Formyloxyacetoxyphenylmethane as an N-Formylating Reagent for Amines, Amino Acids, and Peptides

Article abstract of DOI:10.1021/acs.orglett.7b02382

Formyloxyacetoxyphenylmethane is a stable, water-tolerant, N-formylating reagent for primary and secondary amines that can be used under solvent-free conditions at room temperature to prepare a range of N-formamides, N-formylanilines, N-formyl-α-amino acids, N-formylpeptides, and an isocyanide.

Full text of DOI:10.1021/acs.orglett.7b02382

Letter
pubs.acs.org/OrgLett
Formyloxyacetoxyphenylmethane as an N‑Formylating Reagent for
Amines, Amino Acids, and Peptides
Robert S. L. Chapman,‡ Ruth Lawrence,‡ Jonathan M. J. Williams, and Steven D. Bull*
Department of Chemistry, University of Bath, Bath BA2 7AY, U.K.
S
* Supporting Information
ABSTRACT: Formyloxyacetoxyphenylmethane is a stable, water-tolerant, N-
formylating reagent for primary and secondary amines that can be used under
solvent-free conditions at room temperature to prepare a range of N-formamides,
N-formylanilines, N-formyl-α-amino acids, N-formylpeptides, and an isocyanide.
N-Formylation reactions of primary and secondary amines are
important transformations in organic chemistry because they
provide direct access to the highly versatile formamide group.1
Highlighting their synthetic utility, N-formyl derivatives can be
used as precursors for the synthesis of formamidines,2 ureas,3
carbamates,3 aryl amides,4 isocyanates,5 nitriles,6 and isocya-
nides.7 Consequently, they have often been used as intermediates
for the synthesis of pharmaceuticals.8 Alternatively, the N-formyl
group may be used as a protecting group for peptide synthesis,9
while many naturally occurring formamides exhibit important
medicinal and biological activities.10 The formamide moiety is
also present in pharmaceuticals, including leucovorin (chemo-
therapeutic),11a formoterol (asthma)11b and orlistat (antiobesi-
ty).11c
As part of our investigations into the Baeyer−Villiger oxidation
reactions of α,β-unsaturated ketones, we found that treatment of
benzylidene acetone 1 with 4 equiv of m-chloroperoxybenzoic
acid (m-CPBA) in toluene for 24 h gave FAPM (5) in 84%
isolated yield (Scheme 1a).14 In this remarkable one-pot, four-
Scheme 1. Syntheses of Formyloxyacetoxyphenylmethane 5
via (a) m-CPBA-Mediated Oxidation Reaction of Benzylidene
Acetone 1 and (b) Nucleophilic Attack of Formic Acid on α-
Chlorobenzyl Acetate 6
Due to their importance, a number of N-formylating reagents
for primary and secondary amines have been developed,1
including the use of formic acid,12a formic acid in the presence
of coupling reagents (e.g., DCC),12b acetic formic anhydride,12c
formate esters,12d N-formyl-saccharin,12e trialkyl orthoforma-
tes,12f enol formates,12g ammonium formate,12h and N-
formylbenzotriazole.12i However, many of these reagents are
only moderately reactive toward sterically hindered or electroni-
cally deactivated amines, often requiring elevated temperatures,
extended reaction times, or the use of excess reagent for their N-
formylation reactions to proceed to completion.1 A number of
these formylating reagents are also susceptible to hydrolysis,
while some reagents can decompose to liberate hazardous
byproducts (e.g., CO).1 Given these limitations, a number of
catalytic N-formylation protocols have also been developed that
employ N-formyl donors in combination with Brønsted acid
catalysts, Lewis acids, organocatalysts, metal catalysts, and
biocatalysts.13
Given the limitations of using many N-formylating reagents
under catalyst-free conditions, we now report herein that
formyloxyacetoxyphenylmethane (FAPM, 5) can be used as a
bench-stable formylating reagent for primary/secondary amines
under solvent-free conditions at room temperature. Importantly,
the stability of FAPM (5) toward hydrolysis enables it to be used
as a catalyst free N-formylating reagent for α-amino acids and
peptides in aqueous-based solvent systems.
