Iron chloride enhancement of dimethylzinc-mediated radical conjugate addition of ethers and an amine to alkylidenemalonates

Article abstract of DOI:10.1016/j.tetlet.2009.08.034

The addition of FeCl₃ and the use of DMSO as a solvent enabled the radical conjugate addition of a cyclic acetal and a cyclic amine to alkylidenemalonates using a reagent amount (12.5 equiv) of the radical precursors to give Michael addition pr

Full text of DOI:10.1016/j.tetlet.2009.08.034

Tetrahedron Letters 50 (2009) 6040–6043
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iron chloride enhancement of dimethylzinc-mediated radical conjugate
addition of ethers and an amine to alkylidenemalonates
*
Ken-ichi Yamada, Masaru Maekawa, Yasutomo Yamamoto, Mayu Nakano, Tito Akindele, Kiyoshi Tomioka
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2009
Revised 14 August 2009
Accepted 17 August 2009
Available online 20 August 2009
The addition of FeCl3 and the use of DMSO as a solvent enabled the radical conjugate addition of a cyclic
acetal and a cyclic amine to alkylidenemalonates using a reagent amount (12.5 equiv) of the radical pre-
cursors to give Michael addition products in up to 84% yield. This represents a great improvement over
the 5% yield obtained under the previously reported conditions.
Ó 2009 Elsevier Ltd. All rights reserved.
Radical chemistry has rapidly progressed in the past two dec-
ades and has become one of the most powerful tools of organic
synthesis.1 We previously reported the direct generation of
carbon-centered radicals from ethers2 or unfunctionalized cycloal-
kanes3 through C–H bond cleavage by the action of dimethylzinc4
and air, and their addition to imines in excellent yields. We also
reported their reactions with aldehydes,5 arylamines, alkoxyam-
4a or 6 was produced, indicating that the reaction of dimethylzinc
with intermediate radical A (Scheme 1), generated by the addition
of THF-2-yl radical to 1a, was inefficient.
To overcome this problem, we investigated the reaction with
transition metal salt as an additive. Transition metal salt would
be reduced to lower oxidation state by homolytic methyl–metal
bond cleavage (step a) following ligand exchange with dimethyl-
zinc. We expected that the reduced metal would facilitate the
reduction of A to the enolate of malonate (step b) to prevent autox-
idation and a retro-Michael-type reaction of A.
ines, dialkylhydrazines,6 and ,b-unsaturated N-tosyl imines.7 Fur-
a
thermore, asymmetric addition of a cyclic acetal to chiral N-sulfinyl
imines has been achieved, providing a reasonably efficient meth-
odology for the asymmetric synthesis of amino alcohol deriva-
tives.8 Recently, we developed radical conjugate addition to
alkylidenemalonates (Table 1, entry 1).9,10 In these radical reac-
tions, however, more than 200 equiv of the ethers was required
as radical precursors.11 The reduction of the amount of a radical
precursor is a challenging goal in the field of synthetic radical
