Divergent synthesis of isonitriles and nitriles by palladium- catalyzed benzylic substitution with TMSCN

Article abstract of DOI:10.1021/acs.joc.0c01861

Ligand-controlled palladium-catalyzed divergent synthesis of isonitriles and nitriles from benzylic carbonates and TMSCN has been developed. The BINAP- or DPEphos-ligated palladium catalyst selectively provides the corresponding benzylic isonitriles, wher

Full text of DOI:10.1021/acs.joc.0c01861

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Article
Divergent Synthesis of Isonitriles and Nitriles by
Palladium-Catalyzed Benzylic Substitution with TMSCN
Kento Asai, Koji Hirano, and Masahiro Miura
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01861 • Publication Date (Web): 09 Sep 2020
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The Journal of Organic Chemistry
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Divergent Synthesis of Isonitriles and Nitriles by
Palladium-Catalyzed Benzylic Substitution with
TMSCN
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Kento Asai, Koji Hirano,* and Masahiro Miura*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita,
Osaka 565-0871, Japan
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
k_hirano@chem.eng.osaka-u.ac.jp; miura@chem.eng.osaka-u.ac.jp
Ligand-controlled palladium-catalyzed divergent synthesis of isonitriles and nitriles from
benzylic carbonates and TMSCN has been developed.
The BINAP- or DPEphos-ligated
palladium catalyst selectively provides the corresponding benzylic isonitriles, whereas their
regioisomers, benzylic nitriles, are formed exclusively under phosphine-ligand-free conditions.
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Mechanistic studies reveal that the isonitrile is the primary product under both conditions, but
it is isomerized into the nitrile in the absence of ancillary phosphine ligands.
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The Journal of Organic Chemistry
Introduction
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Isonitriles and nitriles are regioisomers to each other, and both are important nitrogen-
containing compounds in organic chemistry. The former is not only the well-known reactant
in Passerini and Ugi multi-component coupling reactions1 but also frequently occurring in
natural products.2 The latter is also found in biologically active compounds3 as well as the
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valuable synthetic intermediate for amines and carbonyl compounds.4
Therefore, their
selective synthesis has been one of the long-standing research subjects in synthetic
communities. Among numerous reports,5 the metal-mediated substitution reaction of carbon
electrophiles with “CN” nucleophiles is the most classical but the most reliable strategy.
However, the “CN” nucleophiles have the ambident character; they can work as both the N-
terminus nucleophile and C-terminus nucleophile to form the corresponding isonitrile and
nitrile, respectively (Scheme 1a). Accordingly, the control of reaction regioselectivity (N-attack
vs C-attack) is a great synthetic challenge. Extensive screening of catalysts/ligands, “CN”
reagents, additives, and reaction conditions often provided one regioisomer selectively, but
another regioisomer was generally difficult to access by simple ligand modifications.6,7,8 Herein,
we report ligand-controlled palladium-catalyzed divergent synthesis of regioisomeric benzylic
isonitriles and nitriles: a bisphosphine-ligated palladium catalyst couples the benzyl carbonates
with TMSCN to form the corresponding benzylic isonitriles with high N-terminus selectivity
(Scheme 1b). On the other hand, the benzylic nitriles are obtained exclusively under ancillary
phosphine ligand-free conditions. The newly developed protocols can provide a divergent
approach to isonitriles and nitriles from the readily available benzyl carbonates.
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Scheme 1. Substitution Approaches to Isonitriles and Nitriles from Carbon Electrophiles
and Ambident “CN” Nucleophile
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Results and Discussion
Recently, our research group focused on the unique reactivity of benzylic C–O electrophiles
and succeeded in the development of palladium-catalyzed benzylic substitution reactions with
various nucleophiles including azoles, terminal alkynes, active methylenes, amides/amines,
phenols, sulfinates, phosphonates, and olefins.9
During the continuing interest in this
chemistry, we tested some “CN” nucleophiles in the reaction of tert-butyl diarylmethyl carbonate
1a-Boc with CpPd(3-C3H5) catalyst, rac-BINAP ligand, and MeCN solvent at 80 ˚C. After initial
brief screening, TMS-CN was found to uniquely promote the reaction (Table 1). Additionally,
the corresponding benzylic isonitriles 2a-NC was mainly formed (67% 1H NMR yield) along with
1
a small amount of nitrile 2a-CN (6% H NMR yield; entry 1). This preliminary but intriguing
isonitrile selectivity prompted us to further investigate the reaction conditions.
Several
bidentate phosphine ligands bearing relatively large bite angles worked, but only with DPEphos
proving efficiency and isonitrile/nitrile selectivity comparable to rac-BINAP (entries 2–4). On
the other hand, the bisphosphine ligands with smaller bite angles such as dppbz completely shut
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down the reaction (entry 5). Additional investigations of Pd catalyst precursors revealed that
Pd(CH2TMS)2(cod) showed somewhat better performance even at lower temperature (60 ˚C), and
finally the corresponding isonitrile 2a-NC was isolated in 77% yield (entries 6 and 7). In sharp
contrast, without any external phosphine ligands the regioselectivity was switched, giving the
regioisomeric benzyl nitrile 2a-CN predominantly (entry 8). For the nitrile synthesis, the methyl
carbonate 1a-CO2Me was the better starting substrate from the viewpoints of reactivity and
nitrile/isonitrile selectivity, and the desired 2a-CN was obtained in 71% isolated yield with high
regioselectivity (entry 9), while the reaction of 1a-Piv and 1a-OH was sluggish even at higher
temperature (entries 10 and 11). We confirmed no conversion of 1a-Boc in the absence of any
Pd sources (entry 12), thus indicating that Pd catalysts are necessary for both isonitrile and nitrile
formations. Some additional observations are to be noted: other potential “CN” nucleophiles
such as acetone cyanohydrin, benzoyl cyanide, and tetrabutylammonium cyanide resulted in no
conversion. The reaction was unique to the MeCN solvent, and neither less polar nor much
polar solvents gave satisfactory results (see the Supporting Information for more detailed
optimization studies).