step reaction, benzylidene acetone 1 first undergoes an m-CPBA-
mediated Baeyer−Villiger reaction to afford enol acetate 2,
whose electron-rich alkene bond is then epoxidized by a second
equivalent of m-CPBA to afford epoxy acetate 3. This unstable
epoxy acetate 3 then undergoes intramolecular rearrangement to
afford aldehyde 4, which then undergoes a further m-CPBA-
mediated Baeyer−Villiger reaction to afford FAPM (5). The
Received: August 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02382
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Letter
formation of intermediates 2 and 4 in this oxidation reaction
were confirmed by 1H NMR spectroscopic analysis of a series of
control reactions that were carried out using fewer equivalents of
m-CPBA over shorter periods of time (see the Supporting
Information (SI) for details).15
A second route to FAPM (5) was also developed using a
variant of a protocol previously developed by Rephaeli and co-
workers for the synthesis of nonsymmetric acyloxyalkyl esters.16
This involved treatment of benzaldehyde with 1.5 equiv of acetyl
chloride in the presence of a catalytic amount of p-
toluenesulfonic acid to afford α-chlorobenzyl acetate 617 that
was subsequently reacted with formic acid and Et3N in acetone to
afford FAPM 5 in 76% yield (Scheme 1b).18
FAPM (5) proved to be a bench-stable liquid that could be
stored at room temperature under nitrogen for up to 6 months
without decomposition. We reasoned that FAPM (5) might act
as a selective N-formyl donor for amines, which was confirmed by
reacting 1.5 equiv of FAPM (5) with 1 equiv of benzylamine 7a in
THF at rt for 4.5 h to give N-formylbenzylamine 8a and imine 9
in 90% and 10% conversion, respectively (Table 1, entry 1).
carried out in mixed aqueous solvents in the hope that the
presence of bulk water would perturb the reaction equilibrium
away from imine formation. Gratifyingly, use of 1:1 mixtures of
THF/H2O, MeCN/H2O, and 1,4-dioxane/H2O (Table 1,
entries 8−10) gave good conversions to N-formylbenzylamine
8a, with ≤1% of imine 9 being formed in each case. The tolerance
of FAPM (5) toward hydrolysis in aqueous systems was
confirmed by carrying out an N-formylation reaction in
water,19 with 1.5 equiv of FAPM (5) resulting in complete
conversion of benzylamine to N-formylbenzylamine 8a (Table 1,
entry 11). Finally, FAPM (5) could also be used under solvent-
free conditions (Table 1, entry 12), resulting in clean N-
formylation of benzylamine, with only 2% of imine 9 being
produced.20
1H NMR spectroscopic analysis of the N-formylation reaction
of benzylamine in d8-toluene revealed that complete con-
sumption of benzylamine 7a occurred after 1 h. Analysis after
15 min revealed the presence of a 87:13 mixture of formamide
8a/imine 9, which subsequently equilibrated to a 99:1 mixture of
formamide 8a:imine 9 after 1 h. With this information in hand,
we employed 1.5 equiv of FAPM to N-formylate a range of 16
primary and secondary amines 7a−p to afford a series N-
formamides 8a−p in 53−96% yield after chromatographic
purification (Scheme 2). Most of these N-formylation reactions
Table 1. Solvent Screen To Optimize the N-Formylation
a
Reaction of Benzylamine with FAPM 5
Scheme 2. FAPM 5 as an N-Formylating Reagent for the
a
Synthesis of N-Formamides 8a−p
entry
solvent
formamide 8a
imine 9
1
THF
90
88
10
12
8
2
EtOH
3
dioxane
92
4
MeCN
96
4
5
CH2Cl2
100
100
98
6
toluene
7
EtOAc
2
1
8
THF/H2O (1:1)
MeCN/H2O (1:1)
dioxane/H2O (1:1)
H2O
99
9
100
99
10
11
12
1
2
100
98
neat
a
Product ratios determined from integrals of diagnostic resonances for
1
8a and 9 in H NMR spectra of crude reaction products.
