Generation of Halomethyl Radicals by Halogen Atom Abstraction and Their Addition Reactions with Alkenes

Article abstract of DOI:10.1021/jacs.9b05921

α-Aminoradicals undergo halogen atom abstraction to form halomethyl radicals in reactions initiated by the combination of tert-butyl hydroperoxide, aliphatic trialkylamine, halocarbon, and copper(I) iodide. The formation of the α-aminoradical circumvents preferential hydrogen atom transfer in favor of halogen atom transfer, thereby releasing the halomethyl radical for addition to alkenes. The resulting radical addition products add the tert-butylperoxy group to form α-peroxy-β,β-dichloropropylbenzene products that are convertible to their corresponding β,β-dichloro-alcohols and to novel pyridine derivatives. Computational analysis clearly explains the deviation from traditional HAT of chloroform and also establishes formal oxidative addition/reductive elimination as the lowest energy pathway.

Full text of DOI:10.1021/jacs.9b05921

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Article
Generation of Halomethyl Radicals by Halogen Atom
Abstraction and Their Addition Reactions with Alkenes
Robynn K. Neff, Yong-liang Su, siqi liu, Melina Rosado, Xinhao Zhang, and Michael P Doyle
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b05921 • Publication Date (Web): 01 Oct 2019
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Generation of Halomethyl Radicals by Halogen Atom Abstraction and
Their Addition Reactions with Alkenes
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Robynne K. Neff,‡,a Yong-Liang Su,‡,a Siqi Liu,b Melina Rosado,a Xinhao Zhang,*,c Michael P. Doyle*,a
a. Department of Chemistry, The University of Texas at San Antonio, San Antonio, Texas 78249, United States
b. College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
c. Lab of Computational Chemistry and Drug Design, State Key Laboratory of Chemical Oncogenomics, Peking
University Shenzhen Graduate School, Shenzhen 518055, China
ABSTRACT: -Aminoradicals undergo halogen atom abstraction to form halomethyl radicals in reactions initiated by the
combination of tert-butyl hydroperoxide, aliphatic trialkylamine, halocarbon, and copper(I) iodide. The formation of the -
aminoradical circumvents preferential hydrogen atom transfer in favor of halogen atom transfer, thereby releasing the
halomethyl radical for addition to alkenes. The resulting radical addition products add the tert-butylperoxy group to form -
peroxy-,-dichloropropylbenzene products that are convertible to their corresponding ,-dichloro-alcohols and to novel
pyridine derivatives. Computational analysis clearly explains the deviation from traditional HAT of chloroform and also
establishes formal oxidative addition/reductive elimination as the lowest energy pathway.
INTRODUCTION
addition of CHCl2 and the tert-butylperoxy radical to
styrenes, resulting in α-peroxy-β, β-dichloropropylbenzene
products in moderate to high yields (Figure 1c), and their
conversion to the corresponding ,-dichloro-alcohols and
novel pyridine derivatives. Experimental data along with
DFT calculations demonstrate the essential role of the α-
aminoradical that changes the preference of atom
extraction from CHCl3. A excellent correlation is found to be
valuable for selecting appropriate radical and a general
mechanism are also proposed.
Radical addition reactions of alkenes with dissociable
molecular species (X-Y) provide convenient access to
vicinal disubstituted products with increased molecular
and functional complexity (Figure 1a). The initiation of
these reactions effects atom transfer that forms radical Y
which adds to the carbon-carbon double bond to form a
carbon radical that abstracts X from X-Y to enter the
catalytic cycle. In one of the most notable examples of these
reactions, Kharasch reported in 1945 the acetyl peroxide-
induced Markovnikov addition of Cl and CCl3 from CCl4 to
alkenes.1 The Kharasch reaction has been extensively
investigated,2,3 and numerous examples of atom-transfer
radical addition using transition metal catalysts to initiate
CCl3 radical generation have been reported.4-7 However,
when this process was applied with chloroform (Figure 1b),
the initiation step generated the CCl3 radical by H atom
transfer (HAT), rather than form the dichloromethyl radical
by chlorine atom transfer.1 In fact, the dichloromethyl
radical can be generated by a HAT from CH2Cl2,8 albeit
indirectly via an aryl radical formed from a boronic acid or
an aryldiazonium salt, and a catalytic methodology has been
reported to utilize the chloroform analog CHCl2Br in the
presence of stoichiometric amounts of tri- and tetra-tertiary
amines as an alternative.9 Transition metal compounds,
especially those of low valent platinum,10 are well known to
undergo oxidative addition with halocarbon solvents, but
there has not been a report of a catalytic process through
which the dichloromethyl radical has been generated from
chloroform. We wish to report an effective indirect
methodology for preferential chlorine atom abstraction
from chloroform and its application to the regioselective
General addition of X-Y to olefins:
X
X
Y
Y
a)
X
Y
Kharasch 1945:
Cl
H
CCl4
CCl3
CCl3
via:
R
R
Cl atom abstraction
O
O
O
b)
R
O
Me
or
O
Me
O
H atom abstraction
O
O
2 mol %
CHCl3
This work:
OOtBu
CHCl2
tBuOO CuIII
I
CuI (1 mol %)
-CuI
c)
CHCl2
Ar
Ar
TBHP, DIPEA,
CHCl3/Acetone, rt
Ar
Cl atom abstraction
18 examples
52-97% yields
Figure 1. (a) General approach to functionalize olefins by
dissociable molecular species. (b) Kharasch’s first examples of
halogen atom abstraction from carbon tetrachloride and HAT
from chloroform. (c) Selective chlorine atom abstraction from
chloroform to form α-peroxy-β,β-dichloropropylbenzenes.
