Rapid Organocatalytic Formation of Carbon Monoxide: Application towards Carbonylative Cross Couplings

Article abstract of DOI:10.1002/chem.202002746

Herein, the first organocatalytic method for the transformation of non-derivatized formic acid into carbon monoxide (CO) is introduced. Formylpyrrolidine (FPyr) and trichlorotriazine (TCT), which is a cost-efficient commodity chemical, enable this decarbonylation. Utilization of dimethylformamide (DMF) as solvent and catalyst even allows for a rapid CO generation at room temperature. Application towards four different carbonylative cross coupling protocols demonstrates the high synthetic utility and versatility of the new approach. Remarkably, this also comprehends a carbonylative Sonogashira reaction at room temperature employing intrinsically difficult electron-deficient aryl iodides. Commercial ¹³C-enriched formic acid facilitates the production of radiolabeled compounds as exemplified by the pharmaceutical Moclobemide. Finally, comparative experiments verified that the present method is highly superior to other protocols for the activation of carboxylic acids.

Full text of DOI:10.1002/chem.202002746

Accepted Article
Accepted Article
Title: Rapid Organocatalytic Formation of Carbon Monoxide:
Application towards Carbonylative Cross Couplings
Authors: Ben Zoller, Josef Zapp, and Peter Huy
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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the VoR from the journal website shown below when it is published
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To be cited as: Chem. Eur. J. 10.1002/chem.202002746
Link to VoR: https://doi.org/10.1002/chem.202002746
01/2020

10.1002/chem.202002746
Chemistry - A European Journal
RESEARCH ARTICLE
Rapid Organocatalytic Formation of Carbon Monoxide:
Application towards Carbonylative Cross Couplings
Ben Zoller,[a] Josef Zapp,[b] and Peter H. Huy*[a]
[a]
Ben Zoller, MSc, Dr. Peter Helmut Huy, Saarland University, Organic Chemistry, P. O. Box 151150, 66041 Saarbrücken, Germany
E-mail: peter.huy@uni-saarland.de; homepage: peterhuylab.de
[b]
Dr. Josef Zapp, Institute of Pharmaceutical Biology, Saarland University, Campus C 2.3, 66123 Saarbrücken, Germany
Supporting information for this article is given via a link at the end of the document.
Abstract: Herein, the first organocatalytic method for the
transformation of non-derivatized formic acid into carbon monoxide
(CO) is introduced. Formylpyrrolidine (FPyr) and trichlorotriazine
(TCT), which is a cost-efficient commodity chemical, enable this
decarbonylation. Utilization of dimethylformamide (DMF) as solvent
and catalyst even allows for a rapid CO generation at room
temperature. Application towards four different carbonylative cross
coupling protocols demonstrates the high synthetic utility and
versatility of the new approach. Remarkably, this also comprehends
a carbonylative Sonogashira reaction at room temperature employing
intrinsically difficult electron-deficient aryl iodides. Commercial 13C-
enriched formic acid facilitates the production of radiolabeled
compounds as exemplified by the pharmaceutical Moclobemide.
Finally, comparative experiments verified that the present method is
highly superior to other protocols for the activation of carboxylic acids.
Introduction
Carbon monoxide (CO) is one of the most important building
blocks in chemistry in both, academia and industry.[1,2]
Fundamental applications are, for example, carbonylative cross
couplings and hydrocarbonylations of alkenes and alkynes
(Scheme 1 A). Since CO is a highly toxic and flammable, odorless
gas, its utilization is inevitably associated with severe safety
hazards and risks. Therefore, compounds that liberate CO under
controlled conditions in stoichiometric quantities have been
developed (Scheme 1 B).[2] These so-called CO surrogates are
either directly added to the reaction mixture for the in situ CO
production, or CO is formed ex situ in a separate reaction vessel.
In the latter case, the CO generating and consuming process are
spatial separated, for which they do not need to be compatible.
Beneficially, this facilitates the substitution of gaseous CO
through a CO surrogate significantly. A gas exchange is secured
by a connection of the two chambers. Several two chamber gas
reactors have been constructed for the ex situ gas synthesis,[2,3a]
whereby some devices are even commercially available.[4]
Examples of common commercial CO surrogates[2] are (1)
carboxylic acid chlorides like COgen 1 and sila derivatives such
as SilaCOgen 2, which have been implemented by Skrydstrup
and Lindhardt mainly for the ex situ CO preparation.[2c,e,f,4] (2) N-
Formyl saccharin (3), the application of which has been pioneered
by Manabe (in situ) and Fleischer (ex situ).[2b,5] (3) Aryl formates
like 4, which have been discovered by Manabe for the in situ CO
production,[2b,g,6] and (4) metal carbonyl complexes like 5 as
introduced by Larhed for the in and ex situ CO release.[2i,7]
Scheme 1. Previous and this work. [TM] = transition metal catalyst, dba =
dibenzylidene acetone, DIPEA di-iso-propyl ethyl amine, FPyr N-
formylpyrrolidine, TCT = 2,4,6-trichloro-1,3,5-triazine, rt = room temperature.
