing a convenient route to substituted α,α- dichloro-β-hydroxyketones and related molecules. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc39147g

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Reduction of 2,2,2-trichloro-1-arylethanones by RMgX:
mechanistic investigation and the synthesis of
substituted a,a-dichloroketones†
Ali H. Essa,ab Reinner I. Lerrick,ac Floriana Tuna,d Ross W. Harrington,a
William Clegga and Michael J. Hall*a
Cite this: Chem. Commun., 2013,
49, 2756
Received 21st December 2012,
Accepted 19th February 2013
DOI: 10.1039/c3cc39147g
www.rsc.org/chemcomm
Table 1 Reaction of PhMgBr with substituted 2,2,2-trichloro-1-(1H-pyrrol-2-
yl)ethanonesa
2,2,2-Trichloro-1-arylethanones undergo high yielding reductions
to the corresponding 2,2-dichloro-1-arylethanones in the presence
of RMgX. A single electron transfer mechanism for the reaction is
proposed based on trapping experiments. Reaction of the intermediate
enolates with a range of electrophiles is described, providing a
convenient route to substituted a,a-dichloro-b-hydroxyketones
and related molecules.
Entry
R
X
PhMgBr
Temp.
Product
Yieldb (%)
a,a-Dichlorocarbonyls are versatile synthetic intermediates,
typically formed by a-chlorination of carbonyls,1 chlorination
of silyl enolates,2 electrochemical or metal mediated reductions,3
aldol reactions4 or cycloadditions with dichloroketene.5 a,a-Dichloro-
carbonyl groups have been employed in intramolecular radical
cyclisations,6 have been converted to chloroalkenes,7 chlorooxiranes
allowing access to a-keto esters8 and heteroaromatics,9 have been
used as chlorinating agents10 and were found in the natural
product chlorotonil A.11 In designing new routes to function-
alised a,a-dichlorocarbonyls, we decided to investigate condi-
1
2
3
4
5
6
7
H
H
H
Me
H
H
H
H
H
H
H
Cl
Br
I
1.1 eq.
1.1 eq.
2.2 eq.
1.0 eq.
2.0 eq.
2.0 eq.
2.0 eq.
0 1C
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
2a
2a
2a
2b
2c
2d
2e
50
55
90
94
87
95
93
a
The reactions were performed by reverse addition of 1 mmol of ketone
b
in 1 mL of THF to a 2 M solution of PhMgBr in THF. Isolated yields.
tions for the reduction of 2,2,2-trichloro-1-arylethanones. We With the use of 1.1 equivalents of PhMgBr, at either 0 1C or r.t.,
envisaged that 2,2,2-trichloro-1-arylethanones being sterically the reaction resulted in the isolation of 2,2-dichloro-1-(1H-
hindered and electron-deficient aromatic ketones, would form pyrrol-2-yl)ethanone (2a) in 50–55% yield (Table 1, entries 1
reactive ketyl radical anions in the presence of a suitable single and 2), formally a C–Cl to C–H reduction.
electron donor such as a Grignard reagent.12 Further reaction
We postulated that the reaction may not go to completion
of the intermediate ketyl radical anion would then provide a due to competing deprotonation of the pyrrolic NH. Thus we
new route towards substituted a,a-dichloroketones. re-examined the reaction of compound 1a with 2.2 equivalents
Our initial investigations involved the addition of commer- PhMgBr at r.t., and the reaction of compound 1b (an analogous
cially available 2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethanone (1a) to N-methylated compound) with 1.0 equivalents of PhMgBr
PhMgBr, followed by quenching with excess aqueous NH4Cl. (Table 1, entries 3 and 4). In both cases near-quantitative yields
of the corresponding reduced compounds 2a and 2b were
a School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne,
isolated after quenching of the reaction. In addition three
di-halogenated pyrrole derivatives (1c–e) were also submitted
to the optimised reaction conditions, again yielding the corres-
ponding reduced products (2c–e) in high yield. Observation of
this C–Cl to C–H reduction prompted us to investigate the
mechanism in more detail.
NE1 7RU, UK. E-mail: m.hall@ncl.ac.uk; Fax: +44 (0)191 222 6929;
Tel: +44 (0)191 222 7321
b Department of Chemistry, College of Science, University of Basrah, Basrah, Iraq
c School of Chemistry, Nusa Cendana University, Indonesia
d School of Chemistry and Photon Science Institute, The University of Manchester,
Oxford Road, Manchester, M13 9PL, UK
† Electronic supplementary information (ESI) available: Experimental proce-
dures, 1H and 13C spectra and X-ray structures. Crystallographic data for 1d, 3a,
3b, 3f, 3g and 3h, have been deposited with the CCDC, deposition nos: CCDC
916095–916100. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c3cc39147g
After the reaction of 1a–e with PhMgBr and quenching with
aqueous NH4Cl, a major by-product was observed by H NMR
spectroscopy of the crude reaction mixtures, which on isolation
by silica gel chromatography was identified as 1,10-biphenyl.
