Cobalt-Catalyzed, N-H Imine-Directed Arene C-H Benzylation with Benzyl Phosphates

Article abstract of DOI:10.1021/acs.joc.9b01775

A cobalt-catalyzed ortho-C-H benzylation reaction of pivalophenone N-H imines with benzyl phosphates is reported. The reaction is promoted at room temperature by a ternary catalytic system comprising Co(acac)₃, a pyridylphosphine ligand, and a Grignard reagent and tolerates a series of substituted pivalophenone imines and benzyl phosphates to afford various diarylmethane derivatives in moderate yields.

Full text of DOI:10.1021/acs.joc.9b01775

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Note
Cobalt-Catalyzed, N–H Imine-Directed Arene
C–H Benzylation with Benzyl Phosphates
Roshayed Ali Laskar, and Naohiko Yoshikai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01775 • Publication Date (Web): 07 Aug 2019
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Cobalt-Catalyzed, N–H Imine-Directed Arene C–H
Benzylation with Benzyl Phosphates
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Roshayed Ali Laskar and Naohiko Yoshikai*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371, Singapore
E-mail: nyoshikai@ntu.edu.sg
Abstract. A cobalt-catalyzed ortho C–H benzylation reaction of pivalophenone N–H imines with
benzyl phosphates is reported. The reaction is promoted at room temperature by a ternary catalytic
system comprised of Co(acac)3, a pyridylphosphine ligand, and a Grignard reagent, and tolerates a
series of substituted pivalophenone imines and benzyl phosphates to afford various diarylmethane
derivatives in moderate yields.
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Diarylmethane skeletons are prevalent in biologically active compounds and pharmaceuticals, such as
papaverine and beclobrate, and hence their efficient and selective construction represents an important
subject in synthetic organic chemistry. A representative classical approach to access diarylmethanes is
the Friedel–Crafts-type, acid-catalyzed electrophilic aromatic substitution (SEAr) reactions of electron-
rich aromatic compounds with benzyl halides.1 Meanwhile, the transition metal-catalyzed cross-
coupling between aryl halides and benzylmetal reagents or between benzyl halides and arylmetal
reagents has been developed as an alternative approach.2 Nevertheless, these well-established
approaches have some intrinsic drawbacks. Despite notable progress in benzylating agents,3 the scope of
the Friedel–Crafts approach is inherently limited by the requirement for electron-rich arenes, and also
by the difficulty of regiocontrol. The cross-coupling reaction necessitates two prefunctionalized starting
materials, while the reductive, cross-electrophile coupling approach has emerged to allow for bypassing
the preparation of organometallic reagents.4 In this context, the transition metal-catalyzed C–H
benzylation of arenes has attracted interest as another viable approach to diarylmethanes.5,6 In particular,
benzylations involving directing group-assisted C–H activation have been achieved with precious
transition metals such as ruthenium,7 palladium,8 and rhodium,9 as well as with earth-abundant
transition metals such as cobalt,10 nickel,11 and iron.12
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Over the last decade, we and others have developed a series of directed arene C–H functionalizations
with organic electrophiles under low-valent cobalt catalysis.13 As for C–H benzylation, a C2-
benzylation reaction of N-pyridylindole with benzyl phosphate, reported by Ackermann in 2012,
represents the first example.10a Later in 2015, our group disclosed ortho-benzylation of N-aryl imines
derived from aryl alkyl ketones with benzyl phosphates.10b Meanwhile, our recent studies have
demonstrated that N–H imine, that of pivalophenone in particular, serves as a powerful and
transformable directing group for a variety of cobalt-catalyzed C–H functionalization reactions
including hydroarylation to alkenes14 as well as alkylation, arylation, and alkenylation with the
corresponding electrophiles (Scheme 1).15,16 Prompted by the need for efficient benzylation methods
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and the utility of N–H imine directing group, we have developed a cobalt-catalyzed directed C–H
benzylation reaction of pivalophenone N–H imines, which is reported herein.
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Scheme 1. Cobalt-Catalyzed N–H Imine-Directed C–H Functionalization
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The present study began with a screening of reaction conditions for the coupling between
pivalophenone N–H imine 1a and benzyl diethyl phosphate 2a (Table 1). A catalytic system comprised
of CoBr2 (10 mol %), IMes•HCl (10 mol %), and t-BuCH2MgBr (2 equiv) promoted the reaction at
room temperature to afford the desired benzylation product 3aa in 14% yield (entry 1). Other NHC
preligands such as IPr•HCl and N,N’-diisopropyl derivatives L1 and L2 displayed similar performances
as IMes•HCl (entries 2–4). No particular improvement was observed using monodentate phosphines
such as PPh3 and bidentate nitrogen ligands such as 1,10-phenanthroline (entries 5 and 6). A slight but
finite improvement was observed using 2-(2-(diphenylphosphanyl)ethyl)pyridine (pyphos), which
afforded 3aa in 21% yield (entry 7). Using pyphos as the ligand, the use of CoI2 or Co(acac)3 as the
cobalt source improved the yield of 3aa to 31% or 40%, respectively (entries 8 and 9). Finally, the yield
of the latter reaction was further improved to 50% (51% isolated yield) using a slightly larger amount
(2.4 equiv) of the Grignard reagent (entry 10). Outside this optimization table, we have extensively
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screened various reaction conditions and parameters including cobalt sources, ligands, Grignard
reagents, temperatures, equivalences, and concentrations. Nevertheless, we were unable to improve the
reaction efficiency further. The difficulty appears to be partly due to the background reaction, both
catalyzed and uncatalyzed,17 between the Grignard reagent and the benzyl phosphate. In fact, 2a was
generally fully consumed, while the conversion of 1a reached only 80% even under the optimized
conditions. Under the optimized conditions, the desired product was accompanied by ortho-
neopentylation of 1a (10%), cross-coupling between the Grignard reagent and 2a (3%), and
homocoupling of 2a (4%).
