Microwave-assisted atom transfer radical addition of polychlorinated compounds to olefins without addition of metal catalysts

Article abstract of DOI:10.1016/j.tetlet.2012.06.027

A new operationally simple and robust protocol for the metal-free atom transfer radical reaction (ATRA) has been developed. Polychlorinated compounds were effectively reacted with unactivated terminal olefins to generate 1,3-dichlorinated adducts under microwave irradiation in the presence of silicon carbide (SiC) as a heating element. The present microwave-assisted ATRA proceeds under essentially neutral conditions; thus, polar functionalities are well tolerated. In addition, an oxygen or a nitrogen unit was introduced to the internal side of the carbon chain via nucleophilic cyclization of the 1,3-dichlorinated adducts, and single-step formation of the six-membered carbocycle was realized through cyclization of the intermediate radical. The present methodology provides an expeditious way to prepare synthetically useful molecules from simple and unactivated terminal olefins.

Full text of DOI:10.1016/j.tetlet.2012.06.027

Tetrahedron Letters 53 (2012) 4368–4371
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted atom transfer radical addition of polychlorinated
compounds to olefins without addition of metal catalysts
⇑
Shin Kamijo , Shoko Matsumura, Masayuki Inoue
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new operationally simple and robust protocol for the metal-free atom transfer radical reaction (ATRA)
has been developed. Polychlorinated compounds were effectively reacted with unactivated terminal
olefins to generate 1,3-dichlorinated adducts under microwave irradiation in the presence of silicon car-
bide (SiC) as a heating element. The present microwave-assisted ATRA proceeds under essentially neutral
conditions; thus, polar functionalities are well tolerated. In addition, an oxygen or a nitrogen unit was
introduced to the internal side of the carbon chain via nucleophilic cyclization of the 1,3-dichlorinated
adducts, and single-step formation of the six-membered carbocycle was realized through cyclization of
the intermediate radical. The present methodology provides an expeditious way to prepare synthetically
useful molecules from simple and unactivated terminal olefins.
Received 27 April 2012
Revised 1 June 2012
Accepted 6 June 2012
Available online 12 June 2012
Keywords:
Microwave
Atom transfer radical addition
Cyclization
Olefin
Ó 2012 Elsevier Ltd. All rights reserved.
Polychlorinated compounds
Atom transfer radical addition (ATRA) to olefins enables forma-
tion of two contiguous sp3-carbon centers in a single step (Scheme
1).1,2 In situ generated radical species in ATRA exhibit both high
reactivity and chemoselectivity toward unactivated non-polarized
When a chlorobenzene solution11 of 2a was heated to 130 °C using
an oil bath, clean recovery of the starting olefin 1a was observed
(entry 1). On the other hand, microwave irradiation realized appli-
cation of higher temperature (200 °C) to the same mixture,12 and
successfully promoted the regioselective addition (entry 2). How-
ever, the expected adduct 3aa was obtained only in 29% yield.
We then employed silicon carbide (SiC) as a heating element to
accelerate the reaction, because SiC is known to absorb microwave
energy and effectively transfer the generated thermal energy to the
solution.13,14 The reaction in the presence of SiC indeed completed
within 1 h, and the yield of the regioselective adduct 3aa was in-
creased to 88% (entry 3). The present microwave-assisted ATRA
necessitated no special precaution against moisture or air, and pro-
duced 3aa (71% yield, entry 4) even in the presence of the radical
inhibitor galvinoxyl (0.1 equiv). Indifference of the protocol to
the potentially inhibitive contaminants demonstrated its robust-
ness and practicality.
C–C p-bonds without reacting with a wide array of polar function-
alities. Since its anion counterparts such as the Michael reaction3
generally require carbonyl-attached double bonds with full protec-
tion of acidic functional groups, ATRA can be more suitable for con-
struction of highly oxygenated molecules with multiple sp3-carbon
centers.4,5
We have been particularly interested in ATRA of polychlori-
nated compounds (2: Cl2CXY), because the resultant bis-substi-
tuted product
3 can be converted into various oxygenated
structures in a few steps.6 In addition to radical initiators or photo
irradiation, Cu-, Ru-catalyst,2,7 or photocatalyst8 have been em-
ployed for high-yielding addition of radical species to C–C p-bonds.
