Asmic: An Exceptional Building Block for Isocyanide Alkylations

Article abstract of DOI:10.1021/acs.orglett.8b02574

Asmic addresses the long-standing challenge of alkylating isocyanides, providing access to isocyanides with diverse substitution patterns. The o-anisylsulfanyl group serves a critical dual role by facilitating deprotonation-alkylation and providing a latent nucleophilic site through an unusual arylsulfanyl-lithium exchange.

Full text of DOI:10.1021/acs.orglett.8b02574

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asmic: An Exceptional Building Block for Isocyanide Alkylations
Embarek Alwedi,† J. A∥rmando Lujan-Montelongo,‡ Bhaskar R. Pitta,§ Allen Chao,
∥
́
Rodrigo Cortes-Mejía, Jorge M. del Campo, and Fraser F. Fleming*
Department of Chemistry, Drexel University, 32 South 32nd Street, Philadelphia, Pennsylvania 19104, United States
S
* Supporting Information
ABSTRACT: Asmic addresses the long-standing challenge of
alkylating isocyanides, providing access to isocyanides with
diverse substitution patterns. The o-anisylsulfanyl group serves
a critical dual role by facilitating deprotonation−alkylation
and providing a latent nucleophilic site through an unusual
arylsulfanyl−lithium exchange.
socyanides are prized reactants in an array of multi-
I
component1 and transition metal insertion processes.2 The
versatility of isocyanides, particularly in generating pharma-
ceutical leads,3 obscures two major deficiencies, namely, their
limited commercial availability4 and the difficulty in synthesiz-
ing substituted congeners.5 Typically, isocyanides are accessed
through late-stage formylation−dehydration of amines or
activated alcohols that build on a pre-existing carbon scaffold.6
The challenge lies in developing a method for rapidly
assembling diverse isocyanides.
Figure 1. Two representative bioactive cyclohexyl isocyanides.
Unlike virtually any other electron-withdrawing group,
alkylation adjacent to the isocyanide functionality is extremely
difficult; metalation is efficient only for alkyl isocyanides with
proximal chelating or electron-withdrawing groups7 and
methyl isocyanide, a toxic, noxious isocyanide.8 The challenge
in alkylating isocyanides is captured in the LiTMP deproto-
nation of cyclohexyl isocyanide (1), where trapping with
benzaldehyde proceeds in only 6% yield (1 → 2 → 3a; Scheme
1).9 The difficulty stems from the low acidity of alkyl
Exploratory attempts to alkylate 1 revealed the inherent
problem; the slow deprotonation generates a reactive, unstable
organometallic (2) that is prone to attack the isocyanide
functionality in the reactant and product. Optimal conditions
to alkylate 1 employed (TMP)2Mg·LiCl with excess propyl
iodide in situ to rapidly intercept the lithiated isocyanide (1 →
4a). Although successful, the in situ protocol places significant
constraints on the electrophile. The inherent difficulty of the
deprotonation−alkylation requires a conceptually orthogonal
strategy, one in which the nucleophilic isocyanide is rapidly
generated and then selectively intercepted by external
electrophiles.
Scheme 1. A Prototypical Cylohexyl Isocyanide Alkylation
Sulfoxide−metal exchange appeared to be attractive for
generating metalated isocyanides 8 because the rapid exchange
offered the potential to circumvent competitive self-condensa-
tion (Scheme 2). An extensive investigation with several
sulfoxide-substituted isocyanides 7 validated the concept13 (7
→ 8 → 9) but identified several intractable problems: a high
propensity of 7 to eliminate sulfenic acid, irreversible
adsorption on silica gel, and extensive decomposition. The
instability of sulfoxide-substituted isocyanides 714 stimulated a
different strategy predicated on a rare arylsulfanyl exchange−
alkylation (11 → 8 → 9; Scheme 2).15
isocyanides,10 the temperature sensitivity of the resulting
metalated isocyanides,11 and their propensity toward self-
condensation.12 The deprotonation constraint is problematic
because the most bioactive isocyanide-containing natural
products feature fully substituted cyclohexanes.6 Illustrative
of the bioactivity of cyclohexyl isocyanides are kahlahinol F
(5), a potential lead for treating copper accumulation, and
amphilectadiene 6, which is a potent antimalarial agent (Figure
1).6
The requisite arylsulfanylmethyl isocyanide precursors 10
were rapidly assembled through a two-step Mannich
condensation (arylthiol, paraformaldehyde, and formamide)
Received: August 10, 2018
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.8b02574
Org. Lett. XXXX, XXX, XXX−XXX

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methoxyphenyl substituent in 12d was particularly efficacious.