1
c
2756 Chem. Commun., 2013, 49, 2756--2758
This journal is The Royal Society of Chemistry 2013

View Article Online
Communication
ChemComm
Table 2 Reaction of RMgX/R0MgX with ketone 1b
Yieldsa (%)
Entry
RMgX
R0MgX
R–R
R–R0
R0–R0
1
2
3
4
4-Me(C6H4)MgI
4-Me(C6H4)MgI
4-MeO(C6H4)MgI
4-MeO(C6H4)MgBr
4-Me(C6H4)MgI
PhMgI
4-Me(C6H4)MgI
PhMgBr
66
14b
43
0
—
24b
0
—
23
16
20
43
Fig. 1 (A) X-band EPR spectrum at 270 K of a THF solution resulting from the
reaction of PhMgBr with ketone 1b, in the presence of DMPO; (B) simulated
spectrum of the Ph–DMPO adduct with the parameters: g = 2.0096; a(1H) =
20.3 G and a(14N) = 13.87 G; (C) simulated spectrum of the Ph2–DMPO adduct,
with g = 2.0095 and a(14N) = 13.87 G. (100 kHz modulation frequency, 1 G
modulation amplitude, 0.27 mW incident microwave power).
a
b
Isolated yields. Products not separable, yield determined by GC-MS.
Table 3 Reaction trapping with D2O
In the case of entry 3, 40 mg of 1,10-biphenyl could be isolated,
corresponding to approximately 50% of the total added
PhMgBr. The formation of significant quantities of 1,10-biphenyl
is most likely to arise from the dimerisation of phenyl radicals
generated during the reaction.13,14
Ar
Product
Yield of 2a (%)
% Db
1-Methyl-1H-pyrrol-2-yl
p-Tolyl
1-(4-(tert-Butyl)phenyl)
(2-d)-2b
(2-d)-2f
(2-d)-2g
86
50
96
89
>95
93
To examine this supposition further we carried out an in situ
EPR experiment. Solutions containing ketone 1b and PhMgBr
in THF were added sequentially to an EPR tube cooled in liquid
N2. Further addition of the spin trap 5,5-dimethyl-1-pyrroline
N-oxide (DMPO) and subsequent warming to 270 K of the
reaction mixture produced a species with a well-resolved, 6-line
EPR spectrum (Fig. 1), corresponding to a Ph–DMPO adduct
(2,2-dimethyl-5-phenylpyrrolidin-1-olate radical) with distinc-
tive 1H and 14N hyperfine coupling constants: a(1H) = 20.3 G
and a(14N) = 13.87 G. A minor product, the 2,2-dimethyl-5,5-
diphenylpyrrolidin-1-olate radical, was also observed in the EPR
spectrum (3 lines, a(14N) = 13.87 G). In the absence of ketone 1b
neither adduct was observed, indicating that the Ph radical is
generated under the reaction conditions.
To further probe 1,10-biphenyl formation we examined the
reaction between ketone 1b and a number of other RMgX
species, where R was a para-substituted phenyl group (Table 2).
Reaction of 4-Me(C6H4)MgI with ketone 1b (Table 2, entry 1)
gave 4,40-dimethyl-1,10-biphenyl as a single regioisomer. One to one
mixtures of para-substituted phenyl Grignard regents (Table 2,
entries 2–4) gave in each case a mixture of 4,40-disubstituted-1,10-
biphenyl products. This suggests that the aryl–aryl bond is being
formed at the position of the original C–Mg bond, supporting
the formation 1,10-biphenyl products via a radical coupling
mechanism. This suggests that the RMgX is donating a single
electron from the R–Mg bond to the substrate.
a
b
Isolated yields. % Deuterium incorporation estimated by 1H NMR.