Here, we report new metal-free, microwave-assisted bis-function-
alizations of unactivated terminal olefins 1 with polychlorinated
compounds 2. The present protocol is robust and operationally
simple to provide synthetically versatile 1,3-dichloro compounds
3 in high yields.
Scheme 2 illustrates the proposed mechanism for regioselective
formation of 3aa. Upon microwave irradiation in the presence of
At the outset of our investigation, the reaction between trichlo-
roacetate 2a9,10 and unactivated terminal olefin 1a was examined
to optimize the reaction conditions of metal-free ATRA (Table 1).
X
Y
Cl
Cl
2
Cl
Cl
X
Y
R
metal catalyst
R
1
3
atom transf er
⇑
Corresponding author. Tel.: +81 3 5841 1354; fax: +81 3 5841 0568.
radical reaction
E-mail address: inoue@mol.f.u-tokyo.ac.jp (M. Inoue).
Present address: Graduate School of Science and Engineering, Yamaguchi
University, Yoshida, Yamaguchi 753-8511, Japan.
Scheme 1. Metal-catalyzed atom transfer radical addition (ATRA) of polychlori-
nated compounds with olefins.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.027

S. Kamijo et al. / Tetrahedron Letters 53 (2012) 4368–4371
4369
Table 1
Table 2
Optimization of reaction conditions for ATRA between trichloroacetate 2a and olefin
Bis-functionalization of various terminal olefins 1 with trichloroacetate 2a via ATRAa
1aa
Cl Cl
2a
, MW
Cl
CO2Et
R
R
Cl
Cl
Cl
2a
n
n
PhCl (1 M), SiC
200 °C, 1 h
Cl
Cl
CO2Et
Cl
CO2Et
1
3
BzO
BzO
4
4
PhCl (1 M)
1a
3aa
Yieldb (%)
Entry
Temperature (°C)
Heating element
Time (h)
Yieldb (%)
Entry
Compound
R
n
1c
130
200
200
200
None
None
SiC
24
1
1
0d
29f
88g
71
1
1a
1b
1c
1d
1e
1f
OBz
4
4
4
4
4
4
2
88 (3aa)
55 (3ba)d
79 (3ca)
54 (3da)
55 (3ea)e
68 (3fa)
98 (3ga)
2e
2c
3
OBOM
OTBDPS
OH
NHTs
Cl
3e
4e,h
SiC
1
4
5c
6
a
Conditions: olefin 1a, CCl3CO2Et 2a (5 equiv), PhCl (1 M), silicon carbide (SiC)
(200 mg/mmol of 1a) as a heating element.
Yield was calculated based on NMR analysis of the crude mixture unless
otherwise noted.
7
1g
Ph
b
a
Conditions: olefin 1, trichloroacetate 2a (5 equiv), PhCl (1 M), SiC (200 mg/
mmol of 1) as a heating element, heated at 200 °C by microwave irradiation for 1 h
unless otherwise noted.
c
Oil bath was used.
Olefin 1a was recovered in 93% yield.
Microwave irradiation was employed.
Olefin 1a was recovered in 69% yield.
d
e
b
Isolated yield.
The reaction was conducted at 170 °C.
Olefin 1b was recovered in 17% yield.
Olefin 1e was recovered in 27% yield.
f
c
g
d
Isolated yield.
h
e
The reaction was conducted in the presence of galvinoxyl (0.1 equiv).
SiC, 2a is in equilibrium with minute amounts of A and the Cl rad-
1d was efficiently converted into the corresponding adduct 3da
in 54% yield (entry 4). The nitrogen functionality (1e) and chloride
moiety (1f) were retained under the reaction conditions to produce
adducts 3ea in 55% yield and 3fa in 68% yield, respectively (entries
5 and 6). When the non-functionalized substrate 1g was used, ad-
duct 3ga was formed in excellent yield (entry 7).
