Cascade radical reaction induced by polarity-mismatched perfluoroalkylation

Article abstract of DOI:10.1055/s-0030-1261167

Cascade radical addition-cyclization-trapping reaction proceeded via the unfavorable polarity-mismatched addition of electrophilic perfluoroalkyl radicals to electron-deficient acceptors. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1261167

LETTER
2085
Cascade Radical Reaction Induced by Polarity-Mismatched
Perfluoroalkylation
P
olarity-Misma
i
tchedP
t
erfluor
o
oalkylation Yoshioka, Kentefu, Xin Wang, Shigeru Kohtani, Hideto Miyabe*
School of Pharmacy, Hyogo University of Health Sciences, Minatojima, Kobe 650-8530, Japan
Fax +81(78)3042794; E-mail: miyabe@huhs.ac.jp
Received 27 May 2011
1–4). We were amazed to find the unfavorable mis-
matched path a giving 2a as a major course. Particularly,
Zn(OTf)2 accelerated the present cascade sequence to
form the products 2a and 3a in 71% combined yield and
73:27 ratio (entry 1).15 Interestingly, square planar
Cu(OTf)2 led to an enhancement of ratio into 94:6, al-
though the chemical yield diminished to 54% (entry 3).16
Perfluoroalkyl radicals exhibit extraordinary reactivity,
relative to their hydrocarbon counterparts.17,18 Therefore,
the enhanced reactivity of perfluoroalkyl radicals allowed
for the polarity-mismatched perfluoroalkylation of an
electron-deficient acceptor, though an electron-rich ac-
ceptor belongs to same molecule. In our previous investi-
gation using substrate 1 and nucleophilic alkyl radicals,
no cyclic product was obtained in the absence of Lewis
acid.10a In marked contrast, the enhanced reactivity of per-
fluoroalkyl radical promoted the cyclization even without
the geometry-control by Lewis acid (entry 4). Similar re-
gioselectivity and chemical efficiency were observed
when primary n-C4F9I was employed in the presence of
Zn(OTf)2 (entry 5). The branched secondary perfluoro-
Abstract: Cascade radical addition–cyclization–trapping reaction
proceeded via the unfavorable polarity-mismatched addition of
electrophilic perfluoroalkyl radicals to electron-deficient acceptors.
Key word: radical, fluoro, cyclization, enantioselective, cascade
Over the last fifteen years, enantioselective radical reac-
tions, particularly intermolecular radical reactions have
made great advances.1 However, enantiocontrol in radical
cyclizations still remains a major challenge,2 although sig-
nificant progress has been made recently by several ap-
proaches.3–10 Moreover, less is known about
stereoselective reactions of perfluoroalkyl radicals.11
Therefore, there have been no studies on perfluoroalkyl
radical mediated enantioselective cyclizations.
In contrast to nucleophilic alkyl radicals which generally
react with electron-deficient alkenes, perfluoroalkyl radi-
cals are classified into electrophilic radicals (Scheme 1).12
As expected from their electrophilic property, the reported
studies have concentrated on the reaction with electron-
rich alkenes including p-sufficient aromatic compounds.13
The polarity-mismatched additions of perfluoroalkyl rad-
icals to electron-deficient alkenes are rare,14 which are fre-
quently plagued by the formation of dimeric or polymeric
by-products. Therefore, the development of the cascade
transformations involving such process is a challenging
task. In this communication, we report new cascade addi-
tion–cyclization–trapping reactions involving the unfa-
vorable mismatched perfluoroalkylation, together with
the control of enantioselectivities on the basis of our cy-
clization strategy.10 With the objective to study the polar-
ity-mismatched interaction of perfluoroalkyl radicals, the
substrate 1, having both electron-deficient and electron-
rich acceptors, was employed, since the direct comparison
of two competitive reaction pathways (path a and path b)
could lead to informative suggestions regarding the dom-
inant factors controlling perfluoroalkylation step in cas-
cade process.