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Table 1. Benzylation of Pivalophenone N–H Imine 1a with Benzyl Phosphate 2aa
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Entry
CoXn
Ligand
Yield (%)b
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1
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoI2
IMes•HCl
IPr•HCl
L1•HBF4
L2•HBr
PPh3
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1,10-phenanthroline
pyphos
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pyphos
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Co(acac)3
Co(acac)3
pyphos
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10c
pyphos
50 (51)d
aThe reaction was performed using 0.1 mmol of 1a, 0.2 mmol of 2a, and 0.2 mmol of t-BuCH2MgBr.
bDetermined by GC using n-tridecane as an internal standard. 0.24 mmol of t-BuCH2MgBr was used.
c
dIsolated yield for a 0.4 mmol-scale reaction.
With the best reaction conditions in hand, we explored the scope of the present C–H benzylation.
First, a variety of substituted pivalophenone N–H imines were subjected to the benzylation with the
parent benzyl phosphate 2a (Scheme 2). A variety of para-substituted imines participated in the reaction
to afford the desired benzylation products 3ba–3ha in 40–65% yields, showing tolerance to electron-
donating groups such as tert-butyl and methoxy groups and electron-withdrawing groups such as
trifluoromethoxy, fluoro, and chloro groups. No cross-coupling between the chloro-substituted imine
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and the Grignard reagent was observed (see 3ha and 3ka). The reaction between 1a and 2a could be
scaled up to 4 mmol scale to afford 3aa in a higher yield (58%) than that of the small-scale reaction
(51%). The imines bearing meta-methyl or –chloro substituent underwent regioselective benzylation at
the less hindered ortho position, affording the corresponding products 3ia and 3ka, respectively, in
modest yields. On the other hand, the meta-fluorinated imine was benzylated at the proximity of the
fluorine atom, presumably due to the secondary directing effect (see the product 3ja).14b,15b The ortho-
methyl-substituted imine failed to participate in the present benzylation reaction. Note also that the
reaction between benzophenone N–H imine and 2a under the present conditions was sluggish, affording
the corresponding monobenzylated product in low yield (15% as estimated by GC analysis; not isolated)
along with substantial recovery of the imine (43%).
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Scheme 2. Benzylation of Substituted Pivalophenone N–H Imines with 2aa
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aThe reaction was performed on a 0.4 mmol scale under the conditions in Table 1, entry 10.
Next, we examined the reaction of the N–H imine 1a with different benzyl phosphates (Table 2).
Benzyl phosphates derived from para-substituted benzyl alcohols participated in the reaction to afford
the corresponding diarylmethane products in 48–66% yields (entries 1–4). Phopshates derived from
meta-substituted benzyl alcohols also afforded the desired products in somewhat lower yields (entries
5–8). The benzyl phosphate derived from ortho-chlorobenzyl alcohol furnished the benzylation product
in a lower yield of 29%, presumably due to the steric effect (entry 9). Nonetheless, these examples again
demonstrated the tolerance of the present reaction to an aryl–Cl moiety, which did not undergo cross-
coupling with the Grignard reagent (see entries 4, 8, and 9).
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Table 2. Benzylation of 1a with Different Benzyl Phosphatesa
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Entry
Ar
Yield (%)b
66 (3ab)
50 (3ac)
57 (3ad)
48 (3ae)
53 (3af)
42 (3ag)
39 (3ah)
35 (3ai)
29 (3aj)
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4-MeC6H4 (2b)
4-t-BuC6H4 (2c)
4-FC6H4 (2d)
4-ClC6H4 (2e)
3-MeC6H4 (2f)
3-MeOC6H4 (2g)
3-FC6H4 (2h)
3-ClC6H4 (2i)
2-ClC6H4 (2j)
aThe reaction was performed on a 0.4 mmol scale under the conditions in Table 1, entry 10. bIsolated
yield.
