OPHA (oxidation-passerini-hydrolysis-alkylation) strategy: A four-step, one-pot improvement of the alkylative passerini reaction

Article abstract of DOI:10.1021/ol500813p

Multicomponent reactions are often recognized for their efficiency and convergency, if compared with multistep organic synthesis. Nevertheless, we here demonstrate that a four-step-one-pot approach (named OPHA strategy for the initials of the four steps involved) is not only able to afford compounds that could not be obtained by an alkylative Passerini reaction but also capable of generating them with minimal loss of atoms and high operational simplicity, as in a typical multicomponent approach.

Full text of DOI:10.1021/ol500813p

Letter
pubs.acs.org/OrgLett
OPHA (Oxidation−Passerini−Hydrolysis−Alkylation) Strategy: a Four-
Step, One-Pot Improvement of the Alkylative Passerini Reaction
Fabio De Moliner, Martina Bigatti, Luca Banfi, Renata Riva, and Andrea Basso*
Department of Chemistry and Industrial Chemistry, University of Genova, Via Dodecaneso 31, 16146 Genova, Italy
S
* Supporting Information
ABSTRACT: Multicomponent reactions are often recognized for their efficiency and convergency, if compared with multistep
organic synthesis. Nevertheless, we here demonstrate that a four-step-one-pot approach (named OPHA strategy for the initials of
the four steps involved) is not only able to afford compounds that could not be obtained by an alkylative Passerini reaction but
also capable of generating them with minimal loss of atoms and high operational simplicity, as in a typical multicomponent
approach.
Scheme 1. Synthesis of Triazolo-Fused Benzoxazepines and
Benzoxazepinones
he Passerini three-component (P3C) reaction is one of
Tthe most important multicomponent reactions. This
reaction is a three-component condensation of aldehydes,
isocyanides, and carboxylic acids to give α-acyloxy amides in
one step.1
Various modifications of this reaction have already been
developed, mainly involving replacement of the carboxylic acid.
For example, trimethylsilyl azide,2 phenols,3 thioacids,4 or
silanol5 have been efficiently employed. Very recently, we
reported that the carbonyl component can also be replaced by a
ketene, and captodative olefins can be assembled through a
photoactivated process.6 The use of a free aliphatic alcohol
instead of a carboxylic acid has also been realized, as reported
by Taguchi.7 The reaction is performed with the alcohol used as
the solvent in the presence of a Lewis acid at 80 °C. The use of
trimethyl orthoformate is found beneficial for the final
outcome, and good results are obtained with aromatic or α,β-
unsaturated aldehydes with the catalysis by lanthanoid(III)
triflates.
This method, however, is limited in scope as the alcohol
component is also the solvent of the reaction; therefore,
construction of libraries of α-alkoxy amide derivatives is
somehow prevented. In addition, a second addition of
isocyanide, catalyst, and additive is required to improve the
overall yield.
between an azidobenzaldehyde 5, and isocyanide, and a
propargyl alcohol could serve the purpose (Scheme 2).
As the original method developed by Teguchi seemed rather
inconvenient when dealing with valuable building blocks such
Scheme 2. Multicomponent Approach to Adducts 1 Based
on the Alkylative Passerini Reaction
We recently became interested in the synthesis of
compounds of general structure 1 and 2 to be subjected to
intramolecular dipolar cycloaddition8 for the preparation of
unprecedented triazolo-fused benzoxazepines 3 and benzox-
azepinones 4, respectively. In particular, compound 3 seemed
very promising for biological applications, lacking the easily
hydrolizable lactone moiety (Scheme 1).
