Efficient and simple preparation of functionalized 1,1-dibromoenol phosphates

Article abstract of DOI:10.1007/s00706-015-1613-6

The preparation of functionalized 1,1-dibromoalkenyl phosphates is described. The protocol developed for their preparation is based on the generation of enolates from α,α-dibromoketones followed by a reaction with dialkyl chlorophosphates. The procedure t

Full text of DOI:10.1007/s00706-015-1613-6

Monatsh Chem (2016) 147:405–412
DOI 10.1007/s00706-015-1613-6
ORIGINAL PAPER
Efficient and simple preparation of functionalized
1,1-dibromoenol phosphates
1
1
Vladislav Kotek1 Peter Polak Tomas Tobrman
´ˇ
•
•
´
Received: 7 October 2015 / Accepted: 19 November 2015 / Published online: 9 December 2015
Ó Springer-Verlag Wien 2015
Abstract The preparation of functionalized 1,1-dibro-
moalkenyl phosphates is described. The protocol
developed for their preparation is based on the generation
of enolates from a,a-dibromoketones followed by a reac-
tion with dialkyl chlorophosphates. The procedure tolerates
various functional groups including ester, ketone, and
nitrile, and the yields are generally high.
chlorides, and iodides [1–5]. Besides halides, substrates
with activated C–O bonds, for instance tosylates, triflates,
and nonaflates, represent new types of partner suitable for
cross-coupling reactions. Significant progress has been
achieved in the case of alkenyl or aryl phosphates. The
cross-coupling methodologies using phosphates as the
starting material have been summarized in several reviews
[6–10]. Moreover, the recent literature shows that phos-
phates are successfully used in Suzuki [11–14], Stille [15],
Kumada-Corriu [16–18], Hiyama coupling reactions [19],
or C–H activation [20]. In addition to the above-mentioned
applications, phosphates can be coupled with diaryliodo-
nium triflates [21] and the phosphate moiety can be used as
a directing group during C–H activation of aryl phosphates
[22–24].
Graphical abstract
Tri- and tetrasubstituted alkenes form a large group of
naturally occurring or biologically active substances. Sig-
nificant progress has been achieved within the
stereoselective approach to trisubstituted alkenes [25–28],
including cross-coupling reactions of enol phosphates [29,
30]. On the other hand, the current methods suitable for the
stereoselective synthesis of tetrasubstituted alkenes are
based on direct carbometalation of internal alkynes [31–
40], transition metal-catalyzed cascade reactions [41–44],
the oxidative Heck reaction [45, 46], the cross-coupling
reaction of multimetalated alkene templates [47–50], and
others [51–57]. To the best of our knowledge, no reports on
the employment of dibromoenol phosphates in the syn-
thesis of tetrasubstituted alkenes have been made until
recently, when we reported a procedure for the stereose-
lective synthesis of tetrasubstituted alkenes starting from
dibromoenol phosphates [58]. During our synthetic work
on the stereoselective preparation of tetrasubstituted alke-
nes the starting phosphates were prepared via the Perkow
reaction of tribromoketones 2 that are easily available from
Keywords Bromination Á Alkynes Á Phosphates Á
Enols
Introduction
The formation of carbon–carbon bonds still represents an
important goal in organic synthesis. Within a couple of
decades, many methods describing the construction of C–C
bonds have been published. The majority of published
procedures relies on the application of easily available
substrates including aryl, alkenyl, or alkyl bromides,
´ˇ
& Tomas Tobrman
tomas.tobrman@vscht.cz
1
Department of Organic Chemistry, University of Chemistry
´
and Technology, Prague, Technicka 5, 166 28 Prague 6,
Czech Republic
123

406
V. Kotek et al.
amount of trifluoroacetic acid was used, the yield of 5a
decreased to 84 % (Table 1, entry 4). On the other hand,
running the same reaction in the presence of 10 mol%
perchloric acid increased the yield of 5a to 99 % (Table 1,
entry 5). These results indicate that the 2-oxy-1,1-dibromi-
nation reaction of phenylacetylene proceeds at ambient
temperature and the reaction can be catalyzed by protic
acids. Optimized reaction conditions were used to screen the
reactivity of other terminal alkynes in the 2-oxy-1,1-di-
bromination reaction. Aromatic alkynes bearing electron-
withdrawing groups including ester, aldehyde, ketone, and
amide functionalities were transformed to ketones in yields
ranging from 75 % up to 89 % (Table 1, entries 7–10).
4-Nitrophenylacetylene required heating to 50 °C to achieve
full conversion and ketone 5f was then isolated in 35 %
yield (Table 1, entry 11). Acetylenes bearing simple butyl,
3-chloropropyl, and 3-cyanopropyl groups underwent 2-oxy-
1,1-dibromination in good yields (Table 1, entries 13–15).
However, the reaction of 2-thienylacetylene with NBS in the
presence of a catalytic amount of perchloric acid led to a
mixture of the expected ketone 5 l and a ketone with
Scheme 1
the corresponding aldehydes 1 (Scheme 1) [58]. Developed
methodology suffered by use of toxic Cr(VI) based oxi-
dation reagent jointly with the average yields. Therefore,
we sought a general and widely applicable methodology
for the synthesis of functionalized dibromoenol phosphates
3. The literature survey revealed that the preparation of
only a couple of simple dibromoenol phosphates bearing
simple unfunctionalized aryl and alkyl groups has been
reported [59, 60]. Therefore, we have proposed a novel
route leading to dibromoenol phosphates 3 (Scheme 1).