To gain mechanistic insight, several control experiments were performed. First, the benzylation
reaction in the presence of a free radical scavenger, TEMPO, afforded the desired product in 45% yield
(Scheme 3a). Interestingly, this observation is in sharp contrast to our previously reported ortho-
benzylation of N-aryl imines, where the reaction was completely shut down by TEMPO.10b This may
suggest that the mechanism of the benzylic C–O cleavage and/or the nature of the resulting benzylic
species is substantially different between the present and the previous benzylation reactions. Second,
comparison of parallel individual reactions of 1a and its deuterated analogue 1a-d5 indicated virtually no
kinetic isotope effect (Figure 1). Thus, C–H activation is unlikely to be the rate-determining step. This is
also distinct from the benzylation of N-aryl imine, where a sizable KIE of 1.6 was observed.10b
A
competition reaction using a mixture of the para-methyl- and fluoro-substituted imines (1b and 1g)
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resulted in predominant benzylation of the latter, demonstrating more facile activation of the electron-
deficient C–H bond (Scheme 3b). Another competition reaction using a mixture of the para-tert-butyl-
and -fluoro-substituted benzyl phosphates (2c and 2d) preferentially afforded the product of the latter,
more electron-poor phosphate (Scheme 3c). We also probed the background reaction between 2a and t-
BuCH2MgBr, which produced 3,3-dimethylbutylbenzene and bibenzyl through cross-coupling and
homocoupling, respectively (Scheme 3d). While the cross-coupling was dominant in the absence of the
cobalt catalyst, the homocoupling outcompeted the cross-coupling under the catalytic conditions. In
either case, high conversion of 2a (>95%) was observed.
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Scheme 3. Control Experiments
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Figure 1. Comparison of individual benzylation reactions of 1a and 1a-d5.
A possible catalytic cycle for the present benzylation reaction is shown in Scheme 4. As was proposed
for the alkylation and arylation reactions,15a we assume that the present reaction is initiated by
cyclometalation of a magnesium alkylideneamide 1•MgBr, generated by the deprotonation of the N–H
imine with the Grignard reagent, with a neopentylcobalt species A. The resulting cobaltacycle
intermediate B would undergo oxidative addition of the benzyl phosphate 2, followed by reductive
elimination of the aryl(benzyl)cobalt species C to give the product 3•MgBr. The alkylcobalt species A
would be regenerated through transmetalation between cobalt phosphate D and the Grignard reagent.
The lack of inhibition by TEMPO may suggest a two-electron mechanism for the oxidative addition,
while an alternative mechanism involving single electron transfer and rapid cobalt/benzyl radical
recombination may not be excluded.
Scheme 4. Possible Catalytic Cycle
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Finally, we attempted on transformation of the imine functionality of the benzylation product under
aerobic copper-catalyzed conditions (Scheme 5). Unlike the imine-to-nitrile conversion achieved for the
ortho-alkylated and –arylated pivalophenone imines,15a,d,18 exposure of the product 3aa to catalytic
Cu(OAc)2 under O2 atmosphere in DMF at 80 °C resulted in the formation of diketone 4 in 30% yield,
accompanied by other intractable products. Benzonitrile derivative 5 and oxygenated benzonitrile
derivative 6 were not detected. The formation of 4 would be rationalized by a mechanism for analogous
benzylic oxygenation reaction developed by Chiba,19 which is proposed to involve the formation of
iminylcopper(II) species, its oxidation by O2, benzyl-to-N 1,5-hydrogen atom transfer, and interception
of benzyl radical by peroxycopper(II) species.
Scheme 5. Aerobic Benzylic C–H Oxygenation of 3aa
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In summary, we have developed a cobalt-catalyzed, N–H imine-directed aromatic C–H benzylation
reaction with benzyl phosphates. The reaction proceeds at room temperature and tolerates a range of
substituted pivalophenone imines and benzyl phosphates to afford diarylmethane derivatives in
moderate yields. The N–H imine moiety of the product can be used to trigger oxygenation of the
benzylic C–H bond, allowing access to a 1,2-diacylbenzene derivative. Further exploration of N–H
imine-directed C–H functionalization reactions is underway.
Experimental Section
General Methods. All the reactions dealing with air- and moisture-sensitive compounds were
performed in oven-dried reaction vessels under nitrogen atmosphere. Thin-layer chromatography (TLC)
was performed on Merck 60 F254 silica gel plates. Flash column chromatography was performed using
40-63 μm silica gel (Si 60, Merck). 1H, 13C and 31P NMR spectra were recorded on Bruker AV-300 (300
1
13
MHz), AV-400 (400 MHz), or AV-500 (500 MHz) NMR spectrometers. H and C NMR spectra are
reported in parts per million (ppm) downfield from an internal standard, tetramethylsilane (0 ppm), and
31P NMR spectra are reported in reference to 85% H3PO4 (ppm) as an external standard. Gas
chromatography (GC) analysis was performed on a Shimadzu GC-2010 system equipped with glass
capillary column DB-5 (Agilent J&W, 0.25 mm i.d. x 30 m, 0.25 μm film thickness). High-resolution
mass spectra (HRMS) were obtained with a Q-Tof Premier LC HR mass spectrometer. Melting points
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were determined using a capillary melting point apparatus and are uncorrected. Unless otherwise noted,
commercial reagents were purchased from Sigma-Aldrich, Alfa Aesar, and other commercial suppliers
and were used as received. Co(acac)3 and 2-(2-(diphenylphosphanyl)ethyl)pyridine were purchased
from Alfa Aesar and Strem Chemicals, respectively, and were used as received. THF was distilled over
Na/benzophenone. Neopentylmagnesium bromide was prepared from neopentyl bromide and
magnesium turnings in THF, and titrated before use.
