Formation of quaternary carbons through cobalt-catalyzed C(sp3)-C(sp3) Negishi cross-coupling

Article abstract of DOI:10.1039/d0cc02734k

Formation of all-carbon-substituted quaternary carbons is a key challenge in organic and medicinal chemistry. We report a cobalt-catalyzed C(sp3)-C(sp3) cross-coupling that allows for the introduction of benzyl, heteroarylmethylzinc and allyl groups to halo-carbonyl substrates. The cross-coupling reaction is selective for C(sp3)-over C(sp2)-halides, in contrast to most used catalytic metals, and allows access to novel scaffolds of pharmaceutical interest. NMR mechanistic studies suggest the presence of Co(0) complexes as catalytic species. This journal is

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DOI: 10.1039/D0CC02734K
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Formation of quaternary carbons through cobalt-catalyzed C(sp3)-
C(sp3) Negishi cross-coupling.
Received 00th January 20xx,
Accepted 00th January 20xx
Eduardo Palao,a Enol López,b Iván Torres-Moya,b Antonio de la Hoz,b Ángel Díaz-Ortiz,b Jesús
Alcázar*a
DOI: 10.1039/x0xx00000x
Formation of all-carbon-substituted quaternary carbons is a key
challenge in organic and medicinal chemistry. We report a cobalt-
catalyzed C(sp3)-C(sp3) cross-coupling that allows for the
introduction of benzyl, heteroarylmethylzinc and allyl groups to
halo-carbonyl substrates. The cross-coupling reaction is selective
for C(sp3)- over C(sp2)-halides, in contrast to most used catalytic
metals, and allows access to novel scaffolds of pharmaceutical
interest. NMR mechanistic studies suggest the presence of Co(0)
complexes as catalytic species.
CoBr2 (10 mol%),
Ligand (20 mol%),
Additive (10 mol%)
EtO2C
Br
EtO2C
BrZn
+
1 h, Solvent, T
2
1
3
(2 equiv)
Table 1. Optimization of reaction conditions.
Entry
1b,c
2c,d
3 d
4 d
5 d
6 d
7
Ligand
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppe
dppe
dppp
dppb
Xantphos
Josiphos
Symphos
Binap
(Et)2P-Et-
P(Et)2
dppbz
-
Solvent
DMF
DMF
T(ºC)
rt
rt
3:1 ratioa
25:75
45:55
48:52
65:35
16:84
6:94
Escaping flatland is a clear requirement in drug discovery with
the aim of improving success rate.1 In order to increase the
C(sp3) fraction in bioactive molecules new procedures for alkyl-
alkyl cross-coupling are required. Despite the evolution in this
field the formation of all-carbon-substituted quaternary
carbon atoms remains a complex challenge.2
In the last few years, several Ni and Pd catalysed alkyl-alkyl
cross-coupling reactions have been described in literature.3
Their scope of these transformations is rather limited due to -
hydrogen elimination side reactions.4 Recently cobalt has
appeared as an inexpensive and less toxic alternative for cross-
coupling.5 However, alkyl-alkyl bond formation using cobalt
remains a challenge. The first Co-catalysed C(sp3)-C(sp3)
coupling was reported by Cahiez and co-workers using
Grignard reagents as nucleophiles.6 The methodology allows
the preparation of secondary and tertiary carbon centres and
shows limited functional group tolerance.
DMF
40
40
40
40
40
40
40
40
40
40
40
40
40
40
DMF/THF
Toluene/THF
THF
DMF/THF
DMF/THF
DMF/THF
DMF/THF
DMF/THF
DMF/THF
DMF/THF
DMF/THF
DMF/THF
DMF/THF
97:3 (45%)
100:0 (55%)
94:6
100:0 (49%)
41:59
8
9e
10
11
12
13
14
15
16
40:60
100:0 (38%)
50:50
6:94
1:99
17
18
19f
DMF/THF
DMF/THF
DMF/THF
40
40
40
27:73
4:94
0:100
In the context of Drug Discovery projects, the development of
methods with wide functional group tolerance is essential for
the functionalization of advanced synthesis intermediates and
drug candidates. Organozinc reagents are known to be more
functional group tolerant nucleophiles than Grignard ones,7
and
-
aReaction progression as 3/1 ratio by GC/MS, isolated yields in brackets; bZn as additive;
cOvernight reaction: dMg as additive; eCoBr2 (5 mol%); fReaction in the absence of CoBr2.