Para and para−meta methoxy substrates 12e and 12f did not
engage in an arylsulfanyl−lithium exchange, implying that the
o-methoxyphenyl group (12d) facilitates the exchange through
chelation rather than through electronic activation. Consistent
with the chelating role of the o-MeO group, the presence of
additional methoxy substitution at the meta and para positions
was tolerated in 12g but provided no advantage over a single o-
methoxy substituent. The o-methoxy, o-trifluoromethylphenyl-
substituted isocyanide 12h proved to be particularly delicate,
decomposing upon storage and chromatography; an attempted
exchange−alkylation afforded a complex mixture.
The efficacy of Asmic-derived isocyanide 12d led to an
exploration of the generality of the exchange−alkylation (Table
1). Optimization experiments revealed the sulfanyl−lithium
exchange to be complete in less than 5 min at −78 °C.
Electrophilic trapping was performed at −78 °C because
warming of the solution of the putative lithiated isocyanide to
25 °C followed by addition of an electrophile led to only trace
amounts of the alkylated isocyanide.11 Alkyl iodides and
bromides (entries 1−5) efficiently afforded alkyl isocyanides;
tributylstannyl chloride afforded stannyl isocyanide 4f in an
exceptionally high yield (entry 6). The carbonyl electrophile
methyl benzoate gave ketone 4g (entry 7), whereas methyl
cyanoformate gave ester 4h (entry 8). Cyclohexenone cleanly
afforded the keto isocyanide resulting from a conjugate
addition, but the isolated yield was compromised by the
limited stability of 4i (entry 9). Trapping with cyclohexanone
afforded oxazoline 3b through attack of the initial alkoxide on
the isocyanide (entry 10). Access to stannyl isocyanide 4f
provided an independent lithiation route to oxazoline 3b with
virtually identical efficiency, suggesting that the same lithiated
isocyanide is generated in both processes.20 Successful
alkylation of 12d with α-bromoacetophenone to afford 3c
required prior transmetalation with Et2Zn to prevent
competitive deprotonation of the acidic methylene (entry
11).21 Collectively, these alkylations demonstrate the efficacy
of the Asmic sulfanyl−lithium exchange−alkylation over prior
deprotonation strategies (cf. 1 → 3a; Scheme 1) by providing
an efficient method to access a range of substituted cyclohexyl
isocyanides.
Scheme 2. Sulfur-Based Isocyanide Alkylations
followed by dehydration.16 Exploratory alkylations employed
naphthylsulfanylmethyl isocyanide (10a) (10, Ar = C10H7)
because the relatively stable solid avoids the odiferous and
noxious nature of the closely related phenyl and pyridyl
analogues (10, Ar = phenyl, 2-pyridyl).17 Alkylation of 10a
with 1,5-dibromopentane was guided by developing chemistry
on a prototype that would address the challenge of accessing
substituted cyclohexyl isocyanides.6 The double alkylation of
10a proved straightforward with NaH in DMF, though
subsequent alkylations with Asmic (10d) (10, Ar = o-
methoxyphenyl) identified BuLi in THF as superior; sequential
deprotonation−alkylation cycles of 10d with BuLi allowed two
different electrophiles to be introduced in one synthetic
operation.