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Table 1. Optimization Studies for Palladium-Catalyzed Benzylic Substitution of
Diarylmethanol Derivatives 1a with TMSCNa
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yield (%)b
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entry
1a
Pd/ligand
2a-NC
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trace
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(77)
5
2a-CN
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1a-Boc
1a-Boc
1a-Boc
1a-Boc
1a-Boc
1a-Boc
1a-Boc
1a-CO2Me
1a-Piv
CpPd(3-C3H5)/rac-BINAP
CpPd( 3-C3H5)/dppf
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CpPd( 3-C3H5)/DPEphos
CpPd( 3-C3H5)/xantphos
CpPd( 3-C3H5)/dppbz
Pd(cod)(CH2TMS)2/rac-BINAP
Pd(cod)(CH2TMS)2/rac-BINAP
Pd(cod)(CH2TMS)2/none
Pd(cod)(CH2TMS)2/none
Pd(cod)(CH2TMS)2/none
Pd(cod)(CH2TMS)2/none
none/none
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(71)
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1a-OH
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1a-Boc
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a Conditions: 1a (0.20 mmol), TMSCN (0.30 mmol), Pd (0.010 mmol), ligand (0.010 mmol), MeCN
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b
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(1.5 mL), 80 ˚C, 4 h, N2.
Estimated by H NMR with CH2Br2 or 1-methylnaphthalene as the
internal standard . Isolated yields in parentheses. c With TMSCN (0.80 mmol) and rac-BINAP
(0.011 mmol) at 60 ˚C for 19 h. d For 18 h. e At 100 ˚C for 2 h.
To check the generality of ligand-controlled regioselectivity switching observed in Table 1, we
next examined the reaction of various benzylic carbonates 1 with TMSCN under both isonitrile
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and nitrile conditions (entries 7 and 9 in Table 1, respectively). The representative results are
shown in Scheme 2. For the isonitrile selective synthesis (right side in Scheme 2), some minor
modifications of reaction temperature and time were often necessary, but the corresponding
benzylic isonitriles 2-NC were obtained with good regioselectivity (isonitrile/nitrile = 79:21–
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>99:1).
Namely, in addition to the model substrate 1a-Boc, the methoxy- and chloro-
substituted benzylic carbonates were also selectively converted to 2b-NC and 2c-NC,
respectively. Exceptionally, the introduction of highly electron-withdrawing trifluoromethyl
group interfered with the conversion (2d-NC); however, which can provide the useful
information about the reaction mechanism (vide infra). The ortho- and meta-substituted
carbonates could also be employed (2e-NC and 2f-NC). The replacement of phenyl ring with
the thiophene was also possible (2g-NC). The 2-naphthalene ring in the model substrate 1a-
Boc could also be replaced with the methoxy-substituted 2-naphthalene, 1-naphthalene, and
higher fused phenanthrene systems (2h-NC–2j-NC).
Moreover, the heteroaromatic
benzothiophene-, benzofuran-, and dibenzothiophene-substituted carbonates were viable to
afford the corresponding isonitriles 2k-NC–2m-NC in good yields with high isonitrile selectivity.
It should be noted that the palladium catalyst was compatible with the monocyclic substituents
such as the biphenyl (2n-NC) and even simple phenyl groups (2o-NC), which are generally
challenging substrates in the related cross-coupling reactions with C–O electrophiles.10 The
alkyl-substituted secondary benzyl carbonate (2p-NC) and the primary substrate (2q-NC) were
reluctant to the palladium catalysis. Particularly in the former case, the competitive elimination
reaction occurred, and the corresponding vinylnaphthalene was observed. As the ancillary
ligand, rac-BINAP generally provided the best performance, but in specific cases with the highly
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sterically congested substrates, DPEphos resulted in better efficiency (2e-NC, 2i-NC, and 2j-NC).
Additionally, the reaction was easily conducted on a 1.0 mmol scale (2a-NC) with the
maintenance of yield and isonitrile selectivity, thus suggesting the reliability and reproducibility
of this protocol.
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In almost all cases of nitrile synthesis (left side in Scheme 2), the much better regioselectivity
was observed (nitrile/isonitrile = 89:11–>99:1).
As seen in the isonitrile synthesis, the
trifluoromethyl-substituted substrate suffered from the low conversion (2d-CN), but the reaction
was tolerated to the para-methoxy, para-chloro, ortho-methyl, and meta-methoxy substituents
to furnish the corresponding nitriles 2b-CN, 2c-CN, 2e-CN, and 2f-CN in good to high yields.
