Facile Synthesis of Cyanide and Isocyanides from CO

Article abstract of DOI:10.1002/anie.202105909

The reaction of K[N(SiMe₃)₂] with ¹³CO proceeds in C₆D₆ or THF affording K¹³CN and O(SiMe₃)₂ under mild conditions as confirmed by crystallographic characterization of K(18-crown-6)CN. Similarly reaction of the alkali metal amides, M[N(SiR₃)R′] (M=Li, K; R=Ph, Me; R′=alkyl, aryl) provides the corresponding ¹³C labeled isocyanide RN¹³C and MOSiR₃, generally in high yields. In some instances, the use of the sterically bulky Ph₃Si-substituent is required to preclude 1,2-silyl migration affording the silylcarbamoyl salt M[Me₃SiC(O)NR′]. These reactions have been used to obtain 19 examples of ¹³C labelled isocyanides, and several examples of gram scale reactions are reported. The mechanism of the reactions is probed via reliable DFT calculations.

Full text of DOI:10.1002/anie.202105909

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Accepted Article
Title: Facile synthesis of cyanide and isocyanides from CO
Authors: Douglas Wade Stephan, Maotong Xu, Bastiaan Kooij,
Tongtong Wang, Jack H. Lin, Zheng-wang Qu, and Stefan
Grimme
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202105909
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Facile synthesis of cyanide and isocyanides from CO
Maotong Xua, Bastiaan Kooija,b, Tongtong Wanga,c, Jack H. Lina, Zheng-wang Qud*, Stefan Grimme,d
Douglas W. Stephana*
This work is dedicated to the memory of Professor Richard H. Holm.
a Mr. M. Xu, Mr. J.H. Lin, Professor Dr D.W. Stephan
Department of Chemistry, University of Toronto,
80 St. George St., Toronto, Ontario, Canada M5S3H6
Email: dstephan@chem.utoronto.ca
b. Mr. B. Kooij
Van ‘t Hoff Institute for Molecular Sciences, University of Amsterdam
1090 GD Amsterdam, The Netherlands
c. Ms. T. Wang
School of Chemistry, Faculty of Chemical, Environmental and Biological Science and Technology,
Dalian University of Technology, Dalian, 116023, China
d. Dr. Z.-W. Qu, Prof. Dr. Stefan Grimme
Mulliken Center for Theoretical Chemistry, Institut für Physikalische und Theoretische Chemie
Rheinische Friedrich-Wilhelms-Universität Bonn
Beringstrasse 4, 53115 Bonn, Germany
Email: qu@thch.uni-bonn.de
Electronic Supplementary Information (ESI) available: Synthetic and spectral data as well as DFT-computed energies and Cartesian coordinates are
deposited. X-ray crystallographic data can be obtained from the CCDC 2080562-2080564.
Abstract: The reaction of K[N(SiMe3)2] with 13CO proceeds in C6D6 or
THF affording K13CN and O(SiMe3)2 under mild conditions as
confirmed by crystallographic characterization of K(18-crown-6)CN.
Similarly reaction of the alkali metal amides, M[N(SiR3)R] (M= Li, K;
R = Ph, Me; R = alkyl, aryl) provides the corresponding 13C labeled
isocyanide RN13C and MOSiR3, generally in high yields. In some
instances, the use of the sterically bulky Ph3Si-substituent is required
to preclude 1,2-silyl migration affording the silylcarbamoyl salt
M[Me3SiC(O)NR]. These reactions have been used to obtain 19
examples of 13C labelled isocyanides, and several examples of gram
scale reactions are reported. The mechanism of the reactions is
probed via reliable DFT calculations.