RESULTS AND DISCUSSION
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We envisioned that generation of the dichloromethyl
N
radical from chloroform would be a function of the relative
energies for C-Cl versus C-H homolytic bond cleavage from
various radical initiators. Those atom transfer agents that
5
5.6
14.7
12.8 1.9
t
have been reported (tBuOO, BuO, OH, and Ar) favor C-H
bond cleavage,8a,11 but this list is limited.12 As shown in
Scheme 1, we expected that reversing radical polarity
would lead to free radical species that could favor C-Cl bond
cleavage and thereby provide a viable pathway for the
generation of halogenated carbon radicals.
6
7
8
7
14.6
13.3
17.2
13.6 1.0
15.8 -2.5
21.9 -4.7
O
7.1
8.3
O
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A search for appropriate radicals were initiated with
examining adiabatic ionization potentials (IPs) of carbon
radicals.13 The calculated IPs and differences in free energy
barriers of hydrogen atom transfer (HAT) vs. chlorine atom
transfer (CAT) (GH ≠ – GCl ≠ ) are listed in Table 1 and
plotted in Figure 2.
9
8.1
5.4
10.7 -5.3
On this basis we searched for those reactants that
preferentially form an intermediate radical capable of
undergoing chlorine atom abstraction from chloroform to
produce the CHCl2 radical.15 Tertiary amines were surveyed,
but with the caveat that generation of α-amino radicals is
subject to the oxidation potential of the amine. Specifically,
electron transfer (ET) is the initial step in the catalytic
oxidation of N,N-dialkylanilines to their corresponding
iminium ions by tert-butyl hydroperoxide (TBHP),16
whereas hydrogen atom transfer (HAT) occurs
preferentially as the initial step in the similar oxidation of
tetrahydroquinolines.17
Scheme 1. Different polar effects of atom transfer
reaction.



CCl3
+
R Cl CCl3
H
R
CHCl3
+
R


R

Cl
+ CHCl2
H
R
CHCl2
Indeed, the IPs indicate the potential of releasing an
electron and a good correlation between IP and the
preference of HAT vs. CAT was found. Results in Table 1 and
Figure 2 suggested that α-amino radicals would favor C-Cl
homolytic cleavage to generate the dichloromethyl
radical.14 More specifically, α-amino radicals were indicated
to have the highest potential to undergo chlorine atom
abstraction with energy differences greater than those of α-
alkoxy carbon radicals (Table 1, entries 1-6). Alkyl, α-
carbonyl, and phenyl radicals, in contrast, have a higher
preference for C-H bond homolytic cleavage (Table 1,
entries 7-9).
Table 1. Calculated Gibbs free energy barrier
≠
≠
≠
(ΔGX )/energy differences (ΔGH -ΔGCl
) of various
radicals
GX
GH
+ H-CX
CHX
2
R
+ CX
+ X-CHX
R
+
R-X
R-H
3
3
2
Figure 2. A correlation between IPs and the difference in free
energy barrier of HAT vs. CAT.
