Chemoselective oxidative hydrolysis of EWG protected α-arylamino vinyl bromides to α-arylamino-α′-bromoacetones

Article abstract of DOI:10.1016/j.tetlet.2013.05.118

Vinyl bromides bearing an arylamino group in the vicinal position are chemoselectively transformed into interesting α-arylamino-α′- bromoacetones through a straightforward oxidative hydrolysis promoted by calcium hypobromite under mild acidic conditions. Significantly, this particular combination [vinyl bromides and Ca(BrO)₂] avoids bromination at both the aromatic ring and activated positions in groups substituting the amine nitrogen. The usefulness of this class of brominated ketones has been shown in a Wittig homologation.

Full text of DOI:10.1016/j.tetlet.2013.05.118

Accepted Manuscript
Chemoselective oxidative hydrolysis of EWG protected α-arylamino vinyl bro‐
mides to α-arylamino-α ’-bromoacetones
Vittorio Pace, Laura Castoldi, María J. Hernáiz, Andrés R. Alcántara, Wolfgang
Holzer
PII:
S0040-4039(13)00909-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.05.118
TETL 43018
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
26 April 2013
22 May 2013
27 May 2013
Please cite this article as: Pace, V., Castoldi, L., Hernáiz, M.J., Alcántara, A.R., Holzer, W., Chemoselective
oxidative hydrolysis of EWG protected α-arylamino vinyl bromides to α-arylamino-α ’-bromoacetones,
Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.05.118
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Chemoselective oxidative hydrolysis of EWG
protected α-arylamino vinyl bromides to α-
arylamino-α’-bromoacetones
Leave this area blank for abstract info.
Vittorio Pace, Laura Castoldi, María J. Hernáiz, Andrés R. Alcántara and Wolfgang Holzer
PG
N
O
PG Br
N
Br
Ca(BrO)2 (2.0 equiv.)
R
R
MeCN-AcOH (5:2 v/v)
H2O, 0 °C, 1h
PG = Ac, Moc, Boc, Ts, 4-Ns
R = H, Me, NO2, CN, F

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Chemoselective oxidative hydrolysis of EWG protected α-arylamino vinyl bromides
to α-arylamino-α’-bromoacetones.
Vittorio Pace,a, Laura Castoldi,a María J. Hernáiz,b Andrés R. Alcántarab and Wolfgang Holzera
a Department of Drug and Natural Product Synthesis, University of Vienna, Althanstrasse 14, Vienna,1090, Austria.
b Department of Organic and Pharmaceutical Chemistry, Complutense University, Pza. Ramón y Cajal s/n, Madrid, 28040, Spain.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Vinyl bromides bearing an arylamino group in the vicinal position are chemoselectively
transformed into interesting α-arylamino-α’-bromoacetones through a straightforward oxidative
hydrolysis promoted by calcium hypobromite under mild acidic conditions. Significantly, this
particular combination [vinyl bromides and Ca(BrO)2] avoids bromination at both the aromatic
ring and activated positions in groups substituting the amine nitrogen. The usefulness of this
class of brominated ketones has been shown in a Wittig homologation.
Available online
Keywords:
Ketones
2009 Elsevier Ltd. All rights reserved.
Halogens
Amino group
Oxidation
Wittig
———
Corresponding author. Tel.: +43-1-4277-55623; fax: +43-1-4277-9556; e-mail: vpace@farm.ucm.es

