Alkenyl Isocyanide Conjugate Additions: A Rapid Route to γ-Carbolines

Article abstract of DOI:10.1002/anie.201612574

Isocyanides are exceptional building blocks, the wide deployment of which in multicomponent and metal-insertion reactions belies their limited availability. The first conjugate addition/alkylation to alkenyl isocyanides is described, which addresses this deficiency. An array of organolithiums, magnesiates, enolates, and metalated nitriles add conjugately to β- and β,β-disubstituted arylsulfonyl alkenyl isocyanides to rapidly assemble diverse isocyanide scaffolds. The intermediate metalated isocyanides are efficiently trapped with electrophiles to generate substituted isocyanides incorporating contiguous tri- and tetra-substituted centers. The substituted isocyanides are ideally functionalized for elaboration into synthetic targets as illustrated by the three-step synthesis of γ-carboline N-methyl ingenine B.

Full text of DOI:10.1002/anie.201612574

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201612574
German Edition: DOI: 10.1002/ange.201612574
Conjugate Addition
Alkenyl Isocyanide Conjugate Additions: A Rapid Route to
g-Carbolines
Sergiy V. Chepyshev, J. Armando Lujan-Montelongo, Allen Chao, and Fraser F. Fleming*
Abstract: Isocyanides are exceptional building blocks, the
wide deployment of which in multicomponent and metal-
insertion reactions belies their limited availability. The first
conjugate addition/alkylation to alkenyl isocyanides is de-
scribed, which addresses this deficiency. An array of organo-
lithiums, magnesiates, enolates, and metalated nitriles add
conjugately to b- and b,b-disubstituted arylsulfonyl alkenyl
isocyanides to rapidly assemble diverse isocyanide scaffolds.
The intermediate metalated isocyanides are efficiently trapped
with electrophiles to generate substituted isocyanides incorpo-
rating contiguous tri- and tetra-substituted centers. The sub-
stituted isocyanides are ideally functionalized for elaboration
into synthetic targets as illustrated by the three-step synthesis of
g-carboline N-methyl ingenine B.
complexation with transition metals, hydrolysis, and oxida-
tion.[1] The tendency of isocyanides to ligate to transition
metals results from strong s-donation of the electron pair on
the carbon atom coupled with removal of electron density
[8]
ꢀ
from the metal into the RN C p* orbitals.
The high reactivity and delicate nature of isocyanides,
combined with their propensity to coordinate to transition
metals, means that there are few methods available for
manipulating the carbon scaffold while retaining the isocya-
nide functionality.[1] Most isocyanides are installed through
a late-stage, three-step sequence: amine deprotection, for-
mylation, and dehydration.[9] Described below is the first
conjugate addition/alkylation of alkenyl isocyanides by
employing main-group organometallics, which effectively
expands the limited repertoire of isocyanide-based bond
constructions.
I
socyanides are unusual carbon-based functional groups in
that they formally contain a carbon atom with a free electron
The viability of using main-group organometallics to
develop a general conjugate addition to unsaturated isocya-
nides was predicated on sporadic additions of Grignards[10]
and sulfur ylides[11] to isocyanoacrylates. Initial attempts to
develop the conjugate addition employed the alkenyl isocy-
anide 3a, derived from TosMIC (2a, Scheme 1).[12] Explor-
atory additions of BuMgCl, Me2CuLi, and Et2BuZnLi[13] to 3a
pair.[1] The carbene-like structure (Figure 1)[2] confers ambi-
Figure 1. Isocyanide representations.
philic reactivity on the isocyanide carbon atom that results in
an exceptionally diverse reactivity for one functional group:
metal insertion,[3] radical additions,[4] nucleophilic additions,[1]
and electrophilic alkylations.[5] The high reactivity toward
disparate reagents is particularly valuable for multicompo-
nent reactions,[5] heterocycle synthesis,[6] and accessing acyclic
nitrogenous scaffolds.[6]
Isocyanide-containing metabolites, mostly from marine
sources,[7] epitomize the challenge of working with isocya-
nides. The reactive carbene-like carbon center confers
biological activity through the same type of bonding that
creates a susceptibility of the R-NC unit toward irreversible
Scheme 1. Synthesis of and addition to sulfonylisocyanide 3a.
afforded complex mixtures of products, thus suggesting that
the process involves more than a simple addition to a vinyl
sulfone.[14] Further screening led to promising additions with
BuLi (24%) and the magnesiate Bu3MgLi[15] (62%,
Scheme 1).
