Rhodium-Catalyzed Enantioselective Radical Addition of CX4 Reagents to Olefins

Article abstract of DOI:10.1002/anie.201704074

We describe the synthetically useful enantioselective addition of Br?CX₃ (X=Cl or Br) to terminal olefins to introduce a trihalomethyl group and generate optically active secondary bromides. Computational and experimental evidence supports an asymmetric atom-transfer radical addition (ATRA) mechanism in which the stereodetermining step involves outer-sphere bromine abstraction from a [(bisphosphine)Rh^IIBrCl] complex by a benzylic radical intermediate. This mechanism appears unprecedented in asymmetric catalysis.

Full text of DOI:10.1002/anie.201704074

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Rhodium-Catalyzed Enantioselective Radical Addition of CX4
Reagents to Olefins
Authors: Joseph M. Ready, Bo Chen, Cheng Fang, and Peng Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201704074
Angew. Chem. 10.1002/ange.201704074
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10.1002/anie.201704074
Angewandte Chemie International Edition
COMMUNICATION
Rhodium-Catalyzed Enantioselective Radical Addition of CX4
Reagents to Olefins
Bo Chen, Cheng Fang, Peng Liu* Joseph M. Ready*
Abstract: We describe an enantioselective addition of Br-CX3 (X =
Cl or Br) to terminal olefins that introduces a trihalomethyl group and
generates optically active secondary bromides. Computational and
experimental evidence supports an asymmetric atom transfer radical
addition (ATRA) mechanism in which the stereodetermining step
species would form the new C-X bond. Thus, the metal catalyst
would be present in the stereodetermining step, offering the
possibility to induce asymmetry with chiral ligands on the metal
(see TS-B)
a. Kharasch addition
X
involves
outer-sphere
bromine
abstraction
from
a
X CX3
+
X3C
R
R
(bisphosphine)Rh(II)BrCl complex by a benzylic radical intermediate.
Beyond the synthetic utility, this mechanism appears unprecedented
in asymmetric catalysis.
1
(X = halide)
olefin feedstocks
b. Mechanistic possibilities
X3C X
X3C
(±)-1
X3C X
R
initiator
TS-A: chain transfer (racemic)
Radical additions to olefins provide effective methods to
increase molecular complexity. For example, in 1945 Kharasch
described the addition of CX4 across terminal olefins to form a
new C-C bond, introduce a new CX3 group and generate a new
C-X bond (Figure 1a).[1] This addition generally occurs with high
Markovnikov selectivity and good functional group tolerance.[2]
More broadly, free radicals are prized intermediates in organic
synthesis because they possess exceptional reactivity, although
controlling that reactivity remains difficult.[3] In this context, the
development of an enantio-selective Kharasch addition reaction
appeared valuable for both practical and fundamental reasons. It
X3C
X3C
R
MnL*
X
R
2
X
-L*Mn-1
X3C
X3C
R
R
TS-B: enantioselective pathway
Figure 1. Addition of CX4 reagents to olefins.
While the transition state envisioned in TS-B could lead to an
enantioselective reaction, it appears largely unprecedented.
More generally, asymmetric radical reactions of any type are
rare, although notable successes have been achieved
recently.[7] Most existing asymmetric radical reactions fall into
one of three mechanistic classes. Most commonly, a radical
adds to an olefin that is associated with a chiral metal complex
(3, Figure 2A). Examples include the addition of nucleophilic
radicals,[8] aminomethyl radicals,[9] and photolytically generated
4
]
would provide optically active alkyl halides,[
and the
trihalomethyl group finds utility as metabolically stable
a
replacement for –CH3 groups. Finally, an asymmetric platform
for the Kharasch addition reaction could potentially be expanded
to other C-X (X = halide) and X-Y (Y = SR, NR2) reagents.
10
]
alkyl radicals[
to α,β-unsaturated carbonyl compounds.
