Batch and Continuous-Flow One-Pot Processes using Amine Diazotization to Produce Silylated Diazo Reagents

Article abstract of DOI:10.1002/anie.201612235

A novel synthesis of trimethylsilyldiazomethane (TMSCHN₂) by diazotization of trimethylsilylmethylamine (TMSCH₂NH₂) is reported using batch and continuous flow synthesis. The latter affords a daily production of 275 g (2.4 mol) of TMSCHN₂. Other silylated methylamines were also successfully reacted under the developed reaction conditions to furnish various silicon-bearing diazomethane reagents. The applicability of the process is highlighted by disclosure of batch and continuous flow one-pot esterification and 1,3-dipolar cycloaddition processes. Furthermore, the high-yielding esterification of carboxylic acids with silylated and substituted methylamines in continuous flow is disclosed. Finally, work-up and purification procedures are reported for the preparation of a 2-MeTHF solution of TMSCHN₂, which can be used in rhodium-catalyzed methylenation and homologation reactions.

Full text of DOI:10.1002/anie.201612235

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201612235
German Edition: DOI: 10.1002/ange.201612235
Diazo Compounds
Batch and Continuous-Flow One-Pot Processes using Amine
Diazotization to Produce Silylated Diazo Reagents
Clꢀment Audubert, Oscar Javier Gamboa Marin, and Hꢀlꢁne Lebel*
Abstract: A novel synthesis of trimethylsilyldiazomethane
example, diazomethane has been generated in flow from
ꢀ[9]
(
(
TMSCHN ) by diazotization of trimethylsilylmethylamine
commercially available Diazald
and N-methyl-N-nitro-
2
[
10]
TMSCH NH ) is reported using batch and continuous flow
sourea (MNU; Scheme 1). The continuous flow synthesis of
diazoesters and aryldiazomethanes from hydrazones has also
2
2
synthesis. The latter affords a daily production of 275 g
2.4 mol) of TMSCHN . Other silylated methylamines were
[
11]
(
been described.
2
also successfully reacted under the developed reaction con-
ditions to furnish various silicon-bearing diazomethane
reagents. The applicability of the process is highlighted by
disclosure of batch and continuous flow one-pot esterification
and 1,3-dipolar cycloaddition processes. Furthermore, the
high-yielding esterification of carboxylic acids with silylated
and substituted methylamines in continuous flow is disclosed.
Finally, work-up and purification procedures are reported for
Scheme 1. Continuous-flow approaches to synthesizing diazo
[9–11]
reagents.
EWG=electron-withdrawing group.
the preparation of a 2-MeTHF solution of TMSCHN , which
2
can be used in rhodium-catalyzed methylenation and homo-
logation reactions.
However, to the best of our knowledge, neither an
alternative synthesis to Shioiriꢁs procedure for TMSCHN2
D
iazo compounds are useful reagents which display
has been reported, nor a procedure to synthesize TMSCHN
2
[
12]
a unique reactivity. Because of the release of N , the various
by continuous flow (Scheme 2). This deficit may be because
2
ꢀ
addition and cycloaddition applications for which they
are utilized, furnish the corresponding products in a thermo-
dynamically irreversible fashion. However, the use of
these highly reactive intermediates is often limited by safety
concerns, particularly in the case of diazomethane. To
overcome these issues, safer alternative reagents have
been studied. For example, trimethylsilyldiazomethane
the TMS analogue of both Diazald and MNU is not readily
available. Furthermore, the instability associated with for-
[13]
mylsilanes
has precluded the use of methods involving
hydrazones to prepare TMSCHN2.
(
TMSCHN ), an easily handled stable liquid (b.p. 968C),
2
has been recognized as a safe substitute for hazardous
[
1,2]
diazomethane (CH N ).
TMSCHN has been used exten-
2
2
2
[
2,3]
sively in various reactions.
Improved chemoselectivity
relative to CH N is often observed because of the reactivity
Scheme 2. Possible strategies to synthesize TMSCHN .
