Facile and efficient preparation of α-halomethyl ketones from α-diazo ketones catalyzed by iron(III) halides and silica gel

Article abstract of DOI:10.1016/j.tetlet.2018.02.024

An efficient and mild method for the synthesis of α-halomethyl ketones from α-diazo ketones was developed using ferric chloride or bromide as the halogen source and silica gel as the hydrogen source, with good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2018.02.024

Accepted Manuscript
Facile and efficient preparation of α-halomethyl ketones from α-diazo ketones
catalyzed by iron(III) halides and silica gel
Xinxia Shi, Lingqiong Zhang, Pengfei Yang, Han Sun, Yilan Zhang, Chunsong
Xie, Zhen Ou-yang, Min Wang
PII:
S0040-4039(18)30194-1
https://doi.org/10.1016/j.tetlet.2018.02.024
TETL 49709
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 December 2017
8 February 2018
9 February 2018
Please cite this article as: Shi, X., Zhang, L., Yang, P., Sun, H., Zhang, Y., Xie, C., Ou-yang, Z., Wang, M., Facile
and efficient preparation of α-halomethyl ketones from α-diazo ketones catalyzed by iron(III) halides and silica gel,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.02.024
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
1

Facile and efficient preparation of α-halomethyl ketones from
α-diazo ketones catalyzed by iron(III) halides and silica gel
Xinxia Shi,a+ Lingqiong Zhang,a+ Pengfei Yang, a Han Sun, a Yilan Zhang,a Chunsong Xie,a Zhen
Ou-yang,b Min Wang*a
a
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University,
Hangzhou 310036, China
b School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
+ These authors contributed equally to this work.
Fax: +86-571-28867899.
E-mail: mwang@hznu.edu.cn
ABSTRACT: An efficient and mild method for the synthesis of α-halomethyl ketones from
α-diazo ketones was developed using ferric chloride or bromide as the halogen source and silica
gel as the hydrogen source, with good to excellent yields.
Key words: Iron (III) chloride, Iron (III) bromide, α-Halomethyl ketone, α-Diazo-ketones, Silica
gel
Recently, α-halomethyl ketones have become increasingly important building blocks
in organic synthesis,1 and have been widely applied in various fields, including
pharmaceutical synthesis, pesticides, and spices. 2 Several methods for constructing
α-halomethyl ketones have been developed in the past decade. Generally, these
processes involve the direct halogenation of ketones or their derivatives, using
N-halosuccinimides (NBS, NCS, NBA, NCA),3 metal halides,4 halogens,5 or
DCDMH/DBDMH,6 to form α-mono- or α,α-dichloroketones as halogenating
reagents.7On the other hand, a new approach involving the hydration of haloalkynes
or oxyhalogenation of alkynes has been developed in recent years and become a hot
topic.8 However, the aforementioned halogen reactions are inefficient due to their
long reaction times, costly catalysts, or use of strong protic acids. Another method
involves the addition of α-diazoacetophenones with monohalides, or molecular
halogens to obtain α-haloketones in good yields.9 But this has the relative
disadvantages of using a strong acid as catalyst and harsh reaction conditions.
Considering these challenges, we herein report a mild and efficient synthesis of
α-halomethyl ketones from α-diazo ketones in the presence of FeCl3 or FeBr with
silica gel in good to excellent yields at room temperature. More significantly,
compared with the traditional method using strong protic acids, iron halides are easy
to operate.
Initially, the reaction conditions were optimized using α-diazoacetophenone10 (1a)
as a model substrate for chlorination. Compound 1a was treated with 0.5 equiv. of
FeCl3 in dichloromethane (DCM), with the results shown in Table 1. The temperature
had almost no effect on the reaction (entries 1–3), with similar yields obtained at
2

