Three-component coupling approach for the synthesis of diverse heterocycles utilizing reactive nitrilium trapping

Article abstract of DOI:10.1021/ol500328t

The formation of an unexpected heterocyclic scaffold, a benzoxazole, in a three-component reaction between a ketone, isocyanide, and 2-aminophenol was encountered. This reaction involved a benzo[b][1,4]oxazine intermediate resulting from intramolecular attack of the aminophenol hydroxyl group on the nitrilium ion. Unlike previous literature examples, the trapped nitrilium benzo[b][1,4]oxazine could readily be subjected to ring opening with bis-nucleophiles. The reaction scope includes simple linear as well as complex cyclic ketones and substituted 2-aminophenols. A representative benzoxazole product could be further diversified to yield drug-like compounds.

Full text of DOI:10.1021/ol500328t

Letter
pubs.acs.org/OrgLett
Three-Component Coupling Approach for the Synthesis of Diverse
Heterocycles Utilizing Reactive Nitrilium Trapping
Andras Varadi,†,‡ Travis C. Palmer,†,‡ Paula R. Notis,†,‡ Gabriel N. Redel-Traub,†,‡ Daniel Afonin,†,‡
́
́
Joan J. Subrath,†,‡ Gavril W. Pasternak,†,‡ Chunhua Hu,§ Indrajeet Sharma,‡ and Susruta Majumdar*,†,‡
†Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States
‡Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, United
States
§Department of Chemistry, New York University, 100 Washington Square East, New York, New York 10003, United States
S
* Supporting Information
ABSTRACT: The formation of an unexpected heterocyclic scaffold, a
benzoxazole, in a three-component reaction between a ketone, isocyanide,
and 2-aminophenol was encountered. This reaction involved a benzo[b]-
[1,4]oxazine intermediate resulting from intramolecular attack of the
aminophenol hydroxyl group on the nitrilium ion. Unlike previous literature
examples, the trapped nitrilium benzo[b][1,4]oxazine could readily be
subjected to ring opening with bis-nucleophiles. The reaction scope includes
simple linear as well as complex cyclic ketones and substituted 2-
aminophenols. A representative benzoxazole product could be further
diversified to yield drug-like compounds.
ulticomponent reactions (MCRs) involve the simulta-
neous reaction of more than two starting materials to
Scheme 1. Synthesis of Heterocyclic Scaffolds Using Our
Three-Component Reaction
M
form a single product.1 The extreme variety of products that
can be achieved through the reaction of readily available
reagents as well as their one-pot nature and high atom
efficiency make MCRs suitable for the synthesis of highly
diverse drug-like libraries.2 Isocyanide-based reactions form the
backbone of today’s MCR armada, among which the most
widely applied examples commonly employ amines, aldehydes
or ketones, isocyanides, carboxylic acids, and phenols.3
Heterocycles play a critical role in the design and synthesis of
bioactive small molecules: the vast majority of marketed drugs
contain at least one heterocyclic ring. Numerous nitrogen-
containing heterocycles including dihydrothiazoles, benzoxa-
zoles, benzothiazoles, and benzimidazoles possess biological
activity.4 The synthesis of heterocycles is traditionally
accomplished through multistep routes and/or harsh reaction
conditions, particularly of benzoxazoles,5 and while MCR
approaches can also be taken,6 there is a need for a more
resource-efficient, preferably one-pot method for their syn-
thesis.7 Metal catalyzed insertions of isocyanides leading to
heterocycles are known and usually utilize harsh conditions and
have somewhat limited scope in terms of diversity.8
Herein we report a novel MCR between a ketone, 2-
aminophenol, and isocyanide that leads to the synthesis of
benzoxazoles and other heterocycles (Scheme 1). The
postulated reaction route proceeds via a benzo[b][1,4]oxazine
(benzoxazine intermediate). The formation of benzoxazine
occurs by intramolecular trapping of the reactive nitrilium ion
by the adjacent phenolic hydroxyl of 2-aminophenol. While
trapping of nitrilium species by heteroatoms is a known
process,9 the novelty of our approach is the reactive nature of
the trapped intermediate. Owing to its reactivity, the oxazine
ring of the trapped nitrilium intermediate can be opened up by
a second molecule of aminophenol or other bis-nucleophiles
leading to the elimination of an isocyanide-derived amine,
finally yielding benzoxazoles or other heterocyclic scaffolds.
The reaction generates two additional points of diversity that
were utilized to synthesize various bis-heterocyclic scaffolds.