chemistry: to the best of our knowledge, there are only a few
examples of radical addition through direct C–H bond cleavage
using smaller excess amounts (e.g., 10 equiv) of radical precur-
sors.12 Herein, we report the promoting effect of iron salts13,14 on
the radical addition of ethers and an amine to alkylidenemalonates
mediated by dimethylzinc, which enabled the use of 12.5 equiv of
radical precursors to give products in good to high yield (40–84%).
First, we investigated the reaction of THF (2a) with 1a to deter-
mine the suitable conditions. Table 1 shows the effects of the
amount of THF (2a) on the addition to benzylidenemalonate (1a)
under the previously reported conditions.9 Although the reaction
was fast and the yield of product 3a was high with 250 equiv of
2a, the yield dramatically dropped and the reaction time increased
as the amount of 2a was decreased from 250 to 100 to 50 equiv
(entries 1–3). The reaction with 12.5 equiv of 2a gave only 5% yield
of Michael adduct 3a, and malonate 1a was recovered in 15% yield
To our delight, the addition of first-row transition metal salts,
such as CrCl3, MnCl2, FeCl3, and CoCl2, drastically improved the
yield of 3a as well as the reaction rate (Table 2, entries 1–12). Cop-
per salts only promoted the addition of the methyl group to give 5
in good yield (entries 13 and 14).15 The second-row transition me-
tal salts were less effective (entries 15–19). When FeCl3 or MnCl2
was used, the formation of 4a and 6 was significantly suppressed
(entries 3 and 4). Without BF3ÁOEt2, the reaction became slower,
giving 3a in low yield (entry 5). Reaction without dimethylzinc
failed to proceed and 1a was recovered in 86% yield (entry 6).
These results clearly demonstrate that BF3ÁOEt2 significantly accel-
erated the reaction and that the reaction required dimethylzinc to
proceed, even in the presence of the iron salt. The use of other ir-
on(III) salts, such as FeCl3Á6H2O, Fe(NO3)3Á9H2O, and Fe(acac)3,
was not effective (entries 9–11). Air bubbling into a reaction
mixture accelerated the reaction to give 3a in 45% yield (entry
7). Iron(II) salt gave comparable results (entry 8). Thus, among
those investigated, the conditions in entries 7 and 8 were the best.
With a suitable additive FeCl3 in hand, we turned our attention
to the reaction using 4,4,5,5-tetramethyl-1,3-dioxolane (2b),16
where the acetal moiety of product 3b was convertible to a
hydroxymethyl group.9 The reaction under the conditions men-
tioned above with 12.5 equiv of 2b resulted in a 31% yield of the
desired adduct 3b, along with 27% yield of 5 and 24% yield of 7 (Ta-
ble 3, entry 1). We speculated as follows: The formation of 5 and 7
(Table 1, entry 4). In the latter two reactions, a-oxygenated adduct
* Corresponding author. Tel.: +81 75 753 4553; fax: +81 75 753 4604.
E-mail address: tomioka@pharm.kyoto-u.ac.jp (K. Tomioka).
would indicate that the trapping of initial product
B with
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.034

