Micelle-Enabled Photoassisted Selective Oxyhalogenation of Alkynes in Water under Mild Conditions

Article abstract of DOI:10.1021/acs.joc.7b03143

Using micelles of FI-750-M, visible light, photocatalysts, and inexpensive halogenating reagents, such as N-bromosuccinimide and N-chlorosuccinimde, selective oxyhalogenations of alkynes were achieved in water under very mild conditions. No halogenation at the aromatic rings was detected, and control experiments revealed the radical pathway. The easily conducted protocol exhibited high reproducibility, was readily adjusted to gram scale, and allowed for recycling of reaction medium and catalyst.

Full text of DOI:10.1021/acs.joc.7b03143

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Article
Micelles-Enabled Photo-Assisted Selective
Oxyhalogenation of Alkynes in Water Under Mild Conditions
Lucie Finck, Jeremy Brals, Bhavana Pavuluri, Fabrice Gallou, and Sachin Handa
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03143 • Publication Date (Web): 09 Feb 2018
Downloaded from http://pubs.acs.org on February 9, 2018
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The Journal of Organic Chemistry
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Micelles-Enabled Photo-Assisted Selective Oxyhalogenation of Al-
kynes in Water Under Mild Conditions
Lucie Finck,§ Jeremy Brals,§ Bhavana Pavuluri,§ Fabrice Gallou,‡ Sachin Handa*§
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§Department of Chemistry, University of Louisville, 2320 S. Brook Street, Louisville, Kentucky 40292, United States
‡Novartis Pharma AG, Basel CHꢀ4002 Switzerland
We dedicate this work to Prof. Michael Nantz on the occasion of his upcoming 60th birthday.
Supporting Information Placeholder
proline linker in FIꢀ750ꢀM, i.e., the micellar interface,
could be further synergistically utilized as a binding site
photocatalyst, and inexpensive halogenating reagents,
ABSTRACT: Using micelles of FIꢀ750ꢀM, visibleꢀlight,
for a reactant/reagent to facilitate a desired transforꢀ
mation. Along these lines, Nꢀbromosuccinimide (NBS)
or Nꢀchlorosuccinimde (NCS) may effectively bind with
i.e., NBS and NCS, selective oxyhalogenations of alꢀ
kynes were achieved in water under very mild condiꢀ
tions. No halogenation at the aromatic rings was detectꢀ
a proline linker of FIꢀ750ꢀM which could enhance the
ed, and control experiments revealed the radical pathꢀ
solubility of NBS or NCS at the micellar interface at
way. The easily conducted protocol exhibited high reꢀ
room temperature.2c,7 A catalyst in close proximity could
producibility, was readily adjusted to gramꢀscale, and
then assist the homolytic N–X (X = Br, Cl) bond cleavꢀ
allowed for recycling of reaction medium and catalyst.
age, thus facilitate useful chemical transformations, such
as the oxyhalogenation of alkynes to achieve α,αꢀ
Introduction. In the pursuit of novel technologies to
rigorously support the essential chemical events that
dihaloketones in much sustainable fashion (Figure 1).8
Br
O
meet current challenges of sustainable chemical catalyꢀ
sis, micellar catalysis is one of the idiosyncratic one that
addresses many current important issues by following
the Nature’s lead.1 A selection of salient features of miꢀ
cellar catalysis includes obviation of toxic organic solꢀ
vent as reaction media,2 inꢀflask catalyst recycling,3
support for nanocatalysis,3 and the as yet underexplored
leveraging of the hydrophobic effect for better reactivity
and selectivity.1c Lipshutz2a,4 and Kobayashi5 have pioꢀ
neered this field, especially with their highly practical
work pertaining to chemical catalysis with a very low
catalyst loading.6 Further advancing the field, very reꢀ
cently, our group developed an inexpensive, environꢀ
mentally benign, and potentially biodegradable amꢀ
phiphile, FIꢀ750ꢀM, to mimic toxic polar organic solꢀ
vents such as DMF, 1,4ꢀdioxane, NMP, DMAc, etc.2c
When dissolved in water, FIꢀ750ꢀM forms spherical naꢀ
nomicelles with lowꢀhydrophobicity interiors that soluꢀ
bilize polar reactants and catalysts which would otherꢀ
wise require such toxic and polar aprotic organic solꢀ
vents. Accordingly, arylation of nitroalkanes is now posꢀ
sible in water under mild conditions with a low catalyst
loading. Similarly, selective sulfonylation of perꢀ
fluoroarenes can also be achieved in water at room temꢀ
perature without use of a polarꢀaprotic solvent as gross
reaction medium.2d
Br
Br
Br
O
Br
Br
Br
O
O
Br
Br
Br
O
Br
sustainable, mild conditions
no use of toxic organic solvents
functional group tolerance
O
Br
recyclable catalyst and medium
single step oxyhalogenation
O
N
Br
Br
O
Me
O
O
N
O
O
Figure 1. Micellar oxyhalogenation of alkynes promotꢀ
ed by the FIꢀ750ꢀM proline linker.
