Unexpected metal-free transformation of gem-dibromomethylenes to ketones under acetylation conditions

Article abstract of DOI:10.1002/asia.201403277

Novel conditions for the transformation of gem-dibromomethylenes to ketones are described. gem-Dibromo compounds were treated with acetic anhydride and triethylamine in dichloromethane/water at room temperature under an air atmosphere to give the corresponding ketones in moderate yields. A radical mechanism is proposed based on experimental results.

Full text of DOI:10.1002/asia.201403277

DOI: 10.1002/asia.201403277
Full Paper
Radical Reactions
Unexpected Metal-Free Transformation of gem-
Dibromomethylenes to Ketones under Acetylation Conditions
Rino Kimura,[a] Yusuke Sawayama,[a] Atsuo Nakazaki,[a] Kazunori Miyamoto,[b, c]
Masanobu Uchiyama,[b, c] and Toshio Nishikawa*[a]
This paper is dedicated to Professor Minoru Isobe on the occasion of his 70th birthday.
Abstract: Novel conditions for the transformation of gem-di-
bromomethylenes to ketones are described. gem-Dibromo
compounds were treated with acetic anhydride and triethyl-
amine in dichloromethane/water at room temperature
under an air atmosphere to give the corresponding ketones
in moderate yields. A radical mechanism is proposed based
on experimental results.
Introduction
In the course of our synthetic studies on saxitoxin,[1] a well-
known paralytic shellfish poison, we incidentally found a new
transformation of a gem-dibromomethylene to the correspond-
ing enol acetate, as shown in Scheme 1.[2] When we attempted
acetylation of compound 1, which was synthesized by a cas-
cade bromocyclization developed in this laboratory,[3] under
conventional conditions (acetic anhydride and triethylamine in
dichloromethane at room temperature), enol acetate 2 was ob-
served as an unstable product. This unstable product was iso-
lated as alcohol 3 in 64% yield after successive treatment with
NaBH4 and K2CO3 in methanol. The mechanism of this reaction
was unclear at that time; however, because of the highly func-
tionalized structure of 1, we suspected that an intrinsic neigh-
boring group participation reaction was involved.
Scheme 1. Discovery of an unusual reaction of gem-dibromide 1 to enol ace-
tate 2 under conventional acetylation conditions.
Fortunately, this reaction could be employed as one of the
key reactions in the total synthesis of a natural analogue of
saxitoxin (Scheme 2).[2] Intermediate 4 was successfully trans-
[a] R. Kimura, Dr. Y. Sawayama, Dr. A. Nakazaki, Prof. Dr. T. Nishikawa
Graduate School of Bioagricultural Sciences
Nagoya University
Chikusa, Nagoya, 464-8601 (Japan)
Fax: (+81)52-789-4111
E-mail: nisikawa@agr.nagoya-u.ac.jp
[b] Dr. K. Miyamoto, Prof. Dr. M. Uchiyama
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Scheme 2. The novel transformation of a gem-CBr2 group to enol acetate fol-
lowed by reduction, employed in the total synthesis of an analogue of saxi-
toxin.
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
[c] Dr. K. Miyamoto, Prof. Dr. M. Uchiyama
Advanced Elements Chemistry Research Team
RIKEN Center for Sustainable Resource Science
and
formed to 6 via enol acetate 5, although the yield was poor
(32% yield in two steps from 4). Since the discovery of the re-
action of 1, we have investigated this unusual reaction in
order to elucidate the reaction mechanism and to improve the
yield of compound 6, the details of which we discuss herein.
Elements Chemistry Laboratory
RIKEN
2-1 Hirosawa, Wako-shi, Saitama 351-0198 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201403277.
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complete consumption of starting material 7 and slightly im-
proved the yield of 8 (entry 7, Table 1).[6]
Results and Discussion
We systematically examined the reaction conditions using
a simpler racemic compound 7, which was readily synthesized
from benzyl glycidyl ether;[4] representative results are shown
in Table 1. Surprisingly, when compound 7 was treated with
Ac2O and Et3N in CH2Cl2 at room temperature (the conditions
employed in Schemes 1 and 2), the expected corresponding
We applied the successful conditions to the reaction of inter-
mediate 4 in the synthesis of the saxitoxin analogue, as de-
scribed in Scheme 2. To our delight, when the reaction of 4
was carried out using the conditions of entry 2 in Table 1,
ketone 10 and enol acetate 5 were obtained as a 1:1.6 mixture
in 53% combined yield, and the starting material 4 was recov-
ered in 20% yield (Scheme 3).[7] When the mixture was retreat-
Table 1. Reaction conditions for the conversion of gem-dibromide 7 to
ketone 8.[a]
Entry
Ratio to CH2Cl2
[v/v]
Atmosphere
Product [%]
Ac2O
Et3N
8
9
7
1[b]
2
0.1
0.1
0.1
0.1
0.1
0
0.2
0.2
0.2
0.2
0
air
air
Ar
O2
air
air
air
46
60
–
42
–
29
18
–
0
20
–
37
–
42
0
3[c]
4
detected[d]
5[c]
6
7[e]
–
0.2
0.4
22
65[f]
detected[d]
8
0.1
[a] 0.033–0.041 mmol of 7 in CH2Cl2 (0.6 mL) was employed for entries 1
to 6. [b] Water was not added. [c] No reaction was observed. [d] The
yields were not determined. [e] 0.041 mmol of 7 in CH2Cl2 (3 mL) was em-
ployed. [f] See Ref. [6].