We then explored the applicability of a series of polychlorinated
compounds 2 for radical-based bis-functionalization of olefin 1a
under the optimized conditions (Table 3). In contrast to the excel-
lent reactivity of trichloroacetate 2a (entry 1), ATRA of dichloroace-
Å
ical (Cl ) due to the relatively weak C–Cl bond of 2a (66.7 kcal/
mol).15 The generated radical A is both highly electron-deficient
and stable, because the two carbon-attached chloro groups and
one carbonyl group have
of a chloro group as well as the
ally stabilize the adjacent carbon radical.16 Radical A then adds to
the electron-rich unactivated C–C -bond from the less hindered
r
-withdrawal effects, and the lone-pair
p-bond of a carbonyl group gener-
p
side, leading to formation of the more electron-rich and less-stabi-
lized secondary radical B. Halogen transfer from 2a to B in turn af-
fords adduct 3aa and regenerates the stable radical A. This cycle
produces A continuously,17 while Cl is formed slowly from the
Å
homolytic cleavage of 2a. Accordingly, the higher concentration
of A permits its exclusive addition to the olefin in the presence
of Cl . Moreover, ATRA of the product 3aa is inhibited: its C–Cl
Table 3
Applicability of polychlorinated compounds 2 for olefin bis-functionalization via
ATRAa
Å
X
Y
Cl
Cl
bond is only activated by one chloro group and one carbonyl group,
thus, the radical formation from 3aa is disfavored in comparison to
2a.13 These physicochemical characteristics of the molecules in
Scheme 2 should contribute to high-yielding formation of 3aa.
Next, we demonstrated the functional group compatibility of
microwave-assisted ATRA (Table 2). Terminal olefins 1 having var-
ious functionalities on the side chain were successfully reacted
with 2a under the optimized conditions. Similar to benzoyl pro-
tected 1a (entry 1), the reactions of benzyloxymethyl- (1b) and
TBDPS-protected alcohols (1c) both proceeded smoothly to provide
adducts 3ba in 55% yield and 3ca in 79% yield, respectively (entries
2 and 3). Furthermore, it was found that the alcohol protective
group was not necessary for the present transformation. Alcohol
2
Cl
Cl
X
Y
MW
BzO
BzO
4
4
PhCl (1 M), SiC
200 °C, 1 h
1a
3a
Entry
Compound
X
Y
Yieldb (%)
1
2
3
4
2a
2b
2c
2d
2e
2e
2f
Cl
H
CO2Et
CO2Me
CO2Me
CO2Ph
COCl
88 (3aa)
0 (3ab)c
0 (3ac)c
87 (3ad)
64 (3aa)
61 (3ae0)
79 (3af)
64 (3ag)
78 (3ah)
Me
Cl
5d,e
6d,f
7d
8
Cl
Cl
Cl
COCl
CN
2g
2h
CO2Me
CN
CO2Me
CN
9d,g
a
Conditions: olefin 1a, polychlorinated compound 2 (5 equiv), PhCl (1 M), SiC
Cl
Cl
Cl
Cl
+ Cl•
(200 mg/mmol of 1a) as a heating element, heated at 200 °C by microwave irradi-
CO2Et
2a
Cl CO2Et
ation for 1 h unless otherwise noted.
A
b
Isolated yield.
Olefin 1a was recovered in 99% yield.
The reaction was conducted at 170 °C.
The crude mixture was treated with EtOH (5 equiv) and Et3N (5 equiv) at rt for
Cl
Cl
c
BzO
Cl
CO2Et
BzO
d
4
1a
4
e
3aa
3 h to give ester 3aa.
The crude mixture was diluted with PhCl and treated with NH3 gas (excess) and
Et3N (5 equiv) at rt for 2.5 h to give amide 3ae0.
2a
f
Cl
Cl
BzO
Cl
Cl
CO2Et
Cl
CONH2
4
3ae'
BzO
B
4
g
The reaction was conducted in toluene instead of PhCl.
Scheme 2. Proposed mechanism for the present ATRA under microwave
irradiation.