The proposal consists of the transformation of terminal
alkynes 4 to dibromomethyl ketones 5 followed by eno-
lization and the reaction with chlorophosphate.
1
brominated thiophene ring 5 m in a 1:1 ratio based on H
NMR of the crude reaction mixture (Table 1, entry 17).
Further addition of NBS did not change the ratio of
5 l:5 m. This shows that electrophilic aromatic bromination
of 2-thienylacetylene proceeds as a side reaction with a
similar reaction rate compared to that of the 2-oxy-1,1-di-
bromination of the triple bond. On the other hand, the
product of the 2-oxy-1,1-dibromination of 2-thienyl-
acetylene 5 l did not react with NBS in terms of the
substitution reaction. An example of (4-methylphenyl)ace-
tylene illustrates that oxy-1,1-dichlorination is also feasible
under the developed conditions (Table 1, entry 18).
Results and discussion
Initially, we focused on the selection of the methodology for
the preparation of dibromomethyl ketones from alkynes. A
procedure for the 2-oxy-1,1-dihalogenation of alkynes
reported by Liu and co-workers [61] was chosen from a
wide variety of suitable methods. The similar method was
also used for the preparation of a,a-dibromodimethyl ketals
[62]. In this report [61], dibromoketones were prepared by
the reaction of terminal alkynes with NBS in THF-water at
80 °C. The reaction was catalyzed by FeCl3Á6H2O. Harsh
reaction conditions led us to reinvestigate the reaction
course. Moreover, based on the hydrolytic properties of
iron(III) chloride, we reasoned that the 2-oxy-1,1-dibromi-
nation reaction is actually catalyzed by a protic acid.
Therefore, the reaction of phenylacetylene with NBS was
optimized with respect to lower the reaction temperature and
to screen for suitable catalysts. The summarized results
show that when phenylacetylene was treated with 2.5 eq. of
NBS and FeCl3Á6H2O in THF-H2O at ambient temperature,
the ketone 5a was obtained in 82 % yield (Table 1, entry 1).
The use of MeCN-H2O increased the yield of 5a to 96 %
(Table 1, entry 2). A similar yield of 5a was achieved using
CuCl2 as the catalyst (Table 1, entry 3). When a catalytic
Having established an efficient and convenient route to
1,1-dibromoketones, we turned our attention to the for-
mation of dibromoenol phosphates 3 (Scheme 2). The
prepared dibromoketones 5 were dissolved in dry THF and
the reaction with LiHMDS at low temperature followed by
immediate addition of diethyl chlorophosphate afforded the
desired phosphates 3. The methodology is suitable for the
preparation of aromatic phosphates bearing nitro, ester, and
ketone functionalities 3a–3c (Scheme 2, entries 1–3). It is
noteworthy to mention the preparation of phosphate 3b. In
this case, the starting dibromoketone 5d contains two dif-
ferent acetyl groups; however, the action of the base led to
the chemoselective formation of the kinetically preferred
enolate, exclusively. Aromatic ketones bearing methyl and
N,N-dimethylamino groups 5g, 5o and simple 1,1-dibro-
mohexane-2-one (5h) furnished phosphates 3d–3f in high
yields (Scheme 2, entries 4–6). Analogously to ketone 5h,
high yields of phosphates 3g, 3h were achieved with other
aliphatic ketones 5j, 5i. Even heteroaromatic ketones 5l,
5m were smoothly converted to phosphates 3j, 3k in 73
123

Efficient and simple preparation of functionalized 1,1-dibromoenol phosphates
407
Table 1 Preparation of 1,1-dibromoketones 5 using 2-oxy-1,1-dibromination of terminal alkynes
Entr.
R1
Catalysta, time/h
Yield/%b,c
1
C6H5
FeCl3Á6H2O, 3
FeCl3Á6H2O, 3
CuCl2, 3
5a, 82d
5a, 96
2
C6H5
3
C6H5
5a, 94
4
C6H5
CF3COOH, 3
HClO4, 3
5a, 84
5
C6H5
5a, 99
5a, 95d
6
C6H5
HClO4, 3
7
4-CHOC6H4
4-CH3OOCC6H4
4-CH3COC6H4
4-Me2NCOC6H4
4-NO2C6H5
4-CH3C6H4
CH3CH2CH2CH2
NC(CH2)3
Cl(CH2)3
HClO4, 24
HClO4, 6
5b, 75
8
5c, 89
9
HClO4, 3
5d, 82
10
11
12
13
14
15
16
17
HClO4, 12
HClO4, 6e
HClO4, 3
5e, 86
5f, 35
5g, 95
HClO4, 3
5h, 92
HClO4, 12
HClO4, 12
HClO4, 17f
HClO4, 12
5i, 86
5j, 65
C6H5COOCH2
2-Thienyl
5k, 86
5l, 28 (R1 = 2-thienyl)
5m, 28 (R1 = 5-bromo-2-thienyl)
5n, 92g
18
4-CH3C6H4
HClO4, 8f
a
10 mol% of the catalyst was used
b
c
Isolated yield
Typical reaction conditions: a solution of alkyne (1.0 eq.) and NBS (2.5 eq.) in MeCN-H2O 2:1 (cm3/mmol) was stirred for time period
indicated in Table 1 at ambient temperature
d
THF/H2O (2:1) was used as the solvent
e
50 °C
f
40 °C
NCS was used instead of NBS. The product of the reaction is 4-(dichloroacetyl)toluene (5n)
g
and 86 % yield, respectively (Scheme 2, entries 10, 11).