If the reaction pathway is not very selective, alkyne
oxyhalogenation could lead to many side products, inꢀ
cluding αꢀhaloketones, α,αꢀdihaloketones, and vinyl halꢀ
ides.9 α,αꢀDihaloketones are highly valuable structural
motifs, especially due to their applications in the syntheꢀ
sis of medicinally important heterocycles,10 fine chemiꢀ
cals,11 agrochemicals,12 pharmaceuticals,13 and intermeꢀ
diates for natural products.14 For their synthesis at least
Beyond control of solubility, amphiphiles may also
more directly impact reactivity. We hypothesized that the
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conditions: 1 (0.5 mmol), 2 (1.0 mmol), catalyst (5 mol%), 1.0
mL 3 wt% surfactant in H2O, rt, 3 h, visibleꢀlight (9 W), argon
atmosphere. BPO = benzoyl peroxide; all yields are isolated.
one harsh or nonꢀsustainable reaction parameter is inꢀ
deed always required (e.g., use of a transitionꢀmeta l
catalyst,9b,15 expensive/toxic halogenating reagent,9a,16
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mild conditions. Our investigation began with reaction
of phenylacetylene with NBS in various aqueous surfacꢀ
tants in the presence of visibleꢀlight and organocatalyst
eosin Y (Figure 2), which can assist the cleavage of the
halo radical from NBS or NCS and subsequently proꢀ
mote oxidation of a vinyl halide intermediate to obtain
the desired product 3 (Table 1).
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Although the reaction slowly proceeded in TPGSꢀ750ꢀ
M and Triton Xꢀ100, FIꢀ750ꢀM was found to be superior
in terms of reaction kinetics and yield (Table 1, entries
1ꢀ3). SDS surfactant showed inferior results and only
42% isolated yield was obtained (entry 4). The reaction
also proceeded in the absence of any catalyst (entry 4),
however, in many other cases from Table 2, conversions
were not very clean and fast. Use of benzoylperoxide as
a catalyst did not improve reaction yield (entry 6), which
may be due to possibility of other side reactions. The
low yield obtained when conducting the reaction on waꢀ
ter (entry 7) revealed the importance of surfactant. Full
optimization study revealed the importance of visibleꢀ
light, eosin Y, 3 wt% aqueous FIꢀ750ꢀM, and 2.0 equivaꢀ
lents of halogen source (NBS) for optimal reactivity.
Notably, in the absence of light and catalyst, only 9% of
product 3 was obtained (entry 7).
Figure 2. Structures of different amphiphiles and eosin
Y.
corrosive oxidant,17 or toxic organic solvents9,15), and
the results suffer from moderate to poor selectivity and
poor functional group tolerance, especially for boc, cbz,
and nitro groups.
Results and Discussion. In light of the aforementioned
drawbacks of oxyhalogenation and the special structural
features of FIꢀ750ꢀM, we herein report a mild, general,
sustainable, photo assisted oxyhalogenation protocol that
can be applied to synthesize α,αꢀdibromooketones as
well as α,αꢀdichloro ketones with the use of inexpensive
and stable reagents NBS and NCS in water under very
Table 2. Substrate scope of micellar oxybromination
Table 1. Optimization of micellar oxyhalogenation
entry
catalyst
eosin Y
eosin Y
eosin Y
eosin Y
ꢀ
solvent
aq. TPGSꢀ750ꢀM
aq. Triton Xꢀ100
aq. FIꢀ750ꢀM
aq. SDS
% yield 3
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80
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35
9
aq. FIꢀ750ꢀM
aq. FIꢀ750ꢀM
neat water
BPO
eosin Y
conditions: alkyne (0.5 mmol), 2 (1.0 mmol), eosin Y (5 mol%),
1.0 mL 3 wt% FIꢀ750ꢀM in H2O, argon atmosphere, visibleꢀlight
(9 W), rt; †reaction temperature 45 °C.