Scheme 3. Improved yields for the reaction of 4.
ed under the same conditions, the mixture converged to enol
acetate 5. These results indicated that under these conditions,
the reaction of 4 yielded ketone 10 first, which then enolized
to 5. For comparison with the results shown in Scheme 2, the
mixture of 10 and 5 was reduced with NaBH4 to provide prod-
ucts 6 and 11 in 46% and 20% yield, respectively, from 4
(Scheme 3). Thus, we successfully established a procedure for
the synthesis of compounds 6 and 11 from compound 4 as
the key reaction in our synthesis of saxitoxin derivatives.
We investigated the substrate scope of this reaction using
different sizes of cyclic gem-dibromides 12–15 and an acyclic
gem-dibromide 16 (Table 2).[8] We found that all the substrates
were transformed into their corresponding ketones in moder-
ate yields under the conditions of entry 7 (Table 1).[9] These re-
actions also proceeded on 1 mmol scale.[10] These results con-
firmed that this reaction does not lead to the direct synthesis
of enol acetates from gem-dibromomethylenes, but instead to
the synthesis of the ketones, which, under these unusual con-
ditions, is formally hydrolysis of a gem-dibromomethylene. The
successful reaction of simple substrates, as shown in Table 2,
ruled out our initial suggestion of a neighboring group partici-
pation mechanism.
enol acetate was not observed, but instead ketone 8 was ob-
tained in 46% yield along with compound 9 in 29% yield as
a by-product (entry 1, Table 1).[5] Incidentally, we found that
the addition of water improved the yield of this reaction. The
reaction conducted with Ac2O and Et3N in CH2Cl2 and water
(1:1) with vigorous stirring provided ketone 8 and byproduct 9
in 60% and 18% yield, respectively, although 20% of starting
material 7 was recovered (entry 2, Table 1). When the same re-
action was carried out under an argon atmosphere, no reac-
tion was observed (entry 3, Table 1). On the other hand, the
yield of 8 decreased when the same reaction was carried out
under an oxygen atmosphere (entry 4, Table 1). These results
indicate that molecular oxygen was necessary for this reaction
to occur; however, a larger amount of oxygen was detrimental.
Et3N was also indispensable for this reaction (entry 2 vs.
entry 5, Table 1), whereas Ac2O was not essential but improved
the yield of product 8 (entry 2 vs. entry 6, Table 1). We noticed
that the reaction mixture was acidic following the reaction,
which likely indicated that Et3N was neutralized by hydrobro-
mic acid and acetic acid that were generated under the reac-
tion conditions. Following further extensive investigations, we
found that utilizing a larger excess amount of Et3N resulted in
To probe the mechanism of this reaction, further experi-
ments were carried out with compound 7. When the reaction
of 7 was conducted in the presence of TEMPO as a radical
scavenger, the reaction did not proceed (Scheme 4). On the
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this investigation. The rapid formation of enol acetate
5 from 4 should avoid exchange with water. Thus, 4
was treated with Et3N and Ac2O in CH2Cl2 under 18O2
without water, and provided 18O-5 in 29% yield
(Scheme 5).[13] The MS spectra of product 5 indicated
about 95% 18O incorporation into the ketone.
Table 2. Transformation of gem-dibromides to ketones.[a]
Entry
1
Substrate
Ketone
Yield [%]
RSM [%][b]
Based on these experiments and the results shown
in Table 1, we propose a radical chain mechanism in-
volving Et3N as a radical mediator, although further
studies are needed. There are several possible mech-
anisms for the initiation of this radical reaction. Two
plausible mechanisms are shown in Scheme 6: (i) Et3N
is directly oxidized by molecular oxygen in water
through single electron-transfer from Et3N, which is
a good electron donor.[14] The resulting radical cation
reacts with molecular oxygen to form peroxy radical
A, which undergoes hydrogen abstraction from an-
other Et3N to generate radical F. (ii) gem-Dibromide B
generates radical intermediate C in the presence of
oxygen,[15,16] which reacts with molecular oxygen to
form peroxy radical D.[17] Abstraction of the hydrogen
of Et3N by radical D provides radical F. The resulting
radical F plays the role of a radical carrier, as shown
in Scheme 6. We assume that hydroperoxide E collap-
ses to ketone I under these reaction conditions, al-
50
(42)
trace
(0)
12
17
44
(42)
trace
(0)
2
13
18
64
(61)
30
(33)
3
4
5
14
15
16
19
20
21
78
(75)
12
(10)
44
(54)
0
(0)
[a] Reaction was performed using 0.055–0.209 mmol of substrate under the conditions
of entry 7 in Table 1. The yields on 1.00 mmol scale are shown in parentheses. [b] Re-
covered starting material.
though the mechanism is unclear.[18] According to this mecha-
nism, 1-bromo-N,N-diethylethanamine G should be formed. In
Scheme 5. 18O-labeling experiment.
Scheme 4. Evidence of the involvement of a radical intermediate.
other hand, when 7 was treated
with Bu3SnH under an air atmos-
phere at room temperature, the
corresponding methylene com-
pound 22 was afforded in 57%
yield.[11] These results strongly
suggest that the reaction in-
volves radical intermediate(s),
and the gem-dibromomethylene
unit can generate the corre-
sponding carbon radical without
a radical initiator, such as AIBN.
We attempted to identify the
source of oxygen in the ketone
formed in this transformation. As
the ketone oxygen of 8, which
was obtained from 7, is easily
exchangeable with water,[12]
compound 4 was employed in Scheme 6. A proposed mechanism for the transformation of gem-dibromides to ketones.