(kcal/mol) for free energy barriers of hydrogen atom transfer
(kcal/mol) for free energy barriers of halogen atom transfer
GH
GX
Because of their demonstrated suitability for free radical
addition reactions, styrenes were selected as the target
substrates.18 Reactions were performed in various solvents
containing excess chloroform, amines capable of HAT, and
selected catalysts known to form the tert-butylperoxy
radical. Table 2 provides an abbreviated selection of various
screening parameters (see Supporting Information for full
screening parameters). As expected, trialkylamine bases
performed well under the reaction conditions in the
presence of Rh2(cap)4 (Table 2, entries 1-3). When 3
benzylamines and anilines were used, no conversion of the
styrene reactant to product was observed (Table 2, entries
4-5). Rh2(OAc)4 was ineffective at room temperature or 65
°C, and silver based catalysts showed moderate product
formation (Table 2, entries 7-8). However, use of CuI gave
nearly quantitative formation of the desired product (Table
ΔGCl
≠
≠
Entry
Radical
IP
ΔGH
ΔGH≠-ΔGCl
≠
N
1
2
4.7
17.4
12.9
9.2
8.2
N
4.9
6.7
6.2
N
3
4
5.3
5.1
24.2
12.9
17.9 6.3
7.8 5.1
Ph
N
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15c
16c
17c
18c
DIPEA
DIPEA
DIPEA
-
CuBr
82%
82%
0%
2, entry 9). No significant drop in yield was observed at
ambient temperature, although the low solubility of CuI in
organic solvents led to inconsistent initiation/yields. To
overcome this problem acetone was used as a co-solvent,
and this change provided high reproducibility to these
reactions (Table 2, entry 10). Furthermore screening of the
amine and the copper catalyst showed that the DIPEA and
CuI provide the best result (Table 2, entries 11-16). No
product could be detected without both 3 aliphatic amine
and CuI (Table 2, entries 17-18 and SI).18
Cu(ACN)4PF6
-
CuI
0%
aReaction conditions: unless indicated otherwise, the
reaction of 1a (1.0 mmol), catalyst (1 mol%), TBHP (5.0 eq.),
amine (5.0 eq.) was carried out in CHCl3 (5.0 mL) at 65 °C.
bIsolated yield. cCHCl3:acetone were used in a 1:1 ratio as co-
solvents (5.0 mL) at rt.
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The optimum catalyst, amine, and reaction conditions
were applied to substituted styrenes, and the results
obtained showed generality for this transformation
(Scheme 1). Styrenes with both electron-rich and electron-
deficient substituents at the para-, meta-, and ortho-
positions of the phenyl moiety furnished product in
Scheme 2. Substrate scope of alkenes for
dichloromethyl radical additiona
tBuOO
Cl
R1
CuI (1 mol %)
R
R
Cl
TBHP (5.0 eq.), DIPEA (5.0 eq.)
CHCl3 : Acetone (1:1, 0.2M), rt
R1
1
2
moderate to high yields (2a
- 2k). Furthermore,
2a,
R = CH3, 95%
R = Ph, 94%
R = Cl, 84%
R = Br, 87%
R = OMe, 81%
R = F, 81%
tBuOO
Cl
2b,
2c,
2d,
2e,
2f,
tBuOO
Cl
Cl
substitution at the α-position of styrene also gave product
with good yields (2l - 2m), and 1-vinylnaphthalene and 2-
vinylnaphthalene were also compatible with this catalytic
process (2n - 2o). In reactions with vicinal disubstituted
alkenes, however, an additional 3.0 eq. of TBHP were
necessary to obtain higher yields (2p - 2q). Cumyl peroxide
was also compatible under the reaction conditions (2r).
However, di-tert-butylperoxide (DTBP) and benzoyl
peroxide were unreactive.
2i,
R = 3-Cl, 97%
2j, R = 2-CH3, 92%
2k,
Cl
R
Cl
R = 2,4,6-CH3, 61%
R
2g,
2h,
R = CF3, 65%
R = H, 86%
tBuOO
tBuOO
Cl
tBuOO
Ph
Cl
tBuOO
Cl
Cl
Cl
H3C
Ph
Cl
Cl
79%
tBuOO
Ph
2l,
2n,
2o,
89%
52%
73%
Cl
2m,
Me
Me
Ph
tBuOO
Cl
Cl
Cl
O
O
Cl
Other perhalogenated compounds that could undergo
hydrogen atom abstraction were also found to be selective
for halogen atom abstraction (Table 3, except entry 1, 5 and
6). Several methodologies undergo similar addition of alkyl
halides but often times are limited to substrates wherein α-
halogens are excluded.19 Under our standard reaction
conditions where mixed
Cl
Me
Me
b
b
2p,
2q,
95%
65%
c
2r,
83%
1.8:1 d.r.