act as potent photo-reductants thus finding applications as
photosensitizers.[14]
Isocyanides (RNC) are versatile reagents in synthetic chemistry,
acting as nucleophiles and electrophiles,[1] as well as participating
in radical reactions.[2] This has led to applications in chemistry
across the discipline. For example, isocyanides have been widely
utilized in macromolecular[3] and polymer chemistry.[4] In more
recent years, diastereomeric polyisocyanides[5], light-responsive
polyisocyanides[6] and cross linked polyisocyanides[7] have been
emerged. In bioorganic chemistry, isocyanides have been
exploited for multicomponent reactions,[8] to prepare α-acyl
carboxamides or dipeptides. In these cases, diastereoselective
and enantioselective versions of these reactions[9] provide
access to valuable products for drug discovery and
development.[10] Isocyanides have also been exploited in
biological chemistry as incorporation into amino acids provides
opportunities for biorthogonal chemistry and protein labeling.[11]
Isocyanides have also been extensively studied as ligands in
coordination chemistry as they provide both a strong σ donor and
π-acceptor properties. These features give rise to a variable
coordination modes where isocyanides act as 2, 4 and 6
e- donors,[12] and have been employed in transition metal
complexes and main group chemistry.[13] In addition, isocyanides
Scheme 1. (a) known routes to 13C enriched isocyanides (b) schematic of the
present chemistry. (Nacnac) = [ArNC(tBu)]2CH, Ar' = 2,6-iPr2C6H3, Cy =
cyclohexyl
Given this broad utility and the convenience of 13C NMR
spectroscopy, it is perhaps surprising to note the paucity of
synthetic routes to isotopically labelled RN≡13C. Indeed, our
survey of the literature revealed only a few synthetic routes.
Mindiola and coworkers prepared a 13C enriched aryl isocyanide
from the stoichiometric reaction of a titanium−imide and 13CO2
(Scheme 1a) in 2006.[15] In the same year, Kira and coworkers
described the Si-C coupling reaction of a silylene and isocyanide
and used the reaction of 13C enriched chloroform with amines to
prepare 2,6-(iPr)2C6H3N13C.[16] More recently, Yamashita used
the same protocol to prepare tBuN13C for use in the examination
1
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of diborane reactivity.[17] In 2021, Islamova et al[18] synthesized
cyclohexyl-N13C from sodium 13C-formate for use as a ligand in
transition metal chemistry.
(Figure 1). The K-C-N angle of is 130(1)º. These data affirm the
remarkable and facile transformation of CO to CN-.
Targeting a facile route to 13C enriched products, we noted
our recent demonstration of reactions of both lithium amides and
phosphides[19] with CO affording products with N-C and P-C
bonds. Herein, we demonstrate the facile reactions of silylamides
M[N(SiMe3)2] and M[N(SiR3)R] (M= Li, K; R = Ph, Me; R = alkyl,
aryl) with 13CO provides convenient access to 13CN− and 13C-
labeled alkyl and aryl isocyanides. The mechanism of these
reactions is discussed, and the protocol is adapted to gram scale
syntheses.
In 1965, reaction of Na[N(SiMe3)2], with CO at 80 °C and
100 atm pressure in petroleum ether or benzene was reported to
give NaCN.[20] We began by examining the reaction of
K[N(SiMe3)2] in C6D6 with 1 atm pressure of COin a J-young tube.
No reaction was observed after 24 h at room temperature (Table
1, entry 1). However, heating to 50°C for 24 h, led to the formation
of KCN in 64% yield (Table 1, entry 2), consistent with the
appearance of the 13C resonance at 166.6 ppm in D2O and
DMSO-d6 and the concurrent appearance of the 1H NMR
resonance attributable to O(SiMe3)2. Repeating the reaction in
THF at room temperature, affording K13CN in 13% yield after 24
hours (Table 1, entry 3), however the yield improved to 89% at
elevated temperature (50°C, Table 1, entry 4). Alternatively,
elevating the pressure to 4 atm of 12CO gave 78% yield after 24 h
at room temperature (Table 1, entry 5). Under analogous
conditions using Li[N(SiMe3)2], Li13CN was obtained in <1% yield
(Table 1, entry 6). Addition of 18-crown-6 ether to K[N(SiMe3)2] in
THF at 50 °C, (Table 1, entry 7) led to poor reactivity. This was
attributed to partially deprotonation of the crown ether by
K[N(SiMe3)2]. However, this was avoided in THF or 1,4-dioxane
at ambient temperature under 1 atm 13CO. These reactions led to
the formation of [(18-crown-6)K13CN] 1 as colorless crystals after
24 h in 88 and 99% yields, respectively (Table 1, entry 8, 9). This
optimized, mild protocol provides a facile route to isotopically
labeled cyanide. We note that previous routes employed 13CO2
and requires a Ru/Pt catalyst, H2, NH3 and forcing conditions.[21]
Figure 1 POV-ray depiction of one of the molecules in the asymmetric unit of 1,
hydrogen atoms are omitted for clarity. C: black, O: red, N: blue.