2
2
2
profile of the more hindered and less basic TMSCHN . For
2
example, in the methylenation of aldehydes and ketones
disclosed by our group, CH N2 proved to be unreactive,
whereas high yields were obtained with TMSCHN2.
The diazotization of amines is an alternative strategy to
synthesize diazo reagents and is known to be efficient for the
2
[4,5]
[
14]
The synthesis of TMSCHN by the diazo-transfer reaction
production of electron-deficient diazo esters
and fluo-
2
[15]
[16]
of TMSCH MgCl with diphenyl phosphoryl azide has been
roalkyl-substituted diazomethane [Eq. (1)].
2
largely adopted because of the facile scalability of the
[
6]
process.
Despite these advantages, a few drawbacks
remain, including long reaction times (> 20 h), as well as the
tedious distillation of ether from TMSCHN . Continuous-
2
[7]
flow processes have been developed to safely prepare diazo
reagents and mitigate some of these challenges. For
[
8]
Such a method has, however, not been reported in the
preparation of nucleophilic diazo reagents, such as
[
*] C. Audubert, O. J. Gamboa Marin, Prof. Dr. H. Lebel
Dꢀpartement de chimie, Universitꢀ de Montrꢀal (Canada)
E-mail: helene.lebel@umontreal.ca
[
17]
TMSCHN2. Herein we disclose a novel batch and contin-
uous-flow synthesis of TMSCHN from TMSCH NH . One-
2
2
2
pot processes to perform esterification and 1,3-dipolar cyclo-
addition processes are described. Notably, the esterification
process is compatible with other amines, including secondary
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201612235.
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amines. Rhodium-catalyzed methylenation and homologation
reactions with a process-friendly 2-MeTHF solution of
studied. Such processes are highly advantageous as the
starting material is a simple amine and the isolation of the
diazo is avoided. For instance, esterification of various
carboxylic acids proceeded in high yields (Table 2). As the
reaction conditions are mild, no racemization was observed
for the synthesis of esters 3–5 and 7. Moreover, unprotected
indoles and free alcohols were tolerated, thus furnishing
esters 6 and 7 in quantitative yields.
TMSCHN are also delineated.
2
The synthesis of TMSCH NH (also commercially avail-
2
2
able) has been previously described to proceed in two steps
from TMSCH Cl via the corresponding azide reagent
2
18]
[
(
TMSCH N ). An alternative and direct route would be
2 3
highly desirable to avoid the use of the potentially explosive
azide (TMSCH N ), which necessitates distillation. To pre-
2
3
pare TMSCH NH in an inexpensive fashion, the reaction of
2
2
Table 2: One-pot esterification of carboxylic acids with TMSCH NH .
2
2
TMSCH Cl with NH OH in continuous flow was investigated
2
4
and the targeted amine was obtained in 48% yield following
purification (Scheme 3).
Scheme 3. Continuous-flow synthesis of TMSCH NH .
2
2
To mitigate this undesired byproduct, we applied a dini-
trite reagent, propyldinitrite [Pr(ONO) ], in 2-MeTHF to
2
afford TMSCHN in 62% yield using AcOH (Table 1,
2
[
19]
entry 1). Under these reaction conditions, the formation
of AcOMe, although observed at the end of the reaction, was
Yield is that of the isolated product. Boc=tert-butoxycarbonyl.
sufficiently slow to allow the production of TMSCHN . The
2
use of the more sterically hindered 1-adamantanecarboxylic
acid (AdCO H) and 4-nitrophenol (4-NO C H OH) pro-
Similarly, alkynes could be added to the crude TMSCHN2
mixture, and pyrazoles were produced in good to excellent
yields (Table 3). Ester pyrazoles 8–10 were synthesized in
high yields, whereas amide pyrazole 11 was obtained in good
yields. Pyridine-substituted alkynes were successfully reacted
to produce pyrazoles 12 and 13. Aromatic pyrazoles 14 and 15
were also synthesized in good yields using this process.
2
2
6
4
duced TMSCHN in 71 and 72% yield, respectively, with
2
a reaction time of 20 minutes (entries 2 and 3). The reaction
conditions were compatible with other silylated methyl-
amines: dimethylphenyl- and diphenylmethylsilyl diazome-
thane were produced under similar reactions in up to 77 and
7
3% yield, respectively (entries 5 and 6).