Importantly, 1H NMR spectroscopic analysis revealed no
evidence of any N-acetylbenzylamide having been formed via
competing N-acyl transfer from FAPM (5). Mechanistically, we
propose that benzylamine 10a attacks the reactive formyl group
of FAPM to irreversibly afford formamide 8a, with benzaldehyde
and acetic acid being generated as byproducts. Unwanted
formation of imine 9 then occurs through acid-catalyzed reaction
of benzylamine 7a with the benzaldehyde byproduct (see the SI
for reaction mechanism). A solvent screen was carried out with
the aim of identifying conditions that would suppress formation
of imine 9. Use of ethanol and 1,4-dioxane (Table 1, entries 2 and
3) also afforded significant amounts of the unwanted imine 9
byproduct (8−12%). Carrying out the N-formylation reaction in
MeCN (Table 1, entry 4) gave reduced amounts of imine (4%),
while CH2Cl2, toluene, and EtOAc (Table 1, entries 5−7) gave
excellent conversion to N-formylbenzylamine 8a with only trace
amounts of imine 9 (≤2%) being formed. Since imine formation
is potentially reversible, a series of N-formylation reactions were
a
Reaction conditions: (a) 2 mmol of amine, 1.5 equiv of FAPM 5, 1 h,
rt; (b) 2 mmol of amine, 1.5 equiv of FAPM 5, EtOAc, 1 h, rt; (c) 2
mmol of amine, 1.5 equiv of FAPM 5, EtOAc, rt, 24 h.
were carried out under solvent-free conditions by dissolving the
amine in neat FAPM and stirring at rt, followed by purification by
silica chromatography. In those cases where the parent amine
was insoluble in FAPM (5), EtOAc was employed as a cosolvent
to afford a homogeneous reaction mixture. N-Formylation
reactions of primary aliphatic amines proved particularly facile,
typically affording their corresponding formamides 8a−e in good
B
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to excellent yields (81−95%). Pleasingly, amines containing acid-
sensitive functionalities, such as furan and dimethyl acetal, were
well tolerated, affording formamides 8b and 8e in 81% and 95%
yields, respectively. FAPM (5) reacted exclusively with the
primary amine functionality of tryptamine to afford formamide
8d in 90% yield. While the formamide 8f of sterically congested
benzhydrylamine was formed in good 83% yield, formylation of
tert-butylamine gave N-formamide 8g in only 53% isolated yield,
arising from losses during reaction workup due to its volatility.
(S)-Valine methyl ester afforded N-formamide 8h in an excellent
93% yield with no evidence of any racemization having occurred.
Acyclic and cyclic secondary amines were also formylated using
FAPM 5, with moderate to excellent 58−96% yields of N-
formamides 8i−k being isolated. Pleasingly, electron-deficient
aniline and its secondary N-methyl derivative gave their
corresponding formamides 8l,m in excellent 90% and 91%
yields, respectively. However, formylation of anilines containing
deactivating halogen or ester groups required extended reaction
times of 24 h for their corresponding N-formamides 8o,p to be
formed in 87−95% yields, respectively. Alternative workup
procedures were then developed to allow these N-formylation
reactions to be carried out on scale, without the need for
chromatographic purification (see the SI for details).