polarity-matched alkenes with radicals
perfluoroalkyl radical
alkyl radical
•CnHm
•CnFm
nucleophilic
electrophilic
electron-rich
alkenes
electron-deficient
alkenes
EDG
EWG
reaction of substrate having polarity-inverted radical acceptors
O
electron-rich
acceptor
electron-deficient
acceptor
N
Me
ML
OBn
1
O
O
FmCn
N
I
Bn
Me
ML
O
path a
O
mismatched
addition
path a
N
Bn
2
Me
•CnFm
The reactions of 1 having two kinds of polarity-inverted
radical acceptors were performed with triethylborane as a
radical initiator in CH2Cl2 at 20 °C (Scheme 2). At first, n-
C3F7I was employed as a primary perfluoroalkyl radical
source and Lewis acids were evaluated (Table 1, entries
O
O
I
N
Bn
matched
Me
addition
path b
path b
CnFm
3
SYNLETT 2011, No. 14, pp 2085–2089
x
x
.x
x
.2
0
1
1
Advanced online publication: 10.08.2011
DOI: 10.1055/s-0030-1261167; Art ID: U04511ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Cascade radical reaction of substrate 1 with perfluoro-
alkyl radical; ML = Lewis acid

2086
E. Yoshioka et al.
LETTER
alkyl radicals are known to exhibit greater electrophilici- is lower than that of nucleophilic isopropyl radical;12 thus,
ties than primary perfluoroalkyl radicals.19 The use of the final iodine atom-transfer process is relatively slow.
secondary iso-C3F7 and cyclo-C6F11 radicals had a moder- Therefore, it can be assumed that the slow trapping step
ate impact on two competitive pathways and the forma- and the high stability of intermediate radical A would al-
tion of 3c and 3d increased via the matched path b (entries low the reversibility between radical A and cyclized radi-
6–8).
cal, leading to low cis/trans diastereoselectivity.
1) stability of radicals
O
O
Lewis acid
RI, Et3B
OBn
OBn
stabilized by
resonance
ML
O
ML
O
O
R
N
I
R
N
I
O
1
Me
Me
•
CH2Cl2, 20 °C
2–20 h
+
FmCn
N
Bn
N
Bn
Me
Me
•
a: R = n-C3F7
b: R = n-C4F9
c: R = i-C3F7
d: R = c-C6F11
e: R = i-Pr
cis-2a–e
trans-2a–d
O
CnFm
ML
A
B
OBn
I
N
2) polar effect
+
Me
ML
O
O
δ–
O
O
N Bn
FmCn
N
Bn
R
δ+
Me
3a–d
Me
δ–
δ+
mismatched
polarization
matched
polarization
Scheme 2 Regiochemical courses in cascade radical reaction of 1
•CnFm
C
D
The regiochemical courses are controlled by two factors:
(1) the stability of intermediate radicals and (2) the polar
effect by fluorine’s potent s inductive electron-withdraw-
ing property (Figure 1).20 With regard to factor 1, the sta-
bilization of an intermediate radical A by resonance
promotes the polarity-mismatched addition path a. With
regard to factor 2,20 the mismatched perfluoroalkyl radical
addition path a leads to the matched polarization C in cy-
clization step, whereas matched path b gives the polarity-
mismatched interaction D. For the comparison, the result
using more nucleophilic isopropyl radical is shown in en-
try 9 (Table 1), which had selectively afforded the product
2e with high cis selectivity.10a At this stage, erosion of cis/
trans diastereoselectivities in perfluoroalkyl radical reac-
tions is questioned. The stability of perfluoroalkyl radicals
Figure 1 Two factors directing regiochemical courses
Introduction of a substituent at b-position of an electron-
deficient acceptor apparently inhibits the mismatched ad-
dition due to steric effects (Scheme 3). The reaction of
substrate 4 having a b-methyl group gave the cyclized but
ethylidene product 5 and the simple adduct 6 predomi-
nantly through the matched addition. Notably, the forma-
tion of uncyclized adduct 6 supports our hypothesis of
polar effect on cyclization step (see: E).
The circumstances in the presence of a chiral Lewis acid
promoted the polarity-mismatched perfluoroalkylation of
the electron-deficient acceptor in 1 (Scheme 4, Table 2).