=
=
In fact, formic acid (6) is an even simpler and significantly cheaper
source of CO, which has been initially applied in situ for
hydrocarbonylations of alkenes and alkynes and carboxylations
of aryl halides, respectively.[8,9] Furthermore, the group of Wu
published a range of protocols for carbonylative cross couplings
using the mixed anhydride of formic and acetic acid, which was
synthesized from Ac2O and HCO2H in prior.[10] In addition, the
same team discovered that carbodiimides promote the in situ
development of CO directly from methanoic acid.[11]
Certain heterogeneous catalysts[12] and Brønsted acids like
[13]
H2SO4
facilitate the ex situ decarbonylation of formic acid.
Eventually, Cantat and co-workers recently described a chemical
looping strategy for the decarbonylation of formic acid.[14] Therein,
methyl formate was transformed ex situ to CO and MeOH by
means of MeOK as transition metal-free catalyst.
So far, decarbonylation of methanoic acid typically requires
high reaction temperatures of 75-190 °C.[8-14] Lower temperatures
were only accomplished in rather specific cases.[10a,11b,12a] Under
1
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10.1002/chem.202002746
Chemistry - A European Journal
RESEARCH ARTICLE
consideration of the cost-efficiency of formic acid, the
development of approaches for its ex situ decarbonylation under
milder conditions (e.g. at room temperature) and with a broader
applicability constitutes an indispensable task.
Lately, our group discovered that Lewis bases[15] like 1-
formylpyrrolidine (FPyr) and dimethylformamide (DMF) catalyze
the transformation of carboxylic acids into the respective acid
chlorides by means of trichlorotriazine (TCT), which is also
denoted as cyanuric chloride (see Scheme
1
C
for
structure).[16a,17b] Indeed, TCT is the most cost-efficient reagent for
the activation of OH groups like in alcohols and acids besides
phosgene (COCl2).[16a] Since cyanuric chloride contains three Cl
atoms, it can be applied in substoichiometric quantities down to
33 mol% with respect to the substrate (100 mol%). In fact, the
beneficially low stoichiometry is facilitated by formamide catalysis.
Against this background, we envisioned a novel ex situ CO
formation approach based on formic acid (Scheme 1 C).
Activation of formic acid should either yield formyl chloride
7 or an intermediate like I, which bears a similarly good leaving
group as chloride. Actually, formic acid chloride is known to be
labile towards decarbonylation, wherefore a rapid decomposition
to CO was predicted.[18] Surprisingly, CO evolution from
methanoic acid using common chlorination agents has not been
reported in the realm of transition metal catalyzed transformations
so far.[19] Actually, organocatalytic conversion of HCO2H into CO
is a challenging task, which has so far only been accomplished
through preceding derivatization to methyl formate.[14,20] Herein, a
novel operationally simple method for the transformation of formic
acid into CO based on organocatalysis and ex situ application
towards four different carbonylative cross couplings is disclosed.
Results and Discussion
Figure 1. Gas volumetry to follow CO formation. n(gas) = amount of gas as
determined by the ideal gas equation, n0(HCO2H) = initial amount of formic acid,
At the outset, the reaction of methanoic acid with TCT was
investigated by means of gas volumetry (Figure 1, see chp. 2 of
the supporting information = SI for details). The use of DMF as
solvent and catalyst enabled a rapid CO generation already at
room temperature (Figure 1 A, see chp. 2.2 of the SI). Notably,
DMF is a common and inexpensive organic solvent. When TCT
was applied in excess (41 mol% = 1.2 equiv) with respect to
methanoic acid (1.0 equiv), already after 4.5 min (= t2/3) a gas
yield n(gas)/n0(HCO2H) of >67% was noted (green points). Since
at room temperature solvent and HCl evaporation can be
neglected, the gas yield is equivalent to the yield of CO and
consequently also conversion of formic acid. In the present work,
at most 1.5 equiv of HCO2H were engaged in the carbonylative
transformations (see Scheme 2 and 3). Hence, 67% conversion
comply to 1 equiv of CO being generated. After 75 min 98% gas
yield were reached, which substantiates an almost quantitative
conversion of 6. Such a fast CO generation was not expected,
since under catalytic conditions a similarly rapid conversion of
carboxylic acids into acid chlorides afforded heating to 80 °C.[16a]
To the best of our knowledge, only SilaCOgen (2), which is more
THF
=
tetrahydrofuran, EtOAc
=
ethyl acetate, 2-MeTHF
=
2-
methyltetrahydrofurane.