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Et3N (0.12 mL) at room temperature under air atmosphere (bal-
loon). The mixture was vigorously stirred for 1 h at the same tem-
perature. H2O (0.5 mL) was added and the resulting mixture was
extracted with CH2Cl2 (ꢁ3). The combined extract was washed with
H2O (ꢁ2) and passed through a short column packed with anhy-
drous Na2SO4. The filtrate was concentrated under reduced pres-
sure. The residue was purified by flash column chromatography
(AcOEt/hexane=1:2 to 1:1 to 2:1) to afford ketone 8 (8.7 mg,
60%), by-product 9 (2.2 mg, 18%) and recovered gem-dibromo-
methylene 7 (4.0 mg, 20%).
the reactions of the gem-dibromides in this study, significant
amounts of N,N-diethylacetamide H were detected in the
1H NMR spectra of the crude products. Compound H could be
derived from 1-bromo-N,N-diethylethanamine G through hy-
drolysis followed by acetylation.[19]
Conclusions
In summary, we have developed new conditions for the trans-
formation of gem-dibromides to ketones and proposed a radi-
cal mechanism for the reaction. Although similar reactions,
such as the hydrolysis of gem-CBr2 using AgNO3 in aqueous or-
ganic solvents, have been reported,[20] the new metal-free con-
ditions developed in this study give the corresponding ketone
more reliably.[21] Highly functionalized compounds 1 and 4
were inert under the precedent conditions using silver cation-
mediated hydrolysis, whereas attempted hydrolysis of the sim-
pler compounds, such as 12 and 14, provided the alkenylbro-
mide (through elimination of HBr) as the major product. As the
new conditions are very mild, this novel transformation should
be widely applicable in combination with the bromocyclization
procedures developed in this laboratory.[1] Application of this
procedure to the syntheses of other natural products and
transformation of the gem-dibromomethylene unit to function-
al groups other than ketone are currently under way in this
laboratory.
Experiment of entry 7: To a mixture of 7 (23.0 mg, 0.041 mmol) in
CH2Cl2 (3 mL) and H2O (3 mL) were added Ac2O (0.3 mL) and Et3N
(1.2 mL) at room temperature under air atmosphere (balloon). The
mixture was vigorously stirred for 1 h at the same temperature. 1N
HCl aqueous solution (2.0 mL) was added and the resulting mixture
was extracted with CH2Cl2 (ꢁ3). The combined extract was washed
with H2O (ꢁ2) and passed through a short column packed with an-
hydrous Na2SO4. The filtrate was concentrated under reduced pres-
sure. The residue was purified by flash column chromatography
(AcOEt/hexane=1:2 to 1:1) to afford ketone 8 (5.8 mg, 37%), by-
product 9 (1.8 mg, 12%) and N-acetylated ketone of 8 (5.3 mg,
28%). Then to a solution of the N-acetylated ketone in CH2Cl2
(1 mL) was added silica gel (100 mg). After being stirred for 2 h,
the suspension was filtered through a cotton pad and washed
with CH2Cl2 and MeOH (10:1). The filtrate was concentrated under
reduced pressure. The residue was purified by preparative TLC
(AcOEt/hexane=2:1) to afford ketone 8 (4.7 mg, quant).
Experiments for Scheme 3
Transformation of 4 to 10 and 5: To a mixture of 4 (16.1 mg,
0.033 mmol) in CH2Cl2 (0.6 mL) and H2O (0.6 mL) were added Ac2O
(0.06 mL) and Et3N (0.12 mL) at room temperature under air atmos-
phere (balloon). The mixture was vigorously stirred for 1 h at the
same temperature. H2O was added, and the resulting mixture was
extracted with CH2Cl2 (ꢁ3). The combined extract was washed with
H2O (ꢁ2) and passed through a short column packed with anhy-
drous Na2SO4. The filtrate was concentrated under reduced pres-
sure. The residue was purified by preparative TLC (AcOEt:hexane=
1:1) to afford a mixture of ketone 10 and enol acetate 5 (6.4 mg,
53%, 1:1.6 by 1H NMR) and recovered gem-dibromomethylene 4
(2.5 mg, 20%). 10: ½aꢁ3D1 = +141 (c=1.0ꢁ10ꢀ3, CHCl3); IR (film): n˜ =
3293, 2922, 2118, 1767, 1639, 1580, 1502, 1392, 1323, 1266, 1225,
Experimental Section
Experiments for Table 1
Experiment of entry 1: To a solution of 7 (18.6 mg, 0.033 mmol) in
CH2Cl2 (0.6 mL) were added Ac2O (0.06 mL) and Et3N (0.12 mL) at
room temperature under air atmosphere (balloon). After being vig-
orously stirred for 1 h at room temperature, the reaction mixture
was concentrated under reduced pressure with toluene. The resi-
due was purified by flash column chromatography (silica gel,
AcOEt/hexane=1:2 to 1:1 to 2:1) to afford ketone 8 (6.8 mg, 46%)
as a colorless oil and by-product 9 (3.5 mg, 29%) as a colorless oil.
