Mild Esterification of Carboxylic Acids via Continuous Flow Diazotization of Amines

Article abstract of DOI:10.1021/acs.orglett.7b02231

A new continuous flow protocol for the diazotization of methylamine with 1,3-propanedinitrite in THF is reported. The synthesis of methyl esters was achieved in high yields from a variety of carboxylic acids in 20 min at 90 °C. Additionally, this protocol was extended to other aryl and alkyl amines, namely secondary amines, to produce various substituted esters in high yield using 2-MeTHF as a solvent. The reaction conditions were compatible with many functional groups, namely nitrogen-containing heterocycles, alkynes, alkenes, alcohols, and phenols. Mechanistic investigations reveal that the reaction appears to proceed through a transient diazonium species rather than a diazo intermediate.

Full text of DOI:10.1021/acs.orglett.7b02231

Letter
pubs.acs.org/OrgLett
Mild Esterification of Carboxylic Acids via Continuous Flow
Diazotization of Amines
Clement Audubert and Helene Lebel*
́
́
̀
Dep
Montrea
́
artement de Chimie, Center for Green Chemistry and Catalysis, Universite
l, Quebec, Canada H3C 3J7
́ ́
de Montreal, C.P. 6128, Succursale Centre-ville,
́
́
S
* Supporting Information
ABSTRACT: A new continuous flow protocol for the
diazotization of methylamine with 1,3-propanedinitrite in THF
is reported. The synthesis of methyl esters was achieved in high
yields from a variety of carboxylic acids in 20 min at 90 °C.
Additionally, this protocol was extended to other aryl and alkyl
amines, namely secondary amines, to produce various sub-
stituted esters in high yield using 2-MeTHF as a solvent. The
reaction conditions were compatible with many functional
groups, namely nitrogen-containing heterocycles, alkynes, alkenes, alcohols, and phenols. Mechanistic investigations reveal
that the reaction appears to proceed through a transient diazonium species rather than a diazo intermediate.
he esterification of carboxylic acids with alcohols is
T
typically achieved under acid catalysis.1 For more
challenging sterically hindered or highly functionalized
substrates (namely with acid sensitive functionality), the
activation of the acid or the alcohol is often necessary.2,3 An
alternative strategy for the synthesis of methyl esters applies
diazomethane as the methylating reagent.4 Under these mild
reaction conditions, highly functionalized carboxylic acids are
cleanly esterified in excellent yields. Despite all the advantages
associated with this method, the toxicity and explosive nature of
this reagent limit its applicability. To overcome the safety issues
related to diazo compounds, alternatives strategies for their
synthesis have been developed, namely using continuous flow
processes.5 Over the past decade, continuous flow chemistry6
has appeared as a relevant tool for the safe generation and use
of hazardous materials.7 For example, diazomethane has been
produced in continuous flow from nitrosoamine derivatives
such as Diazald8 or N-nitrosomethylurea (MNU).9,10 The
subsequent reaction with carboxylic acids furnishes the
corresponding methyl esters. Alternatively, the batch oxidation
of silylated hydrazones,11 or free hydrazones,12 with respec-
tively difluoroiodobenzene and manganese oxide, afforded the
corresponding diazo compound that was reacted in situ with a
carboxylic acid to synthesize the corresponding ester in high
yields (eq 1). The diazotization of amines13 is another method
to produce various diazo compounds that have been adapted to
continuous flow processes.14 Recently we have reported the
diazotization of trimethylsilylmethylamine (TMSCH2NH2)
with 1,3-propanedinitrite (Pr(ONO)2) to yield trimethyl-
silyldiazomethane (TMSCHN2) using batch and continuous
flow synthesis.15 Herein, we report the esterification of
carboxylic acids via the diazotization of various amines,
including methylamine (eq 2). The reaction appears to proceed
via a diazonium intermediate that undergoes an SN2 or SN1
reaction, depending on the substitution of the transiently
formed diazonium. The corresponding diazo compound does
not appear to be an intermediate, mitigating safety concerns
and adverse side reactions associated with this class of reagents.
We first investigated the reaction of 4-phenylbenzoic acid
with the commercially available methylamine THF solution in
the presence of a variety of nitrites at 90 °C, for various
residence times.16 We were pleased to discover that methyl 4-
phenylbenzoate (1) was obtained in quantitative yield when the
acid was reacted with 1.6 equiv of 1,3-propanedinitrite
(Pr(ONO)2)17 and 2 equiv of methylamine for 10 min (eq
3). These reaction conditions were then applied to a variety of
carboxylic acids (Scheme 1). In order to account for less
reactive substrates, the residence time was extended to 20 min.