Reactions of 1 with perfluoroalkyl iodides were per-
Table 1 Cascade Reaction of 1 with Perfluoroalkyl Radicals
Entry
1c
RI
Lewis acid
Zn(OTf)2
Yb(OTf)3
Cu(OTf)2
none
Product
2a + 3a
2a + 3a
2a + 3a
2a + 3a
2b + 3b
2c + 3c
2c + 3c
2d + 3d
2e
Ratioa of 2:3
73:27
Yield (%)b
cis/transa
59:41
58:42
60:40
54:46
63:37
79:21
81:19
77:23
>98:2
n-C3F7I
n-C3F7I
n-C3F7I
n-C3F7I
n-C4F9I
i-C3F7I
i-C3F7I
c-C6F11I
i-PrI
71
60
54
49
74
77
36
66
41
2c
73:27
3c
94:6
4c
72:28
5c
Zn(OTf)2
Zn(OTf)2
Cu(OTf)2
Zn(OTf)2
Zn(OTf)2
72:28
6c
62:38
7c
78:22
8c
61:39
9d
a Determined by 1H NMR spectroscopic analysis.
b Combined yield of the isolated products.
c Reactions were carried out with perfluoroalkyl iodides (5 equiv), Lewis acid (1 equiv), and Et3B in hexane (1.0 M, 5 equiv).
d Reaction was carried out with isopropyl iodides (30 equiv), Zn(OTf)2 (1 equiv), and Et3B in hexane (1.0 M, 5 equiv); see ref. 10a.
Synlett 2011, No. 14, 2085–2089 © Thieme Stuttgart · New York

LETTER
Polarity-Mismatched Perfluoroalkylation
2087
O
C3F7 radical in CH2Cl2 gave the cyclic product cis-2c with
90% ee in 92:8 cis/trans selectivity, although product ra-
tio diminished to 82:18 due to high electrophilicity of sec-
ondary perfluoroalkyl radicals (entry 4). Similar result
was also obtained in CH2Cl2–toluene (entry 5). In the
presence of activated 4 Å molecular sieves, cis-2c was
formed with 92% ee (entry 6). Reaction with cyclo-C6F11
radical was also facile to give cis-2d in 91% ee with good
cis/trans diastereoselectivity (entry 7).
Zn(OTf)2
n-C3F7I, Et3B
Me
N
CH2Cl2, 20 °C, 20 h
OBn
4
O
O
OBn
Me
N
I
Me
+
N
OBn
n-C3F7
5 (19%)
6 (29%)
n-C3F7
Zn(OTf)2
O
I
O
O
O
O
O
Me
N
Bn
Me
N
Bn
N
N
5
O
δ+
mismatched
polarization
OBn
δ–
E
R
N
I
n-C3F7
•n-C3F7
Me
ligand 7
Zn(OTf)2, RI, Et3B
trans-2a–d
3a–d
+
+
‘uncyclized’
iodine-atom transfer
1
6
cis-2a–d
Scheme 3 Reaction of substrate 4 having a b-methyl group
Scheme 4 Reaction in the presence of chiral Lewis acid
formed at –78 °C in the presence of chiral Lewis acid pre-
pared from box ligand 7 and Zn(OTf)2.10 In general, the
use of ligand 7 led not only to an enhancement in product
ratio but also an improvement in cis/trans diastereoselec-
tivity. The reaction of 1 with a n-C3F7 radical in CH2Cl2
proceeded effectively to form the products 2a and 3a in
95:5 ratio and 88% combined yield (entry 1). Although
cis/trans diastereoselectivity was still low, the major
product cis-2a was isolated in 76% ee along with trans-2a
in 88% ee.21 The addition of hexafluoro-2-propanol
(HFIP) as an acidic solvent led to lower product ratio and
enantioselectivity (entry 2). In contrast, higher enantiose-
lectivities were obtained, when the reaction was carried
out in CH2Cl2–toluene (1:1; entry 3). The enantioselectiv-
ities and cis/trans diastereoselectivities were increased by
changing the perfluoroalkyl radicals from primary to sec-
ondary (entries 4–7). The reaction with secondary iso-
These results indicate that the three-dimensional arrange-
ment of two radical acceptors was efficiently controlled
by a ternary complex of ligand, Lewis acid and substrate
at low temperature. Assuming that there is a tetrahedral or
cis-octahedral geometry around the zinc center,22 tenta-
tive model of octahedral complex is proposed for account-
ing the product stereochemistry (Figure 2). In this
organization, two oxygen atoms of substrate 1 occupy two
equatorial directions and the aryl group of ligand 7 shields
the electron-rich allyl group of substrate 1.
