Bromine-Radical-Mediated Synthesis of β-Functionalized β,γ- and δ,?-Unsaturated Ketones via C-H Functionalization of Aldehydes

Article abstract of DOI:10.1055/s-0036-1588494

The bromine-radical-mediated allylation reaction of aldehydes was studied. In the presence of V-65 as radical initiator, the reaction of aldehydes with allyl bromides gave β,γ-unsaturated ketones in good yields (13 examples, 45-84%). The reaction is trigg

Full text of DOI:10.1055/s-0036-1588494

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
en
T. Kippo et al.
Letter
Synlett
Bromine-Radical-Mediated Synthesis of β-Functionalized β,γ- and
δ,ε-Unsaturated Ketones via C–H Functionalization of Aldehydes
Takashi Kippoa
Yuki Kimuraa
mediated acylation
Br
Mitsuhiro Uedaa
Takahide Fukuyamaa
Ilhyong Ryu*a,b
O
EWG
+
O
O
EWG
EWG
radical initiator
Br
R
H
R
R
a Department of Chemistry, Graduate School of Science,
Osaka Prefecture University, Sakai, Osaka 599-8531,
Japan
O
EWG
+
Br
+
R
H
ryu@c.s.osakafu-u.ac.jp
b Department of Applied Chemistry, National Chiao Tung
University, Hsinchu 30010, Taiwan
R = alkyl, aryl
EWG = CO2Me, CN, SO2Ph, COMe
Received: 26.04.2017
Accepted after revision: 15.06.2017
Published online: 29.06.2017
We also envisaged that in the presence of both electron-de-
ficient alkenes and allyl bromides, δ,ε-unsaturated ketones
would be synthesized by three-component radical cascades
via the acyl radical (Scheme 1, eq. 2). In this paper, we re-
port on the results of the bromine-radical-mediated syn-
thesis of β,γ- and δ,ε-unsaturated ketones based on C–H
functionalization of aldehydes.
DOI: 10.1055/s-0036-1588494; Art ID: st-2017-b0292-l
Abstract The bromine-radical-mediated allylation reaction of alde-
hydes was studied. In the presence of V-65 as radical initiator, the reac-
tion of aldehydes with allyl bromides gave β,γ-unsaturated ketones in
good yields (13 examples, 45–84%). The reaction is triggered by hydro-
gen abstraction from the aldehyde by bromine radical to form an acyl
radical, which undergoes an SH2′-type addition–elimination reaction
with allyl bromides to give coupling products with liberation of bromine
radical. Three-component coupling reactions comprising aldehydes,
electron-deficient alkenes, and methallyl bromide also proceeded to
give δ,ε-unsaturated ketones.
this work
EWG
Br
Br
O
O
O
EWG
(1)
(2)
R
H
R
R
Key words bromine radical, SH2′ reaction, β,γ-unsaturated ketones,
δ,ε-unsaturated ketones, three-component reaction
HBr
Br
R
R'
EWG
,
R'
O
EWG
Br
β,γ-Unsaturated ketones are an important class of car-
bonyl compounds which are found in natural products and
used as a building block in the synthesis of heterocyclic
compounds such as furans and pyrroles.1,2 We previously
reported that β,γ-unsaturated ketones can be synthesized
by three-component radical reactions comprising alkyl ha-
lides, CO, and allyltributyltin, in which acyl radicals,3 gener-
ated by radical carbonylation,4 add to allyltributyltin with
extrusion of the tributyltin radical.5 In the presence of an
electron-deficient alkene and allyltributyltin, δ,ε-unsatu-
rated ketones can be synthesized by related four-compo-
nent radical cascades.6 In these cases, allyltributyltin acts as
a unimolecular chain transfer (UMCT) reagent to generate
tin radical upon β-fragmentation.7 As allyl bromides can
also act as a UMCT reagent to generate bromine radical,8–10
we believed that the bromine radical formed would have
the ability to abstract formyl hydrogen from aldehydes to
generate acyl radicals.11 The acyl radicals could be com-
bined well with the subsequent SH2′ process with allyl bro-
mides leading to β,γ-unsaturated ketones (Scheme 1, eq. 1).