While performing a Ugi four-component reaction in 2,2,2-
trifluoroethanol (TFE) with 1 equiv of 2-aminophenol, 1 equiv
of N-methyl-4-piperidone, 1 equiv of 4-methoxyphenyl
isocyanide, and 1 equiv of acetic acid at 55 °C, an unusual
heterocyclic (benzo[d]oxazol-2-yl)-1-methylpiperidine (ben-
zoxazole) product 1 in 50% yield with only trace amounts of
Received: January 30, 2014
© XXXX American Chemical Society
A
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Letter
the expected Ugi four-component reaction product was
observed.
Scheme 2. Scope of Heterocycle-Forming MCR with Various
Ketones and Substituted 2-Aminophenols
Because the carboxylic acid substrate was not incorporated
into the product, the reaction was carried out without the
addition of any carboxylic acid. Benzoxazole 1 was obtained
again, suggesting that the product formation proceeded via a
three-component MCR between 2-aminophenol, isocyanide,
and ketone. The formation of benzoxazole 1 was then
optimized (Table 1). By using 3 equiv of 2-aminophenol, the
Table 1. Yield of Benzoxazole 1 under Different Reaction
Conditions
entry
catalyst (equiv)
solvent
yield [%]
1
2
3
4
5
6
7
none
MeOH
TFE
0
84
none
Sc(III)OTf (0.1)
Zn(II)OTf (0.1)
HOTf (0.1)
HOTf (0.1)
HOTf (0.1)
TFE
58
TFE
62
TFE
100
82
MeOH
toluene
24
Table 2. Yield of Heterocycle-Forming MCR with Different
Isocyanides
yield of the isolated product increased to 84% (entry 2).
Performing the reaction at room temperature afforded lower
yields (42%). Similarly, heating the mixture to 80 °C gave no
improvement in yield. The role of solvent in product formation
was investigated next, and to our surprise the reaction failed in
all solvents (including methanol, the solvent of choice for
traditional MCRs) except TFE, suggesting the slight acidity of
the solvent (pKa = 12.37) played a crucial role in the reaction.
Because MCRs have been shown to be catalyzed by acids,10 the
reaction was investigated using an array of Lewis and Brønsted
acids. Transition metal triflates gave no advantage in yields.
However, using 0.1 equiv of trifluoromethanesulphonic acid
(HOTf) afforded quantitative yields of benzoxazole 1 (entry 5).
The HOTf-catalyzed reaction also afforded a high yield (82%)
in methanol (entry 6), a solvent in which benzoxazole
formation had previously failed. The acid catalyzed reaction
in toluene yielded 24% (entry 7) product suggesting that,
besides acid catalysis, a polar solvent is preferred for this
reaction to proceed to completion.
With the optimized conditions in hand the scope of this
reaction was investigated by using different ketones and
substituted 2-aminophenols (Scheme 2). The desired benzox-
azole products (2−8, 9a−d) were obtained in good yields in
most cases. The reaction was effective for a variety of ketones
including the complex, multifunctional semisynthetic natural
product-like naloxone (7), a clinically used opioid antagonist,
highlighting the good functional group tolerance of this
reaction. The scope of this heterocycle-forming MCR was
investigated using various isocyanides (Table 2).
entry
R1
yield [%]
1
2
3
4
5
6
7
cyclohexyl
4-OMe-Ph
4-F-Ph
70
100
28
59
90
61
0
naphth-2-yl
tBu
1-adamantyl
2,6-diMe-Ph
aryl or alkyl amine moiety acts as the leaving group, leading to
an insertion of only the isocyanide carbon into the benzoxazole
moiety.
We were surprised to find that 2,6-dimethylphenyl
isocyanide, instead of benzoxazole 1, yielded a spiro[benzo[b]-
[1,4]oxazine]imine (benzoxazine) scaffold 10 in good yield
(Table 3). The synthesis, isolation, and structure elucidation of
this derivative provided us the first clues about the mechanism
of this reaction (Figure 1).
When another, albeit sterically somewhat less hindered
isocyanide, 2-chloro-6-methyl isocyanide, was used, 11 was
isolated, which possessed the same benzoxazine scaffold as 10.
The reaction, however, also afforded benzoxazole 1. Fur-
thermore, the yield for 11 was significantly lower than that of
10, highlighting the importance of steric hindrance in stabilizing
the benzoxazine structure. Benzoxazines (12 and 13) were
isolated even when sterically nonhindered isocyanides were
While 4-methoxyphenyl isocyanide provided the best yield
(entry 2), nearly all other isocyanides were also effective in the
reaction, except 2,6-dimethylphenyl isocyanide (entry 7). It
should be pointed out that the isocyanide contributes only one
carbon atom toward benzoxazole 1; therefore the reaction
outcome is independent of the nature of isocyanide used. The
B
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Letter
solvent TFE) thereby facilitating an attack by the isocyanide
yielding the highly reactive nitrilium B. The phenolic OH of 2-
aminophenol then participates in an intramolecular nucleo-
philic attack on the reactive nitrilium carbon, thus trapping the
nitrilium to give the benzoxazine intermediate C.
