Quaternary Centers by Nickel-Catalyzed Cross-Coupling of Tertiary Carboxylic Acids and (Hetero)Aryl Zinc Reagents

Article abstract of DOI:10.1002/anie.201814524

This work bridges a gap in the cross-coupling of aliphatic redox-active esters with aryl zinc reagents. Previously limited to primary, secondary, and specialized tertiary centers, a new protocol has been devised to enable the coupling of general tertiary systems using nickel catalysis. The scope of this operationally simple method is broad, and it can be used to simplify the synthesis of medicinally relevant motifs bearing quaternary centers.

Full text of DOI:10.1002/anie.201814524

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Quaternary Centers via Ni-Catalyzed Cross-Coupling of Tertiary
Carboxylic Acids and Aryl Zinc Reagents
Authors: Phil S. Baran, tie-gen chen, haolin zhang, pavel k mykhailiuk,
rohan merchant, Courtney smith, and tian qin
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201814524
Angew. Chem. 10.1002/ange.201814524
Link to VoR: http://dx.doi.org/10.1002/anie.201814524
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10.1002/anie.201814524
Angewandte Chemie International Edition
COMMUNICATION
Quaternary Centers via Ni-Catalyzed Cross-Coupling of Tertiary
Carboxylic Acids and Aryl Zinc Reagents
Tie-Gen Chen, Haolin Zhang, Pavel K. Mykhailiuk, Rohan R. Merchant, Courtney A. Smith, Tian Qin,
and Phil S. Baran*
extensive investigations that are fully summarized in the
Supporting Information. The reaction was amenable to a one-pot
procedure involving in situ activation (entry 2). Although the
reaction required a TCNHPI- rather than the NHPI-based RAE
(entry 3), the aryl zinc species could be either a diaryl or arylzinc
halide, requiring 1.5 or 3.0 equiv., respectively (entry 4).
Consistent with Molander’s observations, the addition of ZnBr2
had a slight but meaningful effect (ca. 10%) on the yield (entries
5 and 6) whereas a lower yield was observed in the presence of
Mg-based analogs (entries 7 and 8). A solvent screen identified
the DMI/THF mixture as superior to THF alone or DMF in place
of DMI (entry 9). Lowering the catalyst loading to 10%
decreased the reaction yield to 65% (entry 10). Finally, a screen
of metal catalysts and ligands demonstrated that Fe- and Co-
catalysts were not interchangeable (entry 11); while Ni(dpm)-
2•xH2O was optimum (entries 1, 12-17).
Abstract: This work bridges a gap in the cross-coupling of aliphatic
redox-active esters with aryl zinc reagents. Previously limited to
primary, secondary and specialized tertiary centers, a new protocol
has been devised to enable the coupling of general tertiary systems
using Ni-catalysis. The scope of this operationally simple method is
broad and can be used to simplify the synthesis of medicinally
relevant motifs bearing quaternary centers.
Recent interest in expanding rapid access to unique
chemical space through the enablement of new cross-coupling
methods has been enormous.1 This, in part, is due to the
retrosynthetic logic employed widely in discovery sciences
towards medicines, agrochemicals, and materials, placing
emphasis on convergent, modular disconnections.2 Such
pathways have been further stimulated by the myriad of vendors
selling specialized building blocks rendering an almost limitless
variety of subunits available to industrial chemists.3 Within this
context, we were specifically drawn to the problem of
constructing quaternary carbons, specifically those connected to
an arene. Such motifs are found throughout the patent literature
and are usually accessed through multi-step sequences (Figure
1A).4 Over the past decade, an explosion of interesting new
techniques have emerged for achieving direct cross-couplings
using alkyl halides,5 boronic acid derivatives,6 Grignard
reagents,7 and most recently, olefins.8 While certainly useful, the
substituents on such precursors (R1, R2, R3) are not easily
programmable in addition to the fact that tertiary halides, borates,
and Grignard reagents can be difficult to access. In contrast, a
carboxylate coupling partner, of which thousands are available,
are inherently diversifiable as R2 and/or R3 substituents can be
installed via sequential alkylation chemistry. Here, building on
recent findings on the use of redox-active ester (RAE)
derivatives for programmed radical cross-coupling,9-11 we
present a Ni-catalyzed protocol for the union of tertiary alkyl
carboxylic acids with aryl zinc reagents.
