Ni-Catalyzed Reductive Liebeskind-Srogl Alkylation of Heterocycles

Article abstract of DOI:10.1021/jacs.8b13534

Herein we present a Ni-catalyzed alkylation of C-SMe with alkyl bromides for the decoration of heterocyclic frameworks. The protocol, reminiscent to the Liebeskind-Srogl coupling, makes use of simple C(sp²)-SMe to be engaged in a reductive coupling. The reaction is suitable for a preponderance of highly valuable heterocyclic motifs. In addition to cyclic bromides, noncyclic alkyl bromides are well accommodated with exquisite levels of retention over isomerization. The protocol is scalable and permits orthogonal couplings in the presence of other functionalization handles.

Full text of DOI:10.1021/jacs.8b13534

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Communication
Ni-catalyzed Reductive Liebeskind-Srogl Alkylation of Heterocycles
Yuanhong Ma, Jose Cammarata, and Josep Cornella
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b13534 • Publication Date (Web): 16 Jan 2019
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Ni-catalyzed Reductive Liebeskind-Srogl Alkylation of Heterocycles
Yuanhong Ma, Jose Cammarata and Josep Cornella*
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, Mülheim an der Ruhr, 45470, Germany.
Supporting Information Placeholder
(Scheme 1C). The method is characterized by the presence of a vari-
ety of aromatic heterocycles, thus permitting rapid decoration of
pharmaceutically relevant scaffolds. The utility of this protocol is
demonstrated by the facile scalability to gram-scale and the sequen-
tial modification of a heterocyclic framework via orthogonal cou-
plings.
ABSTRACT: Herein we present a Ni-catalyzed alkylation of C‒SMe
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with alkyl bromides for the decoration of heterocyclic frameworks.
The protocol, reminiscent to the Liebeskind-Srogl coupling, makes
use of simple C(sp2)‒SMe to be engaged in a reductive coupling. The
reaction is suitable for a preponderance of highly valuable heterocy-
clic motifs. In addition to cyclic bromides, non-cyclic alkyl bromides
are well accommodated with exquisite levels of retention over isom-
erization. The protocol is scalable and permits orthogonal couplings
in the presence of other functionalization handles.
The functionalization of heterocycles via cross-coupling has be-
come a powerful tool towards the diversification of biologically ac-
tive compounds.1 In this context, the vast majority of electrophiles
utilized rely primarily on the use of a heteroaryl halide as coupling
partner due to its large availability.2 Nevertheless, in certain occa-
sions, issues arising from stability and fast hydrolysis rates of het-
eroaryl halides had led to a reconsideration of such couplings and al-
ternatives have been investigated.3 In this sense, the venerable
Liebeskind-Srogl (L‒S) coupling opened the door to the use of robust
and stable C‒SMe bonds as handles for C(sp2)‒C(sp2) coupling uti-
lizing boronic acids (Figure 1A).4 This approach has proven highly
versatile in the derivatization of heteroaromatic groups as well as thi-
oester derivatives.5 The widespread presence of thioether as modifi-
cation handles has led to the development of a wide variety of cross-
coupling strategies with a breadth of different organometallic rea-
gents.6,7 Indeed, the majority of reported methods require the use of
a prefunctionalized alkyl nucleophile, thus requiring several steps of
synthesis for its preparation and, in some instances, the tolerance of
functionality becomes a synthetic hurdle. Hence, alternatives to effi-
ciently forge such bonds in a straightforward fashion would be highly
desirable.
Figure 1. (A) The Liebeskind-Srogl reaction. (B) Overview of the aryl coun-
terparts in cross-electrophile coupling. (C) Ni-catalyzed reductive L‒S alkyl-
ation of heteroaromatic thioethers.
