Pd-Catalyzed Allylic Isocyanation: Nucleophilic N-Terminus Substitution of Ambident Cyanide

Article abstract of DOI:10.1021/acscatal.9b00858

In the presence of catalytic amount of Pd(OAc)₂, allylic phosphates reacted with trimethylsilyl cyanide (TMSCN) to afford the corresponding allylic isonitriles exclusively. No allylic nitriles, which are selectively obtained in the traditional

Full text of DOI:10.1021/acscatal.9b00858

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Letter
Pd-Catalyzed Allylic Isocyanation: Nucleophilic
N-Terminus Substitution of Ambident Cyanide
Taiga Yurino, Ryutaro Tani, and Takeshi Ohkuma
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00858 • Publication Date (Web): 15 Apr 2019
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ACS Catalysis
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Pd-Catalyzed Allylic Isocyanation: Nucleophilic N-Terminus
Substitution of Ambident Cyanide
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Taiga Yurino,* Ryutaro Tani and Takeshi Ohkuma*
Division of Applied Chemistry and Frontier Chemistry Center, Faculty of Engineering, Hokkaido University, Kita 13, Nishi
8, Sapporo, Hokkaido 060-8628, Japan
ABSTRACT: In the presence of catalytic amount of Pd(OAc)2, allylic phosphates reacted with trimethylsilyl cyanide (TMSCN) to
afford the corresponding allylic isonitriles exclusively. No allylic nitriles, which are selectively obtained in the traditional Pd(0)-
catalyzed reaction, were observed. The use of phosphate as the leaving group was crucial to achieve complete regioselectivity of the
ambident cyanide species as the N-terminus nucleophile. The reaction was applicable to a series of aromatic, hetero-aromatic,
vinylic, and aliphatic substituted allylic phosphates. The mechanistic studies suggested that the allylic isocyanation was catalyzed
by the Pd(II) species, and not by Pd(0).
Keywords: isonitrile, palladium, allylic substitution, ambident,
Lewis acid catalysis, nucleophilic substitution
presence of Pd(II) catalyst, affording the linear isonitriles
selectively. The
R–X
+
CN
R–NC
or
R–CN
+
X
(eq. 1)
A nucleophilic substitution using an ambident reagent,
which has two alternative reactive sites, affords at least two
possible products. A reliable method for controlling the
reactive site is indispensable in order to synthesize the desired
products selectively.1,2 Cyanide is one of the most typical
ambident nucleophiles and reacts with an electrophile (R–X: R
= alkyl, allyl, etc.; X = leaving group) at the C- and N-
terminus, yielding either the nitrile (R–CN) or the isonitrile
(R–NC) (Scheme 1, equation 1).3 According to the traditional
Kornblum’s rule,4 which is applied for prediction of the
regioselectivity of ambident nucleophiles, the N-terminus of
cyanide preferentially reacts in the SN1-type substitution.
However, even in those reactions, the C-terminus of the
cyanide reacts prior to the N-terminus, because the formation
of the nitrile is both kinetically and thermodynamically more
favorable in most cases.3,5–9 Therefore, development of a
selective synthetic method of isonitrile by the nucleophilic
substitution is highly desirable.10 Realizing such a method by
the catalytic procedure is more challenging.
N-addition
C-addition
C-addition is both kinetically and thermodynamically favorable.