Table 3. Isolation of Trapped Nitrilium Intermediates,
Benzoxazines 10−13
While C could be isolated (10−13), we found that it is very
susceptible to nucleophilic attack by a second molecule of the
bis-nucleophile 2-aminophenol. There is literature precedence
for the intramolecular trapping of the nitrilium ion.9 It must be
noted that products formed in most cases are stable and easily
isolable, while benzoxazines (11−13) in the present case are
extremely reactive to nucleophiles. The unique, reactive nature
of this intramolecular nitrilium trapping allowed us to utilize
benzoxazine intermediates to synthesize substituted benzox-
azoles and other heterocyclic systems as shown later.
Ar
product
yield (%)
79
2,6-diMe-Ph
2-Me-6-Cl-Ph
4-OMe-Ph
10
a
11 + 1
12 + 1
13 + 1
37 (4)
a
39 (24)
a
naphth-2-yl
33 (12)
a
Yield of 1.
To test our proposed mechanism that the benzoxazine C is
an intermediate in the synthesis of benzoxazoles, intermediate
12 was reacted with 2 equiv of 2-aminophenol in the presence
of 0.1 equiv of HOTf in TFE, mimicking our one-pot reaction;
benzoxazole 1 could be isolated in good yields (Table 4).
Table 4. Conversion of Benzoxazine Intermediate 12 to
Diverse Heterocycles with Bis-Nucleophiles
Figure 1. Molecular structure of benzoxazine intermediate 10.
Another conformer with a slightly different conformation was
identified in the crystal structure (shown in the Supporting
Information).
bis-nucleophile
2-aminophenol
product
yield (%)
1
87
63
98
93
44
2-amino-4-chlorophenol
1,2-diaminobenzene
2-aminothiophenol
cysteamine
14
15
16
17
involved, in lower yields. A mixture of benzoxazole 1 and the
appropriate benzoxazine was observed in these cases.
We hypothesized that benzoxazine 12 was an intermediate in
the reaction route leading to benzoxazole 1. The following
reaction mechanism for the formation of benzoxazoles was
envisioned (Scheme 3): the ketone first forms a Schiff base
(imine, A) with 2-aminophenol, which in turn is activated by
the acidity of the system (the acid catalyst HOTf and/or the
4-Chloro-2-aminophenol was also reacted with 12. Thus, a
benzoxazole with a chloro substituent (14) was isolated
increasing the diversity of this reaction. The scope was further
enhanced by reacting the isolated benzoxazine intermediate
with a series of bis-nucleophiles including 1,2-diaminobenzene,
2-aminothiophenol, and cysteamine to synthesize benzimida-
zole, benzothiazole, and dihydrothiazole derivatives (15−17),
respectively. Owing to the hindered sterics of the system,
benzoxazine 10 derived from sterically hindered 2,6-dimethyl-
phenyl isocyanide was significantly more resistant to
nucleophilic attack by bis-nucleophiles. Reactions at 55 °C
failed in most cases, and only low conversion to the
corresponding heterocycles was seen even at 85 °C.
Scheme 3. Proposed Mechanism for the Formation of
Benzoxazole 1
To enhance the diversity and thus the possible biological
relevance of the benzoxazole scaffold we decided to exploit the
free phenolic OH and secondary aromatic amine of 1 to make
second generation derivatives (Figure 2). The NH and the OH
were cyclized using carbonyldiimadazole to make the bis-
heterocyclic 18 carrying a benzoxazolone ring.11 The phenolic
OH was also alkylated (22), carbamoylated (24), acylated (25),
and converted to triflate. The triflate was in turn taken into
Suzuki coupling12 with 2-bromophenylboronic acid, followed
by Buchwald−Hartwig amination13 to generate a carbazole
scaffold 21.14 The versatile leaving group triflate could be
converted to a nitrile15 (23) which opens up routes to
C
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Letter
authors would like to thank Rashad Karimov at MSKCC,
Molecular Pharmacology and Chemistry Program for his
suggestions and critically reading this manuscript. The authors
wish to thank George Sukenick and Rong Wang of the NMR
Analytical Core Facility at MSKCC for their assistance with
NMR and MS instruments and experiments. We thank the
NYU Molecular Design Institute for the purchase of the Bruker
SMART APEXII Diffractometer.
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ASSOCIATED CONTENT
* Supporting Information
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: majumdas@mskcc.org.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by research grants from the National
Institute of Drug Abuse to S.M. (DA034106-01) and G.W.P.
(DA06241, DA02165, and DA07242) and a core grant from
the National Cancer Institute to MSKCC (CA08748). The
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