lower temperatures, so room temperature was chosen for subsequent experiments.
Regarding solvent selection, as protic solvents would attack the carbine carbon,
leading to the formation of acetophenone or a mixed product (entries 4 and 5), only
nonprotic solvents were tested for this reaction. Unfortunately, the reaction did not
proceed in THF, a result which remains to be explored (entry 6). Halogenated solvents
were more appropriate, affording the best yields of up to 70%, while toluene only
produced yields of up to 60% (entries 1 and 7). When using nitrogenous solvents,
such as CH3CN or DMF, only poor yields were obtained (entries 10 and 11). When
other metal chlorides were screened, stronger Lewis acids participated in the reaction,
but afforded slightly lower yields (entries 13 and 14). When CuCl2 or neutral salt KCl
was used, no product was found (entries 15 and 16). When a protic acid was used
instead of silica gel, a lower yield was obtained (entry 18).
Table 1 Optimization of experimental conditionsa
Entry
1
Lewis Acid Temperature
Solvent
DCM
DCM
DCM
H2O
Yieldb(%)
70
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl2
InCl3
TiCl4
CuCl2
KCl
RT
0 oC
-30 oC
RT
2
71
3
70
4
mix
85c
NR
60
5
RT
CH3OH
THF
6
RT
7
RT
PhCH3
CHCl3
DCE
8
RT
63
9
RT
67
10
11
12
13
14
15
16
17
18
RT
CH3CN
DMF
DCM
DCM
DCM
DCM
DCM
DCM
DCM
mix
mix
36
RT
RT
RT
37
RT
63
RT
NR
NR
70d
15e
RT
FeCl3
FeCl3
RT
RT
a Reaction conditions: 1a (0.5 mmol), Lewis Acid (0.25 mmol, 0.5 equiv.) and silica gel 100 mg in
2 mL solvent with 10 mins.
b Isolated yields.
c The resulting product was acetophenone.
d The reaction time was 1h.
e 2.0 equiv. acetic acid was used instead of silica gel, 24h.
3

Based on the above optimization, we next examined the substrate scope of this
reaction. Various substituents on the phenyl ring afforded the corresponding
α-chloromethyl ketones in moderate to good yields. Firstly, the efficiency of different
halogen-substituted substrates was investigated. The results showed that the
substituent position had a significant effect on the reaction (Table 2, entries 2–5). For
example, ortho-iodoacetophenone gave a higher yield (2c, entry 3) than its
para-substituted counterpart (entry 5). Other para-substituted substrates, with either
electron-donating or electron-withdrawing groups, reacted smoothly, giving desired
products 2e–2h in 56–75% yield. Among these, para-methyl-substituted 1h gave a
lower yield of 56% (entry 8), para-acetyl-substituted 1i gave the yield of 70%
comparing with similar para-benzoyl-substituted structure was reported by using HCl
to give the yield of 25%.11 Furthermore, the substrate bearing a naphthyl ring gave the
highest yield, with corresponding product 2l isolated in 82% yield (entry 10). Dialkyl
ketone substrates were also tested, with 1k reacting smoothly under the optimized
conditions to give the desired nitrile 2k in a highest yield of 68%. When 1l, 1m, 1n
were subjected to this optimal conditions, the expected products 2l, 2m, 2n was
isolated with similar lower yield about 45%. Unfortunately, substituting a methoxy
group at the ortho position of the substrate failed to provide the desired chloric
product, instead affording coumaranone in excellent yield (97%), which is commonly
obtained from same starting material using a large excess of protic acid as catalyst,
such as HCl, AcOH, or CF3COOH.12, 13
Table 2 Chlorination of various α-diazo-methyl ketonesa
Entry
Substrate
Product
Yield(%)b
1
70
1a
1b
1c
1d
1e
2a
2
3
4
5
65
81
65
73
2b
2c
2d
2e
4

6
7
75
65
56
70
82
1f
1g
1h
1i
2f
2g
2h
2i
8
9
10
1j
1k
1l
2j
2k
2l
11
68
45
12
13
14
15
40
50
97
1m
1n
2m
2n
1o
2o
a Reaction conditions: 1a (0.5 mmol), FeCl3 (0.25 mmol, 0.5 equiv.) and silica gel 100 mg in 2 mL
solvent, room temperature, 10 mins.
b Isolated yields.
In order to understand well this reaction mechanism, some designed experiments were
carried out. As previously reported by Xiang and Zhang,14 α-chloro/bromo methyl
ketones could be obtained when 1,2-dichloroethane or 1,2-dibromoethane were used
5

