Synthesis of Vinyl Isocyanides and Development of a Convertible Isonitrile

Article abstract of DOI:10.1021/acs.orglett.6b00483

The reaction of isocyanomethylenetriphenylphosphorane, generated in situ from the corresponding phosphonium salt, with a diverse set of aldehydes afforded vinyl isocyanides in good to high yields. Excellent E-selectivity was observed for aliphatic aldehydes and 2,6-disubstituted aromatic aldehydes, whereas Z-olefins were formed predominantly with ortho-substituted aryl aldehydes. (Z)-1-Bromo-2-(2-isocyanovinyl)benzene (5l) was found to be a truly universal isonitrile since, after Ugi reaction, the resulting secondary amide unit (RNHCO-) is convertible under both acidic and basic conditions. The application of 5l in the synthesis of polyheterocycles is also illustrated.

Full text of DOI:10.1021/acs.orglett.6b00483

Letter
pubs.acs.org/OrgLett
Synthesis of Vinyl Isocyanides and Development of a Convertible
Isonitrile
Martina Spallarossa,†,# Qian Wang,† Renata Riva,# and Jieping Zhu*,†
†Laboratory of Synthesis and Natural Products, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fed
́ ́
erale de
Lausanne, EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne, Switzerland
#Department of Chemistry and Industrial Chemistry, University of Genova, Via Dodecaneso 31, 16146 Genova, Italy
S
* Supporting Information
ABSTRACT: The reaction of isocyanomethylenetriphenyl-
phosphorane, generated in situ from the corresponding
phosphonium salt, with a diverse set of aldehydes afforded
vinyl isocyanides in good to high yields. Excellent E-selectivity
was observed for aliphatic aldehydes and 2,6-disubstituted
aromatic aldehydes, whereas Z-olefins were formed predominantly with ortho-substituted aryl aldehydes. (Z)-1-Bromo-2-(2-
isocyanovinyl)benzene (5l) was found to be a truly universal isonitrile since, after Ugi reaction, the resulting secondary amide
unit (RNHCO−) is convertible under both acidic and basic conditions. The application of 5l in the synthesis of polyheterocycles
is also illustrated.
socyanomethylenetriphenylphosphorane, synthesized in
1985 by Fehlhammer,1 has remained a laboratory curiosity.
Indeed, coordination to transition metal and subsequent [3 +
2] cycloaddition with carbon disulfide is the only reported
transformation known to date.2 This is in sharp contrast to
truly universal isonitrile since the resulting secondary amide
after Ugi reaction is convertible under both acidic and basic
conditions.
I
Vinyl isocyanides such as xanthocilins (6a, 6b)6 and B371
(7)7 exist in nature and display potent antimicrobial activities.
Three main strategies have been developed, viz. (a)
dehydration of N-vinylformamides,8 (b) isomerization of allyl
isocyanides,9 and (c) condensation of α-functionalized
isonitriles 2 or 3 with carbonyl compounds.10,11 Notwithstand-
ing its straightforwardness, the last method is not without
problems due to the competitive formation of oxazolines and
N-vinylformamides.10,11 Therefore, the development of an
efficient synthesis of vinyl isocyanides is still highly demanding,
especially in light of recent developments on the elaboration of
this family of building blocks to complex heterocycles.12
Isocyanomethyltriphenylphosphonium chloride (1) was
synthesized on multigram scale by reaction of trimethylsilyl-
methyl isocyanide13 with PPh3 and C2Cl6 in THF at room
temperature following Fehlhammer’s procedure. We noted that
highly pure reagent 1 was obtained in 70% yield by simple
filtration and washing with THF when this operation was
carried out in a glovebox. In view of the aforementioned
importance of vinyl isocyanides, the Wittig reaction of 1 was
investigated using benzaldehyde (8a) as a test substrate.
Sodium amide, used by Fehlhammer for the generation of
phosphorane from 1, was found to be inefficient for the desired
Wittig reaction (entry 1, Table 1). Therefore, a systematic
survey of reaction conditions varying the base, the solvent, and
the temperature was carried out,14 and the most relevant results
are summarized in Table 1. Key observations are noted below:
(a) there was a significant counterion effect, with KHMDS
other α-functionalized isonitriles such as Schollkopf’s diethyl
̈
isocyanomethylphophonate (2), isocyanoacetate 3a (X = OR),
isocyanoacetamide 3b (X = NR2),3 and Van Leusen’s TosMic
4,4 whose chemistry has been extensively exploited (Figure 1).
Figure 1. α-Functionalized isonitriles, vinyl isocyanides, and
convertible isonitriles.