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Preparation of N–H Imines: General Procedure. An oven-dried Schlenk flask (100 mL) equipped
with a stir bar was charged with aryl nitrile (20 mmol), CuBr (58 mg, 0.4 mmol), and THF (20 mL)
under N2 atmosphere. To the mixture was added tert-butylmagnesium chloride (11 mL, 2 M in THF, 22
mmol), and the reaction mixture was stirred at 80 °C for 16 h. The resulting solution was cooled in an
ice bath and quenched with methanol (20 mL). After stirring for 10 min, the ice bath was removed and
the mixture was stirred for additional 1 h. The volatile materials were evaporated under reduced
pressure. The residue was diluted with Et2O (50 mL) and filtered thorough Celite. The resulting filtrate
was concentrated under reduced pressure, and the crude oil was purified with Kugelrohr distillation to
afford the desired N–H imine as light yellow oil. Except 1c, the N–H imines (1a,20 1b,15a 1d,15a 1e,21 1f-
g,15a 1h,18a 1i,15a 1j-1k,18a and 1l18b) are known compounds and their spectral data showed good
agreement with the literature data.
1-(4-(tert-Butyl)phenyl)-2,2-dimethylpropan-1-imine (1c). Light green solid (1.96 g, 90%); m.p.
1
62.7-62.9 °C; H NMR (300 MHz, CDCl3) δ 9.13 (brs, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 7.5
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Hz, 2H), 1.32 (s, 9H), 1.25 (s, 9H); C NMR (75 MHz, CDCl3) δ 190.5, 151.0, 139.5, 126.3, 124.9,
34.7, 31.4, 28.7; HRMS (ESI) Calcd for C15H24N [M + H]+ 218.1909, found 218.1911.
Preparation of Benzyl Phosphates. Benzyl phosphates were prepared from the corresponding benzyl
alcohols and diethyl chlorophosphates according to the literature procedure22 and purified using silica
gel chromatography. Except 2j, the benzyl phosphates (2a,22 2b,22 2c,10b 2d,23 2e,22 and 2f-i,10b) are
known compounds and their spectral data showed good agreement with the literature data.
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2-Chlorobenzyl diethyl phosphate (2j). Colorless oil (1.30 g, 47%); H NMR (300 MHz, CDCl3) δ
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7.53-7.50 (m, 1H), 7.38-7.33 (m, 1H), 7.30-7.24 (m, 2H), 5.17 (d, J = 7.2 Hz, 2H), 4.17-4.07 (m, 4H),
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1.32 (t, J = 7.2 Hz, 6H); C NMR (75 MHz, CDCl3) δ 134.0 (d, JC-P = 7.8 Hz), 133.0, 129.7, 129.6,
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129.4, 127.0, 66.2 (d, JC-P = 4.9 Hz), 64.1 (d, JC-P = 5.8 Hz), 16.2 (d, JC-P = 6.6 Hz); P (121 MHz,
CDCl3) δ -0.4; HRMS (ESI) Calcd for C11H17ClO4P [M + H]+ 279.0553, found 279.0565.
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General Procedure for C–H Benzylation. A dry 10 mL Schlenk tube equipped with a stir bar was
charged with Co(acac)3 (14.3 mg, 0.040 mmol) and 2-(2-(diphenylphosphanyl)ethyl)pyridine (pyphos,
11.7 mg, 0.040 mmol), and THF (1.0 mL) under N2 atmosphere. The resulting solution was cooled in an
ice bath, followed by dropwise addition of t-BuCH2MgBr (1.0 M in THF, 0.96 mL, 0.96 mmol). After
stirring for 30 min, N–H imine (0.40 mmol) and benzyl phosphate (0.80 mmol) were added
sequentially. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The
resulting mixture was filtered through a short pad of silica gel while washing with EtOAc (10 mL x 3).
The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel
chromatography (eluent: hexane/EtOAc/NEt3 = 50/1/1) to afford the benzylation product.
1-(2-Benzylphenyl)-2,2-dimethylpropan-1-imine (3aa). Light yellow oil (51 mg, 51%); Rf 0.50
(hexane/EtOAc = 4/1); 1H NMR (500 MHz, CDCl3) δ 9.21 (brs, 1H), 7.26-7.10 (m, 8H), 7.06 (dd, J = 1
13
Hz, 1H), 3.86 (s, 2H), 1.22 (s, 9H); C NMR (125 MHz, CDCl3) δ 190.1, 141.6, 140.8, 137.0, 130.5,
129.1, 128.6, 127.9, 126.32, 126.26, 125.6, 40.6, 39.5, 28.8; HRMS (ESI) Calcd for C18H22N [M + H]+
252.1752, found 252.1747.
