Ti-Catalyzed Radical Alkylation of Secondary and Tertiary Alkyl Chlorides Using Michael Acceptors

Article abstract of DOI:10.1021/jacs.8b08605

Alkyl chlorides are common functional groups in synthetic organic chemistry. However, the engagement of unactivated alkyl chlorides, especially tertiary alkyl chlorides, in transition-metal-catalyzed C-C bond formation remains challenging. Herein, we describe the development of a Ti^III-catalyzed radical addition of 2° and 3° alkyl chlorides to electron-deficient alkenes. Mechanistic data are consistent with inner-sphere activation of the C-Cl bond featuring Ti^III-mediated Cl atom abstraction. Evidence suggests that the active Ti^III catalyst is generated from the Ti^IV precursor in a Lewis-acid-assisted electron transfer process.

Full text of DOI:10.1021/jacs.8b08605

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Article
Ti-Catalyzed Radical Alkylation of Secondary and
Tertiary Alkyl Chlorides Using Michael Acceptors
Xiangyu Wu, Wei Hao, Ke-Yin Ye, Binyang Jiang, Gisselle Pombar, Zhidong Song, and Song Lin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b08605 • Publication Date (Web): 10 Oct 2018
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Ti-Catalyzed Radical Alkylation of Secondary and Tertiary Alkyl Chlorides Using Michael Acceptors
Xiangyu Wu†, Wei Hao†‡, Ke-Yin Ye†, Binyang Jiang†, Gisselle Pombar†, Zhidong Song†, Song Lin†*
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†Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States
Supporting Information Placeholder
(e.g., via -H elimination). Indeed, current examples using
such a strategy are limited to the use of special 3° alkyl
chlorides that cannot undergo -H elimination due to
geometric constraints. Recently, Fu et al. reported a Cu-
catalyzed photochemical cyanation reaction,17 which
constitutes a rare example in which a simple, unactivated 3°
R–Cl was engaged toward C–C formation. However, it was
noted in the report that this method currently cannot be
generalized to other tertiary substrates.
ABSTRACT: Alkyl chlorides are common functional
groups in synthetic organic chemistry. However, the
engagement of unactivated alkyl chlorides, especially
tertiary alkyl chlorides, in transition-metal-catalyzed C–C
bond formation remains challenging. Herein, we describe
the development of a TiIII-catalyzed radical addition of 2°
and 3° alkyl chlorides to electron-deficient alkenes.
Mechanistic data are consistent with inner-sphere activation
of the C–Cl bond featuring TiIII-mediated Cl atom
abstraction. Evidence suggest that the active TiIII catalyst is
generated from the TiIV precursor in a Lewis-acid assisted
electron transfer process.
Scheme 1. Ti-catalyzed alkylation of unactivated alkyl
chlorides: challenges and rationale
Introduction
Carbon-chlorine bonds are prevalent structural units in
organic molecules. In particular, alkyl chlorides are
frequently found in natural products1 and synthetic
intermediates.2 These compounds can be readily prepared
from common functional groups including alkenes,3
alcohols,4 ketones,5 epoxides,6 and alkanes.7 Nevertheless,
methods that engage alkyl chlorides in organic synthesis are
largely confined to the 2-electron regime via canonical SN2
and Grignard reactions. New protocols that can selectively
activate and functionalize alkyl chlorides may further
expand the use of these electrophiles in complex target
synthesis.8 Recent advances in radical chemistry enabled the
engagement of common functional groups (e.g.,
carboxylates,9 alcohols,10 and alkenes11, and alkanes12) in C–
C bond forming reactions. Inspired by these seminal
contributions and given our research interests in Ti radical
catalysis, we aimed to develop a new approach for the
activation and alkylation of unactivated 2° and 3° alkyl
chlorides by employing the rich redox chemistry of Ti
complexes.
A second strategy relies on the direct, single-electron
reduction of the alkyl chloride electrophile using a chemical
reductant or a photocatalyst.19 This possibility is hampered
by the very negative reduction potential of unactivated R–Cl
(E  –2.5 V vs Fc+/0).
