Nickel-Catalyzed Cross-Electrophile Reductive Couplings of Neopentyl Bromides with Aryl Bromides

Article abstract of DOI:10.1021/acs.joc.0c00549

5-Cyanoimidazole was identified as an inexpensive ligand for nickel-catalyzed cross-electrophile couplings by screening a diverse set of pharmaceutical compound library. A strategic screening approach led to the discovery of this novel ligand, which was successfully applied in the preparation of various alkylated arene products with good to high yields. Furthermore, the properties of this ligand allowed expanding the scope of reductive couplings to challenging substrates, such as sterically hindered neopentyl halides, which are known to generate motifs that are prevalent in biologically active molecules.

Full text of DOI:10.1021/acs.joc.0c00549

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Note
Nickel-Catalyzed Cross-Electrophile Reductive
Couplings of Neopentyl Bromides with Aryl Bromides
Soumik Biswas, Bo Qu, Jean-Nicolas Desrosiers, Younggi Choi, Nizar
Haddad, Nathan K Yee, Jinghua J. Song, and Chris H Senanayake
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00549 • Publication Date (Web): 26 May 2020
Downloaded from pubs.acs.org on May 26, 2020
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Nickel-Catalyzed Cross-Electrophile Reductive Couplings of Neopentyl Bromides
with Aryl Bromides
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Soumik Biswas, Bo Qu*, Jean-Nicolas Desrosiers*,†, Younggi Choi‡, Nizar Haddad,
Nathan K. Yee, Jinghua J. Song, Chris H. Senanayake§
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Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road,
Ridgefield, Connecticut 06877, USA
EtO2C
N
NiCl2(DME) (10 mol%)
L31
Br
CN
(10 mol%)
Br
N
H
+
R
R
NaI, Zn, TFA
DMA, 60 °C, 16 h
EtO2C
R = H, OMe, alkyl, aryl
62 - 75% yield
L31
Abstract
5-Cyanoimidazole was identified as a new ligand for nickel-catalyzed cross-
electrophile couplings by screening a diverse set of pharmaceutical compound library. A
strategic screening approach led to the discovery of this novel ligand; which was
successfully applied in the preparation of various alkylated arene products with good to
high yields. Furthermore, the properties of this ligand allowed expanding the scope of
reductive couplings to challenging substrates, such as sterically hindered neopentyl
halides, which are known to generate motifs that are prevalent in biologically active
molecules.
Ni-catalyzed cross-electrophile couplings have expanded the field of cross-
coupling reactions which were dominated by typical palladium-catalyzed electrophile-
nucleophile couplings. Such reductive transformation enables the direct coupling of two
electrophiles between an sp2-carbon and an sp3-carbon without pre-functionalization of a
requisite carbon nucleophile coupling partner.1 Cross-electrophile coupling has become
one of the most useful synthetic methods2 to access sp3-hybridized carbons in drug
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molecules, which were correlated to improved biological and physicochemical properties
comparing to the less saturated analogues.3
Nitrogen-based bidentate and tridentate ligands including carbenes,4 bipyridines,
1,10-phenanthrolines5, bisoxazoline6 and Pybox7 derivatives were proven to be effective
ligands to facilitate nickel-catalyzed cross-electrophile reductive coupling reactions.