Preparative-Scale Synthesis of 3aa. A dry 50 mL Schlenk tube equipped with a stir bar was charged
with Co(acac)3 (143 mg, 0.40 mmol), pyphos (117 mg, 0.40 mmol), and THF (10.0 mL) under N2
atmosphere. The resulting solution was cooled in an ice bath, followed by dropwise addition of t-
BuCH2MgBr (1.0 M in THF, 9.6 mL, 9.6 mmol). After stirring for 30 min, 2,2-dimethyl-1-
phenylpropan-1-imine (1a, 645 mg, 4.0 mmol) and benzyl diethyl phosphate (2a, 1.96 g, 8.0 mmol)
were added sequentially. The reaction mixture was allowed to warm to room temperature and stirred for
12 h. The resulting mixture was filtered through a short pad of silica gel while washing with EtOAc (50
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mL x 3). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel
chromatography (eluent: hexane/EtOAc/NEt3 50/1/1) to afford 1-(2-benzylphenyl)-2,2-
=
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dimethylpropan-1-imine (3aa) as a light yellow oil (587 mg, 58%).
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1-(2-Benzyl-4-methylphenyl)-2,2-dimethylpropan-1-imine (3ba). Light yellow oil (66 mg, 62%);
Rf 0.50 (hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3) δ 8.87 (brs, 1H), 7.26 - 7.23 (m, 2H), 7.18-
7.09 (m, 3H), 6.95-6.91(m, 3H), 3.82 (s, 2H), 2.25(s, 3H), 1.20 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
190.3, 141.0, 139.0, 137.6, 136.8, 131.1, 129.1, 128.6, 126.33, 126.28, 126.22, 40.7, 39.5, 28.9, 21.3;
HRMS (ESI) Calcd for C19H24N [M + H]+ 266.1909, found 266.1915.
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1-(2-Benzyl-4-(tert-butyl)phenyl)-2,2-dimethylpropan-1-imine (3ca). Light yellow oil (49 mg,
40%); Rf 0.55 (hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3) δ 9.19 (brs, 1H), 7.29-7.25 (m, 2H),
7.20-7.18 (m, 3H), 7.12 (d, J = 7.2 Hz, 2H), 7.01 (d, J = 8 Hz, 1H), 3.89 (s, 2H), 1.26 (s, 9H), 1.23 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 190.3, 150.7, 141.1, 139.0, 129.0, 128.6, 127.7, 126.2, 126.0,
122.5, 40.7, 39.8, 34.6, 31.4, 28.9; HRMS (ESI) Calcd for C22H30N [M + H]+ 308.2378, found
308.2382.
1-(3-Benzyl-[1,1'-biphenyl]-4-yl)-2,2-dimethylpropan-1-imine (3da): Light yellow oil (60 mg,
46%); Rf 0.45 (hexane/EtOAc = 4/1); 1H NMR (500 MHz, CDCl3) δ 9.26 (brs, 1H), 7.54-7.52 (m, 2H),
13
7.44-7.40 (m, 4H), 7.36-7.28 (m, 3H), 7.23-7.18 (m, 4H), 3.97 (s, 2H), 1.30 (s, 9H); C NMR (125
MHz, CDCl3) δ 190.0, 140.8, 140.7, 140.6, 137.5, 129.3, 129.1, 128.9, 128.7, 127.6, 127.2. 126.8,
126.4, 124.4, 40.7, 39.7, 28.9; HRMS (ESI) Calcd for C24H26N [M + H]+ 328.2065, found 328.2059.
1-(2-Benzyl-4-methoxyphenyl)-2,2-dimethylpropan-1-imine (3ea): Light yellow oil (60 mg, 53%);
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Rf 0.43 (hexane/EtOAc = 4/1); H NMR (300 MHz, CDCl3) δ 9.24 (brs, 1H), 7.31-7.26 (m, 2H), 7.21-
7.18 (m, 1H), 7.17-7.13 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 6.73 (dd, J = 8.4, 2.7 Hz, 1H), 6.66 (d, J = 2.4
13
Hz, 1H), 3.87 (s, 2H), 3.73 (s, 3H), 1.24 (s, 9H); C NMR (75 MHz, CDCl3) δ 189.9, 159.0, 140.6,
138.8, 134.4, 129.1, 128.6, 127.4, 126.4, 116.0, 110.8, 55.3, 40.8, 39.7, 28.9; HRMS (ESI) Calcd for
C19H24NO [M + H]+ 282.1858, found 282.1862.