4370
S. Kamijo et al. / Tetrahedron Letters 53 (2012) 4368–4371
tate 2b and dichloropropanoate 2c did not proceed, and the start-
ing olefin 1a was quantitatively recovered (entries 2 and 3). These
negative results were expected, considering that the dichlorinated
product 3aa is inert under the reaction conditions (entry 1). Never-
theless, efficiency in homolytic cleavage of the C–Cl bond of 2 was
confirmed to correlate with the number of radical-stabilizing
chloro group attached at the latent carbon radical center. In fact,
both the trichloro derivatives 2d and 2f18 participated in the pres-
ent ATRA (entries 4–6). While adduct 3ad was produced from phe-
nyl trichloroacetate 2d in high yield (entry 4), the acid chloride
adduct tentatively formed from trichloroacetyl chloride 2f was
converted into ethyl ester 3aa (64% yield) and amide 3ae0 (61%
yield) upon treating with EtOH/Et3N and NH3/Et3N, respectively,
in the same flask. ATRA of trichloroacetonitrile 2f also proceeded
to form the corresponding adduct 3af in 79% yield. Dichlorinated
compounds underwent microwave-assisted ATRA, when the chloro
group was substituted by another radical stabilizing carbonyl or ni-
trile group (entries 8 and 9). Dichloromalonate 2e19 and dichloro-
malononitrile 2h,6,20,21 were converted into 3ag in 64% yield and
3ah in 78% yield, respectively.
O
O
Cl
Cl
Cl
Cl
2i
BzO
Cl
4
6
BzO
(45%)
MW
4
+
toluene (1 M), SiC
200 °C, 2 h
1a
Cl Cl
Cl
O
BzO
4
3ai (24%)
O
Cl
O
Cl
Cl
BzO
BzO
Cl
4
4
B'
B''
Scheme 4. The reaction between trichloroacetophenone 2i and olefin 1a.
acid chloride, and cyanides can be utilized as the starting halides 2,
and their reactivity as a radical precursor is successfully controlled
by the number of radical-stabilizing functional groups (Cl, C=O or
CN) attached at the latent carbon radical center. In addition, an
oxygen or a nitrogen unit is introduced to the internal side of the
carbon chain via the intramolecular reaction of the adducts, and
formation of the two C–C bonds is realized through the tandem
radical reaction. The present methodology provides an expeditious
way to prepare various synthetically useful molecules from simple
and unactivated terminal olefins.
The newly formed C–Cl bonds of adducts 3aa and 3ae0 were
converted into C–O or C–N bonds via a single intramolecular reac-
tion (Scheme 3). Treatment of ester 3aa with 1.1 equiv of NaOH in
EtOH resulted in formation of lactone 4 without touching the ben-
zoate moiety.22 The same lactone 5 was obtained in good yield
simply by heating amide 3ae0 in aqueous EtOH.23 On the other
hand, formation of the C–N bond was accomplished by treating
amide 3ae0 under basic conditions (K2CO3 in EtOH/H2O) to produce
lactam 5 in good yield. Therefore, by taking advantage of the reac-
tivity of the C–Cl bond and the carbonyl moiety, the synthetically
useful oxygen and nitrogen units were successfully installed.
Finally, one-step formation of the six-membered ring from the
terminal olefin was realized, when trichloroacetophenone 2i was
used (Scheme 4). Microwave-assisted ATRA of 2i to olefin 1a affor-
ded the dihydronapthalenone derivative 6 as a major product
along (45% yield) with ATRA adduct 3ai (24% yield).24 In this reac-
tion, cyclization of the secondary radical of B0 to the phenyl ring
was faster than the Cl-transfer, resulting in formation of the fused
bicycle 6 through B00. The present tandem radical reaction is poten-
tially useful for construction of various functionalized carboskel-
etons, which are not readily available via other methods.25
In conclusion, we developed a new operationally simple and ro-
bust protocol for chemo- and regioselective ATRA of polychlori-
Acknowledgments
This research was financially supported by the Funding Pro-
gram for Next Generation World-Leading Researchers (JSPS) to M.I.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.06.
027.
References and notes
1. (a) Kharasch, M. S.; Jensen, E. V.; Urry, W. H. Science 1945, 102, 128; (b)
Kharasch, M. S.; Urry, W. H.; Jensen, E. V. J. Am. Chem. Soc. 1945, 67, 1626.