Searching for a straightforward method to prepare
compound 1, we envisaged that an alkylative Passerini reaction
Received: March 18, 2014
Published: April 10, 2014
© 2014 American Chemical Society
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Letter
as propargylic alcohols, we performed preliminary experiments
with 2-azidobenzaldehyde 5a, tert-butyl isocyanide, and 2-
propanol. When the third component was employed as the
solvent, following the procedure developed by Teguchi,
compound 6 could be isolated in a modest 39% yield, and
no improvement was achieved by replacing conventional
heating with microwave. On the other hand, when the alcohol
was used, even in large excess, in the presence of an alternative
solvent such as THF or DMF, formation of the desired product
was not observed (Scheme 3).
propargyl bromides (Scheme 5). Such an approach could
maintain the same advantages of an alkylative Passerini reaction
Scheme 5. Four-Step, One-Pot Alternative to the Alkylative
Passerini Reaction
Scheme 3. First Attempts to an Alkylative Passerini Reaction
with 2-Azidobenzaldehydes
in terms of convergency and, in addition, could directly use 2-
azidobenzyl alcohols 9 as starting materials. Notably,
azidobenzaldehydes 5 are not commercially available and are
usually prepared by oxidation of the corresponding alcohols.11
We envisioned, however, one criticism to this OPHA
(oxidation−Passerini-hydrolysis−alkylation) strategy: that is
the use of a sacrificial carboxylic acid that would not be
incorporated in the final product, thus contradicting the
principles of atom economy.12 This was, however, only an
apparent problem, as the carboxylic acid (acetic acid) would
already be part of the reaction medium in case the oxidation of
azidobenzyl alcohols was carried out with the TEMPO-
bis(acetoxy)iodobenzene system.13
Intrigued by this straightforward approach, we initially
studied the distinct steps individually. As the main concern
was on the regioselectivity of the alkylation reaction, we
prepared compound 8 by reacting 5-chloro-2-azidobenzalde-
hyde 5b with cyclohexyl isocyanide and acetic acid, followed by
basic hydrolysis of the ester bond. After column chromatog-
raphy, the truncated Passerini adduct was obtained in
quantitative yield. Conditions for the selective alkylation of
the hydroxyl group were then investigated, and the best results
were obtained under phase-transfer conditions, adapting a
method reported by Lamberth14 and Li.15
In a second set of experiments, 2-propanol was replaced by
propargyl alcohol and 2-azidobenzaldehyde by benzaldehyde.
The results were even worse, as the product of the alkylative
Passerini reaction could be isolated only in traces (7%), even
employing the alcohol as the solvent. Although discouraged by
these results, we attempted the synthesis of compound 1 by
performing the reaction of 5a with tert-butyl isocyanide and
propargyl alcohol as the solvent. The desired product was not
detected in the reaction mixture, while cyclic acetal 7, deriving
from the combination of one molecule of 5a and two molecules
of the alcohol in an acetalyzation/cycloaddition sequence, was
recovered as the major product, albeit with low purity (Scheme
4).
Scheme 4. Alkylative Passerini Reaction Does Not Afford the
Expected Compound
When the reaction was performed with 2-hexynyl bromide,
compound 1a was isolated in 81% yield, while when propargyl
bromide was used instead, a mixture of compound 1b and
cyclized adduct 3b was isolated in overall 84% yield (Scheme
6). This prompted us to investigate conditions for the 1,3-
dipolar cycloaddition, which was found to proceed smoothly in
toluene at 100 °C with the aid of microwave heating.16
As the conditions employed for the alkylation step could also
be effectively applied to the hydrolysis of the Passerini adducts,
compound 9, prepared in 82% yield reacting 2-azidobenzalde-
hyde 5a with tert-butyl isocyanide and acetic acid, was reacted
under the same conditions developed previously, employing
phenylpropargyl bromide as alkylating agent. The desired
adduct 1c was isolated in 86% yield, thus demonstrating that
hydrolysis and alkylation could be performed concurrently and
that acetate ion, probably dissolved in the water phase, did not
interfere as a nucleophile (Scheme 7).