In the synthesis of thiophene-substituted 2g-CN, the corresponding starting methyl carbonate
1g-CO2Me was too unstable to be prepared in a pure form, but the use of more stable tert-butyl
carbonate 1g-Boc afforded an acceptable yield. The palladium catalysis also accommodated
the 2-methoxynaphthalene (2h-CN) and more fused aromatics (2i-CN and 2j-CN) as well as
heteroaromatic substrates (2k-CN–2m-CN). Additionally notable is the successful conversion
of the monocyclic systems (2n-CN and 2o-CN) and primary benzyl carbonate (2q-CN). Only
one exception is the alkyl-substituted secondary benzyl carbonate: the targeted nitrile 2p-CN
and regioisomeric isonitrile 2p-NC were formed only in 15% and 19% yield, respectively.
Additionally, as same under the isonitrile conditions, the elimination byproduct was observed in
the crude mixture. Also in the nitrile synthesis, the scale-up reaction was feasible without any
erosion of yield and nitrile/isonitrile selectivity (2a-CN).
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Scheme 2. Synthesis of Isonitriles 2-NC and Nitriles 2-CN by Ligand-Controlled Palladium-
Catalyzed Regiodivergent Benzylic Substitution of Benzyl Carbonates 1 with TMSCNa
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a Isonitrile conditions: 1-Boc (0.20 mmol), TMSCN (0.80 mmol), Pd(CH2TMS)2(cod) (0.010 mmol),
rac-BINAP or DPEphos (0.011 mmol), MeCN (1.5 mL), 60 ˚C, 19 h, N2; Nitrile conditions: 1-CO2Me
(0.20 mmol), TMSCN (0.30 mmol), Pd(CH2TMS)2(cod) (0.010 mmol), MeCN (1.5 mL), 80 ˚C, 18 h,
N2. Isolated yields of pure isonitrile or nitrile are shown. The ratios of isonitrile/nitrile (right
side) or nitrile/isonitile (left side) in the crude mixture are also shown. b On a 1.0 mmol scale.
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c At 40 ˚C. d For 36 h. e At 40 ˚C for 28 h. f At 40 ˚C for 24 h. g 1H NMR yield. The lower isolated
is due to the partial decomposition of 2o-NC during column purification. h At 70 ˚C. i With 2 mol
% of Pd(CH2TMS)2(cod). j At 100 ˚C. k With 0.80 mmol of TMSCN. l At 60 ˚C for 1 h using 1g-Boc.
m With 10 mol % of Pd(CH2TMS)2(cod) and TMSCN (0.80 mmol) at 120 ˚C for 18 h.
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To get insight into the reaction mechanism, particularly, about the isonitrile/nitrile selectivity,
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we monitored the reaction progress by using H NMR.
Under the isonitrile conditions,
alongside the consumption of starting 1a-Boc, the corresponding isonitrile 2a-NC gradually
formed. On the other hand, the regioisomeric nitrile 2a-CN was detected after 180 min, but its
amount was kept in less than 5% in 6 h reaction periods (Figure 1a). In contrast, under the
nitrile conditions ca. 20% of 1a-CO2Me was rapidly converted to the isonitrile 2a-NC just within
the initial 2 min periods, and its amount reached to ca. 40% in 10 min. After that, the isonitrile
2a-NC gradually decreased, and instead the nitrile 2a-CN increased to become the major
product in 35 min (Figure 1b). These phenomena suggest that the isonitrile 2a-NC is kinetically
favored primary product under both nitrile and isonitrile conditions, but it can be isomerized
into the regioisomeric nitrile 2a-CN only under the phosphine-free nitrile conditions. Actually,
the isolated isonitrile 2a-NC was converted to the nitrile 2a-CN under the nitrile conditions with
Pd(CH2TMS)2(cod) and TMSCN (Scheme 3a),11 whereas the much slower isomerization was
observed under the isonitrile conditions using Pd(CH2TMS)2(cod)/rac-BINAP and TMSCN
(Scheme 3b). A similar isonitrile-to-nitrile isomerization was reported in the presence of strong
Lewis acids such as AgClO46d and TiCl4.7a On the other hand, no conversion of the nitrile 2a-
CN occurred under the isonitrile conditions (Scheme 3c).
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Figure 1. Reaction progresses under a) isonitrile conditions and b) nitrile conditions monitored
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by 1H NMR.
Scheme 3. Attempt to Isomerize Isonitrile 2a-NC into Nitrile 2a-CN and Nitrile 2a-CN into
Isonitrile 2a-NC
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Additional information was obtained from the control experiments with optically active
substrates (Scheme 4a). If the reaction proceeds via a Pd(0)/Pd(II) redox process involving a -
or -benzylpalladium intermediate,12 the stereochemical information should be transferred to
the products to some extent.9b,d-h,12c,f On the other hand, if the reaction includes free benzylic
cation species,6d,g,7a,e-g the corresponding racemates could be formed. Upon treatment of
enantioenriched (S)-1a-Boc and (S)-1a-CO2Me under the isonitrile and nitrile conditions,
respectively, the corresponding isonitrile 2a-NC and nitrile 2a-CN were obtained in the
complete racemic forms. Additionally, the independently prepared optically active isnonitrile
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2a-NC was also isomerized to nitrile 2a-CN with the almost complete racemization. These
outcomes are suggestive of the free benzyl cation intermediates rather than the benzylpalladium
ones under both the isonitrile and nitrile conditions.13 The lower conversion of CF3-substituted
substrates 1d-Boc and 1d-CO2Me (Scheme 2) is also consistent with the cation-mediated
mechanism. Actually, the negative slope of  = – 1.8 was obtained from the Hammet plot with
p for the conversion (in 20 min) of some para-substituted substrates 1-Boc under the isonitrile
conditions (Figure 2).14 Additional experiments with the methally-containing substrate 1r-Boc
can further support the benzyl cation intermediacy (Scheme 4b): only a mixture of 6-endo
cyclized olefinic products was observed. The corresponding 5-exo cyclized products and/or
directly substituted products at the benzylic position were not detected at all.