Table 4 Influence of R and X substituents
Yield/2a (%) Yield/R2 (%)
b
Entry R
X
Ar
1
2
3
4
5
6
7
8
Et Br 1-Methyl-1H-pyrrol-2-yl (1b) 50
i-Pr Cl 1-Methyl-1H-pyrrol-2-yl (1b) 42
Ph Cl 1-Methyl-1H-pyrrol-2-yl (1b) 61
Ph Br 1-Methyl-1H-pyrrol-2-yl (1b) 94
nd
nd
45
52
62
nd
nd
35
38
71
39
58
Ph
I
1-Methyl-1H-pyrrol-2-yl (1b) 94
Et Br p-Tolyl (1f)
i-Pr Cl p-Tolyl (1f)
Ph Cl p-Tolyl (1f)
Ph Br p-Tolyl (1f)
33
33
47
68
96
9
10
11
12
Ph
I
p-Tolyl (1f)
Ph Br 1-(4-(tert-Butyl)phenyl) (1g) 71
Ph
I
1-(4-(tert-Butyl)phenyl) (1g) 98
a
b
Isolated yields. Yield based on total RMgX added.
A comparison of Et, i-Pr and Ph groups (Table 4) showed that
the highest yields resulted from the use of aryl Grignards.15 In
We postulated that the overall reaction involves a late stage addition, reaction yields showed the trend: X = I > Br > Cl.
enolate intermediate, which is quenched by aqueous NH4Cl to
Variation of solvent (THF, Et2O and hexane) and concentration
give the observed reduction product. To confirm this, ketones had little effect on reaction outcomes. Only with extreme dilution
1b, 1f and 1g were reacted with PhMgBr and quenched with was any influence noticeable (see ESI†).
D2O to give, in 50–96% yield, the corresponding deuterated
products 2b, 2f, and 2g with high levels of D incorporation Grignard-mediated reduction of trichloroacetyl-substituted
(Table 3). aromatics. We suggest that the first step of the reaction is a
We then investigated the influence of the R (aryl, alkyl) and single electron transfer from the Grignard reagent to the
Therefore we propose a potential mechanism for the
X (halogen) groups of the Grignard reagent (Table 4).
ketone. This intermediate radical anion then either: (a) loses
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 2756--2758 2757

View Article Online
ChemComm
Communication
investigations into subsequent synthetic modification of
the a,a-dichloroketones formed will be discussed in future
publications.
The authors thank the Iraqi Ministry of Education (A.H.E.)
and the Indonesian Ministry of National Education (R.I.L.) for
funding, ESPRC for X-ray facilities at Newcastle (EP/F03637X/1),
the EPSRC National EPR Facility, the EPSRC National Mass
Spectrometry Service, Prof. W. McFarlane and Dr C. Wills (NCL)
for NMR support, and O. Aslan, M. Dunn, A. Nag and E. Çiftçi
(NCL) for synthesis of 1d–g.
Notes and references
Fig. 2 Proposed reaction pathways.
1 F. Bellesia, F. Ghelfi, F. Reverberi, F. Danna, V. Frenna, F. Felluga,
A. F. Parsons and D. Spinelli, Synthesis, 2012, 605; Z. Chen, B. Zhou,
H. Cai, W. Zhu and X. Zou, Green Chem., 2009, 11, 275; R. Akula,
M. Galligan and H. Ibrahim, Chem. Commun., 2009, 6991; J.-J. Kim,
D. H. Kweon, S.-D. Cho, H.-K. Kim, S.-G. Lee and Y.-J. Yoon, Synlett,
2006, 194; R. V. Hoffman, W. S. Weiner and N. Maslouh, J. Org.
Chem., 2001, 66, 5790.
Table 5 RMgX mediated reduction/functionalisation of 2,2,2-trichloro-1-(1-
methyl-1H-pyrrol-2-yl)ethanone
2 Y. Zhang, K. Shibatomi and H. Yamamoto, J. Am. Chem. Soc., 2004,
126, 15038.
´
´
´
3 G. Quintanilla, I. Perez, L. Zakova, C. Uth and F. Barba, Eur. J. Org.
Chem., 2011, 4681; T. Imanishi, Y. Fujiwara, Y. Sawama,
Y. Monguchi and H. Sajiki, Adv. Synth. Catal., 2012, 354, 771.
4 H. Sasai, S. Arai and M. Shibasaki, J. Org. Chem., 1994, 59, 2661;
R. Imashiro and T. Kuroda, J. Org. Chem., 2003, 68, 974.
Producta
Electrophile
R
Yieldb (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
PhCHO
PhCH(OH)
81c
85c
94
ˇ´
´
5 C. Roche, K. Kadlecıkova, A. Veyron, P. Delair, C. Philouze,
A. E. Greene, D. Flot and M. Burghammer, J. Org. Chem., 2005,
70, 8352.