Limited examples of catalytic nucleophilic isocyanation:
(a) Zn-catalyzed isocyanation of epoxide
ZnI2 (0.5 mol%)
OSiMe3
NC
Me3SiCN (2.0 equiv)
O
CH2Cl2, reflux
73% yield
(b) Sc-catalyzed isocyanation of tertiary alcohol derivative
H
H
H
H
H
Sc(OTf)3 (3 mol%)
Me3SiCN (15 equiv)
+
neat, 22 ºC
H
OTFA
Me
NC
Me
NC
Me
76% yield
12% yield
Scheme 1. Ambident Nucleophilic Properties of Cyanide
and Examples of Catalytic Isocyanation
Pd(0)-catalyzed allylic substitution is known as the Tsuji–
Trost-type reaction, which proceeds through the π-allyl–Pd(II)
intermediate.16 Tsuji and coworkers applied this protocol to
the allylic cyanation of an allyl acetate with TMSCN as the C-
nucleophile catalyzed by Pd(PPh3)4 (Scheme 2b).17 The
complete reversal of regioselectivity between these two
reactions was ascribed to the change of the Pd catalyst
precursor and the leaving group of the allylic substrate, and it
suggests that the Pd-catalyzed isocyanation proceeds without
formation of the π-allyl–Pd(II) species.18
To date, only two types of catalytic systems have permitted
the production of isonitrile by nucleophilic substitution.
Gassman and coworkers demonstrated the ZnI2-catalyzed ring-
opening isocyanation of epoxides and oxetanes with
trimethylsilyl cyanide (TMSCN) (Scheme 1a).11 Other metal
salts, such as Pd(CN)2, SnCl2 and Me3Ga, were also reported
to show catalytic activity for the isocyanation.12 A chiral
BINOL–Ga(III) complex promoted a similar isocyanation with
moderate enantioselectivity.13 Recently, Shenvi and coworkers
reported the isocyanation of tertiary alcohol derivatives with
TMSCN catalyzed by Sc(OTf)3 (Scheme 1b).14,15 The reaction
using trifluoroacetate as an electrophile gave the best result,
forming the isonitrile with stereoinversion selectively.
Our study commenced with optimization of the reaction
conditions in catalytic allylic isocyanation (Table 1).
Cinnamyl diethyl phosphate was employed as the model
substrate for the optimization. In the presence of Pd(OAc)2 (2
mol%), the substrate reacted smoothly with TMSCN (2.0
equiv) in toluene at 80 °C under an argon atmosphere in 3 h to
Herein we describe the first successful example of a
catalytic allylic isocyanation (Scheme 2a). An allylic
phosphate reacts with TMSCN as the N-nucleophile in the
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afford the linear allylic isonitrile 1a in 96% yield (entry 1).
Page 2 of 6
diphenyl ester. The imidate gave 1a in synthetically usable
yield accompanied by a small amount of the branched isomer
2a. The trifluoroacetate, which was the appropriate leaving
group in the Shenvi’s Sc(OTf)3-catalyzed substitution, was not
applicable to this reaction. Some leaving groups frequently
used in the Tsuji–Trost-type allylic substitution, such as
acetate, carbonate, and bromide, were not replaced with
cyanide at all. Cinnamyl alcohol reacted with TMSCN to form
the corresponding silylether under the typical conditions. No
substitution product was observed.
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The product was isolated with column chromatography in 82%
(a) Pd(II)-catalyzed allylic isocyanation of the phosphate substrate (this work)
R2
R2
Pd(OAc)2 (2 mol%)
Me3SiCN (2.0 equiv)
toluene, 80 ºC
R1
OP(O)(OEt)2
R1
NC
R3
R3
(b) Pd(0)-catalyzed allylic cyanation of the acetate substrate (previous work)
Pd(PPh3)4 (5 mol%)
Me3SiCN (2.0 equiv)
R
OAc
R
CN
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THF, reflux
up to 98% yield
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Table 2. Leaving Group-Dependency on the Catalytic
Allylic Isocyanationa
Scheme 2. Pd-Catalyzed Allylic Isocyanation and
Cyanation
yield. Notably, neither branched isomer 2a nor cinnamyl
nitrile was observed at all. No substrate consumption was
observed without Pd catalyst (entry 2). PdCl2 was also a usable
precursor, but the major linear product 1a was contaminated
with a small amount of the branched isonitrile 2a (entry 3).
Pd(PPh3)4 was far less reactive, and afforded a mixture of 1a
and 2a in moderate yield (entry 4). Unexpectedly, no
detectable amount of the nitrile compounds was produced.