2
Tetrahedron
α-Halo carbonyl compounds are versatile building blocks in
organic synthesis.1,2 In fact, the presence of two
electrophilic vicinal carbons makes them suitable for
reactions with different nucleophiles. In particular, α-bromo
derivatives are excellent substrates to carry out nucleophilic
displacements (both in synthetic and bio-organic processes)
which are often not straightforward when run on chlorinated
analogues.1,3 Moreover, the connection of the α-bromo
ketone motif with a substituted amino group at the α’-
position turns the resulting structure into a particularly
attractive moiety from the perspective of a synthetic
medicinal chemist, because of the usefulness of such
analogues in the preparation of HIV-protease inhibitors (e.g.
amprenavir, Scheme 1 - top).4,5 As a consequence of the
social relevance of the AIDS disease, the synthesis of these
analogues continues to be an attractive field of research.
Thus,the quest for safer alternatives to Arndt-Eistert based
strategies6-10 (Scheme 1 – lower trace) to access the
intermediates α-bromo ketones III is urgently demanded by
both academia and chemical companies.
epibromohydrins with an arylamines.19 Also, the use of the
lithium carbenoid strategy can be affected by the high
instability of these reagents as pointed out by Köbrich in his
pioneering studies.20
Scheme 2. Oxidative hydrolysis of vinyl halides to the corresponding
α-haloketones.
Therefore, the preparation of α-arylamino-α’-bromopropan-
2-ones VII has not been addressed yet and, in this Letter,
we report a chemoselective and straightforward method via
the bromination of N-(2-bromoallyl)anilines VI with
Ca(BrO)2 (Scheme 2, lower trace), a mild oxidizing
bromonium source recently described in our group for the
chemoselective oxidation of allylic sulfides to the
corresponding sulfoxides.21
As a matter of fact, this work was based on the quest for a
masked α-bromoketone functionality that in the presence of
a bromonium source would deliver directly the desired α-
bromo carbonyl derivative. Evidently, such approach would
overcome the chemoselective drawbacks related to multi-
chlorinations observed when the reaction was attempted on
vinyl chlorides in the presence of hypochlorites.16
Scheme 1. Example of a HIV-protease inhibitor and its synthesis via a
α-amino-α’-bromo ketone intermediate. NMM = N-methylmorpholine
Indeed, these multi-functionalized ketones are very reactive
entities because of the well known self-condensation they
undergo via intermolecular addition of the amino group to
the carbonyl.11,12 As it can be foreseen, this particular
behaviour is related to the nitrogen nucleophilicity and thus,
the presence of suitable electron-withdrawing groups is
pivotal for avoiding any decomposition processes.13,14 It
becomes clear that their effectiveness should be a balance
between the capability to stabilize the resulting α-amino-α’-
haloketone and the possibility to manipulate them in a
chemoselective fashion.
In this regard, in order to circumvent the difficulties of
using 1,3-dichloroacetone in nucleophilic displacements,15
recently our group has reported a series of protocols to
access α-arylamino-α’-chloropropan-2-ones (V, Scheme 2,
top) through oxidative hydrolysis of vinyl chlorides with
Ca(ClO)2,16 oxidation of the corresponding chlorohydrins17
or via chloromethylation of Weinreb amides with the
carbenoid chloromethyllithium.18 As a common feature,
these procedures are severely affected by the nature of the
EWG employed. For instance, the oxidative hydrolysis of
vinyl chlorides IV could be efficiently used only in the
presence of a strongly electron-withdrawing trifluoroacetyl
group on the nitrogen atom.16 This strict requirement is due
to the evidence that it is the only one able to suppress any
concomitant halogenation of the aromatic ring IVa or of
potential activated positions (i.e. the methyl group of a
simple acetamide). In addition, the direct oxidation of
bromohydrins is limited by the chemoselective opening of
The starting point for our studies was an easy preparation of
the required vinyl bromides through
a
sequential
chemoselective KF-Celite mediated synthesis of N-(2-
bromoallyl)anilines 1a-j,22,23 followed by the introduction of
various N-EWGs via CaO-acylation with acid chlorides to
obtain the corresponding disubstituted vinyl bromides 2a-
h
24 or via the reaction with Boc2O in EtOH25 for compounds
2i-j (Scheme 3 – via a). Interestingly, N-tosyl- and N-(4-
nosyl) - protected vinyl bromides 2k and 2l were prepared
in one step from N-tosyl-type anilines and 2,3-
dibromopropene in the presence of KF-Celite (Scheme 3 –
via b).

