Reductive Halogenation Reactions: Selective Synthesis of Unsymmetrical α-Haloketones

Article abstract of DOI:10.1021/acs.orglett.9b02324

A method for the selective synthesis of unsymmetrical α-haloketones has been developed. The key transformation is a triphenylphosphine oxide catalyzed reductive halogenation of an α,β-unsaturated ketone in which trichlorosilane is the reducing reagent and an N-halosuccinimide is the electrophilic halogen source. This method allows for a halogen atom to be installed selectively at either of two very similarly substituted sites adjacent to a ketone group.

Full text of DOI:10.1021/acs.orglett.9b02324

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Reductive Halogenation Reactions: Selective Synthesis of
Unsymmetrical α‑Haloketones
Zhiqi Lao,† Huimiao Zhang, and Patrick H. Toy*
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. of China
S
* Supporting Information
ABSTRACT: A method for the selective synthesis of
unsymmetrical α-haloketones has been developed. The key
transformation is a triphenylphosphine oxide catalyzed
reductive halogenation of an α,β-unsaturated ketone in
which trichlorosilane is the reducing reagent and an N-
halosuccinimide is the electrophilic halogen source. This
method allows for a halogen atom to be installed selectively at
either of two very similarly substituted sites adjacent to a
ketone group.
α-Haloketones are versatile building blocks that are useful for
the synthesis of a wide range of heterocyclic compounds.1 For
example compounds such as A can be converted into furans,2
imidazoles,3 pyrroles,4 thiazoles,5 and many other structures
(Scheme 1a). However, a survey of the literature reveals that in
perhaps the Ir-catalyzed isomerization/halogenation reactions
of allylic alcohols reported by Martin-Matute and co-workers
represents the best such method for the synthesis of these
compounds (Scheme 2a), and this has been described in a
series of publications only relatively recently.9
́
Against this backdrop, we have been inspired by the work of
Nakajima and co-workers who showed that Lewis bases such as
hexamethylphosphoramide (HMPA, 1) and triphenyl-
phosphine oxide (2) can catalyze conjugate reduction and
reductive aldol reactions of enones using Cl3SiH (3) as the
reducing reagent (Scheme 2b).10 We subsequently built upon
this reactivity by using one-pot Wittig reactions, in which a
phosphorane was generated in situ, to produce the enone
substrates, and used the waste 2 formed in the Wittig reaction
directly as the catalyst for the reductive aldol reactions
(Scheme 2c).11 Herein we wish to report an extension of this
research where we replaced the aldehyde electrophile of the
reductive aldol reactions with an electrophilic halogen source
to develop what is to our knowledge the first reductive
halogenation method that directly converts α,β-unsaturated
ketones into unsymmetrical α-haloketones (Scheme 2d). It
should be noted that up to now it seems the concept of
reductive halogenation has only been used in the organic
chemistry literature to describe the conversion of epoxides12
and carbonyl functional groups13 into corresponding alkyl
halides. In describing our work, we are using this phrase in a
context that is analogous to reductive aldol reactions.14,15
In order to test our hypothesis that an electrophilic halogen
source, such as N-bromosuccinimide (NBS, 6), could replace
an aldehyde in reductive aldol-like reactions, we chose enone
4a16 as a test substrate with the aim of converting it into α-
bromoketone 5a (Table 1).17 Based on our previous research
regarding reductive aldol reactions involving the catalyst/
Scheme 1. Synthesis of Heterocyclic Compounds from α-
Haloketones
virtually all cases the α-haloketones used for such purposes are
derived from ketones that either are symmetrical, such as
acetone, or can only form an enol to one side of the ketone
group, such as acetophenone. It seems that the use of α-
haloketones derived from unsymmetrical ketones that can
tautomerize to form enols on both sides of the ketone group is
somewhat rare. This lack of structural diversity of the α-
haloketones used severely impacts the range of compounds
that can be synthesized from them, and thus medicinal
chemistry in general, since many heterocyclic compounds have
interesting biological activities. For example, access to either B
or C would allow for the selective synthesis of D or E (Scheme
1b), both of which have not been previously reported in the
literature,6 despite their rather simple structures. One of the
reasons for the current situation could be a lack of simple and
general methods for the selective synthesis of unsymmetrical α-
haloketones with two enolizable α-positions.7,8 In this regard,
Received: July 5, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02324
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
did not improve the yield of 5a, and using 8 resulted in no
formation of 5a (entries 5 and 6). Thus, since 6 is relatively
inexpensive, widely available, and an easy to dispense solid at
room temperature, as are N-chlorosuccinimide (NCS, 9) and
N-iodosuccinimide (NIS, 10), we chose to use 6 for further
studies. Finally, we assessed the scalability of our method by
performing the reductive bromination of 4a on a 1.0 g (5.1
mmol) scale using the optimized reaction conditions. Gratify-
ingly 5a was isolated in 62% yield from this reaction (entry 7).
