Cascade radical reaction of substrates with a carbon-carbon triple bond as a radical acceptor

Article abstract of DOI:10.3762/bjoc.9.128

The limitation of hydroxamate ester as a chiral Lewis acid coordination moiety was first shown in an intermolecular reaction involving a radical addition and sequential allylation processes. Next, the effect of hydroxamate ester was studied in the cascade

Full text of DOI:10.3762/bjoc.9.128

Cascade radical reaction of substrates with a
carbon–carbon triple bond as a radical acceptor
Hideto Miyabe*1,2, Ryuta Asada2 and Yoshiji Takemoto*2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1148–1155.
1School of Pharmacy, Hyogo University of Health Sciences,
Minatojima, Chuo-ku, Kobe 650-8530, Japan and 2Graduate School
of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan
doi:10.3762/bjoc.9.128
Received: 08 April 2013
Accepted: 22 May 2013
Published: 13 June 2013
Email:
Hideto Miyabe* - miyabe@huhs.ac.jp; Yoshiji Takemoto* -
takemoto@pharm.kyoto-u.ac.jp
This article is part of the Thematic Series "Organic free radical chemistry".
Guest Editor: C. Stephenson
* Corresponding author
© 2013 Miyabe et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
cascade; cyclization; enantioselective; free radical; Lewis acid; radical
Abstract
The limitation of hydroxamate ester as a chiral Lewis acid coordination moiety was first shown in an intermolecular reaction
involving a radical addition and sequential allylation processes. Next, the effect of hydroxamate ester was studied in the cascade
addition–cyclization–trapping reaction of substrates with a carbon–carbon triple bond as a radical acceptor. When substrates with a
methacryloyl moiety and a carbon–carbon triple bond as two polarity-different radical acceptors were employed, the cascade reac-
tion proceeded effectively. A high level of enantioselectivity was also obtained by a proper combination of chiral Lewis acid and
these substrates.
Introduction
Strategies involving a cascade process offer the advantage of also directed our efforts toward the development of new and
multiple carbon–carbon and/or carbon–heteroatom bond forma- efficient cascade approaches for the construction of
tions in a single operation. Radical chemistry has been devel- carbon–carbon/heteroatom bonds based on radical chemistry.
oped as one of the most powerful tools for carbon–carbon bond These approaches can be classified into two categories
formation in organic synthesis [1-20]. Particularly, the advan- according to their reaction mechanism (Figure 1) [37-43].
tages for utilizing the radical methodologies are the high func-
tional group tolerance and the mild reaction conditions, because Enantioselective radical reactions have been intensively studied
radical intermediates are not charged species. Therefore, a over the past fifteen years. Compared with stereocontrol studies
number of extensive investigations into sequential radical reac- on intermolecular radical reactions, the enantioselective stereo-
tions have been reported over the past fifteen years and signifi- control in radical cyclizations still remains a major challenge
cant progress has been made in recent years [21-36]. We have [44-68]. We have also investigated a new type of chiral Lewis
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Beilstein J. Org. Chem. 2013, 9, 1148–1155.
uated in CH2Cl2 at −78 °C by employing isopropyl iodide,
allyltin reagent, and Et3B as a radical initiator. The enan-
tiomeric purities of products were checked by chiral HPLC
analysis. The effect of the substituents R1 and R2 of hydroxa-
mate esters 3A–C on yield and selectivity was evaluated in the
presence of a chiral Lewis acid prepared from box ligand L1
and Zn(OTf)2. The results are shown in Scheme 1. Although
good enantioselectivities were not observed, the size of the
substituents had an impact on enantioselectivity with the larger
group leading to lower ee. These observations indicate that the
formation of the rigid ternary complex of hydroxamate ester,
Zn(OTf)2 and the ligand L1 is required for enantioselective
transformation. A similar trend was observed in our studies on
Figure 1: Cascade bond formation based on radical reactions.
