Asmic Isocyanide-Nitrile Isomerization-Alkylations

Article abstract of DOI:10.1002/ejoc.201900903

Anisylsulfanylmethylisocyanide, Asmic, is a versatile building block whose alkylations provide a range of substituted isocyanides. The anisylsulfanyl group plays a critical role in the sequenced deprotonation-alkylation and the subsequent sulfanyl-lithium exchange. Complexation of the anisylsulfanyl group to BuLi in the presence of TMEDA affords a lithiated isocyanide whose alkylations generate trisubstituted isocyanides. In the absence of TMEDA, BuLi triggers cyanide expulsion to afford a transient carbene; reorientation of cyanide with attack at the carbene affords a lithiated nitrile whose alkylations afford quaternary nitriles. The complexation-induced isocyanide-nitrile rearrangement is exceptionally facile, occurring within 5 min at –78 °C. Detailed mechanistic and computational analyses identify the importance of chelation in the bifurcating mechanism: internal chelation favors cyanide extrusion to form a carbene whereas chelating agents favor arylsulfanyl-lithium exchange to generate a lithiated isocyanide. The combined experimental and computational analyses reveal a new mechanism for isocyanide-nitrile isomerization which provides valuable insight for rapidly assembling substituted isocyanides.

Full text of DOI:10.1002/ejoc.201900903

DOI: 10.1002/ejoc.201900903
Full Paper
Isocyanide Isomerization
Asmic Isocyanide-Nitrile Isomerization-Alkylations
Embarek Alwedi,[a] J. Armando Lujan-Montelongo,[b] Rodrigo Cortés-Mejía,[c]
Jorge M. del Campo,*[c] Bilal Altundas,[d] and Fraser F. Fleming*[d]
Abstract: Anisylsulfanylmethylisocyanide, Asmic, is a versatile quaternary nitriles. The complexation-induced isocyanide-nitrile
building block whose alkylations provide a range of substituted rearrangement is exceptionally facile, occurring within 5 min at
isocyanides. The anisylsulfanyl group plays a critical role in the –78 °C. Detailed mechanistic and computational analyses iden-
sequenced deprotonation-alkylation and the subsequent sulf- tify the importance of chelation in the bifurcating mechanism:
anyl-lithium exchange. Complexation of the anisylsulfanyl internal chelation favors cyanide extrusion to form a carbene
group to BuLi in the presence of TMEDA affords a lithiated iso- whereas chelating agents favor arylsulfanyl-lithium exchange to
cyanide whose alkylations generate trisubstituted isocyanides. generate a lithiated isocyanide. The combined experimental
In the absence of TMEDA, BuLi triggers cyanide expulsion to and computational analyses reveal a new mechanism for iso-
afford a transient carbene; reorientation of cyanide with attack cyanide-nitrile isomerization which provides valuable insight for
at the carbene affords a lithiated nitrile whose alkylations afford rapidly assembling substituted isocyanides.
Introduction
cyanide that efficiently traps electrophiles to provide a range of
di- and tri-substituted isocyanides (3, R3 = H or R, respectively).
Anisylsulfanylmethylisocyanide (Asmic, 1) is a versatile isocyan-
ide building block that provides rapid access to a range of iso-
cyanides (Scheme 1).[1] Deprotonating Asmic (1) with LDA, NaH,
or BuLi rapidly generates a potent nucleophile that intercepts
an array of electrophiles through sequential deprotonation-
alkylation cycles to install two substituents in one synthetic op-
eration (1→2). Subsequent addition of BuLi to isocyanide 2 trig-
gers an arylsulfanyl-lithium exchange affording a lithiated iso-
Results and Discussion
During the development of Asmic,[1] the sulfanyl-lithium ex-
change-alkylation of several isocyanides 2 afforded not the ex-
pected isocyanide 3 but the corresponding nitrile 4 (Scheme 2).
Addition of BuLi to a –78 °C, THF solution of the acyclic and
cyclic isocyanides 2a–2c followed by BnBr triggered a remarka-
bly facile synthesis of the corresponding benzylated nitriles 4a–
4c (Scheme 2). The rapid rearrangement at –78 °C in less than
5 minutes is extremely unusual[2] because isomerization of iso-
cyanides to their thermodynamically more stable nitrile coun-
terparts typically requires temperatures in excess of 200 °C.[3]
The limited stability of metalated isocyanides[4] suggested
that the rearrangement might involve cyanide expulsion with
formation of a carbene. Subsequent reorientation with attack
from the carbon of the cyanide ion on the carbene[5] would
generate a lithiated nitrile whose alkylation would afford the
corresponding quaternary nitrile.[6] The speculation led to
screening several additives known to suppress carbene forma-
tion:[7] HMPA, 18-crown-6, LiCl, DMPU, DME, KOtBu and TMEDA.
