N-Formylation of amines by methanol activation

Article abstract of DOI:10.1021/ol400639m

The homogeneous catalyzed dehydrogenation of methanol in a synthetically valuable cross-coupling reaction was achieved. By the use of a simple ruthenium-N-heterocyclic carbene complex, MeOH and primary or secondary amines can be converted into formamides.

Full text of DOI:10.1021/ol400639m

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
N‑Formylation of Amines
by Methanol Activation
Nuria Ortega, Christian Richter, and Frank Glorius*
€
€
€
Westfalische Wilhelms-Universitat Munster, Organisch-Chemisches Institut,
Corrensstrasse 40, 48149 Mu€nster, Germany
glorius@uni-muenster.de
Received March 11, 2013
ABSTRACT
The homogeneous catalyzed dehydrogenation of methanol in a synthetically valuable cross-coupling reaction was achieved. By the use of a
simple ruthenium-N-heterocyclic carbene complex, MeOH and primary or secondary amines can be converted into formamides.
Methanol, the simplest alcohol, is a raw material used to
prepare hundreds of products present in our daily life, and
by volume, it is one of the top five chemicals shipped around
the world per year. As one of the most basic chemicals,
methanol can be converted into key building blocks, such
as acetic acid, formaldehyde, and olefins, and can also be
used as a fuel source.1 However, all the industrial trans-
formations of methanol to higher oxidation states require
the use of harsh conditions and significant energy con-
sumption. Consequently, an alternative to these processes
that could activate methanol to form interesting building
blocks in a greener and more sustainable manner would
be highly desirable.2
previous reports concerning this transformation, the
breakthrough in this field was made by Milstein, utilizing
Pincer complexes based on ligand cooperativity of a pyridine
aromatization/dearomatization process.3 This pioneering
work opened the door to the application of this concept to
very creative and elegant approaches, which led to different
types of substrates, such as amides,4 imines,5 imides,6 acetals,7
and even heterocycles, including pyrroles8 (Scheme 1).
Despite significant advances in the activation of alco-
hols, the use of smaller alcohols still constitutes a big
challenge. Even though the potential in terms of further
applications of the oxidized intermediate is very appealing,
limited progress has been made in the dehydrogenation of
In recent years, great advances have been made in the
area of alcohol activation. A remarkable example is the
acceptorless dehydrogenative coupling of primary alco-
hols (ADC) to give the corresponding esters, which is an
environmentally friendly and atom-efficient alternative to
the classic approach based on the esterification of car-
boxylic acids. Established methods typically require acti-
vation of the carboxylic acid or the use of stoichiometric
amountsof condensing reagents, generating a considerable
amount of waste. In stark contrast, the ADC transforma-
tiongenerates hydrogen gas as the only byproduct. Despite
(3) (a) Zhang, J.; Leitus, G.; Ben-David, Y.; Milstein, D. J. Am.
Chem. Soc. 2005, 127, 10840. (b) Gunanathan, C.; Milstein, D. Acc.
Chem. Res. 2011, 44, 588. (c) Milstein, D. Top. Catal. 2010, 53, 915.
(4) (a) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007,
317, 790. (b) Prechtl, M. H. G.; Wobser, K.; Theyssen, N.; Ben-David,
Y.; Milstein, D.; Leitner, W. Catal. Sci. Technol. 2012, 2, 2039. (c)
Prechtl, M. H. G.; Ben-David, Y.; Giunta, D.; Busch, S.; Taniguchi, Y.;
€
Wisniewski, W.; Gorls, H.; Mynott, R. J.; Theyssen, N.; Milstein, D.;
Leitner, W. Chem.;Eur. J. 2007, 13, 1539.
(5) Gnanaprakasam, B.; Milstein, D. Angew. Chem. 2010, 122, 1510.
Angew. Chem., Int. Ed. 2010, 49, 1468.
(6) Zhang, J.; Senthilkumar, M.; Gosh, S. C.; Hong, S. H. Angew.
Chem. 2010, 122, 6535. Angew. Chem., Int. Ed. 2010, 49, 6391.
(7) Gunanathan, C.; Shimon, L. J. W.; Milstein, D. J. Am. Chem.
Soc. 2009, 131, 3146.
(8) Schley, N. D.; Dobereiner, G. E.; Crabtree, R. H. Organometallics
2011, 30, 4171.
(9) (a) Morton, D.; Cole-Hamilton, D. J. J. Chem. Soc., Chem.
Commun. 1988, 1154. (b) Shinoda, S.; Yamakawa, T. J. Chem. Soc.,
Chem. Commun. 1990, 1511. (c) Pearson, D. M.; Waymouth, R. M.
Organometallics 2009, 28, 3896.
(1) For more detailed information about methanol production and
use, see: www.methanol.org.
(2) Constable, D. J.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.;
Leazer, J. L., Jr.; Linderman, R. L.; Lorenz, K.; Manley, J.; Pearlman,
B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411.
r
10.1021/ol400639m
XXXX American Chemical Society