The third strategy entails metal-promoted Cl atom
abstraction20 to form the corresponding carbon-centered free
radical. This pathway is the reversal of atom transfer radical
addition but is challenged by the relatively high dissociation
energy of C–Cl bonds (e.g., BDE of tBu–Cl ca. 85 kcal/mol).
In principle, three strategies may be envisioned for the
activation of alkyl chlorides to form the corresponding
carbon-centered radicals or their equivalents (Scheme 1A).
First, metal insertion13 to the C–Cl bond can form metal-
alkyl intermediates. In this context, first-row transition
metals including Ni,14 Co,15 Fe,16 and Cu17 have been shown
to be capable of engaging alkyl chlorides in C–C bond
forming reactions. However, these methods are not suitable
for transforming 3° R–Cl18 because the corresponding metal-
alkyl species are susceptible to unproductive side reactions
We were interested in using the third strategy for the
activation of alkyl chlorides, as it could allow the
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engagement of 3° R–Cl, a largely untapped class of
with –1.12 V with Cp*TiCl3; see discussion below and the
SI). As previously discussed, titanocene complexes
Cp*2TiCl2 (Ep/2 = –1.55 V) and Cp2TiCl2 (E1/2 = –1.19 V)
were substantially less reactive (entries 3, 4).
electrophiles,21 in C–C forming reactions. In theory, TiIII is
a well-suited catalyst for such a process because (Scheme
1B): (1) TiIII compounds are versatile catalysts22 in the
reductive activation of common functional groups (e.g.,
carbonyls23 and epoxides24) and (2) TiIV shows great affinity
with highly electronegative, “hard” anions, making Cl atom
abstraction thermodynamically favorable (e.g., BDE of
TiIV–Cl in TiCl4 is 96 kcal/mol).25 This activation would lead
to the formation of a carbon-centered radical that can
participate in subsequent reactions in the presence of a
radical acceptor. In a related study, Kambe achieved an
elegant alkene carbomagnezation through the activation of
3° R–Cl.26 This reaction, however, relies on the formation of
highly reducing TiII species generated in the presence of
nBuMgCl, thus limiting the reaction scope to only
unfunctionalized substrates. Huang recently reported the
reductive addition of α-hydroxylactams to Michael
acceptors using the Nugent-RajanBabu reagent.20b This
reaction was proposed to undergo the intermediacy of α-
chlorolactams—a highly activated class of electrophiles; it
also required the use of Mg0 to achieve high efficiency,
which limited the functional group compatibility.
1
2
3
4
5
6
7
8
Scheme 2. Rationale for catalyst optimization
E
Previous studies: [3+2]
R
E
NBz
R
O
N
[TiIV
]
(with Cp*TiCl3; ref 28a)
E
Ph
R
R
N
O
R
R
[TiIII]
E
9
Ph
NHBz
R
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R
(with Cp*2TiCl2; ref 28b)
Rationale for the current study:
X
X
TiIII
TiIII
vs.
Cl
Cl
R3
R2
R3
X
R2
less sterically
hindered active site
R1
R1
R3
R1
E
E
R3
R1
R2
R2
Table 1. Ti-Catalyzed Alkylation and Control Experiments
In this article, we report the development of a Ti-catalyzed
alkylation of unactivated alkyl chlorides using Michael
acceptors. In particular, 3° R–Cl, a largely untapped class of
electrophiles in transition metal catalysis, were successfully
engaged in C–C bond formation. Our new method displays
a reaction scope and functional group compatibility that are
complementary to existing protocols for accessing similar
types of products.