3:1 d.r.
aReaction conditions: unless indicated otherwise, reactions of
1 (1.0 mmol), CuI (1 mol%), TBHP (5.0 eq.), DIPEA (5.0 eq.)
were carried out in CHCl3/acetone (1:1, 5.0 mL) at rt. bAfter 30
minutes, an additional 3.0 eq. of TBHP were added. cCumyl
hydroperoxide was used as an alternative to TBHP, and an
additional 3.0 eq. of cumyl hydroperoxide were added after 30
minutes.
Table 2. Optimization of reaction conditions for
dichloromethyl radical additiona
tBuOO
Cl
Cat. (1 mol%)
Cl
halogenated compounds were used, selectivity for I > Br >
Cl > F removal was observed (Table 3, entries 1-3) in
moderate to high yields. Carbonyl substrates containing α-
halogenated esters also underwent addition in good yields
(Table 3, entries 4-5). Finally, while reactivity remained
high for chloroform derivatives and bromoform (Table 3,
entry 7) and for chlorine atom transfer from
tetrachloromethane (Table 3, entry 6), iodoform (Table 3,
entry 8) consistently led to lower conversions, possibly due
to subsequent reactions.
Me
TBHP (5.0 eq.), Amine (5.0 eq.)
CHCl3, Temp.
Me
1a
2a
Entry
1
Amine
NEt3
Catalyst
Yieldb
71%
71%
87%
0%
Rh2(cap)4
2
NCy2Me
DIPEA
N(Bn)3
PhNMe2
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
NEt3
Rh2(cap)4
Rh2(cap)4
Rh2(cap)4
Rh2(cap)4
Rh2OAc4
AgOTf
AgOAc
CuI
3
4
5
0%
6
0%
Table 3. Substrate scope of alkyl halide for addition to
aryl alkenesa
7
55%
61%
97%
95%
62%
67%
36%
74%
8
Alkyl
Entry
1
Product
Yieldb
81%
9
Halide
10c
11c
12c
13c
14c
CuI
tBuOO
Br
Br
F
Br
Br
CuI
Br
F
3a
Me
NCy2Me
N(Hex)3
DIPEA
CuI
CuI
CuOAc
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tBuOO
Cl
OH Cl
tBuOO
tBuOO
R
Zn dust (5.0 eq.)
HOAc, rt
R
Cl
Cl
I
CF3
2
3
4
5
6
7
8
CF3
83%
53%
69%
71%
91%
73%
43%
2
4
3b
Me
Me OH Cl
OH Cl
OH Cl
Cl
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
2a
Me
Me
a
4a
4b
4c
, 96%
, 91%
, 85%
tBuOO
9
O
O
OH Cl
OH Cl
OH Cl
Br
CO2Et
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OEt
Cl
Cl
, 86%
MeO
3c
F3C
MeO
Cl
tBuOO
b
b,c
4e
4f
, 70%
4d
, 79%
F
F
F
F
CO2Et
Br
Cl
aAfter 48 hours an additional 3.0 eq. of Zn dust was added.
bAfter 48 hours, an additional 5.0 eq. of Zn dust was added.
cProduct yield includes 10% acetate ester.
3d
OEt
Me
Me
Me
Me
tBuOO
Cl
Cl
Cl
Cl
Cl
Cl
A further example of the utility of the dichloromethyl
addition process is evident in the conversion of the addition
products to substituted pyridine derivatives, a recent
example of which is a palladium-catalyzed condensation of
acetonitrile with homopropargylic alcohols.23 We were
delighted to observe that formation of substituted pyridines
occurred in moderate yields in the presence of KOtBu in
acetonitrile (Scheme 4). A similar process, known as the
Thorpe-Ziegler reaction, is used in the self-condensation
reactions of aliphatic nitriles that results the synthesis of
enamines that provides ketone products after acid
hydrolysis.24 The X-ray structure of 5b was obtained for full
characterization. A full study of this reaction and its
implications is ongoing.
3e
tBuOO
tBuOO
Br
Br
Br
H
Br
Br
I
3f
I
I
I
I
H
3g
aReaction conditions: unless indicated otherwise, the
reaction of 1 (1.0 mmol), R-X (5.0 eq.), CuI (1 mol%),
TBHP (5.0 eq.), DIPEA (5.0 eq.) was carried out in acetone
(5.0 mL) at rt. bIsolated Yields.
Moreover, the dichloromethyl addition reaction could be
carried out on a gram scale with high product yield using
only 0.025 mol% of CuI (eq 1). Considering that the reaction
does not give 2a without the CuI catalyst (Table 2, entry 17),
we conclude that CuI is very efficient but also essential.
Furthermore, without the 3o aliphatic amine the reaction
takes an entirely different course.
Scheme 4. Transformation of peroxide products into
substituted pyridines.
CN
tBuOO
Cl
KOtBu (4.0 eq.)