methanol.9 Apparently, the energybarrier tothe activation
of smaller alcohols appears to be too uphill for the
established catalysts.10 So far the use of methanol has been
only successfully applied by Beller very recently,11 who
reported a Ru catalyzed dehydrogenation of methanol to
generate hydrogen gas, as well as the Ir catalyzed hydro-
xymethylation by direct coupling of methanol with allenes
by Krische.10 Yet, in the field of smaller alcohols activa-
tion, in the past year Beller12 and Gusev13 reported the first
catalytic acceptorless dehydrogenations of ethanol to form
ethyl acetate, by the development of new Ru and Os based
catalysts. Consequently, weproposedthattheactivationof
carbene (NHC) system which can reduce quinoxalines,15
benzofurans,16 thiophenes, and benzothiophenes17 with
high levels of regio- and enantioselectivity. During these
studies, the Ru-NHC complex (3) used for the racemic
reactions proved to be a highly reactive and efficient
catalyst in most of the transformations. Therefore, we
decided to test this catalyst as a promoter for ADC
processes. As test reactions we explored ester and amide
formation. To our delight, on heating 1-nonanol in an
open system under an argon flow in refluxing toluene, in
the presence of 0.1 mol % of the Ru complex 3, we
obtained the corresponding ester in 97% isolated yield.
Moreover, we also obtained the corresponding amide in
99% isolated yield under similar conditions starting from
1-nonanol and cyclohexylamine (Scheme 2). Although the
acceptorless dehydrogenative coupling processes using
Ru-NHC complexes were previously reported,18 these
require basic conditions and additional ligands for activa-
tion of the catalyst (such as phosphines, pyridine or
acetonitrile). The present system, in contrast, is base- and
phosphine-free. The reaction proceeds equally well using
the isolated complex 3, or by preforming the catalyst
starting from a commercially available Ru precursor, the
corresponding imidazolium salt, and base in the reaction
vessel.
Scheme 1. Selected Examples of Acceptorless Dehydrogenative
Coupling
With these promising results in hand, we proceeded to
test the activity of our Ru catalyst in the challenging
methanol activation, in particular, in a synthetically valu-
able cross-coupling reaction with amines. In this reaction
methanol and thereof successful application into interest-
ing transformations may be achieved by the design of new
and more reactive catalytic systems.
Scheme 2. Formation of Esters and Amides Catalyzed by
Complex 3a
An interesting feature of Milstein-type complexes is
that, under a hydrogen atmosphere, they can catalyze
the reverse reaction of the ADC, promoting the hydro-
genolysis of esters, amides, ketones, or ureas under mild
and neutral conditions, to the corresponding alcohols and
amines.14 Based on our interest in the development of new
catalysts for the hydrogenation of (hetero)aromatic com-
pounds, we recently reported a ruthenium-N-heterocyclic
(10) Moran, J.; Preetz, A.; Mesch, R. A.; Krische, M. J. Nat. Chem.
2011, 3, 287.
(11) Nielsen, M.; Aberico, E.; Baumann, W.; Drexler, H.-J.; Junge,
a Ester formation: Catalyst 3 (0.015 mmol), nonanol (15 mmol), and
toluene (15 mL) were heated at reflux under an Ar flow for 24 h. Amide
formation: Catalyst 3 (0.03 mmol), nonanol (2.25 mmol), cyclohexyl-
amine (1.5 mmol), and toluene (1.5 mL) were heated at reflux under an
Ar flow for 24 h. Isolated yields are given. Cy = cyclohexyl.
H.; Gladiali, S.; Beller, M. Nature 2013, 495, 85.
(12) (a) Nielsen, M.; Junge, H.; Kammer, A.; Beller, M. Angew.
Chem. 2012, 124, 5809. Angew. Chem., Int. Ed. 2012, 51, 5711. (b)
Nielsen, M.; Kammer, A.; Cozzula, D.; Junge, H.; Gladiali, S.; Beller,
M. Angew. Chem. 2011, 123, 9767. Angew. Chem., Int. Ed. 2011, 50,
9593.
(13) (a) Spasyuk, D.; Smith, S.; Gusev, D. A. Angew. Chem. 2012,
124, 2826. Angew. Chem., Int. Ed. 2012, 51, 2772. (b) Spasyuk, D.;
Gusev, D. A. Organometallics 2012, 31, 5239.
(15) Urban, S.; Ortega, N.; Glorius, F. Angew. Chem. 2011, 124,
3844. Angew. Chem., Int. Ed. 2011, 50, 3803.
(16) (a) Ortega, N.; Urban, S.; Beiring, B.; Glorius, F. Angew. Chem.
2012, 124, 1742. Angew. Chem., Int. Ed. 2012, 51, 1710. (b) Ortega, N.;
Beiring, B.; Urban, S.; Glorius, F. Tetrahedron 2012, 68, 5185.
(17) Urban, S.; Beiring, B.; Ortega, N.; Paul, D.; Glorius, F. J. Am.
Chem. Soc. 2012, 134, 15241.
(18) (a) Nordstrøm, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc.
2008, 130, 17672. (b) Dam, J. H.; Osztrovszky, G.; Nordstrøm, L. U.;
Madsen, R. Chem.;Eur. J. 2010, 16, 6820. (c) Ghosh, S. C.; Muthaiah,
S.; Zhang, Y.; Xu, X.; Hong, S. H. Adv. Synth. Catal. 2009, 351, 2643. (d)
Chen, C.; Zhang, Y.; Hong, S. H. J. Org. Chem. 2011, 76, 10005.
(14) (a) Zhang, J.; Leitus, G.; Ben-David, Y.; Milstein, D.; Balaraman,
E.; Ben-David, Y.; Milstein, D. Angew. Chem. 2006, 118, 1131. Angew.
Chem., Int. Ed. 2006, 45, 1113. (b) Balaraman, E.; Gnanaprakasam, B.;
Shimon, L. J. W.; Milstein, D. J. Am. Chem. Soc. 2010, 132, 16756. (c)
Balaraman, E.; Ben-David, Y.; Milstein, D. Angew. Chem. 2011, 123,
11906. Angew. Chem., Int. Ed. 2011, 50, 11702. (d) Langer, R.; Leitus, G.;
Ben-David, Y.; Milstein, D. Angew. Chem. 2011, 123, 2168. Angew.
Chem., Int. Ed. 2011, 50, 2120. (e) Balaraman, E.; Fogler, E.; Milstein, D.
Chem. Commun. 2012, 48, 1111. (f) Tanaka, R.; Yamashita, M.; Nozaki,
K. J. Am. Chem. Soc. 2009, 131, 14168.
B
Org. Lett., Vol. XX, No. XX, XXXX