8: IR (film): n˜ =3265, 2892, 1767, 1624, 1541, 1455, 1388,
1222 cmꢀ1 1H NMR (300 MHz, CDCl3): d=1.73 (1H, dd, J=13,
;
1152 cmꢀ1 1H NMR (400 MHz, CDCl3): d=2.67 (1H, ddd, J=19, 9,
;
11 Hz, -NHCHCHaHb-), 1.79 (1H, dd, J=13, 5 Hz, -NHCHCHaHb-),
2.53–2.74 (2H, m, -COCH2-), 3.38 (1H, t, J=9.5 Hz, BnOCHaHb-), 3.56
(1H, dd, J=9.5, 4 Hz, BnOCHaHb-), 3.90 (1H, m, -NHCH-), 4.12–4.28
(2H, m, -OCH2-), 4.52 (1H, d, J=12 Hz, PhCHaHb-), 4.57 (1H, d, J=
12 Hz, PhCHaHb-), 5.08 (2H, s, PhCH2O-), 7.24–7.39 ppm (10H, m,
Ar); 13C NMR (100 MHz, CDCl3): d=29.5, 34.6, 45.9, 61.3, 66.4, 71.6,
73.4, 83.6, 127.7, 127.8, 127.9, 128.0, 128.3, 128.5, 137.0, 137.3,
157.8, 163.0, 208.1 ppm; HR-MS (ESI, positive): calcd. for C23H26N3O5
[M+H]: 424.18670; found, 424.18554. 9: IR (film): n˜ =3264, 2923,
6 Hz, -COCHaHb-), 2.79 (1H, ddd, J=19, 9, 5 Hz, -COCHaHb-), 3.86
(1H, ddd, J=11, 9, 6 Hz, -NCHaHb-), 3.99 (1H, ddd, J=11, 9, 5 Hz,
-NCHaHb-), 4.03 (1H, m, -NHCH-), 4.19 (1H, dd, J=9, 3 Hz, -OCHaHb-
), 4.34 (1H, d, J=9 Hz, -OCHaHb-), 4.37 (1H, d, J=3 Hz, -CHN3-), 5.15
(2H, s, BnOCH2-), 7.27–7.38 (3H, m, aromatic), 7.40–7.45 (2H, m, ar-
omatic), 9.56 ppm (1H, br, -NH-); 13C NMR (100 MHz, CDCl3): d=
34.4, 40.1, 53.4, 55.9, 67.1, 78.1, 88.1, 127.9, 128.2, 128.4, 136.9,
157.9, 164.1, 204.4. HR-MS (ESI, positive): Calcd for C17H20N6O5
(M+MeOH+H): 389.15679; found, 389.15633. 5: ½aꢁ2D8 =ꢀ48 (c=
3.1ꢁ10ꢀ3, CHCl3). IR (film): n˜ =3279, 2925, 2099, 1764, 1628, 1601,
1725, 1646, 1238, 1073 cmꢀ1 1H NMR (400 MHz, CDCl3): d=2.55
;
1245, 1195 cmꢀ1 1H NMR (400 MHz, CDCl3): d=2.26 (3H, s, CH3-),
;
(1H, dd, J=16.5, 8.5 Hz, -COCHaHb-), 2.70 (1H, dd, J=16.5, 6 Hz,
-COCHaHb-), 3.41 (1H, dd, J=9.5, 7 Hz, -BnOCHaHb-), 3.55 (1H, dd,
J=9.5, 7 Hz, BnOCHaHb-), 3.90 (1H, m, -NHCH-), 4.55 (2H, s, PhCH2-
), 5.14 (2H, s, PhCH2-), 7.27–7.41 ppm (10H, m, aromatic); 13C NMR
(100 MHz, CDCl3): d=32.8, 48.4, 67.2, 71.1, 73.5, 127.7, 128.1 (3),
128.4, 128.5, 128.6, 136.3, 137.0, 157.1, 167.2 ppm; HR-MS (ESI, pos-
itive): calcd. for C20H21N3O4 [M+H]: 368.16048; found, 368.16045.
3.96 (1H, m, -NHCH-), 4.14 (1H, dd, J=9, 3 Hz, -OCHaHb-), 4.23 (1H,
d, J=3.5 Hz, -CHN3-), 4.29 (1H, d, J=9 Hz, -OCHaHb-), 4.31 (1H, dd,
J=16, 2 Hz, -NCHaHb-), 4.36 (1H, dd, J=16, 2 Hz, -NCHaHb-), 5.11
(1H, d, J=12 Hz, BnOCHaHb-), 5.15 (1H, d, J=12 Hz, BnOCHaHb-),
6.26 (1H, t, J=2 Hz, -CH=COAc-), 7.26–7.37 (3H, m, aromatic),
7.40–7.44 (2H, m, aromatic), 9.49 ppm (1H, br, J=4.5 Hz, -NH-);
13C NMR (100 MHz, CDCl3): d=21.0, 49.2, 52.9, 54.6, 66.9, 76.4, 95.5,
115.2, 127.8, 128.2, 128.3, 137.1, 138.4, 156.5, 164.1, 167.3. HR-MS
Experiment of entry 2: To a mixture of 7 (19.6 mg, 0.035 mmol) in
CH2Cl2 (0.6 mL) and H2O (0.6 mL) were added Ac2O (0.06 mL) and
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(ESI, positive): Calcd for C18H18N6O5 [M+H]: 399.14114; found,
399.14250.
only) to afford 12 (1.88 g, 41% based on the crude hydrazine
(3.00 g, ca. 12.0 mmol)) as a colorless solid. 12: m.p.79–818C; IR
(film): n˜ =3027, 1493, 1455 cmꢀ1 1H NMR (300 MHz, CDCl3): d=
;
Transformation of 4 to alcohol 6 and 11: To a mixture of 4 (19.9 mg,
0.040 mmol) in CH2Cl2 (0.7 mL) and H2O (0.7 mL) were added Ac2O
(0.07 mL) and Et3N (0.14 mL) at room temperature under air atmos-
phere (balloon). The mixture was stirred for 1 h at the same tem-
perature. H2O (1 mL) was added and the resulting solution was ex-
tracted with CH2Cl2 (ꢁ3). The combined extract was washed with
H2O (ꢁ2) and passed through a short column packed with anhy-
drous Na2SO4. The filtrate was concentrated under reduced pres-
sure. The residue was dissolved in MeOH (1 mL), then NaBH4
(3.2 mg, 0.08 mmol) was added at room temperature. After being
stirred for 35 min, the reaction mixture was cooled with an ice-
bath and then water (2 mL) was added. The mixture was extracted
with AcOEt (ꢁ3) and the combined extract was washed with H2O
and passed through a short column of anhydrous Na2SO4. The fil-
trate was concentrated under reduced pressure. The residue was
purified by flash column chromatography (neutral silica gel, AcOE-
t:hexane=2:1 to AcOEt only) to afford a mixture of alcohol 6[2]
and 11 (9.9 mg, 69%) and recovered 4 (3.3 mg, 17%). Further pu-
rification of mixture by preparative TLC (AcOEt) afforded alcohol 6
(6.5 mg, 45%) and alcohol 11 (2.8 mg, 20%) as colorless oil. 11:
½aꢁ2D7 =ꢀ22 (c=1ꢁ10ꢀ3, CHCl3); IR (film): n˜ =3297, 2923, 2116,
3.20–3.41 (4H, m, -CH2-), 4.00 (2H, m, -CH-), 6.85 (4H, m, aromatic),
6.98–7.08 ppm (6H, m, aromatic); 13C NMR (75 MHz, CDCl3): d=
48.2, 57.1, 63.6, 126.3, 127.9, 128.6, 139.5 ppm; elemental anal.