darkꢀno
cat.
aq. FIꢀ750ꢀM
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After arriving at final optimized conditions, substrate
1
scope was explored for both oxybromination and oxꢀ
ychlorination while paying attention to sterics, electronꢀ
ics, functional group tolerance. Both oxybromination
and oxychlorination were smoothly achieved using opꢀ
timal conditions. However, this protocol was not sucꢀ
cessful for oxyfluorination of alkynes, regardless of
what fluorinating agent was used (i.e., Selectfluor, Olah
reagent,18 etc.). Notwithstanding a few substrates needꢀ
ing mild heating at 45 °C to enhance the reaction rate,
most of products were obtained at room temperature
without investing additional energy. Where used, heating
may merely serve to enhance the solubility of poorly
soluble alkynes; indeed, use of THF as a coꢀsolvent in
lieu of heat also facilitated such cases.
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Notably, aromatic halogens did not display any hyꢀ
drodehalogentaion (Table 2, 4 and 5). In all examples,
the potential side reaction of bromination on the aroꢀ
matic ring was not observed. Substrates containing an
active methylene substituent (7) or an amine nucleophile
(8) were very well tolerated. No bromination at the aceꢀ
tyl carbon was observed (7). Although intermolecular a
nucleophilic substitution reaction was expected during
formation of 8, no such side reaction was observed due
to the extremely mild conditions. Both electronꢀrich (6,
8, 9) and ꢀdeficient (5, 7, 10ꢀ13) substrates displayed
good reactivity. Good functional group tolerance was
also observed, and boc (10), cbz (12), and nitro (13)
groups were very well tolerated. Very clean and full
conversion was observed in all cases, and the few cases
conditions: alkyne (0.5 mmol), NCS (1.0 mmol), eosin Y (5
mol%), 1.0 mL 3 wt% FIꢀ750ꢀM in H2O, argon atmosphere, visiꢀ
bleꢀlight (9 W), 45 °C.
of moderate yield were attributable to the small scale,
volatile nature, and instability of the compounds over
silica gel.
Table 3. Substrate scope of micellar oxychlorination
Likewise, alkyne oxychlorination was achieved with
excellent functional group compatibility and reactivity.
Although oxychlorinations were generally slower, they
followed the same reactivity trends as described for oxꢀ
ybrominations in Table 2. Notably, the substrate containꢀ
ing a nitro residue displayed better reactivity in oxychloꢀ
rination (Table 3, 24) than for oxybromination; 82%
isolated yield was obtained at such a low scale.
Control experiments were also conducted to confirm
the roles of light, catalyst, and oxygen (Scheme 1). With
ambient air exposure, only ca. 18% of desired product 3
was obtained. In darkness and the absence of catalyst,
less than 10% of product 3 was obtained, indicating the
significant role of light in generating the bromo radical.
However, as shown in Table 1, without use of catalyst
but in the presence of light, moderate yield was obꢀ
tained. However, this was not general with all examples;
use of eosin Y in such cases was still preferred in order
to generalize the protocol. The reaction was also conꢀ
ducted in the presence of 1.0 equivalent of TEMPO,
which significantly dropped the yield from 80% to 35%,
suggesting the significance of the radical pathway.
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point, carbons of starting alkyne are now saturated and
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7
no further halogenation was observed. This technology
did not work well for aliphatic alkynes since radical
from aliphatic alkynes are not as stable as those from
aromatic alkynes, e.g., a and d in Scheme 3.
conditions: 1 (0.5 mmol), 2 (1.0 mmol), eosin Y (5 mol%), 1.0
mL 3 wt% FIꢀ750ꢀM in H2O, eosin Y (5.0 mol%), visibleꢀlight (9
W), rt (for details, see SI).