K. Yamada et al. / Tetrahedron Letters 50 (2009) 6040–6043
6041
Table 1
Radical conjugate addition of THF to benzylidenemalonatea
O
O
R
Me
Me2Zn, air
BF3•OEt2
R
2a
+
CO2Me
CO2Me
Ph
Ph
+
rt
CO2Me
CO2Me
3a: R=H
4a: R=OH
CO2Me
5: R=H
6: R=OH
Ph
CO2Me
1a
Entry
2a (equiv)
Me2Zn (equiv)
Time (h)
3a (%)
4a (%)
5 (%)
6 (%)
1
2
250
100
50
3
1.5
6
24
24
86
72
36
5d
0
0
28
0
3
10
13
15
0
0
0
6b
6b
6
3
4c
12.5
26
a
The indicated amount of a hexane solution of Me2Zn (1 M) and 1 equiv of BF3ÁOEt2 was used. Air, passed through a NaOH tube, was introduced into the reaction mixture
through a bubbler at the rate of 0.5 L/(h mol). The isolated yields are presented.
b
Dimethylzinc (3 equiv each) was added portionwise.
The reaction was conducted under ordinary atmosphere without air bubbling.
15% recovery of 1a.
c
d
Table 2
dimethylzinc and/or iron(II) species is inefficient so that B under-
goes a retro-Michael-type reaction17 to give back 1a and a dioxo-
lan-2-yl radical. Methyl adduct intermediate C, whose retro-
reaction is slow because of the instability of the methyl radical,
undergoes coupling with dioxolan-2-yl radical under this highly
concentrated condition to give 7 (Scheme 2). Accordingly, we ex-
pected that the use of zinc species bearing a ligand that forms a
more stable radical than the methyl radical, such as a peroxyl rad-
ical, would improve the yield of 3b (Scheme 3). As expected, the
addition of tert-butylhydroperoxide (TBHP), which would result
in the formation of zinc peroxide,18 prevented the production of
7 (Table 3, entries 2À4).19 The use of 2 equiv of TBHP gave the best
results, giving 3b in 43% yield (entry 3).
The solvent in the above-mentioned reactions (0.50 mmol of
1a) was a mixture of 2b (0.9 mL) and hexane (1.5 mL) due to the
use of 2b (12.5 equiv) and dimethylzinc (3 equiv, 1 M in hexane).
Another solvent (5 mL) was added to examine the effect of co-sol-
vents in this reaction (Table 4). Reactions in non-coordinating sol-
vents, toluene and CH2Cl2, as well as coordinating solvents, DMF
and CH3CN, did not improve the yield of 3b (entries 1À4). The
use of DMSO as a co-solvent, however, significantly increased the
yield of 3b to 63%, and suppressed the formation of 5 (entry 5).
Again, the necessity for dimethylzinc was clearly confirmed by
the reaction under the conditions in entry 5 without dimethylzinc,
which resulted in the quantitative recovery of 1a.
THF addition in the presence of transition metal saltsa
Me2Zn 2 equiv
BF3•OEt2 1 equiv
additive 10 mol %
1a
3a + 4a + 5 + 6 + 1a
+
2a
12.5 eq
rt
Time (h) 3a (%) 4a (%) 5 (%) 6 (%) 1a (%)
Entry Additive
1
2
3
4
None
CrCl3
MnCl2
FeCl3
FeCl3
FeCl3
FeCl3
FeCl2
24
2
2
5
31
32
31
14
0
45
43
38
8
30
21
Trace
Trace
10
4
0
6
0
0
13
0
0
0
4
0
15
45
41
53
18
0
35
30
27
21
39
22
82
83
24
16
14
18
25
26
0
0
0
10
0
0
0
0
4
0
10
0
0
31
3
4
12
5
15
0
0
0
1
86
0
0
0
0
0
0
0
0
15
37
10
10
0
5
5b
6c
7d
8d
9
24
24
2
2
5
FeCl3Á6H2O
10
Fe(NO3)3Á9H2O 24
11
12
13
14
15
16
17e
18
19
Fe(acac)3
CoCl2
CuCl
4
4
1
0
15
0
CuCl2
MoCl3
RuCl3
PdCl2
RhCl3
AgCl
1
0
24
24
24
24
24
15
11
4
0
0
5
14
7
a
The reactions were conducted under an air atmosphere. A 1 M hexane solution
The optimized conditions for the reaction of 2b with 1a were
also applicable to radical conjugate addition involving substituted
of Me2Zn was used. The isolated yields are presented.
b
Without BF3ÁOEt2.
c
Without Me2Zn.
d
Air, passed through a NaOH tube, was introduced into the reaction mixture
through a bubbler at a rate of 0.5 L/(h mol).
e
O
Epoxide of 1a was obtained in 42% yield.
O
Me2Zn
OMe
O
OMe
O
Ph
MeO
Ph
MeO
ZnMe
benzylidenemalonates 1. The reactions of 1 having a chloro or
methyl substituent gave adducts in 43% and 40% yield, respectively
(Scheme 4). The optimized conditions, however, were not advanta-
geous for the reaction of THF (2a), giving 3a and 5 in slightly lower
yields (36% and 29% yield, respectively) than those in Table 2, entry
7 (45% and 35% yield, respectively).
Mtl
O
O
Mtl–X + Me2Zn
Mtl–Me
b
a
Mtl•
Me•
1a
The above-mentioned conditions were applicable to the direct
O
O
O
generation and conjugate addition of an a-aminoalkyl radical from
pyrrolidine 2c.20,21 The reaction of 2c with 1a gave the desired
product 3e in 84% yield after 8 h (Scheme 5).
CO2Me
CO2Me
MeH
H
Ph
A
The reaction of N-tosyl imine 8 was also accelerated by the
addition of the iron salt (Scheme 6). Although the reaction with 8
Scheme 1. Expected catalytic cycle of transition metal salts.