We finally explored the reaction of substrate 8 having a
methyl group at a terminal of electron-rich acceptor
(Scheme 5). As expected, the steric effect had an impact
on regiochemical courses and promoted the polarity-mis-
matched perfluoroalkylation exclusively. The reaction
with a n-C3F7 radical gave the four stereoisomeric cyclic
Table 2 Enantioselective Cascade Radical Reaction of 1a
Entry
RI
Solvent
Time
(d)
Ratiob
Yield
(%)c
cis/transb
ee (%)d
of 2:3
cis-2
trans-2
88
1
2
3
4
5
6e
7
n-C3F7I
n-C3F7I
n-C3F7I
i-C3F7I
i-C3F7I
i-C3F7I
c-C6F11I
CH2Cl2
2
3
1
5
5
5
3
95:5
88
78
78
44
46
40
73
62:38
86:14
64:36
92:8
76
6
CH2Cl2–HFIP (9:1)
CH2Cl2–toluene (1:1)
CH2Cl2
78:22
97:3
13
87
90
91
92
91
90
82:18
81:19
79:21
74:26
CH2Cl2–toluene (1:1)
CH2Cl2
92:8
94:6
CH2Cl2
92:8
a Reactions were carried out with perfluoroalkyl iodides (5 equiv), Zn(OTf)2 (1 equiv), ligand 7 (1 equiv), and Et3B in hexane (1.0 M, 5 equiv)
at –78 °C.
b Determined by 1H NMR spectroscopic analysis.
c Combined yield.
d Determined by HPLC analysis.
e The reaction was carried out in the presence of activated 4 Å molecular sieves.
Synlett 2011, No. 14, 2085–2089 © Thieme Stuttgart · New York

2088
E. Yoshioka et al.
LETTER
(2) (a) Miyabe, H.; Takemoto, Y. Chem. Eur. J. 2007, 13, 7280.
(b) Yoshioka, E.; Kohtani, S.; Miyabe, H. Heterocycles
2009, 79, 229.
(3) (a) Nishida, M.; Hayashi, H.; Nishida, A.; Kawahara, N.
Chem. Commun. 1996, 579. (b) Hiroi, K.; Ishii, M.
Tetrahedron Lett. 2000, 41, 7071.
(4) (a) Yang, D.; Gu, S.; Yan, Y.-L.; Zhu, N.-Y.; Cheung, K.-K.
J. Am. Chem. Soc. 2001, 123, 8612. (b) Yang, D.; Gu, S.;
Yan, Y.-L.; Zhao, H.-W.; Zhu, N.-Y. Angew. Chem. Int. Ed.
2002, 41, 3014. (c) Yang, D.; Zheng, B.-F.; Gao, Q.; Gu, S.;
Zhu, N.-Y. Angew. Chem. Int. Ed. 2006, 45, 255.
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1999, 121, 11012. (b) Bruch, A.; Ambrosius, A.; Fröhlich,
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47, 7957.
•CnFm
X
from top side
O
N
X
O
N
Bn
Zn
N
O
FmCn
I
Me
O
Figure 2 Tentative model
products 9 in 91% combined yield [cis-9 (major)/cis-9
(minor)/trans-9 (major)/trans-9 (minor) = 50:23:21:6].23
The major isomer of cis-9 was obtained with 87% ee,
along with the minor isomer of cis-9 (75% ee) and the ma-
jor isomer of trans-9 (87% ee).
O
ligand 7, Zn(OTf)2
n-C3F7I, Et3B
N
Me
(7) Gansäuer, A.; Shi, L.; Otte, M. J. Am. Chem. Soc. 2010, 132,
11858.