Having established reaction conditions to synthesize
TMSCHN , one-pot processes, in which the substrate is
directly added to the crude solution of the diazo reagent, were
2
Table 3: One-pot 1,3-dipolar cycloaddition of alkynes with TMSCH NH .
2
2
Table 1: Diazotization of R SiCH NH .
3
2
2
[
a]
Entry
R3Si
Acid
Yield [%]
1
2
3
4
5
6
7
Me Si
AcOH
62
71
72
63
77
3
Me Si
AdCO H
3
2
Me Si
4-NO C H OH
3
2
6
4
Me PhSi
AdCO H
2
4-NO C H OH
2 6 4
2
Me PhSi
2
[
b]
c]
MePh Si
AdCO H
73
71
2
2
[
a] RT, 60 h. [b] The 1,3-dipolar cycloaddition was performed in contin-
[
MePh Si
4-NO C H OH
À1
2
2
6
4
uous flow at 1008C for 30 min with a flow rate of 1.33 mLmin . [c] 508C,
36 h. [d] The 1,3-dipolar cycloaddition was performed in continuous flow
1
[
a] Yield determined by H NMR analysis using 1,2-diphenylethane as an
internal standard. [b] Reaction time=10 min. [c] Reaction time=40
min. THF=tetrahydrofuran.
at 1008C for 15 min, then 1208C for 15 min with a flow rate of
À1
1.33 mLmin
.
2
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[
20,21]
The crude reaction mixture of TMSCHN , containing
A one-pot continuous-flow esterification process
in
2
nitrite residues from the diazotization, cannot always be used,
which the carboxylic acid substrate was also used as the
reagent to perform the diazotization reaction, was next
as these inhibit some reactions, namely the metal-catalyzed
methylenation process. A work-up procedure using a mixture
of sodium sulfite and thioglycerol was thus developed to
remove the nitrite residues from the TMSCHN2 solution
developed. A solution of TMSCH NH2 in a mixture 2-
2
MeTHF and MeOH was mixed with a solution a propyldini-
trite and the carboxylic acid substrate in 2-MeTHF, then
[
Eq. (2)]. Distillation then afforded a 1.3m 2-MeTHF solution
heated at 908C in the reactor (Table 5). TMSCHN was thus
2
[
19]
of TMSCHN with greater than 99% purity.
2
Table 5: Continuous-flow esterification of carboxylic acids with amines.
The 2-MeTHF solution of TMSCHN was used in the
2
rhodium-catalyzed methylenation reaction of aldehydes. The
reaction conditions were compatible with 2-MeTHF (previ-
ously THF was the solvent of the reaction) and the
corresponding terminal alkenes were isolated in good to
excellent yields (Table 4).
Table 4: Rhodium-catalyzed methylenation of aldehydes with TMSCHN2
in 2-MeTHF.
2
[
a] 0.5m of TMSCH NH , 0.25m of R CO H and 0.4m of Pr(ONO) was
2
2
2
2
1
used. [b] R NH was in 2-MeTHF (no MeOH). [c] 0.5m of RNH , 0.1m of
R CO H and 0.16m of Pr(ONO) was used. [d] The reaction was
2
2
2
2
2
performed in batch for 20 min at 808C (no MeOH). [e] The reaction was
performed in CH Cl .
2
2
formed in situ and immediately consumed by the substrate in
the same reactor, thus producing esters 2, 4, 6, and 7 in high
yields after a 20 minute residence time. The versatility of
Yield is that of the isolated product.
[22]
this process was illustrated by the use of various substituted
amines to afford benzyl esters 20 and 21, allyl ester 22,
sterically hindered 1-phenylethyl ester 23, isopropyl ester 24,
and cyclohexyl ester 25 in excellent yields. The daily
production of 24 and 25 is, respectively, 605 mmol (153 g)
and 677 mmol (198 g). It is also possible to use the current
reaction conditions in batch to prepare 21, 23, and 25 in good
yields. Not only are these esters, derived from secondary
alcohols, notoriously difficult to prepare by standard esterifi-
cation processes, but no practical synthetic method is
currently available to prepare the corresponding diazo
reagents.