Significant functional group tolerance was reported including substrates containing
highly acidic protons such as alcohols and amines.5b Standard reaction conditions are
chemoselective for electrophilic C-X bond in the presence of nucleophilic C-B, C-Si or
C-Sn bonds,5b which in turn provide a handle for further functionalization. Ligands that
complex nickel are essential for enabling the reactivity and selectivity of the desired
cross-electrophile coupling reactions. However, unlike the diverse and large libraries of
phosphine ligands, the development of nitrogen-based ligand libraries to complex first-
row transition metals lags far behind. To speed up the ligand identification process and
discover new ligand structures for effective Ni-catalyzed cross-electrophile coupling
reactions, Hansen and Weix took a strategic approach of mining Pfizer’s structurally
diverse and nitrogen-heterocycle-rich discovery research compound libraries.8 Indeed,
these efforts enabled the identification of pyridyl carboxamidines as a new class of
ligand, which effectively promotes the reductive coupling of two electrophiles with
comparable or significantly improved yields.8,9
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O
Cl
Me
Me
Me
EtO
Me
OEt
N
O
N
H
HN
Me
Me
OH
O
N
Me
selective -3 adrenergic agonist
fungicide
O
HO
O
Me
Me
Me
O
Me
Me
N
Cl
N
H
O
N
H
OH
Cl
calcium receptor antagonist
HCV polymerase inhibitor
Scheme 1: Representative molecules containing neopentyl type fragments
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Significant progress has been made to enable the coupling of Csp2-Csp3 for a
direct synthesis of alkyl-aryl derivatives of biological importance. For example,
neopentyl-type fragments are prevalent in biologically active molecules11 due to their
interesting sp3 characters (Scheme 1). Despite their desirable properties, cross-coupling
reactions involving alkyl halides with increased steric hindrance, such as neopentyl
halides, remains a challenge. Low yields were reported from the coupling of aryl iodides
and neopentyl iodides.5a Trace amount of product was detected with neopentyl bromide.5b
Improved yield was realized for the synthesis of methyl 4-neopentylbenzoate under
photoredox catalysis conditions with silyl radical activation of the neopentyl bromide.10
To identify an effective ligand for the direct cross-electrophile coupling of neopentyl
bromides and aryl bromides, we took a similar approach8,12 mining Boehringer Ingelheim
library of more than 2 million compounds (Figure 1).
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The sub-structure search was first focused on bidentate ligand-like fragments
including N-(CH2)2-N, N-(CH2)3-N and N-(CH2)2-O. Several filters13 were applied
including a starting point of molecular weight below 500 g/mol. Molecules containing
undesired functional groups such as halides, isocyanates, acid chlorides were excluded
(Figure 1). This resulted in 18,730 compounds that were considered for further clustering.
Among these, a search of nitrogen-containing five-, or six-membered hereocycles
narrowed down the selection to 28 compounds. Initial testing of these compounds as
ligands for the reductive coupling of ethyl 4-bromobenzoate with (3-
bromopropyl)benzene identified nitrile-containing imidazoles as a promising new class of
ligand. Subsequent focused screens based on the initial hits led to the identification of 5-
cyanoimidazole as an effective new ligand for Ni-catalyzed cross-electrophile couplings.
Furthermore, 5-cyanoimidazole was found effective for the reductive coupling of
challenging neopentyl halides with aryl halides.
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Figure 1. Strategies employed for mining BI compound library for new ligands
The results of the initial evaluation using model compounds ethyl 4-
bromobenzoate and (3-bromopropyl)benzene with the first twenty eight ligand structures
identified from the compounds library was shown in Scheme 2. Reaction conditions
utilized for this screening were composed of 10 mol% NiCl2(DME), 10 mol% ligand, 25
mol% NaI, 2 equiv Zn dust, and 10 mol% TFA in 0.3 M N,N-dimethylacetamide (DMA)
at 60 °C for 16 h. Among the ligands tested, cyano-imidazole ligand L1 resulted in a
moderate yield of 40% for the desired cross coupling product. All other compounds
tested within this initial subset provided low amount of product formation.