MeCN, rt
R
R
Cl
N
Me
5
2
tBuOO
Cl
CN
Me
CN
Me
Me
CuI (0.025 mol%)
(1)
Cl
TBHP (5.0 eq.), DIPEA (5.0 eq.)
CHCl3:Acetone (1:1, 0.2 M), rt, 4h
N
Me
N
Me
1a:
10 mmol
2a:
2.56 g, 88% yield
Me
5b
X-ray of
5a
5b
5d
, 61%
, 69%
The synthetic utility of the peroxide products was studied
next.20 Different from “Russell mechanism” where the
alcohol is a derived in a 1:1 mixture with their
corresponding carbonyl products,21 the peroxide products
can be easily converted to their alcohol counterparts by a
rarely applied reduction that occurs in acetic acid with zinc
dust (Scheme 3).22 In all cases, once starting material was
consumed a simple basic aqueous work up led to the
desired product with no need for additional purification.
For the p-methoxyphenyl substrate, the main product was
the alcohol 4d, but 10% of acylated 4d´ was also isolated.
CN
Me
CN
Me
CN
Me
N
N
N
MeO
F
F3C
5c
5e
, 57%
, 54%
, 55%
The radical nature of the transformation is suggested by
the reaction conditions that have been employed, but
additional experimentation confirms this inference
(Scheme 5). Reaction of 1a under standard reaction
conditions along with TEMPO as an additive provided no
conversion of the starting material (Scheme 5, eq 1).
Additionally, using vinylcyclopropane 6 as the substrate to
ascertain the fate of the initially-formed reaction
intermediate and its lifetime, several products were formed
in addition to 7a: ketone 7b and ring opening products 7c
and 7c´(Scheme 5, eq 2). Major product 7a is consistent
with the overall addition process from which products 7c
and 7c´ are formed and whose yields suggest the relative
Scheme 3. Transformation of peroxide products to
benzyl alcohols
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rates for capture by the tert-butylperoxy radical versus ring
stoichiometric uses of tertiary amine bases (Scheme 8, eq
1)9. The requirement for amines may also indicate that the
amine plays an important role in the generation of the
dichloromethyl radical rather than being only a ligand or
base. Under our conditions with CuI, TBHP, and DIPEA,
reaction with TMS-azide produces the same azide addition
product as was reported by Wang and coworkers [in
competition with formation of 2a (Scheme 8, eq 2)]; and
increasing the stoichiometric amount of TMSN3 also
increases the yield of the azide 13 relative to 2a (see
Supporting Information); this outcome suggests that the
indirect methodology makes possible a broad spectrum of
radical oxidative addition processes.
opening/hydrogen atom transfer.25 The formation of
cleavage product 7b is due to the initial addition of the tert-
butylperoxy radical to 6, and its formation in reactions with
O2 or H2O2 as the oxidant has been reported.26
Scheme 5. Mechanistic experiments to probe the radical
pathway.
CuI (1 mol%)
TEMPO (1.2 eq.)
No Reaction
10
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(1)
TBHP (5.0 eq.), DIPEA (5.0 eq.)
Me
CHCl3:Acetone (1:1, 0.2 M), rt
1a
CHCl2
OOtBu
O
Scheme 7. 1H NMR spectral observation of iminium ion
11 and acetaldehyde 12 in the standard reaction.
+
CuI (1 mol%)
7a
, 42%
7b
, 15%
(2)
CHCl2
CHCl2
TBHP (5.0 eq.), DIPEA (5.0 eq.)
CHCl3/Acetone = 1:1 (0.2 M), rt
6
tBuOO
Cl
Cl
N
Me
CuI (1 mol %)
+
Cl
N
Me
+
+
TBHP in decane (1.0 eq.)
CDCl3
Me
7c+7c'
, 9%
Me
1a
10
2a
11
From a mechanistic standpoint, the most likely initiation
of this reaction is by TBHP and CuI to form the tert-
butylperoxy radical by hydrogen atom transfer from TBHP
to the initially formed tert-butoxy radical27 (Scheme 6). This
process has been extensively studied.28 The CuII species
produced by this oxidative reaction, (HO)CuI, is proposed to
be in equilibrium with ICu-OOtBu (8).29 A HAT of the tert-
butylperoxy radical with the trialkylamine generates the -
aminoradical (9) that is the key intermediate which
preferentially undergoes chlorine atom abstraction from
chloroform. The CHCl2 radical generated from chloroform
adds regioselectively to the terminal carbon of styrene to
generate the benzyl radical.