TMEDA proved optimal in suppressing the rearrangement, al-
lowing for sulfanyl-lithium exchange-alkylations for a variety of
electrophiles;[1] the exchange-stannylation of 2b to afford iso-
cyanide 2d[8] is representative (Scheme 2).
Scheme 1. Asmic alkylation route to substituted isocyanides 3.
[a] Merck Inc.,
90 E. Scott Ave, Rahway, NJ 07065, USA
[b] Departmento de Química Centro de Investigación y de Estudios Avanzados
(Cinvestav),
Av. Instituto Politécnico Nacional, 2508 Ciudad de México,
México 07360
https://quimica.cinvestav.mx/lujan/
E-mail: jalujanm@cinvestav.mx
[c] Departamento de Física y Química Teórica, Facultad de Química,
Universidad Nacional Autónoma de México,
CP 04510, México, CDMX, México. Corresponding author for computations.
E-mail: jmdelc@unam.mx
Access to the stannyl isocyanide 2d provided an independ-
ent route to access the lithiated isocyanide to probe the rear-
rangement. Addition of BuLi to the stannyl isocyanide 2d and
trapping with BnBr provided benzyl isocyanide 3a without any
trace of the corresponding nitrile[9] (Scheme 2). Efficient benzyl-
ation of the lithiated isocyanide prepared by stannyl-lithium ex-
https://quimica.unam.mx/perfil/jorge-martin-del-campo-ramirez/
[d] Drexel University,
32 South 32nd Street Philadelphia, PA 19104, USA
E-mail: fleming@drexel.edu
http://www.pages.drexel.edu/~fff27/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201900903.
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MeI afforded isocyanide 3b (66 % yield). The logical inference is
that the anisylbutylsulfane produced during the anisylsulfanyl-
lithium exchange is not responsible for the isocyanide-nitrile
isomerization.
The lithiation-alkylations of the isocyanide 5 are in distinct
contrast to the lithiation-alkylations of the Asmic-like isocyanide
2e (Scheme 3). Sequential addition of BuLi and methyl iodide
to isocyanide 2e afforded the nitrile 4d, pinpointing the crucial
role of the anisylsulfanyl substituent in triggering the rearrange-
ment. Repeating the sulfanyl-lithium exchange under identical
conditions but with the addition of TMEDA gave only isocyan-
ide 3b (Scheme 3, bottom). The addition of TMEDA completely
suppressed formation of the nitrile 4d.
The efficacy of TMEDA to inhibit the isocyanide-nitrile isom-
erization suggested a role in disrupting internal complexation,
possibly between lithium and the isocyanide π-electrons (8,
Scheme 4).[13] Related metal complexation with nitrile π-elec-
trons profoundly influence a range of reactions.[14] Speculating
that an analogous lithium-π coordination might promote the
isocyanide-nitrile isomerization, MeLi was added to the isocyan-
ides 9a and 9b to promote rearrangement through the lithium
alkoxide 10 (M = Li); no isocyanide-to-nitrile-rearrangement
was observed. An analogous addition of MeMgBr to 9b af-
forded the hydroxyisocyanide 11b in 95 % yield, again without
formation of the corresponding nitrile.
Scheme 2. BuLi-induced isocyanide to nitrile isomerization.
change implies that the isocyanide-nitrile isomerization must
occur prior to the formation of the lithiated isocyanide. The
macroscopic stability of the lithiated isocyanide is consistent
with a previous stannyl-lithium exchange of a stannylmethyl
isocyanide.[10]
Insight into the low temperature isocyanide-nitrile isomeriza-
tion was gleaned from comparative lithiations of benzylic iso-
cyanides 5 and 2e (Scheme 3). Key to these lithiations is the
direct deprotonation of benzylic isocyanides with BuLi[11] which
provides a point of comparison for the exchange-lithiation of
the anisylsulfanylisocyanide 2e. Direct deprotonation of 5 fol-
lowed by trapping with MeI, o-anisyl disulfide, or benzaldehyde
afforded only the corresponding isocyanides 3b and 2e, or the
oxazoline 7 derived from cyclization of an intermediate alkoxy
isocyanide (Scheme 3).[12] Addition of exogenous anisylbutyl-
sulfane (AnSBu), the disulfide produced in Asmic exchange-
alkylations, to the lithiated isocyanide 6 prior to the addition of
Scheme 4. Probing chelation in isocyanide-nitrile rearrangement.