Results and Discussion
A. Reaction discovery and catalyst optimization
Our initial attempts to achieve the radical activation and
addition of 3° alkyl chloride 1 to acrylate 2 proved
challenging using the Nugent-RajanBabu reagent (Cp2TiCl2)
or its derivative, Cp*2TiCl2. We hypothesize that the active
site of these titanocenes is likely hindered by the pair of
cyclopentadienyl ligands, rendering it difficult for the
sterically demanding 3° R–Cl to approach (Scheme 2). We
recently demonstrated the use of Cp*TiCl3—a catalyst
frequently employed in polymerization reactions27 but is
underexplored in radical chemistry—in the [3+2]
cycloaddition of alkenes with N-acylaziridines28a or
cyclopropyl ketones.23b The removal of a Cp* ligand
decreased the steric profile of these catalysts but maintained
their redox properties. As such, the cyclization of a carbon-
centered radical onto the Ti-bound (aza)enolate can occur
smoothly (see Scheme 2). In contrast, bulkier Cp*2TiCl2
provided the open chain product instead.28b
Extending the reaction time to 12 h led to the quantitative
conversion of 1 to 3 (entry 5). Using the optimal conditions,
we conducted control experiments to elucidate the role of
each reaction component. As expected, the exclusion of the
Ti catalyst completely shut down the C–C coupling
reactivity (entry 6). Both the reductant and the ammonium
salts are required to obtain appreciable amounts of 3 (entry
7). Collidine·HCl salt instead of Et3N·HCl as a proton
source provided the product in nearly identical yield (entry
8). Notably, Mn instead of Zn is inactive (entry 9). Although
Mn is more reducing than Zn, we observed no color change
from red (TiIV) to green (TiIII), which was apparent in the Zn-
promoted reaction. This finding indicated that Mn is
incapable of reducing the precatalyst in our reaction medium
(see discussion below). Nonpolar and poorly coordinating
solvents, such as DCM or ethyl acetate, were compatible
Indeed, the use of Cp*TiCl3 as the catalyst provided a
positive lead result in the reductive C–C coupling between 1
and acrylate 2 (Table 1). Upon optimization, the desired
alkylation product 3 was obtained in 70% yield using Zn as
the stoichiometric reductant, Et3N·HCl as the proton source
in toluene, and a reaction time of 1 h (entry 1). The
unsubstituted CpTiCl3 complex proved inferior (entry 2),
presumably due to the less negative reducing potential of the
corresponding TiIII active catalyst (E1/2 = −0.79 V, compared
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(entries 10 and 11), whereas MeCN and THF strongly
chlorides also proved suitable substrates (entries 12–18).
Achieving high yields, however, sometimes required the use
of higher loadings of Zn, Et3N·HCl, or Ti catalyst as well as
prolonged catalyst preactivation before substrate addition.
We also investigated secondary benzyl chloride and primary
alkyl chloride. (1-Chloroethyl)benzene was fully consumed,
yielding 2,3-diphenylbutane via radical dimerization as the
major product (ca. 50%) along with a small amount of
desired alkylation adduct (ca. 15%; see SI). (3-
Chloropropyl)benzene was largely unreactive and afforded
the alkylation product in ca. 10% yield. Primary alkyl
chlorides are frequently suitable electrophilies for metal-
catalyzed C–C formation in the literature14–17. Therefore, our
Ti-catalyzed reaction offers a complementary selectivity
profile and can be used for the selective functionalization of
polysubstituted R–Cl in the presence of their primary
counterparts (see Table 2, entry 3).
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8
inhibited the formation of 3 (entry 12).
B. Substrate scope
We then explored the reaction scope under the optimal
conditions. Substituted acrylates (Table 2, entries 1-8) were
transformed to their corresponding products smoothly.
Various functional groups, including trifluoromethyl (5) and
tertiary amine (13) motifs, were also tolerated. Importantly,
our protocol was compatible with aryl bromide (14) and aryl
boronate (16), functional groups that would likely induce
catalyst promiscuity under previous conditions reported for
alkyl chloride activation (e.g., Ni catalysis14). Notably,
primary alkyl chloride (6) remained untouched, presumably
because primary carbon-centered radicals are more difficult
to generate than their tertiary congeners. Various other
Michael acceptors (entries 9-13) provided the corresponding
products in good to excellent yields. Interestingly,
bicyclobutanes (28, 30)29 also underwent strain-relieving
radical addition to provide disubstituted cyclobutene in
useful yields. Enones are currently incompatible presumably
due to competing reductive transformations30 that did not
involve the alkyl chloride.
