Fluoroalkyl-Substituted Diazomethanes and Their Application in a General Synthesis of Pyrazoles and Pyrazolines

Article abstract of DOI:10.1002/chem.201601707

A novel continuous-flow approach for the synthesis of fluoroalkyl-substituted diazomethanes has been developed. Utilizing a cheap, self-made microreactor fluoroalkyl-substituted amines were transformed into the corresponding diazomethanes using tert-butyl nitrite and acetic acid as catalyst. These diazomethanes were employed in [2+3] cycloaddition reactions with olefins and alkynes, yielding valuable pyrazolines and pyrazoles in good to excellent yields.

Full text of DOI:10.1002/chem.201601707

DOI: 10.1002/chem.201601707
Communication
&
Diazo Compounds
Fluoroalkyl-Substituted Diazomethanes and Their Application in
a General Synthesis of Pyrazoles and Pyrazolines
Lucas Mertens+, Katharina J. Hock+, and Rene M. Koenigs*[a]
Abstract: A novel continuous-flow approach for the syn-
thesis of fluoroalkyl-substituted diazomethanes has been
developed. Utilizing a cheap, self-made microreactor fluo-
roalkyl-substituted amines were transformed into the cor-
responding diazomethanes using tert-butyl nitrite and
acetic acid as catalyst. These diazomethanes were em-
ployed in [2+3] cycloaddition reactions with olefins and
alkynes, yielding valuable pyrazolines and pyrazoles in
good to excellent yields.
The synthesis of functionalized, fluorinated heterocycles is of
major interest to both the pharmaceutical and agrochemical
industry. Fluorinated compounds often possess highly desired
properties, such as high lipophilicity and favorable metabolic
stability. Thus, the incorporation of fluorine into pharmaceuti-
cally active molecules plays a significant role in lead finding/
optimization processes. New operationally simple and broadly
applicable synthetic methods are highly desired to streamline
synthesis of this important class of building blocks.[1,2]
Figure 1. Fluoroalkyl-substituted pyrazoles.
Fluoroalkyl-substituted pyrazoles are a privileged class of
heterocycles and find widespread application in drug discovery
programs (Figure 1).[3,4] For example, COX inhibitors Celecoxib
1a[4a,b] and Deracoxib 1b[4b] contain a tri- and a difluoromethy-
lated central pyrazole moiety, respectively. Similarly, the antivi-
ral AS-136 A 3,[4c] factor Xa inhibitor Razaxaban 5,[4d] and TRPV-
1 modulator 6[4e] possess a central trifluoromethylated pyrazole
ring. Moreover, sulfonyl-substituted fluoroalkylated pyrazoles
4[4f] as well as long-chain perfluoroalkylated pyrazoles (RF =
C2F5, 2)[4g] find prominent applications as insecticides or as li-
gands of PtII complexes in opto-electronic devices (RF =C3F7,
C4F9).[4h]
Recently, the synthesis of trifluoromethyl diazomethane from
primary amines has been reported.[5–7] Morandi and Carreira re-
ported on the utilization of inorganic nitrites for the prepara-
tion of trifluoromethyl diazomethane and applications in cyclo-
propanation reactions.[5a] The synthetic applicability of trifluor-
omethyl diazomethane was further investigated in the past
years by different research groups,[5] for example in cyclopro-
panation[5b,d] and cycloaddition reactions.[5e,f] Recently, Mykhai-
liuk reported a new strategy for the preparation of these versa-
tile reagents using an organic nitrite for the acid-catalyzed syn-
thesis of difluoromethyldiazomethane and its application in
[2+3] cycloaddition reactions.[6,7] Yet, a generally applicable
method for the simple preparation of fluoroalkyl-substituted
diazomethanes and their application to organic synthesis is
still highly desired.
Thus, the development of new, efficient, easily scalable, and
broadly applicable synthetic methods for the rapid synthesis of
fluoroalkyl-substituted pyrazoles is of high interest. The [2+3]
cycloaddition reaction of fluoroalkyl-substituted diazome-
thanes with olefins and alkynes provides an atom-economic
approach for the direct synthesis of this structural class.
The challenge when working with diazomethanes is risk haz-
ards, which renders the utilization of special glass equipment
necessary. In particular, scale-up and multi-gram synthesis of
small molecules for development programs of drug candidates
require strong safety precautions when working with diazo
compounds. Thus the development of a safe and robust
method for the continuous-flow synthesis of diazomethane an-
alogues is of great interest.[8,9]
[a] L. Mertens,+ K. J. Hock,+ Prof. Dr. R. M. Koenigs
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: rene.koenigs@rwth-aachen.de
[+] These authors contributed equally to this work.
Herein, we report on the continuous-flow synthesis of fluo-
roalkyl-substituted diazomethanes[9m] using commercially avail-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201601707.