Scheme 3. FAPM 5 as an N-Formylating Reagent for the
Synthesis of N-Formyl-α-amino Acids 11a−f
Scheme 4. FAPM 5 for the Synthesis of (a) N-
Formylmethionylleucylphenylalanine (f-MLP) 14 and (b) N-
Formyldecapeptide 16
Although several reagents have been developed for the N-
formylation of amino ester derivatives,21 extension of these
methods to unprotected α-amino acids has not been widely
reported. This is due to the instability of many formylating
reagents toward hydrolysis in aqueous media and the insolubility
of α-amino acids in nonaqueous solvents. Currently, N-formyl-α-
amino acids are most commonly prepared via treatment of the
parent α-amino acids with a large excess of Ac2O and formic acid
(via formation of formyl acetate in situ), which often requires
forcing conditions and/or extended reaction times.22 N-
Formylation of α-amino acids using formic acid in water has
been reported; however, this protocol requires Oxyma as a
stoichiometric coupling reagent.23 Given the observed stability of
FAPM in aqueous solvents, a range of six L-amino acids 10a−f
were treated with 1.5 equiv of FAPM in water containing 5 equiv
of NaHCO3 as a base, which resulted in 80−85% conversion to
their corresponding formamides 11a−f after 16 h. However, we
subsequently found that modifying these formylation reactions,
by incorporating addition of a second portion of FAPM 5 (1.5
equiv) after 8 h, resulted in complete consumption of each α-
amino acid, giving N-formylamino acids 11a−f in good to
excellent 71−89% isolated yields, with no racemization having
occurred (Scheme 3).
Formamides are often employed for the synthesis of
isocyanides,7 and so we investigated whether FAPM 5 could be
used to develop a stepwise “one-pot” protocol to directly convert
an amine into its corresponding isocyanide. 4-Bromoaniline 7n
and FAPM (5) (1.5 equiv) were stirred in CH2Cl2 at rt for 24 h to
afford its corresponding formamide 8n in situ (confirmed by 1H
NMR spectroscopic analysis). Sequential dropwise addition of
diisopropylamine (4 equiv) and POCl3 (1.2 equiv) to this
solution of formamide 8n in CH2Cl2 at 0 °C, followed by stirring
at 0 °C for 2 h and rt for 4 h, gave 1-bromo-4-isocyanobenzene 17
in 74% yield over two steps (Scheme 5).
N-Formylmethionineleucylphenylalanine (f-MLP, 14) is a
chemotactic N-formyltripeptide that is a potent chemoattractant
for leukocytes and a macrophage activator that is involved in
triggering the innate immune response toward bacterial
pathogens.24 Consequently, it was chosen as a suitable target
to test the utility of FAPM for the N-formylation of peptidic
substrates. The parent tripeptide ester 12 was treated with 1.5
equiv of FAPM in EtOAc for 5 h to afford formamide 13 in 87%
yield, which was then hydrolyzed using NaOH/MeOH to afford
f-MLP 14 in 93% yield (Scheme 4a). Similarly, a decapeptide
with the sequence Ac-ADGIVNGVKA-NH2 15 containing N-
acetamide and C-primary amide termini was reacted with 5 equiv
of FAPM in a mixture of MeCN/H2O (pH 8.0) containing a few
drops of DMSO. This resulted in N-formylation of the free ω-
amino group of its lysine residue affording N-formyldecapeptide
16, as confirmed from HRMS analysis (Scheme 4b).
Scheme 5. FAPM 5 for the One-Pot Synthesis of Isocyanide 17
In conclusion, two practical syntheses of formyloxyacetox-
yphenylmethane (5) have been developed and its use as a water-
tolerant N-formylating reagent for primary and secondary
amines under solvent-free conditions demonstrated. Its potential
as a reagent for the synthesis of N-formyl-α-amino acids and N-
formylpeptides in aqueous systems has been established, and it
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02382.
Complete experimental procedure and relevant spectra
(13C and 1H NMR spectra) for all compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: s.d.bull@bath.ac.uk.
ORCID
Steven D. Bull: 0000-0001-8244-5123
Author Contributions
‡R.S.L.C. and R.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of Bath, EPSRC, and the Centre for
Doctoral Training in Sustainable Chemical Technologies (EP/
L016354/1) for funding. We thank Dr. Jody Mason (Depart-
ment of Biology, University of Bath) for donating a sample of
decapeptide 15 that was prepared using conventional solid-phase
peptide synthesis.
(15) A similar mechanistic rationale was proposed to explain formation
of mixed acylals 19 and 20; see ref 14b,c for details.
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A. J. Med. Chem. 2005, 48, 1042−1054.
(17) Su, W. K.; Can, J. J. Chem. Res. 2005, 2005, 88−90.
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