The methodology is also applicable for the preparation of
dichloroenol phosphates, as demonstrated by the prepara-
tion of dichloro alkene 3l, which was formed quantitatively
(Scheme 2, entry 12). The scope of the developed protocol
was also extended to the preparation of phenyl esters of
phosphoric acid. Thus, ketones with simple butyl, 4-nitro-
phenyl, and 4-N,N-dimethylaminophenyl groups 5f, 5h, 5o
were transformed to phosphates 3m, 3n, 3p using the above
methodology and diphenyl chlorophosphate instead of
diethyl chlorophosphate. The only exception to the gener-
ally high yields of phosphates 3 was the preparation of
diphenyl and diethyl phosphates 3i, 3o bearing a benzoyl-
oxymethyl group that were prepared starting from the
corresponding ketone 5k in moderate yields only
(Scheme 2, entries 9, 15).
Conclusion
To conclude, we have developed a novel and general
methodology for the preparation of dibromoenol phos-
phates which is based on the reaction of 1,1-
dibromoketones with LiHMDS followed by treating with
dialkyl or diaryl chlorophosphates in dry THF. The
methodology provides easy, efficient, and rapid access to
functionalized dibromoenolphosphates. Further studies
including the application of prepared phosphates for the
123

408
V. Kotek et al.
Scheme 2
preparation of functionalized tetrasubstituted alkenes are
ongoing in our laboratory.
as 70 % solution. 4-Ethynylacetophenone [63], 4-ethynyl-
N,N-dimethylbenzamide [64], 2,2-dibromo-40-(dimethyl-
amino)acetophenone 5o [65] were prepared according to
reported procedures, other alkynes and compounds were
purchased and used as received.
Experimental
All reactions were performed under an argon atmosphere.
NMR spectra were measured on a Varian Gemini 300
spectrometer (1H, 300.07 MHz, 13C, 75.46 MHz) at 298 K.
Mass spectra were measured on ZAB-SEQ (VG Analyti-
cal). The solvents were dried and degassed by standard
procedures; silica gel (Merck, silica gel 60, 40–63 lm) was
used for column chromatography. Perchloric acid was used
General procedure for the conversion
of a,a-dibromoketones to enolphosphates 3
LiHMDS (1.1 cm3, 1.10 mmol) was added to a solution of
a,a-dibromoketones 5 (1.0 mmol) in dry THF (5 cm3/
mmol) cooled to -78 °C. The resultant mixture was stirred
5 min at -78 °C, and the phosphorylated reagent
123

Efficient and simple preparation of functionalized 1,1-dibromoenol phosphates
409
2,2-Dibromo-1-[4-(N,N-dimethylamino)phenyl]ethenyl
diethyl phosphate (3e, C14H20Br2NO4P)
(1.25 mmol) was added. The mixture was warmed to
ambient temperature and stirred for 2 h. Then, the reaction
mixture was quenched with 5 vol % ammonia (5 cm3/
mmol), diluted with ether (10 cm3/mmol) and the organic
layer was extracted with HCl (1 M, 5 cm3/mmol), water
(5 cm3/mmol), and brine (5 cm3/mmol). The organic layer
was dried over MgSO4, concentrated under reduced pres-
sure and column chromatography on silica gel gave the
final product.
Yellow oil; 0.349 g 5o (1.0 mmol) was converted to
0.290 g 3e (63 %); Rf = 0.2 (EtOAc-hexane, 1:2); 1H
NMR (300 MHz, CDCl3): d = 7.43–7.40 (m, 2H, CH),
6.69 (d, J = 9.0 Hz, 2H, CH), 4.11–3.92 (m, 4H, CH2),
2.99 (s, 6H, CH3), 1.25–1.19 (m, 6H, CH3) ppm; 13C NMR
(75.45 MHz, CDCl3): d = 150.5, 148.0 (d, J = 7.8 Hz),
130.4, 120.1, 111.3, 81.9 (d, J = 12.1 Hz), 64.4 (d,
J = 6.1 Hz), 40.3, 15.8 (d, J = 7.2 Hz) ppm; HRMS
(APCI): m/z calc. for C14H20Br2NO4P ([M ? H]?)
457.9549, found 457.9548.
2,2-Dibromo-1-(4-methoxycarbonylphenyl)ethenyl diethyl
phosphate (3a, C14H17Br2O6P)
Yellow oil; 0.672 g 5c (2.0 mmol) was converted to
0.926 g 3a (98 %); Rf = 0.4 (EtOAc-hexane, 1:1); 1H
NMR (300 MHz, CDCl3): d = 8.07 (d, J = 8.4 Hz, 2H,
CH), 7.62 (d, J = 8.4 Hz, 2H, CH), 4.03–3.95 (m, 4H,
1,1-Dibromohexen-2-yl diethyl phosphate (3f)
Yellow oil; 0.514 g 5h (2.0 mmol) was converted to
0.715 g 3f (91 %); Rf = 0.40 (EtOAc-hexane, 1:2); 1H
NMR in accordance with Ref. [58].