H2O
O
H
12
Scheme 8. Copper-catalyzed dichloromethylazidation
of alkene using CHBrCl2 or CHCl3 as the
dichloromethylating reagent.
Wang's work: CHBrCl2 as the dichloromethylating reagent
N3
Cu(OH)2 (10 mol%)
Me6TREN (20 mol%)
N
N
CHCl2
N
+
CHBrCl2
(2.0 eq)
N
(1)
(2)
Me
TMSN3 (1.5 eq.)
Me
1a
K2CO3, CH3OH, 50o
C
Me6TREN
Scheme 6. Initiation of the process leading to the
dichloromethyl radical through formation of -
aminoradical 9.
13
, 87%
Under our conditions: CHCl3 as the dichloromethylating reagent
CuI (1 mol%)
DIPEA (5.0 eq.)
TBHP (3.0 eq.)
N3
OOtBu
CHCl2
CHCl2
+
Me
TMSN3 (3.0 eq.)
CHCl3/ Acetone (1:1), rt
tBuOOH
CuI
Me
Me
1a
13
, 65%
2a
, 5%
tBuOOH
HOCuI
As we were submitting this manuscript for publication, Li
tBuOOH
tBuOO
tBuO
and coworkers reported the use of cobalt(II)
acetylacetonate as a catalyst and triethylamine as a base for
difluroalkylation-peroxidation of arylalkenes (eq 2).15d In
their survey of applicable halogenation reagents they
reported one example using chloroform in which the
dichloromethyl product 2h was formed in 41% yield, and
we have confirmed this result. The role of trimethylamine
was proposed to be solely that of a base to neutralize acid
formation, but the results that we report suggests that the
tertiary amine is essential for halogen atom abstraction.
R2NCH2CH3
tBuOH
tBuOO-CuI
H2O
8
R2NCH-CH3
tBuOOH
9
That the -aminoradical is the key intermediate is not
only inferred from the calculations reported in Table 1, but
its involvement is strongly supported by the direct
1
observation of iminium ion 11 using H NMR spectral
analysis under the standard conditions (Scheme 7).
Addition of H2O sequestered the intermediate
quantitatively to acetaldehyde 12. The reaction was also
monitored by 1H NMR under the standard reaction
conditions, and acetaldehyde was observed to ultimately
form in a 1:1 ratio to the peroxide product (see Supporting
Information).
R2
R1
ROO
R3
R2
Co(acac)2, NEt3
MeCN, rt, 3 h
(2)
+ ROOH + X-CF2CO2Et
R3
R1
CF2CO2Et
The selectivity of CAT versus HAT for the generation and
oxidative addition of the dichloromethyl radical was
subjected to DFT analysis (Scheme 9). Hydrogen atom
abstraction from the -position of DIPEA to the tert-
butylperoxy radical occurs with a relatively low activation
barrier of 15.8 kcal/mol. The HAT from chloroform to the
DIPEA radical was calculated to have a higher energy
barrier (23.5 kcal/mol) than the CAT from chloroform to
Hydrogen atom abstraction from tertiary amine bases is
key to understanding the formation of the dichloromethyl
radical from chloroform, and may also contribute to
understanding recently published copper(II) hydroxide
catalyzed generation of the dichloromethyl radical from
CHCl2Br whose transformations are dependent on the
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HOOtBu
tBuOO
Cl
the DIPEA radical (12.7 kcal/mol). This preference is
sufficiently great to direct the reaction exclusively to the
dichloromethyl radical.
HOtBu
OtBu
CuI
I
Cl
2
OOtBu
HOOtBu
The formation of peroxide products 2 and 3 in relatively
high yields narrows the possible outcomes to three distinct
pathways (Scheme 10). In Pathway A a single electron
transfer (SET) by CuII would yield a benzyl carbocation
which could be intercepted by TBHP or, in theory, by other
suitable nucleophiles, including water in T-HYDRO.
However, when the reaction was conducted in the presence
of alternative nucleophiles, no deviation in product
selectivity for 2 was observed (i.e., with MeOH, NaOH/H2O,
indole). In Pathway B the formation of 2 occurs through a
two-step outer sphere ligand transfer between ICu-OOtBu
and the benzyl radical. Alternatively, in Pathway C addition
of CuII to the benzyl radical, resulting in CuIII species 14,
followed by reductive elimination regenerates the catalyst
and affords the observed product. This pathway has been
used to explain other copper catalyzed addition reactions
involving TBHP,30 but there has not been experimental
evidence for this pathway, and asymmetric induction from
the use of chiral ligands for copper(I) (and, alternatively, for
dirhodium(II) carboxamidates) offered an attractive
experiment that might distinguish this Pathway from
Pathway B. However, only borderline enantioselectivity
was observed in the presence of chiral ligands (see
Supporting Information), possibly due to ineffective metal-
ligand coordination. Since the lack of enantioselectivity
does not fully discredit this particular pathway, we turned
to DFT calculations to further distill the key reaction
intermediates as well as which route was more plausible.