Table 3 Control variable method to investigate the halogen sourcea
Entry
FeCl3(mol%)
Yield(%)b
1
2
3
4
10
20
30
50
31
54
65
70
a Reaction conditions: 1a (0.5 mmol), FeCl3 (0.25 mmol, 0.5 equiv.) and silica gel 100 mg in 2 mL
solvent, room temperature, 10 mins.
b Isolated yields.
as solvent. Therefore, chloride or bromide apparently came from the halogenated
reaction solvent. To better understand where the halide came from in our reaction, we
verified our conjecture by loading with different amounts of FeCl3, as shown in Table
3. When 10–30% FeCl3 was used, the product yield increased from 31% to 65%
(entries 1–3). Increasing the amount of Lewis acid to 50% and 100%, the yield was
not enhanced as expected, which indicated that the halogen atom of the product came
from the three chlorine atoms of FeCl3. If iron (III) chloride on silica gel (5 wt. %
loading) was used, very similar yield could be obtained. But when FeCl3/silica gel
.
was replaced by FeCl3 6H2O as both of chloride and hydrogen source or
CuCl2/Fe(OTf)3 with silica gel as chloride source, the yield of the desired product 2a
was significant decreased even with long reaction time (Scheme 2). These results
demonstrated that the Lewis activity and hydrogen source dramatically effect this
transformation. In addition, when FeCl3 was added to the reaction, the bubble was
produced immediately, which showed that an iron carbene intermediate II was
formed.15 Subsequently, the Cl anion was inserted, which was trapped through a
Scheme 1. Some control experiments.
Scheme 2. The proposed reaction mechanism.
6

proton transfer step from the silica gel to give chloroacetophenone 2a and release an
iron species (Scheme 2).
Encouraged by these results, we further explored the scope of this transformation
using FeBr3 as catalyst. As shown in Table 4, the yields for α-bromination were
generally higher than those of α-chlorination. Treatment of 1a under standard
conditions provided 3a in 84% yield (Table 4, entry 1). The substituent groups
normally had little effect on the yields. However, the substrate bearing a nitro group
generated the highest yield, with corresponding desired product 3e isolated in 95%
yield (Table 3, entry 4). Alkylated compounds were also proved be suitable substrates.
When 1-diazo-3-phenylpropan-2-one 1l was tested, giving the expected bromination
product 3l with 81% yield, which could be obtained in the yield of 50% through the
directly bromiation of 2-pentanone by using Br2 as bromine source.16 Finally, when
cyclohexyl 2-diazoethanone 1m and diazotridecanone 1n were subjected to this
standard condition, the expected products 3m and 3n could be afforded with 63% and
85% yield, respectively. Unfortunately, when FeF3 was used in the place of FeCl3
under the optimal condition, the expected fluorination process did not happen.
Table 4 Bromination of various α-diazo-methyl ketonesa
Entry
1
Substrate
Product
3a
Yieldb(%)
84
1a
1b
1g
1h
2
3
4
80
85
95
3b
3c
3d
5
6
86
55
1i
1f
3e
3f
7