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able amines and tert-butyl nitrite and the application of these
valuable reagents in cycloaddition reactions. For the continu-
ous-flow synthesis of diazomethanes we utilize a simple, self-
made microreactor based on cheap, commercially available
PTFE tubing (inner diameter: 0.8 mm, length: 2 m, reactor
volume: 1 mL and an additional 20 psi back pressure regula-
tor). Using this technology, we could realize a broadly applica-
ble general protocol for the continuous-flow synthesis of fluo-
roalkyl-substituted diazomethanes and their subsequent appli-
cation in the synthesis of pyrazoles and pyrazolines.
Table 1. Substrate scope of difluoromethyl substituted pyrazoles and
pyrazolines.[a]
Dipolarophile
Product Yield[b]
We started our investigations towards the synthesis of fluo-
roalkyl-substituted diazomethanes by evaluating our self-made
microreactor in the synthesis of difluoromethyl diazomethane
and the subsequent addition to ethyl propiolate as a model
substrate (Scheme 1).
Scheme 1. Continuous-flow generation of difluoromethyl diazomethane and
subsequent application in [2+3] cycloaddition reactions (BPR=back-pres-
sure regulator).
First, we evaluated the role of the Brønsted acid catalyst for
the preparation of difluoromethyl diazomethane by monitoring
the yield of the addition reaction to ethyl propiolate. To our
surprise, acetic acid proved to be the best catalyst for the syn-
thesis of difluoromethyl diazomethane; all other Brønsted
acids examined provided the difluoromethylated product in
significantly decreased yield. Using chloroform as solvent,
5 mol% of acetic acid catalyst and a reaction temperature of
558C for the preparation of difluoromethyl diazomethane
proved to be the optimal reaction conditions, and we could
isolate the desired pyrazole 10a in excellent yield (93%).[10]
With the optimal conditions in hand, we investigated next
the reaction of difluoromethyl diazomethane, generated in
continuous-flow from primary amines and tert-butyl nitrite,
with a range of different, structurally diverse, electron-poor al-
kynes and olefins (Table 1).
[a] Reaction conditions: 0.5 mmol 9a–9l, 2,2-difluoroethylamine (2 eq),
tert-butyl nitrite (2.4 eq), AcOH (0.1 eq). A 0.1 mmolLÀ1 solution of 2,2-di-
fluoroethylamine and AcOH and tBuONO in CHCl3 was added using a sy-
ringe pump (flow rate 100 mLminÀ1) into a microreactor heated to 558C
(PTFE tubing, volume 1 mL, 20 psi BPR). The solution was added into a re-
action flask containing substrate and stirred for 14 h at RT. [b] Isolated
yield. [c] 0.25 mmol 9e, 2,2-difluoroethylamine (4 eq), tert-butyl nitrite
(4.8 eq), AcOH (0.2 eq). [d] Mixture of diastereoisomers.
find widespread use as agrochemicals. In a similar way, cyclic
olefins 9l react to the corresponding bicyclic systems 10l.
We also investigated the reaction of vinyl sulfones with fluo-
roalkyl-substituted diazomethanes for the first time, which
opens up a highly efficient atom-economic path towards fluo-
roalkylated, sulfonated pyrazolines 10j and 10k. This structural
class is important for applications in pharmaceutical and agro-
chemical industry for bioisosteric replacement of carbonyl
groups. Surprisingly, only few applications have been disclosed
yet, which might be due to limited synthetic methods for their
rapid synthesis.
We were able to show that the addition of difluoromethyl
diazomethane to different propiolic (9a–c) and acrylic acid
esters (9g) provided the desired pyrazoles and pyrazolines in
good to excellent yields. Further investigations on electron-
poor alkynes and olefins revealed that the ketones 9d and 9h
as well as disubstituted alkynes 9e and 9 f and olefins 9i pro-
vided the desired difluoromethylated pyrazoles and pyrazo-
lines in very good yields and with excellent selectivities. In par-
ticular, we could demonstrate, that double fluoroalkyl-substi-
tuted pyrazole 10e and pyrazoline 10i could be easily ob-
tained using this methodology. This structural class is of partic-
ular importance as double fluoroalkyl-substituted pyrazoles
In further investigations we applied this protocol to the con-
tinuous-flow preparation of trifluoromethyl diazomethane. In
contrast to previously described methods, we employed an or-
ganic nitrite and catalytic amounts of acetic acid for the prepa-
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ration of trifluoromethyl diazomethane. The advantage of this
method being, that no extraction, other workup, or purification
procedure is necessary for the application of this reagent in
chemical synthesis. We examined the [2+3] cycloaddition with
a selection of different alkynes and olefins, which reacted
smoothly to the desired trifluoromethylated pyrazoles and pyr-
azolines (Table 2).