IPr
Reductive
HO CuII
I
N
10
Elimination
HAT
I
Pr
H2
O
HOOtBu
Pathway C
IPr
N
IPr
tBuOO CuIIII Cl
tBuOO CuII
I
Oxidative
Coupling
Cl
CHCl3
14
IPr
Cl
N
Cl
11 IPr
ICuOOtBu
Cl
9
Cl
CHCl2
Ligand
Exchange
Cl
SET
CuI
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
tBuOO
Cl
Cl
Pathway B
OOtBu
Cl
Cl
2
Pathway A
The three pathways for C-O bond formation were probed
(Scheme 11). A single electron transfer to form the benzylic
carbocation was calculated to have the highest energy
profile (Pathway A) which explains why no product loss due
to the presence of other nucleophiles is observed. The direct
t
outer sphere BuOO ligand transfer had the next highest
energy barrier (TS4-Dis in Pathway B) whereas the formal
oxidative addition of copper to styrene followed by
reductive elimination (TS4-Re in Pathway C) was
calculated to have the lowest activation free energy for the
two steps and, so, is considered to be the most favorable
pathway. The Cu—C and O—C distances (2.45Å and 2.39Å)
in TS4-Re are much longer than the reported
enantioselective cases.31 Such ineffective coordination
accounts for the experimental observation of the lack of
enantioselectivity (see Supporting Information).
Scheme 11. Computed free energy diagram for C-O bond
formation. Calculations were at the B3LYP-D3 level and
distances are in Å.
Scheme 9. Computed free energy diagram for -amino
radical mediated reactions with chloroform.
Calculations were at the B3LYP-D3 level.
tBuOOCuI
+
G(E)
kcal/mol
CHCl2
Ph
2.41
1.94
-0.8 (-13.7)
1.86
2.44
H
CCl3
G(E
kcal/mol
Cl CHCl2
3.28
N
N
2.39
2.45
Cu
Sol
OOtBu
TS4-Dis
I
OOtBu
H
TS2-CAT
TS2-HAT
TS4-Dis
TS4-Re
TS4-Re
OOtBu
A
CHCl2
TS2-HAT
23.5 (12.3)
CCl3
+
R2NCHR'
-18.5 (-41.5)
Sol
I
TS1
15.8 (4.3)
-22.9
(-49.3)
Cu
R2NCH2R'
-23.2
(-34.9)
CHCl3
TS2-CAT
B
CHCl2
TS3
12.7 (3.0)
10.5 (11.3)
Ph
TS3
-24.6
(-36.4)
-27.2 (-53.7)
4.6 (-5.8)
tBuOOH
CHCl2
0.0 (0.0)
CHCl3
C
5.4 (5.6)
Ph
Ph
OOtBu
I
Sol
tBuOO
R2NCHR'
Cu
Sol
+
Cu
+
I
tBuOOCuI
+
-6.1 (-5.8)
CHCl2
R2NCH2R'
OOtBu
+
Ph
1/2[Cu]2
CHCl2
+
R2NCHClR'
14
-23.2 (-34.9)
N
R2NCH2R'=
CHCl2
2.45
1.83
Ph
CHCl2
Ph
2.05
1/2[Cu]2
-61.4
(-92.3)
O
Scheme 10. Three possible mechanistic pathways for
product formation
Sol=
OOtBu
CHCl2
I
Ph
[Cu]2
=
Sol
Sol
Cu Cu
I
2
CONCLUSIONS
In conclusion, a previously unrealized chlorine atom
transfer from chloroform was achieved by an indirect
process through which catalytic TBHP-induced formation of
an -aminoradical causes chlorine atom transfer from
chloroform forming the dichloromethyl radical that
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Promoted Free-Radical Reactions in Organic Synthesis: The
undergoes regioselective addition to the carbon-carbon
double bond of styrenes. This process was optimized to
Formation of Carbon-Carbon Bonds. Chem. Rev. 1994, 94, 519. (c)
Gossage, R. A.; van de Kuil, L. A.; van Koten, G. Diaminoarylnickel(II)
“Pincer” Complexes: Mechanistic Considerations in the Kharasch
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Transition Metal Catalysts. Acc. Chem. Res. 1998, 31, 423. (d) Clark,
A. J. Atom transfer radical cyclisation reactions mediated by copper
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Addition Reactions of CCl4, CHCl, and p-Tosyl Chloride Catalyzed by
Cp’Ru(PPh3)(PR3)Cl Complexes. Organometallics. 2009, 28, 4681.