2. Muñoz-Molina, J. M.; Belderrain, T. R.; Pérez, P. J. Eur. J. Inorg. Chem. 2011, 3155.
3. Perlmutter, P. Conjugated Addition Reactions in Organic Synthesis; Pergamon:
Oxford, 1992.
4. Semmelhack, M. F. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 4.
nated compounds
2 to unactivated olefins 1. The present
microwave-assisted ATRA proceeds without a metal catalyst under
essentially neutral conditions; thus, various polar functionalities
such as benzoyloxy, benzyloxymethyloxy, siloxy, hydroxy, tosyla-
mide, and chloro groups are well tolerated. Polychlorinated esters,
5. (a) Giese, B. Radicals in Organic Synthesis: Formation of Carbon–Carbon Bonds;
Pergamon: Oxford, 1986; (b) Curran, D. P. In reference 4; p 715.
6. Kamijo, S.; Yokosaka, S.; Inoue, M. Tetrahedron 2012, 68, 5290.
7. For
a review of transition metal-catalyzed radical reactions in organic
synthesis, see: Iqbal, J.; Bhatia, B.; Nayyar, N. K. Chem. Rev. 1994, 94, 519.
8. Wallentin, C.-J.; Nguyen, J. D.; Finkbeiner, P.; Stephenson, C. R. J. J. Am. Chem.
Soc. 2012, 134, 8875.
MW
9. For representative examples of intermolecular ATRA employing CCl3CO2R as a
reactant, see: (a) Dupont, G.; Dulou, R.; Pigerol, C. Bull. Soc. Chim. Fr. 1955, 1101;
(b) Murai, S.; Sonoda, N.; Tsutsumi, S. J. Org. Chem. 1964, 29, 2104; (c)
Matsumoto, H.; Nikaido, T.; Nagai, Y. J. Org. Chem. 1976, 41, 396; (d) Tsuji, J.;
Sato, K.; Nagashima, H. Tetrahedron 1985, 41, 393; (e) Thommes, K.; Içli, B.;
Scopelliti, R.; Severin, K. Chem. Eur. J. 2007, 13, 6899; (f) Quebatte, L.; Thommes,
K.; Severin, K. J. Am. Chem. Soc. 2006, 128, 7440; (g) Oe, Y.; Uozumi, Y. Adv.
Synth. Catal. 2008, 350, 1771.
10. As far as we examined, the microwave-assisted ATRA employing bromides
instead of chlorides hardly produced the expected adducts. In some cases,
formation of small amounts of dibrominated olefin was observed.
11. The reaction also proceeded in other aromatic solvents, such as anisole,
toluene, trifluoromethylbenzene, and benzonitrile, to give adduct 3aa (62–
85%).
12. (a) Loupy, A. Microwaves in Organic Synthesis; Wiley-VCH: Weinheim, 2003; (b)
Kappe, C. O.; Dallinger, D.; Murphree, S. S. Practical Microwave Synthesis for
Organic Chemists: Strategies, Instruments, and Protocols; Wiley-VCH: Weinheim,
2009.
13. (a) Kremsner, J. M.; Kappe, C. O. J. Org. Chem. 2006, 71, 4651; (b) Razzaq, T.;
Kremsner, J. M.; Kappe, C. O. J. Org. Chem. 2008, 73, 6321; (c) Obermayer, D.;
Gutmann, B.; Kappe, C. O. Angew. Chem., Int. Ed. 2009, 48, 8321.
NaOH (1.1 equiv)
EtOH (0.25 M)
100 °C, 5 min
O
Cl Cl
Cl
CO2Et
76%
O
BzO
BzO
Cl
Cl
BzO
4
3aa
4
MW
4
EtOH/H2O (5/1, 0.1 M)
100 °C, 1 h
78%
Cl Cl
Cl
CONH2
MW
4
K2CO3 (10 equiv)
EtOH/H2O (5/1, 0.1 M)
80 °C, 30 min
79%
3ae'
O
HN
4
Cl
Cl
BzO
5
Scheme 3. Functional group manipulations for installation of oxygen and nitrogen
units.