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Another our concern is connected with the active palladium species generated in situ. In the
recent work on the related palladium-catalyzed isocyanation of allylic phosphates with TMSCN
by Yurino and Ohkuma, the reaction of Pd salts with TMSCN immediately furnishes the
corresponding Pd(CN)2 and their ate-type complexes such as (TMS)n[Pd(CN)2+n].6f Thus, we
checked the reactivity of Pd(CN)2 (Scheme 4c). A stoichiometric reaction of 1a-Boc with
Pd(CN)2 and rac-BINAP just decomposed 1a-Boc, and neither 2a-NC nor 2a-CN were detected.
Similarly, any substituted products were not formed from 1a-CO2Me and Pd(CN)2 in the absence
of rac-BINAP. On the other hand, Pd(CN)2 could replace Pd(CH2TMS)2(cod) to catalyze the
reaction with TMSCN under both the isonitrile and nitrile conditions, albeit somewhat lower
efficiency and isonitrile/nitrile selectivity. Thus, Pd(CN)2 and/or its related species can be
involved also in our reaction systems.
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Scheme 4. Mechanistic Investigations
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The Journal of Organic Chemistry
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y = -1.8064x - 0.0046
R² = 0.9119
H (1a)
Cl (1c)
OMe (1b)
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-0.2
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Figure 2. Hammet plot of para-substituted 1-Boc under isonitrile conditions.
Finally, to clarify whether the reaction systems were homogeneous or heterogeneous, we
performed the hot filtration test (Figure 3). Under the isonitrile conditions, we monitored the
successful initial reaction progress, and then the solution was filtered through a pad of Celite in
20 min. Further monitoring the resulting filtrate revealed that the reaction proceeded to
convert 1a-Boc to 1a-NC (Figure 3a). On the other hand, under the nitrile conditions the
conversion of starting 1a-CO2Me was completely shut down after the hot filtration in 11 min
(Figure 3b).
These outcomes suggest that the isonitrile conditions using the rac-BINAP
phosphine ligand involve the homogeneous palladium catalyst while some heterogeneous
palladium species is generated under the phosphine-free nitrile conditions.
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The Journal of Organic Chemistry
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filtration
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Figure 3. Hot filtration tests under a) isonitrile conditions and b) nitrile conditions monitored by
1H NMR.
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The Journal of Organic Chemistry
Conclusions
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We have developed ligand-controlled palladium-catalyzed divergent synthesis of isonitriles
and nitriles from readily available benzyl carbonates and TMSCN. Under the bisphosphine-
ligated homogeneous Pd catalysis, the corresponding benzylic isonitriles are selectively formed.
On the other hand, without external phosphine ligands the more electrophilic heterogeneous
Pd species is formed, and the initially formed benzylic isonitriles are isomerized into the
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regioisomeric benzyl nitriles with high efficiency and selectivity.
modification of ancillary ligands, both isonitriles and nitriles of high synthetic values can be
obtained from the single diarylmethanol derivatives.
Further mechanistic studies15 and
Thus, by the simple
development of related stereoselective palladium catalysts are ongoing in our laboratory.
Experimental Section
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19
Instrumentation and Chemicals 1H, C{1H}, and F{1H}NMR spectra were recorded at 400
MHz, 100 MHz, and 376 MHz, respectively, for CDCl3 solutions. HRMS data were obtained by EI
using a magnetic sector. TLC analyses were performed on commercial glass plates bearing 0.25-mm
layer of Merck Silica gel 60F254. Silica gel (60 N, spherical neutral, Kanto Chemical Co.) was used for
column chromatography. Gel permeation chromatography (GPC) was performed by LC-20AR (pump,
SHIMADZU, 7.5 mL/min ethyl acetate) and SPD-20A (UV detector, SHIMADZU, 254 nm) with two in-
line YMC-GPC T2000 (20 x 600 mm, particle size: 10 m) (preparative columns, YMC).
Unless otherwise noted, materials obtained from commercial suppliers were used without further
purification. MeCN was dried on a Glass Contour Solvent dispensing system (Nikko Hansen & Co.,
Ltd.) prior to use. Pd(CH2TMS)2(cod) was prepared according to the literature.16 All tert-butyl and
methyl carbonates 1 were synthesized from the corresponding carbinols.9 The enantioenriched 2a-NC
(Scheme 4a) was obtained by optical resolution of racemic 2a-NC with a preparative chiral HPLC
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(CHIRAL ART Cellulose-SJ (YMC), hexane/CHCl3 = 9:1, 9.45 mL/min, UV detection at 250 nm, 25
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˚C). All reactions were carried out under nitrogen atmosphere unless otherwise noted.