The role of chelation was further probed through compara-
tive alkylations of the glycol-containing isocyanide 12 and the
anisylsulfanyl-containing isocyanide 2f (Scheme 5). Incorporat-
ing a glycol provides a complementary chelation motif to pre-
vent lithiated isocyanide 13 from evolving to a carbene.[15] Ad-
dition of BuLi to 12, in the absence of TMEDA, followed by
Scheme 3. Probing rearrangement-alkylations with benzylic isocyanides.
Scheme 5. Glycol complexation to prevent isocyanide-nitrile rearrangement.
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MeI or AnSSAn afforded the isocyanides 14 and 2f, respectively. the two carbons affords the lithiated azirine 20.[20] Cyanide
Sequential addition of BuLi and MeI to the anisylsulfanyl iso- ejection[21] from 20 via transition structure 21 exposes a formal
cyanide 2f afforded isocyanide 14 in a similar yield as from carbene that suffers a carbon-centered attack by cyanide[5] to
12 with no trace of the corresponding nitrile. Comparing the afford the π complexed lithiated nitrile 22.[22]
structurally similar isocyanides 2e and 2f (Scheme 3 and
Scheme 5, respectively) implies that the glycol out-competes
chelation of BuLi to the anisylsulfanyl moiety to suppress the
isocyanide-nitrile rearrangement.
Experimentally, the presence of TMEDA effectively prevents
evolution of the lithiated isocyanide to the corresponding lithi-
ated nitrile. Calculations that incorporate TMEDA were carried
out in analogy with the carbene path (Figure 1). Isocyanide 2b,
Strong support for the involvement of a carbene in the iso- TMEDA, and BuLi afforded complex 23 in which the lithium
cyanide-nitrile rearrangement came from a serendipitous at- atom is bound to the butyl fragment with interactions with the
tempt to stannylate isocyanide 2g (Scheme 6). Sequential addi- two TMEDA nitrogen atoms, the isocyanide π-electrons, and
tion of BuLi and Bu3SnCl to 2g afforded 1,3-diphenylpropene sulfur (Figure 2). Fragmentation of 23 to lithiated isocyanide 24
(16) presumably through insertion of the intermediate carbene directly parallels the computational progression in the absence
of 15 into one of the four benzylic C-H bonds.[16]
of TMEDA (cf. Figure 1) except that subsequent evolution of 24
through the distorted transition structure 25 to the lithiated
azirine 26 requires
a significantly higher energy barrier
(38.1 kcal/mol for 24 to 25 vs. 29.7 kcal/mol for 18 to 19). The
higher energy barrier to rearrangement with coordinated
TMEDA allows interception of the lithiated isocyanide 24 by
electrophiles.
Scheme 6. Putative carbene insertion during sulfanyl-lithium exchange.
The bifurcation of the sulfanyl-lithium exchange in the pres-
ence or absence of chelators implicates a key role of lithium-
isocyanide complexation in the rearrangement. Insight into the
precise interplay between the exchange and isomerization was
gained from computational modelling (Figure 1).[17] Calcula-
tions using a solvent continuum identified formation of the low
energy complex 17 from BuLi and isocyanide 2b in which lith-
ium is coordinated to the oxygen and sulfur atoms of the
sulfanyl ether. Fragmentation of 17[18] leads to the lithiated iso-
cyanide 18 in which lithium has η3-bonding with the isocyanide
π-system and O- and S-coordination with the sulfanyl ether. The
η3 bonding correlates with prior metalated isocyanide struc-
tures identified in computational analyses.[19]
Figure 2. Influence of TMEDA in the sulfanyl-lithium exchange.
Exploring the precise orientation of the five-membered ring
revealed an isomerization path that is dependent upon the cy-
clopentane conformation (Figure 3). The low-energy complex
18 that evolves from complex 17 (both common to Figure 1),
can be distorted through bending of the central isocyanide
nitrogen to access transition structure 27 (Figure 3). Compared
to the analogous structure 19, the five-membered ring is bent
in a different orientation which is considerably higher in energy.