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C. Tandem chlorination and Ti-catalyzed alkylation
We then demonstrated the reductive alkylation reaction on
synthetically relevant scales. Four alkyl chlorides were
readily prepared from common functionalities using
established protocols. Deoxychlorination of alcohols4 and
hydrochlorination3c and chlorofunctionalization3g,h of
alkenes led to structurally diverse alkyl chlorides in a single
step in high efficiency (Scheme 3). Various other literature
methods for the preparation of alkyl chlorides are provided
in the SI. The resulting intermediates were then subjected to
the described Ti catalyzed conditions on a 1-mmol scale to
afford the alkylation products with minimal changes in yield
from 0.1 mmol scale. In particular, owing to the large variety
of alkene chlorofunctionalization reactions available in the
literature, the two-step procedure comprising tandem
Table 2. Alkene Scope of Ti-Catalyzed Alkylation
Cp*TiCl3 (10 mol%)
Cl
R1
Zn (1.5 equiv), Et3N·HCl (1.5 equiv)
Me
R1
Product
3
+
Me
Me
Ph
Ph
Me
toluene, 22 °C
1
Entry
Alkene
Entry
9
Alkene
Product
Yield (%)
97
Yield (%)
Me
CO2tBu
CO2tBu
1
2
19
21
23
98a
2
O
CF3
18
5
95
O
O
10
40c
chlorination and reductive alkylation constitutes
a
4
O
O
convenient and versatile method for the synthesis of
vicinally difunctionalized products (e.g., 43, 45, 51). We
also conducted gram-scale synthesis of 27, which resulted in
a slightly decreased but synthetically useful yield (68%)
likely as a result of the heterogeneity of the reaction system.
Efforts are underway to improve the efficiency of gram-
scale synthesis.
Cl
3
4
7
9
97a,b
20
22
O
6
Me
11
12
13
50
68c
89c
O
CO2Me
63
O
8
O
25
27
CN
24
5
6
11
13
86
78c,d
70
O
OMe
10
12
Scheme 3. Synthetic scale (1-mmol or greater) preparation
and Ti-catalyzed alkylation of alkyl chlorides
O
SO2Ph
26
NMe2
O
O
O
14
15
29
31
89a
7
8
15
17
OPh
O
dr = 1.6:1
Br
28
14
O
81(70e)
46a,f
SO2Ph
30
O
dr = 2:1
Bpin
16
All reactions werer conducted on 0.1 mmol scale unless otherwise noted with isolated
yields reported. aEtOAc as the solvent. b40 instead of 1. cWith 2 equiv of Zn, Et3N·HCl,
and alkene. d40 oC. e1.0 mmol scale. fAlCl3 (1 equiv) used as Lewis acid additive.
The Ti-catalyzed alkylation proceeded smoothly with an
array of structurally diverse 3 alkyl chlorides (Table 3,
entries 1–11). In particular, alkylated furanoindoline 45 was
obtained in
a synthetically useful yield from the
corresponding organochloride, and the structure was
identified with X-ray crystallography. Secondary alkyl
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Table 3. Alkyl Chloride Scope of Ti-Catalyzed Alkylation
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To gain further insight into the compatibility of various
functional groups with our reaction conditions, we examined
the impact of additives (1.0 equiv) on the efficiency of the
coupling process (Table 4). We found that adding
benzofuran, N-Me indole, 4-phenylbutene, 4-octyne, 2-
bromoethylbenzene, cyanobenzene, or phenyl methyl
sulfide has no adverse impact on the yield of the reaction,
with the additives recovered after the reaction. An aliphatic
ketone has a moderate inhibition effect on the reaction, with
product 3 isolated in 55% yield after 12 h. The presence of
phenols, alcohols, epoxides, or pyridines, however, impedes
the Ti catalysis, presumably by competitive coordination to
the oxophilic metal center.