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Typical Procedure for Synthesis of Isonitriles 2-NC by Pd-Catalyzed Benzylic Substitution
of tert-Butyl Diarylmethyl Carbonates 1-Boc with TMSCN. The synthesis of 2a-NC (0.20
mmol scale) is representative (Scheme 2). [Pd(CH2TMS)2(cod)] (3.9 mg, 0.010 mmol) and rac-
BINAP (6.9 mg, 0.011 mmol) were placed in a Schlenk tube in a glovebox filled with nitrogen.
MeCN (0.5 mL) was added to the reaction tube, and suspension was stirred for 10 min. A solution
of TMSCN (79.4 mg, 0.80 mmol) in MeCN (1.0 mL) was added to the suspension. The reaction
tube was sealed with a septum and taken out of the glovebox. tert-Butyl (naphthalen-2-
yl(phenyl)methyl) carbonate (1a-Boc; 66.9 mg, 0.20 mmol) was then added to the reaction tube.
The suspension was stirred for 19 h at 60 °C (oil bath). The resulting mixture was filtered
through a short pad of activated alumina and sodium sulfate, and the filtrate was concentrated
in vacuo. 1-Methylnaphthalene (13.5 mg) was added as an internal standard, and the resulting
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mixture was analyzed by H NMR in CDCl3 solution. Concentration in vacuo and subsequent
purification by column chromatography on neutral silica gel with hexane/ethyl acetate (20/1) as
an eluent gave 2-(isocyano(phenyl)methyl)naphthalene (2a-NC, 38 mg, 0.15 mmol) in 77% yield.
1.0 mmol Scale Synthesis of 2a-NC. [Pd(CH2TMS)2(cod)] (19.5 mg, 0.050 mmol) and rac-
BINAP (34.1 mg, 0.055 mmol) were placed in a Schlenk tube in a glovebox filled with nitrogen.
MeCN (2.5 mL) was added to the reaction tube, and suspension was stirred for 10 min.
A
solution of TMSCN (396.6 mg, 4.0 mmol) in MeCN (5.0 mL) was added to the suspension. The
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The Journal of Organic Chemistry
reaction tube was sealed with a septum and taken out of the glovebox. tert-Butyl (naphthalen-
2-yl(phenyl)methyl) carbonate (1a-Boc; 334.2 mg, 1.0 mmol) was then added to the reaction
tube. The suspension was stirred for 19 h at 60 °C (oil bath). The resulting mixture was filtered
through a short pad of activated alumina and sodium sulfate, and the filtrate was concentrated
in vacuo. 1-Methylnaphthalene (14.8 mg) was added as an internal standard, and the resulting
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mixture was analyzed by H NMR in CDCl3 solution. Concentration in vacuo and subsequent
purification by column chromatography on neutral silica gel with hexane/ethyl acetate (20/1) as
an eluent gave 2-(isocyano(phenyl)methyl)naphthalene (2a-NC, 171 mg, 0.70 mmol) in 70%
yield.
2-(Isocyano(phenyl)methyl)naphthalene (2a-NC). Purified by silica gel column chromatography
with hexane/ethyl acetate (20/1, v/v): 38 mg (77%, 0.20 mmol scale); pale yellow solid; m.p. 73.0-74.0
oC; 1H NMR (CDCl3, 400 MHz):  7.89-7.82 (m, 4H), 7.55-7.49 (m, 2H), 7.42-7.32 (m, 6H), 6.07 (s, 1H).
13C{1H} NMR (CDCl3, 100 MHz):  158.6, 137.5, 134.8, 133.08, 133.03, 129.1, 129.0, 128.6, 128.2,
127.8, 126.80, 126.76 (overlapping, 2C), 125.6, 124.1, 62.2 (t, J = 6.1 Hz). HRMS (EI) m/z (M)+ calcd
for C18H13N: 243.1043, found: 243.1048.
2-(Isocyano(4-methoxyphenyl)methyl)naphthalene (2b-NC). Purified by silica gel column
chromatography with hexane/ethyl acetate (20/1, v/v): 34 mg (62%, 0.20 mmol scale); white solid; m.p.
128.2-129.2 oC; 1H NMR (CDCl3, 400 MHz):  7.88-7.82 (m, 4H), 7.55-7.49 (m, 2H), 7.35 (dd, J = 8.6,
1.9 Hz, 1H), 7.32-7.28 (m, 2H), 6.92-6.88 (m, 2H), 6.03 (s, 1H), 3.80 (s, 3H). 13C{1H} NMR (CDCl3, 100
MHz):  159.7, 158.1, 135.0, 133.1, 133.0, 129.7, 129.0, 128.2, 128.1, 127.7, 126.8, 126.7, 125.4, 124.1,
114.3, 61.6, 55.4. HRMS (EI) m/z (M)+ calcd for C19H15NO: 273.1148, found: 273.1155.
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2-((4-Chlorophenyl)(isocyano)methyl)naphthalene (2c-NC). Purified by silica gel column
chromatography with hexane/ethyl acetate (20/1, v/v): 30 mg (55%, 0.20 mmol scale); red brown solid;
m.p. 71.9-72.9 oC; 1H NMR (CDCl3, 400 MHz):  7.89-7.82 (m, 4H), 7.57-7.50 (m, 2H), 7.38-7.32 (m,
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129.2, 128.2 (overlapping, 2C), 127.8, 126.9 (overlapping, 2C), 125.7, 123.9, 61.5. HRMS (EI) m/z (M)+
calcd for C18H12ClN: 277.0653, found: 277.0661.