4-MeO(C6H4)CHO
4-I(C6H4)CHO
5-Me(C4H2O)CHO
C6F5CHO
4-NO2(C6H4)CHO
4-NO2(C6H4)CH2Cl
4-NO2(C6H4)COCl
(EtO2C)2CO
4-MeO(C6H4)CH(OH)
4-I(C6H4)CH(OH)
5-Me(C4H2O)CH(OH)
C6F5CH(OH)
4-NO2(C6H4)CH(OH)
4-NO2(C6H4)CH2
4-NO2(C6H4)C(O)
(EtO2C)2C(OH)
C6H5C(O)
6 D. Yang, Y.-L. Yan, B.-F. Zheng, Q. Gao and N.-Y. Zhu, Org. Lett.,
2006, 8, 5757.
7 Z. T. Narumi, T. Kobayakawa, H. Aikawa, S. Seike and H. Tamamura,
Org. Lett., 2012, 14, 4490; D. K. Barma, A. Kundu, H. Zhang,
C. Mioskowski and J. R. Falck, J. Am. Chem. Soc., 2003, 125, 3218.
8 D. Yang, M. Yang and N.-Y. Zhu, Org. Lett., 2003, 5, 3749.
70
70
96c
37c
95c
75
´
9 G. R. Lawton, H. Ji, P. Martasek, L. J. Roman and R. B. Silverman,
3j
C6H5COCl
50
`
Beilstein J. Org. Chem., 2009, 5, No. 28; F. Serra, P. Coutrot, M. Esteve-
a
1b was reacted in THF with PhMgBr at r.t. for 1 h, after which a
Quelquejeu, P. Herson, T. K. Olszewski and C. Grison, Eur. J. Org.
Chem., 2011, 1841.
analysis showed that the reaction was complete. Isolated yields. 10 H. Wack, A. E. Taggi, A. M. Hafez, W. J. Drury III and T. Lectka, J. Am.
suitable electrophile was added and the mixture stirred at r.t. until TLC
b
c
Structures confirmed by single-crystal X-ray analysis.
Chem. Soc., 2001, 123, 1531.
11 N. Rahn and M. Kalesse, Angew. Chem., Int. Ed., 2008, 47, 597.
12 E. C. Ashby and A. B. Goel, J. Am. Chem. Soc., 1981, 103, 4983;
E. C. Ashby, Pure Appl. Chem., 1980, 52, 545; E. C. Ashby, Acc. Chem.
Res., 1988, 414.
a chlorine atom, (b) accepts a second electron and subsequently
loses chloride or (c) loses chloride followed by addition of a second
electron, to give the corresponding magnesium enolate (Fig. 2).16
Since the intermediate magnesium enolates can be intercepted
by electrophiles, we have exploited this chemistry as a convenient
13 Trace 2-phenyltetrahydrofuran could also be detected by 1H NMR
and GCMS, when reactions were carried out in THF. We postulate
that this is formed through radical
H abstraction from the
a-position of THF, followed by coupling of resulting THF derived
radical with a phenyl radical.
‘‘one-pot’’ reductive-functionalisation of 2,2,2-trichloro-1-(1-methyl- 14 Commercial PhMgBr was shown to contain o2 mg of Ph2 per mmol.
15 J. Villieras and B. Castro, Bull. Soc. Chim. Fr., 1970, 3, 1189;
1H-pyrrol-2-yl)ethanone (1b) to give substituted a,a-dichloro-
K. Maruyama, Y. Matano and T. Katagiri, J. Phys. Org. Chem.,
1991, 4, 501.
ketones. Reaction with 1-(chloromethyl)-4-nitrobenzene gave only
a moderate yield of the expected product. Good yields were however 16 No evidence of atomic chlorine or bromine was observed by EPR.
Neither C6H5Cl nor C6H5Br (the coupling products of phenyl radical
and atomic halogen) could be detected by GCMS of the crude
reaction mixture leading to 2b.
obtained on reaction with diethyl 2-oxomalonate, aryl acid
chlorides or aryl aldehydes (Table 5).17
In conclusion we have demonstrated a new approach 17 The corresponding magnesium enolate can be prepared from 2b
through deprotonation with NaH in THF, followed by ion exchange
to functionalised a,a-dichloroketones, via the reaction of com-
mercially available RMgX reagents with 2,2,2-trichloro-1-aryl-
ethanones. Additional examination of the substrate scope and
with MgCl2. The enolate was reacted with D2O to give a 78% yield
(84% deuterium incorporation by 1H NMR) of (2-d)-2b or
4-NO2(C6H4)CHO to give a 47% yield of 3f.
c
2758 Chem. Commun., 2013, 49, 2756--2758
This journal is The Royal Society of Chemistry 2013