calcd for C17H16Br2: C, 53.72; H, 4.24; found: C, 53.70; H, 4.14.
2-Benzyl-1,1-dibromocyclopentane (13) was prepared in 41% yield
in two steps from 18[23] (1.46 g, 8.39 mmol) according to the gener-
al procedure described for 12. IR (film): n˜ =2946, 1495, 1454 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d=1.52–1.71 (3H, m), 1.88 (1H, m), 2.30
(1H, tdd, J=11, 8, 3 Hz, -CH-), 2.60 (1H, dd, J=13.5, 11 Hz, -CHaHb-
Ph), 2.71 (1H, m, -CHaHb-CBr2-), 2.92 (1H, m, -CHaHb-CBr2-), 3.33 (1H,
dd, J=13.5, 3 Hz, -CHaHb-Ph), 7.18–7.33 ppm (5H, m, aromatic);
13C NMR (100 MHz, CDCl3): d=20.5, 27.2, 38.5, 50.7, 59.5, 75.1,
126.2, 128.4, 128.9, 140.0 ppm; Elemental anal. calcd for C12H14Br2:
C, 45.32; H, 4.44; found: C, 45.33; H, 4.30.
1,1-Dibromo-4-phenylcyclohexane (14) was prepared in 74% yield in
two steps from commercially available 19 (2.62 g, 15.0 mmol) ac-
cording to the general procedure described for 12. Mp. 47–488C.
IR (film): n˜ =2940, 1492, 1439, 1094, 987 cmꢀ1 1H NMR (300 MHz,
;
CDCl3): d=1.76 (1H, m, -CHaHb-CHPh-), 2.05 (1H, dtd, J=14, 12.5,
3.5 Hz, -CHaHb-CHPh-), 2.52 (1H, ddd, J=15, 13, 4 Hz, -CHaHb-CBr2-),
2.62 (1H, tt, J=12.5, 4 Hz, -CHPh-), 2.83 (1H, m, -CHaHb-CBr2-),
7.19–7.25 (3H, m, aromatic), 7.29–7.36 ppm (2H, m, aromatic);
13C NMR (100 MHz, CDCl3): d=32.4, 42.5, 49.5, 70.6, 126.5, 126.8,
128.5, 145.3 ppm; Elemental anal. calcd for C12H14Br2: C, 45.32; H,
4.44; found: C, 45.24; H, 4.30.
1640, 1574, 1325, 1152 cmꢀ1 1H NMR (400 MHz, CDCl3): d=1.81
;
(1H, m, -NCH2CHaHb-), 2.18 (1H, br, -OH), 2.31 (1H, m, -NCH2CHaHb-
), 3.22 (1H, td, J=11, 7 Hz, -NCHaHb-), 3.75 (1H, dd, J=11, 9 Hz,
-NCHaHb-), 4.04 (1H, dt, J=5, 3 Hz, -NHCH-), 4.14 (1H, dd, J=9,
3 Hz, -OCHaHb-), 4.16 (1H, d, J=3 Hz, -CHN3-), 4.20 (1H, br, -CHOH-),
4.31 (1H, d, J=9 Hz, -OCHaHb-), 5.09 (1H, d, J=12 Hz, BnOCHaHb-),
5.15 (1H, d, J=12 Hz, BnOCHaHb-), 7.26–7.36 (3H, m, aromatic),
7.39–7.43 (2H, m, aromatic), 9.46 ppm (1H, br, -NH-); 13C NMR
(100 MHz, CDCl3): d=30.2, 42.1, 53.0, 54.7, 66.9, 70.1, 92.4, 127.8,
128.2, 128.3, 137.2, 157.3, 164.1 ppm; HR-MS (ESI, positive): Calcd
for C16H18N6O4 [M+H]: 359.14623; found, 359.14604.
7,7-Dibromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene (15) was pre-
pared in 57% yield in two steps from 20[24] (162 mg, 1.013 mmol)
according to the general procedure described for 12. 15: m.p.107–
1098C; IR (film): n˜ =2944, 1450, 1182, 1001, 937 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d=2.30–3.30 (8H, br, CH2 ꢁ4), 7.14 ppm (4H, m,
aromatic); 13C NMR (75 MHz, CDCl3): d=33.5, 50.4, 76.0, 126.8,
129.2, 140.9 ppm; Elemental anal. calcd for C11H12Br2: C, 43.46; H,
3.98; found: C, 43.33; H, 3.86.
Experiments for Table 2
2,2-Dibromo-4-phenylbutane (16) was prepared in 77% yield in two
steps from 21[8] (795 mg, 5.37 mmol) according to the general pro-
cedure described for 12.