for instance, Knochel and co-workers reported recently the use
of aryl zinc reagents in cobalt catalysed C(sp2)-C(sp3) coupling
with -bromolactones for the preparation of tertiary carbon
centers.8a This prompted us to explore the reactivity of
organozinc reagents under cobalt catalysis for preparation of
C(sp3)-C(sp3) bonds, specifically focusing on the formation of
all-carbon-substituted quaternary centres that remains a
challenge in organic and medicinal chemistry. In the course of
our investigations Knochel et al. published the first cobalt
a. Discovery Chemistry, Janssen Research and Development, Janssen-Cilag, S.A., C/
Jarama 75A, Toledo, Spain. E-mail: jalcazar@its.jnj.com.
b. Facultad de Ciencias y Tecnologías Químicas, Universidad de Castilla-La Mancha,
Ciudad Real, Spain.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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catalysed Negishi type C(sp3)-C(sp3) coupling with primary and ligands with different electronic and coordinating properties
View Article Online
secondary alkyliodides.8b
were then tested (Entries 7-17 and supporting information).
DOI: 10.1039/D0CC02734K
For our initial screening of reaction conditions, we selected Bidentate phosphorus ligands with diaryl substitution pattern
ethyl 1-bromocyclobutane-1-carboxylate 1 and benzylzinc (Entry 8), and bite angles between 85°-93° (Entries 7, 8, 10 and
bromide 2 as model substrates and CoBr2 as cobalt source 13) resulted in better conversions.10 From all ligands dppe was
(Table 1). As we anticipated that cobalt(II) was not going to be the best performing leading to product 3 in 55% of isolated
the active catalytic species, we investigated its reduction to yield (Entry 8). Triarylphosphines (Entries 15 and 17) failed to
Co(I) or Co(0) using zinc or magnesium additives.9 Initial work despite the appropriate bite angle (see supporting info),
reaction with Zn(0) as additive showed 25:75 conversion to 3 suggesting that electron density around phosphorous atoms
(Entry 1), however the use of Mg(0) improved this conversion may play an important role in the reaction outcome. An
(Entry 2). Increasing the temperature to 40oC resulted in a attempt to reduce the catalyst loading to 5% was slightly
slightly increased 48:52 conversion (Entry 3).
detrimental for the reaction conversion (Entry 9). The
Solvent screening showed that a mixture of DMF/THF (1:1) importance of both ligand and catalyst was confirmed
provided the best results (Entries 3-6). To our surprise, in the performing the corresponding blank experiments (Entries 18
absence of additive a 97:3 conversion was observed and and 19).
product 3 was isolated in 45% yield (Entry 7). A variety of
Scheme 1. Scope of cobalt catalysed cross-coupling.
EWG
R1
X
CoBr2 (10 mol%), dppe (20 mol%)
EWG
R1
R
R
+
BrZn
R2
R2
DMF/THF 1:1, 40ºC, 1 h
(2 equiv)
(X = Br)
EtO2
MeO2
C
O
MeO2
C
C
EtO2
C
highlight the compatibility with halogenated derivatives
which would allow further derivatization of the phenyl ring
in the reaction products 13-15. Furthermore, electron rich
(18) or electron deficient (19-20) heteroarylmethylzinc
bromides were successfully used in this transformation
providing the desired products in practical yields. More
complex organozinc derivatives, such as those containing
an -unsaturated ester, were also fruitful partners in
this transformation, as demonstrated with the preparation
of compound 21.
O
HO
O
3, 55%
4, 40%
5, 46%
6, 51%
7, 44%
O
O
MeO2
C
MeO2C
O
PthN
OCF3
CO2Me
O
N
H
O
Ph
8, 59%
9, 56%
10, 45%
11, 64% (X = Cl)
12, 53%
Br
Cl
F3C
SO2Me
MeO2
C
MeO2
C
MeO2
C
MeO2
C
MeO2C
Br
13, 60%
14, 59%
15, 47%
16, 27%
17, 46%
Br
Cl
O
CF3
O
O
N
BnO2C
MeO2
C
MeO2
C
O
O
O
N
N
PthN
OEt
N
O
Boc
18, 41%
19, 35%
20, 64%
21, 56%
22, 43%
Br
Br
Br
Br
Next, we evaluated the reactivity of an array of
heterocyclic scaffolds of common use in medicinal
chemistry. In this regard, four to six membered cyclic
amine bromoesters yielded the corresponding coupling
compounds 22-26 in satisfactory yields. Interestingly, a
carboxylic acid function did not affect the reaction
outcome and compound 24 was obtained in comparable
yield to the match-pair ester 23. A pyrrolidine derivative (25)
was prepared from the commercially available bromocyano
precursor, highlighting the ability of the nitrile group to
promote this transformation. This finding prompted us to
explore additional cyano-substituted precursors as an
alternative to carboxyl group. Gladly the nitrile derivatives 26
and 27 were obtained in satisfactory yields. Noteworthy,
chloro derivatives could also be successfully used in the
reaction and derivatives 11, 25, 27 and 29 were isolated in
moderate to good yields (34-68%), broadening the scope in
terms of suitable halogenated derivatives. Compound 24 was
scaled up at gram scale for a side reaction study. A
reproducible isolated yield was obtained (37%), being
dehalogenation (16%) and -elimination (13%) the main side
products observed (see supporting information).