CH2), 3.93 (s, 3H, CH3), 1.16–1.21 (m, 6H, CH3) ppm; 13
C
NMR (75.45 MHz, CDCl3): d = 146.2 (d, J = 7.7 Hz),
137.0, 130.9, 129.3, 129.1, 85.3 (d, J = 11.0 Hz), 64.5 (d,
J = 6.1 Hz), 52.1, 15.6 (d, J = 7.2 Hz) ppm; HRMS
(APCI): m/z calc. for C14H17Br2O6P ([M ? H]?)
472.9182, found 472.9187.
1,1-Dibromo-5-chloropenten-2-yl diethyl phosphate
(3g, C9H16Br2ClO4P)
Yellow oil; 0.556 g 5j (2.0 mmol) was converted to
0.724 g 3g (87 %); Rf = 0.5 (EtOAc-hexane, 1:2); 1H
NMR (300 MHz, CDCl3): d = 4.24 (p, J = 6.9 Hz, 4H,
CH2), 3.56 (t, J = 6.3 Hz, 2H, CH2), 2.82 (dt, J = 1.5,
7.5 Hz, 2H, CH2), 2.12–2.07 (m, 2H, CH2), 1.37 (dt,
J = 1.2, 6.9 Hz, 6H, CH3) ppm; 13C NMR (75.45 MHz,
CDCl3): d = 148.7 (d, J = 7.8 Hz), 82.8 (d,
J = 11.60 Hz), 64.8 (d, J = 6.6 Hz), 43.5, 30.2, 28.7 (d,
J = 1.1 Hz), 15.9 (d, J = 7.2 Hz) ppm; HRMS (APCI): m/
z calc. for C9H16Br2ClO4P ([M ? H]?) 414.8894, found
414.8897.
2,2-Dibromo-1-(4-acetylphenyl)ethenyl diethyl phosphate
(3b, C14H17Br2O5P)
Yellow oil; 0.233 g 5d (0.728 mmol) was converted to
0.242 g 3b (73 %); Rf = 0.4 (EtOAc-hexane, 1:1); 1H
NMR (300 MHz, CDCl3): d = 7.96 (d, J = 8.1 Hz, 2H,
CH), 7.63 (d, J = 8.1 Hz, 2H, CH), 4.03–3.98 (m, 4H,
CH2), 2.60 (s, 3H, CH3), 1.23–1.15 (m, 6H, CH3) ppm; 13
C
NMR (75.45 MHz, CDCl3): d = 197.0, 146.2 (d,
J = 7.7 Hz), 137.4, 137.2 (d, J = 0.4 Hz), 129.5 (d,
J = 1.1 Hz), 127.8, 85.3 (d, J = 11.6 Hz), 64.6 (d,
J = 6.1 Hz), 26.5, 15.6 (d, J = 7.2 Hz) ppm; HRMS
(APCI): m/z calc. for C14H17Br2O5P ([M ? H]?)
456.9233, found 456.9237.
1,1-Dibromo-5-cyanopenten-2-yl diethyl phosphate
(3h, C10H16Br2NO4P)
Yellow oil; 0.538 g 5i (2.0 mmol) was converted to
0.776 g 3h (96 %); Rf = 0.2 (EtOAc-hexane, 1:1); 1H
NMR (300 MHz, CDCl3): d = 4.29–4.19 (m, 4H, CH2),
2.85–2.79 (m, 2H, CH2), 2.41 (t, J = 7.2 Hz, 2H, CH2),
2.00 (p, J = 7.2 Hz, 2H, CH2), 1.41–1.36 (m, 6H, CH3)
ppm; 13C NMR (75.45 MHz, CDCl3): d = 147.8 (d,
J = 7.7 Hz), 118.6, 83.4 (d, J = 11.1 Hz), 64.9 (d,
J = 6.1 Hz), 21.8 (d, J = 1.7 Hz), 31.3, 16.1, 15.8 (d,
J = 7.2 Hz) ppm; HRMS (APCI): m/z calc. for C10H16-
Br2NO4P ([M ? H]?) 405.9236, found 405.9234.
2,2-Dibromo-1-(4-nitrophenyl)ethenyl diethyl phosphate
(3c, C12H14Br2NO6P)
Yellow oil; 0.646 g 5f (2.0 mmol) was converted to
0.680 g 3c (74 %); Rf = 0.4 (EtOAc-hexane, 1:2); 1H
NMR (300 MHz, CDCl3): d = 8.26 (d, J = 8.4 Hz, 2H,
CH), 7.75 (d, J = 8.4 Hz, 2H, CH), 4.10–4.02 (m, 4H,
CH2), 1.23 (t, J = 7.2 Hz, 6H, CH3) ppm; 13C NMR
(75.45 MHz, CDCl3): d = 148.0, 145.2 (d, J = 7.8 Hz),
139.1 (d, J = 1.7 Hz), 130.5 (d, J = 1.1 Hz), 123.2, 86.6
(d, J = 11.0 Hz), 64.9 (d, J = 6.1 Hz), 15.8 (d,
J = 7.2 Hz) ppm; HRMS (APCI): m/z calc. for C12H14-
Br2NO6P ([M ? H]?) 459.8978, found 459.8983.