The flow rate for the methylamine solution was adapted, in
such way that the commercially available 2 M solution in THF
could be used directly without any further dilution. Aliphatic
methyl esters 1a−1h were isolated in excellent yields.
Several functional groups, including ketones, thioethers,
halides, sulfoxide, and pyridines, were tolerated under the
reaction conditions. Sterically congested carboxylic acids were
Received: July 20, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02231
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
diazomethane. The esterification of probenecid proceeded in
quantitative yields to afford ester 1i. The hindered ester 1j was
isolated in 81% yield. Importantly, carboxylic acids with this
substitution are known to be difficult to esterify.2b Both
boronate ester and nitro groups were also tolerated (1k).
Heteroaromatic carboxylic acids containing a free indole,
thiophene, and thiazole unit were finally tested and produced
the corresponding ester 1l−1n in excellent yields.
Scheme 1. Synthesis of Methyl Esters from Carboxylic Acids
by Diazotization of Methylamine
The scope of amines was then investigated. The esterification
reaction with aromatic methylamines was first explored
(Scheme 2). A solution of benzylamine in 2-MeTHF was
a
Scheme 2. Synthesis of Benzylic Esters from Carboxylic
a
Acids by Diazotization of Aromatic Methylamines
a
Isolated yields using ArCH2NH2 (2 equiv) and Pr(ONO)2
b
c
(1.6 equiv). Performed in batch for 16 h. An ArCH2NH2 and
RCO2H solution was mixed with a solution of Pr(ONO)2 in THF.16
d
i-AmONO (3.5 equiv) was used for 40 min (tR).
reacted with various carboxylic acids to afford benzyl esters 2a
(derived from an amino acid), and 2b in excellent yields. When
the carboxylic acid is only partially soluble in 2-MeTHF, the
reaction was run in batch. For example, coumarin 2b was
obtained in 79% yield after 16 h of reaction. The reaction
conditions are compatible with an easily oxidizable ferrocenyl
derivative, and benzyl ester 2c was produced in 67% yield. A
substituted aromatic methylamine was tested and afforded 2d
in excellent yields. Furfuryl amine was reacted with an alkyne-
substituted nicotinic acid affording 2e in quantitative yield. No
side reaction was observed with the alkyne moiety, a
functionality known to react with diazo compounds. Quinoline
a
Isolated yields using MeNH2 (2 equiv) and Pr(ONO)2 (1.6 equiv).
b
A MeNH2 and RCO2H solution was mixed with a solution of
Pr(ONO)2 in THF.16 MeNH2 (4 equiv) and Pr(ONO)2 (2 equiv)
were used. Starting from the corresponding Bpin carboxylic acid;
esterification was followed by NaIO4 cleavage to produce boronic acid
1j.
c
d
also successfully reacted to afford 1e and methyl podocarpate
(1h) in high yields. We were pleased to observe that the
reaction was tolerant to free alcohols (1g) and phenols (1h), as
these have been reported to be problematic in the reaction with
B
DOI: 10.1021/acs.orglett.7b02231
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
derivative 2f was produced in quantitative yields on 1 mmol
scale. The reaction on the 50 mmol scale afforded the desired
compound 2f in a slightly lower, although acceptable, yield. The
reaction could also be performed using commercially available
i-AmONO with a residence time of 40 min producing 2f in
77% yield. Finally, licholic acid was reacted with 2-
aminomethylthiophene and 2g was isolated in 88% yield with
no side reaction on the alcohol functionality.
resulting from the reaction of a sterically hindered acid and
isopropylamine is quite remarkable. Good yields were also
obtained for the reaction with cyclic amines producing 3h and
3i. The reaction conditions are again tolerant with many
functional groups, such as alkenes, alkynes, protected amines,
pyridines, and thiophenes. The reaction of N-Boc protected
hexane diamine and piperazine proceeded smoothly, producing
3j and 3k in good yields. The reactions were performed in
batch due to the low solubility of the starting amines.