BnO2
C
HO2
C
NC
NC
N
NC
OCF3
N
N
Boc
Boc
27, 68% (X = Cl)
Br
23, 40%
24, 36% (3 eq. R-ZnBr)
25, 34% (X = Cl)
26, 52%
Br
Br
O
Boc
N
O
EtO2
C
MeO2
C
HO
O
MeO2
C
N
N
Boc
Boc
32, 0%
28, 48%
29, 65% (X = Cl)
30, 0%
31, 0%
33, 0%
Conditions described in Table 1, Entry 8 were chosen as
optimal and used to explore the reaction scope (Scheme 1).
First, different tertiary -bromo esters were studied. The
reaction conditions were compatible with cyclic and acyclic
halogenated derivatives and coupling products 3-6 were
obtained in moderate yields. The transformation was also
compatible with the presence of heteroatoms either at the
alkyl substituents 6 or at the ester alkoxy group 7,8. Thus
hydroxy- (7) and phthalimide-containing (8) esters were
isolated in 44 and 59% yield respectively. Cyclic esters were
suitable coupling partners and lactone 9 could be isolated in
56% yield. Interestingly, secondary amides underwent the Co-
catalyzed Negishi-type coupling affording the corresponding
product in comparable yield (10, 45% vs 4, 40%).
To expand the reaction scope a set of diverse organozinc
reagents was prepared following our previously published
protocol.11 Different benzyl zinc bromides were compatible
with the reaction. Among these groups it is noteworthy to
In addition to the formation of quaternary carbons, this
chemistry was tested for the preparation of tertiary carbon
centers. As proof of our concept, 2-halogenated-2-
phenylacetates were reacted with benzyl zincbromides under
2 | J. Name., 2012, 00, 1-3
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Figure 1. NMR studies: a) Reaction used for mechanistic studies; b) Evolution of
standard conditions. Interestingly, compounds 28 and 29 were
successfully prepared in reasonable yields. However, the
reaction did not provide the desired compound when -
bromoester group was replaced by ketone, alcohol and acetyl
moieties (30-32). Reaction also failed when a non-benzylic
alkylzinc was used (33). Probably this class of organozinc
reagents are no able to reduce Co(II) and no effective reaction
was observed.
compound 40 at different concen-trations of CoBr2.
View Article Online
DOI: 10.1039/D0CC02734K
a)
F3
C
CF3
CF3
EtO2
C
EtO2
C
Br
CoBr2, dppe
DMF/THF
BrZn
+
+
CF3
16
41
40
39
b)
As mentioned above, the fact that the reaction is compatible
with halogenated benzyl zinc derivatives provides
opportunities for further derivatization of the coupling
products. For instance, the spiroquinolone 34 could be
prepared in 65% yield from compound 14 after Buchwald
coupling with 3-methylaniline followed by intramolecular
cyclization (Scheme 2a). This exemplifies the value of this
chemistry to access novel scaffolds of pharmaceutical interest.
Scheme 2. Applications of cobalt catalysed cross-coupling: a) preparation of
a)
19F-NMR. dppe + 2 eq. 39 + CoBr2 to give 1,2-bis(2-trifluoromethyl)phenylethane 40.
BrettPhos Pd G3 (1 mol%)
X-Phos (1 mol%)
NatOBu (1.2 equiv.)
Br
N
+
CO2Me
In order to identify the catalytic species involved in the
reaction mechanism 19F-NMR and 31P-NMR experiments were
performed. For this study the cross coupling reaction of 2-
(trifluoromethyl)benzylzinc bromide 40 with ethyl 1-bromo-1-
cyclohexylcarboxylate 39 to give the coupling product 16 was
chosen (Figure 1a). Experiments were performed in a mixture
of non-deuterated DMF/THF to identify and assign the signals
corresponding to the reagents, possible products and by-
products of the reaction (Figures S1-S6 in Supporting
Information). This study showed that products 16 and 1,2-
bis(2-trifluoromethyl)phenylethane 41, a common by-product
from the oxidation of the organozinc reagent with different
metals, are formed in the reaction. Interestingly the dimer of
the organozinc reagent (41) formed relatively fast in the
mixture and the signals of product 16 started to increase after
the signals of the dimer became stable. This suggests an
activation step is needed for to the formation of the catalytic
complex (Figure S8 in Supporting information). It should be
noted that due to the quadrupolar character of 59Co, signals
became broad preventing their proper integration.17
1,4-dioxane, 100 ºC
O
H2
N
1.2 equiv.