A. Tertiary Alkyl Electrophiles: Precursors for Quaternary Centers
R1
R2
Br
R1
R2
BF3K
R1
R2
MgX
R1
R4
R3
R3
R3
R2
olefins
Grignards
halides
borates
(Ref 8)
[difficult to prepare] (Refs 5-7)
Previous Work
[programmable]
[easy to access]
This
Work
O
[R2]; [R3]
O
R
R1
R2
R1
R2
R1
OH
OR
sequential
alkylations
R3
R3
1º, 2º & 3º acids
Ubiquitous
quaternary center
tertiary acids
B. Optimization of Ni-catalyzed Arylation with Tertiary RAEsa
O
Me
Ph2Zn (2, 1.5 equiv.)
Me
OA*
Ni(dpm)2•xH2O (20 mol%)
ZnBr2 (1.0 equiv.)
DMI/THF (3:4), 0 °C to rt
TsN
1 (A* from TCNHPI)
TsN
3
Previous experience in Negishi-couplings of RAEs using
bidentate amine ligands under Ni-catalysis showed that only
primary and secondary systems were viable. Switching to an Fe-
catalyzed system enabled the generation of quaternary centers
but only in the context of bridged systems such as cubane,
adamantane, and [2.2.2]-bicycles. Unstrained cyclic and acyclic
tertiary RAEs remained a glaring limitation of both the Fe- and
Ni-systems. Path-pointing studies by Gong5 and Molander6c in
their related cross-couplings aided initial feasibility screens
suggesting the use of dicarbonyl-based ligands for Ni and Lewis
acid as additives. The optimum conditions, shown in Figure 1B
for the conversion of tertiary RAE 1 to 3 (entry 1), emerged after
entry
yield (%)b
82 (78)c
57
13
77
71
74
deviation from above
None
in situ from acid
A* from NHPI
PhZnBr (3.0 equiv.)
without ZnBr2
1
2
3
4
5
6
7
8
9
10
ZnCl2 instead of ZnBr2
MgCl2 instead of ZnBr2
MgBr2•Et2O instead of ZnBr2
DMF instead of DMI
10 mol% Ni(dpm)2•xH2O
13
24
49
65
Fe(dpm)3 or Co(dpm)3
Ni(acac)2•xH2O
Ni(dibm)2
11
12
13
14
15
16
17
ND
35
21
27
63
52
36
Ni(hfac)2•2H2O
Ni(fdh)2•2H2O
Ni(btfa)2•2H2O
Ni(dbm)2•2H2O
Figure 1. (A) Access to quaternary centers via cross coupling: Prior art. (B)
Optimization on Ni-catalyzed cross coupling of tertiary RAEs with arylzinc
reagents. a0.1 mmol. bYield determined by 1H NMR with CH2Br2 as an internal
standard. cIsolated yield. See Supporting Information for details. DMI = 1,3-
[a]
[b]
Dr. T.-G. Chen, H. Zhang, Dr. P. K. Mykhailiuk, Dr. R. R. Merchant,
C. A. Smith, Dr. T. Qin, Prof. P. S. Baran
Department of Chemistry, Scripps Research, North Torrey Pines
Road, La Jolla, CA 92037, United States
E-mail: pbaran@scripps.edu
Dr. P. K. Mykhailiuk
Enamine Ltd.; Chervonotkatska 78, 02094 Kyiv (Ukraine) and Taras
Shevchenko National University of Kyiv; Chemistry Department;
Volodymyrska 64, 01601 Kyiv (Ukraine)
dimethyl-2-imidazolidinone, ND
tetramethylheptane-3,5-dione, acac = acetylacetone, dibm = iPrCOCH2COiPr,
hfac hexafluoroacetylacetone, fdh 1,1,1-trifluoro-5,5-dimethyl-2,4-
hexanedione, btfa = 3-benzoyl-1,1,-trifluoroacetone, dbm = dibenzoylmethane
Ts tosyl, TCNHPI N-hydroxytetrachlorophthalimide, NHPI N-
hydroxyphthalimide.
=
not detected. dpm
=
2,2,6,6-
=
=
=
=
=
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10.1002/anie.201814524
Angewandte Chemie International Edition
COMMUNICATION
[tertiary acid]
O
[redox–active ester]
[arylzinc]
[quaternary center]
• >40 examples
• mild conditions
• linear and
20 mol% Ni(dpm)2•xH2O
ZnBr2 (1.0 equiv.)