Toluene and THF were the preferable solvents (entries 1 and
5). The polar aprotic solvents MeCN and DMF, which are
frequently used in the SN2-type reactions, were not suitable for
this reaction (entries 6 and 7). The reaction without solvent
also resulted in poor yield of the product (entry 8). The
isocyanation under atmospheric air proceeded smoothly to
afford 1a in comparable yield to that under argon (entry 9).
The catalyst loading could be decreased to 0.2 mol% and the
reaction furnished the product in 81% yield with prolongation
of the reaction time from 3 h to 25 h (entry 10).
We next investigated the scope of allylic phosphates for the
isocyanation under the optimized reaction conditions (Table
3). The reactions were conducted under argon (black
characters), but comparable results were obtained under
atmospheric air (red characters). No cyanation product was
observed in all cases. Cinnamyl phosphates with a methyl
group on the phenyl ring were converted into the linear allylic
isonitriles, 1b–1d, in around 90% yield irrespective of the
substituted position. The E/Z ratio of 1d was slightly increased
compared to that of the substrate. The corresponding branched
products were not detected. The reaction allowed the
substitution of both electron-withdrawing Br and -donating
MeO, affording the desired isonitriles, 1e and 1f, in high yield.
Notably, the C–Br bond was left intact under the reaction
conditions, suggesting that the active Pd(0) species was not
included in the catalyst system. The thienyl- and indolyl-
substituted allylic phosphates were also converted to the linear
isonitriles, 1g and 1h, exclusively. The reaction of the
conjugated 2,4-dienyl phosphate predominantly afforded the
linear dienyl isonitrile 1i in 91% yield. No detectable amounts
of the γ- and ε-substituted isomers were produced. An 8.8:1
E/Z mixture (18:1 under air)19 of γ-methyl cinnamyl isonitrile
1j was obtained in the reaction of the E-configured γ-methyl
cinnamyl phosphate. This indicated the presence of the E/Z-
isomerization pathway, as discussed later. In contrast, the β-
methyl cinnamyl phosphate reacted with TMSCN to give a
2.9:1 mixture of the E-configured linear β-methyl cinnamyl
isonitrile (1k) and the branched isomer in 94% yield. The Z
isomer of 1k was not observed. The relatively unstable
branched isomer of 1k was decomposed through the isolation
procedure, resulting in the linear-enriched product. The
aliphatic substrates were applied to the substitution reaction.
The cyclohexyl-substituted allylic phosphate was converted to
Table 1. Optimization of the Reaction Conditions
NC
Pd(OAc)2 (2 mol%Pd)
Me3SiCN (2.0 equiv)
OP(O)(OEt)2
NC
+
toluene, 80 ºC, Ar, 3 h
1a
2a
Yield (%)a
Entry
Deviation from the "Standard" Conditions
None
1a
2a
0
1
2
96(82)
0
No Pd cat. was used
0
3
PdCl2 instead of Pd(OAc)2
Pd(PPh3)4 instead of Pd(OAc)2
THF instead of toluene
MeCN instead of toluene
DMF instead of toluene
No solvent was used
85
8
4
21
14
0
5
95
6
26
0
7
34
7
8
39
5
9
Reaction under air
95(83)
81
0
10
0.2 mol% of catalyst was usedb
0
a 1H NMR yield. The isolated yield was given in parentheses. bThe reaction time was 25 h.
The Pd(OAc)2-catalyzed allylic isocyanation was
remarkably affected by the nature of the leaving groups, as
shown in Table 2. The phosphate was exceptionally well-
suited for the reaction, even in the case of the corresponding
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the linear product 1l in high yield. The reaction of 5-phenyl-2-
pentenyl phosphate, a primary alkyl-substituted compound,
afforded a 3.4:1 mixture of the linear isonitrile 1m and the
corresponding branched isomer. A 3.1:1 mixture of linear
(1n)/branch isomers was obtained in the reaction of geranyl
phosphate. The reaction of (Z)-cinnamyl phosphate under the
typical conditions resulted in an approximately 2:1 E/Z
(1a/1a’) mixture of the isonitrile (Scheme 3).