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2-(Isocyano(4-(trifluoromethyl)phenyl)methyl)naphthalene (2d-NC). Purified by silica gel column
chromatography with hexane/ethyl acetate (20/1, v/v): 13 mg (21%, 0.20 mmol scale); red brown oil; 1H
NMR (CDCl3, 400 MHz):  7.88-7.84 (m, 4H), 7.66 (d, J = 8.2 Hz, 2H), 7.57-7.52 (m, 4H), 7.35 (dd, J =
8.6, 1.9 Hz, 1H), 6.12 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz):  159.7, 141.1, 133.9, 133.2, 133.0,
131.0 (q, J = 32.7 Hz), 129.4, 128.2, 127.8, 127.13, 127.05, 127.02, 126.1 (q, J = 3.7 Hz), 125.9, 123.81
(q, J = 270.1 Hz), 123.78, 61.7. 19F{1H} NMR (CDCl3, 376 MHz):  -62.72 (s). HRMS (EI) m/z (M)+
calcd for C19H12F3N: 311.0916, found: 311.0926.
2-(Isocyano(o-tolyl)methyl)naphthalene (2e-NC). Purified by silica gel column chromatography with
hexane/ethyl acetate (20/1, v/v) and then by GPC (ethyl acetate): 27 mg (53%, 0.20 mmol scale); yellow
solid; m.p. 61.3-62.3 oC; 1H NMR (CDCl3, 400 MHz):  7.85-7.82 (m, 4H), 7.54-7.50 (m, 2H), 7.44-7.42
(m, 1H), 7.34 (dd, J = 8.6, 1.9 Hz, 1H), 7.32-7.27 (m, 2H), 7.23-7.21 (m, 1H), 6.24 (s, 1H), 2.33 (s, 3H).
13C{1H} NMR (CDCl3, 100 MHz):  158.2, 135.5, 135.2, 133.8, 133.1, 133.0, 131.2, 128.9, 128.8, 128.2,
127.7, 127.6, 126.8, 126.7 (overlapping, 2C), 125.9, 124.4, 59.5, 19.4. HRMS (EI) m/z (M)+ calcd for
C19H15N: 257.1199, found: 257.1204.
2-(Isocyano(3-methoxyphenyl)methyl)naphthalene (2f-NC). Purified by silica gel column
chromatography with hexane/ethyl acetate (20/1, v/v): 29 mg (53%, 0.20 mmol scale); pale yellow oil;
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1H NMR (CDCl3, 400 MHz):  7.89-7.82 (m, 4H), 7.55-7.49 (m, 2H), 7.38 (dd, J = 8.6, 1.9 Hz, 1H), 7.30
(t, J = 8.0 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.95-6.94 (m, 1H), 6.87 (dd, J = 8.1, 2.6 Hz, 1H), 6.03 (s,
1H), 3.79 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz):  160.4, 158.6, 138.9, 134.7, 133.1, 133.0, 130.1,
129.1, 128.2, 127.7, 126.77, 126.75, 125.6, 124.1, 119.1, 113.8, 112.6, 62.1, 55.4. HRMS (EI) m/z (M)+
calcd for C19H15NO: 273.1148, found: 273.1152.
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2-(Isocyano(naphthalen-2-yl)methyl)thiophene (2g-NC). Purified by silica gel column
chromatography with hexane/ethyl acetate (20/1, v/v): 24 mg (48%, 0.20 mmol scale); red brown oil; 1H
NMR (CDCl3, 400 MHz):  7.95 (s, 1H), 7.90-7.85 (m, 3H), 7.57-7.52 (m, 2H), 7.47 (dd, J = 8.6, 1.9 Hz,
1H), 7.31 (dd, J = 5.1, 1.3 Hz, 1H), 7.08-7.06 (m, 1H), 6.97 (dd, J = 5.1, 3.6 Hz, 1H), 6.29 (s, 1H). 13C{1H}
NMR (CDCl3, 100 MHz):  158.8, 141.0, 134.2, 133.3, 133.0, 129.2, 128.3, 127.8, 126.93 (overlapping,
2C), 126.88, 126.8, 126.5, 125.4, 123.8, 57.8. HRMS (EI) m/z (M)+ calcd for C16H11NS: 249.0607, found:
249.0610.
2-(Isocyano(phenyl)methyl)-6-methoxynaphthalene (2h-NC). Purified by silica gel column
chromatography with hexane/ethyl acetate (20/1, v/v): 35 mg (63%, 0.20 mmol scale); white solid; m.p.
144.6-145.6 oC; 1H NMR (CDCl3, 400 MHz):  7.79-7.72 (m, 3H), 7.42-7.31 (m, 6H), 7.18 (dd, J = 8.9,
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2.6 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.04 (s, 1H), 3.92 (s, 3H). C{1H} NMR (CDCl3, 100 MHz):
 158.3 (overlapping, 2C), 137.6, 134.3, 132.6, 129.6, 129.0, 128.48, 128.46, 127.9, 126.7, 125.5, 124.7,
119.6, 105.7, 62.1, 55.4 (d, J = 2.1 Hz). HRMS (EI) m/z (M)+ calcd for C19H15NO: 273.1148, found:
273.1153.
1-(Isocyano(phenyl)methyl)naphthalene (2i-NC). Purified by silica gel column chromatography with
hexane/ethyl acetate (20/1, v/v): 31 mg (64%, 0.20 mmol scale); pale yellow oil; 1H NMR (CDCl3, 400
MHz):  7.93-7.86 (m, 3H), 7.62 (d, J = 6.9 Hz, 1H), 7.54-7.47 (m, 3H), 7.41-7.31 (m, 5H), 6.62 (s, 1H).