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Scheme 1. Control experiments suggesting an involveꢀ
ment of a radical in mechanism.
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Validity of our protocol was also tested on a gramꢀ
scale reaction (Scheme 2). A clean conversion to desired
product 3 was observed with 87% isolated yield. The
yield on a gramꢀscale reaction was in fact higher than
the smallꢀscale reaction.
conditions: 1 (9.79 mmol), NBS (19.6 mmol), eosin Y (5 mol%),
10 mL 3 wt% FIꢀ750ꢀM in H2O, argon atmosphere, rt, 3 h.
Scheme 2. Gramꢀscale reaction in FIꢀ750ꢀM.
Scheme 4. Measure of greenness by E factor and recycle
study.
Based on control experiment and photoꢀphysical propꢀ
erties of eosin Y (EY)19 a plausible mechanism is deꢀ
scribed in Scheme 3. Upon reaction of alkyne, NBS (or
Mostly, these micelleꢀenabled transformations did not
display side reactions. Eosin Y was found to be more
soluble in aqueous FIꢀ750ꢀM compared to diethyl ether
or MTBE; consequently, MTBE (methyl tertꢀbutyl ether)
was used in minimal amounts as a solvent for product
extraction to better facilitate catalyst recycling. To assess
protocol greenness the Eꢀfactor20 was determined for the
model reaction after 4 recycles. Recycle reactions were
performed with full recovery of catalyst and FIꢀ750ꢀM
(Scheme 4). Reuse of micellar reaction media did not
affect outcome of reactions in terms of yield and reacꢀ
tion time. After obtaining 3 in the zeroth cycle, recovꢀ
ered aqueous solution of nanomicelles containing cataꢀ
lyst was reused for first recycle to obtain 3. A similar
process was repeated up to four recycles to obtain deꢀ
sired product. Eꢀfactor = 6.7 was found which advocates
the greenness21 of this protocol. Aqueous micellar media
can be potentially recycled even beyond the fourth recyꢀ
cle.
Scheme 3. Plausible mechanism of selective oxyhaloꢀ
genation.
Conclusion. In summary, this work demonstrates the
development of a green and sustainable reaction protoꢀ
col that involves use of environmentally benign amꢀ
phiphiles, mild conditions, and, above all, no toxic orꢀ
ganic solvents, transition metal catalyst, or harsh oxiꢀ
dants. The protocol is scalable, involves commercially
available and inexpensive reagents, and no special preꢀ
cautions are required in reaction setup. In addition to
mimicking toxic polar organic solvents such as acetoniꢀ
trile, the inherent structure of amphiphile FIꢀ750ꢀM apꢀ
NCS), and singleꢀelectron from EY*, halo vinyl radical
a is formed (step I). Radical cation of EY generated in
the first step accepts electron and forms strained interꢀ
mediate b (step II), which reacts very fast with hydroxꢀ
ide ion that is generated in step I to form αꢀhydroxy
halostyrene intermediate c (step III). Another halogenaꢀ
tion occurs with the aid of singleꢀelectron transfer from
EY* to form αꢀhydroxy dihaloradical d (step IV). Hyꢀ
droxide ion generated in step IV and radical cation of
EY mediate the formation of e as final product. At this
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pears to assist with catalysis through anticipated hydroꢀ under 9 W compact fluorescent bulb and allowed to stir
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gen bonding.
at room temperature or 45 °C.
After complete consumption of starting material, as
monitored by TLC or GCMS, 1.0 mL ethyl acetate and
1.0 mL water was added to the reaction mixture, which
was then gently stirred for 2 min. The organic layer was
separated via centrifuge. This extraction was repeated
using additional 1.0 mL EtOAc. The combined extracts
were dried over anhydrous sodium sulfate and volatiles
were evaporated under reduced pressure at room temꢀ
perature to obtain crude product, which was further puriꢀ
fied by flash chromatography (wet load in DCM) over
silica gel using hexanes/ethyl acetate as eluent. Note:
For compound 14, the reaction was set up in a 1.8 mL
vial.