DMI/THF, 0 ºC to rt
Cl
O
O
TCNHPI,
DIC, DCM
Zn
Cl
Cl
R
R1
OH
R2
R3
R1
R2
cyclic acids
R1
R2
+
R
O
N
• orthoaryl zincs
• heteroaryl zincs
• natural products
and drugs
R3
2
R3
3 - 47
[activation]
[cross-coupling]
O
(1.5 equiv.)
Cl
[isolated] or [in situ]
A Aryl Zinc
Me
Me
MeO
O
OMe
R
R = H; 3: (78%)
R = OMe; 4: (65%)
R = OCF3; 5: (44%)
R = Me; 6: (74%)
R = Ph; 7: (69%)
O
Me
OMe
Me
Me
Me
Me
Me
Me
Me
OMe
R = CH2CH2OTBS; 8: (60%)
R = CF3; 9: (60%)
R = F; 10: (45%)
N
Ts
N
Ts
N
Ts
N
Ts
N
Ts
N
Ts
N
Ts
R = Br; 11: (45%)
12: (73%)
13: (69%)
14: (74%)
15: (69%)
16: (71%)
17: (35%)
Me
N
Cl
O
S
N
N
OMe
S
Me
Me
Me
Me
Me
Me
N
Ts
N
Ts
N
Ts
N
Ts
N
Ts
N
Ts
18: (40%)a
19: (39%)a
20: (32%)b
21: (30%)c
22: (31%)a
23: (34%)a
[x-ray]
B Tertiary Acids
Me Me
Me Me
Me Me
Me Me from gemfibrozil
(Lopid®)
R
Me
O
Ph
MeO2C
26: (52%)
BocHN
Me
PhthN
29: (55%)
27: (46%)d
28: (55%)
OMe
Me
OMe
R = H; 24: (63%)
R = F; 25: (51%)d
OMe
Me
Me
Br
X
X
Me
OMe
OMe
OMe
OMe
O
S
34: (51%)
Me
OMe
OMe
Me
Me
Me
O
35: (60%)
36: (61%)
37: (70%)
Me
Me
OMe
O
Me
O
O
O
OMe
Me
X = Cl; 32: (59%)
X = F; 33: (51%)
31: (40%)e
30: (62%)
N
Ts
F
Me
38: (65%)
OMe
39: (63%)
40: (46%)
[Previous] 2-4 steps
[Current] 1 step
F
Me
Ph
Me
CO2Me
41: (57%)
from
18-β-glycyrrhetinic acid
OMe
O
Et
Bn
Me
Me Me
H
Me
H
Me
MeO
N
Ts
N
Ts
NTs
44: (72%)
HO
46: (40%)
4:1 dr
47: (45%)
H
Me Me
42: (50%)
43: (31%)
45: (53%)
[x-ray]
Scheme 1. Scope of the Ni-catalyzed arylation of tertiary RAEs. Reaction conditions: Redox-active ester (1 equiv), Ni(dpm)2•xH2O (20 mol%), Ar2Zn (1.5 equiv),
ZnBr2 (1 equiv) in THF/DMI (4:3) at rt for 12 h. [Isolated] refers to yields from the isolated redox-active ester, and [in situ] refers to yields from the carboxylic acid.
a With Ni(dpm)2•xH2O (40 mol%) and Ar2Zn (2.5 equiv). b With Ni(dpm) 2•xH2O (40 mol%) and Ar2Zn (2.5 equiv) at 60 ºC. c With Ni(dpm)2•xH2O (40 mol%) and
Ar2Zn (2.5 equiv) in THF/DMF at 60ºC. d With Ni(dpm)2•xH2O (20 mol%) and Ar2Zn (2.5 equiv). e In situ from carboxylic acid (1.0 equiv.), TCNHPI (1.1 equiv.),
DIC (1.1 equiv.) and DMAP (0.1 equiv.). Ts: tosyl; TBS: tert-butyldimethylsilyl; Boc: tert-butyloxycarbonyl; Phth: phthalimido; DIC: N,N’-diisopropylcarbodiimide.