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Br
NiCl2(DME) (10 mol%)
L
(10 mol%)
O
Br
O
+
5
6
Zn (2 equiv), TFA
DMA, 60 °C, 16 h
O
O
3a
2a
1a
7
8
9
N
N
O
O
O
N
N
O
O
H2N
H2N
Me
O
N
N
S
N
N
NH2
N
NH2
NH2
NH2
NH2
H2N
N
N
Ph
N
N
H
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N
H
O
N
H
N
NH2
CN
, 40%
O
Ph
L6
Me
HN
L3
L4
L7
, 12%
L5
, <10%
L1
L2
, 12%
, 14%
, 13%
, 16%
O
O
Me
O
O2N
O2N
Me
O
N
N
N
HN
O
NH2
N
N
N
NH2
N
NH2
NH2
N
NHMe
N
NH2
N
N
N
N
N
H
N
H
N
H
NH2
H
O
O
Me
L12
, <10%
L13
, <10%
L8
L9
L10
L14
, <10%
, <10%
, 11%
L11
, <10%
O
, <10%
O
O
S
NH
O
H
N
N
O
tol
N
O
O
O
N
H
N
S
N
H
O
N
N
NH
OH
N
H
O
NH
tol
O
Et
N
H
S
N
O
H
O
O
L19
, <10%
L20
L21
, <10%
N
, <10%
L17
, <10%
L18
, <10%
L16
, <10%
L15
, <10%
O
H
N
H
N
NO2
N
N
N
N
N
N
N
N
N
NH2
N
H
O
N
N
H
O
Me
HO
O
OMe
L22
, <10%
L23
L24
, <10%
, <10%
L28
L27
, <10%
L25
L26
, <10%
, <10%
, <10%
Scheme 2. Results of the initial evaluation of the twenty eight ligand structures. Reaction
conditions: 1a (0.5 mmol), 2a (0.75 mmol), NiCl2(DME) (0.05 mmol), ligand (0.05
mmol), Zn dust (1.0 mmol), NaI (0.125 mmol), TFA (0.05 mmol) in DMA (0.3 M) at 60
°C for 16 h. The reaction yield was measured by GC with dodecane as the internal
standard.
The encouraging result of the nitrile-containing heterocycle L1 prompted us to
evaluate additional compounds with a similar substitution pattern (Scheme 3).
Interestingly, it was found that the nitrile functionality in the ligand structure is essential
for increased reactivity. Unsubstituted imidazole L39 provided 10% yield for 3a. The 2-
carbonitrile-substituted 1H-imidazole L30 increased the yield to 75%. On the other hand,
the N-Me-2-carbonitrile imidazole L33 provided the product in 35% yield. The best
result was obtained with 5-carbonitrile-substituted 1H-imidazole L31 where 94% yield of
the cross-coupling product 3a was obtained. Low levels of impurities including homo-
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dimerization, β-hydride elimination and hydrodehalogenation were observed with
this ligand. Notably, the 6-membered heterocycle picolinonitrile L42 also provided
the product in 84% yield.
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Br
NiCl2(DME) (10 mol%)
L
(10 mol%)
O
Br
O
+
Zn (2 equiv), TFA
DMA, 60 °C, 16 h
O
O
3a
2a
1a
CN
N
N
N
N
N
N
N
CN
CN
, 56%
NH2
CN
CN
N
CN
CN
N
N
H
N
O
N
N
CN
N
N
H
H
H
H
Me
L33
Me
L29
L30
L31
L32
L34
, 25%
L35
, 30%
L36
, 75%
, 94%
, 35%
, 41%
, 54%
O
O
F
CN
NC
N
N
N
N
NH2
N
CN
N
N
H
NC
CN
N
CN
N
N
NC
N
N
H
NH2
N
H
NC
L41
H
H
L39
L42
L44
, 10%
L40
, 52%
, 84%
L43
, 65%
L38
, 52%
, 11%
, 76%
L37
, 25%
O
F
CN
F
N
N
Me
CN
N
CN
NC
N
CN
N
N
Me2N
CN
N
F
N
N
N
CN
CN
H2N
L45
L46
L47, 37%
L48
, 19%
L49
, 66%
L50
L52
, 33%
, 58%
, 67%
, 36%
L51
, 19%
Scheme 3: Focused ligand screen with carbonitrile-containing molecules. Reaction
conditions: 1a (0.5 mmol), 2a (0.75 mmol), NiCl2(DME) (0.05 mmol), ligand (0.05
mmol), Zn dust (1.0 mmol), NaI (0.125 mmol), TFA (0.05 mmol) in DMA (0.3 M) at 60
°C for 16 h. The reaction yield was measured on GC with dodecane as the internal
standard.