1,1-Dibromo-3-(benzyloxycarbonyl)propen-2-yl
diethyl phosphate (3i, C14H17Br2O6P)
Brown oil; 0.672 g 5k (2.0 mmol) was converted to
0.396 g 3i (42 %); Rf = 0.3 (EtOAc-hexane, 1:2); 1H
NMR (300 MHz, CDCl3): d = 8.10–8.07 (m, 2H, CH),
7.58–7.55 (m, 2H, CH), 7.47–7.44 (m, 2H, CH), 5.24 (d,
J = 1.2 Hz, 2H, CH2), 4.24–4.18 (m, 4H, CH2), 1.31 (dt,
J = 1.2, 7.2 Hz, 6H, CH3) ppm; 13C NMR (75.45 MHz,
CDCl3): d = 165.4, 144.2 (d, J = 7.7 Hz), 133.2, 129.6 (d,
J = 3.8 Hz), 129.0, 128.2, 88.5 (d, J = 11.1 Hz), 64.9 (d,
2,2-Dibromo-2-(4-methylphenyl)ethenyl diethyl phosphate
(3d)
Yellow oil; 0.584 g 5g (2.0 mmol) was converted to
0.793 g 3d (93 %); Rf = 0.4 (silica gel, EtOAc-hexane,
1
1:2); H NMR in accordance with Ref. [58].
123

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V. Kotek et al.
J = 6.0 Hz), 61.6, 15.7 (d, J = 7.2 Hz) ppm; HRMS
(APCI): m/z calc. for C14H17Br2O6P ([M ? H]?)
472.9182, found 472.9181.
m/z calc. for C20H14Br2NO6P ([M ? H]?) 555.8978, found
555.8977.
1,1-Dibromohexen-2-yl diphenyl phosphate
2,2-Dibromo-1-(2-thienyl)ethenyl diethyl phosphate
(3j, C10H13Br2O4PS)
(3n, C18H19Br2O4P)
Yellow oil; 0.514 g 5h (2.0 mmol) was converted to
0.852 g 3n (87 %); Rf = 0.7 (EtOAc-hexane, 1:2); 1H
NMR (300 MHz, CDCl3): d = 7.39–7.19 (m, 10H, CH),
2.64 (t, J = 7.2 Hz, 2H, CH2), 1.53–1.48 (m, 2H, CH2),
1.32–1.24 (m, 2H, CH2), 0.86 (t, J = 7.2 Hz, 3H, CH3)
ppm; 13C NMR (75.45 MHz, CDCl3): d = 150.2 (d,
J = 6.8 Hz), 150.1 (d, J = 5.5 Hz), 129.7 (d,
J = 1.1 Hz), 125.6 (d, J = 1.7 Hz), 120.0 (d,
J = 5.0 Hz), 83.0 (d, J = 11.6 Hz), 32.8, 27.9 (d,
J = 1.1 Hz), 21.8, 13.6 ppm; HRMS (APCI): m/z calc.
for C18H19Br2O4P ([M ? H]?) 490.9440, found 490.9445.
Brown oil; 0.568 g 5l (2.0 mmol) was converted to 0.609 g
3j (73 %); Rf = 0.4 (EtOAc-hexane, 1:2); 1H NMR
(300 MHz, CDCl3): d = 7.51–7.50 (m, 1H, CH),
7.47–7.45 (m, 1H, CH), 7.06–7.03 (m, 1H, CH),
4.17–4.05 (m, 4H, CH2), 1.29–1.24 (m, 6H, CH3) ppm;
13C NMR (75.45 MHz, CDCl3): d = 141.8 (d,
J = 8.8 Hz), 133.2 (d, J = 1.1 Hz), 130.9 (d,
J = 1.1 Hz), 128.5, 126.5, 85.1 (d, J = 10.5 Hz), 64.7
(d, J = 6.1 Hz), 15.8 (d, J = 6.6 Hz) ppm; HRMS (APCI):
m/z calc. for C10H13Br2O4PS ([M ? H]?) 420.8691, found
420.8693.
1,1-Dibromo-3-(benzyloxycarbonyl)propen-2-yl diphenyl
phosphate (3o, C22H17Br2O6P)
2,2-Dibromo-1-(5-bromo-2-thienyl)ethenyl diethyl phos-
phate (3k, C10H12Br3O4PS)
Colorless oil; 0.672 g 5k (2.0 mmol) was converted to
0.657 g 3o (59 %); Rf = 0.7 (EtOAc-hexane, 1:2); 1H
NMR (300 MHz, CDCl3): d = 8.00–7.97 (m, 2H, CH),
7.54–7.52 (m, 2H, CH), 7.40–7.14 (m, 11H, CH), 5.24 (d,
J = 0.9 Hz, 2H, CH2) ppm; 13C NMR (CDCl3,
75.45 MHz): d = 165.4, 150.0 (d, J = 7.2 Hz), 144.0 (d,
J = 8.3 Hz), 133.2, 129.8, 129.7, 128.9, 128.2, 125.6 (d,
J = 1.4 Hz), 119.9 (d, J = 5.5 Hz), 90.0, 61.8 ppm;
HRMS (APCI): m/z calc. for C22H17Br2O6P ([M ? H]?)