Nevertheless, after 90 min 80% yield in terms of CO had
been accomplished. This verifies the partial substitution of the
third Cl atom of TCT, as also observed in the cases of carboxylic
acid and alcohol chlorinations (see mechanism in Scheme
4).[16a,17b] From a solvent screening using 10 mol% of FPyr at
70 °C MeCN and THF emerged as optimal (chp. 2.3 in the SI).
Remarkably, the initial rate of gas formation in DMF at room
temperature was four times faster than in MeCN at 70 °C.
Eventually, a variation of the catalyst loading in MeCN
demonstrated the tremendous effect of FPyr (Figure 1 C, chp. 2.4
in the SI). In these measurements the reaction mixture was
heated to 70 °C for 60 min. Both, the gas yield after cooling down
to ambient temperature and the initial rate clearly increased from
5 over 10 to 30 mol% of FPyr (green points). Interestingly, a
slower development of gas was observed using 10 mol% of DMF
(yellow points) than with 5 mol% FPyr, which attests the latter as
superior organocatalyst. The blue data points indicate the
formation of gas in the absence of TCT, which was similar to
heating MeCN to 70 °C (see chp. 2.4, SI). Therefore, the formed
gas consists only of evaporated solvent. As an important aspect,
the gas amount was even slightly lower in the absence of FPyr
(red points). This highlights the importance of FPyr as catalyst:
Without this formamide basically no CO is created at all.
expensive than formic acid, allows
a similarly fast gas
development.[4b] Although very limited kinetic data is available,
based on the reported reaction temperatures the current
approach enables a considerably faster CO formation than other
procedures using formic acid.[8-14] With an excess of formic acid
(2 equiv) with regard to TCT (33 mol% = 1 equiv) the evolution of
gas is slower (yellow points).
2
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To probe the synthetic utility, in several carbonylative cross
couplings either gaseous CO or another CO surrogate was
substituted by the present approach (Scheme 2). These reactions
were carried out in a commercial two chamber gas reactor named
COware from Sytracks, which facilitates the spatially separated
ex situ formation of CO (see Scheme 1 C and chp. 3.2 in the SI).[4]
In carbonylative transformations at elevated temperatures CO
was generated using 10 mol% of FPyr in reaction chamber 1
(Scheme 2 A). As a first example, SilaCOgen (2)[4b] and
Mo(CO)6,[7c] respectively, were replaced by the present method in
the aminocarbonylation of aryl halides 8 (Scheme 2 B). An
increase of the NEt3 amount in the chamber 2, in which the
amincarbonylation was carried out, by the amount of methanoic
acid employed (1.5 equiv) facilitated the neutralization of HCl,
which arose from the decarbonylation.
Importantly, production of CO using different solvents
furnished amide 10a in good yields of 81-91% at 80 °C, which was
required for the C-N cross coupling (Scheme 2 C). Albeit the
solvent has a significant impact on the rate of CO evolution (see
above), the mitigated effect on the yield of 10a may be explained
by a rather sluggish direct coupling of butyl amine and aryl iodide
8a. In addition, CO production at room temperature in DMF
afforded 10a in 84% yield (for conditions see Scheme 3 A). Thus,
different solvents can be engaged in the CO generating and
consuming process, cross diffusion causes no considerable
difficulties. In general, CO formation in DMF is recommended for
carbonylative transformations that are carried out at temperatures
below 70 °C. At higher temperatures catalytic CO release
preferably in MeCN, THF or dioxane is basically equally efficient.
In fact, FPyr could also be substituted by the twofold amount
of simpler DMF, which furnished the amide 10a in 85% yield. Also
aryl bromides 11 could be engaged as starting materials, when
the reaction temperature was increased to 100 °C. Worthy of note,
in situ CO preparation is in general less suitable for
aminocarbonylations, since CO surrogates are usually
electrophilic and hence react with amines.[7c] Indeed, attempted in
situ CO release in one reaction vessel furnished 10a only in minor
traces ≤3%, which testifies the crucial role of two chamber gas
reactor. A high synthetic utility is witnessed by the preparation of
the insecticide DEET (10c) and the pharmaceutical Moclobemide
10b (Scheme 2 D). Actually, the use of commercial H13CO2H as
CO surrogate afforded isotopically labeled 10b. This example
also unambiguously accounts for formic acid as CO source and
is, to the best of our knowledge, the first example for the
application of 13C enriched formic acid in a carbonylative
transformation. Moreover,
a
reasonable scalability was
demonstrated by the gram synthesis of amide 10j.