Progression through transition structure 27 leads to the lithi-
ated azirine 28 which ruptures the ring carbon–nitrogen bond
progressing through transition structure 29 to the lithiated
nitrile 30. Transition structure 29 does not show the carbene-
like character present in structure 19. The key difference be-
tween the evolution of 18 through transition structures 27 and
Figure 1. Computational identification of reactive intermediates in the
sulfanyl-lithium exchange.
In the absence of TMEDA, the lithiated isocyanide 18 evolves 29 (Figure 3) vs. 19 and 21 (Figure 1) is their much higher
to a lithiated azirine similar to the thermal isocyanide-nitrile energies (43.4 kcal/mol for 18 → 27 and 40.3 kcal/mol for 28
mechanism.[3] Distortion of 18 through a bending at the central → 29); the former isomerization pathway through 19 benefits
nitrogen leads to transition structure 19 in which lithium main- from a delocalized interaction of the π-electrons with lithium
tains an interaction with the formally anionic carbon (2.10 Å) that is not available in 27 or 29. The value of these calculations
and the isocyanide carbon (2.76 Å). Scission of the more substi- lies in showing that conformation plays a role in the isocyanide-
tuted lithium–carbon bond with concomitant bonding between nitrile isomerization, casting light on why the conformationally
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less mobile 6-membered isocyanides may not isomerize in the low temperature isocyanide-nitrile rearrangement-alkylation is
absence of TMEDA.[1]
highly unusual. Mechanistic experiments, supported by compu-
tational analyses, are consistent with formation of a carbene
intermediate formed by ejection of isocyanide in the form of
lithium cyanide. Reorientation and attack of cyanide on the
carbene generates a lithiated nitrile that effectively alkylates
electrophiles. Interrupting the cyanide ejection is readily
achieved through addition of external TMEDA or with a glycol
substituent. Effective lithium chelation allows efficient ex-
change-alkylations by preventing the isocyanide-to-nitrile
isomerization. Collectively, the computational and mechanistic
analyses provide insight into the isocyanide-nitrile rearrange-
ment and provide robust conditions to prepare an array of sub-
stituted nitriles or isocyanides.
Experimental Section
Full experimental details including the computational analyses are
provided in the supporting information.
Figure 3. Effect of ring distortion over non-TMEDA path in the sulfanyl-lithium
exchange.
The computational and mechanistic analyses are summa-
rized in Scheme 7. Addition of BuLi to the anisylsulfanyl iso-
cyanide 2 leads to chelation between lithium, the isocyanide π-
cloud, and the oxygen and sulfur moieties (31). The three-point
binding of BuLi facilitates nucleophilic attack on sulfur with
concomitant ejection of cyanide (31 → 32). Reorientation of
cyanide with attack on the carbene 32 generates the lithiated
nitrile 33 whose alkylation affords the quaternary nitrile 4. In
the presence of TMEDA, addition of BuLi to 2 or substrates with
an internal glycol-linker prevents complexation between lith-
ium and the isocyanide allowing sulfur-lithium exchange to af-
ford lithiated isocyanide 34. Alkylation of 34 affords the substi-
tuted isocyanide 3.
Acknowledgments
Financial support from Drexel University and initially from the
NIH (2R15AI051352–04) is gratefully acknowledged. JMC thanks
the LANCAD-UNAM-DGTIC-270 project for the use of computa-
tional resources, the DGAPA-UNAM for grant IN114418, and the
CONACYT for grant 282791. JALM thanks CONACYT (241445)
for support.
Keywords: Isocyanide · Rearrangement · Asmic ·
Carbenes · Alkylation
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Conclusions
Asmic provides a versatile route to substituted isocyanides
through a unique series of alkylations. The anisylsulfanyl group
is critical for the sulfanyl-lithium exchange, an unusual process
that affords a lithiated isocyanide or a lithiated nitrile depend-
ing on the presence or absence of TMEDA, respectively. The
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Received: June 24, 2019
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Isocyanide Isomerization
Carbene intermediates are implicated
for the first time in an extremely un-
usual low temperature, isocyanide-to-
nitrile isomerization. Chelators such as
TMEDA redirect the exchange to a lith-
iated isocyanide whose alkylation af-
fords trisubstituted isocyanides.
E. Alwedi, J. A. Lujan-Montelongo,
R. Cortés-Mejía, J. M. del Campo,*
B. Altundas, F. F. Fleming* .............. 1–6
Asmic Isocyanide-Nitrile Isomeriza-
tion-Alkylations
DOI: 10.1002/ejoc.201900903
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