With the identification of the new ligand 5-carbonitrile imidazole L31, we next
tested the coupling reaction of heteroaryl 2-bromopyridine with (3-bromopropyl)benzene
2a. The corresponding product 3b was successfully isolated in 72% yield. We then
decided to tackle more challenging substrates of un-activated secondary heteroatom-
containing alkyl bromides (Figure 2). There are still limited methods to access aryl-
substituted nonaromatic heterocycles including piperidines and azetidines.14 Under the
standard conditions using ligand L31, base-sensitive methyl ketone aryl bromide coupled
efficiently with N-Boc-4-bromopiperidine to provide product 3c in 81% yield. CF3-,
ester-, and sulfonamide-containing aryl bromides all worked well. Products 3d, 3e and 3f
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were produced in 71%, 72% and 64% yields, respectively. Acetal group was tolerated to
yield product 3g in 52% yield. Coupling of N-Boc-3-bromoazetidine and 4-bromoanisole
provided the product 3h in 41% comparable yield.13
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Figure 2: Substrate scope for Ni-catalyzed cross-electrophile couplingsa,b
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NiCl2(DME) (10 mol%)
L31
(10 mol%)
N
Br
Br
NaI (25 mol%), Zn (2 equiv)
CN
N
H
L31
+
DMA [0.3 M], 60 °C, 16 h
TFA (0.1 equiv)
O
CF3
CO2Et
Ph
Ph
N
3b
BocN
BocN
c
3c
3d
, 71%
, 70% (72% )
, 81%
3a
, 94%
O
O
O
S
BocN
OEt
EtO2C
NH2
O
O
OMe
BocN
BocN
3e
, 72%
3h
, 41%
3g
, 52%
3f
, 64%
a Reaction conditions: Ar-Br (0.5 mmol), alkyl-Br (0.75 mmol), NiCl2(DME) (0.05
mmol), L31 (0.05 mmol), Zn dust (1.0 mmol), NaI (0.125 mmol), TFA (0.05 mmol) in
DMA (0.3 M) at 60 °C for 16 h. b Isolated yields. c With 2.0 mmol of 2-bromopyridine.
The conditions with 5-cyanoimidazole ligand L31 were also applied to the direct
reductive coupling of 4-bromobenzoate bromide with more sterically challenging
neopentyl-type alkyl bromides. Ligand L31 effectively promoted the reductive coupling
of hindered neopentyl-type bromides (Figure 3) that are typically known to lead to
sluggish conversions. The reaction of 1-bromo-2-methylpropane with ethyl 4-
bromobenzoate yielded product 3i in 73% yield. Increasing the steric hindrance on alkyl
bromides successfully furnished similar yields including 1-bromo-2,2-dimethylpropane
(3j, 68% yield), (1-bromo-2-methylpropanyl)benzene (3k, 62% yield) and 1-
(bromomethyl)-1-methylcyclohexane
(3l,
75%
yield).
1-bromo-2-methoxy2-
methylpropane was tolerated to give 65% yield of product 3m. 2-Methyl-2-phthalimido-
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1-bromopropane coupled with ethyl 4-bromobenzoate to yield product 3n in 72% yield.
Upon deprotection, phentermine derivative is directly generated and could be applied for
the synthesis of biologically active molecules such as the HCV Polymerase inhibitor
listed in Scheme 1. The scope of neopentyl-derived products clearly exemplifies the new
type of reactivity obtained from the use of the novel 5-cyanoimidazole ligand L31.15
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Figure 3: Reductive Coupling of Aryl Bromides with Neopentyl-type Bromidesa,b
NiCl2(DME) (10 mol%)
Br
EtO2C
L31
(10 mol%)
Br
NaI (25 mol%), Zn (2 equiv)
+
R
EtO2C
EtO2C
R
DMA [0.3 M], 60 °C, 16 h
TFA (0.1 equiv)
EtO2C
EtO2C
Ph
Me
H
c
3j
, 68%
3k
O
, 65% (62% )
3i
, 73%
CO2Et
EtO2C
EtO2C
N
OMe
O
3l
3m
, 65%
, 75%
3n
, 72%
a Reaction conditions: Ar-Br (0.5 mmol), alkyl-Br (0.75 mmol), NiCl2(DME) (0.05
mmol), L31 (0.05 mmol), Zn dust (1.0 mmol), NaI (0.125 mmol), TFA (0.05 mmol) in
DMA (0.3 M) at 60 °C for 16 h. b Isolated yields. c With 2.0 mmol of Ar-Br.