568.9182, found 568.9183.
Brown oil; 0.726 g 5m (2.0 mmol) was converted to
0.856 g 3k (86 %); Rf = 0.4 (EtOAc-hexane, 1:2); 1H
NMR (300 MHz, CDCl3): d = 7.28 (d, J = 3.9 Hz, 1H,
CH), 7.01 (d, J = 3.9 Hz), 4.19–4.12 (m, 4H, CH2), 1.30
(dt, J = 1.2, 7.2 Hz, 6H, CH3) ppm; 13C NMR (CDCl3,
75.45 MHz): d = 141.1 (d, J = 8.8 Hz), 134.6 (d,
J = 1.7 Hz), 131.1 (d, J = 1.1 Hz), 129.4, 116.1, 85.6
(d, J = 10.6 Hz), 64.9 (d, J = 6.1 Hz), 15.9 (d,
J = 6.6 Hz) ppm; HRMS (APCI): m/z calc. for C10H12-
Br3O4PS ([M ? H]?) 498.7796, found 498.7799.
2,2-Dibromo-1-[4-(N,N-dimethylamino)phenyl]ethenyl
diphenyl phosphate (3p, C22H20Br2NO4P)
2,2-Dichloro-1-(4-methylphenyl)ethenyl diethyl phosphate
(3l, C13H17Cl2O4P)
Orange oil; 0.698 5o (2.0 mmol) was converted to
1.016 g 3p (89 %); Rf = 0.6 (EtOAc-hexane, 1:2); 1H
NMR (300 MHz, CDCl3): d = 7.41 (d, J = 8.7 Hz, 2H,
CH), 7.29–7.26 (m, 4H, CH), 7.19–7.09 (m, 6H, CH),
6.63 (d, J = 8.4 Hz, 2H, CH), 2.97 (s, 6H, CH3) ppm;
13C NMR (75.45 MHz, CDCl3): d = 150.7, 150.2 (d,
J = 7.8 Hz), 147.8 (d, J = 8.3 Hz), 130.5 (d,
J = 1.1 Hz), 129.5, 125.3 (d, J = 1.1 Hz), 120.04,
119.97, 111.1, 82.8 (d, J = 12.8 Hz), 40.1 ppm; HRMS
(ESI): m/z calc. for C22H20Br2NO4P ([M ? H]?)
553.9549, found 553.9547.
Yellow oil; 0.406 g 5n (2.0 mmol) was converted to
0.671 g 3l (99 %); Rf = 0.4 (EtOAc-hexane, 1:2); 1H
NMR (300 MHz, CDCl3): d = 7.43 (d, J = 8.1 Hz, 2H,
CH), 7.20 (d, J = 8.1 Hz, 2H, CH), 4.08–3.94 (m, 4H,
CH2), 2.37 (s, 3H, CH3), 1.23–1.17 (m, 6H, CH3) ppm; 13
C
NMR (75.45 MHz, CDCl3): d = 143.9 (d, J = 8.3 Hz),
139.9, 128.8 (d, J = 1.1 Hz), 128.6, 114.2 (d,
J = 11.0 Hz), 64.4 (d, J = 5.6 Hz), 21.2, 15.6 (d,
J = 7.2 Hz) ppm; HRMS (APCI): m/z calc. for C13H17-
Cl2O4P ([M ? H]?) 339.0314, found 339.0323.
2,2-Dibromo-1-(4-nitrophenyl)ethenyl diphenyl phosphate
(3m, C20H14Br2NO6P)
General procedure for the preparation
of a,a-dibromoketones 5
Orange oil; 0.646 g 5f (2.0 mmol) was converted to
0.950 g 3m (86 %) Rf = 0.7 (EtOAc-hexane, 1:2); 1H
NMR (300 MHz, CDCl3): d = 8.12–8.09 (m, 2H, CH),
7.64–7.61 (m, 2H, CH), 7.31–7.26 (m, 4H, CH), 7.21–7.18
(m, 2H, CH), 7.11–7.07 (m, 4H, CH) ppm; 13C NMR
(75.45 MHz, CDCl3): d = 149.8 (d, J = 7.7 Hz), 148.1,
145.0 (d, J = 8.3 Hz), 138.5, 130.4, (d, J = 1.7 Hz),
129.7, 125.7 (d, J = 1.7 Hz), 123.3, 119.8 (d,
J = 5.0 Hz), 87.8 (d, J = 11.5 Hz) ppm; HRMS (APCI):
Acetonitrile (2 cm3/mmol), water (1 cm3/mmol), and
HClO4 (10 mol %) was added to a mixture of alkyne 4
(1.0 mmol) and NBS (2.5 mmol). The resultant mixture
was stirred for the time indicated in Table 1. Then, the
reaction mixture was diluted with Et2O (8 cm3/mmol) and
washed with a saturated solution of Na2CO3 (3 cm3/mmol),
Na2S2O3 (3 cm3/mmol), water (3 cm3/mmol), and brine
123

Efficient and simple preparation of functionalized 1,1-dibromoenol phosphates
411
(3 cm3/mmol). The organic layer was dried over MgSO4,
concentrated under reduced pressure and column chro-
matography on silica gel afforded the a,a-dibromoketones
5.