Furthermore, in the alkoxycarbonylation of aryl bromides 11
an atmosphere of CO[21a] and formic acid decarbonylation at
150 °C using zeolite,[12b] respectively, were substituted by the
current methodology (Scheme 2 E). This process and the
aforementioned aminocarbonylation allowed the synthesis of the
products 10d, 12a and 12b with acid-labile functions (Scheme 2
F). These precedents evidence that the simultaneous HCl
formation exerts no influence on the functional group compatibility.
Thereby, particularly remarkable is example 12b, which bears a
highly acid susceptible acyclic acetal. Furthermore, formamide
catalyzed CO release could replace COgen (1) in the preparation
of -nitro ketone 13a from nitromethane and the respective iodide
8a (Scheme 2 G).[21b]
Scheme 2. Application of the organocatalytic CO formation (A) towards various
carbonylative cross couplings at elevated temperatures (B-G). Yields refer to
isolated material after chromatographic purification. For detailed reaction
conditions see SI. Bn = benzyl, PMP = para-methoxyphenyl.
3
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Ultimately, in a challenging carbonylative Sonogashira
coupling at room temperature gaseous CO[22a] was substituted by
the present approach using DMF as solvent (Scheme 3). Albeit in
most cases CO was formed at room temperature in DMF as
solvent (Scheme 3 A), examples 15a+b show that catalytic CO
release at 80 °C is also feasible. Especially in the case of electron
deficient aryl iodides of type 8 the direct Sonogashira coupling
without CO incorporation usually is predominant.[23]
levels of CO incorporation. As an important feature, the present
method is operationally simple and does not require a reaction
setup in a glove box to exclude air like some other CO surrogates
(see also graphical procedure in chp. 3.2.2 in the SI).
To the best of our knowledge, reactions of formic acid with
ordinary chlorination agents like oxalyl and thionyl chloride have
so far not been harnessed to access CO for carbonylative
transformations. Against this background, a rigorous comparative
assessment against other protocols for the activation of carboxylic
acids was carried out (Scheme 4). Thereby, several experiments
for each method were conducted under variation of the amount of
base, which is why ranges of yields are stated (see also chp. 1.2
in the SI).
Scheme 4. Comparative aminocarbonylations. For detailed reaction conditions
see SI, yield determined with internal standard. [a] isolated yield. NMM = N-
methylmorpholine.
Indeed, reaction of formic acid with either thionyl or oxalyl chloride
(SOCl2 or C2O2Cl2)[19] afforded the model amide 10a in low yields
of 5-8% and 44-54%, respectively, while the current method
provides this amide in 81% yield. Despite in situ use of the mixed
anhydride of formic and acetic acid allows carbonylative cross
couplings,[10] ex situ preparation from Ac2O and 6 delivered 10a
in synthetically non-useful yields of 37-42%. TCT and the amine
base NMM have been engaged for the activation of carboxylic
acids as mixed anhydrides with cyanuric acid.[24] When this
protocol was applied to methanoic acid, amide 10a arose in yields
of 51-56%. Hence, the current organocatalytic approach is indeed
superior to other carboxylic acid activation strategies.
Scheme 3. A CO formation and B carbonylative Sonogashira coupling at room
temperature. mTol = meta-tolyl, a. For conditions see Scheme 2 A. b. Prepared
from 2.5 equiv of formic acid and 95 mol% TCT. EWG = electron withdrawing
group, mTol = meta-tolyl.
The gas volumetric measurements confirmed that basically
no decarbonylation takes place without FPyr (Figure 1 C). In
contrast, the amide 10a was still obtained in 35-42% yield, when
FPyr was omitted. A likely explanation for this result is the
diffusion of NEt3 from the CO consuming chamber 1 into the CO
producing chamber 2, which could effect mixed anhydride
activation as in the case of TCT/NMM (see above).
In alignment to our previous work,[16a] the CO formation
should be initiated by a nucleophilic aromatic substitution (SNAr)
of a Cl atom of TCT through FPyr (Scheme 5). The emerging
intermediate IIa shows structural similarities to the Vilsmeier
Haack reagent. Next, substitution with formic acid would deliver
salt I and dichlorohydroxytriazine (16). Intermediate I possesses
a good leaving group and could undergo decarbonylation directly.