Furthermore, the homologation of a ketone was success-
fully performed, thus affording the corresponding alkyne 19
in high yields [Eq. (3)].
The diazotization reaction of TMSCH NH2 was then
2
performed in continuous flow (Scheme 4). A 0.65m solution
of TMSCHN was produced after a 16 minute residence time,
In conclusion, a novel synthesis of TMSCHN by diazo-
2
2
thus allowing a daily production of 2.4 mol (275 g).
tization of TMSCH NH has been developed in batch and in
2
2
continuous flow. This new protocol was used to synthesize
other silylated diazo reagents. A work-up procedure was
devised to produce a 2-MeTHF solution of TMSCHN with
2
9
9% purity, and it was successfully used in transition metal
catalyzed methylenation and homologation reactions.
TMSCHN was also used to produce pyrazoles in good to
2
excellent yields. Finally, one-pot esterification processes were
also reported, namely a continuous flow reaction which
allowed the in situ esterification of carboxylic acids with
Scheme 4. Continuous-flow synthesis of TMSCH N .
2
2
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various amines (including ones for which the diazo reagent is
currently not readily available) to produce esters in excellent
yields. The process is particularly suitable to prepare esters
derived from secondary alcohols.
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[
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 Canada Research Chair
Program, the Universitꢂ de Montrꢂal, and the Centre in
Green Chemistry and Catalysis (CGCC). We would like to
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2
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[
2
[11] Diazo reagents from hydrazones: a) H. E. Bartrum, D. C.
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Chem. Int. Ed. 2017, 56, 837; Angew. Chem. 2017, 129, 855.
[
12] TMSCHN has never been prepared, either by diazotization or
2
Conflict of interest
in continuous-flow synthesis. However, a commercially available
TMSCHN solution has been used in flow, namely to prepare
2
The authors declare no conflict of interest.
diazo ketones: see L. J. Martin, A. L. Marzinzik, S. V. Ley, I. R.
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[
13] a) R. B. Silverman, X. Lu, G. M. Banik, J. Org. Chem. 1992, 57,
Keywords: amines · diazo compounds · flow chemistry ·
esterification · synthetic methods
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2
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[
1] Seminal discovery: a) M. F. Lappert, J. Lorberth, Chem.
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[
[
[
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2
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1
[
[
3] According to Scifinder, TMSCHN has been used in over 5000
2
2016, 22, 9542.
publications since the year 2000.
4] a) H. Lebel, V. Paquet, C. Proulx, Angew. Chem. Int. Ed. 2001,
17] TMSCHN is 10000 times more nucleophilic than ethyl diazo-
2
acetate, and as nucleophilic as Danishefskyꢁs diene, according to
the nucleophilic scale established by Mayr:and co-workers T.
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[
5] This method had proven particularly useful for the methylena-
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[
[
[
19] See the Supporting Information for details.
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[
22] In contrast, previously reported diazomethane esterification in
continuous flow were all based on the generation of diazo-
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addition of the carboxylic acid; see References [9,10].
[
[
6] T. Shioiri, T. Aoyama, S. Mori, Org. Synth. 1990, 68, 1.
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Manuscript received: December 16, 2016
Final Article published: && &&, &&&&
4
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Communications
Diazo Compounds
Diazo made easy: The diazotization of
various amines, namely TMSCH NH to
2
2
C. Audubert, O. J. Gamboa Marin,
produce TMSCHN , is reported using
2
H. Lebel*
&&& — &&&
batch and continuous-flow synthesis.
One-pot esterification and 1,3-dipolar
cycloaddition processes are disclosed.
The esterification process combines the
in situ formation of the diazo reagent and
its immediate consumption by the sub-
strate, a process which is particularly
suitable for the preparation of esters from
secondary amines.
Batch and Continuous-Flow One-Pot
Processes using Amine Diazotization to
Produce Silylated Diazo Reagents
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