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1-(2-Benzyl-4-(trifluoromethoxy)phenyl)-2,2-dimethylpropan-1-imine (3fa): Light yellow oil (87
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mg, 65%); Rf 0.43 (hexane/EtOAc = 4/1); H NMR (400 MHz, CDCl3) δ 9.37 (brs, 1H), 7.32-7.21 (m,
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6
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4H), 7.14-7.11 (m, 3H), 7.06-7.04 (m, 1H), 6.95 (d, J = 1.2 Hz, 1H), 3.89 (s, 2H), 1.24 (s, 9H); C
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NMR (100 MHz, CDCl3) δ 190.0, 148.8, 139.7, 129.1, 128.9, 127.8, 126.8, 122.8, 121.8, 119.3, 118.0,
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40.8, 39.4, 28.7; F NMR (282 MHz, CDCl3) δ -57.8; HRMS (ESI) Calcd for C19H21F3NO [M + H]+
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336.1575, found 336.1583.
1-(2-Benzyl-4-fluorophenyl)-2,2-dimethylpropan-1-imine (3ga): Light yellow oil (59 mg, 54%); Rf
0.45 (hexane/EtOAc = 4/1); 1H NMR (300 MHz, CDCl3) δ 9.28 (brs, 1H), 7.38-7.20 (m, 3H), 7.13 (d, J
= 7.2 Hz, 2H), 7.07 (dd, J = 8.4, 6 Hz, 1H), 6.89 (td, J = 8.4, 2.4 Hz, 1H), 6.80 (dd, J = 9.9, 2.4 Hz, 1H),
13
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3.87 (s, 2H), 1.24 (s, 9H); C NMR (75 MHz, CDCl3) δ 189.4, 162.2 (d, JC-F = 245.1 Hz), 140.1 (d,
3JC-F = 7.1 Hz), 139.9, 137.5 (d, 3JC-F = 3.1 Hz), 129.2, 128.8, 127.9 (d, 3JC-F = 8.1 Hz), 126.7, 117.1 (d,
2JC-F = 21.5 Hz), 112.7(d, JC-F = 21.5 Hz), 40.8, 39.5, 28.8; F NMR (282 MHz, CDCl3) δ -113.8;
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HRMS (ESI) Calcd for C18H21NF [M + H]+ 270.1658, found 270.1660.
1-(2-Benzyl-4-chlorophenyl)-2,2-dimethylpropan-1-imine (3ha): Light yellow oil (62 mg, 54%); Rf
0.44 (hexane/EtOAc = 4/1); 1H NMR (300 MHz, CDCl3) δ 9.29 (brs, 1H), 7.32-7.22 (m, 3H), 7.20-7.10
(m, 4H), 7.05-7.02 (m, 1H), 3.86 (s, 2H), 1.23 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 189.1, 139.9,
139.8, 139.4, 133.8, 130.4, 129.1, 128.9, 127.7, 126.7, 125.9, 40.8, 39.4, 28.7. HRMS (ESI) Calcd for
C18H21NCl [M + H]+ 286.1363, found 286.1357.
1-(2-Benzyl-5-methylphenyl)-2,2-dimethylpropan-1-imine (3ia); Light yellow oil (30 mg, 28%); Rf
0.65 (hexane/EtOAc = 4/1); 1H NMR (300 MHz, CDCl3) δ 9.21 (brs, 1H,), 7.31-7.27 (m, 2H), 7.23-7.13
13
(m, 3H), 7.08-7.01 (m, 2H), 6.91 (s, 1H), 3.86 (s, 2H), 2.34 (s, 3H), 1.27 (s, 9H); C NMR (75 MHz,
CDCl3) δ 190.3 (NH=C), 141.7, 141.1, 135.1, 133.9, 130.4, 129.1, 128.7, 128.6, 126.8, 126.3, 40.6,
39.2, 28.9, 21.2; HRMS (ESI) Calcd for C19H24N [M + H]+ 266.1909, found 266.1911.
1-(2-Benzyl-5-fluorophenyl)-2,2-dimethylpropan-1-imine (3ja): Light yellow oil (56 mg, 52%); Rf
1
0.45 (hexane/EtOAc = 4/1); H NMR (400 MHz, CDCl3) δ 9.28 (brs, 1H), 7.36-7.32 (m, 3H), 7.3-7.28
(m, 1H), 7.23-7.21 (m, 2H), 7.14 (t, J = 8.4 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 4.03 (s, 2H), 1.30 (s, 9H);
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13C NMR (100 MHz, CDCl3) δ 188.5, 161.8 (d, 1JC-F = 245.6 Hz), 143.8, 139.8, 128.6, 128.3, 127.6 (d,
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3JC-F = 8.8 Hz), 126.3, 122.2 (d, JC-F = 2.8 Hz), 115.0 (d, JC-F = 22.7 Hz), 40.6, 33.3, 28.8; 19F NMR
(282 MHz, CDCl3) δ -113.1; HRMS (ESI) Calcd for C18H21NF [M + H]+ 270.1658, found 270.1651.