3a exclusively (Scheme 4b). When the π-allyl–Pd(II)
phosphate prepared from the η3-cinnamyl–Pd(II) dimeric
complex and silver phosphate was employed for the reaction
with TMSCN, a complex mixture including 3a (approximately
3%) was obtained (Scheme 4c). There was no trace of
isonitrile 1a in the mixture. These results indicated that the
allylic isocyanation proceeded without forming the π-allyl–
Pd(II) species, which was the key intermediate of the Pd(0)-
catalyzed allylic cyanation. The cinnamyl phosphate does not
form the π-allyl–Pd(II) compound under the reaction
conditions even with the Pd(PPh3)4, a typical Pd(0) catalyst.
Indeed, Pd(CN)2(PPh3)2 was obtained through the reaction
between Pd(PPh3)4 and TMSCN (5 equiv) in 86% yield. The
resulting Pd(II) complex was catalytically active for the allylic
isocyanation (Scheme 4d). Again the formation of 3a was not
observed.
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Table 3. Substrate Scope of the Allylic Phosphate for the
Isocyanationa,b
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R2
R2
Pd(OAc)2 (2 mol%)
Me3SiCN (2.0 equiv)
R1
OP(O)(OEt)2
R1
NC
toluene, 80 ºC, time
R3
R3
NC
NC
NC
NC
Me
Me
Me
1a
1b
1c
1dc
3 h: 96% (82%)
3 h: 95% (83%)
4 h: 91% (79%)
4 h: 80% (71%)
4 h: 92% (79%)
4 h: 89% (76%)
4 h: 90% (78%)d
4 h: 91% (78%)d
NC
NC
NC
NC
S
N
Br
Ts
MeO
1e
1f
1g
1h
4 h: 83% (74%)
4 h: 82% (71%)
9 h: 80% (79%)
9 h: 81% (71%)
5 h: 73% (58%)
5 h: 68% (55%)
9 h: 74% (57%)
16 h: 63% (49%)
Me
NC
NC
NC
Me
1i
1j
1k
12 h: 91% (79%)
12 h: 86% (76%)
6 h: 78% (70%)e
5 h: 72% (64%)f
12 h: 94% (67%)g
12 h: 93% (64%)h
NC
NC
NC
1l
1m
1n
5 h: 72% yieldi
9 h: 67% yieldi,j
5 h: 81% yieldi,k
aThe results of reactions under argon and atmospheric air are indicated with in black and red
characters respectively. b 1H NMR yield. The isolated yield is given in parentheses. cThe E/Z ratio
of the substrate was 13/1. dThe E/Z ratio of the product was >20/1 (>20/1). eThe E/Z ratio of the
product was 8.8/1 (11/1). fThe E/Z ratio of the product was 18/1 (>20/1). gThe l/b ratio of the
product was 2.9/1 (15/1). hThe l/b ratio of the product was 3.4/1. iIsolated yield. The l/b ratio of
j
the product was 3.4/1. kThe l/b ratio of the product was 3.1/1.