Alternative approaches to accessing the same type of
products from alkyl chlorides frequently entail the
generation of corresponding Grignard reagents followed by
Michael addition31 or Sn-mediated radical processes,19a the
latter of which are often carried out in an intramolecular
fashion to avoid competitive hydrogen atom transfer (HAT)
and other side reactions. Our Ti-catalyzed reaction thus
provides an alternative platform for accessing these products
with significantly improved ease of operation, substrate
scope, and selectivity. Recently, several seminal
contributions in the area of radical catalysis made it possible
to obtain similar Giese-type products from common
functional groups (e.g., carboxylates,9 alcohols,10 and
alkenes11) other than alkyl chlorides. These methods,
however, cannot provide a general access to vicinally
difunctionalized products as described previously. In
addition, our reaction displays a different scope comparing
to many existing methods in terms of functional group
tolerance.32 Therefore, our Ti-catalyzed activation of alkyl
chlorides provides a complementary approach to the
catalytic radical reactions currently in place and allows an
additional class of common functional groups (R–Cl) to be
engaged in radical C–C bond formation.
Table 4. Additive effect on the Ti-catalyzed alkylation.
tBu
OH
Ph
N
O
Me
68
69
70
71
88%
>99%
22%
90%
OH
O
O
nPr
nPr
Ph
Ph
Me
Ph
Me
72
73
74
75
81%
16%
55%
<10%
CN
D. Mechanistic understanding of potential reaction
pathways
Br
S
tBu
N
Ph
Ph
Me
76
77
78
79
Spin trapping experiments support the intermediacy of
carbon-centered radicals in the alkylation reaction. In the
presence of 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and
96%
<5%
76%
90%
aYields of product 3 were determined with 1H NMR.
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1,4-cyclohexadiene (CHD), persistent nitroxyl radical 80 (Figure 1). In stark contrast, with Mn alone, catalyst
1
2
3
4
5
6
7
8
and HAT product 82 were formed, respectively (Scheme 4).
The HAT reaction also constitutes an efficient alternative
approach to the reduction of alkyl chlorides under Sn-/heavy
metal-mediated conditions. The stereochemical infidelity of
the reaction involving diastereomerically pure 66 also
accord with the radical mechanism. An alternative, non-
radical mechanism entails the in situ formation of an
alkylzinc species from Zn and the alkyl chloride followed by
Ti-catalyzed Michael addition. This possibility was ruled out
using a reaction with stoichiometric Ti, wherein the Zn dust
remaining after catalyst reduction was removed via filtration
before addition of the alkyl chloride and acrylate. Product 3
was still formed in 40% yield.33 Currently, a pathway
reduction was sluggish.
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involving Ti-catalyzed alkylzinc formation via
a
transmetallation process34 cannot be ruled out. This
mechanism, however, cannot account for the observed
hydrodehalogenation in the presence of CHD.
Scheme 4. Spin trapping experiments
Ph
DMPO (50 mol%)
Cp*TiCl3 (10 mol%)
Zn (1.5 equiv), Et3N·HCl (1.5 equiv)
Me
Me
N
Me
1
Me
toluene, 22 oC, 30 min
O
ESR:
80
g value = 2.006
mass = 260.20081
calc. for M+ = 260.20025
Cp*TiCl3 (10 mol%)
H
H
Zn (2.0 equiv), Et3N·HCl (2.0 equiv)
toluene, 22 oC, 12 h
N
Ph
Me
Me
38
+
O
81 (2.0 equiv)
82 (55%)
Figure 1. Reduction of Cp*TiCl3 by Mn in the presence or
absence of AlCl3. Top: UV-vis spectra showing the
reduction in the presence of AlCl3; the peaks at 450 and 330
nm are assigned to Cp*TiCl3 and its corresponding reduced
form, respectively. Bottom: Change in absorption at 450 nm
showing the reduction of Cp*TiCl3.
1H NMR experiments showed that in the presence of
AlCl3, a new Ti complex emerged. Cp*TiCl3 in toluene-d8
displays two CH3 resonances (2.12 and 1.95 ppm)
presumably arising from different aggregation states. We
tentatively assign these peaks to the monomeric and Cl-
bridged dimeric36 Ti complexes.37 Upon addition of AlCl3,
both resonances converged into a single signal at 1.93 ppm.