In conclusion, we identified 5-cyanoimidazole as a new ligand for effective Ni-
catalyzed cross-electrophile reductive couplings by mining Boehringer Ingelheim’s
diverse set of pharmaceutical compound library. The identified ligand was successfully
applied in the preparation of various alkylated arene products with good to high yields
including the sterically challenging neopenyl-type alkyl halides. Future efforts will be
focused on determining the nickel-5-cyanoimidazole complex properties and its
applications towards new transformations.
EXPERIMENTAL SECTION
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General Information. All reactions were carried out under an atmosphere of argon or
nitrogen in dry glassware with magnetic stirring. Commercially available Ar-Br and
alkyl-Br, catalyst, ligand, Zn dust and solvents were used as received. NMR spectra were
recorded on Bruker spectrometers (400, 500, and 600 MHz) and are reported relative to
residual solvent signals. Data for 1H NMR spectra are reported as follows: chemical shift
(δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, non
= nonet, m = multiplet, dd = doublet of doublet, dt = doublet of triplet, dq = doublet of
quartet, tt = triplet of triplet, br = broad), coupling constant (Hz) and integration are
referenced to the residual solvent peak 7.26 ppm for CDCl3. Data for 13C NMR are
reported in terms of chemical shift (at 100, 125 or 150 MHz) and are referenced to the
residual solvent peak 77.15 for CDCl3. High resolution mass spectra data (HRMS) were
obtained on a LTQ FT Ultra Mass Spectrometer using DART source ionization at 50,000
resolving power with a Fourier Transform ion cyclotron resonance (FT-ICR) MS
detector.
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General experimental procedure: Anhydrous DMA was sparged with argon for 15 min
prior to usage. Ar-Br (0.5 mmol), alkyl-Br (0.75 mmol), NiCl2(DME) (0.05 mmol, 11.0
mg), L31 (0.05 mmol, 4.7 mg), NaI (0.125 mmol, 19.0 mg) and Zn dust (1.0 mmol, 65.0
mg) were added to a vial on benchtop, followed by addition of DMA (1.7 mL). The vial
was sealed with a septa cap. The mixture was evacuated and backfilled with argon five
times. Then TFA (0.05 mmol, 4 uL, 0.1 equiv) was added to the vial. The reaction
mixture was heated in a heating block on EASYMAX that was preheated to 60 C. The
mixture was stirred for 16 h before quenching with water (5 mL). The organic layer was
extracted with DCM (3 x 5 mL), then washed with water (5 mL) and dried with
anhydrous Na2SO4. The product was purified by column chromatography using silica gel.
Ethyl 4-(3-phenylpropyl)benzoate (3a): The title compound was prepared according to
the general procedure and purified using hexanes as eluent to give the product as
colorless oil, 126 mg, 94% yield. 1H NMR spectrum was in accordance with the reported
one:16 (500 MHz, CDCl3) δ 7.96 (d, J = 8.2 Hz, 2H), 7.17-7.29 (m, 7H), 4.36 (q, J = 7.1
Hz, 2H), 2.70 (t, J = 7.7 Hz, 2H), 2.64 (t, J = 7.7 Hz, 2H), 1.97 (quint, J = 7.7 Hz, 2H),
1.38 (t, J = 7.1 Hz, 3H). HRMS-ESI (m/z) [M+H]+ calcd for C18H21O2, 269.1542; found
269.1536.
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2-(3-phenylpropyl)pyridine (3b): The title compound was prepared according to the
general procedure and started with 2.0 mmol of 2-bromopyridine (316 mg). The other
reagents were added accordingly: 3.0 mmol (3-bromopropyl)benzene (597 mg), 0.2
mmol NiCl2(DME) (44.0 mg), 0.2 mmol L31 (18.8 mg), 0.5 mmol NaI (76 mg), 4.0
mmol Zn dust (260 mg), 6.8 ml DMA and 0.2 mmol TFA (16 uL). The product was
purified using 20% EtOAc in hexanes as eluent to give colorless oil, 284 mg, 72% yield.
