Radical additions to allyl bromides. A synthetically useful, 'Tin-Free' method for carbon-carbon bond formation

Article abstract of DOI:10.1016/j.tetlet.2009.02.154

The scope and limitations of a novel free radical chain process involving the addition of benzyl radicals to substituted allyl bromides were examined and extended to explore the effect of α-substitution on the allyl bromide (R′), and the use of pyrrolidine amides and oxazolidinone as activating substituents (Z) as the first steps toward the development of a stereoselective, radical-based C-C bond-forming reaction which is environmentally benign.

Full text of DOI:10.1016/j.tetlet.2009.02.154

Tetrahedron Letters 50 (2009) 2119–2120
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Radical additions to allyl bromides. A synthetically useful, ‘Tin-Free’ method
for carbon–carbon bond formation
b
c
John A. Struss a, , Mitra Sadeghipour , James M. Tanko
*
a Department of Chemistry and Physics, The University of Tampa, 401 W. Kennedy Blvd., Tampa, FL 33606-1490, United States
b Department of Chemistry, Frostburg State University, 101 Braddok Road, Frostburg, MD 21532, United States
c Department of Chemistry, Virginia Tech, 107 Davidson Hall, Blacksburg, VA 24061-0001, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The scope and limitations of a novel free radical chain process involving the addition of benzyl radicals to
Received 10 December 2008
Revised 11 February 2009
Accepted 19 February 2009
Available online 25 February 2009
substituted allyl bromides were examined and extended to explore the effect of
a-substitution on the
allyl bromide (R0), and the use of pyrrolidine amides and oxazolidinone as activating substituents (Z)
as the first steps toward the development of a stereoselective, radical-based C–C bond-forming reaction
which is environmentally benign.
Ó 2009 Elsevier Ltd. All rights reserved.
Benzyl and cumylradicals readily add to various b-substitutedal-
lyl bromides 1 using peroxide initiators at elevated temperatures.1
This reaction is unique because it does not rely on the use of toxic
metalsforfree radicalgeneration.2 Thereactionmechanisminvolves
hydrogen abstraction by BrÅ producing a benzylic radical (RÅ), which
subsequently adds to the allyl bromide. b-Elimination of BrÅ com-
pletes the chain radical (Scheme 1). Earlier work focused on addi-
tions to relatively simple allyl bromides, Z = H, Ph, CO2Et, and CN.
We now expand on this theme to include methyl ester, pyrrolidine
amide, and oxazolidine functional groups. Also, to explore the viabil-
ity of developing this reaction into a stereoselective process, we
studied additions of prochiral radicals (using ethyl benzene as our
amide (Eq. 1). The yields for these reactions using toluene were
57% for the methyl ester (13 h) and 69% for the pyrrolidine amide
(12 h). The use of ethyl benzene in an analogous reaction resulted
in a complex mixture of products including some with rearranged
carbon-carbon double bonds (Eq. 2).
Z
Z
Br
DTBPO
ð1Þ
PhCH3, Δ
CH3
CH3
Kinetic chain lengths were determined by comparing the rate of
product formation with respect to the rate of initiator disappear-
ance.4 These experiments were carried out in the presence of
1,2-epoxybutane as an HBr scavenger. The chain length data are
summarized in Table 2.
radical precursor) and a-methyl-substituted allyl bromides.
The mode of initiation of these reactions involves H-abstraction
by the initiating radical (InÅ) from the starting alkylaromatic. Di-t-
butylperoxide (DTBPO) has proven to be an especially effective ini-
CO2Me
t
tiator because BuOÅ does not add readily to double bonds.
DTBPO
Br
The results of this study are summarized in Table 1. Overall,
yields were typically 50% or greater lending credence to the syn-
thetic usefulness of this reaction. With allyl bromide (Z = H, entry
a), the absence of an activating substituent leads to low yields
and low reaction rates (only 33% yield after 94 h). However, when
Z is a strong electron-withdrawing group (e.g., Z = CN, CO2R), the
reaction gave good yields over a short reaction time with both
cumyl and benzyl radicals (entries j and k). Because of their affinity
toward electrophilic substrates, alkyl radicals have been described
as being nucleophilic.3
PhCH2CH3, Δ
CH3
CH3 CO2Me
CH3 CO2Me
+
ð2Þ
+
Ph
CH3
CH3
Ph
CH3
CH3 CH3
CO2Me
Ph
CH3
Relative rates of addition of PhCHÅ2 to the various allyl bromides
were determined by competition experiments. The results of these
studies are summarized in Table 3. These data are similar to those
described by Giese, attributable to a b-effect, and demonstrate that
the overall rate increases with the electron-withdrawing ability of
This reaction was expanded to include a-methyl-substituted al-
lyl bromides where Z was either a methyl ester or a pyrrolidine
* Corresponding author. Tel.: +1 813 253 3333; fax: +1 813 258 7881.
E-mail addresses: jstruss@ut.edu (J.A. Struss), jtanko@vt.edu (J.M. Tanko).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.154