Br
Scheme 1 The concept: bromine-radical-based approach for the syn-
thesis of β-functionalized β,γ- and δ,ε-unsaturated ketones
Initially, we tested the reaction of nonanal (1a) with al-
lyl bromide (2a, Table 1). When a benzene solution of 1a,
2a, and 2,2′-azobis(2,4-dimethylvaleronitrile) (V-65) as rad-
ical initiator, was heated at 60 °C for one hour in the pres-
ence of K2CO3, only a trace amount of the desired allyl octyl
ketone (3a) was obtained (Table 1, entry 1). To compensate
for a lack of the reactivity of 2a, a large excess of 2a was
used; however, in this case, 3a was obtained in 10% yield
(Table 1, entry 2). Since acyl radicals act as nucleophilic rad-
icals toward C–C double bonds, we then changed to a more
electrophilic allylic bromide, methyl 2-(bromomethyl)acry-
late (2b), which gave the corresponding β,γ-unsaturated ke-
tone 3b in 68% yield (Table 1, entry 3). The use of three
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
T. Kippo et al.
Letter
Synlett
equivalents of 2b was effective to improve the yield of 3b
up to 84% (Table 1, entry 4). When the reaction was con-
ducted with the use of AIBN (2,2′-azobis(isobutyronitrile))
as a radical initiator at 80 °C for four hours, the reaction
proceeded well but the isomerization of 3b to α,β-unsatu-
rated ketone was also observed (Table 1, entry 5).12
Next, a variety of aliphatic and aromatic aldehydes 1a–h
and allyl bromides 2b–d were examined in this allylation
reaction, and the results are summarized in Table 2. The re-
action of a branched aldehyde 1b took place to give β,γ-un-
saturated ketone 3c in 71% yield (Table 2, entry 2). Primary
alkyl aldehydes 1c and 1d having a phenyl and nitrile func-
tionality gave the corresponding enones 3d and 3e in 64%
and 74% yield, respectively (Table 2, entries 3 and 4). Aryl
aldehydes 1e–g also participated in the radical allylation to
give the corresponding aromatic enones 3f–h in modest to
good yields (Table 2, entries 5–7). It should be noted that
since the ketone carbonyl group can be reduced to the cor-
responding alcohols, all these products are potential pre-
cursors for the synthesis of 2-methylene γ-butyrolac-
tones.13
Table 1 Radical Reaction of Nonanal 1a with Allyl Bromides 2a and 2ba
V-65
K2CO3
O
R
+
Br
H
C6H6
60 °C, 1 h
1a
2a (R = H)
2b (R = CO2Me)
O
R
3a or 3b
We also examined two more substituted allyl bromides:
both β-bromomethylacrylonitrile (2c) and 3-bromo-2-
(phenylsulfonyl)propene (2d) reacted well, albeit the reac-
tions take 6–12 hours to go to completion. For example, the
reaction of 1a or 1e with 2c proceeded to give β-cyano-sub-
stituted β,γ-unsaturated ketones 3i and 3j in 70% and 53%
yields, respectively (Table 2, entries 8 and 9). The reaction
of 1a or 1e with 2d gave β-benzenesulfonyl-substituted β,γ-
unsaturated ketones 3k and 3l in 62% and 53% yields, re-
spectively (Table 2, entries 10 and 11). The reaction of the
dialdehyde 1,9-nonanedial (1h) with 2b gave diketone 3m
in 58% yield (Table 2, entry 12).
Entry
2 (equiv)
C6H6 (M)
Yield (%)b
1
2a (2)
2a (58)
2a (2)
2b (3)
2b (3)
0.1
–
trace
10
2
3
0.1
0.1
0.1
68
4
84
5c
67 (15)d
a Reaction conditions: 1a (0.5 mmol), V-65 (0.1 mmol), K2CO3 (1.0 mmol),
60 °C, 1 h under argon atmosphere.
b Isolated yield after column chromatography on SiO2.
c AIBN was used instead of V-65 (80 °C, 4 h).
d Yield of isomerized α,β-unsaturated ketone.