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13C{1H} NMR (CDCl3, 100 MHz):  158.7, 136.9, 134.0, 132.3, 129.8, 129.7, 129.1, 129.0, 128.5, 126.94,
126.92, 126.1, 126.0, 125.3, 123.0, 59.5. HRMS (EI) m/z (M)+ calcd for C18H13N: 243.1043, found:
243.1046.
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9-(Isocyano(phenyl)methyl)phenanthrene (2j-NC). Purified by silica gel column chromatography
with hexane/ethyl acetate (20/1, v/v): 29 mg (49%, 0.20 mmol scale); white solid; m.p. 123.7-124.7 oC;
1H NMR (CDCl3, 400 MHz):  8.76 (d, J = 8.2 Hz, 1H), 8.69 (d, J = 8.2 Hz, 1H), 7.95-7.93 (m, 2H), 7.87
(d, J = 7.5 Hz, 1H), 7.74-7.63 (m, 3H), 7.58-7.54 (m, 1H), 7.46-7.43 (m, 2H), 7.40-7.34 (m, 3H), 6.63 (s,
1H). 13C{1H} NMR (CDCl3, 100 MHz):  159.1, 136.7, 131.1, 130.8, 130.7, 130.4, 129.2, 129.1, 128.7,
128.5, 127.7, 127.3, 127.2, 127.14, 127.08, 126.9, 124.1, 123.5, 122.6, 60.1. HRMS (EI) m/z (M)+ calcd
for C22H15N: 293.1199, found: 293.1201.
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2-(Isocyano(phenyl)methyl)benzo[b]thiophene (2k-NC). Purified by silica gel column
chromatography with hexane/ethyl acetate (20/1, v/v): 28 mg (56%, 0.20 mmol scale); pale yellow
solid; m.p. 94.9-95.9 oC; 1H NMR (CDCl3, 400 MHz): δ 7.77-7.73 (m, 2H), 7.49-7.40 (m, 5H), 7.38-
7.30 (m, 2H), 7.29 (s, 1H), 6.17 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz): δ 159.3, 141.4, 140.1, 138.8,
136.4, 129.17, 129.15, 126.5, 125.1, 124.8, 124.1, 122.9, 122.4, 58.3. HRMS (EI) m/z (M)+ calcd for
C16H11NS: 249.0607, found: 249.0610.
2-(Isocyano(phenyl)methyl)benzofuran (2l-NC). Purified by silica gel column
chromatography with hexane/ethyl acetate (20/1, v/v): 28 mg (61%, 0.20 mmol scale); pale yellow
solid; m.p. 62.1-63.1 oC; 1H NMR (CDCl3, 400 MHz): δ 7.54 (d, J = 7.7 Hz, 1H), 7.51-7.48 (m, 2H),
7.46-7.40 (m, 4H), 7.30 (td, J = 7.8, 1.3 Hz, 1H), 7.23 (td, J = 7.5, 1.0 Hz, 1H), 6.65 (t, J = 0.9 Hz,
1H), 6.05 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz): δ 159.5, 155.4, 152.1, 134.1, 129.2, 129.1, 127.5,
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126.8, 125.1, 123.3, 121.4, 111.5, 105.3, 56.3. HRMS (EI) m/z (M)+ calcd for C16H11NO: 233.0835,
found: 233.0841.
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chromatography with hexane/ethyl acetate (20/1, v/v): 36 mg (61%, 0.20 mmol scale); pale yellow
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solid; m.p. 128.9-129.9 C; H NMR (CDCl3, 400 MHz): δ 8.19-8.14 (m, 2H), 7.88-7.84 (m, 2H),
7.51-7.45 (m, 2H), 7.44-7.33 (m, 6H), 6.10 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz): δ 158.7, 140.1,
139.7, 137.7, 136.1, 135.1, 134.2, 129.2, 128.7, 127.3, 126.8, 125.3, 124.7, 123.5, 123.0, 121.9, 119.7,
62.1. HRMS (EI) m/z (M)+ calcd for C20H13NS: 299.0763, found: 299.0764.
4-(Isocyano(phenyl)methyl)-1,1'-biphenyl (2n-NC). Purified by silica gel column chromatography
with hexane/ethyl acetate (20/1, v/v): 40 mg (74%, 0.20 mmol scale); yellow solid; m.p. 112.6-113.6 oC;
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1H NMR (CDCl3, 400 MHz): δ 7.61-7.55 (m, 4H), 7.46-7.33 (m, 10H), 5.95 (s, 1H). C{1H} NMR
(CDCl3, 100 MHz): δ 158.4, 141.5, 140.2, 137.5, 136.5, 129.1, 128.9, 128.6, 127.72, 127.68, 127.1, 127.0,
126.6, 61.8. HRMS (EI) m/z (M)+ calcd for C20H15N: 269.1199, found: 269.1204.
(Isocyanomethylene)dibenzene (2o-NC). Purified by silica gel column chromatography with
hexane/ethyl acetate (20/1, v/v) and then by GPC (ethyl acetate): 16 mg (41%, 0.20 mmol scale); colorless
oil; 1H NMR (CDCl3, 400 MHz):  7.41-7.31 (m, 10H), 5.91 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz):
 158.3, 137.6, 129.0, 128.5, 126.6, 62.0 (t, J = 6.5 Hz). HRMS (EI) m/z (M)+ calcd for C14H11N:
193.0886, found: 193.0892.