Initial attempts to perform an arylsulfanyl exchange−
alkylation were not promising (Figure 2). The addition of
The bioactivity-driven decision to explore the exchange−
alkylation with isocyanide 12d containing a six-membered ring
as a prototype proved to be fortuitous. Performing the same
BuLi-induced exchange with isocyanide 13 containing a five-
membered ring and trapping with benzyl bromide efficiently
afforded not the expected isocyanide but the corresponding
nitrile 14a (eq 1). The facile rearrangement−alkylation is
a
Figure 2. Exchange−benzylations with arylthio isocyanides. Alkyla-
tion was performed with methyl cyanoformate in place of BnBr.
various organometallics to naphthyl isocyanide 12a followed
by benzyl bromide as a test electrophile afforded a complex
reaction mixture.18 Close inspection of the crude reaction
mixtures revealed the presence of varying amounts of naphthyl
butyl sulfide, which was optimistically interpreted as evidence
for the critical arylsulfanyl−lithium exchange. Building on this
lead, a series of arylsulfanylmethyl isocyanides 12 were
synthesized in which the aromatic substituent was varied to
optimize the exchange−alkylation.
Initial screening focused on heteroatom-substituted arylsul-
fanylcyclohexyl isocyanides 12 (Figure 2) because heteroatom
coordination was speculated both to facilitate delivery of BuLi
to the sulfide and to stabilize the resulting lithiated
isocyanide.19 Although neither o-methylthiophenyl (12b) nor
o-phenoxyphenyl (12c) substituents were effective, the o-
extremely unusual, as isocyanide−nitrile isomerizations
typically require temperatures in excess of 200 °C.22 Surmising
that the lithiated isocyanide might exhibit carbene character,
several metal chelators were added (HMPA, 18-crown-6, LiCl,
DMPU, DME, KOt-Bu, and TMEDA) in an attempt to
suppress the rearrangement.23 Among these, the introduction
of TMEDA to a −78 °C THF solution of 13 before the
B
DOI: 10.1021/acs.orglett.8b02574
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Letter
alkylations with a range of cyclic and acyclic isocyanides (Table
2). The BuLi-induced exchange−alkylation with isocyanides
Table 1. Exchange−Alkylation of Asmic-Derived Isocyanide
12d
Table 2. Diverse Isocyanide Exchange−Alkylations
13 and 16 containing five- and seven-membered rings
membered efficiently afforded the corresponding trisubstituted
isocyanides 15 and 17, respectively (Table 2, entries 1−3).
Similarly, acyclic isocyanides 18 and 20 afforded isocyanides
19 and 21, respectively (Table 2, entries 4−6). The use of
NH4Cl as an electrophile (Table 2, entry 4) illustrates how
Asmic can provide a route to disubstituted isocyanides, which
like their trisubstituted counterparts are challenging to
access.25 The exchange−alkylation of 20 proceeds from a
diastereomeric mixture to a single diastereomer,26 which is
consistent with the rapid configurational equilibration of
lithiated isocyanides.27
Asmic is a powerful new building block that provides rapid
modular assembly of di- and trisubstituted isocyanides. The
efficient alkylation, the first generalized isocyanide alkylation
method, is predicated on an anisylsulfanyl substituent that both
facilitates deprotonation and engages in a highly unusual
sulfanyl−lithium exchange. The Asmic exchange−alkylation
strategy overcomes the long-standing challenge of alkylating
isocyanides, provides diverse isocyanides that were previously
difficult to access, and gives insight into the reactivity of
lithiated isocyanides.
addition of BuLi was found to afford only isocyanide 15a,
completely suppressing the formation of the nitrile 14a.24
Including TMEDA in the Asmic exchange suppressed the
isocyanide−nitrile rearrangement, allowing smooth exchange−
C
DOI: 10.1021/acs.orglett.8b02574
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
̈
(b) Stafforst, D.; Schollkopf, U. Liebigs Ann. Chem. 1980, 1980, 28−
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02574.
■
36.
S
(12) Bittner, G.; Witte, H.; Hesse, G. Liebigs Ann. Chem. 1968, 713,
1−11.
(13) Fleming, F. F. Composition, Synthesis, and Use of Isonitriles.
U.S. Patent 8,269,032, Sept 18, 2012.
(14) van Leusen, A. M. The Effect of Sulfur-Substituents on the
Chemistry of Alkyl Isocyanides. In Perspectives in the Organic
Chemistry of Sulfur; Zwanenburg, B., Klunder, A. J. H., Eds.; Elsevier:
Amsterdam, 1986; pp 119−144.