As a continuation of our research program dealing with α-
functionalized isonitriles,5 we became interested in the
chemistry of Fehlhammer’s phosphonium salt 1, hypothesizing
that selective manipulation of the functionalities in 1 should
provide us with rich synthetic opportunities. As a prelude, we
report herein that 1 is an excellent reagent undergoing the
Wittig reaction with a diverse set of aldehydes to afford vinyl
isocyanides 5 in good to high yields. We also document that 5
is a new class of convertible isonitriles, and in particular, 5l is a
Received: February 19, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00483
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Letter
Table 1. Wittig Reaction of 1: Survey of Reaction Conditions
Scheme 1. Synthesis of Vinyl Isocyanides
b
c
entry
base
t1 (°C) t2 (°C) time (h)
E/Z
yield (%)
1
2
3
4
5
6
7
NaNH2
0
−78
−78
−78
−78
−78
−78
rt
rt
72
1
0
trace
10
20
50
8
LiHMDS
LiHMDS
NaHMDS
NaHMDS
KHMDS
KHMDS
54/46
54/46
70/30
70/30
70/30
70/30
−20
−20
−20
−20
−20
1
1
d
1
0.3
0.3
57
e
70
a
Reaction conditions: 1 (0.12 mmol), THF (1.0 mL), base (0.12
mmol), at t1 (°C) for 30 min, then add 8a (0.10 mmol) and raise the
b
c
temperature to t2 (°C). Determined by NMR. Isolated yield after
d
flash column chromatographic (FCC) purification on silica gel. With
2.0 equiv of base. Purification by FCC on Al2O3 (activity IV). The E/
e
Z isomers were inseparable using Al2O3 as support.
providing the highest yield of vinyl isocyanide 5a (entries 6, 7);
(b) an excess amount of base reduced the yield of 5a (entry 5
vs 4); and (c) flash column chromatographic (FCC)
purification was better performed on Al2O3 support (activity
IV) since partial decomposition of 5a was observed during
purification on silica gel (entry 7 vs 6).15 Overall, the optimum
conditions consisted of treatment of 1 with KHMDS at −78 °C
for 30 min followed by adding 8a and stirring the reaction
mixture at −20 °C for 20 min. FCC purification on Al2O3
support afforded 5a in 70% yield.
a
1
The ratio was determined by the H NMR spectrum of the crude
With the optimum conditions in hand, the scope of this
Wittig reaction was next examined. As shown in Scheme 1,
both aromatic and aliphatic aldehydes underwent Wittig
reaction with phosphonium salt 1 to provide the corresponding
vinyl isocyanides 5 in good to high yields. 4-Substituted
benzaldehydes, regardless of the electronic nature of the
substituents (NO2, OMe, 5b, 5c) and heterocycles including 2-
and 3-formylfuran, 3-formylthiophene, 2-formylpyrrole, 3-
formylindole (5d−i), and α,β-unsaturated aldehyde 5j, all
participated in the olefination reaction to afford the
corresponding vinyl isocyanides with low to moderate E/Z
selectivity. Interestingly, reaction of 2-substituted benzalde-
hydes with 1 afforded Z-vinyl isocyanides in high yields with
excellent Z-selectivity (Z/E ≥ 94/6, 5l-5q). However, 2-
methylbenzaldehyde was an exception as compound 5k was
formed as a mixture of two isomers (E/Z = 65/35). Reaction of
4-bromo-3-formylindole also afforded Z-vinyl isocyanide with a
reasonable Z selectivity (5r, E/Z = 14/86). On the other hand,
a highly E-selective olefination occurred with 2,6-disubstituted
benzaldehydes to afford E-vinyl isocyanides in good yields (E/Z
≥ 98/2, 5s−u). Aliphatic aldehydes participated in the reaction
with 1 to give E-vinyl isocyanides with excellent selectivity
(5v−x), albeit with slightly diminished yields. The above
observed substrate-dependent Z- and E-selectivity is in line with
that of benzylidene(triphenyl)phosphorane,16 and therefore, we
can consider isocyanomethylenetriphenylphosphorane as a
semistabilized ylide.
product. In some cases, the ratio changed after FCC purification.
After purification, the ratio became 75/25.
b
two different ways. The Horner−Wadsworth−Emmons re-
action [R = (EtO)2PO] or Knoevenagel condensation (R =
COOR, or CONR1R2) pathway would provide vinyl isocyanide
5 (pathway a, Scheme 2), while intramolecular addition of the
Scheme 2. Reaction Manifold Involving the Condensation of
α-Functionalized Isonitriles and Aldehydes
alkoxide to the pendant isocyano group would lead to 10
which, upon proton transfer and electrocyclic ring reversion,
would afford enamide 12 (pathway b). However, the situation
would be completely different with Fehlhammer’s reagent 1
since it is now firmly established that oxaphosphetane 14 is
formed directly from phosphorane 13 and aldehydes without
the intermediacy of betaine 9 (FG = Ph3P+).17 Therefore,
pathway b would be impossible, and vinyl isocyanides 5 would
be formed following pathway c (Scheme 2).