7
8
79
81
63
85
1l
1l
3g
3l
9
1m
1n
3m
3n
10
a Reaction conditions: 1a (0.5 mmol), FeBr3 (0.25 mmol, 0.5 equiv.) and silica gel 100 mg in 2
mL solvent, room temperature, 10 mins.
b Isolated yields.
In conclusion, we have developed a fast and efficient method to prepare α-halomethyl
ketones from α-diazo ketones using FeCl3 or FeBr3 with silica gel in modern to good
yields under protic acid free conditions. Furthermore, this method can also be used for
the efficient synthesis of coumaranones.
Acknowledgements
This work was supported by the NSFC (Nos. 21372056, 21642011, 81573529), Changjiang
Scholars and Innovative Research Team in Chinese University (IRT 1231) and Hangzhou Normal
University (2012QDL001) for their financial support.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://
References
1. (a) Ostrowski, T.; Golankiewicz, B.; De Clercq, E.; Andrei, G.; Snoeck, R. Eur. J. Med. Chem.
2009, 44, 3313; (b) Hintermann, L.; Labonne, A. Synthesis 2007, 1121; (c) Conde, S.; Pérez, D. I.;
Martínez, A.; Perez, C.; Moreno, F. J. J. Med. Chem. 2003, 46, 4631; (d) Erian, A.; Sherif, S.;
Gaber, H. Molecules 2003, 8, 793; (e) Arabaci, G.; Guo, X.-C.; Beebe, K. D.; Coggeshall, K. M.;
Pei, D. J. Am. Chem. Soc. 1999, 121, 5085.
2. (a) Moragas, T.; Correa, A.; Martin, R. Chem.-Eur. J. 2014, 20, 8242; (b) Gribble, G. W.
Heterocycles 2012, 84, 157; (c) Gribble, G. W. Chem. Soc. Rev. 1999, 28, 335; (d) (e) Gribble, G.
W. Acc. Chem. Res. 1998, 31, 141.
3. (a) Zheng, Z. B.; Li, Z. Z.; Han, B. B.; He, Z. M.; Shi, T. F.; Cheng, P. Tetrahedron Lett. 2015,
56, 2219; (b) Song, S.; Li, X.; Sun, X.; Yuan, Y.; Jiao, N. Green Chem. 2015, 17, 3285; (c) Pravst,
I.; Zupan, M.; Stavber, S. Tetrahedron 2008, 64, 5191; (d) He, W.; Xie, L.; Xu, Y.; Xiang, J.;
Zhang, L. Org. Biomol. Chem. 2012, 10, 3168; (e) Podgorsek, A.; Stavber, S.; Zupan, M.; Iskra, J.
Green Chem. 2007, 9, 1212; (f) Ranu, B. C.; Adak, L.; Banerjee, S. Aust. J. Chem. 2007, 60, 358.
4. (a) Tang, S.-Z.; Zhao, W.; Chen, T.; Liu, Y.; Zhang, X.-M.; Zhang, F-M. Adv. Synth. Catal. 2017,
8

