One-Step Transformation of Trichloroacetamide into Isonitrile

Article abstract of DOI:10.1021/acs.orglett.6b03583

A one-step transformation of trichloroacetamide, a protective group for the amine function, into isonitrile was successfully developed. The substrate scope and functional group tolerance of this procedure are also described.

Full text of DOI:10.1021/acs.orglett.6b03583

Letter
pubs.acs.org/OrgLett
One-Step Transformation of Trichloroacetamide into Isonitrile
Masaatsu Adachi,* Tadachika Miyasaka, Honoka Hashimoto, and Toshio Nishikawa*
Laboratory of Organic Chemistry, Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
S
* Supporting Information
ABSTRACT: A one-step transformation of trichloroacetamide, a protective
group for the amine function, into isonitrile was successfully developed. The
substrate scope and functional group tolerance of this procedure are also
described.
sonitrile1,2 is a unique functional group possessing dual
Scheme 1. Discovery of an Unexpected Transformation of
Trichloroacetamide 1 into Isonitrile 3
I
nucleophilic and electrophilic character that has been used as
an important reactant in multicomponent condensations such
as Passerini and Ugi reactions3 for the syntheses of a variety of
functionalized peptides and synthetic intermediates. For some
years now, two classical methods have generally been used to
prepare isonitrile compounds: (i) carbylamine reaction between
a primary amine and dichlorocarbene4 and (ii) dehydration of
N-substituted formamide utilizing a toxic phosgene or
Vilsmeier reagent.5 To date, biomimetic synthesis using Ritter
reactions has also been reported as an alternative strategy for
the preparation of tertiary-type isonitrile compounds.6
Recently, Shenvi and co-workers reported a chemoselective
and stereoselective synthesis of tertiary alkyl isonitrile facilitated
by a Lewis acid catalyzed solvolysis of the tertiary alcohol
derivative through attack of the contact ion pair.7
In the course of our synthetic studies on tetrodotoxin and its
analogues,8a we have developed several unique and useful
reactions involving the trichloroacetamide (N-trichloroacetyl
group),8b such as site-selective hydroxylation using neighbor-
ing-group participation,9 guanidine synthesis,10 a one-pot
transformation into carbamates,11 and mild chemoselective
deprotection to amines.12 These established methods asso-
ciated with trichloroacetamide have played important roles in
the syntheses of tetrodotoxins, a densely functionalized class of
natural products.9a−d,13−18 Recently, we incidentally encoun-
tered a new reaction that allowed us to transform
trichloroacetamide into isonitrile when we attempted the
synthesis of allylic alcohol 2 from epoxytrichloroacetamide
119 by use of the neighboring trichloroacetamide. The
epoxytrichloroacetamide 1 was treated with an excess amount
of LDA in THF to give an unexpected isonitrile 3 as a sole
product (Scheme 1). Since this transformation of trichlor-
oacetamide has never been reported before, we embarked on a
detailed investigation of the reaction conditions, substrate
scope, and functional group tolerance of the new procedure.
We first examined several conventional bases utilizing a
tertiary-type allylic trichloroacetamide 4 as a substrate, which
was prepared from the Overman rearrangement of farnesol in
two steps.20 When 4 was treated with LDA at −78 °C, followed
by gradually increasing the reaction temperature to 0 °C, the
isonitrile 5 was obtained in moderate yield (Table 1, entry 1).
Treatment of the trichloroacetamide 4 with LHMDS did not
give the expected isonitrile 5, but rather the starting material 4
was recovered quantitatively, even when an excess amount of
the base was employed (entry 2). Extensive experimentation
led us to find that 3.5 equiv of n-BuLi in THF at −78 °C were
the optimal conditions for this transformation, giving the
desired isonitrile 5 in 82% yield as a single product (entry 3).
Reaction with 1.0 equiv of n-BuLi in THF at −78 °C gave
dichloroacetamide 6 as a major side product along with the
isonitrile 5, and a significant amount of starting material was
recovered (entry 4). This result indicates that a carbanion of
dichloroacetamide 6 would be generated as one of the initial
intermediates from trichloroacetamide 4. Thus, the isolated
dichloroacetamide 6 was subjected to the optimized conditions
to give the desired isonitrile 5 in 85% yield as a sole product,
whereas no intermediates were observed by TLC monitoring.
We therefore established the efficient conditions for the
transformation of trichloroacetamide into isonitrile.
We next examined the scope and limitations of the newly
developed conditions for various substrates including tertiary-,
secondary-, and primary-type trichloroacetamide. The results
Received: December 1, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03583
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Letter
Table 1. Optimization for Transformation of
Trichloroacetamide 4 into Isonitrile 5
Table 2. Transformation into Isonitriles under the
Optimized Conditions
a
yield (%)
b
entry
base
LDA
base (equiv) temp (°C)
5
6
4
1
2
3
4
10
10
−78 to 0
−78 to rt
−78
58
0
0
0
0
LHMDS
quant
0
n-BuLi
3.5