Kharasch noted, “Strange as the reactions cited may appear,
the explanation of their mechanisms is not too difficult.”[1] These
atom-transfer radical additions proceed through addition of the
CX3 radical to an olefin, followed by abstraction of bromine
radical to form the secondary C-Br bond (Figure 1B). Transition
metals, heat or peroxides can initiate the reaction by generating
the CX3 radical. Importantly, in this scenario the initiator does not
participate in the stereodetermining step, which involves
Additionally, enolates coordinated to a chiral-at-metal Ir complex
can combine with electrophilic trichloromethyl radicals[11 ] and
electron-poor benzylic radicals.[12],[13]
A
second mechanistic platform for asymmetric radical
reactions features organocatalysts (Figure 2B). Chiral enamines
4 can undergo single electron transfer to generate a chiral
radical species that then combines with a radical electrophile, as
described by the Sibi[14] and MacMillan[15] laboratories.[16,17]
A third mechanism for enantioselective catalysis involving
radical intermediates relies on inner-sphere bond formation from
organometallic intermediates (Figure 2C). The Fu group defined
a Ni-catalyzed cross-coupling of racemic alkyl bromides with a
variety of electrophiles.[18] In these transformations a secondary
radical likely combines with an alkyl metal species to provide a
dialkyl metal species 6. Reductive elimination generates the
optically active cross-coupled product (7).[19] More recently Liu
abstraction of X radical from CX4 to complete the propagation
[5]
cycle (see TS-A).[3],
Accordingly, asymmetric induction is
impossible with this mode of initiation.[6]
We hypothesized that radical abstraction of a halide from CX4
by a metal catalyst (Mn) would generate the CX3 radical and an
M(n+1)-X species. Radical addition to the terminal olefin would
generate the secondary radical as in the radical propagation
mechanism. In the key step, abstraction of X from the M-X
and Stahl reported
a
related Cu-catalyzed benzylic
cyanation.[ 20 , 21 ] Cu-catalyzed α-amination of amides[ 22 ] and
difunctionalization of olefins[ 23 ] likely operate through similar
inner-sphere mechanisms, although complete mechanistic
details are not available.
[a]
[b]
[c]
Dr. B. Chen, Prof. R. Joseph
Department of Biochemistry, UT Southwestern Medical Center,
5323 Harry Hines Blvd, Dallas, Texas 75390-9038 USA.
E-mail: Joseph.ready@utsouthwestern.edu
C. Fang, Prof. P. Liu
Department of Chemistry University of Pittsburgh, Pittsburgh, PA
15260 USA
E-mail: pengliu@pitt.edu
C. Fang
Computational Modeling & Simulation Program University of
Pittsburgh, Pittsburgh, PA 15260 USA
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201704074
Angewandte Chemie International Edition
COMMUNICATION
active transition metals including Fe, Mn, Ni, Rh, Ru, Ir and Cu
A. Addition to coordinated olefin
B. enamine catalysis
A.
O
P(p-Tol)2
(15 mol%)
P(p-Tol)2
ML*
ML*
D
D
O
O
NR2*
R'
-e-
R
Br
Ar
CX3
R
R'
[Rh(COD)Cl]
2 (5 mol%)
R
R'
R'
+
Br CX3
R'
R'
4
toluene/hex, -78 o
isolated yieldsa
CCl3
C
5
R
Ar
Br
3
1
D = donor group (e.g. carbonyl, O-)
ML* = Optically active metal complex
Br
CCl3
CCl3
Br
C. Inner-sphere functionalization
MnL* +
D. Outer-sphere functionalization
Mn+1L*
R Mn+1L*
R Mn+2L*
R
Me
X
X
+
MnL*
R
1a
98%, 93:7 er
1b (2-Me): 62%, 92:8 er
1c (3-Me): 90%, 90:10 er
1d (4-Me): 64%, 95:5 er
R1 R2
R1 R2
1e (R = OMe): 44%, 89:11 er
1f (R = F): 80%b, 91:9 er
R1 R2
R1 R2
R1 R2
7
6
9
• this work
1g (R = tBu): 61%, 94:6 er
1h (R = iPr): 57%, 92:8 er
1i (R = Ph): 78%b, 87:13 er
1j (R = TMS): 70%, 88:12 er
1k (R = OAc): 70%, 89:11 er
1l (X = F): 60%, 92:8 er
Figure 2. Mechanisms of asymmetric radical reactions. A. Radical
addition to metal-coordinated substrate. B. Oxidation of chiral enamine
intermediates followed by radical trapping. C. Metal capture of radical
intermediates follwed by reductive elimination. D. Outer-sphere ligand
abstraction by pro-chiral radical.
Br
CCl3
Br
CCl3
1o (2-naphth.): 90%
90:10 er
1p (1-naphth.): <5%
In contrast to the three mechanistic classes described above,
a fourth potential mechanism remains essentially unexplored.
Specifically, we wondered if it might be possible to effect an
enantioselective outer-sphere bromine abstraction from an
optically active metal bromide (Figure 2D). We are aware of only
three examples of asymmetric Kharash addition reactions: The
addition of CCl3Br to acrylates and styrene in up to 22% ee[24]
and 30% ee, respectively.[25] Alternatively, ArSO2Cl added to
styrene in up to 40% ee.[26] More generally, we are aware of no
asymmetric reactions that have been shown to involve outer-
sphere abstraction of one of the ligands (halide in our case) by a
radical, although the Jacobsen epoxidation likely involves radical
addition to a metal oxo species.[ 27] Accordingly, the development
of an enantioselective Kharasch addition could solve a long-
standing challenge in asymmetric synthesis and provide a new
mechanistic platform for the development of a variety of
enantioselective reactions.