Enticed by the chance to gain a combinatorial-friendly entry
into benzoxazepines 3, which to date have been solely prepared
in a single example with methodologies unsuitable for parallel
synthesis purposes,9 we therefore decided to search for other
strategies. With the aim of assembling compound 1 in one pot
from simple building blocks, a viable option was found in the
design of a pathway encompassing an oxidative Passerini
reaction,10 followed by ester hydrolysis and O-alkylation with
In another experiment, 5-chloro-2-azidobenzaldehyde 5b was
reacted in dichloromethane with acetic acid and cyclohexyl
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Scheme 6. Alkylation of Truncated Passerini Adducts
Scheme 9. One-Pot Oxidation, Passerini Reaction,
Hydrolysis, and Alkylation
short silica pad afforded a compound sufficiently pure for the
subsequent cyclization step, which was performed according to
the conditions described above.
Scheme 7. Hydrolysis and Alkylation of Passerini Adducts
The scope of this approach was investigated preparing a
small set of benzoxazepines 3, as illustrated in Table 1.
Table 1. Small Library of Benzoxazepines 3 Has Been
Prepared According to the above-Described Methodology,
Followed by a Cycloaddition Reaction
a
isocyanide; upon consumption of the starting materials, the
phase-transfer catalyst, the 30% NaOH solution, and phenyl-
propargyl bromide were added,17 and after 24 h adduct 1d was
isolated, upon chromatographic purification, in quantitative
yield (Scheme 8).
compd
R1
R2
R3
yield (%)
b
3a
3b
3c
3d
3e
3f
5-Cl
5-Cl
H
c-Hex
c-Hex
t-Bu
Pr
H
79 (81)
c
68 (−)
86 (87)
b
Ph
Ph
b
5-Cl
H
c-Hex
t-Bu
77 (79)
b
3-MeO-Ph
47 (59)
c
Scheme 8. One-Pot Passerini Reaction, Hydrolysis, and
Alkylation
H
n-Bu
t-Bu
H
74 (−)
65 (−)
c
3g
H
Pr
a
b
Overall isolated yield after OPHA and cycloaddition. Yield of
alkoxyamide 1. Alkoxyamide was not isolated due to partial
c
spontaneous cyclization.
In conclusion, a straightforward methodology able to
overcome the limitations of the alkylative Passerini reaction
has been developed; it is also capable of generating alkoxyamide
derivatives 1 with minimal loss of atoms and high operational
simplicity, as in a typical multicomponent approach, and its
versatility has been demonstrated by the synthesis of a small
library of benzoxazepines. Further applications of this novel
OPHA strategy will be reported in due course.
Finally, the one-pot procedure starting from 2-azidobenzy-
lalcohol 9 was attempted, this was dissolved in dichloro-
methane together with a catalytic amount of TEMPO and a
stoichiometric amount of bis(acethoxy)iodobenzene.18 When
the oxidation was complete, tert-butylisocyanide was added and
formation of the Passerini adduct was monitored. Then, 3-
methoxyphenylpropargyl bromide was added together with the
other reagents for the hydrolysis/alkylation step and adduct 1e
was obtained in 59% overall yield (Scheme 9). At this stage, it
was found that a quick filtration of the crude material over a
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, product characterization, and copies
1
of the H and 13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: andrea.basso@unige.it.
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Letter
cycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John
Wiley & Sons, Inc.: New York, 2002; pp 623−679. (b) Appukkattan,
P.; Mehta, V. P.; Van Der Eycken, E. V. Chem. Soc. Rev. 2010, 39,
1467−1477.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(17) Vidyasagar Reddy, G.; Iyengar, D. S. Ind. J. Chem. B 1999, 38B,
130−132.
■
We thank Andrea Armirotti (Istituto Italiano di Tecnologia)
and Lorenzo Sonaglia (Univerista
(18) Di Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J. Org. Chem. 1997, 62, 6974−6977.
̀
di Genova) for HRMS. We
also acknowledge PRIN 2009 (“Synthetic Methodologies for
Generation of Biologically Relevant Molecular Diversity”),
University of Genova for financial support, and Lamberti SpA
for a generous donation.
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