Based on their great catalytic activity in reductive cross-electrophile
couplings, we started our investigations exploring the use of a Ni cat-
alyst in the presence of a reducing agent. Initially, thiomethyl ether 1
and CyBr (2) were used as model substrates for the coupling.14 We
anticipated that an electron-rich ligand for the Ni would be necessary
for the activation of the strong C‒SMe bond. Indeed, catalytic
amounts of NiBr2·diglyme and dppf in the presence of Zn (2.5 equiv.)
and K2HPO4 (2.0 equiv.) afforded the desired C‒C product 3 in 72%
isolated yield (Table 1, entry 1).
Recently, reductive cross-couplings between two electrophiles
have arisen as powerful, simple and practical strategies to circumvent
the preparation of reactive organometallic reagents (Figure 1B).8 Al-
beit a plethora of methodologies have been reported in this area, the
vast majority have focused on the use of aryl halides or pseudo-hal-
ides where the C(sp2)‒X bond is polarized due to the electronegative
nature of the X element (inductive effect).9 On the other hand, reduc-
tive couplings with C(sp2)‒X, where X is electronically contributing
to the aryl ring via additional resonance effects through the lone pair
pose a significant challenge and still remain elusive.10 Contrarily to
the activation of simple aryl (pseudo)halides, C(sp2)‒SMe bonds re-
quire highly nucleophilic catalysts for its activation. This results in
chemoselectivity issues arising from the alkyl halide counterpart ul-
timately leading to undesired side-reactivity. Consequently, a fine
compromise between reactivity and selectivity is crucial if this reduc-
tive coupling is to be realized. Additionally, the tendency of SMe an-
ions to tightly bind to metal centers also poses a potential hurdle for
achieving catalytic turnover without poisoning the metal catalyst.11
As part of our program on developing catalytic strategies for the mod-
ification of heterocyclic frameworks,12 we envisaged that a catalytic
reductive cross-coupling between heteroaromatic thioethers and sim-
ple alkyl bromides would be highly beneficial for synthetic pur-
poses.13 Herein, we report a practical and efficient Ni-catalyzed pro-
tocol based on the activation of C‒SMe bonds, which are primed for
reductive cross-coupling with a variety of secondary alkyl bromides
Table 1. Optimization of the reaction.a
a1 (1 equiv, 0.2 mmol), 2 (2.0 equiv.), NiBr2·diglyme (10 mol%), dppf (10
mol%), K2HPO4 (2.0 equiv.), Zn (2.5 equiv.), 4Å MS in DMA (0.6 mL) at
100 °C, 6 h. bYields calculated by GC-FID using dodecane as internal stand-
ard. cIsolated yield.
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As highlighted in the optimization studies, omission of molecular
benzoxazole thioethers as exemplified by 12. With the aim of expand-
sieves led to a slight decrease on the yield (Table 1, entry 2). Moreo-
ver, the basicity of the additive utilized seemed a crucial element as
demonstrated by the lower yields obtained when tri- or monobasic
phosphates of potassium were used (entries 4 and 5). Interestingly,
the use of Mn in place of Zn as reducing agent completely suppressed
the reactivity (entry 6). Other NiCl2 salts bearing glyme instead of
diglyme also led to lower conversion and yield (entry 7). The low
yields of 3 obtained when using Fc-P(Cy2)2 highlight the crucial elec-
tronic aspects of dppf for successful catalysis (entry 8). The use of a
bidentate phosphine with a wider bite angle such as Xantphos also
afforded the desired product 3 albeit in much lower yields, thus sug-
gesting the need for a rigid cis-chelating phosphine (entry 9). As an-
ticipated, the use of commonly utilized dinitrogenated ligands such
as dtbpy led to traces of C‒C formation (entry 10).8 Finally, lower
temperatures reduced dramatically the amount of cross-coupling
product (entry 11).
ing the methodology to a wider chemical space, a variety of structur-
ally distinct heterocyclic frameworks was surveyed. Gratifyingly, the
protocol was applicable to 2-pyridines (13, 14, 19), 2-quinolines (15),
1-isoquinoline (16), 2-pyrimidine (17) and 3-pyridazine (18). The
ability to forge C‒C bonds in compounds bearing Lewis-basic N-con-
taining motifs highlights the potential of the method when applied to
complex drug-like settings. Compound 1 successfully coupled with a
variety of alkyl bromides; 4-, 5- and 7- membered cycloalkyls (20-
22) as well as bicyclic norbornyl (23) afforded good yields of cou-
pling product. Heterocyclic bromides such as 4-tetrahydropyrane
(24) and 4-piperidine (25 and 26) smoothly reacted in good yields.