R
1m (X = Cl): 61%, 89:11 er
1n (X = Br): 58%, 86:14 er
Br
CCl3
Br
CCl3
Br
CCl3
Me
Me
Me
Me
1r: 60%, 89:11 er
1q: 60%, 92:8 er
1s: 62%, 92:8 er
Br CCl3
Br
CX3
Br
CCl3
1v (CBrCl2): 59%, 94:6 er
1w (CBr2Cl): 56%, 94:6 er
1x (CBr3): 60%, 94:6 er
N
N
Ts
Me
1t: 55%, 81:19 er
1u: < 5%
x
B.
We initiated our investigations by evaluating the addition of
BrCCl3 to styrene (Figure 3). We evaluated a variety of redox-
N3
SAc
Br
CCl3
CCl3
KSAc
NaN3
CCl3
EtOH/H2O
40 oC, 48 h
MeCN
rt, 48 h
Br
1a
93:7 er
11
[Rh(cod)Cl]2 (5 mol%)
CCl3
12
50%, 91:9 er
(95% es)
ligand (15 mol%)
70%, 91:9 er
(95% es)
Br CCl3
+
toluene, -78 oC
1a
Figure 4. A. Substrate scope for the addition of tetrahalomethanes
to vinyl arenes. aReactions carried out with 0.25 mmol olefin, 0.5
mmol CX4, in 2.5 mL toluene/hexanes (1:1 v/v). Er's determined by
HPLC. btoluene solvent. B. Derivitization of secondary bromide 1a.
Ar =
O
O
Me
3-Me (10k): 42% yield, er 48:52
2-Me (10l): <5% yield
in our initial survey, and discovered that Rh(I) complexes
promoted the reaction at room temperature and below.
Ar2P
Ar =
PAr2
DIOP
R
R
er*
Therefore, we combined [Rh(COD)Cl]2 with
a variety of
R
R
O
R
O
Me, Me 89:11
10a
10m
monodentate and bidentate ligands and evaluated the ability of
the resulting complexes to catalyze the Kharasch reaction at -78
oC. Monodentate phosphines and phosphoramidites did not yield
active catalysts. Likewise, the complexes derived from BINAP,
DuPhos and Trost’s ligand[28] proved largely inactive. By contrast,
chelating phosphines of the form Ph2P-(CH2)n-PPh2 proved more
promising. Interestingly, we noticed a profound impact on bite
angle such that bis(diphenylphosphino)butane generated the
racemic product in quantitative yield whereas bis-phosphines
with longer or shorter linkers were markedly less effective. DIOP
features a similar 4-carbon bridge between phosphines, and it is
also a diaryl, alkyl phosphine. We were therefore gratified to
discover that the complex derived from DIOP (10a) and a Rh(I)
cPent
89:11
85:15
88:12
er*
R
DIOP
10n cHex
10a
10b
10c
10d
10e
10f
10g
10h Ph
10i OMe
10j OH
H
Cl
F
Me
Et
89:11
87:13
86:14
93:7
86:14
76:24
70:30
64:36
90:10
No Rxn
10o cHep
Ph2P
PPh2
10p
Ph, Ph 80:20
* >80% yield
i
Pr
tBu
O
O
Me
Ph2P
Me
PPh2
10q, 10r: Either C2 isomer:
No Rxn
* >80% yield unless noted
Figure 3. Discovery of an enantioselective Kharasch reaction
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10.1002/anie.201704074
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COMMUNICATION
source provided the secondary bromide in 89:11 er. p-Tol-DIOP
(10d) emerged as the optimal ligand. In detail, small electron-
donating groups (Me, OMe) at the 4-position of the phenyl ring
Existing data implicates radical intermediates (Figure 5B). In
particular, when styrene was exposed to CCl4 and CBr4 in the
presence of ClRh(DIOP), we obtained the cross-over product 1a
along with the expected product 1x (eq 1). At cryogenic
temperatures, benzyl chloride formation is not observed, but the
generation of 1a suggests that CCl3 radical was generated. After
addition to styrene, the corresponding benzylic radical
abstracted a bromine from a Rh(II)Br species, which was
generated from CBr4.[30] The low yields even at high Rh loadings
are likely because the (DIOP)RhCl2 formed from CCl4 is
A. Potential mechanisms for the asymmetric Kharasch addition.
i
t
improved er’s while larger (Me > Et > Pr > Bu) alkyl groups or
halogens decreased enantioselectivity. Substitution on the 2 or 3
position had deleterious effects on reactivity and selectivity (10k,
10l). The ketal substitution on DIOP had little impact on
reactivity or selectivity (10a, 10m – 10p). However, the reaction
appears very sensitive to steric effects on the ligand because
methyl substitution adjacent to the phosphine totally inhibited the
reaction (10q, 10r). Finally, we observed modest increases in
enantioselectivity (depending on substrate) when the reaction
was carried out in a 1:1 mixture of hexane and toluene. Other
modifications to the reaction conditions did not improve
selectivity including lower or higher temperatures, alternative
Rh(I) sources, or different solvent mixtures.29
The addition of BrCCl3 to vinyl arenes tolerates functional
groups such as alkyl, halides, ester, methoxy, and TMS groups
(Fig 4, 1b-1n). The substituents on the aromatic ring could be in
the ortho, meta, or para position (1b-1d). The addition is
relatively insensitive to sterics at the para-position, and electron-
donating and modestly electron withdrawing groups are suitable.
In contrast, strongly electron-withdrawing groups (CN, CF3) lead
to poor enantioselectivity. Multiply- substituted styrenes are also
suitable substrates for this reaction (1q-1s). 3-Vinyl pyridine
afforded the adduct in moderate yield and ee (1t), while vinyl
indole generated an unstable product (1u). Similarly, 2-vinyl
naphthalene was an excellent substrate (1o), but the product
derived from 1-vinyl naphthalene (1p) could not be isolated.
Other polyhalomethanes could react to give similar Kharasch
Thus, a –CCl3, –CBrCl2, –CBr2Cl and a –CBr3 group could all be
introduced with similar selectivity and yield (1v-1x). With bromo-
chloro-methanes, exclusive formation of the benzylic bromide
was observed, and we have not isolated any benzylic chloride
products when the reaction is performed at -78 oC.
Benzylic bromides are synthetically valuable as substrates for
stereospecific SN2 substitutions. We have performed preliminary
experiments to evaluate the range of suitable nucleophiles for
substitution reactions. Specifically, the C-Br bond can be
transformed into a C-N (11) and C-S (12) bond with high
stereochemical fidelity and moderate yield. Currently, attempted
substitution with carbon nucleophiles (cyanide, enolates) leads
to elimination.
Two general mechanisms for the asymmetric ATRA
appeared reasonable, one closed shell and one radical in nature.
Shown in Figure 5A is a Rh(I)-Rh(III) cycle featuring oxidative
addition to Br-CX3 to give a Rh(III) complex 13. Stereospecific
and enantioselective olefin insertion would generate a benzylic
Rh species 14. Final reductive elimination would provide the
observed product 1. Alternatively, bromine radical abstraction
could generate the CX3 radial and a Rh(II)BrCl species 16;
addition to styrene could then yield the benzylic radical 2 (Figure
5A, bottom). Radical 2 could recombine with Rh(II) to provide
the Rh(III) intermediate 14, which could again undergo reductive
elimination to product. Alternatively, it could directly abstract
bromine from the Rh(II)BrCl species in an outer-sphere
mechanism to give the observed product 1 (see 17).
Cl
Rh(I)
P
Br
BrCCl3
*
Cl3C
P
Ar
1
Rh(I)-(III)
Ar
CCl3
Rh(III)
P
P
Cl3C
Br Rh(III)L*
*
13
14
Br
Cl
Cl
Ar
1
P
P
BrCCl3
*
Rh(I)
Cl
15
Ar
P
P
Cl
Cl
P
Rh(I)-Rh(II)-Rh(III)
or
Rh(II)
*
Cl3C
Rh(II)
*
Br Rh(III)L*
P
Br
+
Br
Rh(I)-Rh(II)
Cl
16
14
CCl3
Ar
P
P
Cl
Rh(II)
CX3
Ar
*
17
Br
+
Ar
Cl3C
2
B. Mechanistic Experiments
Cross-over experiment
(-)-DIOP
(45 mol%)
CCl4
(0.5 equiv)
[Rh(COD)Cl]2
(15 mol%)
Br
Br
Ph
CCl3
CBr3
(1)
+
Ph
toluene, -78 oC
1 equiv
Ph
CBr4
(0.5 equiv)
1a
6% yield
1x
26% yield
ca. 83:17 er
ca. 79:21 er
(-)-DIOP
Stereochemical probe
D
(15 mol%)
[Rh(COD)Cl]2
(5 mol%)
Br
D
+
BrCCl3
CCl3
1i-d; dr = 1:1
er = 83.5 :16.5,
52% yield
toluene, -78 oC
Br
Br
18-d (>95% E, 90%-d)
(2)
Figure 5. A. Potential Rh(I)-Rh(III) catalytic cycle (top) and two
catalytic cycles involving radical intermediates (bottom). B.