The high synthetic efficiency and great application scope
encountered in the reaction of 1 with aldehydes distinguished it
from other α-functionalized isocyanides (2−4). Mechanisti-
cally, the condensation of the Schollkopf’s reagent (2), α-
̈
isocyanoacetate (3a), and α-isocyanoacetamide (3b) with
aldehydes under basic conditions would be initiated by the
aldol reaction to afford the alkoxide 9, which could evolve in
B
DOI: 10.1021/acs.orglett.6b00483
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In most of the isocyanide-based multicomponent reactions
including the powerful Ugi-4CR,5 Passerini-3CR,18 and Ugi−
Smiles reaction,19 the isonitrile (RNC) is converted to a
secondary amide (RNHCO−). While the formation of
secondary amide is of self-importance, its selective manipu-
lation was nevertheless difficult due to its relatively high
chemical stability. To overcome this shortcoming, a term of
convertible isonitrile was advanced to define a specific family of
isonitriles (RNC) in which the R residue is designed in such a
way that the corresponding secondary amides (RNHCO−) are
susceptible to selective functionalization under mild con-
ditions.20 Among them, the 1-isocyanocyclohex-1-ene, first
reported by Ugi,21 has been extensively exploited by Armstrong
to conceptualize the idea of convertible isonitrile.22 One
drawback associated with this isonitrile is that it is unstable and
cleavable only under strong acidic conditions, and therefore, it
cannot be applied to adducts having acid-sensitive functions.
Other isonitriles, convertible under acidic or basic conditions,
have therefore been developed.23−30 While all vinyl isocyanides
enlisted in Scheme 1 are potentially convertible isonitriles, we
were particularly interested in the vinyl isocyanide 5l as it is
stable and nonvolatile and has no disagreeable odor. In
addition, we thought that it should in principle be convertible
under both acidic and basic conditions. This assumption was
verified as shown in Scheme 3. The Ugi four-component
Therefore, 5l is a truly universal isonitrile as its amide
equivalent is convertible under both acidic and basic conditions.
To further demonstrate the synthetic utility of vinyl
isocyanide 5l, an efficient two-step synthesis of indolo[2,1-
a]isoquinolinone 23 was developed by an Ugi-post function-
alization sequence.33 Ugi reaction of benzylamine (15), 2-
bromobenzaldehyde (24), propionic acid (17), and 5l in
methanol afforded the four-component adduct 25 in 70% yield
(Scheme 4). Pd-catalyzed double cyclization of 25 [Pd(PPh3)4
Scheme 4. Further Synthetic Application of Vinyl Isocyanide
5l
(0.1 equiv), KOAc (2.5 equiv), DMF, 105 °C, 16 h] afforded
indole 23 in 82% yield via a sequence of intramolecular N-
arylation followed by a regioselective C−H functionalization.34
In conclusion, we have developed a novel and efficient
synthesis of vinyl isocyanides by the Wittig reaction of
isocyanomethylenetriphenylphosphorane with aldehydes. (Z)-
1-Bromo-2-(2-isocyanovinyl)benzene (5l) has been identified
as a truly universal isonitrile whose amide equivalent is
convertible under both acidic and basic conditions. The utility
of 5l in the synthesis of polyheterocycles such as indolo[2,1-
a]isoquinolinone has also been demonstrated.
Scheme 3. Vinyl Isocyanide 5l Is a Convertible Isonitrile
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00483.
Experimental procedures, product characterization data,
1H and 13C NMR spectra for new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
reaction of benzylamine (15), 3-phenylpropanal (16),
propionic acid (17), and 5l in methanol afforded the adduct
18 in 79% yield (Scheme 3). No double-bond isomerization
occurred in this process. Treatment of a solution of 18 in
ethanethiol or in methanol with acyl chloride afforded thioester
19 (eq 1) and methyl ester 20 (eq 2) in yields of 80% and 90%,
respectively. If one targeted the synthesis of 20, then isolation
of 18 would not be necessary. After completion of the Ugi
reaction, simply adding AcCl and heating the reaction mixture
to 55 °C provided 20 directly in 72% yield. On the other hand,
intramolecular Buchwald−Hartwig N-arylation of 1831
[Pd2(dba)3, t-Bu3P, Cy2NMe, toluene, 100 °C, 16 h] afforded
N-acylindole 21 in 85% yield. This transformation effectively
converted the acid-cleavable enamide function to a base
cleavable N-acylindole unit.32 Indeed, treatment of 21 with
NaOMe or LiOH afforded methyl ester 20 (eq 2) or carboxylic
acid 22 (eq 3) in yields of 82% and 85%, respectively.
*E-mail: jieping.zhu@epfl.ch.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank EPFL (Switzerland) and the Swiss National Science
Foundation (SNSF) for financial support. M.S. is an exchange
Ph.D. student from the University of Genova.
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