Having validated our hypothesis by showing that reductive
bromination of 4a to form 5a was possible using a catalyst/
reagent combination of 2 and 3 for the reduction and 6 as the
electrophilic reagent, we next synthesized enones 4b−p in two
steps from the common starting material 11 (Scheme 3).17
Scheme 2. Literature Precedent and Reductive
Halogenation for the Synthesis of Unsymmetrical α-
Haloketones
Scheme 3. Synthesis of Enone Substrates 4b−p
Table 1. Triphenylphosphine Oxide (2) Catalyzed
Reductive Bromination of Enone 4a To Produce α-
a
Bromoketone 5a
b
entry
2
3
X+ source
yield (%)
1
2
3
4
5
6
7
0.2 equiv
0.2 equiv
0.2 equiv
0.1 equiv
0.2 equiv
0.2 equiv
0.2 equiv
2.0 equiv
1.5 equiv
1.2 equiv
1.5 equiv
1.5 equiv
1.5 equiv
1.5 equiv
6 (2.0 equiv)
6 (1.5 equiv)
6 (1.2 equiv)
6 (1.5 equiv)
7 (1.5 equiv)
8 (1.5 equiv)
6 (1.5 equiv)
84
85
73
74
67
0
c
62
a
Conditions: 2, 3, and 4a (1.0 mmol) in dry CH2Cl2 (2 mL) under Ar
at rt were stirred for 4 h followed by the addition of 6, 7, or 8 (1.5
b
c
mmol) and stirring for 16 h more. Isolated yield. Reaction was
performed on a using 5.1 mmol of 4a.
reagent combination of 2 and 3, we started our studies using
0.2 equiv of 2 with 2.0 equiv of 3 in dry CH2Cl2. After 4 h, 6
(1.5 equiv) was added and the reaction was stirred for 16 h
more. Gratifyingly these reaction conditions afforded the
desired product 5a in very high isolated yield (entry 1).
Reducing the amount of 3 to 1.5 equiv did not affect the
obtained yield, but lowering it further resulted in a lower yield
(entries 2 and 3). Reducing the loading of 2 to 0.1 equiv also
resulted in a lower yield (entry 4), so 0.2 equiv of 2 was used
for all future reactions. Replacing 6 with Snyder’s reagent 718
This was deprotonated, and then alkylated with an alkyl halide
(12) to generate 13.19 Phosphoranes 13 were then reacted in
Wittig reactions with aldehydes 14 to generate enones 4b−p.
Enones 4b−p were then converted into the corresponding
α-bromoketones 5b−p (Figure 1) using the optimized reaction
conditions (Table 1, entry 2). As is readily apparent from the
structure of 5b, when the ketone has two equivalent enolizable
α-positions, the bromine substituent can be introduced at one
of them selectively, even when the difference between the two
side chains is very minor and remote from the position being
B
DOI: 10.1021/acs.orglett.9b02324
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. α-Chloro- and α-iodoketones synthesized using NCS (9)
and NIS (10).
Scheme 4. One-Pot Tandem Wittig/Reductive
Halogenation Reactions
reductive aldol reactions11 and the selective α.β-reduction of
conjugated polyunsaturated ketones21 supports the idea
originally proposed by Nakajima and co-workers10 that a six-
membered cyclic transition state such as F may be involved
(Scheme 5).
Scheme 5. Mechanism of the Reductive Halogenation
Reactions
Figure 1. α-Bromoketones synthesized.
functionalized, as in 5c−e. We even extended this concept by
synthesizing pairs of compounds in which the bromine
substituent is introduced into either of the similar enolizable
α-positions, such as 5f and 5g, 5h and 5i, 5j and 5k, 5l and 5m,
and 5n and 5o. In all cases the reductive bromination reaction
occurred with high yield (ca. 75−85%). Even a double
reductive bromination reaction to produce 5p was highly
efficient. Thus, 5b−p could all be selectively synthesized in
only three steps from phosphorane 11.