1.0
82
13
0
n-BuLi
−78
21
49
a
b
Isolated yield. Recovery of the starting material.
are summarized in Table 2. The transformation of tertiary-type
allylic trichloroacetamides 721 and 822 proceeded smoothly
under the optimized conditions to give the allylic isonitriles 16
and 17 in 85% and 61% yield, respectively (entries 1 and 2).
The sterically hindered tertiary-type alkyl trichloroacetamides,
such as 923 and 10,24 could also be transformed into the
corresponding isonitriles 18 and 19 in good yields (entries 3
and 4). Unfortunately, the same conditions were not applicable
for secondary- and primary-type allylic trichloroacetamides;
exposure of the secondary-type allylic trichloroacetamides
(11,20 1220) and the primary-type allylic trichloroacetamide
1424 to the optimized conditions did not give the
corresponding desired isonitriles but rather complex mixtures
of products (entries 5, 6, and 8). On the other hand, the
reaction of secondary- and primary-type alkyl trichloroaceta-
mides 1324 and 1525 under the same conditions provided the
isonitriles 22 and 24 in 49% and 52% yields, respectively
(entries 7 and 9).26 Although the reason for the failure of this
transformation for secondary- and primary-type allylic trichlor-
oacetamides was not clarified, the markedly contrasting results
might be attributable to the removal of acidic protons from the
allylic methylene and methine moieties adjacent to the
trichloroacetamides or to the instability of the generated allylic
isonitriles under the basic conditions.
The successful transformation of trichloroacetamides de-
scribed above indicated that acetonide and alkene (vinyl and
trisubstituted alkene) were compatible with the conditions
employed. Further functional group tolerance and utility of this
transformation were investigated using various other function-
alized substrates as shown in Table 3. The tertiary-type allylic
trichloroacetamides 119 and 259d bearing an epoxide were
transformed into epoxy isonitriles 28 and 29 in 75% and 74%
yield, respectively. The conventional protective groups such as
benzyl ether (25) and TBS and TBDPS silyl ethers (26,27 2715)
were also tolerated, giving the corresponding isonitriles in good
yields without any problems.
One of the possible reaction mechanisms for the formation
of isonitrile is proposed in Scheme 2.28 At first, the halogen−
lithium exchange reaction of trichloroacetamide A with n-BuLi
proceeds to give a carbanion intermediate B, which undergoes
an intramolecular proton abstraction from the amide group.
Then, the resulting enolate C is cyclized to an imino oxirane
a
Isolated yield.
D,29 which finally yields the observed isonitrile E by
fragmentation.5,29d,30 Another possibility that the isonitrile E
would be obtained via an imidoyl chloride adduct G is not
excluded; the imino oxirane D would give the zwitterionic
intermediate F by epoxide opening. Then, elimination of the
chloride moiety followed by attack of the resulting chloride ion
to a nitrilium intermediate affords the imidoyl chloride G.
Finally, nucleophilic addition of the remaining n-BuLi and α-
B
DOI: 10.1021/acs.orglett.6b03583
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
elimination would provide the isonitrile E. The other reaction
pathway of the direct proton abstraction from trichloroaceta-
mide A may also proceed to give the equilibrium intermediate
C′, which is transformed into the isonitrile E via an
intermediate D′ in a similar manner.
Table 3. Compatibility with Several Functional Groups
In summary, we have developed a novel one-step trans-
formation of trichloroacetamide into an isonitrile under mild
conditions by utilizing n-BuLi. Unfortunately, as the conditions
were not applicable for secondary- and primary-type allylic
trichloroacetamides, tertiary-type trichloroacetamides and sec-
ondary-/primary-type alkyl trichloroacetamides could be
successfully converted into isonitriles. We also demonstrated
that the conditions were generally applicable to substrates
containing a wide range of functional groups, such as alkene,
epoxide, acetonide, TBS, TBDPS, and Bn. The present studies
should increase the utility of trichloroacetamides and provide a
new entry for the syntheses of isonitrile-containing natural
products.
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.6b03583.
1
Experimental procedures, characterization data, and H
and 13C NMR spectra for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: madachi@agr.nagoya-u.ac.jp.
*E-mail: nisikawa@agr.nagoya-u.ac.jp.
ORCID
Masaatsu Adachi: 0000-0001-7615-3861
Notes
The authors declare no competing financial interest.
a
b
c
Isolated yield. 4.0 equiv of n-BuLi was used. 6.0 equiv of n-BuLi was
ACKNOWLEDGMENTS
d
■
used. 4.5 equiv of n-BuLi was used.
We are grateful to Mr. S. Kitamura and Mr. M. Honda
(analytical laboratory, Nagoya University) for help with
elemental analyses and mass spectrometry measurements.
This work was financially supported by a Grant-in-Aid on
Innovative Areas ‘‘Chemical Biology of Natural Products’’31
from MEXT and the Daiichi Sankyo Foundation.
Scheme 2. Proposed Mechanism for the Formation of
Isonitrile from Trichloroacetamide
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