1H NMR spectrum was in accordance with the reported one:17 (500 MHz, CDCl3) δ 8.53
(d, J = 4.6 Hz, 1H), 7.59 (t, J = 7.5, 1H), 7.28 (t, J = 7.5 Hz, 2H), 7.08-7.20 (m, 5H), 2.84
(t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H), 2.07 (quint, J = 7.5 Hz, 2H). HRMS-ESI
(m/z) [M+H]+ calcd for C14H16N, 198.1283; found 198.1277.
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Tert-butyl 4-(4-acetylphenyl)piperidine-1-carboxylate (3c): The title compound was
prepared according to the general procedure and purified using 10% EtOAc in hexanes as
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eluent to give the product as light yellow solid, 123 mg, 81% yield. H NMR spectrum
was in accordance with the reported one:14 (500 MHz, CDCl3) δ 7.92 (d, J = 8.3 Hz, 2H),
7.31 (d, J = 8.3 Hz, 2H), 4.28 (d, J = 13.1 Hz, 2H), 2.85 (dt, J = 13.1, 1.9 Hz, 2H), 2.73
(tt, J = 12.2, 3.5 Hz, 1H), 2.59 (s, 3H), 1.85 (m, 2H), 1.66 (dq, J = 12.5, 4.5 Hz, 2H), 1.49
(s, 9H). HRMS-ESI (m/z) [M+H]+ calcd for C18H26NO3, 304.1913; found 304.1908.
Tert-butyl 4-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (3d): The title
compound was prepared according to the general procedure and purified using 10%
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EtOAc in hexanes as eluent to give the product as colorless oil, 117 mg, 71% yield. H
NMR spectrum was in accordance with the reported one:18 (500 MHz, CDCl3) δ 7.55 (d,
J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 4.27 (br s, 2H), 2.79-2.84 (br t, 2H), 2.69 (tt, J
= 12.2, 3.6 Hz, 1H), 1.81-1.84 (m, 2H), 1.64 (dq, J = 12.6, 4.2 Hz, 2H), 1.49 (s, 9H).
HRMS-ESI (m/z) [M+H]+ calcd for C17H23F3NO2, 330.1681; found 330.1677.
Tert-butyl 4-(4-(ethoxycarbonyl)phenyl)piperidine-1-carboxylate (3e): The title
compound was prepared according to the general procedure and purified using 20%
EtOAc in hexanes as eluent to give the product as colorless liquid, 120 mg, 72% yield. 1H
NMR spectrum was in accordance with the reported one:19 (500 MHz, CDCl3) δ 7.98 (d,
J = 8.3 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 4.26 (br d, J = 11.4 Hz,
2H), 2.81 (t, J = 7.1 Hz, 2H), 2.71 (tt, J = 12.1, 3.5 Hz, 1H), 1.81-1.84 (m, 2H), 1.64 (dq,
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J = 12.6, 4.2 Hz, 2H), 1.49 (s, 9H), 1.38 (t, J = 7.1 Hz, 3H). HRMS-ESI (m/z) [M+H]+
calcd for C19H28NO4, 334.2018; found 334.2013.
Tert-butyl 4-(4-sulfamoylphenyl)piperidine-1-carboxylate (3f): The title compound
was prepared according to the general procedure and purified using 30% EtOAc in
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hexanes as eluent to give the product as white solid, 109 mg, 64% yield. H NMR
spectrum was in accordance with the reported one14: (500 MHz, CDCl3) δ 7.87 (d, J = 8.3
Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 5.02 (s, 2H), 4.25 (br s, 2H), 2.81 (br t, 2 H), 2.71 (tt, J
= 12.4, 3.4 Hz, 1H), 1.80-1.83 (m, 2H), 1.64 (dq, J = 12.6, 4.2 Hz, 2H), 1.48 (s, 9H).
HRMS-ESI (m/z) [M+H]+ calcd for C16H25N2O4S, 341.1535; found 341.1531.