Next we examined the possibility of replacing 6 with 9 and
10 in order to synthesize α-chloroketones 15 and α-
iodoketones 16, respectively (Figure 2). Gratifyingly, we
were able to synthesize 15a−d in high yields, and 16a−b in
moderate yields from the corresponding enones.
Lastly we examined the possibility of performing one-pot,
tandem Wittig, and reductive halogenation reactions in which
the 2 formed as a byproduct in the first reaction serves as the
catalyst in the second reaction. This concept was first reported
by Zhou and co-workers in a range of reactions,20 and we
subsequently extended it to tandem Wittig/reductive aldol
reactions (Scheme 2c).11 Gratifyingly, we were able to
generate 4a in situ by reacting phosphorane 11 with 2-
napthaldehyde (14a) and converted it directly into either 5a or
15a in moderate overall yields in one-pot, three-step reactions
(Scheme 4).
In summary, we have developed a method for the reductive
halogenation of enones in reactions that are conceptually akin
to reductive aldol reactions and that result in the selective
synthesis of unsymmetrical α-haloketones. This method
involves a conjugate reduction process involving the catalyst/
reagent combination of 2 and 3. Various electrophilic halogen
sources can be used, and α-chloro-, α-bromo-, and α-
iodoketones can be synthesized in a few steps from simple
building blocks. It is expected that this metal-free method can
greatly expand the addressable chemical space of heterocyclic
compounds since the products it allows access to are versatile
building blocks in this context, and this is the focus of our
current efforts. Additionally we are working to identify more
efficient catalysts for these reactions that can be used with
lower loading levels so as to render this method more
amenable for performing large-scale reactions.
ASSOCIATED CONTENT
■
S
* Supporting Information
With regard to the mechanism of these reductive
halogenation reactions, the sum total of our results presented
here and including those previously reported regarding
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02324.
C
DOI: 10.1021/acs.orglett.9b02324
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Detailed experimental procedures, compound character-
Letter
(12) Aizpurua, J. M.; Palomo, C. Tetrahedron Lett. 1984, 25, 3123.
(13) (a) Bilger, C.; Royer, R.; Demerseman, P. Synthesis 1988, 1988,
902. (b) Li, Z.; Sheng, C.; Yang, C.; Qiu, H. Org. Prep. Proced. Int.
2007, 39, 608. (c) Moriya, T.; Yoneda, S.; Kawana, K.; Ikeda, R.;
Konakahara, T.; Sakai, N. Org. Lett. 2012, 14, 4842. (d) Reyes, J. R.;
Rawal, V. H. Angew. Chem., Int. Ed. 2016, 55, 3077.
(14) For another example of phosphine oxide catalyzed reductive
aldol reactions, see: DePorre, Y. C.; Annand, J. R.; Bar, S.; Schindler,
C. S. Org. Lett. 2018, 20, 2580.
ization data, NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: phtoy@hku.hk.
ORCID
(15) For representative recent publications regarding reductive aldol
reactions that do not require metal-based catalysts and/or reagents,
see: (a) Nuhant, P.; Allais, C.; Roush, W. R. Angew. Chem., Int. Ed.
2013, 52, 8703. (b) Allais, C.; Tsai, A. S.; Nuhant, P.; Roush, W. R.
Angew. Chem., Int. Ed. 2013, 52, 12888. (c) Kister, J.; Ess, D. H.;
Roush, W. R. Org. Lett. 2013, 15, 5436. (d) Satpathi, B.; Dutta, L.;
Ramasastry, S. S. V. Org. Lett. 2019, 21, 170.
Zhiqi Lao: 0000-0001-7663-8308
Huimiao Zhang: 0000-0001-5886-4061
Patrick H. Toy: 0000-0001-6322-0121
Present Address
†Institute of Science, Westlake University, Hangzhou, P. R. of
China.
(16) Yan, R. J.; Xiao, B.-X.; Ouyang, Q.; Liang, H.-P.; Du, W.; Chen,
Y.-C. Org. Lett. 2018, 20, 8000.
Notes
(17) See Supporting Information for detailed experimental
procedures.
The authors declare no competing financial interest.
(18) Snyder, S. A.; Treitler, D. S. Angew. Chem., Int. Ed. 2009, 48,
7899.
ACKNOWLEDGMENTS
■
Our research was funded by the Research Grants Council of
the Hong Kong S. A. R., P. R. of China (Project GRF
17305915).
̈
(19) Ruijter, E.; Schultingkemper, H.; Wessjohann, L. A. J. Org.
Chem. 2005, 70, 2820.
