Protecting-group-free synthesis of hydroxyesters from amino alcohols

Article abstract of DOI:10.1039/d0cc03242e

The synthesis of hydroxyesters from carboxylic acids and unprotected amino alcohols in both continuous flow and batch processes is reported. The formation of a transient diazonium species with a dinitrite reagent is key in this transformation. The reaction conditions are compatible with a variety of functional groups.

Full text of DOI:10.1039/d0cc03242e

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DOI: 10.1039/D0CC03242E
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Protecting-Group-Free Synthesis of Hydroxyesters from Amino
Alcohols
Guillaume Reynard, Eve-Marline Joseph-Valcin and Hélène Lebel*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The synthesis of hydroxyesters from carboxylic acids and
unprotected amino alcohols in both continuous flow and batch
processes is reported. The formation of a transient diazonium
species with a dinitrite reagent is key in this transformation. The
reaction conditions are compatible with a variety of functional
groups.
Protecting group free synthesis improved “atom economy”1 of
a synthetic process and is a particularly important consideration
in the development of novel synthetic methodologies. Typical
esterifications2 involve the reaction between a carboxylic acid
and an alcohol and the synthesis of hydroxy-containing esters
often necessitate a monoprotected diol, or a large excess (>5
equiv) of the diol.3,4,5 Carbodiimide coupling reagents are also
frequently applied in these reactions, adding an additional piece
to the process that is not present in the final product.4
Alternatively, nucleophilic substitutions of bromo alcohols with
carboxylate anions have been delineated in the synthesis of
hydroxyesters.6 However, anhydrous basic conditions are
typically required, and bromo alcohols are not as readily
available and inexpensive as diols (or amino alcohols).
Scheme 1
Synthesis of esters via diazotization of amines.
leaving the alcohol functionality untouched (Scheme 1). The
subsequent reactivity of the diazonium intermediate for an
inter- vs intramolecular process needed to be established.
Herein, we report the protecting-group-free synthesis of
hydroxyesters from amino alcohols using 1,3-propanedinitrite
as a reagent. In contrast to amino alcohols, amino acids affor-
ded the corresponding lactone in high yields via an intra-
molecular reaction. In addition to continuous flow processes,
general batch reaction conditions were also developed.
At the outset of the development, the esterification of benzoic
acid with 3-aminopropan-1-ol was studied in continuous flow.
Tetrahydrofuran (THF) was established as a suitable solvent,
affording a homogeneous solution. A slight excess of 3-amino-
propan-1-ol and 1,3-propanedinitrite was used, and various
residence times and temperatures were studied (Figure 1).
Hydroxyester 1 was isolated in 89% at 70 °C with a residence
time of 60 min. At 60 °C, the conversion was lower, whereas the
use of higher temperature (80 °C and 90 °C) reached a plateau
at 70% after 15 min that was not improved with longer
residence times.
Our group has recently disclosed
a continuous flow
esterification of carboxylic acids via the diazotisation of
alkylamines.7 1,3-Propanedinitrite was the key reagent to
perform the reaction, affording benign residues (nitrogen gas
and 1,3-propanediol), which were easily expunged from the
desired ester product. The reaction demonstrated compatibility
with a variety of functional groups, including hydroxy-
containing carboxylic acids. Challenging amino alcohols, that
could undergo intramolecular etherification, were not
previously tested in the original continuous flow process. It was
hypothesized that the reaction between a carboxylic acid and
an amino alcohol would afford the diazonium intermediate,
Department of Chemistry and Centre in Green Chemistry and Catalysis (CGCC),
Université de Montréal, Montréal, Qc, H3C 3J7, Canada.
Email: helene.lebel@umontreal.ca
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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At 80 °C and 100 °C, the maximum yield was reached after 30
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min residence time, and the yield deDcOreI:a1s0e.1d03w9/hDe0nCCl0o3n2g42eEr
residence time were used. Under the optimal conditions (100
°C, 30 min residence time), ester 24 was produced from an
amino alcohol and a hydroxy-containing acid in 98% yield. The
synthesis of a variety of hydroxyesters were possible under
reaction conditions B (100 °C, tR: 30 min). Hydroxyesters 6–11
derived from substituted benzoic acids were produced in
excellent yields. Ethylene glycol-derived diols were also
successfully incorporated to afford hydroxyesters 12 and 13 in
good yields. The reaction conditions were compatible with
various heteroaromatic acids and hydroxyesters 14–18 were
synthesized in good to excellent yields. A variety of aliphatic
hydroxyesters containing cyclopropane (20), alkyne (21), indole
(22) ketone (23) and alcohol (24) were produced in good to