The diazotization of amines in the presence of carboxylic
acids is a known process to produce diazo compounds.14 A few
control experiments were performed to establish if a diazo
intermediate was involved in the described process. When the
reaction was performed with deuterated isopropylamine, only
the deuterated product was produced with no H-incorporation
(eq 4). This control experiment ruled out the formation of
The method was then extended to aliphatic amines (Scheme
3). Ethyl- and butyl-amine were reacted with highly function-
Scheme 3. Synthesis of Substituted Aliphatic Esters from
a
Carboxylic Acids by Diazotization of Amines
diazo intermediate A (Scheme 4). The carboxylate anion is
likely not basic enough to perform the deprotonation. Instead,
the formation of diazonium B is proposed to take place. This
intermediate can then react via an SN2 or SN1 (via the
formation of carbocation) mechanism. The reaction with
Scheme 4. Proposed Mechanistic Pathways for the
Esterifciation via Diazotization of Amines
a
Isolated yields using RNH2 (2 equiv) and Pr(ONO)2 (1.6 equiv).
b
c
Run in THF. A RNH2 and RCO2H solution was mixed with a
solution of Pr(ONO)2 in THF.16 RNH2 (4 equiv) and Pr(ONO)2 (2
equiv) were used. Run in CHCl3. Performed in batch for 16 h.
d
e
f
alized carboxylic acids to produce 3a−3c. A functionalized
aliphatic amine was also reacted to furnish 3d. The synthesis of
sterically hindered isopropyl esters, known to be challenging to
produce,2b was then investigated. Gratifyingly, the reaction of
isopropylamine with various carboxylic acids produced the
desired isopropyl ester in high yields and chemoselectivity
(3e−3g). Namely, the formation in 94% yield, of ester 3f,
C
DOI: 10.1021/acs.orglett.7b02231
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
isobutylamine afforded ester 5 in 92% yield: no rearrangement
product was observed, suggesting that the reaction proceeds via
an SN2 pathway with primary amines (eq 5).
REFERENCES
■
(1) (a) Otera, J. Angew. Chem., Int. Ed. 2001, 40, 2044. (d) Ishihara,
K. Tetrahedron 2009, 65, 1085.
Conversely, when chiral enantioenriched amines were used,
the racemic product was isolated (eqs 6 and 7). The reaction
appeared then to proceed via an SN1 pathway, involving
carbocation C. To support this hypothesis, the reaction was run
with amantadine: the desired adamantly ester 8 was isolated in
84% yields (eq 8). The formation of such a product can only
take place, if a carbocation intermediate is formed in the
process.
(2) (a) Nahmany, M.; Melman, A. Org. Biomol. Chem. 2004, 2, 1563.
(b) Vorbrueggen, H. Synlett 2008, 2008, 1603.
(3) See also: (a) Luo, F.; Pan, C.; Cheng, J. Synlett 2012, 23, 357.
(b) Tang, S.; Yuan, J.; Liu, C.; Lei, A. Dalton Trans. 2014, 43, 13460.
(c) Gaspa, S.; Porcheddu, A.; De Luca, L. Tetrahedron Lett. 2016, 57,
3433.
(4) Black, T. H. Aldrichimica Acta 1983, 16, 3.
(5) (a) Mueller, S. T. R.; Wirth, T. ChemSusChem 2015, 8, 245.
(b) Deadman, B. J.; Collins, S. G.; Maguire, A. R. Chem. - Eur. J. 2015,
21, 2298.
(6) Cambie, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noel,
T. Chem. Rev. 2016, 116, 10276.
(7) (a) Hessel, V.; Kralisch, D.; Kockmann, N.; Noel, T.; Wang, Q.
ChemSusChem 2013, 6, 746. (b) McQuade, D. T.; Seeberger, P. H. J.
Org. Chem. 2013, 78, 6384. (c) Wiles, C.; Watts, P. Green Chem. 2014,
16, 55. (d) Ley, S. V.; Fitzpatrick, D. E.; Ingham, R. J.; Myers, R. M.
Angew. Chem., Int. Ed. 2015, 54, 3449. (e) Gutmann, B.; Cantillo, D.;
Kappe, C. O. Angew. Chem., Int. Ed. 2015, 54, 6688. (f) Teci, M.;
Tilley, M.; McGuire, M. A.; Organ, M. G. Org. Process Res. Dev. 2016,
20, 1967. (g) Wirth, T. Angew. Chem., Int. Ed. 2017, 56, 682.
(h) Morse, P. D.; Beingessner, R. L.; Jamison, T. F. Isr. J. Chem. 2017,
57, 218.
(8) (a) Proctor, L. D.; Warr, A. J. Org. Process Res. Dev. 2002, 6, 884.
(b) Struempel, M.; Ondruschka, B.; Daute, R.; Stark, A. Green Chem.
2008, 10, 41. (c) Maurya, R. A.; Park, C. P.; Lee, J. H.; Kim, D.-P.