2,2-Dibromo-1-(4-nitrophenyl)ethan-1-one (5f)
Yellow solid; 0.294 g (4-nitrophenyl)acetylene (2.0 mmol)
was converted to 0.226 g 5f (35 %); m.p.: 59.2–60.0 °C
[66]; Rf = 0.4 (EtOAc-hexane, 1:10); H NMR in accor-
1
dance with Ref. [66].
(Dibromoacetyl)benzene (5a)
2,2-Dibromo-1-(4-methylphenyl)ethan-1-one (5g)
White solid; 0.262 g (4-methylphenyl)acetylene (2.25 mmol)
was converted to 0.46 g 5g (70 %); m.p.: 97–98 °C [70];
Rf = 0.4 (EtOAc-hexane, 1:10); 1H NMR in accordance with
Ref. [66].
Yellow solid; phenylacetylene 0.204 g (2.0 mmol) was
converted to 5a 0.550 g (99 %); m.p.: 34–35 °C [70];
Rf = 0.6 (EtOAc-hexane, 1:6); 1H NMR in accordance
with Ref. [61].
4-(Dibromoacetyl)benzaldehyde (5b, C9H6Br2O2)
White solid; 0.260 g 4-ethynylbenzaldehyde (2.0 mmol)
was converted to 0.459 g 5b (75 %); m.p.: 82-85 °C;
Rf = 0.4 (silica gel, EtOAc-hexane, 1:3); 1H NMR (CDCl3,
300 MHz): d = 10.13 (s, 1H, CH), 8.26 (d, J = 8.4 Hz,
2H, CH), 8.02 (d, J = 9.0 Hz, 2H, CH), 6.65 (s, 1H, CH)
ppm; 13C NMR (CDCl3, 75.45 MHz): d = 191.1, 185.3,
139.6, 135.2, 130.3, 129.7, 39.3 ppm; HRMS (APCI): m/
z calc. for C9H6Br2O2 ([M ? H]?) 304.8630, found
304.8632.
1,1-Dibromohexan-2-one (5h)
Yellow oil; 3.44 cm3 1-hexyne (30.0 mmol) was converted
to 7.08 g 5h (92 %); Rf = 0.6 (DCM-pentane, 1:9); 1H
NMR in accordance with Ref. [61].
6,6-Dibromo-5-oxohexanenitrile (5i, C6H7Br2NO)
Yellow oil; 0.930 g hex-5-ynenitrile (10 mmol) was con-
verted to 2.30 g 5i (86 %); Rf = 0.6 (EtOAc-hexane, 1:4);
1H NMR (300 MHz, CDCl3,): d = 5.80 (s, 1H, CH), 3.17
(t, J = 7.2 Hz, 2H, CH2), 2.47 (t, J = 7.2 Hz, 2H, CH2),
2.05 (p, J = 7.2 Hz, 2H, CH2) ppm; 13C NMR
(75.45 MHz, CDCl3): d = 195.3, 118.8, 42.1, 32.9, 16.1,
19.9 ppm; HRMS (ESI): m/z calc. for C6H7Br2NO ([M-
H]-) 265.8822, found 265.8834.
Methyl 4-(dibromoacetyl)benzoate (5c, C10H8Br2O3)
White solid; 0.320 g methyl 4-ethynylbenzoate (2.0 mmol)
was converted to 0.599 g 5c (89 %); m.p.: 50–51 °C;
Rf = 0.5 (EtOAc-hexane, 1:10); 1H NMR (300 MHz,
CDCl3): d = 8.16 (s, 4H, CH), 6.66 (s, 1H, CH), 3.97 (s,
3H, CH3) ppm; 13C NMR (75.45 MHz,CDCl3): d = d
185.4, 165.7, 134.9, 134.1, 129.9, 129.6, 52.6, 39.4 ppm;
HRMS (APCI): m/z calc. for C10H8Br2O3 ([M ? H]?)
334.8736, found 334.8753.
1,1-Dibromo-5-chloropentan-2-one (5j, C5H7Br2ClO)
Yellow oil; 1.025 g 5-chloro-1-pentyne (10.0 mmol) was
converted to 1.80 g 5j (65 %); Rf = 0.6 (EtOAc-hexane,
1:10); 1H NMR (300 MHz, CDCl3): d = 5.81 (s, 1H, CH),
3.61 (t, J = 6.3 Hz, 2H, CH2), 3.16 (t, J = 6.6 Hz, 2H,
CH2), 2.15 (p, J = 6.3 Hz, 2H, CH2) ppm; 13C NMR
(75.45 MHz, CDCl3): d = 195.9, 43.7, 42.4, 31.8,
26.9 ppm; HRMS (APCI): m/z calc. for C5H7Br2ClO
([M ? H]?) 276.8626, found 276.8631.