Table 2 Synthesis of β,γ-Unsaturated Ketones 3a
V-65
O
O
EWG
EWG
K2CO3
+
Br
R
H
R
C6H6
60 °C, 1 h
1
2
3
Entry
1
1
2
3
Yield (%)b
84
O
O
CO2Me
CO2Me
Br
H17C8
1a
H
H17C8
2b
3b
O
O
O
CO2Me
CO2Me
2
3
4
2b
2b
2b
71
64
74
H
H
1b
3c
O
1c
3d
O
O
CO2Me
NC
NC
H
1d
3e
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
T. Kippo et al.
Letter
Synlett
Table 2 (continued)
Entry
1
2
3
Yield (%)b
O
O
CO2Me
5c
2b
2b
61
60
H
1e
3f
O
CO2Me
O
6c
H
3g
MeO
1f
MeO
NC
O
O
CO2Me
7c
2b
45
H
1g
NC
3h
O
CN
CN
8c
1a
70
53
62
53
Br
H17C8
2c
2c
3i
O
CN
9c
1e
1a
1e
3j
O
SO2Ph
SO2Ph
Br
10c
11d
H17C8
2d
3k
O
SO2Ph
2d
3l
MeO2C
O
O
CO2Me
O
O
12e
2b
58
H
H
1h
3m
a Reaction conditions: 1 (0.5 mmol), 2 (1.5 mmol), K2CO3 (1.0 mmol), V-65 (2,2-azobis(2,4-dimethylvaleronitrile), 0.1 mmol), C6H6 (5 mL), 60 °C, 1 h under argon
atmosphere.
b Isolated yield by column chromatography on SiO2 and/or preparative HPLC.
c 6 h.
d AIBN (20 mol%), 12 h.
e Reaction conditions: 2b (6.0 equiv), V-65 (40 mol%), K2CO3 (4.0 equiv), C6H6 (10 mL).
V-65 (0.1 mmol)
O
O
CO2Me
In contrast, the allylation of cyclohexanecarbaldehyde
(1i) with 2b gave the product 3n in only a modest yield. In
this reaction allylated cyclohexane was formed as byprod-
uct, which was obtained via decarbonylation of the key acyl
radical. However, the reaction under a CO atmosphere using
a CO balloon, the undesirable decarbonylation course was
effectively suppressed, and 3n was obtained in 78% yield
(Scheme 2).
CO2Me
Br
K2CO3 (1.0 mmol)
+
H
C6H6 (5 mL)
60 °C, 1 h
under CO (1 atm)
1i (0.5 mmol)
2b (1.5 mmol)
3n
78%
O
CO
Following these studies, we examined three-component
coupling reactions leading to δ,ε-unsaturated ketones in
which methallyl bromide (2e) was used as a UMCT reagent
(Scheme 3). When a benzene solution of 1a, acrylonitrile,
Scheme 2 Synthesis of β,γ-unsaturated ketones 3n under CO atmosphere
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
T. Kippo et al.
Letter
Synlett
4a, and 2,2′-azobis(isobutyronitrile) (AIBN) in the presence
of K2CO3 was refluxed for four hours, the desired δ,ε-unsat-
urated ketone 5a was obtained in 57% yield after purifica-
tion by column chromatography on SiO2 (Scheme 3, eq. 1).
Similarly β-acetyl-substituted δ,ε-unsaturated ketone 5b
was obtained by the reaction of aldehyde 1b, methyl vinyl
ketone (4b), and 2e (Scheme 3, eq. 2).
In summary, we have demonstrated that the bromine-
radical mediated C–H allylation of aldehydes proceeded
well to give β,γ-unsaturated ketones in good yields.14,15 We
also demonstrated that the UMCT process is expanded to
three-component coupling reactions comprising aldehydes,
electron-deficient alkenes, and methallyl bromide, which
led to δ,ε-unsaturated ketones. The capability of the bro-
mine radical to generate acyl radicals from aldehydes can
be successfully combined with radical addition and elimi-
nation sequences for the synthesis of enones. All products
are potential precursors for heterocyclic compounds and
the one-pot protocol and use of readily available starting
compounds are attractive benefits of this methodology.
O
AIBN, K2CO3
CN
+
+
Br
C6H6, 80 °C, 4 h
H17C8
H
1a (0.1 M)
4a (2 equiv) 2e (3 equiv)
O
CN
(1)
5a 57%
O
O
Funding Information
AIBN, K2CO3
+
+
Br
C6H6, 80 °C, 4 h
H
This work has been supported by a Grant-in-Aid for Scientific Re-
search from the MEXT (no. 15H05850). T.K. acknowledges the Re-
search Fellowship of the Japan Society for the Promotion of Science
1b
4b
2e
O
O
for Young Scientists.
M
E
X
T
1(
5
H
0
5
8
5
0)
(2)
5b 51%
Scheme 3 Synthesis of δ,ε-unsaturated ketones 5
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588494.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
A proposed reaction mechanism for the present three-
component coupling reaction leading to 5a is illustrated in
Scheme 4: (i) A bromine radical is generated from β-me-
thallyl bromide in the presence of AIBN, (ii) the bromine
radical abstracts hydrogen from aldehyde 1a to produce the
acyl radical, (iii) the acyl radical adds to acrylonitrile to
form the α-cyano radical, (iv) SH2′ reaction of the resulting
radical with methallyl bromide (2e) gives the δ,ε-unsatu-
rated ketone 5a and, concurrently, regenerates the bromine
radical to sustain the radical chain.