The formation of 1 presumably proceeds via nucleophilic
attack of CO by amide generating a transient carbene species.
Intramolecular 1,3-silyl group migration is followed by a 1,2
elimination of siloxide generating cyanide.
A carbene-like
intermediate was also proposed for the analogous reaction of the
[tBu2P]– anion with CO, where tBu group migration from P to C
afforded [K(18-crown-6)][E-tBuPC(tBu)O].[19b] In the present case,
silyl migration to oxygen is presumably thermodynamically
favored by the strength of Si-O bonds.
Table 1 Conditions for the formation of CN− from CO and M[N(SiMe3)2].
Scheme 2 Proposed reaction pathway to 1.
Ent
Cation
Solv
P
T
t
Yield
(M)
K
K
K
K
K
Li
(atm) (°C) (h) (%)
To further support the proposed mechanism, DFT
calculations were performed at the PW6B95-D3/def2-QZVP +
COSMO-RS // TPSS-D3/def2-TZVP + COMSO level of theory in
THF solution.[22] Consistent with the known crystal structure,[23]
the dimeric form of [K(N(SiMe3)2)]2 is shown to be 1.9 kcal/mol
more stable than the monomer in THF solution. Direct CO
insertion into a K−N bond of [K(N(SiMe3)2)]2 is 15.3 kcal/mol
endergonic over a low free energy barrier of 16.5 kcal/mol (via
transition state TS1) affords the transient intermediate Int1.
Subsequently almost barrierless and highly exergonic 1,3-silyl-
shift to cleave the C−O bond (via TS2) affords the complex
(Me3Si)2NK2OSiMe3 and Me3SiNC. Isomerization of isocyanide
the cyanide Me3SiCN is almost neutral in free energy but slow due
to the barrier of 24.2 kcal/mol, with isocyanide being entropically
favored on heating. Subsequent nucleophilic attack at the Si-
center of Me3SiNC by amide is −19.5 kcal/mol exergonic over a
low barrier of 11.6 kcal/mol (via TS3) yielding the complex
(Me3Si)2NK2CN and O(SiMe3)2. To this point, the reaction is highly
1a
2a
3
C6D6
C6D6
THF
THF
THF
THF
THF
THF
1
1
1
1
4
1
1
1
1
rt 24 <1b
50 24 64b
rt 24 13b
4
50 24
rt 24
89
78
5a
6
rt 24 <1b
7
8
9
K(18-crown-6)
K(18-crown-6)
K(18-crown-6) 1,4-dioxane
50
5
<1b
88
rt 24
rt 24 >99b
a trial done with unlabelled CO. b yield determined by integration of the 1H NMR
spectrum.
A crystallographic study of 1 revealed its formulation as
[K(18-crown-6)CN] with two molecules in the asymmetric unit.
The K+ ion is coordinated to six oxygen atoms of the crown with
K-O distances falling in the range 2.76-2.97 Å. In addition, the K+
ion is bound to a cyanide fragment with an average K-C distance
of 2.70(1) Å and an average C-N bond distance of 1.07(1) Å
2
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10.1002/anie.202105909
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exergonic with a low overall barrier of 16.5 kcal/mol (TS1), and
thus should be facile at room temperature. A very similar
mechanism is also found for monomeric K(N(SiMe3)2 and CO,
however this is kinetically 3.7 kcal/mol less favorable. The
complex (Me3Si)2NK2CN is further stabilized by −2.3 kcal/mol
upon dimerization. The moderate yield of KCN observed
experimentally suggests the possibility of the formation of higher
amide-cyanide aggregates. Coordination of K+ by 18-crown-6
stabilizes the monomeric potassium amide (18-crown-
6)KN(SiMe3)2 by −7.4 kcal/mol and kinetically favors reaction with
CO by 1.8 kcal/mol (see ESI). The corresponding reaction using
[(THF)LiN(SiMe3)2]2 encounters a 4.9 kcal/mol higher barrier (21.4
kcal/mol via TS1Li, see ESI) due to stronger THF coordination
and less ionic Li−N amide bond.