Attempts to expand the conjugate additions to 3a with
additional organometallic reagents led to an effective reac-
tion with lithiated dithiane (Table 1, entry 1) but identified
two limitations: poor tolerance of structural diversity in the
organometallic reagent and a pronounced instability of the
resulting isocyanides toward storage and purification.[16]
These limitations stimulated efforts to tune the electronic
and steric nature of the arylsulfone substituent to maximize
reactivity and stability (Table 1).[17] Electron-deficient aryl-
sulfonyl substituents were anticipated to facilitate the con-
jugate addition, and while the trifluoromethyl-substituted
isocyanide 3b reacted well with Bu3MgLi, the adduct was
particularly unstable (Table 1, entry 2). Incorporating o-CF3
and o-OMe substituents (3c) improved the conjugate addi-
[*] Dr. S. V. Chepyshev, A. Chao, Prof. F. F. Fleming
Department of Chemistry, Drexel University
32 South 32nd St., Philadelphia, PA 19104 (USA)
E-mail: fleming@drexel.edu
Prof. J. A. Lujan-Montelongo
Departmento de Quꢀmica
Centro de Investigaciꢁn y de Estudios Avanzados (Cinvestav)
Av. Instituto Politꢂcnico Nacional 2508
Ciudad de Mꢂxico, 07360 (Mꢂxico)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201612574.
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Table 1: Dependence of conjugate addition efficiency on sulfone struc-
Table 2: Conjugate additions to o-anisylsulfonyl alkenisocyanides 3.
ture.
Entry
1
Sulfonyl isocyanide
Nucleophile
Yield [%] (d.r.)[a]
2
Bu3MgLi
3
4
5
6
PhLi
Bu3MgLi
[a] Use of MeLi afforded a 62% yield (d.r. 1:3.0[22]). [b] The configuration
was unambiguously secured by crystallography.[23] [c] Prepared using
RMgBu2Li. [d] Prepared using NaBH4.
A. Bu3MgLi
B. BuLi
and 8j).[19] The conjugate addition of MeLi to afford 8b,
initially performed between ꢁ100 to ꢁ958C (62% yield), was
found to be cleaner and give higher yield with MeLi·LiBr at
ꢁ788C (72% yield). Selective allyl and benzyl additions[20]
were performed from the mixed organomagnesiates allylMg-
Bu2Li and BnMgBu2Li to afford isocyanides 8k and 8l,
respectively. Lithiated acetonitrile and lithiated cyclohexane-
carbonitrile afforded the nitrile-containing isocyanides 8m–
8o, two of which contain quaternary centers. The lithium
enolate derived from ethyl 2-methylpropionate afforded
ester-isocyanide 8p, with the installation of a quaternary
center. Conjugate reduction with NaBH4 afforded the alky-
lisocyanides 8q to 8s, which provides a valuable route to
branched isocyanides.[21]
The conjugate additions generated metalated isocyanides
that were effectively intercepted by electrophiles (Table 3).
Initial optimization focused on the methylation of the
lithiated isocyanide derived from addition of PhLi to 3e.
Methylation afforded 9a (53%) with incomplete conversion;
addition of HMPA or DMPU (4 equiv) improved the reaction
efficiency to 74% and 79%, respectively (Table 3, entry 1,
HMPA = hexamethylphosphoramide, DMPU = 1,3-dimeth-
[a] The diastereomeric ratios were determined by 1H NMR integration of
diagnostic methine signals. [b] The isocyanide could not be purified for
characterization.
tion with PhLi and lithiated dithiane but the resulting
isocyanides 6a and 6b were prone to decompose during
purification (Table 1, entries 3 and 4).[16] Speculating that the
efficacy of 3c was due to precomplexation between the
organometallic and the o-OMe[18] led to the evaluation of di-
o-methoxyphenylisocyanide 3d and o-anisyl (An) isocyanide
3e. While the addition of Bu3MgLi to 3d afforded a modest
yield of 7a, the o-anisyl isocyanide 3e efficiently reacted with
Bu3MgLi and BuLi to afford stable 8a in 54% and 53% yield,
respectively (Table 1, entry 6).
The generality of the conjugate addition to (o-anisyl)sul-
fonyl alkenyl isocyanides was probed with a variety of
organometallic reagents (Table 2). Diverse organolithiums
with sp3, sp2, and sp hybridization readily added to (o-
anisyl)sulfonyl alkenyl isocyanides 3 (Table 2, 8b–8d, 8e–8i,
2
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Table 3: Conjugate addition/alkylations with alkenyl isocyanide 3e.
isocyanide 11 may retard the alkylation, which DMPU assists
by solvation to a more nucleophilic, and accessible, solvent-
separated ion pair (12 ! 13).
The conjugate addition affords substituted isocyanides
that are ideally functionalized for heterocyclic synthesis.