Preparation of substrates 12–16
General experimental procedure of preparation of gem-dibromo-
methylene compound from the corresponding ketone exemplified
by cis-1,1-dibromo-3,4-diphenylcyclopentane (12): To a suspension
of finely powdered molecular sieves 4 ꢂ (17.1 g) in MeOH (82 mL)
were added hydrazine hydrate (1.6 mL, 33 mmol) and THF (16 mL).
After being stirred for 20 min, a solution of cis-3,4-diphenylcyclo-
pentanone 17[22] (3.89 g, 16.0 mmol) in MeOH (82 mL) and THF
(16 mL) was added dropwise over 30 min. The mixture was stirred
for 2 h at room temperature and then filtered through a pad of
Celite, washed with Et2O and concentrated under reduced pres-
sure. The residue was used for the next reaction without further
purification. To a solution of CuBr2 (16.1 g, 0.072 mmol) in MeOH
(70 mL) was added Et3N (4.8 mL, 0.036 mmol) and the mixture was
stirred for 10 min at room temperature. After the mixture was
cooled to 48C with an ice-bath, a solution of 3.00 g (ca. 12.0 mmol)
of the residue (4.78 g) in MeOH (30 mL) was added dropwise over
15 min. The cooling bath was removed and the mixture was fur-
ther stirred for 1 h at room temperature. The reaction was cooled
with an ice-bath and quenched by addition of 3.5% aqueous NH3
solution. The resulting mixture was filtered through a pad of Celite
and washed with Et2O. The filtrate was portioned and the aqueous
layer was extracted with Et2O (ꢁ2). The combined organic layer
was washed with H2O (ꢁ2) and brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The residue
was purified by neutral silica gel column chromatography (hexane
General experimental procedure exemplified by entry 4
(0.055–0.209 mmol scale)
To a mixture of 15 (66.4 mg, 0.209 mmol) in CH2Cl2 (16 mL) and
H2O (16 mL) were added Ac2O (1.6 mL) and Et3N (6.4 mL) at room
temperature under air atmosphere (balloon). The mixture was
stirred for 1 h at the same temperature, and then cooled with an
ice-bath. 1m HCl aqueous solution (16 mL) was added and the re-
sulting solution was extracted with CH2Cl2 (ꢁ3). The combined ex-
tract was washed with H2O (ꢁ2) and filtered through a short
column packed with anhydrous Na2SO4. The filtrate was concen-
trated under reduced pressure. The residue was purified by open
column chromatography (neutral silica gel, hexane only to hexane/
Et2O=3:1) to afford ketone 20 (27.2 mg, 78%) and recovered 15
(7.7 mg, 12%).
Ketone 17 was obtained from 12 (21.0 mg, 0.055 mmol) in 50%
yield according to the general procedure described for 20.
Ketone 18 was obtained from 13 (19.7 mg, 0.062 mmol) in 44%
yield according to the general procedure described for 20.
Ketone 19 and 14 was obtained from 14 (17.6 mg, 0.055 mmol) in
64% and 30% yield, respectively, according to the general proce-
dure described for 20.
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Ketone 21 was obtained from 16 (49.7 mg, 0.17 mmol) in 44%
yield according to the general procedure described for 20.
73.3, 73.4, 87.9, 127.5, 127.7 (2), 127.9, 128.3, 128.5, 137.4 (2), 157.8,
163.5 ppm; HR-MS (ESI, positive): Calcd for C23H28N3O4 [M+H]:
410.20743; found, 410.20781.
Synthesis of 18O-labelled 5: A 5 mL round-bottom flask (flask A) was
charged with compound 4 (18.3 mg, 0.037 mmol) and CH2Cl2
(0.6 mL) and the outlet was sealed with a septum wrapped with
parafilm. A 10 mL two-necked flask (flask B) was charged with Ac2O
(2.0 mL), and a 10 mL two-necked flask (flask C) was charged with
Et3N (2.0 mL). Flasks B and C were degassed by three freeze-thaw
cycles and filled with Ar. Flask A was degassed by four freeze-thaw
cycles and filled with 18O2. To flask A were added Ac2O (0.06 mL)
and Et3N (0.12 mL) from flask B and C via syringes. The mixture
was vigorously stirred for 1 h and then concentrated under re-
duced pressure. The residue was purified by preparative TLC
(AcOEt/hexane=1:1) to afford enol acetate 18O-5 (4.3 mg, 29%) as
General experimental procedure exemplified by entry 4
(1.00 mmol scale)
Oxygen-bubbled CH2Cl2 and H2O were prepared prior to use as fol-
lows: A 100 mL recovery flask equipped with a rubber septum and
an outlet needle was charged with solvent (80 mL). O2 (ca. 1 L, bal-
loon) was bubbled into the solvent via a Pasteur pipette inserted
through the septum. A 500 mL three-necked round-bottomed flask
equipped with an oval magnetic stirrer bar (5 cmꢁ2 cm), two
rubber septa, and an air balloon was charged with compound 15
(310 mg, 1.00 mmol). To the flask were added the oxygen-bubbled
CH2Cl2 (72 mL), the oxygen-bubbled H2O (72 mL), Ac2O (7.2 mL)
and Et3N (29 mL) at room temperature under an air atmosphere.
The mixture was vigorously stirred for 2 h at the same temperature
and then cooled with an ice-bath. Next, 1m HCl aqueous solution
(55 mL) was added and the resulting solution was extracted with
CH2Cl2 (ꢁ3). The combined extract was washed with H2O (ꢁ2) and
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The residue was purified by open column chromatogra-
phy (neutral silica gel, hexane/Et2O=5:1 to 3:1) to afford ketone
20 (134 mg, 75%) and recovered gem-dibromomethylene 15
(32.3 mg, 10%).