Alternatively, I could also proceed a nucleophilic substitution
to yield formyl chloride (7), which is labile and would consequently
decompose to CO and HCl.[18] As demonstrated through the gas
volumetry with an excess of HCO2H (Figure 1 A), 16 passes
sequential transformation with FPyr and methanoic acid to
generate intermediate I and chlorodihydroxytriazine (17). Finally,
the remaining Cl atom of 17 is at least in part replaced by FPyr to
again afford carboxy iminium salt I and cyanuric acid. This was
In the past, this problem has been circumvented by
exploitation of the expensive and sensitive ligand P(tBu)3.[23b] In
contrast, the present approach allows for the synthesis of the
ynones 15e-h even derived from highly electron poor aryl iodides
containing nitro groups using plain PPh3 (Scheme 3 C). Indeed,
under standard conditions with 1.5 equiv CO ynone 15f, which is
deduced from electron-deficient para-cyanophenyl iodide, was
formed as side-product in 31% yield besides the respective
Sonogashira coupling product in 40% yield (Scheme 3 C and SI).
An increase of the amount of CO to 2.5 equiv resulted in a minor
improvement of the yield to 41%. However, when CuI was omitted,
the desired ketone 15f could be isolated in 69% yield. Moreover,
even electron poorer 4-nitrophenyl iodide could be transformed
into the corresponding carbonylated product 15g in 59-62% yield.
As an important aspect, also more reactive aryl alkynes, are
suitable substrates, as confirmed by the synthesis of ynone 15i.
Again, without CuI the yield could be essential improved from 55
to 91%.
Moreover, the amide 10a was formed in up to 88% yield
when formic acid was engaged as yield-limiting starting material
(1.0 equiv, see chp. 1.3 in the SI). This outcome proves high
4
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RESEARCH ARTICLE
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Scheme 5. Proposed mechanism.
Conclusion
[3]
The first organocatalytic method for the ex situ formation of CO
from non-derivatized formic acid has been presented. Formamide
catalysis enabled the transformation into CO by means of
substoichiometric amounts of the bulk chemical TCT. As an
important aspect, utilization of DMF as solvent and catalyst
facilitates
a rapid CO generation at room temperature.
Implementation to four different carbonylative cross couplings,
which also includes a carbonylative Sonogashira reaction at room
temperature with challenging electron poor aryl iodides, proved
high synthetic value. High levels of practical relevance were
certified by the synthesis of the bioactive compounds, namely
DEET and Moclobemide.
[4]
a) P. Hermange, A. T. Lindhardt, R. H. Taaning, K. Bjerglund, D. Lupp,
T. Skrydstrup, J. Am. Chem. Soc. 2011, 133, 6061-6071; b) S. D. Friis,
R. H. Taaning, A. T. Lindhardt, T. Skrydstrup, J. Am. Chem. Soc. 2011,
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Lindhardt, M. S. Valle, R. P. Freitas, T. Skrydstrup, Org. Lett. 2019, 21,
5775-5778; commercial gas reactors (COWare) are available at Sytracks
(https://www.sytracks.com/) and via Sigma-Aldrich.
In addition, isotopically labeled molecules like the drug
Moclobemide are amenable using commercial 13C-enriched
formic acid. Although HCl is generated simultaneously, even very
acid sensitive functional groups are fully compatible. In order to
exchange gaseous CO or other CO surrogates through the
current methodology, the amount of base simply has to be
adapted according to the amount of formic acid. Finally,
comparison experiments witnessed that the present approach is
superior to other common carboxylic acid activation procedures.
We are convinced that the high levels of synthetic utility and
versatility and the low costs associated will pave the way for a
rapid uptake of the current approach. Current efforts are
dedicated towards the exploitation of CO and HCl for product
incorporation.
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Acknowledgements
We want to thank the German research foundation (DFG) and the
Fonds of the Chemical Industry (Liebig fellowship for P. H.) for
generous support. In addition, we would like to thank Rudolf
Thomes for measuring HR-MS.
Keywords: carbon monoxide • C1 building blocks •
carbonylation • homogenous catalysis • CO surrogates •
organocatalysis
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Entry for the Table of Contents
Double Formicable: A simple formamide catalyst enables the rapid transformation of formic acid into carbon monoxide (CO) using
inexpensive trichlorotriazine (TCT). Application towards four different carbonylative cross couplings down to room temperature
showcases high levels of synthetic utility and versatility. The organocatalytic ex situ formation of CO using commercial H13CO2H
allows the synthesis of radiolabeled compounds such as the drug Moclobemide.
@peterhuylab
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