Pd(OAc)2 (2 mol%)
Me3SiCN (2.0 equiv)
NC
+
toluene, 80 ºC, Ar, 10 h
OP(O)(OEt)2
NC
1a
1a'
Scheme 4. Investigation of the Potential Involvement of the
π-Allyl–Pd(II) Intermediate in the Catalytic Isocyanation
80%, 1a/1a' = 1.7/1; (71%, 1a/1a' = 1.9/1)
Scheme 3. Pd(II)-Catalyzed Allylic Isocyanation of (Z)-
Cinnamyl Phosphate
We next examined the roles of the Pd species in the
catalytic allylic isocyanation (Scheme 5). Pd(OAc)2 exhibited
the best catalyst performance, reacting with an excess amount
of TMSCN in toluene to afford Pd(CN)2 quantitatively
(equation 1). The isolated Pd(CN)2 catalyzed the allylic
isocyanation of cinnamyl phosphate under the typical
conditions for 3 h to give the linear cinnamyl isonitrile 1a and
the branched isomer 2a in 75% and 9% yield, respectively
(equation 2). Pd(CN)2 exhibited a somewhat lower catalyst
efficiency than Pd(OAc)2, achieving 96% yield of 1a under the
same conditions (see Table 1, entry 1). The isolated Pd(CN)2
was hardly soluble in toluene, and it may cause the slower
reaction rate. A stoichiometric amount of Pd(CN)2 without
TMSCN did not react with the cinnamyl phosphate (equation
The unusual isonitrile formation through the Pd-catalyzed
allylic substitution prompted us to perform some mechanistic
experiments. According to Tsuji’s report, cinnamyl acetate
and TMSCN reacted with a catalytic amount of Pd(PPh3)4 in
THF at the reflux temperature to give cinnamyl nitrile in 98%
yield (Scheme 4a).17 The use of cinnamyl phosphate
completely reversed the cyanide regioselectivity under the
same conditions, although the yield of the isonitrile 1a was
moderate. The remarkable influence of the leaving-group on
the cyanide regioselectivity was noteworthy. The reaction of
the isolated η3-cinnamyl–Pd(II) dimeric complex and TMSCN
1
in toluene-d8 monitored by H NMR gave the cinnamyl nitrile
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3). These results suggested that Pd(CN)2 was formed in situ
Page 4 of 6
isomerization observed in the formation of 1j and 1a from the
(Z)-cinnamyl phosphates seems to occur through this process
(see Table 3 and Scheme 3). The E/Z ratio of the product
through the isomerization is dependent on the thermodynamic
stability. The direct linear isonitrile formation increases the
ratio of the Z isomer. The rearrangement forming aliphatic 1m
and 1n from the corresponding branched isomers is slow, and
therefore the branched isomers were observed (see the
Supporting Information).
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from Pd(OAc)2 and TMSCN in the reaction mixture. Pd(CN)2
was not the active nucleophile, but it behaved as the Pd(II)
catalyst or the reservoir. In fact, [Pd(CN)3]– and [Pd(CN)4]2–
were detected on the ESI-MS analysis (negative mode) of the
mixture of Pd(CN)2 and TMSCN, even though the
corresponding signals were not detected on the measurement
of the isolated Pd(CN)2 (see the Supporting Information).
TMS(OAc) showed some catalytic activity for the
isocyanation in the absence of Pd species to afford a mixture
of 1a and 2a in low yield (equation 4). The Lewis acidic TMS
cation appeared to take part in the activation of the allylic
phosphate. These observations are consistent with the
following mechanistic hypothesis shown in Scheme 6:
Pd(OAc)2 is converted to an equilibrium mixture of the neutral
Pd(CN)2 and the ate-complexes of (TMS)[Pd(CN)3] and
(TMS)2[Pd(CN)4] in the presence of an excess amount of
TMSCN. Pd(CN)2 is the most stable Pd species. Not only
Pd(CN)2 but also the TMS cation of the ate-complexes
functions as a Lewis-acid catalyst to activate the allylic
phosphate. [Pd(CN)3]– and [Pd(CN)4]2– as well as TMSCN
react as N-terminus nucleophiles with the activated substrate
to yield the allylic isonitrile. The high leaving ability of the
phosphate in the presence of Lewis acid promotes the smooth
reaction. Moreover, the dissociated phosphate anion rarely
inhibits the catalytic performance. These chemical features
probably make allylic phosphate as the suitable substrate for
the isocyanation.