1
a colorless liquid. H NMR (400 MHz, CDCl3): d=2.26 (3H, s, CH3-),
3.96 (1H, dt, J=5, 3 Hz, -NHCH-), 4.14 (1H, dd, J=9, 3 Hz, -OCHaHb-
), 4.23 (1H, d, J=3 Hz, -CHN3-), 4.29 (1H, d, J=9 Hz, -OCHaHb-), 4.31
(1H, dd, J=16, 2 Hz, -NCHaHb-), 4.36 (1H, dd, J=16, 2 Hz, -NCHaHb-
), 5.11 (1H, d, J=12.5 Hz, BnOCHaHb-), 5.15 (1H, d, J=12.5 Hz, BnO-
CHaHb-), 6.26 (1H, t, J=2 Hz, -CH=COAc-), 7.26–7.37 (3H, m, aro-
matic), 7.40–7.44 (2H, m, aromatic), 9.50 ppm (1H, brd, J=4.5 Hz,
-NH-); 13C NMR (100 MHz, CDCl3): d=21.0, 49.2, 52.9, 54.6, 66.9,
76.4, 95.5, 115.2, 127.8, 128.2, 128.3, 137.1, 138.4, 156.5, 164.2,
167.2 ppm; HR-MS (ESI, positive): Calcd for C18H19N6O418O1 [M+H]:
401.14539; found, 401.14716.
Ketone 17 was obtained from 12 (391 mg, 1.00 mmol) in 42%
yield according to the general procedure described for 20.
Ketone 18 was obtained from 13 (321 mg, 1.00 mmol) in 42%
yield according to the general procedure described for 20.
Acknowledgements
Ketone 19 and 14 was obtained from 14 (327 mg, 1.00 mmol) in
61% and 33% yield, respectively, according to the general proce-
dure described for 20.
This work was supported by Grants-in-Aid on Innovative Areas
‘‘Chemical Biology of Natural Products’’[25] from MEXT, the Daii-
chi Sankyo Foundation of Life Science, and the Yamada Science
Foundation. We are grateful to Prof. Yujiro Hayashi (Tohoku
Univ. Japan) for invaluable advice on the 18O-labeling experi-
ments.
Ketone 21 was obtained from 16 (294 mg, 1.00 mmol) in 54%
yield according to the general procedure described for 20.
Experiments for mechanistic studies
Reaction in the presence of TEMPO (Scheme 4): To a solution of 7
(18.3 mg, 0.032 mmol) and TEMPO (1.5 mg, 0.001 mmol) in CH2Cl2
(0.6 mL) were added H2O (0.6 mL), Ac2O (0.06 mL) and Et3N
(0.12 mL) at room temperature under air atmosphere (balloon).
The mixture was vigorously stirred for 1 h at the same tempera-
ture. Then H2O (0.5 mL) was added and the resulting mixture was
extracted with CH2Cl2 (ꢁ3). The combined extract was washed with
H2O (ꢁ2) and dried through a short column packed with anhy-
drous Na2SO4. The filtrate was concentrated under reduced pres-
sure. NMR analysis showed the starting material was recovered as
a major product, and ketone 8 was not detected.
Keywords: dehalogenation
ketones · radical reactions · synthetic methods
·
gem-dibromomethylenes
·
[1] Y. Sawayama, T. Nishikawa, J. Synth. Org. Chem. Jpn. 2012, 70, 1178–
1186.
[2] Y. Sawayama, T. Nishikawa, Angew. Chem. Int. Ed. 2011, 50, 7176–7178;
Angew. Chem. 2011, 123, 7314–7316.
[3] Y. Sawayama, T. Nishikawa, Synlett 2011, 651–654.
[4] For preparation of compound 7, see the Supporting Information.
[5] The structure of 9 was deduced by analysis of the NMR, IR, and MS
spectra. A possible mechanism for the formation of 9 may be the com-
petitive degradation of a peroxide intermediate (see the Supporting In-
formation), similar to that of E in Scheme 6, although no experimental
evidence has been obtained.
[6] Under the conditions of entry 7, ketone 8 was obtained in 37% yield
along with an acetylated product in 28% yield, which was quantitative-
ly hydrolyzed with silica gel to 8. The reported 65% yield is the com-
bined yield after hydrolysis.
[7] The reaction of 4 under the conditions of entry 7 in Table 1 provided
enol acetate 5 contaminated with inseparable and unidentified by-
products.
[8] The gem-dibromides 12–16 were prepared from the corresponding ke-
tones according to Takeda’s procedure: T. Takeda, R. Sasaki, S. Yamau-
chi, T. Fujiwara, Tetrahedron 1997, 53, 557–566.
Reduction of 6 with nBu3SnH (Scheme 4): A mixture of 7 (22.7 mg,
0.04 mmol) and nBu3SnH (54 mL, 0.20 mmol) in CH2Cl2 (1 mL) was
stirred for 1.5 h at room temperature. The mixture was concentrat-
ed under reduced pressure. The residue was purified by flash
column chromatography (flash silica gel including 10% K2CO3,
AcOEt/hexane=1:1 to 3:1) to afford 22 (9.3 mg, 57%) as a colorless
oil. 22: IR (film): n˜ =3263, 2925, 2872, 1619, 1388, 1224, 1099 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=1.7 (1H, t, J=12.5 Hz, -NHCCHaHb-),
1.89 (1H, dd, J=12.5, 4 Hz, -NHCCHaHb-), 1.95–2.10 (4H, m,
-OCH2CH2CH2-), 3.36 (1H, t, J=9 Hz, BnOCHaCHb-), 3.56 (1H, dd, J=
9, 4 Hz, BnOCHaCHb-), 3.87 (1H, m, -OCHaHb-), 3.91–4.00 (2H, m,
-OCHaHb-, -NHCH-), 4.53 (1H, d, J=12 Hz, PhCHaCHb-), 4.56 (1H, d,
J=12 Hz, PhCHaCHb-), 5.07 (1H, d, J=13 Hz, PhCHaCHbO-), 5.11
(1H, d, J=13 Hz, PhCHaCHbO-), 7.24–7.40 ppm (10H, m, aromatic);
13C NMR (100 MHz, CDCl3): d=24.8, 34.2, 37.4, 46.8, 66.2, 67.1, 72.0,
[9] In terms of yield, the conditions of entry 7 proved to be better than
those of entry 2.