CH2Cl2, –78 °C, 3 d
91%, dr 50:23:21:6
Me
OBn
8
(8) (a) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.;
MacMillan, D. W. C. Science 2007, 316, 582. (b) Jang, H.-
Y.; Hong, J.-B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2007, 129, 7004. (c) Conrad, J. C.; Kong, J.; Laforteza, B.
N.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131,
11640. (d) Rendler, S.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2010, 132, 5027.
O
O
OBn
OBn
n-C3F7
N
I
n-C3F7
N
I
Me
Me
+
Me
Me
(9) (a) Nicolaou, K. C.; Reingruber, R.; Sarlah, D.; Bräse, S.
J. Am. Chem. Soc. 2009, 131, 2086. (b) Nicolaou, K. C.;
Reingruber, R.; Sarlah, D.; Bräse, S. J. Am. Chem. Soc.
2009, 131, 6640.
cis-9 (major): 87% ee
cis-9 (minor): 75% ee
trans-9 (major): 87% ee
Scheme 5 Enantioselective reaction of 8 with n-C3F7 radical
(10) We have reported the strategy using hydroxamate ester as a
coordination tether with a chiral Lewis acid. See:
(a) Miyabe, H.; Asada, R.; Toyoda, A.; Takemoto, Y.
Angew. Chem. Int. Ed. 2006, 45, 5863. (b) Miyabe, H.;
Toyoda, A.; Takemoto, Y. Synlett 2007, 1885.
(11) (a) Yajima, T.; Nagano, H. Org. Lett. 2007, 9, 2513.
(b) Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2009, 131, 10875.
In conclusion, we have developed the cascade radical
reactions24 starting from the polarity-mismatched perfluo-
roalkylation of an electron-deficient acceptor, providing
an enantioselective synthetic approach to chiral g-lac-
tams.
(12) For a review on perfluoroalkyl radicals, see: Dolbier, W. R.
Acknowledgement
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This work was supported in part by a Grant-in-Aid for Scientific
Research (C) (H.M.) and for Young Scientists (B) (E.Y.) from the
Ministry of Education, Culture, Sports, Science and Technology of
Japan.
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Synlett 2011, No. 14, 2085–2089 © Thieme Stuttgart · New York

LETTER
Polarity-Mismatched Perfluoroalkylation
2089
(15) The structures of cis-2a,b, trans-2a,b and 3a,b were
confirmed by HMQC, HMBC, and NOESY experiments.
(16) In general, the copper(II) Lewis acids are unsuitable for
radical reactions due to extinction of radical species. For a
successful example of radical reaction using copper(II)
Lewis acids, see: Friestad, G. K.; Shen, Y.; Ruggles, E. L.
Angew. Chem. Int. Ed. 2003, 42, 5061.
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phase was dried over Na2SO4 and concentrated at reduced
pressure. The residue was roughly purified by preparative
TLC (hexane–EtOAc, 3:1) to give the mixture of products.
The ratio of products was determined by 1H NMR analysis
of the mixture. Second purification of the mixture by
preparative TLC (benzene–EtOAc, 10:1 or hexane–EtOAc,
6:1, 2-fold development) afforded the isolated products.