acid mediated cyclization approach for cascade bond-forming the addition–cyclization–trapping reaction of hydroxamate
reactions via sequential radical–radical processes (Figure 2) esters [39,42]. The chiral Lewis acid promoted the reaction of
[39-43]. In these studies, the control of the enantioselectivities substrate 3A having a bulky 2-naphthylmethyl group as
was achieved by the introduction of a hydroxamate ester as a substituent R2 to form the product 4A in 40% yield with 7% ee.
two-point-binding coordination tether into the middle of Moderate enantioselectivity was observed by employing the
substrates A, together with the control of the rotamer popula- substrate 3B having a benzyl group as R1 and a methyl group as
tion of substrates [39,42]. In this paper, we describe in detail the R2. Particularly, the steric factor of the fluxional substituent R1
cascade addition–cyclization–trapping reaction of substrates affected not only enantioselectivity but also the chemical effi-
with a carbon–carbon triple bond as a radical acceptor as well ciency. The use of 3C having a 2-naphthylmethyl group as R1
as the effect of hydroxamate ester as a Lewis acid coordination led to a decrease in the chemical yield, probably because of the
moiety. Some results have been reported in our preliminary steric repulsion by a bulky substituent R1 leading to the dissoci-
communication [39].
ation of the chiral Lewis acid. In these studies, the absolute con-
figuration at newly generated stereocenters has been not deter-
mined.
W e r e c e n t l y r e p o r t e d i n d e t a i l t h e c a s c a d e
addition–cyclization–trapping reaction of substrates with
Figure 2: Our method for controlling the geometry of substrates and
the stereochemistry of cyclization.
Results and Discussion
Renaud’s group showed in 2002 that hydroxamic acid deriva-
tives are useful achiral templates in enantioselective
Diels–Alder reactions [69,70]. To study the effect of hydroxa-
mate ester as an achiral template in the intermolecular radical
reaction, our experiments began with the investigation of
cascade radical addition–allylation of hydroxamate esters 3A–C
having an acryloyl moiety (Scheme 1). The reactions were eval-
Scheme 1: Effect of hydroxamate ester on intermolecular C–C bond-
forming reactions.
1149

Beilstein J. Org. Chem. 2013, 9, 1148–1155.
carbon–carbon double bonds as two kinds of polarity-different
radical acceptors [42]. On the basis of these results, the possi-
bility of the carbon–carbon triple bond as a radical acceptor and
the hydroxamate ester functionality as a two-point-binding
coordination tether was next studied in detail. To understand the
scope and limitation of the cascade transformation of hydroxa-
mate esters with carbon–carbon triple bonds, the substrates of
choice were 5, 6A–C, 7 and 8 having hydroxamate ester func-
tionality (Figure 3).
Scheme 2: Cascade radical addition–cyclization–trapping reaction of 5
and 6A–C.
such as isopropyl iodide (Figure 4). These selectivities are
controlled by the steric factor around vinyl radicals. The vinyl
radicals are σ-radicals in a very fast equilibrium between
E-isomer B and Z-isomer C. The steric hindrance between the
substituents on the α-carbon atom of radical C and isopropyl
iodide is assumed to lead to selective iodine atom-transfer in
radical B giving 9Aa–9Ca as single Z-isomers.
Figure 3: Substrates for testing the cascade transformation.
At first, we studied the cascade reaction of 5 with an acryloyl
moiety and 6A–C with a methacryloyl moiety as an electron-
deficient acceptor in the absence of a chiral ligand (Scheme 2).
To control the rotamer population of substrates, Zn(OTf)2 was
used as a Lewis acid to coordinate the hydroxamate ester func-
tionality. The reactions were evaluated in CH2Cl2 at 20 °C
under the tin-free iodine atom transfer conditions by using iso-
propyl iodide and Et3B. The reaction of hydroxamate ester 5 did
not give the desired product probably due to polymerization of
5 through the labile acrylamide moiety. In contrast, the reaction
of 6A–C proceeded effectively to give the cyclic products
9Aa–9Ca in good yields. Among them, hydroxamate esters 6A
and 6B, which have a small methyl or benzyl group as R1, have
shown a high reactivity, although a 76% yield of product 9Ca
was obtained even when hydroxamate ester 6C having a
2-naphthylmethyl group was used. Furthermore, the regiochem-
ical course of the initial radical addition to 6A–C was well
controlled. The nucleophilic isopropyl radical reacted selec-
tively with the electron-deficient methacryloyl moiety to give
the single isomers 9Aa–9Ca.