The polycyclic bromide derived from natural cholesterol was also
amenable for coupling under the reaction conditions (27). At this
point we investigated the ability of the catalytic system to accommo-
date challenging open-chain secondary alkyl bromides. Catalytic sys-
tems featuring Ni in combination with bidentate electron-rich phos-
phines has traditionally led to deleterious isomerization events
through degenerated Ni(II) intermediates, thus affording syntheti-
cally unviable branched and linear mixtures.16 However, despite the
use of dppf as ligand, when 2-bromoheptane was subjected to the re-
action conditions, branched product was obtained as single isomer
(28). This observation points out to a mechanism involving different
species than the canonical (dppf)Ni(II)(aryl)(alkyl) intermediate
(vide infra). Despite the effort to accommodate primary alkyl bro-
mides, their reactivity lead to substantially lower yields (29). A vari-
ety of non-cyclic bromides was explored and revealed the possibility
of coupling secondary bromides bearing aromatic groups (30), esters
(32), protected alcohols (31, 33) and amines (34). Alkyl bromides
bearing heterocyclic furan (35) and thiophene esters (36) smoothly
coupled with good yields. Unfortunately, tertiary alkyl bromides
could not be accommodated. The use of other thioethers bearing
longer alkyl chains in place of Me also could be accommodated as
highlighted by the reaction of 37 and 38. It is important to mention
that when a bis-aryl thioether is utilized (39), high regioselectivity in
the C‒S cleavage event was observed in favor of the benzothiazole
unit. The scalability of the process was investigated as exemplified in
Figure 2A: at 10 mmol scale, 1 and 2 successfully afforded gram-
quantities of the desired C‒C bond with minimal erosion of the yield.
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Table 2. Scope of the reductive Liebeskind-Srogl alkylation.a,b
Figure 2. (A) Scalability; (B) Decoration of the benzothiazole core via se-
quential activation of challenging bonds.
aThioether (1 equiv, 0.2 mmol), alkyl bromide (2.0 equiv.), NiBr2·diglyme (10
mol%), dppf (10 mol%), K2HPO4 (2.0 equiv.), Zn (2.5 equiv.), 4Å MS, DMA
(0.6 mL) at 100 °C, 6 h. bIsolated yields. cAlkyl bromide (3.0 equiv.). d50 °C,
24 h. e12 h. fTraces of alkylation at Ph‒S cleavage observed by GCMS.
To test the translational potential of our method in pharmaceutically
relevant contexts, we applied the reductive protocol to the modifica-
tion of the benzothiazole core, a prevalent motif in a wide variety of
biologically active compounds.17 As shown in Figure 2B, after suc-
cessful reductive alkylation (88%), benzothiazole thioether 40 could
be further modified at its C(sp2)‒F through Sawamura’s Ni-catalyzed
amination to afford 81% of the drug-like scaffold 41.18 In the same
manner, piperidyl derivative selectively reacted with 40 to afford ex-
cellent yields of C‒C coupling (71%). Subsequently, a more nucleo-
As shown in Table 2, the protocol was optimal for the coupling of
benzothiazole derivatives bearing a variety of functionalities: nitriles
(4), fluorides, (5), alkyl (6), esters (7), ethers (9, 11), trifluoromethyl
(10) and thiophene groups (8) were all well accommodated. Ni salts
have been shown to activate anisole and arylfluoride derivatives at
high temperatures.15 However, no activation of the C‒F (5) or C‒
OMe (9, 11) was observed and could serve as points for further deri-
vatization. (vide infra). Moreover, the reaction could be expanded to
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philic primary amine could also be incorporated through C‒F amina-
bromopropyl)benzene under reductive conditions afforded exclu-
2
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tion to afford the complex target 42 in 43% without further optimiza-
tion.