Ethyl 3-((1,3-dioxolan-2-yl)methyl)benzoate (3g): The title compound was prepared
according to the general procedure and purified using 10% EtOAc in hexanes as eluent to
give the product as colorless oil, 61 mg, 52% yield. 1H NMR spectrum was in accordance
with the reported one:5a (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.47
(d, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 5.09 (t, J = 4.7 Hz, 1H), 4.37 (q, J = 7.2 Hz,
2H), 3.83-3.94 (m, 4H), 3.02 (d, J = 4.8 Hz, 2H) 1.39 (t, J = 7.2 Hz, 3H). HRMS-ESI
(m/z) [M+H]+ calcd for C13H17O4, 237.1127; found 237.1122.
Tert-butyl 3-(4-methoxyphenyl)azetidine-1-carboxylate (3h): The title compound was
prepared according to the general procedure and purified using 20% EtOAc in hexanes as
eluent to give the product as colorless oil, 54 mg, 41% yield. 1H NMR spectrum was in
accordance with the reported one:14 (500 MHz, CDCl3) δ 7.16 (d, J = 8.6 Hz, 2H), 6.81 (d,
J = 8.6 Hz, 2H), 4.23 (t, J = 8.6 Hz, 2H), 3.86 (dd, J = 8.6, 6.1 Hz, 2H), 3.73 (s, 3H),
3.58-3.63 (m, 1H), 1.39 (s, 9H). HRMS-ESI (m/z) [M+H]+ calcd for C15H22NO3,
264.1600; found 264.1595.
Ethyl 4-isobutylbenzoate (3i): The title compound was prepared according to the
general procedure and purified using hexanes as eluent to give the product as colorless
oil, 75 mg, 73% yield. 1H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 8.2 Hz, 2H), 7.20 (d, J
= 8.2 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 2.52 (d, J = 7.2 Hz, 2H), 1.89 (non, J = 6.7 Hz,
13
1H), 1.38 (t, J = 7.1 Hz, 3H), 0.90 (d, J = 6.6 Hz, 6H). C NMR (125 MHz, CDCl3) δ
166.8, 147.1, 129.4, 129.1, 128.1, 60.7, 45.4, 30.1, 22.3, 14.4. 13C{1H} NMR (125 MHz,
CDCl3) δ 166.8, 147.1, 129.4, 129.1, 128.1, 60.7, 45.4, 30.1, 22.3, 14.4. HRMS-ESI
(m/z) [M+H]+ calcd for C13H19O2, 207.1385; found 207.1380.
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Ethyl 4-neopentylbenzoate (3j): The title compound was prepared according to the
general procedure and purified using 5% EtOAc in hexanes as eluent to give the product
as colorless oil, yield: 76 mg, 68% yield. 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 8.2
Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 2.47 (s, 2H), 1.31 (t, J = 7.1
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Hz, 3H), 0.83 (s, 9H). C{1H} NMR (125 MHz, CDCl3) δ 166.8, 145.2, 130.4, 128.9,
128.1, 60.8, 50.2, 31.9, 29.4, 14.4. HRMS-ESI (m/z) [M+H]+ calcd for C14H21O2,
221.1542; found 221.1536.
Ethyl 4-(2-methyl-2-phenylpropyl)benzoate (3k): The title compound was prepared
according to the general procedure and started with 2.0 mmol of ethyl 4-bromobenzoate
(458 mg). The other reagents were added accordingly: 3.0 mmol (3-
bromopropyl)benzene (639 mg), 0.2 mmol NiCl2(DME) (44.0 mg), 0.2 mmol L31 (18.8
mg), 0.5 mmol NaI (76 mg), 4.0 mmol Zn dust (260 mg), 6.8 ml DMA and 0.2 mmol
TFA (16 uL). The product was purified using hexanes as eluent to give colorless oil, 350
1
mg, 62% yield. H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.2 Hz, 2H), 7.09-7.21 (m,
5H), 6.76 (d, J = 8.2 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.84 (s, 2H), 1.28 (t, J = 7.1 Hz,
3H), 1.25 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.8, 148.3, 144.3, 130.3, 128.7,
128.2, 128.0, 126.2, 125.9, 60.8, 51.1, 38.9, 28.3, 14.4. HRMS-ESI (m/z) [M+H]+ calcd
for C19H23O2, 283.1698; found 283.1693.