34, 65%
14
Br
b)
Br
Br
Br
Standard
conditions
O
O
CO2Me
CO2Me
Br
+
+
O
+
O
BrZn
36
35
37, 37%
38, traces
scaffolds of pharmaceutical interest; b) chemoselectivit1y9 of cobalt-catalysed
:
1
cross-coupling reaction.
Furthermore, to study the chemoselectivity of the reaction, a
competitive study with a mixture of a bromoalkyl (35) and
bromoaryl (36) esters was performed (Scheme 2b).
Gratifyingly, analysis of the reaction crude showed compound
37, product from C(sp3)-C(sp3) pathway, was largely favored
over compound 38 coming from the C(sp3)-C(sp2) process in
competition (ratio 37:38 19:1). This result illustrates the value
of cobalt catalysis for alkyl-alkyl cross couplings over
traditional catalytic process involving Pd,12 Ni13 or Fe14
organometallic complexes.
To determine the relationship between the formation of 41
with the catalyst loading and to stop the reaction at the
formation of the catalytic complex a new set of experiments
was performed in the absence of the alkyl bromide 39.
Recording 19F-NMR in the presence of 0, 5, 20 and 50 mol% of
CoBr2 it was observed that the amount of 41 increased with
the concentration of the metal salt. These results suggest a
redox process between the organozinc derivative 40 and Co(II)
leading to a reduced form of the metal (Figure 1b). The 31P-
NMR spectra contained a new phosphorous signal at = 37.97
ppm (Figure S8 in Supporting Information). Comparison of the
chemical shift observed for this signal with the one of
coordination of dppe with Co(CO)2Cp (= 28.96 ppm, Figure S9
in Supporting Information) and the previously reported dppe
complex with Co4(CO)12 (= 29.9, 30.6 ppm)18 suggests the
potential presence of Co(0) species in the reaction media.
Chemical shifts for dppe Co(I) complexes are described at
lower fields (> 50 ppm).19
In order to shed some light on the reaction mechanism two
approaches were followed: use of radical traps to study the
potential involvement of radical processes and NMR kinetic
studies aiming to identify the active catalytic species.
BHT and 1,1-dipheylethene were selected as radical traps as
other typical reagents used for this purpose, such as TEMPO,
are not compatible with the use of organzinc reagents.15
Neither BHT nor 1,1-diphenylethene quenched the reaction,
which suggests a non-radical pathway, although this cannot be
completely ruled out (see Scheme S2 in Supporting
Information).
However,
when
ethyl
2-bromo-2-
cyclopropylacetate was used as a radical clock reagent,16 the
corresponding ring opened product was obtained in low yield.
This suggest the presence of radicals in the course of the
reaction (see Scheme S3 supporting information).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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and M. R. Gagn, J. Am. Chem. Soc., 2008, 130, 12177; (l) H.
Conclusions
Gong, R. Sinisi and M. R. Gagn, J. Am. Chem. SocV.,ie2w0A0rt7ic,le1O2n9lin,e
DOI: 10.1039/D0CC02734K
In summary, a new cobalt catalyzed C(sp3)-C(sp3) Negishi cross-
coupling protocol has been developed leading to all-carbon-
substituted quaternary carbon centers in an effective manner.
Reaction was performed under mild conditions and did not
require the use of any additives other than the reagents and
the catalytic complex. The use of mono-organozinc reagents
broaden the scope of the reaction as they can be easily
prepared in flow and added directly into the reaction.
Regarding the tertiary alkyl halide, different electron
withdrawing groups such as esters, amides, nitriles and
carboxylic acids are tolerated. The catalytic system showed
strong preference for halides on sp3 hybridized carbon atoms
over typical aryl bromides, a reversed behavior compared to
most used cross-coupling metals. This fact allowed the access
of interesting intermediates for the synthesis of novel useful
scaffolds for medicinal and organic chemists. 19F-NMR and 31P-
NMR mechanistic studies suggest the involvement of radicals
as well as Co(0) complexes in the catalytic cycle. Additional
studies to fully elucidate the reaction mechanism are ongoing
and will be matter of future publications.
1908.
4
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgment
Authors want to thank Dr. Andrés Trabanco for his comments
during the preparation of this manuscript and Dr. Carlos
Martinez for his help in the purification of clock reaction
product.
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