1
Experimental procedures, characterization data, and H
and 13C NMR spectra (PDF)
(15) Nath, D.; Skilbeck, M.; Coldham, I.; Fleming, F. F. Org. Lett.
2014, 16, 62−65.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: fleming@drexel.edu.
ORCID
(16) Lujan-Montelongo, J. A.; Estevez, A. O.; Fleming, F. F. Eur. J.
Org. Chem. 2015, 2015, 1602−1605.
(17) PhSCH2NC is particularly noxious, and 2-PySCH2NC exhibits
similar properties. See: Ranganathan, S.; Singh, W. P. Tetrahedron
Lett. 1988, 29, 1435−1436.
Jorge M. del Campo: 0000-0002-4195-3487
Fraser F. Fleming: 0000-0002-9637-0246
Present Addresses
(18) No sulfanyl−metal exchange was observed with MeLi,
Bu3MgLi, or i-PrMgBr under a variety of experimental conditions.
(19) Monje, P.; Gran
2007, 13, 2277−2289.
̃
a, P.; Paleo, M. R.; Sardina, F. J. Chem. - Eur. J.
†‡E.A.: Merck, 90 E. Scott Ave., Rahway, NJ 07065.
́
́
A.L.-M.: Departmento de Quimica, Centro de Investigacion y
(20) Performing tin−lithium exchange on 4f and trapping with
cyclohexanone afforded oxazoline 3b in 50% yield.
́
de Estudios Avanzados (Cinvestav), Av. Instituto Politecnico
1
́
́
Nacional 2508, Ciudad de Mexico, Mexico 07360.
§B.R.P.: Biophore India Pharmaceuticals, Hyderabad 500033,
India.
(21) H NMR analysis of the crude reaction mixture indicated the
presence of an epoxy−isocyanide that decomposed upon silica gel
chromatography.
∥
́
(22) (a) Kang, H.; Pae, A. N.; Cho, Y. S.; Koh, H. Y.; Chung, B. Y.
Chem. Commun. 1997, 821−822. (b) Cioc, R. C.; Preschel, H. D.; van
der Heijden, G.; Ruijter, E.; Orru, R. V. A. Chem. - Eur. J. 2016, 22,
7837−7842. (c) Cioc, R. C.; Schuckman, P.; Preschel, H. D.; Vlaar,
T.; Ruijter, E.; Orru, R. V. A. Org. Lett. 2016, 18, 3562−3565.
(23) Gessner, V. H. Chem. Commun. 2016, 52, 12011−12023.
(24) The inability to detect rearrangement of the six-membered
isocyanides is speculated to arise from a stereoelectronic stabilization
of the axial isocyanide not present in the conformationally mobile
isocyanides. See: Atabaki, H.; Nori-Shargh, D.; Momen-Heravi, M.;
Niazi, A. Struct. Chem. 2016, 27, 883−896 Further details concerning
the isomerization will be forthcoming.
R.C.-M. and J.M.d.C.: Facultad de Quimica, National
Autonomous University of Mexico, Ciudad de Mexico, Mexico
4510.
́
́
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from Drexel University and initially from the
NIH (2R15AI051352-04) is gratefully acknowledged. J.M.d.C.
thanks the LANCAD-UNAM-DGTIC-270 Project for the use
of computational resources, the DGAPA-UNAM for Grant IN-
114418, and the CONACYT for Grant 282791. Dr. Sergiy
Chepyshev (Temple University) is thanked for developing a
technique for crystallizing Asmic.
(25) Primary isocyanides are not accessible because monosub-
stituted Asmic undergoes deprotonation in preference to anisylsul-
fanyl−lithium exchange.
(26) Fleming, F. F.; Liu, W.; Ghosh, S.; Steward, O. W. Angew.
Chem., Int. Ed. 2007, 46, 7098−7100.
(27) Kapeller, D. C.; Hammerschmidt, F. Chem. - Eur. J. 2009, 15,
5729−5739.
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DOI: 10.1021/acs.orglett.8b02574
Org. Lett. XXXX, XXX, XXX−XXX