2120
J. A. Struss et al. / Tetrahedron Letters 50 (2009) 2119–2120
Table 2
R
+
Z
H-Br
Br
(step 1)
R-H
R
+ Br
Initial chain length data for benzyl radical additions to various allyl bromides
R
+
(step 2)
+
1
R1
Z
R1 R2
R3
R2
3
Z
R'
(t-BuO)2
120 ºC,
Br
(step 3)
(overall)
3
2
Br
+
H
R3
O
R-H
+
1
2 + H-Br
–Z
Initial chain length (relative chain length)
Scheme 1. Mechanism of radical-based allyl transfer reaction.
R
1 = R2 = H
R1 = R2 = H,
R1 = CH3
R1 = R2 = CH3
R3 = H
R3 = H
R
3 = CH3
R2 = R3 = H
H
Ph
10 (1)
–
–
–
–
–
–
100
–
–
400 (40)
800 (80)
400 (40)
700 (70)
50 (5)
60
60
–
400
–
Table 1
CO2Et
CO2Me
CN
COPyr
Ox
Additions of benzyl radicals to substituted allyl bromides
50 (5)
–
3.0 (0.3)
–
Z
R1 R2
R1
R2
H
Z
(t-BuO)2
120 ºC,
1.1 eq. K2CO3
60
20
Br
+
20 (2)
–
A
B
Entry
R1
R2
Z
A (mmol)a
B (mmol)
Time (h)
Yield (%)
Table 3
Relative reactivities of various allyl bromides toward PhCH2Å
ab
b
c
H
H
H
CH3
CH3
H
CH3
H
H
H
CH3
H
H
H
H
H
H
H
Ph
Ph
Ph
47
0.69
0.72
0.72
0.72
0.72
0.77
0.77
3.0
94
93
93
93
93
40
94
3
3
2
2
4
33
82
24
100
66
47
48
63
57
66
80
72
66
53
59
47
krel (80 °C)
krel (120 °C)
Z
2.8d
36
Br
d
CH3
CH3
H
CH3
H
CH3
H
CH3
H
, -Z =
ec
f
Ph
1.4d
47
H
Ph
0.01
0.59
–
1
1.6
–
–
–
0.95
1
–
CO2Et
CO2Et
CO2Me
CO2Me
CN
g
h
i
36
CO2Me
CO2Et
CN
COPyr
Ox
190
160
38
3.0
jb,c
kb
l
0.77
0.77
3.0
3.0
2.2
0.02
0.01
CN
29
–
COPyr
COPyr
Ox
190
160
140
120
m
n
o
CH3
H
CH3
5
8
10
Acknowledgment
H
Ox
2.2
a
All reactions were performed in neat toluene, ethyl benzene, or cumene using
Financial support from the National Science Foundation (CHE-
0548129) is acknowledged and appreciated.
20 mol % di-tert-butylperoxide as the initiator unless otherwise noted.
b
1.1 equiv of 1,2-epoxybutane used as an HBr scavenger.
20 mol % benzoyl peroxide used as an initiator at 80 °C.
In 5 mL benzene.
c
d
Supplementary data
General and detailed experimental procedures. Supplementary
data associated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2009.02.154.
the Z substituent. Steric effects are evident by the diminished reac-
tivity of
by the lower chain lengths observed for these allyl bromides (Table
a
-methyl-substituted allyl bromides toward PhCHÅ2, and
References and notes
2). A similar phenomenon regarding the steric
a-effect has been
previously reported.3c,5
1. Tanko, J. M.; Sadeghipour, M. Angew. Chem., Int. Ed. 1999, 38, 159.
2. (a) Chuang, C. P.; Hart, D. J. J. Org. Chem. 1983, 48, 1782; (b) Danishefsky, S.;
Chackalamannil, S.; Uang, B. J. J. Org. Chem. 1982, 47, 2231; (c) Ladlow, M.;
Pattenden, G. Tetrahedron Lett. 1984, 25, 4317; (d) Burke, S. D.; Fovare, W. B.;
Arminsteadt, D. M. J. Org. Chem. 1982, 47, 3348; (e) Geise, B.; Kretzschmar, G.
Angew. Chem., Int. Ed. Engl. 1981, 20, 965; (f) Huval, C. C.; Singleton, D. A.
Tetrahedron Lett. 1993, 34, 3041.
To summarize, this reaction is limited to substrates which have
activating b-substituents (Z) and an unhindered -carbon. Good
yields are obtainable with -methyl substrates at longer reaction
a
a
times even though the chain-lengths for these compounds are
shorter. However, only benzyl radical (PhCHÅ2) adds without pro-
ducing complex product mixtures, in contrast to additions of the
1-phenylethyl radical (Eq. 2). Presumably, cumyl radical would be-
have similarly. Pyrrolidine amides and oxazolidinone substituents
are suitable activating substituents, and provide the foundation for
developing new stereoselective carbon–carbon bond-forming reac-
tions via the use of chiral Lewis acids.6 Finally, the fact that this
method does not require toxic metals such as mercury or tin for
radical generation makes this reaction especially appealing from
green chemistry standpoint.
3. (a) Geise, B.; Kretzschmar, G. Chem. Ber. 1983, 116, 3267; (b) Geise, B.; Meisner, J.
Chem. Ber. 1981, 114, 2138; (c) Geise, B. Angew. Chem., Int. Ed. Engl. 1983, 22, 753.
t
4. The amount of BuOÅ produced was calculated based on the rate constant
k = 1.72 ꢀ 10ꢁ6 sꢁ1 at 120 °C.
5. (a) Geise, B.; Meisner, J. Angew. Chem., Int. Ed. Engl. 1977, 10, 178; (b) Geise, B.;
Lachhein, S. Angew. Chem., Int. Ed. Engl. 1981, 20, 967.
6. For examples of chiral auxiliary controlled radical additions, see: Curran, D. P.;
Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions, 1st ed.; VCH: New
York, NY, 1996. Chapter 5, p 178.