6042
K. Yamada et al. / Tetrahedron Letters 50 (2009) 6040–6043
Table 3
Reaction with 4,4,5,5-tetramethyldioxolane (2b)a
Me2Zn 3 equiv, air
BF3•OEt2 1 equiv
FeCl3 10 mol %
TBHP 2 equiv
O
O
CO2Me
Me2Zn 3 equiv, air
BF3•OEt2 1 equiv
FeCl3 10 mol%
TBHP
Me
O
2b
12.5 equiv
CO2Me
Ar
+
Ar
CO2Me
CO2Me
DMSO
rt, 10–12 h
CO2Me
O
O
Ph
CO2Me
1
3
1a +
+ 5 +
CO2Me
CO Me
3b
O
7
3b Ar = Ph
3c
3d
63%
43%
40%
O
O
Ph
rt
4-ClC6H4
4-MeC6H4
2b
12.5 equiv
2
Scheme 4. Production of 3.
Entry
TBHP (equiv)
Time (h)
3b (%)
5 (%)
7 (%)
1
2
3
4
0
1
2
3
0.5
3
0.5
3
31
32
43
26
27
23
31
15
24
0
0
Me2Zn 6 equiv, air
BF3•OEt2 1 equiv
FeCl3 10 mol %
TBHP 2 equiv
0
N
PMP
a
Hexane solutions of Me2Zn (1 M) and TBHP (4 M) were used. Air, passed
through a NaOH tube, was introduced into the reaction mixture through a bubbler
at a rate of 0.5 L/(h mol). The isolated yields are presented.
CO2Me
CO2Me
+
1a
N
Ph
PMP
DMSO
rt, 8 h
84%
3e
2c
12.5 eq
PMP = 4-methoxyphenyl
O
O
Scheme 5. Reaction of benzylidenemalonate 1a with pyrrolidine 2c.
Me
O
O
Me•
CO2Me
CO2Me
CO2Me
1a
Ph
O
Ph
CO2Me
C
B
Fe(II) and/or Me2Zn
Me2Zn 6 equiv, air
BF3•OEt2 1 equiv
FeCl3 10 mol %
O
O
O
7
5
3b
Ts
Ts
+
+
2b
Ph
N
Ph
N
H
Scheme 2. Possible mechanism for the formation of 7.
rt, 4 h
53%
12.5 equiv
8
8
9b
9c
Me2Zn 12 equiv, air
BF3•OEt2 1 equiv
FeCl3 10 mol %
Me2Zn
Me•
N
PMP
Ts
O
O
O
O
slow
fast
OMe
O
2c
1a
B
rt, 48 h
60%
12.5 equiv
Ph
N
H
Ph
ZnMe
MeZnOOt-Bu •OOt-Bu
MeO
O
Scheme 6. Reactions with N-tosyl imine 8.
Scheme 3. Expected fast reaction of B and zinc peroxide to give zinc enolate.
failed to give the desired product 9b in DMSO with TBHP, 9b was
obtained in 53% yield after 4 h when a toluene solution of dimeth-
ylzinc was used without DMSO and TBHP. When a hexane solution
of dimethylzinc was used, a significant amount of hexyl adducts
(10%, a regioisomeric and diastereomeric mixture) was isolated
as well as 9b (31%). The reaction of 2c and N-tosyl imine 8 also
gave the desired product 9c in 60% yield.
In summary, the addition of iron salt and TBHP as well as the
use of DMSO as a co-solvent is beneficial in dimethylzinc-mediated
radical conjugate addition reaction of dioxolane 2b reducing the
amount of required 2b from 250 to 12.5 equiv, while still giving
the desired adduct in 63% yield. This condition was applicable to
conjugate addition of the cyclic amine to give the addition product
in 84% yield. Furthermore, reactions with the N-tosyl imine were
similarly improved by the addition of iron salt.
Table 4
Co-solvent effecta
Me2Zn 3 equiv, air
BF3•OEt2 1 equiv
FeCl3 10 mol%
TBHP 2 equiv
Acknowledgments
3b + 5
1a + 2b
solvent
rt
This research was partially supported by the 21st Century Cen-
ter of Excellence Program ‘Knowledge Information Infrastructure
for Genome Science’, a Grant-in-Aid for Young Scientist (B), and a
Grant-in-Aid for Scientific Research (A) from JSPS; a Grant-in-Aid
for Scientific Research on Priority Areas ‘Advanced Molecular
Transformations’ from MEXT; and Targeted Proteins Research Pro-
gram from JST. M.M. and T.A. thank JSPS for a fellowship.
Entry
Solvent
Time (h)
3b (%)
5 (%)
1
2
CH2Cl2
Toluene
MeCN
DMF
7
8
12
24
12
39
29
14
10
63
40
30
11
10
12
3b
4c
5
DMSO
a
A hexane solution of TBHP (4 M) was used. Air, passed through a NaOH tube,
Supplementary data
was introduced into the reaction mixture through a bubbler at a rate of 0.5 L/
(h mol). The isolated yields are presented.
b
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.08.034.
5% of 1a was recovered.
c
15% of 1a was recovered.

K. Yamada et al. / Tetrahedron Letters 50 (2009) 6040–6043
6043
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*
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