2,2-Dibromo-1-(4-acetylphenyl)ethan-1-one
(5d, C10H8Br2O2)
White solid; 0.288 g (4-acetylphenyl)acetylene (2.0 mmol)
was converted to 0.525 g 5d (82 %); m.p.: 74–76 °C;
Rf = 0.5 (EtOAc-hexane, 1:3); 1H NMR (300 MHz,
CDCl3): d = 8.19 (d, J = 8.7 Hz, 2H), 8.07 (d,
J = 8.4 Hz, 2H, CH), 6.65 (s, 1H, CH), 2.66 (s, 3H,
CH3) ppm; 13C NMR (75.45 MHz, CDCl3): d = 197.0,
185.3, 140.9, 134.1, 129.9, 128.5, 39.4, 26.8 ppm; HRMS
(APCI): m/z calc. for C10H8Br2O2 ([M ? H]?) 318.8787,
found 318.8794.
3,3-Dibromo-2-oxopropyl benzoate (5k, C10H8Br2O3)
White solid; 0.320 g propargyl benzoate (2.0 mmol) was
converted to 0.538 g 5k (80 %); m.p.: 77–79 °C; Rf = 0.5
(EtOAc-hexane, 1:10); 1H NMR (300 MHz, CDCl3):
d = 8.12–8.08 (m, 2H, CH), 7.62–7.59 (m, 1H, CH),
7.51–7.46 (m, 2H, CH), 6.01 (s, 1H, CH), 5.47 (s, 2H, CH2)
ppm; 13C NMR (75.45 MHz, CDCl3): d = 190.1, 165.6,
133.7, 129.9, 128.6, 128.5, 63.0, 38.4 ppm; HRMS (APCI):
m/z calc. for C10H8Br2O3 ([M ? H]?) 336.8893, found
336.8894.
4-(Dibromoacetyl)-N,N-dimethylbenzamide
(5e, C11H11Br2NO2)
Colorless solid; 1.730 g 4-ethynyl-N,N-dimethylbenzamide
(10.0 mmol) was converted to 3.0 g 5e (86 %); m.p.:
106–108 °C; Rf = 0.3 (EtOAc-hexane, 1:1); 1H NMR
(300 MHz, CDCl3): d = 8.1 (d, J = 8.2 Hz, 2H), 7.51
(d, J = 8.2 Hz, 2H), 6.68 (s, 1H, CH), 3.11 (s, 3H, CH3),
2.95 (s, 3H, CH3) ppm; 13C NMR (75.45 MHz, CDCl3):
d = 185.3, 169.9, 141.9, 131.4, 129.9, 127.4, 39.4, 39.3,
35.3 ppm; HRMS (ESI): m/z calc. for C11H11Br2NO2
([M ? H]?) 349.9209, found 349.9209.
2,2-Dibromo-1-(2-thienyl)ethanone (5l), 2,2-dibromo-1-
(5-bromo-2-thienyl)ethanone (5m)
Orange oil; 5m, 5.04 g 2-ethynylthiophene (46.7 mmol)
was converted to 4.793 g 5m (28 %); Rf = 0.4 (EtOAc-
hexane, 1:10) and orange oil; 5l, 5.04 g 2-ethynylthiophene
(46.7 mmol) was converted to 3.68 g 5l (28 %) Rf = 0.3
(EtOAc-hexane, 1:10); 2,2-dibromo-1-(2-thienyl)ethanone
1
(5l); H and 13C NMR in accordance with Ref. [67]; 2,2-
123

412
V. Kotek et al.
dibromo-1-(5-bromo-2-thienyl)ethanone (5m); 1H NMR in
accordance with Ref. [68]; 13C NMR (75.45 MHz, CDCl3):
d = 178.6, 137.7, 135.0, 131.6, 125.5, 38.2 ppm.
33. Hall DG, Chapdelaine D, Preville P, Deslongchamps P (1994)
Synlett 660
34. Kennedy JWJ, Hall DG (2002) J Am Chem Soc 124:898
35. Zhu N, Hall DG (2003) J Org Chem 68:6066
36. Patel SJ, Jamison TF (2003) Angew Chem Int Ed 42:1364
37. Hojo M, Murakami Y, Aihara H, Sakuragi R, Baba Y, Hosomi A
(2001) Angew Chem Int Ed 40:621
4-(Dichloroacetyl)toluene (5n)
Yellow
solid;
0.367 g
(4-methylphenyl)acetylene
(2.75 mmol) was converted to 0.514 g 5n (92 %); m.p.:
1
55–56 °C [69]; Rf = 0.5 (EtOAc-hexane, 1:10); H NMR
in accordance with Ref. [66].
38. Xie M, Wang J, Fang K, Wang S, Yan L (2015) Tetrahedron Lett
56:4388
39. Xue F, Zhao J, Hor TSA, Hayashi T (2015) J Am Chem Soc
137:3189
40. Fu L, Niggemann M (2015) Chem Eur J 21:6367
41. Hojo D, Noguhi K, Tanaka K (2009) Angew Chem Int Ed
48:8129
Acknowledgments Financial support from specific university
research (MSMT No. 21/2012 and No. 20/2013).
42. Liu H, El-Salfiti M, Lautens M (2012) Angew Chem 124:9984
43. Tietze LF, Hungerland T, Du¨fert A, Objartel I, Stalke D (2012)
Chem Eur J 18:3286
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