Figure 4: E/Z-selectivity of 9Aa–Ca.
On the basis of the above results, we next studied the reaction
of 6A–C at −78 °C in the presence of Zn(OTf)2 and chiral box
ligands L1–L3 (Scheme 3 and Table 1). A stoichiometric
amount of chiral Lewis acid prepared from Zn(OTf)2 and ligand
L1 accelerated the reaction of hydroxamate ester 6A having a
methyl group as substituent R1 (Table 1, entry 1), although the
reaction of 6A did not proceed effectively at −78 °C in the
absence of box ligand L1. The desired product 9Aa was
It is also important to note that Z-isomers 9Aa–9Ca were selec- isolated as a single isomer in 51% yield with 60% ee after being
tively obtained without the formation of corresponding stirred for 10 h. The use of hydroxamate ester 6B having a
E-isomers. The E,Z-selectivities are determined by capturing benzyl group led to not only an enhancement in chemical yield
the intermediate vinyl radicals with an atom-transfer reagent but also to an improvement in enantioselectivity to give the pro-
1150

Beilstein J. Org. Chem. 2013, 9, 1148–1155.
selectivity was obtained by using ligand L3, surprisingly
resulting in antipode product 9Ba (Table 1, entry 7). The
representative effect of the solvent is shown in Table 1, entries
8–10. No reaction occurred in toluene, owing to the low solu-
bility of the chiral Lewis acid in toluene (Table 1, entry 8).
When the reaction was carried out in toluene/CH2Cl2 (4:1, v/v),
the cyclic product 9Ba was obtained in 67% yield with 77% ee
(Table 1, entry 9). The reaction in the protic solvent MeOH
gave the nearly racemic product, although the high Z-selec-
tivity was maintained (Table 1, entry 10). These results suggest
that the rigid chelation of the chiral Lewis acid to the hydroxa-
mate ester functionality occured in CH2Cl2. In the presence of
chiral Lewis acid, hydroxamate ester 6C had also shown good
reactivity, although the enantioselectivity diminished to 75% ee
(Table 1, entry 11). We next studied the reaction of substrate 6B
Scheme 3: Enantioselective cascade reaction of 6A–C.
duct 9Ba in 87% yield with 80% ee (Table 1, entry 2). Next, the with other radical precursors (Table 1, entries 12–14). Reac-
catalytic nature of the reactions was examined (Table 1, entries tions with cyclohexyl and cyclopentyl radicals were also facile.
3–5). The reactions proceeded equally well with 50 and 30 mol Under analogous reaction conditions, an outstanding level of
% of chiral Lewis acid as with a stoichiometric amount enantioselectivity was observed on employing the bulky tert-
(Table 1, entry 3 and 4). Further reduction of the chiral Lewis butyl iodide as a radical precursor (Table 1, entry 14). A good
acid load to 10 mol % resulted in a decrease of both the chem- yield of the product 9Bd was obtained with 92% ee and high
ical yield and enantioselectivity (Table 1, entry 5). In the case Z-selectivity.
of 10 mol % of the chiral Lewis acid, the ternary complex of the
ligand, the Lewis acid and the substrate were not effectively The absolute configuration at the newly generated stereocenters
formed, and the background reaction giving the racemic pro- of 9Aa–Bd was assumed by similarity between the present
duct proceeded. Additionally, the high Z-selectivity of product reaction and the previously reported reaction of substrates
9Ba indicates that the stereoselective iodine-atom transfer from having the carbon–carbon double bond [39,42]. In these reac-
isopropyl iodide to an intermediate radical proceeded effec- tions, a ternary complex of ligand, Lewis acid and substrate
tively under these catalytic reaction conditions. The reaction would control the three-dimensional arrangement of two radical
using box ligand L2 instead of L1 attenuated the enantio- acceptors. A tetrahedral or cis-octahedral geometry around the
selectivity (Table 1, entry 6). A somewhat lower enantio- zinc center was proposed [71,72]. In Figure 5, a tentative model
Table 1: Reaction of 6A–C in the presence of chiral ligand.