sively the branched product 30-B independently of the phosphine
(Figure 4B). On the contrary, the reaction of 2-pentyl zinc bromide
under the same conditions afforded mixtures of 30-B and 30-L
(1.5:1), thus ruling out well-defined organozinc halides as intermedi-
ates. Taken together, these preliminary investigations suggest that the
Ni is responsible for the radical formation and fast cage-rebound oc-
curs.22 Additionally, the no-isomerization observed with open chain
secondary centers point out to a fast reductive elimination from
higher oxidation states of a Ni/phosphine complex.23 Efforts to eluci-
date these intriguing phosphine-Ni intermediate species are currently
under investigation.
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Intrigued by the high levels of retention over isomerization with the
use of dppf, a series of mechanistic investigations were performed.
Albeit the low reactivity of primary alkyl bromides, we conducted the
coupling of cyclopropylmethyl bromide to explore possible ring-
opening events (Figure 3A). Indeed, 43-D and 43-O were obtained in
1:2 ratio respectively. This result suggests the involvement of carbon-
centered alkyl radical species during the course of the reaction. Ad-
ditionally, the presence of radical scavengers such as TEMPO and
1,1-diphenylethylene was also investigated (Figure 3B). Whereas the
presence of 1 equiv. of TEMPO led to a dramatic decrease in yield of
3, 2 equiv. of TEMPO completely suppressed the reactivity. This in-
hibition could be the result of the interaction with Ni or Zn. However,
1,1-diphenylethylene was used instead, formation of product (3,
19%) was accompanied by the formation of 44 and 44-H2. Although
these results might point out to non-cage events of the alkyl radical,
experiments with a 5-exo-trig cyclization suggest otherwise. If a rad-
ical-chain process is operating, the formation of uncyclized product
should augment when increasing the amount of Ni.9f However the
ratio of uncyclized (46-U) and cyclized (46-C) cross-coupled product
remained unaffected at higher concentrations of catalyst (ca 1:1.5).
Interestingly, when Zn was replaced by the common organic reducing
agent TDAE (tetrakis(dimethylamino)ethylene), no product was ob-
tained (Figure 4A). Due to the unique reactivity of Zn in this system,
we speculated whether an organozinc reagent was formed in situ.19
Precedents in Pd-catalyzed Negishi aryl-alkyl cross-coupling clearly
demonstrated a strong effect of the phosphine ligands in the isomeri-
zation of the nucleophile.16,20 Similarly, reports on the use of Ni as
catalyst for Negishi couplings are restricted to di- or tri-amine based
ligands to obtain high levels of selectivity.21
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Figure 4. (A) Involvement of organozinc species; (B) Effect of the phosphine
ligand in the branched to linear ratio. a2.5 equiv. of Zn was added. bGC yield.
In summary, we have developed a Ni-catalyzed protocol for the di-
rect alkylation of thiomethyl ethers (C(sp2)‒SMe bonds) derived
from heterocycles, which represent important handles commonly en-
countered in medicinal chemistry routes. This protocol has a wide
substrate scope in both coupling partners and a high functional group
tolerance. The high selectivity obtained towards the branched isomer
with the use of simple dppf reveal interesting mechanistic scenarios
which might differ from the canonical reductive cross-electrophile
couplings. The successful coupling of strong C(sp2)‒SMe bonds in
cross-electrophile couplings opens the door to the use of other chal-
lenging partners with strong bonds to be included in the palette of
electrophiles.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and analytical
data (1H, 19F and 13C NMR, HRMS). This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
E-mail: cornella@kofo.mpg.de (J.C.)
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support for this work was provided by Max-Planck-Gesell-
schaft, Max-Planck-Institut für Kohlenforschung and Fonds der
Chemischen Industrie (FCI-VCI). We thank Prof. Dr. A. Fürstner for
discussions and generous support.
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