1-(2-Benzyl-5-chlorophenyl)-2,2-dimethylpropan-1-imine (3ka): Light yellow oil (48 mg, 42%); Rf
0.43 (hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3) δ 9.21 (brs, 1H), 7.34-7.29 (m, 2H), 7.26-7.22
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(m, 2H), 7.15-7.07 (m, 4H), 3.88 (s, 2H), 1.28 (s, 9H); C NMR (100 MHz, CDCl3) δ 188.7, 140.2,
131.9, 131.5, 129.1, 128.8, 128.1, 126.6, 40.7, 39.0, 28.7; HRMS (ESI) Calcd for C18H21NCl [M + H]+
286.1363, found 286.1357.
2,2-Dimethyl-1-(2-(4-methylbenzyl)phenyl)propan-1-imine (3ab); Light yellow oil (70 mg, 66%);
Rf 0.50 (hexane/EtOAc = 4/1); 1H NMR (300 MHz, CDCl3) δ 9.26 (brs, 1H), 7.25-7.00 (m, 8H), 3.84 (s,
2H), 2.31 (s, 3H), 1.25 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 190.2, 141.7, 137.8, 137.3, 135.8, 130.5,
129.3, 129.0, 127.9, 126.2, 125.5, 40.7, 39.2, 28.9, 21.1; HRMS (ESI) Calcd for C19H24N [M + H]+
266.1909, found 266.1913.
1-(2-(4-(tert-Butyl)benzyl)phenyl)-2,2-dimethylpropan-1-imine (3ac): Light yellow oil (62 mg,
50%); Rf 0.53 (hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3) δ 9.22 (brs, 1H), 7.33-7.29 (m, 2H),
13
7.27-7.23 (m, 1H), 7.21-7.17 (m, 2H), 7.11-7.07 (m, 3H), 3.87 (s, 2H), 1.31 (s, 9H), 1.27(s, 9H); C
NMR (100 MHz, CDCl3) δ 190.0, 149.1, 141.6, 137.7, 137.2, 130.6, 128.7, 127.9, 126.2, 125.5, 40.6,
39.1, 34.5, 31.5, 28.9; HRMS (ESI) Calcd for C22H30N [M + H]+ 308.2378, found 308.2384.
1-(2-(4-Fluorobenzyl)phenyl)-2,2-dimethylpropan-1-imine (3ad): Light yellow oil (62 mg, 57%);
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Rf 0.43 (hexane/EtOAc = 4/1); H NMR (300 MHz, CDCl3) δ 9.16 (brs, 1H), 7.26-7.16 (m, 2H), 7.11-
7.07 (m, 4H), 7.00-6.93 (m, 2H), 3.86 (s, 2H), 1.24 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 190.1, 161.6
(d, 1JC-F = 242.8 Hz), 136.8, 136.5, 136.4, 130.5 (d, 3JC-F = 7.8 Hz), 128.0, 126.4, 125.8, 115.4 (d, 2JC-F
=
21.1 Hz), 40.7, 38.7, 28.8; 19F NMR (282 MHz, CDCl3) δ -117.0; HRMS (ESI) Calcd for C18H21NF [M
+ H]+ 270.1658, found 270.1665.
1-(2-(4-Chlorobenzyl)phenyl)-2,2-dimethylpropan-1-imine (3ae): Light yellow oil (55 mg, 48%);
1
Rf 0.47 (hexane/EtOAc = 4/1); H NMR (300 MHz, CDCl3) δ 9.26 (brs, 1H), 7.31-7.21 (m, 4H), 7.15-
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7.10 (m, 4H), 3.90 (s, 2H), 1.29 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 190.0, 141.6, 139.3, 136.4,
132.2, 130.4, 128.7, 128.1, 126.4, 125.8, 40.7, 38.9, 28.8; HRMS (ESI) Calcd for C18H21NCl [M + H]+
286.1373, found 286.1370.
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2,2-Dimethyl-1-(2-(3-methylbenzyl)phenyl)propan-1-imine (3af): Light yellow oil (55 mg, 53%);
Rf 0.50 (hexane/EtOAc = 4/1); 1H NMR (300 MHz, CDCl3) δ 9.24 (brs, 1H), 7.26-7.09 (m, 5H), 7.02 (d,
J = 7.5 Hz, 1H), 6.97-6.93 (m, 2H), 3.87 (s, 2H), 2.32 (s, 3H), 1.27 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 190.1, 141.7, 140.7, 138.2, 137.1, 130.5, 129.9, 128.5, 127.9, 127.1, 126.2, 125.5, 40.6, 39.4, 28.9,
21.6; HRMS (ESI) Calcd for C19H24N [M + H]+ 266.1909, found 266.1912.
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1-(2-(3-Methoxybenzyl)phenyl)-2,2-dimethylpropan-1-imine (3ag): Light yellow oil (47 mg,
42%); Rf 0.33 (hexane/EtOAc = 4/1); 1H NMR (300 MHz, CDCl3) δ 9.28 (brs, 1H), 7.32-7.14 (m, 5H),
6.82-6.75 (m, 3H), 3.93 (s, 2H), 3.83 (s, 3H), 1.31 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 190.1, 159.8,
142.4, 141.7, 136.7, 130.5, 129.6, 127.9, 126.2, 125.6, 121.6, 115.1, 111.5, 55.2, 40.7, 39.5, 28.9;
HRMS (ESI) Calcd for C19H24NO [M + H]+ 282.1858, found 282.1859.