We tentatively assign this species to the Cl-bridged
Drastically different reactivity between Mn and Zn as the
terminal reductant (see Table 1, entry 9) suggested that these
metals do not serve simply as a reducing agent. As
previously discussed, Mn is incapable of reducing Cp*TiCl3
to TiIII in the reaction medium. Given Mn’s more negative
potential than Zn, we reasoned that the byproduct of the
reduction process, Zn2+, likely plays a crucial role in the
activation of the Ti catalyst.35 Indeed, in a control
experiment using Mn as the stoichiometric reductant, the
addition of Zn(OTf)2 restored the alkylation reactivity
(Table 5). Interestingly, other Lewis acids such as Sc(OTf)3
and AlCl3 can also promote the desired reaction.
Table 5. Lewis acid effect on the Ti-catalyzed alkylation.
heterometallic
dimer
with
a
composition
of
[Cp*TiCl3][AlCl3].38 The strong Lewis acidity of Al3+ can
thus facilitate the reduction of the Ti center. The speciation
of the active Ti complexes is currently underway.
NMR yield(%) of 3
Lewis acid (1 equiv)
None
<10
70
Zn(OTf)2
AlCl3
The mechanism of C–Cl activation by TiIII was
investigated using DFT computation (see SI). Cyclic
voltammetry data revealed that the potential required for the
reduction of 1 was at least 1.1 V more negative than that of
Cp*TiCl3 (Figure 2). As such, an outer-sphere electron
transfer from the TiIII catalyst to 1 is highly unlikely. Owing
to the higher dissociation energy of TiIV–Cl bond relative to
C–Cl bond, an inner-sphere Cl atom abstraction by TiIII
displays an energy barrier of only 6 kcal/mol. This
30
46
Sc(OTf)2
Reaction conditions: see Table 1, entry 9 but with Mn instead of Zn as the reductant
and a reaction time of 3 h.
Data from UV-vis experiments revealed that a strong
Lewis acid can indeed accelerate the reduction of Cp*TiCl3
by Mn. In the presence of 10 equiv of AlCl3 (with respect to
Ti), this reduction was nearly completed within 15 min
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mechanism provides an alternative means for the activation
of strong bonds that are conventionally inert to single-
electron transfer.
complimentary to existing protocols. Future efforts are
directed toward (1) understanding the structure of the active
Ti catalyst and its action in activating C–Cl and other strong
chemical bonds, and (2) expanding the new radical reactivity
of alkyl chlorides to other types of synthetically valuable
reactions.
1
2
3
4
5
6
7
8
0
Cp*TiCl3
tBuCl
-50
ASSOCIATED CONTENT
-100
-150
-200
-250
-300
9
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website.
Experimental procedures and characterization data (PDF)
Crystallography data for 45 (CIF)
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AUTHOR INFORMATION
Corresponding Author
-3000
-2500
-2000
-1500
-1000
-500
0
*songlin@cornell.edu
E(mV) vs Fc+/0
Present Addresses
Figure 2. Cyclic voltammetry of Cp*TiCl3 (2 mM) and
tBuCl (2 mM) in DCM (0.2 M Bu4NPF6) with a scan rate of
100 mV/s.
‡Department of Chemistry, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California
92037, United States
Taken together, a catalytic cycle was proposed (Scheme
5). The Cp*TiCl3 first undergoes a Lewis acid-assisted
electron transfer mediated by complex I to generate active
Cp*TiIIICl2.37 This lower-valent complex then abstracts a Cl
atom from the alkyl chloride, furnishing R· and closing the
catalytic cycle. The nascent R· then adds to the Michael
acceptor to form electrophilic radical II, which is
subsequently reduced and protonated to deliver the product,
likely in a Ti-mediated process. An alternative pathway for
the conversion of II to the product involves Cl atom transfer
from the Ti catalyst to II followed by reduction of the
resulting C–Cl bond. This pathway is less likely to operate
on thermodynamic grounds because Ti–Cl bond is
substantially stronger than C–Cl bond  to a carbonyl group
(typically < 80 kcal/mol).39
Notes
The authors declare no competing financial interest.