The conditions developed above proved to be general
across a range of substrates as shown in Table 1 (>40
examples). The scope with regards to the aryl donor was first
evaluated (Table 1A) to furnish adducts 3-23. Notable amongst
these examples is the functional group tolerance of the reaction
with ethers (4, 15, 17), halides (10, 11, 21), benzofurans (19),
and pyridines (20, 21). Heterocycles and ortho-substituted
arenes (17) diminished the yield somewhat but still provided
serviceable quantities of product. Most notably, both electron
rich and electron poor substituted arenes are viable coupling
partners.
The vast scope of employable tertiary acids is described in
Table 1B and features acyclic, cyclic, and those originating from
natural products and medicines. High chemoselectivity is
observed as a multitude of functional groups are compatible
such as esters (26, 47), carbamates (27), ethers (28, 30-33, 39),
imides (29), sulfonamides (38, 42-44), sulfones (36), enones
(46), and even free alcohols (46). Simple acyclic acids as well as
3-, 4-, 5-, 6-, and 7-membered rings can also be enlisted. Of
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10.1002/anie.201814524
Angewandte Chemie International Edition
COMMUNICATION
note here are the oxetane-derived products 30-33 that were
prepared before in 2-4 steps12 that can now be easily accessed
in a single step from the commercial acid. The utility of the
transformation was also demonstrated by the synthesis of
product 28 derived from Gemfibrozil. Late-stage arylation of the
triterpene 18-β-glycyrrhetinic acid furnished product 46 without
protection of the A-ring alcohol. The bridged system 47 can be
viewed as a saturated mimic of a para-substituted benzene,
useful for a variety of medicinal chemistry projects.13 The
structure of products 8, 23 and 41 were confirmed by X-Ray
crystallographic analysis.
standpoint, the chemists were necessarily wedded to a phenyl
group as it originated from the commercial starting material. In
contrast, inexpensive isonipecotic acid ester (49) could be
processed through 3 simple steps, two of which generate key C–
C bonds to deliver key intermediate 50.4a,4b Although the overall
yield is not as high as the prior approach, diversity installation is
completely modular and could, in principle, permit access to a
whole range of substituents at the quaternary carbon by simply
changing alkylation and cross-coupling partners. In a similar
vein, the anti-microbial compound 54 has previously been
accessed using 2-electron retrosynthetic logic commencing from
oxetane 52.4c Access to the quaternary center was enabled
through a conjugate addition of an aryl boronic acid onto an a,b-
The retrosynthetic simplification enabled by this cross-
coupling is further demonstrated with application to two reported
medicinally promising scaffolds (Scheme 2). Thus, construction
of the CCR5 ligand 51 (Scheme 2A) previously commenced with
commercial piperidine 48 and proceeded through a five-step
sequence to deliver 50. Of those steps, only one productively
made a C–C bond with the remainder dedicated to protecting
unsaturated
sulfone
(52’).
Subsequent
deprotection
/SN2/desulfonylation delivered 54. Alternatively, radical
retrosynthesis11 led to precursor 53 that could be subjected to
decarboxylative cross-coupling followed by SN2 to furnish the
same product (54) in only two steps with an order of magnitude
higher overall yield.
group chemistry and redox-fluctuations. From
a
diversity
A Modular, Efficient Synthesis of CCR5 Ligand (51)
CN
[Previous] 5 steps (65%)
DIBAL
H2, Pd
OHC
O
HCl•HN
48 ($30/g)
Boc2O
HWE
DIBAL
[H+]
N
1 step
HN
N
Ref. 4b
[cross-
coupling]
N
Boc
51
N
Boc
50
[α-alkylation]
CO2Me
CCR5 ligand (GSK)
formal synthesis
BocN
49 ($0.3/g)
I
O
43%
[Current] 3 steps (21%)
O
B Convergent Synthesis of Antimicrobial (54)
SO2Ph
Zn
Ph
TBSO
HO
Ph
via
52’
O
O
O
TsCl
SN2
2
Mg, MeOH
Me
HWE
TsCl
N
HO
[cross-coupling];
SN2
ArB(OH)2
Me
O
53
O
TBAF
(50%)
54
(1,4-addition)
52
activity against S. aureus
O
[Previous] 5 steps (2%)
[Current] 2 steps (28%)
Scheme 2. Radical retrosynthesis simplifies the synthesis of bioactive compounds from the patent literature.