entry
substrate
R2
ligand
Lewis acid
(equiv)
product
(% yield)
Z/E
ee (%)
1
6A
6B
6B
6B
6B
6B
6B
6B
6B
6B
6C
6B
6B
6B
iPr
L1
L1
L1
L1
L1
L2
L3
L1
L1
L1
L1
L1
L1
L1
1.0
1.0
0.5
0.3
0.1
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
9Aa (51)
9Ba (87)
9Ba (85)
9Ba (82)
9Ba (49)a
9Ba (76)
9Ba (81)
no reaction
9Ba (67)
9Ba (63)
9Ca (83)
9Bb (82)
9Bc (83)
9Bd (85)
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
60
80
81
81
47
71
–69
2 [39]
3 [39]
4 [39]
5 [39]
6
iPr
iPr
iPr
iPr
iPr
7
iPr
8b
iPr
9c
iPr
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
77
rac
75
81
79
92
10d
11
iPr
iPr
12 [39]
13
c-Hex
c-Pent
t-Bu
14 [39]
astarting substrate 6B was recovered in 29% yield; bin toluene; cin toluene/CH2Cl2 (4:1, v/v); din MeOH.
1151

Beilstein J. Org. Chem. 2013, 9, 1148–1155.
in 78% yield. The results from these studies show that a
carbon–carbon double bond, e.g., a methacryloyl group, of the
electron-deficient acceptor is essential for the successful
cascade transformation.
To gain further insight into the stereocontrol in the cyclization
step, we next studied the opposite regiochemical cyclization by
using the substrate 12 via the intermediate radical F
(Scheme 5). The reaction was carried out in the presence of
Bu3SnH under asymmetric reaction conditions. Although the
reaction proceeded even at −78 °C, the nearly racemic product
13 was isolated in 60% yield. This observation indicates that the
regiochemical course of the cyclization step is an important
Figure 5: Model for the enantioselective reaction.
of an octahedral complex is shown, in which two oxygen atoms factor to achieve the highly asymmetric induction.
of the hydroxamate ester functionality occupy two equatorial
positions.
To study the effect of an electron-deficient acceptor on the
cascade process, the reactions of propiolic acid derivatives 7
and 8 were tested (Scheme 4). At first, the reaction of 7 was
evaluated under asymmetric reaction conditions. However, the
cascade addition–cyclization–trapping reaction did not proceed,
and the simple adduct 10 was formed in 57% yield by the
addition–trapping process. Next, the reaction of propiolic acid
derivative 8 was tested, because we expected the [1,5]-hydrogen
shift from 1,3-dioxolane ring into the reactive vinyl radical as
shown as D. However, the simple adduct 11 was only obtained
Scheme 5: Opposite regiochemical cyclization using substrate 12.
We next investigated the reactivity of internal alkynes as elec-
tron-rich acceptors (Scheme 6). The internal alkyne 14 has
shown a good reactivity comparable to that of the terminal
alkynes 6A–C. In the absence of a chiral ligand, the zinc Lewis
acid accelerated the reaction of alkyne 14 with an isopropyl
radical at 20 °C to give the desired cyclic product 15a in 73%
yield. Under analogous reaction conditions, both cyclohexyl
iodide and cyclopentyl iodide worked well to give 15b and 15c
Scheme 4: Reaction of propiolic acid derivatives 7 and 8.
Scheme 6: Cascade reaction of 14.
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Beilstein J. Org. Chem. 2013, 9, 1148–1155.
in 65% and 68% yields, respectively. However, the reaction
with a bulky tert-butyl radical did not proceed effectively, prob-
ably due to side reactions such as polymerization.