359, 4177; (b) Pravst, I.; Zupan, M.; Stavber, S. Tetrahedron 2008, 64, 5191; (c) Tanemura, K.;
Suzuki, T.; Nishida, Y.; Satsumabayashi, K.; Horaguchi, T. Chem. Commun. 2004, 470; (d)
Nobrega, J. A.; Goncalves, S. M. C.; Peppe, C. Synth. Commun. 2002, 32, 3711.
5. (a) Zarantonello, P.; Bettini, E.; Paio, A.; Simoncelli, C.; Terreni, S.; Cardullo, F. Bioorg. Med.
Chem. Lett. 2011, 21, 2059; (b) Podgor sek, A.; Zupan, M.; Iskra, J. J. Angew. Chem., Int. Ed.
2009, 48, 8424; (c) Hamdi, O.; Disli, A.; Yllmaz, Y.; Türker, L. A. Molecules 2007, 12, 2478; (d)
Rahman, M. T.; Kamata, N.; Matsubara, H.; Ryu, I. Synlett 2005, 2664; (e) Diwu, Z.; Beachdel, C.;
Klaubert, D. H. Tetrahedron Lett. 1998, 39, 4987; (f) Dieter, R. K.; Nice, L. E.; Velu, S. E.
Tetrahedron Lett. 1996, 37, 2377.
6. (a) Zheng, Z. B.; Han, B. B.; Cheng, P. J.; Niu, X.; Wang, A. D. Tetrahedron 2014, 70, 9814; (b)
Chen, Z. Z.; Zhou, B.; Cai, H. H.; Zhu, W.; Zou, X. Z. Green Chem. 2009, 11, 275.
7. (a) Chen, X.; Chong, S.; Du, G.; Huang, D.; Wang, K.; Su, Y.; Hu, Y. Chin. J. Org. Chem. 2016,
36, 1028; (b) Jing, Y.; Daniliuc, C. G.; Studer, A. Org. Lett., 2014, 16, 4932.
8. For very recent examples, see: (a) Wu, C.; Xin, X.; Fu, Z.-M.; Xie, L.; Liu, K.-J.; Wang, Z.; Li,
W.; Yuan, Z.-H.; He, W.-M. Green Chem. 2017, 19, 1983; (b) Zeng, M.; Huang, R.-X.; Li, W.-Y.;
Liu, X.-W.; He, F.-L.; Zhang, Y.-Y.; Xiao, F. Tetrahedron 2016, 72, 3818; (c) Zou, H.; He, W.;
Dong, Q.; Wang, R.; Yi, N.; Jiang, J.; Pen, D.; He, W. Eur. J. Org. Chem. 2016, 116; (d) Ye, M.;
Wen, Y.; Li, H.; Fu, Y.; Wang, Q. Tetrahedron Lett. 2016, 57, 4983; (e) Zou, H.; Jiang, J.; Yi, N.;
Fu, W.; Deng, W.; Xiang, J. Chin. J. Chem. 2016, 34, 1251; (f) Ghosh, N.; Nayak, S.; Prabagar, B.;
Sahoo, A. K. J. Org. Chem. 2014, 79, 2453; (g) Chen, Z.-W.; Ye, D.-N.; Ye, M.; Zhou, Z.-G.; Li,
S.-H.; Liu, L.-X. Tetrahedron Lett. 2014, 55, 1373.
9. (a) Xing, Y.; Zhang, M. Ciccarelli, S.; Lee, J.; Catano, B. Eur. J. Org. Chem. 2017, 781; (b)
Chan, C.-K.; Wang, H.-S.; Hsu, R.-T.; Chang, M.-Y. Synthesis 2017, 49, 2045; (c) Coffey, K.;
Murphy, G. Synlett 2015, 26, 1003; (d) Shariff, N.; Mathi, S.; Rameshkumar, C.; Emmanuvel, L.
Tetrahedron Letters 2015, 56, 934; (e) Lee, Y.; Cho, B.; Kwon, H. Tetrahedron 2003, 59, 9333.
10. α-diazo ketones were prepared by the reaction of TMSCHN2 with carboxylic acid, NBS and
PPh3. See: Cuevas-Yanez, E.; Garcia, M.; De La Mora, M.; Muchowski, J.; Cruz-Almanza, R.
Tetrahedron Lett. 2003, 44, 4816.
11. Zelinski, R. P.; Turnquest, B. W.; Martin, E. C. J. Am. Chem. Soc. 1951, 73, 5521.
12. (a) Murphy, G. K.; West, F. G. Org. Lett. 2006, 8, 4359; (b) Karche, N. P.; Jachak, S. M.;
Dhavale, D. D. J. Org. Chem. 2001, 66, 6323; c) Kitagaki,S.; Yanamoto,Y.; Tsutsui,H.; Anada, M.;
Nakajima,M.; Hashimoto, S. Tetrahedron Lett. 2001, 42, 6361; (d) Hodgson, D. M.; Petroliagi, M.
Tetrahedron: Asymmetry 2001, 12, 877; (e) Ghosh, S.; Banerjee, I.; Baul, S. Tetrahedron 1999, 55,
11537; (f) Ghosh, S.; Datta, I.; Chakraborty, R.; Das, T. K.; Sengupta, J.; Sarkar, D. C.
Tetrahedron 1989, 45, 1441.
13. (a) Shu, C.; Liu, R.; Liu, R.; Li, J.-Q.; Yu, Y.-F.; He, Q.; Lu, X.; Ye, L.-W. Chem. Asian J. 2015,
10, 91; (b) Tsou, H.-R.; MacEwan, G.; Birnberg, G.; Zhang, N.; Brooijmans, N.; Toral-Barza, L.;
Hollander, I.; Ayral-Kaloustian, S.; Yu, K. Bioorg. Med. Chem. Lett. 2010, 20, 2259; c) Nadri, H.;
Pirali-Hamedani, M.; Shekarchi, M.; Abdollahi, M.; Sheibani, V.; Amanlou, M.; Shafiee, A.;
Foroumadi, A. Bioorg. Med. Chem. 2010, 18, 6360.
14. He, W.; Xie, L.; Zhang, L. Org. Biomol. Chem. 2012, 10, 3168.
15. Zhu,S.-F.; Zhou, Q.-L. Nat. Sci. Rev,. 2014, 1, 580.
16. Harikrishna, M.; Mohan, H. R.; Dubey, P. K.; Shankar, M.; Subbaraju, G. V. Synth. Commun.
2012, 42, 1288.
9

1. An operationally simple halogenation of α-diazo ketones is reported.
2. A variety of α-halomethyl ketones are synthesized in moderate to excellent yields.
3. Iron halides and silica gel is an efficient catalyst system for this transformation.
4. 3-Coumaranone can be fast prepared with excellent yield in this process.
10