Representative Products: cis-2a: colorless crystals; mp
99–99.5 °C (hexane). IR (KBr): 2948, 1717, 1458 cm–1. 1H
NMR (CDCl3): d = 7.38–7.50 (m, 5 H), 5.04 (d, J = 11.0 Hz,
1 H), 5.02 (d, J = 11.0 Hz, 1 H), 3.50 (dd, J = 9.2, 6.6 Hz, 1
H), 3.19–3.30 (m, 2 H), 2.73 (t, J = 11.4 Hz, 1 H), 2.39–2.58
(m, 2 H), 2.26 (br dd, J = 37.0, 16.0 Hz, 1 H), 1.32 (d, J = 1.6
Hz, 3 H). 13C NMR (CDCl3): d = 170.8, 134.7, 129.6, 129.3,
128.7, 118.3 (tt, J = 257, 31 Hz), 117.5 (qt, J = 289, 34 Hz),
108.4 (tsext, J = 265, 36 Hz), 76.9, 51.1, 44.5, 44.2, 31.0 (t,
J = 21 Hz), 22.2, 4.1. 19F NMR (CDCl3): d = –80.6 (t, J =
19.5 Hz, 3 F), –106.2 (dm, J = 273 Hz, 1 F), –116.0 (dm, J =
273 Hz, 1 F), –128.3 (br s, 2 F). MS (EI+): m/z = 528 (25)
[M + H+], 91 (100). HRMS (EI+): m/z [M + H+] calcd for
C17H18F7INO2: 528.0270; found: 528.0260. Anal. Calcd for
C17H17F7INO2: C, 38.73; H, 3.25; N, 2.66. Found: C, 38.74;
H, 3.22; N, 2.60. HPLC (Chiralcel AD-H, hexane–2-
propanol, 95:5; flow: 1.0 mL/min, l = 254 nm); tR (major) =
6.7 min, tR (minor) = 8.9 min. A sample of 87% ee by HPLC
analysis gave [a]24D +28.3 (c = 0.40, CHCl3). 3a: colorless
oil. IR (KBr): 2968, 2932, 1714, 1455 cm–1. 1H NMR
(CDCl3): d = 7.34–7.47 (m, 5 H), 5.09 (d, J = 11.0 Hz, 1 H),
5.04 (d, J = 11.0 Hz, 1 H), 3.48 (t, J = 8.5 Hz, 1 H), 3.37 (dd,
J = 8.5, 1.8 Hz, 1 H), 3.23 (d, J = 11.0 Hz, 1 H), 3.05 (d, J =
11.0 Hz, 1 H), 2.45 (m, 1 H), 2.26–2.42 (br m, 2 H), 1.30 (s,
3 H). 13C NMR (CDCl3): d = 170.1, 134.7, 129.5, 129.1,
128.6, 117.6 (qt, J = 288, 34 Hz), 117.4 (tt, J = 256, 32 Hz),
108.4 (tsext, J = 265, 38 Hz), 77.2, 50.1 (d, J = 5 Hz), 44.0,
33.9, 28.1 (t, J = 21 Hz), 25.0, 6.4. 19F NMR (CDCl3): d =
–80.9 (t, J = 9 Hz, 3 F), –113.7 (dm, J = 273 Hz, 1 F), –116.0
(dm, J = 273 Hz, 1 F), –127.8 (dd, J = 290, 5 Hz, 1 F), –128.2
(dd, J = 290, 5 Hz, 1 F). HRMS (ESI): m/z [M + H+] calcd
for C17H18F7INO2: 528.0270; found: 528.0269.
(19) The electrophilicity of perfluoroalkyl radicals followed the
order 1° < 2° < 3°; see ref. 12.
(20) Avilla, D. V.; Ingold, K. U.; Lusztyk, J.; Dolbier, W. R. Jr.;
Pan, H.-Q.; Muir, M. J. Am. Chem. Soc. 1994, 116, 99.
(21) The absolute configuration at the stereocenter of cis-2a–d
was assumed by similarity between the present reaction and
the previously reported study. See ref. 10a.
(22) (a) Sibi, M. P.; Yang, Y.-H. Synlett 2008, 83. (b) Evans, D.
A.; Kozlowski, M. C.; Tedrow, J. S. Tetrahedron Lett. 1996,
37, 7481.
(23) Both cis-9 and trans-9 were respectively obtained as two
diastereomers concerning the newly generated stereocenter
at iodinated carbon.
(24) General Procedure for Enantioselective Radical
Reaction: A solution of substrate 1 or 8 (100 mg or 106 mg,
0.43 mmol), Zn(OTf)2 (156 mg, 0.43 mmol) and ligand 7
(153 mg, 0.43 mmol) in CH2Cl2 (4.3 mL) was stirred for 1 h
under Ar atmosphere at 20 °C. To the reaction mixture were
added RI (2.15 mmol) and Et3B (1.05 M in hexane, 2.05 mL,
2.15 mmol) at –78 °C. After being stirred at the same
temperature for 1–5 d, the reaction mixture was diluted with
sat. NaHCO3 and then extracted with CH2Cl2. The organic
Synlett 2011, No. 14, 2085–2089 © Thieme Stuttgart · New York

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