Ethyl 4-((1-methylcyclohexyl)methyl)benzoate (3l): The title compound was prepared
according to the general procedure and purified using 5% EtOAc in hexanes as eluent to
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give the product as colorless oil, 98 mg, 75% yield. H NMR (500 MHz, CDCl3) δ 7.87
(d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 2.51 (s, 2H), 1.31
(t, J = 7.1 Hz, 3H), 1.16-1.50 (m, 10H), 0.75 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3)
δ 166.8, 144.8, 130.6, 128.8, 128.1, 60.7, 48.8, 37.7, 34.3, 26.4, 24.6, 22.1, 14.4. HRMS-
ESI (m/z) [M+H]+ calcd for C17H25O2, 261.1849; found 261.1845.
Ethyl 4-(2-methoxy-2-methylpropyl)benzoate (3m): The title compound was prepared
according to the general procedure and purified using 20% EtOAc in hexanes as eluent to
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give the product as colorless oil, 76 mg, 65% yield. H NMR (600 MHz, CDCl3) δ 7.97
(d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 3.29 (s, 3H), 2.83
(s, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.15 (s, 6H). 13C{1H} NMR (150 MHz, CDCl3) δ 166.7,
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143.8, 130.4, 129.1, 128.4, 75.1, 60.7, 49.4, 46.3, 24.7, 14.3. HRMS-ESI (m/z) [M+H]+
calcd for C14H21O3, 237.14852; found 237.14855.
Ethyl 4-(2-(1,3-dioxoisoindolin-2-yl)-2-methylpropyl)benzoate (3n): The title
compound was prepared according to the general procedure and purified 20% EtOAc in
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hexanes as eluent to give the product as white solid, 126 mg, 72% yield. H NMR (500
MHz, CDCl3) δ 7.86 (d, J = 8.2 Hz, 2H), 7.74-7.76 (m, 2H), 7.67-7.69 (m, 2H), 7.15 (d, J
= 8.2 Hz, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.32 (s, 2H), 1.76 (s, 6H), 1.35 (t, J = 7.1 Hz,
3H). 13C{1H} NMR (125 MHz, CDCl3) δ 169.8, 166.5, 142.8, 133.9, 131.8, 130.2, 129.3,
128.8, 122.8, 60.9, 60.8, 45.4, 27.6, 14.3. HRMS-ESI (m/z) [M+H]+ calcd for
C21H22NO4, 352.1549; found 352.1544.
Corresponding Authors
*E-mail: bo.qu@boehringer-ingelheim.com
*E-mail: nick.desrosiers@pfizer.com
Supporting Information
NMR spectra of the products. The Supporting Information is available free of charge on
the ACS Publications website.
Present address
† Chemical Research & Development, Pfizer Worldwide Research & Development, 558 Eastern
Point Rd., Groton, CT 06340, USA
‡ Discovery, Alkermes, Inc., 852 Winter St., Waltham, MA 02451, USA
§ TCG Lifesciences USA, 737 North 5th St., Suite 501, Richmond, VA 23219, USA
Competing Financial Interests
The authors declare no competing financial interests.
Acknowledgements
This work was influenced by the on-going efforts of the Non-Precious Metal Catalysis
Alliance between Abbvie, Boehringer Ingelheim Pharmaceuticals and Pfizer. We thank
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Dr. Eric Hansen and Dylan Pedro from Pfizer for helpful discussions. We are grateful to
Drs. Nina Gonnella and Dongyue Xin for NMR analysis of compounds 3l and 3m.
HRMS analysis by Scott Pennino and purification of compounds 3j, 3l and 3m by Dr.
Xiaowen Hou and Amy Gao are greatly appreciated.
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identified ligand would be a compound with low molecule weight. Initial compound
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part of 5-, or 6-heterocycles.
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product was observed.
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ACS Paragon Plus Environment