excellent yields.
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
60 °C
70 °C
80 °C
40
90 °C
0%
0
20
60
Residence time (min)
Figure 1
Continuous flow optimization for the esterification of benzoic acid with
3-aminopropan-1-ol. Yields were determined by NMR using tetrachloroethane as a
standard.
Reaction conditions A (70 °C, tR: 60 min) were used with other
amino alcohols and benzoic acid to produce the corresponding
hydroxyester 2-5 in 77% to 94% yield (Scheme 2). It should be
noted than < 1% of the cyclization product was observed on the
crude material. However, these reaction conditions did not
prove optimal for other substrates: only a few carboxylic acids
produced the desired ester in good yields (products 19 and 25
in Scheme 2). A second optimization using hydroxy isobutyric
acid was then performed (Figure 2). Low conversion for the
synthesis of ester 24 was observed at 40 °C and 60 °C.
100%
80%
60%
40%
20%
40 °C
20
60 °C
30
80 °C
100 °C
0%
0
10
40
50
60
Residence time (min)
Figure 2
Continuous flow optimization for the esterification of hydroxy isobutyric
acid with 3-aminopropan-1-ol. Yields were determined by NMR using tetrachloethane as
a standard.
Scheme 2
Substrate scope of synthesis of hydroxyesters in continuous flow.
This journal is © The Royal Society of Chemistry 20xx
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC03242E
Scheme 4
Substrate scope of synthesis of esters in batch.
Finally, the diazotisation of an amino acid was studied (Scheme
5). In contrast to amino alcohols, the amino acid underwent an
intramolecular cyclisation. Using CBz-protected glutamic acid,
the corresponding lactone 36 was produced in 65% using the
batch procedure. The yield was increased to 93% when the
reaction was run in continuous flow for 30 minutes at 120 °C
using a mixture of tert-butanol and water as solvent.
Scheme 3
Substrate scope of synthesis of hydroxyesters in batch.
Amino acid derivatives, including serine derivative were also
successfully reacted to afford hydroxyesters 25 and 26. A few
substrates afforded lower yields (namely hydroxyester 19) or
could not be executed in continuous flow due to poor solubility.
tert-Butanol was determined to be the ideal solvent for batch
processes at 80 °C for 6 to 16 h (Scheme 3).‡ Hydroxyester 19
derived from palmitic acid was isolated in 99% yield under these
reaction conditions. Other previously described hydroxyesters
(1-5, 12, 14, 15, 18, 22, 23 and 26) were isolated in good to
excellent yields. In addition, quinoline- and benzofuran-derived
carboxylic acids that were not soluble in THF, were successfully
reacted to afford hydroxyesters 27 and 28 in good yields.
Sterically hindered adamantly ester 29 was produced in 98%
yield.
In an effort to broaden the substrate scope in batch, other
amines were reacted, using a novel dinitrite derived from
neopentylglycol, a low-priced chemical reagent (~30$/Kg;
3$/mol) (Scheme 4). The methyl ester 30 and 31 derived
respectively from an aromatic and an aliphatic acid, were
produced in high yields. Thiophenmethyl amine was reacted
with lithocholic acid to afford ester 32 in 87% yield. Adiphenine
33, an anti-cholinergic agent used as a local anesthetic,8 was
synthesized in 98% yield using the procedure. Esters derived
from secondary (34) and tertiary alkyl (35) were also
successfully produced in high yields.
Scheme 5
Intramolecular lactonization of an amino acid.
Conclusions
In conclusion a convenient and general protecting-group-free
synthesis of hydroxyesters has been developed. The reaction
conditions were compatible with a large variety of functional
groups. Benign by-products were generated, and the novel
reaction efficiently replaced carbodiimide coupling reagents.
Finally, while the esterification process via diazotization was
initially reported in continuous flow,7b a batch procedure is now
available and affords the desired product in good to high yields.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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This research was supported by the Natural Science and
Engineering Research Council of Canada (NSERC) under the
CREATE Training Program in Continuous Flow Science, a
discovery grant from NSERC (Canada), the Canada Foundation
for Innovation, the Université de Montréal and the Centre in
Green Chemistry and Catalysis (CGCC). We would like to thank
Vanessa Kairouz and Dr. James J. Mousseau for fruitful
discussions. We would like to thank Dr. Alexander Goldberg,
Amy Cagulada and Nisha Shah from Gilead Sciences, Inc. for
helpful discussions regarding safety issues with dinitrite
reagents. We would like to thank Prof. Dominic Rochefort and
Prof. Christian Pellerin for their help with the DSC-TGA analysis.
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DOI: 10.1039/D0CC03242E
Notes and references
‡ Although no spontaneous degradation of the dinitrite reagent
was observed when heated in solution in tert-butanol, careful
attention and appropriate protection should always be used. See
ESI for details.
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