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General Experimental Details
All manipulations were carried out under argon unless
otherwise noted. TLC plates (UV 254 indicator, glass
backed, thickness 200 mm) and silica gel (standard
grade, 230 – 400 mesh) were purchased from EMD. Diꢀ
ethyl ether, THF, ethyl acetate, methylene chloride, and
hexanes were purchased from Fisher Scientific. Nꢀ
bromosuccinimide (NBS) and Nꢀbromosuccinimide
(NCS) were purchased from Acros Organic and used as
such without any further purification. Eosin YH+ was
purchased from Chemꢀimpex International. Alkynes
were either purchased from Oakwood chemicals, Comꢀ
biꢀblocks, Alfa Aesar, Chemꢀimpex or synthesized by
Sonogashira couplings. Pure NMR solvents were purꢀ
chased from Cambridge Isotopes Laboratories. Bulk
aqueous solution of surfactant FIꢀ750ꢀM2c was prepared
by dissolving neat surfactant wax in HPLC grade water
and thoroughly purged with argon before use. Purificaꢀ
tions of crude compounds were performed on silica gel
(purchased from Sorbtech) using CombiꢀFlash Rfꢀ150
equipment. Catalytic reactions were performed in 4 mL
microwave reaction vials purchased from Biotage. Meltꢀ
ing points were determined using a MELꢀTEMP II meltꢀ
ing point apparatus with samples in KimbleꢀKimex 51
capillaries (1.5ꢀ1.8 x 90 mm). Unless otherwise menꢀ
tioned, all NMR spectra were recorded at 23°C on Variꢀ
an Unity INOVA (400 and 500 MHz) spectrometers.
Reported chemical shifts are referenced to residual solꢀ
vent peaks.22 All HRMS data were recorded either using
electrospray ionization (ESI) or chemical ionization
(CI). Electrospray ionization (ESI) data were recorded
on a Thermo LTQ Orbitrap XL mass spectrometer at
30,000 resolving power and using reserpine (M+H+ =
609.2806) for internal calibration. Electron ionization
(EI) and chemical ionization (CI, 1.5*10ꢀ4 mbar of meꢀ
thane as reagent gas) data were recorded at 5,000 resolvꢀ
ing power on a MATꢀ95 XP magnetic sector mass specꢀ
trometer using perflourokerosene for internal calibration.
IR spectra were obtained on a Perkin Elmer (Spectrum
100 FTꢀIR Spectrometer) apparatus.
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Gram Scale Synthesis of 3
In a 50 mL roundꢀbottom flask (RBF) containing a
PTFEꢀcoated magnetic stir bar, NBS (2 equiv., 19.6
mmol, 3.49 g), eosinꢀYH+ (5 mol%, 0.49 mmol, 318
mg) and phenylacetylene (1 equiv., 9.8 mmol, 1 g) were
sequentially added. The RBF was closed with a rubber
septum and subsequently evacuated and backꢀfilled with
argon. 10 mL volume of 3 wt% aqueous FIꢀ750ꢀM
(freshly sparged with argon) was added to the reaction
mixture. The septum was wrapped with PTFE tape and
black electrical tape. The reaction mixture was irradiated
with a 9 W compact fluorescent bulb and it was allowed
to stir at room temperature for 3ꢀ4 h.
After complete consumption of starting material, as
monitored by GCMS and/or TLC, 25 mL ethyl acetate
and 15 mL water was added to the reaction mixture. The
organic layer was separated using separatory funnel.
This extraction was repeated three times using additional
3 x 10 mL EtOAc. The combined extracts were dried
over anhydrous sodium sulfate and volatiles were evapoꢀ
rated under reduced pressure at room temperature to
obtain crude product as an orange oil, which was further
purified by flash chromatography (wet load in methꢀ
ylene chloride) over silica gel using 1% ethyl aceꢀ
tate/hexanes as eluent. Pure product was obtained as a
yellow oil, Rf = 0.42 (9:1, hexanes/ethyl acetate), yield
2.4 g (87%).