1-(2-(3-Fluorobenzyl)phenyl)-2,2-dimethylpropan-1-imine (3ah): Light yellow oil (42 mg, 39%);
1
Rf 0.43 (hexane/EtOAc = 4/1); H NMR (300 MHz, CDCl3) δ 9.36 (brs, 1H), 7.34-7.24 (m, 3H), 7.19-
7.15 (m, 2H), 6.98-6.87 (m, 3H), 3.94 (s, 2H), 1.30 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 190.0, 163.1
3
3
(d, 1JC-F = 244.4 Hz), 143.4 (d, JC-F = 7.3 Hz), 136.2, 130.5, 130.0 (d, JC-F = 8.3 Hz), 128.1, 126,5,
125.9, 124.8 (d, 3JC-F = 2.8 Hz), 116.0 (d, 2JC-F = 21.2 Hz), 113.3 (d, 2JC-F = 20.9 Hz), 40.7, 39.2, 28.8;
19F NMR (282 MHz, CDCl3) δ -113.3; HRMS (ESI) Calcd for C18H21NF [M + H]+ 270.1658, found
270.1660.
1-(2-(3-Chlorobenzyl)phenyl)-2,2-dimethylpropan-1-imine (3ai): Light yellow oil (40 mg, 35%);
Rf 0.43 (hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3) δ 9.18 (brs, 1H), 7.27-7.17 (m, 4H), 7.11 (d,
13
J = 8.0 Hz, 3H), 7.01 (d, J = 6.4 Hz, 1H), 3.87 (s, 2H), 1.24 (s, 9H); C NMR (100 MHz, CDCl3) δ
190.0, 142.9, 141.7, 136.1, 134.4, 130.5, 129.9, 129.2, 128.1, 127.3, 126.6, 126.5, 125.9, 40.7, 39.1,
28.8; HRMS (ESI) Calcd for C18H21NCl [M + H]+ 286.1363, found 286.1369.
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1-(2-(2-Chlorobenzyl)phenyl)-2,2-dimethylpropan-1-imine (3aj): Light yellow oil (34 mg, 29%),
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Rf 0.51 (hexane/EtOAc = 4/1); H NMR (300 MHz, CDCl3) δ 9.32 (brs, 1H), 7.40-7.37 (m, 1H), 7.23-
7.10 (m, 5H), 7.03-6.96 (m, 2H), 4.00 (s, 2H), 1.27 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 190.1, 138.3,
135.5, 134.4, 131.1, 129.9, 129.7, 128.0, 127.9, 127.0, 126.4, 125.8, 40.8, 37.0, 28.9; HRMS (ESI)
Calcd for C18H21NCl [M + H]+ 286.1363, found 286.1367.
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1-(2-Benzoylphenyl)-2,2-dimethylpropan-1-one (4). In a 25 mL Schlenk tube equipped with a stir
bar were placed 3aa (0.6 mmol) and Cu(OAc)2 (11 mg, 0.06 mmol), followed by the addition of DMF
(6 mL). An oxygen balloon was attached to the Schlenk tube, and the reaction mixture was stirred at 80
°C in an oil bath for 12 h. The mixture was concentrated under reduced pressure, and the residue was
subjected to silica gel chromatography to afford the title compound as a light yellow oil (48 mg, 30%).
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Rf 0.33 (hexane/EtOAc = 4/1); H NMR (400 MHz, CDCl3) δ 7.78-7.76 (m, 2H), 7.60-7.53 (m, 3H),
7.48-7.42 (m, 4H), 1.30 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 213.7, 196.7, 137.5, 137.2, 132.9,
131.0, 130.9, 130.2, 128.5, 128.3, 126.3, 44.7, 27.9; HRMS (ESI) Calcd for C18H19O2 [M + H]+
267.1385, found 267.1383.
Supporting Information Available. The Supporting Information is available free of charge on the
ACS Publications website.
NMR spectra (PDF)
Corresponding Author
*E-mail: nyoshikai@ntu.edu.sg.
ORCID
Naohiko Yoshikai: 0000-0002-8997-3268
Notes
The authors declare no competing financial interest.
Acknowledgments. This work was supported by Nanyang Technological University and Singapore
Ministry of Education (MOE2016-T2-2-043).
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References
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( ) Rueping, M.; Nachtsheim, B. J. A Review of New Developments in the Friedel–Crafts Alkylation
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– from Green Chemistry to Asymmetric Catalysis. Beilstein J. Org. Chem. 2010, 6, 6.
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(2) Liegault, B.; Renaud, J. L.; Bruneau, C. Activation and Functionalization of Benzylic Derivatives
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