Rapid access to the indole-containing isocyanides 8h and 9d
prompted cyclization to the g-carboline scaffold,[25] an emerg-
ing pharmacophore.[26] Optimization experiments revealed
that substoichiometric trifluoroacetic acid (TFA) triggered an
efficient cyclization with (1S*, 2R*)-8h or 9d (Scheme 3).[27]
Generation of the nitrilium ion 14 likely triggers cyclization to
imine 15, which eliminates sulfinic acid to afford g-carboline
16.[28] Rapid access to g-carbolines such as 16a[29] is significant
because of their potential as hepatitis C inhibitors.[30]
The versatility of the isocyanide conjugate addition/
cyclization is illustrated in the synthesis of N-methyl ingen-
ine B (20, Scheme 4).[31] In situ silylation/olefination of 2b[12]
with aldehyde 17[32] afforded alkenyl isocyanide 18, which
participated in a smooth conjugate addition with lithiated N-
methylindole to provide 19 (Scheme 4). (1S*, 2R*)-19[33] was
efficiently converted into N-methyl ingenine B (20)[34] upon
exposure to TFA, a process involving cyclization, sulfinic acid
elimination, and debenzylation.
Entry
1
R1Li
R2I
Alkaneisocyanide yield [%] (d.r.)[a]
PhLi
MeI
2
3
PhLi
PrI
MeI
4
MeI
Main-group organometallics react with (o-anisyl)sulfonyl
alkeneisocyanides in the first conjugate addition/alkylation of
alkenyl isocyanides. Diverse organolithiums, magnesiates,
enolates, and metalated nitriles afford metalated isocyanides
[a] The diastereomeric ratios were determined by 1H NMR integration of
diagnostic methine signals in the crude reaction mixture. [b] The
configuration was unambiguously secured by X-ray diffraction.
yl-3,4,5,6-tetrahydro-2-pyrimidinone).
DMPU-promoted
electrophilic capture led to efficient addition/alkylations of
3e with PhLi and PrI (Table 3, entry 2) and addition/
methylations with lithiated benzofuran and lithiated N-
methyl indole (Table 3, entries 3–4). The conjugate addition/
alkylation provides valuable access to sterically encumbered
alkylisocyanides that are challenging to prepare by direct
alkylation of sulfonylmethylisocyanides such as TosMIC
(2a).[24]
Mechanistically, the conjugate addition likely proceeds
through a preassociation of the organometallic species with
the sulfone and anisyl oxygens (Scheme 2).[18] Close proximity
between the nucleophilic organometallic species and the
alkenyl isocyanide would facilitate intramolecular delivery of
the alkyl group to the b-carbon (10) while preventing attack
on the isocyanide. Complexation within the resultant lithiated
Scheme 3. Isocyanide cyclization to g-carbolines.
Scheme 2. Conjugate addition/alkylation mechanism.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
Scheme 4. Synthesis of N-methyl ingenine B (20).
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Acknowledgements
Financial support for this research initially from NIH
(2R15AI051352-04) and later from Drexel University, is
gratefully acknowledged. Crystallographic analyses per-
formed by Patrick J. Carroll and HRMS analysis conducted
by Timothy P. Wade are gratefully acknowledged.
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´
[20] J. G. Sosnicki, Tetrahedron Lett. 2006, 47, 6809.
Conflict of interest
[21] D. van Leusen, A. M. van Leusen, Synthesis 1991, 531.
[22] The diastereomeric ratios were determined by 1H NMR inte-
gration of diagnostic methine signals in the crude reaction
mixture.
The authors declare no conflict of interest.
[23] (1S*, 2S*)-8d was a crystalline solid, the structure of which was
determined by X-ray crystallography. Determination of the
relative stereochemistry for (1S*, 2S*)-8d allowed assignment of
the diagnostic methine signals that provided a signature for the
assignments of the isocyanides 8 in Table 1. P. Radha Krishna,
Y. L. Prapurna, Synlett 2009, 2613.
Keywords: conjugate addition · isocyanides · organometallics ·
g-carbolines · synthetic methods
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Manuscript received: December 27, 2016
Revised: February 7, 2017
Final Article published: && &&, &&&&
4
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Communications
Conjugate Addition
S. V. Chepyshev, J. A. Lujan-Montelongo,
A. Chao, F. F. Fleming*
&&&& — &&&&
Alkenyl Isocyanide Conjugate Additions:
A Rapid Route to g-Carbolines
Conjugate addition of diverse organome-
tallics to sulfonyl-substituted alkenyl iso-
cyanides overcomes the historical chal-
lenge of rapidly assembling complex
isocyanides that retain the isocyanide
functionality. The strategy affords com-
plex isocyanides that are poised for elab-
oration into heterocycles, as illustrated by
the three-step synthesis of N-methyl
ingenine B.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
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