Optimal General Procedure of Catalytic Oxyhalo-
genation of Alkynes
Analytical Data
In a 4.0 mL reaction vial containing a PTFEꢀcoated
magnetic stir bar, NBS (2.0 equiv., 1.0 mmol, 178 mg)
or NCS (2.0 equiv., 1.0 mmol, 133.5 mg), eosin YH+
(5.0 mol%, 0.025 mmol, 16.2 mg) and alkyne (1.0
equiv., 0.5 mmol) were sequentially added. The reaction
vial was closed with a rubber septum and subsequently
evacuated and backꢀfilled with argon. 1.0 mL volume of
3 wt% aqueous FIꢀ750ꢀM was added to the reaction
mixture. The septum was wrapped with PTFE tape and
black electrical tape. The reaction mixture was irradiated
2,2-dibromo-1-phenylethanone (3)23
Yellow oil, yield 111.2 mg (80%), Rf 0.42 (9:1, hexꢀ
1
anes/ethyl acetate). H NMR (500 MHz, CDCl3) δ 8.09
(d, J = 9,5 Hz, 2H), 7.64 (t, J = 7.5 – 14.5Hz, 1H), 7.51
(t, J = 10 – 15.5 Hz, 2H), 6.71 (s, 1H).
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(w), 2812 (w), 1662 (m), 1581 (s), 1443 (m), 1322 (m),
1286 (s), 1179 (s); HRMS (CI), m/z [M + H]+ calcd for
1
2
3
2,2-dibromo-1-(4-bromophenyl)-ethanone (4)24
C8H8Br2NO 293.8952, found 293.8949.
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5
2,2-dibromo-1-(3-thienyl)-ethanone (9)24,25
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7
8
9
White solid, yield 132.9 mg (75%), Rf 0.48 (9:1, hexꢀ
anes/ethyl acetate), mp = 83ꢀ88°C; H NMR (400 MHz,
CDCl3) δ 7.97 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz,
2H), 6.60 (s, 1H).
1
Yellow oil, yield 112.9 mg (80%), Rf 0.16 (hexanes).
1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.67 (d, J =
5.2 Hz, 1H), 7.37 (d, J = 4.8 Hz, 1H), 6.43 (s, 1H).
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2,2-dibromo-1-(4-chlorophenyl)-ethanone (5)24,25
tert-butyl
(4-(2,2-dibromoacetyl)phenyl)carbamate
(10)
Off white solid, yield 114.5 mg (74%), Rf 0.36 (9:1,
1
hexanes/ethyl acetate), mp = 92ꢀ94°C; H NMR (400
MHz, CDCl3) δ 8.05 (d, J =8.8 Hz, 2H), 7.49 (d, J = 8.8
Hz, 2H), 6.60 (s, 1H).
Orange oil, yield 108.9 mg (56%), Rf 0.30 (8:2, hexꢀ
1
anes/ethyl acetate). H NMR (500 MHz, CDCl3) δ 8.04
(d, J = 7.5 Hz, 2H), 7.50 (d, J = 8 Hz, 2H), 6.81 (s, 1H),
6.67 (s, 1H), 1.53 (s, 9H); 13C NMR (126 MHz, CDCl3)
δ 184.8, 152.0, 144.3, 131.5, 125.0, 117.7, 81.8, 39.9,
28.3; IR ν (cm–1) = 3344 (w), 2979 (w), 1712 (m), 1682
(m), 1586 (m), 1525 (m), 1233 (m), 1152 (s); HRMS
(ESI), m/z [M + Na]+ calcd for C13H15Br2NO3Na
415.9296, found 415.9291.
2,2-dibromo-1-(4-methoxyphenyl)-ethanone (6)24,25
White solid, yield 124.4 mg (81%), Rf 0.31 (9:1, hexꢀ
1
anes/ethyl acetate), mp = 90ꢀ92°C; H NMR (500 MHz,
2,2-dibromo-1-(4-fluorophenyl)-ethanone (11)24,25
CDCl3) δ 8.06 (d, J =9 Hz, 2H), 6.96 (d, J = 8.5 Hz,
2H), 6.68 (s, 1H), 3.88 (s, 3H).
1-(4-acetylphenyl)-2,2-dibromo-ethanone (7) 25,26
Colorless oil, yield 80.6 mg (55%), Rf 0.23 (9:1, hexꢀ
1
anes/ethyl acetate). H NMR (500 MHz, CDCl3) δ 8.16
(m, 2H), 7.19 (t, J = 9 – 17.5 Hz, 2H), 6.61 (s, 1H).