(20) (a) Cao, J.-J.; Zhou, F.; Zhou, J. Angew. Chem., Int. Ed. 2010,
49, 4976. (b) Chen, L.; Shi, T.-D.; Zhou, J. Chem. - Asian J. 2013, 8,
556. (c) Chen, L.; Du, Y.; Zeng, X.-P.; Shi, T.-D.; Zhou, F.; Zhou, J.
Org. Lett. 2015, 17, 1557.
REFERENCES
■
̈
́
(1) Fu
̈
lopova, V.; Soural, M. Synthesis 2016, 48, 3684.
(21) Xia, X.; Lao, Z.; Toy, P. H. Synlett 2019, 30, 1100.
(2) Luo, J.; Lu, D.; Peng, Y.; Tang, Q. Asian J. Org. Chem. 2017, 6,
1546.
(3) (a) Little, T. L.; Webber, S. E. J. Org. Chem. 1994, 59, 7299.
(b) Soh, C. H.; Chui, W. K.; Lam, Y. J. Comb. Chem. 2008, 10, 118.
́
́
(4) (a) Estevez, V.; Villacampa, M.; Menendez, J. C. Chem. Commun.
2013, 49, 591. (b) Lei, T.; Liu, W.-Q.; Li, J.; Huang, M.-Y.; Yang, B.;
Meng, Q.-Y.; Chen, B.; Tung, C.-H.; Wu, L.-Z. Org. Lett. 2016, 18,
2479.
(5) (a) Qiao, Q.; So, S.-S.; Goodnow, R. A., Jr. Org. Lett. 2001, 3,
3655. (b) Kamila, S.; Mendoza, K.; Biehl, E. R. Tetrahedron Lett.
2012, 53, 4921.
(6) It is illustrative to note that a Scifinder search of the exact
structures of B and C on July 4, 2019 resulted in only four and six
reports regarding them, respectively. Furthermore, while a search of
the exact structures of D and E resulted in no results found,
substructure searches of these same structures resulted in 660 and 339
results found, respectively.
(7) For a general review regarding the synthesis of α-bromocarbonyl
compounds, see: Vekariya, R. H.; Patel, H. D. Tetrahedron 2014, 70,
3949.
(8) For methods regarding the multistep synthesis of unsymmetrical
α-chloroketones and α-bromoketones, see: (a) Barluenga, J.; Llavona,
L.; Yus, M.; Concellon, J. M. J. Chem. Soc., Perkin Trans. 1 1991, 2890.
(b) Boyd, R. E.; Royce Rasmussen, C.; Press, J. B. Synth. Commun.
1995, 25, 1045.
(9) (a) Ahlsten, N.; Martín-Matute, B. Chem. Commun. 2011, 47,
8331. (b) Ahlsten, N.; Bartoszewicz, A.; Agrawal, S.; Martín-Matute,
́
B. Synthesis 2011, 2011, 2600. (c) Ahlsten, N.; Gomez, A. B.; Martín-
́
Matute, B. Angew. Chem., Int. Ed. 2013, 52, 6273. (d) Gomez, A. B.;
́
Erbing, E.; Batuecas, M.; Vazquez-Romero, A.; Martín-Matute, B.
Chem. - Eur. J. 2014, 20, 10703. (e) Vazquez-Romero, A.; Gomez, A.
B.; Martín-Matute, B. ACS Catal. 2015, 5, 708. (f) Martinez-Erro, S.;
́
́
́
́
Gomez, A. B.; Vazquez-Romero, A.; Erbing, E.; Martín-Matute, B.
̌
̌
Chem. Commun. 2017, 53, 9842. (g) Sanz-Marco, A.; Mozina, S.;
Martinez-Erro, S.; Iskra, J.; Martín-Matute, B. Adv. Synth. Catal. 2018,
360, 3884.
(10) (a) Sugiura, M.; Sato, N.; Kotani, S.; Nakajima, M. Chem.
Commun. 2008, 4309. (b) Sugiura, M.; Sato, N.; Sonoda, Y.; Kotani,
S.; Nakajima, M. Chem. - Asian J. 2010, 5, 478.
(11) (a) Lu, J.; Toy, P. H. Chem. - Asian J. 2011, 6, 2251. (b) Teng,
Y.; Lu, J.; Toy, P. H. Chem. - Asian J. 2012, 7, 351.
D
DOI: 10.1021/acs.orglett.9b02324
Org. Lett. XXXX, XXX, XXX−XXX