We finally investigated the enantioselective reaction of internal
alkynes 14 and 16 (Scheme 7). The reaction of 14 proceeded
with good enantioselectivities (Table 2). When a stoichiometric
amount of chiral Lewis acid was employed, the reaction with an
isopropyl radical gave the desired product 15a in 86% yield
with 83% ee (Table 2, entry 1). The reaction proceeded equally
well with 30 mol % of chiral Lewis acid as with a stoichio-
metric amount (Table 2, entry 2). The secondary radicals,
Scheme 7: Enantioselective cascade reaction of 14 and 16.
generated from cyclohexyl iodide or cyclopentyl iodide, reacted Particularly, the substrate 16 having a phenyl group gave the
well to afford 15b and 15c with 85% ee and 83% ee, respective- intermediate linear π-radical. Thus, the capture of linear vinyl
ly (Table 2, entry 3 and 4). In marked contrast to the reaction in radical with atom-transfer reagent would be influenced by the
the absence of a chiral ligand (Scheme 6), the use of bulky tert- steric hindrance around the quaternary carbon atom [43].
butyl iodide led to not only an enhancement in chemical yield
but also to an improvement in enantioselectivity (Table 2, Conclusion
entry 5). These observations indicate that the combination of We have shown the cascade radical addition–cyclization–trap-
chiral Lewis acid and hydroxamate ester functionality led the ping reaction of substrates with a carbon–carbon triple bond as
rigid complex promoting the cyclization step and suppressing a radical acceptor as well as the scope and limitation of hydrox-
the background reaction or the undesired side reactions. High amate ester as a coordination site with a chiral Lewis acid. Syn-
chemical yield and enantioselectivity were observed with thetic strategies involving enantioselective radical cyclizations
50 mol % of chiral Lewis acid (Table 2, entry 6), although would be desirable tools for preparing functionalized cyclic
further reduction of the catalyst load to 30 mol % resulted in a compounds with multiple stereocenters. These studies offer
decrease of yield and enantioselectivity (Table 2, entry 7). Both opportunities for further exploration of fascinating possibilities
chemical yield and enantioselectivity decreased by changing in the realm of cascade radical reactions.
Lewis acid from Zn(OTf)2 to MgI2 (Table 2, entry 8). When the
more nucleophilic and stable tert-butyl radical was employed,
Supporting Information
the reaction of substrate 16 having a phenyl group at the
terminal position proceeded smoothly to give the desired pro-
Supporting Information File 1
duct 17 in 89% yield with 67% ee (Table 2, entry 9). It is also
important to note that the high Z/E-selectivity of products was
observed even when internal alkynes 14 and 16 were employed.
These results indicate that the iodine atom-transfer from R2I to
the substituted vinyl radicals proceeded stereoselectively.
General experimental procedures, characterization data of
obtained compounds, and preparation of substrates.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-128-S1.pdf]
Table 2: Reaction of 14 and 16 in the presence of a chiral ligand.
entry
substrate
R2
Lewis acid
(equiv)
yield (%)
ratio
ee (%)
1 [39]
14
14
14
14
14
14
14
14
16
iPr
Zn(OTf)2 (1.0)
Zn(OTf)2 (0.3)
Zn(OTf)2 (1.0)
Zn(OTf)2 (1.0)
Zn(OTf)2 (1.0)
Zn(OTf)2 (0.5)
Zn(OTf)2 (0.3)
MgI2 (1.0)
86
74
87
77
94
94
75
20
89
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
83
81
85
83
90
91
61
54
67
2 [39]
iPr
3 [39]
c-Hex
c-Pent
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
4
5 [39]
6
7
8
9
Zn(OTf)2 (1.0)
1153

Beilstein J. Org. Chem. 2013, 9, 1148–1155.
26.Takai, K.; Matsukawa, N.; Takahashi, A.; Fujii, T.
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scien-
tific Research (C) (H.M.) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan.
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