S. Kamijo et al. / Tetrahedron Letters 53 (2012) 4368–4371
4371
14. Since SiC only contains extremely small amount of transition metals as
contaminants, it is unlikely that a transition metal in SiC acts as a radical
initiator: Wang, Z.; Qiu, D.; Ni, Z.; Tao, G.; Yang, P. Anal. Chim. Acta 2006, 577,
288.
15. The bond dissociation energy of the C–Cl bond of chloroacetates generally
decreases upon attachment of Cl groups [e.g. Cl–CH2CO2Me (72.1 kcal/mol),
Cl–CHClCO2Et (68.8 kcal/mol), and Cl–CCl2CO2Et (66.7 kcal/mol)]: Luo, Y.-R.
BDEs of C-halogen bonds. In Comprehensive Handbook of Chemical Bond
Energies; CRC Press: Boca Rataon, FL, 2007; p 230.
20. For representative examples of intermolecular ATRA employing
chloroacetonitrile derivatives as a reactant, see: (a) Murai, S.; Tsutsumi, S. J.
Org. Chem. 1966, 31, 3000; (b) Julia, M.; Le Thuillier, G.; Saussine, L. J.
Organomet. Chem. 1979, 177, 211; (c) Pews, R. G.; Lysenko, Z. J. Org. Chem. 1985,
50, 5115; (d) Hayes, T. K.; Villani, R.; Weinreb, S. M. J. Am. Chem. Soc. 1988, 110,
5533; (e) Mori, M.; Kubo, Y.; Ban, Y. Heterocycles 1990, 31, 433; (f) Dneprovskii,
A. S.; Kasatochkin, A. N.; Boyarskii, V. P.; Ermoshkin, A. A.; Yakovlev, A. A. Russ.
J. Org. Chem. 2006, 71, 1120; (g) Thommes, K.; Fernández-Zúmel, M. A.; Buron,
C.; Godinat, A.; Scopelliti, R.; Severin, K. Eur. J. Org. Chem. 2011, 249.
21. The reaction in toluene gave cleaner conversion than that in PhCl in the case of
dichloromalononitrile 2h.
22. For a related lactone formation, see: (a) Nakano, T.; Kayama, M.; Matsumoto,
H.; Nagai, Y. Chem. Lett. 1981, 415; (b) Nakano, T.; Kayama, M.; Nagai, Y. Bull.
Chem. Soc. Jpn. 1987, 60, 1049.
23. For a related lactone formation starting from an amide, see: Kang, B.; Chang, S.;
Decker, S.; Britton, R. Org. Lett. 2010, 12, 1716.
16. For selected recent papers, see: (a) Coote, M. L.; Lin, C. Y.; Beckwith, A. L. J.;
Zavitsas, A. A. Phys. Chem. Chem. Phys. 2010, 12, 9597; (b) Menon, A. S.; Henry,
D. J.; Bally, T.; Radom, L. Org. Biomol. Chem. 2011, 9, 3636.
17. Studer, A. Chem. Eur. J. 2001, 7, 1159.
18. For representative examples of intermolecular ATRA employing CCl3COCl as a
reactant, see: (a) Nakano, T.; Shimada, Y.; Sako, R.; Kayama, M.; Matsumoto, H.;
Nagai, Y. Chem. Lett. 1982, 1255; (b) Martin, P.; Steiner, E.; Streith, J.; Winkler,
T.; Bellus, D. Tetrahedron 1985, 41, 4057; (c) Pews, R. G.; Gall, J. A. J. Org. Chem.
1994, 59, 6783.
19. For an example of intermolecular ATRA employing dichloromalonate as a
reactant, see: Thommes, K.; Fernández-Zúmel, M. A.; Buron, C.; Godinat, A.;
Scopelliti, R.; Severin, K. Eur. J. Org. Chem. 2011, 249.
24. Olefin 1a was recovered in 12% yield.
25. Reaction between 1a and 2i in the presence of CuCl/TMEDA (10 mol %) in
xylene at 130 °C afforded 6 (33% yield) and 3ai (55% yield) after 48 h.