2-(1-Isocyanoethyl)naphthalene (2p-NC). Purified by silica gel column chromatography
with hexane/ethyl acetate (20/1, v/v): 6 mg (17%, 0.20 mmol scale); pale yellow solid; m.p. 64.1-
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65.1 oC; 1H NMR (CDCl3, 400 MHz): δ 7.90-7.84 (m, 4H), 7.55-7.49 (m, 2H), 7.45 (dd, J = 8.6, 1.9
Hz, 1H), 5.00 (q, J = 6.6 Hz, 1H), 1.77 (dt, J = 6.9, 2.2 Hz, 3H). 13C{1H} NMR (CDCl3, 100 MHz): δ
156.5, 135.8, 133.2, 133.0, 129.0, 128.0, 127.7, 126.7, 126.5, 124.4, 123.1, 54.0 (t, J = 6.2 Hz), 25.1.
HRMS (EI) m/z (M)+ calcd for C13H11N: 181.0886, found: 181.0889.
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Typical Procedure for Synthesis of Nitriles 2-CN by Pd-Catalyzed Benzylic Substitution
of Diarylmethyl Methyl Carbonates 1-CO2Me with TMSCN. The synthesis of 2a-CN (0.20
mmol scale) is representative (Scheme 2). [Pd(CH2TMS)2(cod)] (3.7 mg, 0.009 mmol) was placed
in a Schlenk tube in a glovebox filled with nitrogen. MeCN (0.5 mL) was added to the reaction
tube, and suspension was stirred for 10 min. A solution of TMSCN (29.7 mg, 0.30 mmol) in
MeCN (1.0 mL) was added to the suspension. The reaction tube was sealed with a septum and
taken out of the glovebox. Methyl (naphthalen-2-yl(phenyl)methyl) carbonate (1a-CO2Me;
58.7 mg, 0.20 mmol) was then added to the reaction tube. The suspension was stirred for 18 h
at 80 °C (oil bath). The resulting mixture was filtered through a short pad of activated alumina
and sodium sulfate, and the filtrate was concentrated in vacuo. 1-Methylnaphthalene (12.1 mg)
was added as an internal standard, and the resulting mixture was analyzed by 1H NMR in CDCl3
solution. Concentration in vacuo and subsequent purification by column chromatography on
neutral silica gel with hexane/ethyl acetate (20/1) as an eluent gave 2-(naphthalen-2-yl)-2-
phenylacetonitrile (2a-CN, 35 mg, 0.14 mmol) in 71% yield.
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1.0 mmol Scale Synthesis of 2a-CN. [Pd(CH2TMS)2(cod)] (7.7 mg, 0.020 mmol) was placed in
a Schlenk tube in a glovebox filled with nitrogen. MeCN (2.5 mL) was added to the reaction
tube, and suspension was stirred for 10 min. A solution of TMSCN (148.9 mg, 1.5 mmol) in
MeCN (5.0 mL) was added to the suspension. The reaction tube was sealed with a septum and
taken out of the glovebox. Methyl (naphthalen-2-yl(phenyl)methyl) carbonate (1a-CO2Me;
292.3 mg, 1.0 mmol) was then added to the reaction tube. The suspension was stirred for 18 h
at 80 °C (oil bath). The resulting mixture was filtered through a short pad of activated alumina
and sodium sulfate, and the filtrate was concentrated in vacuo. 1-Methylnaphthalene (13.6 mg)
was added as an internal standard, and the resulting mixture was analyzed by 1H NMR in CDCl3
solution. After evaporation, purification of the residual solid by column chromatography on
neutral silica gel with hexane/ethyl acetate (20/1) and subsequent GPC (ethyl acetate) gave 2-
(naphthalen-2-yl)-2-phenylacetonitrile (2a-CN, 176 mg, 0.72 mmol) in 72% yield.
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2-(Naphthalen-2-yl)-2-phenylacetonitrile (2a-CN). Purified by silica gel column chromatography
with hexane/ethyl acetate (20/1, v/v): 35 mg (71%, 0.20 mmol scale); pale yellow solid; m.p. 76.5-77.5
oC; 1H NMR (CDCl3, 400 MHz): δ 7.89-7.89 (m, 1H), 7.86-7.82 (m, 3H), 7.55-7.49 (m, 2H), 7.41-7.31
(m, 6H), 5.31 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz): δ 135.8, 133.3, 133.1, 132.8, 129.3 (overlapping,
2C), 128.3, 128.0, 127.9, 127.7, 126.8, 126.73, 126.72, 125.2, 119.6, 42.8. HRMS (EI) m/z (M)+ calcd
for C18H13N: 243.1043, found: 243.1045.
2-(4-Methoxyphenyl)-2-(naphthalen-2-yl)acetonitrile (2b-CN). Purified by silica gel column
chromatography with hexane/ethyl acetate (10/1, v/v): 50 mg (91%, 0.20 mmol scale); white solid; m.p.
136.2-137.2 oC; 1H NMR (CDCl3, 400 MHz):  7.88-7.81 (m, 4H), 7.55-7.48 (m, 2H), 7.35 (dd, J = 8.6,
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