Angew. Chem., Int. Ed. 2011, 50, 5952. (d) Mastronardi, F.; Gutmann,
B.; Kappe, C. O. Org. Lett. 2013, 15, 5590. (e) Dallinger, D.; Pinho, V.
D.; Gutmann, B.; Kappe, C. O. J. Org. Chem. 2016, 81, 5814.
(9) (a) Rossi, E.; Woehl, P.; Maggini, M. Org. Process Res. Dev. 2012,
16, 1146. (b) Lehmann, H. Green Chem. 2017, 19, 1449.
(10) For the synthesis of other diazo compounds in flow, see:
(a) Bartrum, H. E.; Blakemore, D. C.; Moody, C. J.; Hayes, C. J.
Tetrahedron 2013, 69, 2276. (b) Roda, N. M.; Tran, D. N.;
Battilocchio, C.; Labes, R.; Ingham, R. J.; Hawkins, J. M.; Ley, S. V.
Org. Biomol. Chem. 2015, 13, 2550. (c) Levesque, E.; Laporte, S. T.;
Charette, A. B. Angew. Chem., Int. Ed. 2017, 56, 837. (d) Rackl, D.;
Yoo, C.-J.; Jones, C. W.; Davies, H. M. L. Org. Lett. 2017, 19, 3055.
(11) Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126, 12222.
(12) Squitieri, R. A.; Shearn-Nance, G. P.; Hein, J. E.; Shaw, J. T. J.
Org. Chem. 2016, 81, 5278.
(13) (a) Barrett, A. G. M.; Braddock, D. C.; Lenoir, I.; Tone, H. J.
Org. Chem. 2001, 66, 8260. (b) Wurz, R. P.; Charette, A. B. Org. Lett.
2002, 4, 4531. (c) Morandi, B.; Carreira, E. M. Angew. Chem., Int. Ed.
2010, 49, 938. (d) Morandi, B.; Mariampillai, B.; Carreira, E. M.
Angew. Chem., Int. Ed. 2011, 50, 1101. (e) Mykhailiuk, P. K. Eur. J. Org.
Chem. 2015, 2015, 7235. (f) Mykhailiuk, P. K. Angew. Chem., Int. Ed.
2015, 54, 6558.
(14) (a) Maurya, R. A.; Min, K.-I.; Kim, D.-P. Green Chem. 2014, 16,
116. (b) Muller, S. T. R.; Smith, D.; Hellier, P.; Wirth, T. Synlett 2014,
25, 871. (c) Pieber, B.; Kappe, C. O. Org. Lett. 2016, 18, 1076.
(d) Mertens, L.; Hock, K. J.; Koenigs, R. M. Chem. - Eur. J. 2016, 22,
9542.
The proposed pathway involves the formation of diazonium
B, which can undergo either an SN2 (presumably with primary
amines, to avoid the formation of unstable primary
carbocation) or an SN1 reaction with secondary and tertiary
amines (Scheme 4).
In conclusion, a novel method to synthesize esters via the
diazotization of amines has been developed. The reaction is
compatible with highly functionalized and sterically hindered
carboxylic acids. Furthermore, various amines can be used, from
the simple methylamine to functionalized amines, including
sterically hindered amines. According to the mechanistic
investigations, the reaction proceeded presumably through a
diazonium intermediate (with no formation of the correspond-
ing diazo compound) that undergoes either an SN2 or SN1
reaction.
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.7b02231.
Complete experimental and characterization data for all
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: helene.lebel@umontreal.ca.
ORCID
Helene Lebel: 0000-0001-8835-5786
́
̀
(15) Audubert, C.; Gamboa Marin, O. J.; Lebel, H. Angew. Chem., Int.
Ed. 2017, 56, 6294.
Notes
The authors declare no competing financial interest.
(16) See Supporting Information for the details of the optimization.
(17) 1,3-Propanedinitrite was prepared from 1,3-propanediol, sodium
nitrite, and sulfuric acid. The DSC-TGA spectra of 1,3-propane-
dinitrite revealed a slow evaporation of the material with no sudden
decomposition. CAUTION: although we have never experienced any
spontaneous explosion of this material, cautions should be exercised, as
thermal decomposition of 1,3-propanedinitrite results in the formation
of gases. See Supporting Information for details.
ACKNOWLEDGMENTS
■
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 Universite
the Centre in Green Chemistry and Catalysis (CGCC). We
would like to thank Dr. Pauline Ruliere and Dr. James J.
Mousseau for fruitful discussions.
́ ́
de Montreal, and
̀
D
DOI: 10.1021/acs.orglett.7b02231
Org. Lett. XXXX, XXX, XXX−XXX