Table 3. Substrate scope of fluoroalkyl-substituted diazomethanes and
their application in a [2+3] cycloaddition reaction with ethyl propiolate.[a]
Table 2. Substrate scope of the [2+3] cycloaddition of trifluoromethyl di-
azomethane yielding trifluoromethylated pyrazoles and pyrazolines.[a]
Dipolarophile
Product Yield[b]
[a] Reaction conditions: 0.5 mmol 9a, amine 7c–7j (2 eq), tert-butyl ni-
trite (2.4 eq), AcOH (0.1 eq). A 0.1 mmolLÀ1 solution of 7c–7j and AcOH
and tBuONO in CHCl3 was added by syringe pump (flow rate
100 mLminÀ1) into a microreactor heated to 558C (PTFE tubing, volume
1 mL, 20 psi BPR). The solution was added into a reaction flask containing
substrate and stirred for 14 h at RT. [b] Isolated yield. [c] 0.25 mmol 9a,
amine (4 eq), tert-butyl nitrite (4.8 eq), AcOH (0.2 eq).
[a] Reaction conditions: 0.5 mmol 9a–9h, 2,2,2-trifluoroethylamine (7b,
2 eq), tert-butyl nitrite (2.4 eq), AcOH (0.1 eq). A 0.1 mmolLÀ1 solution of
2,2-difluoroethylamine and AcOH and tBuONO in CHCl3 was added by sy-
ringe pump (flow rate 100 mLminÀ1) into a microreactor heated to 558C
(PTFE tubing, volume 1 mL, 20 psi BPR). The solution was added into a re-
action flask containing substrate and stirred for 14 h at RT. [b] Isolated
yield.
trite as a cheap organic nitrite source. Application in the [2+3]
cycloaddition reaction with ethyl propiolate yielded the de-
sired 3H-pyrazoles (Table 3, 17–19) in excellent yields.
Finally, we performed a series of derivatization reactions of
the herein-described pyrazoles 10a and 11 a. Methylation pro-
vided the N-methyl pyrazole 20 in excellent yield and Chan–
Lam coupling proved very efficient for the introduction N-aryl
substituents using aromatic boronic aicds (21,22)
(Scheme 2).[11] This way, we could demonstrate that upon
simple derivatization of previously described building blocks,
valuable intermediates for broad application in medicinal and
agrochemical industry can be obtained, for example for the
synthesis of factor Xa inhibitors or TRPV-1 modulators such as
5 and 6 in Figure 1.
In summary, we herein report on the acid-catalyzed synthe-
sis of fluoroalkyl-substituted diazomethanes in continuous-flow
using an organic nitrite source and the application of these re-
agents in cycloaddition reactions. We were able to demon-
strate for the first time that a range of different linear and sub-
stituted fluoroalkyl diazomethanes can be efficiently generated
in a safe and operationally simple way. These diazomethanes
were applied in [2+3] cycloaddition reactions with a broad va-
riety of different olefins and acetylenes yielding fluoroalkyl-
In a next step, we became interested in the general applica-
bility of this protocol for the preparation of different fluoroalk-
yl-substituted diazomethanes. Thus we decided to investigate
a range of different perfluoroalkyl-substituted methanamines
using our protocol (Table 3).
Indeed, we were able to demonstrate that different perfluor-
oalkyl-substituted methanamines react with tert-butyl nitrite to
the corresponding perfluoroalkyl-substituted diazomethanes.
These diazomethanes were subjected under our standard reac-
tion conditions to the [2+3] cycloaddition with ethyl propio-
late yielding the desired perfluoroalkyl-susbtituted pyrazoles
(Table 3, 12–16) in good to excellent isolated yields. It should
be noted that the corresponding monofluoromethyl substitut-
ed pyrazole was not obtained under these reaction conditions.
Further investigations concentrated on branched primary
amines using our continuous-flow protocol. We could demon-
strate that valuable a-branched trifluoromethyl diazomethanes
could be generated using different aliphatic and aromatic sub-
stituted 2,2,2-trifluoroethylamine derivatives and tert-butyl ni-
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Scheme 2. Application of fluoromethyl substituted pyrazoles in N-alkylations
and N-arylation reactions.
substituted pyrazolines and pyrazoles in good to excellent
yield.
Keywords: cycloaddition
· diazo compounds · fluorine ·
heterocycles · microreactors
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Received: April 12, 2016
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COMMUNICATION
&
Diazo Compounds
L. Mertens, K. J. Hock, R. M. Koenigs*
&& – &&
Fluoroalkyl-Substituted
Diazomethanes and Their Application
in a General Synthesis of Pyrazoles
and Pyrazolines
Fluoroalkyl-substituted diazome-
thanes could be generated from pri-
mary amines using a continuous-flow
microreactor. These valuable reagents
were applied in the synthesis of fluo-
roalkyl-substituted pyrazolines and pyra-
zoles (see scheme).
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