White solid, yield 122.9 mg (77%), Rf 0.21 (8:2, hexꢀ
benzyl(4-(2,2-dibromoacetyl)phenyl)carbamate (12)
1
anes/ethyl acetate), mp = 75ꢀ77°C; H NMR (500 MHz,
CDCl3) δ 8.18 (d, J =8.5 Hz, 2H), 8.05 (d, J = 8.5 Hz,
2H), 6.67 (s, 1H), 2.65 (s, 3H).
1-(4-aminophenyl)-2,2-dibromo-ethanone (8)
Offꢀwhite solid, yield 177.2 mg (83%), Rf 0.39 (8:2,
1
hexanes/ethyl acetate), mp = 133ꢀ135°C; H NMR (500
MHz, CDCl3) δ 8.02 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5
Hz, 2H), 7.35ꢀ7.38 (m, 5H), 7.28 (s, 1H), 6.68 (s, 1H),
5.21 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 185.0,
152.9, 144.8, 135.6, 131.6, 128.8, 128.7, 128.8, 125.4,
118.0, 67.7, 40.0; IR ν (cm–1) = 3352 (m), 3066 (w),
3014 (w), 2921 (w), 2851 (w), 1684 (s), 1589 (m), 1527
Orange solid, yield 88.3 mg (61%), Rf 0.27 (7:3, hexꢀ
1
anes/ethyl acetate), mp = 86ꢀ89°C; H NMR (500 MHz,
CDCl3) δ 7.92 (d, J = 8.5 Hz, 2H), 6.66 (d, J = 8 Hz,
2H), 6.66 (s, 1H), 4,33 (s, 2H); 13C NMR (126 MHz,
CDCl3) δ 184.3, 152.4, 132.5, 120.4, 114.0, 40.3; IR ν
(cm–1) = 3426 (w), 3339 (m), 3229 (w), 3000 (w), 2890
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(s), 1269 (m), 1178 (m); HRMS (CI), m/z [M + H]+
calcd for C16H14Br2NO3 427.9320, found 427.9326.
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4
2,2-dibromo-1-(4-nitrophenyl)-ethanone (13) 25,26
5
6
7
8
White solid, yield 87.6 mg (76%), Rf 0.16 (8:2, hexꢀ
anes/ethyl acetate), mp = 81ꢀ84°C; H NMR (500 MHz,
1
CDCl3) δ 8.19 (d, J =8.5 Hz, 2H), 8.07 (d, J = 8.5 Hz,
2H), 6.64 (s, 1H), 2.66 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 197.1, 185.5, 141.2, 134.6, 130.2, 128.6, 67.9,
27.0; IR ν (cm–1) = 3032 (w), 2925 (w), 1698 (m), 1681
(s); HRMS (ESI), m/z [M + H]+ calcd for C10H9Cl2O2
230.9980, found 230.9984.
9
Colorless oil, yield 67.2 mg (42%), Rf 0.40 (8:2, hexꢀ
anes/ethyl acetate). 1H NMR (500 MHz, CDCl3) 8.36 (d,
J = 9 Hz, 1H), 8.31 (d, J = 9 Hz, 2H), 6.58 (s, 1H).
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2,2-dichloro-1-phenylethanone (14)23,24
1-(4-aminophenyl)-2,2-dichloro-ethanone (19)
Yellow oil, yield 70.3 mg (74%), Rf 0.41 (9:1, hexꢀ
1
anes/ethyl acetate). H NMR (500 MHz, CDCl3) δ 8.09
Orange solid, yield 52.3 mg (52%), Rf 0.25 (7:3, hexꢀ
(d, J =7,5 Hz, 2H), 7.65 (t, J =7.5 – 15Hz, 1H), 7.52 (t, J
= 8 – 16 Hz, 2H), 6.69 (s, 1H).