(7) Ueda, M.; Doi, N.; Miyagawa, H.; Sugita, Takeda, N.; Shinada,
T.; Miyata, O. Reaction of Cyclopropenes with Trichloromethyl
Radical: Unprecedented Ring-Opening Reaction of Cyclopropanes
with Migration. Chem. Commun. 2015, 51, 4204.
(8) (a) Lu, M. Z.; Loh, T. P. Iron-Catalyzed Cascade
Carbochloromethylation of Activated Alkenes: Highly Efficient
Access to Chloro-Containing Oxindoles. Org. Lett. 2014, 16, 4698.
(b) Li, X.; Xu, J.; Gao, Y.; Fang, H.; Tang, G.; Zhao, Y. Cascade
Arylalkylation of Activated Alkenes: Synthesis of Chloro- and
Cyano-Containing Oxindoles. J. Org. Chem. 2015, 80, 2621. (c) Liu,
Y.; Zhang, J.-L.; Song, R.-J.; Li, J.-H. 1,2-Alkylarylation of activated
alkenes with dual C–H bonds of arenes and alkyl halides toward
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64855.
form
various
substituted
α-peroxy-β,β-
dichloropropylarene products and was also suitable for
halogen atom abstraction of additional alkyl halides to form
diverse α-peroxy-β-substituedethylbenzene products. An
excellent correlation between IPs and the difference in free
energy barrier of HAT vs. CAT was found. The correlation
provides a general method to select appropriate radical for
halogen atom transfer reaction. Furthermore, the
mechanism for halogen atom transfer involving α-
aminoradical intermediates unifies disparate reports and
establishes a cohesive framework for further advances. A
detailed computational investigation clearly demonstrated
the deviation from traditional HAT of chloroform and also
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established
a
formal oxidative addition/reductive
elimination as being the lowest energy pathway. The tert-
butylperoxide products formed by this methodology are
reducible to their corresponding alcohols under mild
conditions and are also convertible to highly substituted
pyridine derivatives in acetonitrile.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website. General experimental procedures
and detailed optimization and product analyses, experimental
procedures for mechanistic analyses, computational details,
references, and NMR spectra. CIF file for 5b.
AUTHOR INFORMATION
Corresponding Author
*Email: michael.doyle@utsa.edu
Author Contributions
R. K. N. and Y.-L. S. contributed equally.
(9) (a) Bao, Y.; Wang, G.-Y.; Zhang, Y.-X.; Bian, K.-J.; Wang, X.-S.
Copper-catalyzed formylation of alkenyl C–H bonds using BrCHCl2
as a stoichiometric formylating reagent. Chem. Sci. 2018, 9, 2986.
(b) Zhang, Y-X.; Jin, R-X.; Yin, H.; Li, Y.; Wang, X-S. Copper-Catalyzed
Funding Sources
The authors declare no competing financial interests.
Dichloromethylazidation of Alkenes Using BrCCl2H as
a
Stoichiometric Dichloromethylating Reagent. Org. Lett. 2018, 20,
7283.
(10) Abo-Amer, A.; McCready, M. S.; Zhang, F.; Puddephatt, R. J.
The Role of Solvent in Organometallic Chemistry- Oxidative
Addtion with Dichloromethane or Chloroform. Can. J. Chem. 2012,
90, 46.
ACKNOWLEDGMENT
Financial support from the Welch Foundation (AX-1871) and
the
Shenzhen
Basic
Research
Program
(JCYJ20170412150343516) is gratefully acknowledged.
(11) (a) Ueda, M.; Doi, N.; Miyagawa, H.; Sugita, S.; Takeda, N.;
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One-Pot
Synthesis
of
(Z)-β-
Alkoxyperfluoroalkenone. J. Org. Chem. 2016, 81, 3103. (b) Li, Y,;
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Table of Contents
1
2
3
4
tBuOO
Cl
R1
CuI (1 mol %)
R
R
Cl
CuI
TBHP (5.0 eq.), DIPEA (5.0 eq.)
CHCl3:Acetone (1:1, 0.2M), rt
R1
5
6
7
tBuOO
iPr2NCH2CH3
tBuOOH
Ar
iPr2NCHClCH3
iPr2NCHCH3
+
ICuOOtBu
CHCl2
CHCl3
CHCl2
R1
Ar
R1
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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41
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