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[10] The reaction was performed using 1.00 mmol of substrate under the
conditions of entry 7 in Table 1 with slight modifications. For details,
see the Experimental Section.
[11] The reduction of terminal dibromomethylene and dibromocyclopropyl
groups with Bu3SnH without radical initiators has been reported:
a) B. M. Trost, M. J. Bogdanowicz, J. Kern, J. Am. Chem. Soc. 1975, 97,
2218–2223; b) J. T. Groves, K. W. Ma, J. Am. Chem. Soc. 1974, 96, 6527–
6529; c) D. Seyferth, H. Yamazaki, D. L. Alleston, J. Org. Chem. 1963, 28,
703–706; d) T. D. Golobish, W. P. Dailey, J. Org. Chem. 1995, 60, 7865–
7869.
[12] When compound 8 was stirred vigorously with CH2Cl2-H218O for 20 min
at rt, ESI-MS analysis of the organic layer indicated the incorporation of
18O into compound 8.
[13] These 18O-labelling experiments were carried out with reference to the
following papers and the experimental details provided by Prof. Y. Hay-
ashi (Tohoku Univ.); a) J. P. Shackleford, B. Shen, J. N. Johnston, Proc.
Natl. Acad. Sci. USA 2012, 109, 44–46; b) S. Umemiya, K. Nishino, I. Sato,
Y. Hayashi, Chem. Eur. J. 2014, 20, 15753–15759.
[17] B. Maillard, K. U. Ingold, J. C. Scaiano, J. Am. Chem. Soc. 1983, 105,
5095–5099.
[18] One possibility may be acetylation of peroxide E followed by homolytic
cleavage of the OꢀO bond, producing ketone I. The other possibility
may be reductive cleavage of peroxide E with Et3N. For the stability of
1-chloroalkyl hydroperoxide, see: W. V. Turner, S. Gaeb, J. Org. Chem.
1992, 57, 1610–1613.
[19] The reaction of 7 was conducted with Ac2O-d6 instead of Ac2O to give
1
CD3CONEt2, as observed by H NMR spectroscopy.
[20] Most of the substrates reported possesses gem-CBr2 group at easily hy-
drolyzable benzylic positions. For the several examples, see: a) R. D.
Farn, C. A. Ramsden, N. G. Morgan, J. Heterocycl. Chem. 2008, 45, 887–
896; b) A. Tutar, K. Berkil, R. R. Hark, M. Balci, Synth. Commun. 2008, 38,
1333–1345; c) K. M. Aitken, R. A. Aitken, Tetrahedron 2008, 64, 4384–
4386.
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Curran, Nat. Chem. 2014, 6, 765–773; b) V. P. Mehta, B. Punji, RSC Adv.
2013, 3, 11957–11986; c) E. Shirakawa, T. Hayashi, Chem. Lett. 2012, 41,
130–134; For selected examples of metal-free transformations, see:
d) H. Ueda, K. Yoshida, H. Tokuyama, Org. Lett. 2014, 16, 4194–4197;
e) H. Zhang, R. Shi, A. Ding, L. Lu, B. Chen, A. Lei, Angew. Chem. Int. Ed.
2012, 51, 12542–12545; Angew. Chem. 2012, 124, 12710–12713; f) W.
Liu, H. Cao, H. Zhang, H. Zhang, K. H. Chung, C. He, H. Wang, F. Y.
Kwong, A. Lei, J. Am. Chem. Soc. 2010, 132, 16737–16740.
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Beckwith, P. H. Echinger, B. A. Mooney, R. H. Prager, Aust. J. Chem. 1983,
36, 719–739.
[15] PET (photoinduced electron transfer) may be a possible alternative
mechanism for generation of radical C. However, the reactions of the
gem-dibromides in this study did not require UV or visible light. For
several examples of PET in organic synthesis, see: a) J. Mattay, Synthesis
1989, 233–252; b) J. Cossy, J.-L. Ranaivosata, V. Bellosta, Tetrahedron
Lett. 1994, 35, 8161–8162; c) J. Cossy, N. Furet, S. BouzBouz, Tetrahe-
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1996, 37, 5091–5094; e) C.-K. Sha, K. C. Santhosh, C.-T. Tseng, C.-T. Lin,
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1997, 801–802; b) E. Nakamura, T. Inubushi, S. Aoki, D. Machii, J. Am.
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Received: November 9, 2014
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FULL PAPER
Radical Reactions
Rino Kimura, Yusuke Sawayama,
Atsuo Nakazaki, Kazunori Miyamoto,
Masanobu Uchiyama, Toshio Nishikawa*
Being quite radical: Novel conditions
for the transformation of gem-dibromo-
methylenes to ketones are described.
gem-Dibromo compounds were treated
with Ac2O and Et3N in CH2Cl2/water at
room temperature under an air atmos-
phere to give the corresponding ke-
tones in moderate yields. A radical
mechanism is proposed based on ex-
perimental results.
&& – &&
Unexpected Metal-Free
Transformation of gem-
Dibromomethylenes to Ketones under
Acetylation Conditions
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