1
anes/ethyl acetate), mp = 79ꢀ81°C; H NMR (500 MHz,
CDCl3) δ 7.92 (d, J = 9.0 Hz, 2H), 6.67 (d, J = 9.0 Hz,
2H), 6.64 (s, 1H), 4.35 (s, 2H); 13C NMR (126 MHz,
CDCl3) δ 184.2, 152.5, 132.6, 121.1, 113.9, 68.0; IR ν
(cm–1) = 3408 (m), 3335 (m), 3227 (m), 2924 (w), 2853
(w), 2692 (w), 1678 (m), 1633 (m), 1582 (s), 1560 (s),
1633 (m), 1443 (s), 1321 (s), 1288 (s), 1172 (s), 1138
(s); HRMS (CI), m/z [M + H]+ calcd for C8H8Cl2NO
203.9983, found m/z 203.9984.
2,2-dichloro-1-(4-bromophenyl)-ethanone (15)23,24
Yellow oil, yield 81.3 mg (61%), Rf 0.42 (hexanes).
1H NMR (400 MHz, CDCl3) δ 7.97 (t, J =8.8 Hz, 2H),
7.67 (d, J = 9.2 Hz, 2H), 6.58 (s, 1H).
2,2-dichloro-1-(3-thienyl)-ethanone (20)23,24
2,2-dichloro-1-(4-chlorophenyl)-ethanone (16)23,24
Yellow oil, yield 79.7 mg (82%), Rf 0.16 (hexanes).
1H NMR (500 MHz, CDCl3) δ 8.4 (s, 1H), 7.67 (s, 1H),
7.39 (s, 1H), 6.43 (s, 1H).
Yellow oil, yield 75.5 mg (68%), Rf 0.24 (9:1, hexꢀ
1
anes/ethyl acetate). H NMR (500 MHz, CDCl3) δ 8.05
(d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 6.59 (s,
1H).
tert-butyl-(4-(2,2-dichloroacetyl)phenyl)carbamate
(21)
2,2-dichloro-1-(4-methoxyphenyl)-ethanone (17)23,24
Yellowishꢀorange oil, yield 96.2 mg (63%), Rf 0,29
(8:2, hexanes/ethyl acetate). 1H NMR (500 MHz,
CDCl3) δ 8.04 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz,
2H), 6.81 (s, 1H), 6.64 (s, 1H), 1.53 (s, 9H). 13C NMR
(126 MHz, CDCl3) δ 184.7, 152.0, 144.4, 131.6, 125.5,
117.7, 81.8, 67.7, 67.5; IR ν (cm–1) = 3339 (m), 2987
(w), 1740 (m), 1686 (m), 1583 (m), 1525 (s), 1416 (m),
1318 (m), 1203 (m), 1174 (m); HRMS (ESI), m/z [M +
Na]+ calcd for C13H15Cl2NO3Na 326.0327, found
326.0323.
Yellow oil, yield 81.1 mg (74%), Rf 0.16 (9:1, hexꢀ
1
anes/ethyl acetate). H NMR (500 MHz, CDCl3) δ 8.08
(d, J =8.5 Hz, 2H), 6.98 (d, J = 9 Hz, 2H), 6.64 (s, 1H),
3.90 (s, 3H).
1-(4-acetylphenyl)-2,2-dichloro-ethanone (18)
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ACKNOWLEDGMENT
Page 8 of 10
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2,2-dichloro-1-(4-fluorophenyl)-ethanone (22)23,24
This research work was supported in part by an award from
Kentucky Science and Engineering Foundation as per grant
agreement #KSEFꢀ148ꢀ502ꢀ17ꢀ396 with the Kentucky Sciꢀ
ence and Technology Corporation. We warmly
acknowledge Novartis Pharmaceuticals for partial financial
support. High resolution, accurate mass spectra were recꢀ
orded by Ms. Angela Hansen at the Indiana University
Mass Spectrometry Facility using a MATꢀ95XP mass specꢀ
trometer purchased with NIH grant 1S10RR016657ꢀ01. We
also thank Dr. Yadagiri Dongari for a trial reaction.
Yellow oil, yield 75.6 mg (73%), Rf 0.14 (hexanes).
1H NMR (500 MHz, CDCl3) δ 8.15 (m, 2H), 7.20 (m,
2H), 6.60 (s, 1H).
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benzyl(4-(2,2-dichloroacetyl)phenyl)carbamate (23)
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2,2-dichloro-1-(4-nitrophenyl)-ethanone (24)23,24
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ASSOCIATED CONTENT
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website at
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AUTHOR INFORMATION
Corresponding Author
sachin.handa@louisville.edu
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