evidenced in the 13C{1H} NMR triplet (1JC-N = 5 Hz) at 164 ppm,
another signal at 180 ppm exhibited 29Si satellites with 1JC-Si = 60
Hz was consistent with the formation of the carbamoyl lithium
species, [(Me3Si)C(O)N(4-MeOC6H4)]Li consistent with previous
reports of silylation of amidocarbomoyl lithium species.[24] In the
present case, these two species were present in a ratio of 2:1
(Table 2, entry 11), indicating that 1,3 and 1,2 silyl migrations are
energetically competitive. To sterically favor 1,3 migration of the
silyl group to oxygen the amide [(Ph3Si)(4-MeOC6H4)N]K was
reacted with CO. After 12 h, the isocyanide formed in quantitative
yield (Table 2, entry 12). In a similarly fashion, Ph3Si-derived
amides afforded the alkyl isocyanides RNC (R = iPr 12, Bu 13,
hexyl 14) in good yields (Table 2, entry 13-15). In addition, the
aryl isocyanides RNC (C6H5 15, 3-MeOC6H4 16, 4-Me2NC6H4 17,
4-PhOC6H4 18, 4-iPrC6H4 19) were formed in yields of 74-95%
(Table 2, entry 16-20). Efforts to apply this protocol to picolyl
substituted silylamide led to known cyclization affording imidazo[1,
5-a]pyridine-3-13C 20, via the transient isocyanide intermediate.[25]
Table 2 Conditions for the formation of RN13C from 13CO and M[N(SiR’3)R].
Ent
R’
[Si]
M
Yield
(%)a
> 99b
98
81
93
71
95
97
RN13
C
1
2
3
4
5
6
7
8
tBu
tBu
Adamantyl
2-iPrC6H4
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
Ph3Si
Ph3Si
Ph3Si
Ph3Si
Ph3Si
Ph3Si
Ph3Si
Ph3Si
Ph3Si
Ph3Si
K
Li
Li
Li
K
Li
Li
Li
Li
Li
Li
K
Li
K
K
K
K
2
2
3
4
5
6
7
8
9
10
11
11
12
13
14
15
16
17
18
19
20
2-PhC6H4
2-Me-4-OMeC6H3
2,6-Me2C6H3
2,6-iPr2C6H3
2,4,6-(tBu)3C6H2
2,6-(Ph2CH)2-4-Me C6H2
4-MeOC6H4
4-MeOC6H4
iPr
93
9d
10
11
12
13
14
15
16
17
18
19
20
21d
86c
92
66e
99
98
89
97
74
86
95
87
Figure 2 DFT-computed free energy path (in kcal/mol, 298 K) from CO to CN−.
Bu
Hexyl
C6H5
3-MeOC6H4
4-Me2NC6H4
4-PhOC6H4
4-iPrC6H4
The mechanism infers the formation of intermediates
Me3SiNC with KOSiMe3 suggesting substituted-silyl amides could
provide isocyanides. To that end, the silylamide [(Me3Si)(tBu)N]K
was prepared via deprotonation of the corresponding amine with
one equivalent of benzyl potassium in THF. Subsequent reaction
with 13CO (1 atm) at room temperature for 12 h, led to the
immediate discoloration of the solution and the quantitative
conversion to tBuN13C 2 and Me3SiOK as evidenced by the 13C
resonance at 155.1 ppm (Table 2, entry 1). Similarly, using 1 atm
13CO with [(Me3Si)(tBu)N]Li, the isotopically labeled isocyanide
tBuN13C 2 was obtained in 98% yield (Table 2, entry 2).
To probe the generality of this reactivity, a series of
silylamides [(Me3Si)(R)N]M (M = Li, K) were prepared. The
silylamide [(Me3Si)(Ad)N]Li (Ad = adamantyl) gave AdN13C 3 in
81% yield (Table 2, entry 3). Analogous reactions of arene
substituted amides [(Me3Si)(Ar)N]Li (Ar = 2-iPrC6H4, 2-PhC6H4, 2-
Me-4-MeOC6H3, 2,6-Me2C6H3, 2,6-iPr2C6H3, 2,4,6-(tBu)3C6H2,
2,6-(Ph2CH)2-4-MeC6H2) gave the corresponding isotopically
enriched isocyanides 4-10 in yields ranging from 71 to 97% (Table
2 Entry 4-10).
K
K
K
Li
88
2-Picolyl
91c
ayield determined by13C{1H} NMR spectroscopy using [13C] urea as internal
standard; byield determined by 1H NMR spectroscopy; cisolated yield; d36 h;
eyield determined by relative integration of isocyanide: carbamoyl species.