References and Notes
(1) (a) Estévez, R. E.; Justicia, J.; Bazdi, B.; Fuentes, N.; Paradas, M.;
Choquesillo-Lazarte, D.; Garca-Ruiz, J. M.; Robles, R.; Gansäuer,
A.; Cuerva, J. M.; Oltra, J. E. Chem. Eur. J. 2009, 15, 2774. (b) Yus,
M.; González-Gómez, J. C.; Foubelo, F. Chem. Rev. 2011, 111,
7774. (c) Moody, C. L.; Pugh, D. S.; Taylor, R. J. K. Tetrahedron
Lett. 2011, 52, 2511. (d) Anand, R. C.; Singh, V. Heterocycles
1993, 36, 1333. (e) Yang, W.; Zhou, Y.; Sun, H.; Zhang, L.; Zhao,
F.; Liu, H. RSC Adv. 2014, 4, 15007.
(2) For typical preparative methods, see: (a) Barbier reaction with
nitrile and allylzinc: Lee, A. S.-Y.; Lin, L.-S. Tetrahedron Lett.
2000, 41, 8803. (b) Allylmercury and acid chloride: Larock, R. C.;
Lu, Y.-D. J. Org. Chem. 1993, 58, 2846. (c) Yadav, J. S.; Reddy, B. V.
S.; Reddy, M. S.; Paramala, G. Synthesis 2003, 2390. (d) Gohain,
M.; Gogoi, B. J.; Prajapati, D.; Sandhu, J. S. New. J. Chem. 2003, 27,
1038.
CN
4a
O
H17C8
HBr
O
O
CN
H17C8
H
H17C8
1a
(3) For a review on acyl radicals; see: Chatgilialoglu, C.; Crich, D.;
Komatsu, M.; Ryu, I. Chem. Rev. 1999, 99, 1991.
Br
(4) For reviews on radical carbonylations, see: (a) Ryu, I.; Sonoda, N.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1050. (b) Ryu, I.; Sonoda,
N.; Curran, D. P. Chem. Rev. 1996, 96, 177. (c) Ryu, I. Chem. Soc.
Rev. 2001, 30, 16. (d) Ryu, I. Chem. Rec. 2002, 2, 249. (e) Fusano,
A.; Ryu, I. In Science of Synthesis:Multicomponent Reactions 2;
Müller, T. J. J., Ed.; Thieme: Stuttgart, 2014.
2e
AIBN
2e
Br
(5) Ryu, I.; Yamazaki, H.; Kusano, K.; Ogawa, A.; Sonoda, N. J. Am.
Chem. Soc. 1991, 113, 8558.
O
CN
Br
O
CN
H17C8
(6) (a) Ryu, I.; Yamazaki, H.; Ogawa, A.; Kambe, N.; Sonoda, N. J. Am.
Chem. Soc. 1993, 115, 1187. (b) Ryu, I.; Niguma, T.; Minakata, S.;
Komatsu, M.; Luo, Z.; Curran, D. P. Tetrahedron Lett. 1999, 40,
2367. (c) Uenoyama, Y.; Fukuyama, T.; Ryu, I. Synlett 2006,
2342.
H17C8
5a
Scheme 4 Proposed radical-chain mechanism
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

E
T. Kippo et al.
Letter
Synlett
(7) For examples of the UMCT concept, see: (a) Curran, D. P.; Xu, J.;
Lazzarini, E. J. Am. Chem. Soc. 1995, 117, 6603. (b) Curran, D. P.;
Xu, J.; Lazzarini, E. J. Chem. Soc., Perkin Trans. 1 1995, 3049.
(8) For earlier work, see: (a) Kharasch, M. S.; Sage, M. J. Org. Chem.
1949, 14, 79. (b) Kharasch, M. S.; Büchi, G. J. Org. Chem. 1949, 14,
84.
(9) (a) Tanko, J. M.; Sadeghipour, M. Angew. Chem. Int. Ed. 1999, 38,
159. (b) Struss, J. A.; Sadeghipour, M.; Tanko, J. M. Tetrahedron
Lett. 2009, 50, 2119.
(10) (a) Kippo, T.; Fukuyama, T.; Ryu, I. Org. Lett. 2010, 12, 4006.