Crystallography data for 45 was deposited in the Cambridge
Structural Database (CCDC 1833922).
ACKNOWLEDGMENT
Funding support was provided by Cornell University. S.L.
thanks NSF for a CAREER award (CHE-1751839). This
study made use of the NMR facility (CHE-1531632)
supported by NSF and the ESR facility supported by NIGMS
(P41GM103521). We thank Dr. Terry McCallum for
reproducing experimental results, Gregory Sauer for
assistance with DFT calculations, Dr. Ivan Keresztes for
help with NMR spectral analysis, Dr. Samantha MacMillan
for help with X-ray crystal structure determination, and Dr.
Boris Dzikovski for assistance with ESR data acquisition.
Scheme 5. Proposed catalytic cycle.
Ti
E
E
REFERENCES
R
+e–, +H+
(II)
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B.; Bucher, C.; Burns, N. Z. Mar. Drugs 2016, 14, 206.
R
[M]–Cl (Lewis acid)
Cp*TiIVCl3
E
R
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Cl atom
abstraction
H
product
Cp*
Cl
Cl
Cl
Cl
Cp*
Cl
Cl
TiIII
TiIV
[M]
Cl
(I)
R
tentative structure
Lewis acid-
assisted reduction
[Re] (reductant)
Cp*
Cl
TiIII
Cl
[Re]–Cl + [M]–Cl
R
Cl
(or homodimer)
substrate
Conclusion
To summarize, we report the Ti-catalyzed radical
alkylation of unactivated secondary and tertiary alkyl
chlorides with Michael acceptors. This method provides
alternative means to generate carbon-centered radicals and
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32. For example, hypothetically, aryl bromides (14), alkyl bromides
(76), and aryl boronates (16) might not be compatible with Ni-
catalyzed conditions, tertiary amines (12) might not be compatible with
photoredox conditions, alkenes (66, 71) might not be compatible with
Fe-catalyzed hydroalkylation conditions, and alkyl halides (6, 76) and
ketones (74) might not be compatible with conditions involving Mg or
Grignard reagents.
33. If the reaction goes through the proposed mechanism, the
theoretical yield of reaction using 1 equiv of Cp*TiCl3 is 50%.
34. (a) Fleury, L. M.; Kosal, A. D.; Masters, J. T.; Ashfeld, B. L. J.
18. Ref. 17 shows 1 example of an unactivated 3° alkyl chloride.
Ref. 14e shows 1 example of a 3° benzyl chloride, the alkyl-metal
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Org. Chem. 2013, 78, 253−269. (b) Fleury, L. M.; Ashfeld, B. L. Org.
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reported and their formation in the reaction cannot be ruled out at this
stage.
1
2
3
4
5
6
7
8
35. Effect of metal reductants on the electrochemical behavior of
titanocenes: Enemærke, R. J.; Larsen, J.; Skrydstrup, T.; Daasbjerg, K.
J. Am. Chem. Soc. 2004, 126, 7853–7864.
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see: Paisner, S.N.; Lavoie, G.G.; Bergman, R.G. Inorg. Chim. Acta,
2002, 334, 253–275.
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Chem. 1984, 23, 3289–3292. Higher aggregation numbers have been
38. Cp*TiIIICl2 can exist as a dimer in solution as has been observed
with Cp2TiIIICl (ref. 35).
39. By analogy, BDE(C–Cl) in 2-chloropropionic acid is 72.1
kcal/mol. See: Lagoa, A. L. C.; Diogo, H. P.; Minas da Piedade, M. E.;
Amaral, L. M. P. F.; Guedes, R. C.; Costa Cabral, B. J.; Kulikov, D.
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R
Cl
TiIII
R
+
EWG
EWG
(2° and 3°)
Representative scope:
t
CO2 Bu
t
tBuO2C
CO2 Bu
6
7
8
9
TsN
CF3
O
H
N
Ph
CO2tBu
Me
Me
Me
N
H
Ts
O
Me
Me Me
Me
Me
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O
O
SO2Ph
Ph
Me
Bpin
MeO
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