In the case of the isocyanides RNC (R = 2,6-(iPr)2C6H3 8;
2,6-(Ph2CH)2-4-MeC6H2 10), cocrystalization of reaction products
afforded crystals of the tetra-lithium-siloxide clusters formulated
as [(2,6-(iPr)2C6H3NCLiOSiMe3)]4 and [(THF)2(2,6-(Ph2CH)2-4-
MeC6H2)NC)2(LiOSiMe3)4], respectively (Figure 3a, b). Both
species are LiOSiMe3 pseudo-cubanes where oxygen atoms
bridge the lithium atoms. The coordination spheres of the Li-
atoms are completed with either an isocyanide or THF molecule.
Presumably, the steric bulk of the latter isocyanide precludes the
inclusion of four isocyanides about the Li-O cluster, prompting
THF coordination. The Li-C distances were 2.243(4) and
2.258(17) Å for R = 2,6-(iPr)2C6H3 and 2,6-(Ph2CH)2-4-MeC6H2,
respectively, with N-C distances being 1.154(3) and 1.161(11) Å,
respectively. In the case of, 2,4,6-(tBu)3C6H2NC 9, its differing
In the reaction of the sterically less demanding [(Me3Si)(4-
MeOC6H4)N]Li, while the isocyanide was the major product as
3
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solubility allowed crystallization of the isocyanide in the absence
of the Li-siloxide (Figure 3c). The N-C distance was 1.159(4) Å.
Scheme 3 Examples of gram-scale and one-pot reactions to isocyanides.
In conclusion, the reaction of silylamides with CO provides
a facile and low-pressure protocol to both KCN and isocyanides.
Understanding the mechanism using reliable DFT calculations
has allowed the adaptation of this reaction to the preparation of a
series of 19 isocyanides. This methodology is readily adapted to
the inclusion of 13C isotopic labeling at the cyano or isocyanide
carbons. In addition, it is shown to be viable in gram scale
preparations. We are continuing to explore the reaction chemistry
of alkali-metal species with small molecules.
Acknowledgements
D.W.S. is grateful to NSERC of Canada for research support and
the award of an NSERC Canada Research Chair and to the
Guggenheim Foundation for a 2020 Guggenheim Fellowship and
Killam foundation for the 2021 Killam Prize. Z.W.Q and S.G are
grateful to DFG (project SPP1807 and Gottfried Wilhelm Leibnitz
prize to S.G) for financial support. M.X. is grateful for the award of
Colin H. Bayley Scholarship. T.W. is grateful to China Scholarship
Council for financial support.
Figure
3
POV-ray depictions of the crystal structures of (a) [(2,6-
(b) [(THF)2(2,6-(Ph2CH)2-4-
Keywords: Cyanide • carbon monoxide • isotopic labelling •
small molecule activation• 13C labelled iso cyanides
(iPr)2C6H3NCLiOSiMe3)]4,
MeC6H2)NC)2(LiOSiMe3)4], and (c) 2,4,6-(tBu)3C6H2NC. Hydrogen atoms are
omitted for clarity, C: black, N: blue, O: red, Si: pink, Li: bronze.
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Several examples of these syntheses were performed on a
gram scale. Reactions of 1.1 g of [(Me3Si)(2,6-iPr2C6H3)N]Li or 1.0
g of [(Me3Si)(2,6-(Ph2CH)2-4-MeC6H2)N]Li in THF with CO
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The reactions of K[N(SiMe3)2] with 13CO affords K13CN and O(SiMe3)2 under mild conditions. DFT calculations affirmed this reaction
proceeds via an isocyanide intermediate. This was confirmed experimentally as the alkali metal amides, M[N(SiR3)R] (M= Li, K; R =
Ph, Me; R = alkyl, aryl) are shown to provide a facile route to the 19 13C labeled isocyanide RN13C and MOSiR3 generally in high
yields.
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