Experiments to probe the mechanism of the addition reaction.
catalytically inactive. Similarly, stereochemically pure deuterated
styrene 18-d reacted with Br-CCl3 to yield 1i-d as a 1:1 mixture
of diastereomers (eq 2). This result rules out the Rh(I)-Rh(III)
mechanism
because
olefin
insertion
would
proceed
stereospecifically. By contrast, radical addition to styrene 18-d is
expected to yield a mixture of diastereomers, as observed.
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10.1002/anie.201704074
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COMMUNICATION
We have used experimental[29] and DFT methods to explore the
enantioselective bromination of styrene using [(−)-DIOP]RhCl as
the catalyst (Figure 6). The closed-shell Br−CCl3 oxidative
addition via either a three-centered TS[31] (24-TS) or an SN2-type
linear TS[32,33] (25-TS) both require high activation free energies
(32.5 and 38.0 kcal/mol, respectively). In contrast, the radical
pathway involving bromine atom abstraction by the Rh(I) catalyst
(23-TS) is much more favorable. The resulting CCl3 radical adds
to styrene to form the benzylic radical 2a, which then abstracts
the bromine atom from the Rh(II) complex 16 (via 17-TS) to form
the bromination product (1a) and regenerate the Rh(I) catalyst
15. The Br atom abstraction again requires a very low barrier,
7.6 and 8.1 kcal/mol with respect to 16 and 2a for the formation
of (S)- and (R)-1a, respectively. The closed-shell reductive
elimination from the Rh(III) intermediate 14 (via 27-TS) and the
chain transfer reaction of 2a with BrCCl3 (∆G‡ = 20.2 kcal/mol
with respect to 2a, see SI for details) both require much higher
barriers. Thus, the DFT calculations suggested a Rh(I)/Rh(II)
catalytic cycle with two Br atom abstraction steps. The closed-
shell transition states (24-TS, 25-TS, and 27-TS) are all
destabilized due to the unfavorable steric repulsions between
the Rh center and the CCl3 or benzyl group in the oxidative
addition/reductive elimination transition states.
addition appears to operate through a mechanism that has not
been exploited previously in asymmetric catalysis. Looking
forward, it appears likely that the principles outlined here will
prove applicable to other enantioselective ATRA reactions.
Acknowledgements
Financial support provided by the NIH (R01GM102403), the
Welch Foundation (I-1612), and the University of Pittsburgh.
DFT calculations were performed at the Center for Research
Computing at the University of Pittsburgh and the Extreme
Science and Engineering Discovery Environment (XSEDE)
supported by the NSF.
Conflict of interest
The authors declare no conflicts of interest.
Keywords: asymmetric catalysis• radical addition•
enantioselectivity•
An interesting feature of the Br atom abstraction transition
states (23-TS and 17-TS) is that the Rh−Br−C bond angles are
bent (85~105°) rather than linear, as expected in radical
abstraction TSs involving two organic radicals. The bent
geometry leads to much stronger interactions between the chiral
bisphosphine ligand and the substrate in 17-TS, and thus is
critical to the chiral induction by the Rh catalyst. As shown in
Figure 6, the preferred Br abstraction transition state 17-TS-S is
stabilized by a π/π interaction between the Ph on the benzylic
radical and one of the Ph groups on the DIOP ligand, while in
the disfavored transition state, 17-TS-R, the Ph on the benzylic
radical is pointing away from the ligand.
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COMMUNICATION
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10.1002/anie.201704074
Angewandte Chemie International Edition
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Bo Chen, Cheng Fang, Peng Liu*
Joseph M. Ready*
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O
O
P(p-Tol)2
P(p-Tol)2
Rhodium-Catalyzed Enantioselective
Radical Addition of CX4 Reagents to
Olefins. The first highly enantioselective
Kharasch addition reaction involves CX3
radical addition to olefins followed by
outer-sphere bromine abstraction from a
Rh(II)Br complex. The reaction provides
benzylic bromides in enantioenriched
form and high yields.
Br CX3
+
Br
Ar
CX3
[Rh(COD)Cl]2
Ar
• High ee's
• Radical mechanism
• Outer-sphere Br abstraction
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