The coupling was also amenable to gram-scale as shown
in Scheme 3. Without any modification of the standard
conditions, piperidine 4 could be produced in similar yield (53%)
to that run on 0.1 mmol scale (65% yield). Despite the
([2.1.1] both fully carbon and heteroatom substituted) did not
function well. This chemistry is also currently limited to aryl zinc
reagents as alkyl variants gave low yield.
As one of the most ubiquitous functional groups known,
advantages outlined herein, the reaction is not without limitations. carboxylic acids are an ideal starting point for cross-coupling
For example, α-fluorinated and α-trifluoromethylated aliphatic
acids were unreactive (only recovery of the starting acid was
observed). Tertiary amino acids generally provided low yields
(with the exception of 29) and small strained bicyclic systems
chemistry. When coupled to alkylation or other a-
functionalization methods, tertiary acids that are not already
commercial are easily prepared in a modular fashion. The
simple protocol delineated herein permits simple thermal,
scalable access to convert such building blocks to diverse
arene-flanked quaternary centers with demonstrable value to
society.
OMe
A* = TClNHPI
Ar2Zn (1.5 equiv.)
O
Ni(dpm)2•xH2O
(20 mol%)
Me
Me
OA*
ZnBr2
Acknowledgements
(1.0 equiv.)
DMI:THF (3:4)
0 oC to rt
N
Ts
N
Ts
Financial support for this work was provided by NIH (grant
number GM-118176). We thank Bristol-Myers Squibb (Jennifer
X. Qiao), and Enamine Ltd for providing samples of several
3
2.5 mmol
4
459 mg
53 %
Scheme 3. Gram-scale synthesis of compound 4.
This article is protected by copyright. All rights reserved.

10.1002/anie.201814524
Angewandte Chemie International Edition
COMMUNICATION
Angew. Chem., Int. Ed. 2012, 51, 9110. (e) C.-T. Yang, Z.-Q. Zhang, J.
Liang, J.-H. Liu, X.-Y. Lu, H.-H. Chen, L. Liu, J. Am. Chem. Soc. 2012,
134, 11124. (f) T. Iwasaki, H. Takagawa, S. P. Singh, H. Kuniyasu, N.
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tertiary acids. We gratefully thank Shenzhen Haiwei M&E Co.
Ltd (fellowship to T.-G.C.), Tsinghua University (fellowship to
H.Z.), and the Fulbright foundation (fellowship to P.K.M.). We
also thank Dr. Jie Wang and Dr. Julien Vantourout for the help
with manuscript preparation; Dr. Joel M. Smith for thoughtful
discussions; D.-H. Huang and L. Pasternack (Scripps Research)
for assistance with NMR spectroscopy; J. S. Chen and B.
Sanchez (Scripps Automated Synthesis Facility); A. Rheigold,
M. Gembicky, C. E. Moore (UCSD) for X-ray crystallographic
analysis. CCDC 1884000 (8), 1883999 (23), 1884002 (41),
1884001 (54) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Data Center.
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Keywords: quaternary centers
•
decarboxylative radical
coupling • redox-active esters • practical protocols • tertiary acids
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This article is protected by copyright. All rights reserved.

10.1002/anie.201814524
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Quaternary Center exchange. Fully substituted carbon centers bearing a
carboxylate moiety can engage in decarboxylative cross coupling with aryl zinc
reagents under Ni catalysis, leaving in their wake an arene group.
Tie-Gen Chen, Haolin Zhang, Pavel K.
Mykhailiuk,
Rohan
R.
Merchant,
Courtney A. Smith, Tian Qin, and Phil S.
Baran*
[Previous work]
2 e- logic
[This work]
1 e- logic
Ar
CO2H
R
R
Ar
R’
Quaternary Centers via Ni-Catalyzed
Cross-Coupling of Tertiary Carboxylic
Acids and Aryl Zinc Reagents
5 steps
[non-strategic]
[Ar introduced early]
N
Boc
N
Boc
2–3 steps
[Ar introduced late]
N
Boc
· >40 examples
·mild conditions
·linear and cylic
TCNHPI,
DIC, DCM
Ar2Zn or
ArZnBr
R1
R2
R
·afucnidcstional groups
[activation]
[isolated] or [in situ]
[cross-coupling]
R3
[quaternary
center]
tolerance
This article is protected by copyright. All rights reserved.