3
4
5
Ca(BrO)2 Acetone AcOH
(2.0)
0
0
1
1
85
Ca(BrO)2
(2.0)
CH3CN
CH3CN
CH3CN
DMSO
CH2Cl2
AcOH
HBrb
--
91
89
18
84
42
30
62
52
6
Ca(BrO)2
(2.0)
0
1
7
Ca(BrO)2
(2.0)
0
24
1
8
Ca(BrO)2
(2.0)
AcOH
AcOH
0
9
Ca(BrO)2
(2.0)
0
1
10
11d
12
Ca(BrO)2 Benzene AcOH
(2.0)
0
1
Ca(BrO)2
(2.0)
CH3CN
AcOH
20
-20
1
Scheme 3. Preparation of the N-EWGs protected vinyl bromides.
Ca(BrO)2
(2.0)
CH3CN
AcOH
24
Thus, with the N-(2-bromoallyl)-N-protected anilines series
in hand, we turned our attention to their chemoselective
oxidative bromination into the corresponding α-bromo
ketones, leaving the aromatic and the N-acyl moieties
untouched.
The reaction of N-(2-bromoallyl)-N-acetylaniline 2a was
selected as the model reaction, bearing in mind that the
analogous transformation carried out on the corresponding
chlorocompounds in the presence of NaClO or Ca(ClO)2
gave a mixture of chlorinated compounds both on the
aromatic ring and on the amidic methyl group.16 As shown
in Table 1, a brief screening of various brominating agents
revealed that Ca(BrO)2 was the best one compared to
NaBrO26 or NBS27,28 (entries 1-3). By increasing the loading
of the hypobromite from 1.0 equiv. to 2.0 equiv. (entry 4), it
was possible to obtain 3a in 85% isolated yield. The choice
of the solvent was important in order to obtain satisfactory
a 5:2 v/v mixture of solvent and acid, respectively. b Isolated yields. c
mol %.
5
Significantly, by increasing the temperature from 0 °C to 20
°C (entry 11) showed a deleterious effect on the overall
transformation. On the contrary, running the reaction at -20
°C (entry 12) implies a conspicuous increasing of the time.
It is worth stressing the importance of performing reactions
in the presence of AcOH or a different protic acid (HBr,
entry 6) as a consequence of its capability to properly
deliver the active bromonium through the modification of
the equilibria existing within the brominated species (BrO-,
Br-, HBrO). Evidently, the use of AcOH is preferred (over
HBr) because of its mildness and potential use to apply the
method to acid-sensitive substrates. Thus, in the absence of
protic acids, the conversion of 2a was extremely sluggish,
being it substantially recovered even after 24 h (entry 7).
This optimization study clearly pointed out that the use of a
vinyl bromide as a masked α-bromocarbonyl functionality is
advantageous compared to vinyl chlorides which, as
stressed above, undergo undesired chlorinations within the
molecules skeleton.
results: polar aprotic solvents (entries 4-6, 8), as
a
consequence of their complete miscibility with water, have
a beneficial effect compared to apolar ones (entries 9-10),
being acetonitrile the preferred medium (entries 5-6).
Table 1. Oxidative hydrolysis of the N-EWGs protected vinyl
bromides: reaction optimization.
In order to study the scope of the reaction, the series of the
above prepared vinyl bromides 2b-l, containing various
substituents both on the aromatic ring and on the nitrogen
atom were tested under the established reaction conditions.
As shown in Scheme 4, the reaction is quite general and
chemoselectivity was observed in all cases. The procedure
tolerates the presence of reactive substituents towards the
generated electrophilic bromonium such as the methyl
group on the aromatic rings (3b-d, 3j): no concomitant
bromination was detected at all. Interestingly, also nitro
(3e), cyano (3g) and fluorine substituents (3f) were well
tolerated. Of particular relevance is the complete
chemoselectivity observed in the presence of different N-
substituents: in contrast to the strict needing of using a
strong EWG (i.e. trifluoroacetyl) in the oxidative
chlorination of vinyl chlorides,16 herein carbamates (3h-j),
amide (3b-d, 3f) and tosyl-type substrates (3k-l) could be
successfully employed. It is worth highlighting the mildness
of using Ca(BrO)2 compared to Ca(ClO)2: the latter, as we
previously found, was able to chlorinate the aromatic ring
Entry
Oxidant
(equiv.)
Solvent
Acida
Temp. Reaction Yield
of
(ºC)
Time (h)
3a
(%)b
1
2
NaBrO
(1.0)
Acetone AcOH
Acetone AcOH
0
0
1
1
75
NBS
(1.0)
68
3
Ca(BrO)2 Acetone AcOH
(1.0)
0
1
79

4
Tetrahedron
even in the case of a N-Boc protected vinyl chloride.
Analogously, the methyl group of the tosyl derivative 3k
remained unaffected after the calcium hypobromite
treatment.
Acknowledgements. The University of Vienna is gratefully
thanked for generous financial support. One of the authors
(L. C.) thanks the Austrian Ministry of Education for a
postgraduate Ernst Mach grant. Financial support from
Project CTQ2012-32042, from the Spanish Ministry of
Science and Innovation and Spanish Ministry of Economic
Affairs and Competitiveness is gratefully acknowledged.
Ca(BrO)2 (2.0 equiv.)
R
N
Br
R
N
O
Br
Ar
Ar
MeCN - AcOH (5:2 v/v)
2O, 0 °C, 1h
H
2b-l
3b-l
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N
O
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Scheme 4. Scope of the reaction: synthesis of variously functionalized
α-arylamino-α’-bromoacetones.
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bromoketones, we reacted tosyl derivative 3k with PPh3,
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Representative procedure.
To a solution of the vinyl bromide (1.0 equiv.) in
acetonitrile (10 mL) – acetic acid (4 mL) cooled at 0ºC was
added Ca(OBr)2 (0.33 M, 2.00 equiv.). The solution was
stirred for 1 h at 0ºC and, after the completion indicated by
TLC it was poured into a saturated solution of NaHCO3 and
extracted with dichlorometane (20 mL x 3). The combined
organic phases were dried with anhydrous MgSO4 and the
solvent were removed in vacuo. Whenever necessary, the
crude mixtures were purified by LC to obtain analytical
pure sample of bromoketones.
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5
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