(b) Kippo, T.; Fukuyama, T.; Ryu, I. Org. Lett. 2011, 13, 3864.
(c) Kippo, T.; Hamaoka, K.; Ryu, I. J. Am. Chem. Soc. 2013, 135,
632. (d) Kippo, T.; Ryu, I. Chem. Commun. 2014, 50, 5993.
(e) Kippo, T.; Kimura, Y.; Maeda, A.; Matsubara, H.; Fukuyama,
T.; Ryu, I. Org. Chem. Front. 2014, 1, 755.
(11) (a) Marko, I. E.; Mekhalfia, A. Tetrahedron Lett. 1990, 31, 7237.
(b) Marko, I. E.; Mekhalfia, A.; Ollis, W. D. Synlett 1990, 347. For
a recent example, see: (c) Kraus, G. A.; Liu, F. Tetrahedron Lett.
2012, 53, 111.
(12) This isomerization is presumably due to HBr, byproduct of the
reaction, and probably V-65 has an advantage of running the
radical reaction at lower temperature, which slows down the
isomerization reaction.
(13) (a) Fujiwara, T.; Morita, K.; Takeda, T. Bull. Chem. Soc. Jpn. 1989,
62, 1524. (b) Kuroda, C.; Kobayashi, K.; Koito, A.; Anzai, S. Bull.
Chem. Soc. Jpn. 2001, 74, 1947. (c) Takayama, H.; Sudo, R.;
Kitajima, M. Tetrahedron Lett. 2005, 46, 5795.
momethyl)acrylate (2a, 269 mg, 1.5 mmol), and degassed
benzene (5 mL) were added. The mixture was stirred at 60 °C for
1 h. The reaction mixture was filtered through a short plug of
Celite, and the filtrate was concentrated under reduced pres-
sure. The residue was purified by flash column chromatography
on SiO2 (hexane/EtOAc = 1:0 to 30:1) and preparative HPLC
(chloroform) to give methyl 2-methylene-4-oxododecanoate
(3b, 101 mg, 84%). Colorless oil; Rf = 0.55 (hexane/EtOAc = 5:1).
1H NMR (500 MHz, CDCl3): δ = 0.87 (t, J = 6.9 Hz, 3 H), 1.20–1.33
(m, 10 H), 1.55–1.65 (m, 2 H), 2.47 (t, J = 7.4 Hz, 2 H), 3.40 (s, 2
H), 3.74 (s, 3 H), 5.63 (s, 1 H), 6.33 (s, 1 H). 13C NMR (125 MHz,
CDCl3): δ = 14.02, 22.58, 23.67, 29.10, 29.30, 31.76, 42.63, 45.63,
52.00, 128.53, 134.25, 166.78, 207.42. IR (neat): 2953, 2926,
2855, 1720, 1638 cm–1. MS (EI): m/z (relative intensity): 240
(12) [M]+, 209 (5) [M – OMe]+, 141 (100), 82 (14), 71 (25), 57
(26), 55 (11). HRMS (EI): m/z calcd for C14H23O3 [M]+: 240.1725;
found: 240.1725.
(15) General Procedure for the Synthesis of 5
To a 20 mL two-necked round-bottom flask attached with a
reflux condenser were added AIBN (16 mg, 0.1 mmol) and
K2CO3 (138 mg, 1.0 mmol), and this flask was purged with
argon. Then, 1-nonanal (1a, 71 mg, 0.5 mmol), acrylonitrile (4a,
53 mg, 1.0 mmol), methallyl bromide (2e, 203 mg, 1.5 mmol),
and degassed benzene (5 mL) were added. The mixture was
stirred at 80 °C for 4 h. The reaction mixture was filtered
through a short plug of Celite, and the filtrate was concentrated
under reduced pressure. The residue was purified by flash
column chromatography on SiO2 (hexane/EtOAc = 1:0 to 30:1)
and preparative HPLC (CHCl3) to give 2-(2-methylallyl)-4-oxo-
dodecanenitrile (5a, 71.1 mg, 57%). Compound 5a is known in
literature, and all spectral data matched that reported.6b
(14) General Procedure for the Synthesis of 3
To a 20 mL two-necked round-bottom flask attached with a
reflux condenser were added V-65 (25 mg, 0.1 mmol) and K2CO3
(138 mg, 1.0 mmol), and this flask was purged with argon.
Then, 1-nonanal (1a, 71 mg, 0.5 mmol), methyl 2-(bro-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E