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Scheme 6. Plausible Reaction Pathway of the Allylic
Isocyanation
In conclusion, we reported the first successful example of a
catalytic allylic isocyanation. The allylic phosphate reacted
with TMSCN in the presence of a catalytic amount of
Pd(OAc)2 to afford the allylic isonitrile in high yield. The use
of phosphate as a leaving group was crucial for exclusive
formation into the isonitrile. The corresponding allylic nitriles
were not observed. The reaction could be conducted either
under argon or atmospheric air. A series of aromatic, hetero-
aromatic, vinylic, and aliphatic substituted substrates was
applicable to this reaction. Several mechanistic experiments
suggested that the equilibrating system of Pd(CN)2,
(TMS)[Pd(CN)3], and (TMS)2[Pd(CN)4] catalyzes the allylic
isocyanation. The Lewis acidic Pd(CN)2 and TMS cation
activate the allylic phosphate, and TMSCN, [Pd(CN)3]–, and
[Pd(CN)4]2– act as the N-terminus nucleophiles. Thus, the
isocyanation proceeded without a π-allyl–Pd(II) species,
which was a key intermediate of most allylic substitutions
with Pd(0) catalysts. The Pd(II) species also catalyze the
rearrangement of the branched isonitrile into the linear isomer.
The dual roles of the Pd(II) catalytic system afford the linear
allylic isonitriles in high yields. Further investigations on the
reaction mechanism, especially on the specificity of the allylic
phosphate, are underway in our laboratory.
Scheme 5. Mechanistic Experiments on the Roles of Pd(II)
Species
We also found that the rearrangement of the branched
allylic isonitrile 2a into the linear compound 1a occurred
under the appropriate conditions (equation 5 and Scheme 6):
The reactions in the NMR tubes required longer time. No
rearrangement was observed without Pd(II) species even in the
presence of two equivalents of TMSCN. A catalytic amount of
Pd(CN)2 without TMSCN gradually converted 2a into 1a.20
The rearrangement proceeded smoothly in the presence of
both Pd(CN)2 (2 mol%) and TMSCN (2 equiv) to afford 1a in
93% yield in 15 h. In contrast, no isomerization was observed
with 2 mol% of TMS(OAc), suggesting that the rearrangement
also specifically occurs by Pd(II) catalyst. The E/Z
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
*E-mail: tyurino@eng.hokudai.ac.jp (T. Yurino)
*E-mail: ohkuma@eng.hokudai.ac.jp (T. Ohkuma)
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Direct Cyanation of α-Aryl Alcohols and Thiols. Tetrahedron
2009, 65, 4351–4355. (d) Wang, J.; Masui, Y.; Onaka, M.
Direct Synthesis of Nitriles from Alcohols with Trialkylsilyl
Cyanide Using Brønsted Acid Montmorillonite Catalysts.
ACS Catal. 2011, 1, 446–454. (e) Theerthagiri, P.; Lalitha, A.
Zn(OTf)2-Catalyzed Direct Cyanation of Benzylic Alcohols–
A Novel Synthesis of α-Aryl Nitriles. Tetrahedron Lett. 2012,
53, 5535–5538. (f) Fan, X.; Guo, K.; Guan, Y.–H.; Fu, L.–A.;
Cui, X.–M.; Lv, H.; Zhu, H.–B. Efficient Assembly of α-Aryl
and α-Vinyl Nitriles via Iron-Catalyzed Ether Bond
Activation. Tetrahedron Lett. 2014, 55, 1068–1071.
ORCID
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2
3
4
5
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7
8
Taiga Yurino: 0000-0002-4158-3463
Takeshi Ohkuma: 0000-0002-5467-3169
Notes
The authors declare no conflict of interest.
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
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Trimethylsilyl Cyanide Promoted Cyanation of Tertiary Alkyl
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Multiaction of Zr Catalyst: One-Pot Synthesis of β-
Cyanohydrins from Olefins. J. Am. Chem. Soc. 2001, 123,
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Exceptionally Active Yttrium-Salen Complexes for the
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TMSN3. J. Org. Chem. 2007, 72, 8648–8655.
Experimental procedures, details of experiment and spectral data
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ACKNOWLEDGMENT
This work was supported by Grants-in-Aid from the Japan Society
for the Promotion of Science (JSPS) (No. 15H03802 and No.
16K17900). T.Y. also acknowledges the support of the Sumitomo
Foundation in the form of a Grant for Basic Science Research
Projects (No. 171018) and support from the Feasibility Study
Program of the Frontier Chemistry Center, Faculty of
Engineering, Hokkaido University.
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