the corresponding formamides would be obtained. Form-
amides are very important in the synthesis of pharma-
ceutically active compounds, useful reagents in Vilsmeier
formylation reactions,19 and formamidines.20 Most re-
ported N-formylations of amines involve moisture sensi-
tive, expensive, or toxic reagents,21 and therefore the use of
methanol as a cheap and readily available formylating
agent would be very attractive.22 The most significant
difficulties to overcome in developing this method, besides
the activation of methanol itself, is to control the selectivity
in the cross-coupling reaction and to avoid further reac-
tions of the products.23
Scheme 3. Scope for the N-Formylation of Aminesa
The study for the activation of methanol started using
our previously optimized conditions for amide synthesis.
Unfortunately, under these conditions we observed traces
of the desired product, recovering the cyclohexylamine
unreacted. However, when the amount of methanol was
increased to 3.3 equiv, we obtained N-cyclohexylforma-
midein63% isolatedyield, with no side products observed.
Attempts to improve the yield of the reaction by varying
the equivalents of reactants, concentration, solvent, or
temperature unfortunately were unsuccessful.24 However,
we observed that the reaction also proceeded in a sealed
tube, albeit with a lower yield (26%). It was also noted that
when we opened the reaction vessel, a release of pressure
from the system occurred (presumably from evolution of
hydrogen gas). Thus, we considered the possibility of the
addition of a sacrificial hydrogen acceptor to trap the
hydrogen generated during the catalytic cycle, shifting
the equilibrium and driving the reaction to a better yield.
After testing a series of different additives,24 styrene
proved to be the best choice, leading to a 96% conversion
to the desired formamide under optimized conditions. Even
though the use of styrene as a hydrogen acceptor is not ideal
for green methods, it is a cheap reagent and generates
ethylbenzene, which is nontoxic and is easy to separate from
the products. Interestingly, we never observed methylation
of the amine, which could be generated by reductive amina-
tion of the formaldehyde with the amine, as a consequence
of the borrowing hydrogen process.
a General conditions: [Ru(cod)[2-methylallyl)2] (0.03 mmol), KOt-Bu
(0.075 mmol), and ICy HCl (dicyclohexylimidazolium chloride) (0.06
3
mmol) were stirred at 70 °C in toluene (1.5 mL) for 12 h, with subsequent
addition of the amine 4aÀq (1.5 mmol), methanol (5 mmol), and styrene
b
(4.5 mmol), and the reaction mixture was heated at 125 °C for 24 h.
Reaction carried out with 4% catalyst loading. Isolated yields are given.
yield, and to test the tolerance to functional groups, we
used different benzylamine derivatives (4gÀi). We ob-
served that the reaction is not affected by the presence of
halogens or the methoxy group (no loss or transformation
of these functional groups), but we obtained lower yields
than expected (in comparison to the benzylamine) due to
further reaction of the formamide. In the case of phenyl-
ethylamine (5k), when we used enantiomerically pure
starting material, no erosion of the enantiomeric purity
was observed. The reaction also works well for secondary
amines (which are usually less reactive or not reactive at all
in dehydrogenative processes), presenting good yields for
linear substrates (5lÀm) and good to excellent for cyclic
amines (5nÀq). However, the reaction does not proceedfor
less nucleophilic amines such as anilines or in the presence
of good coordinating groups including pyridines or car-
boxylic acids.
Subsequently, we explored the scope and limitations of
the method, testing a range of different amines (Scheme 3).
Sterically nonhindered primary amines reacted smoothly
to give the desired products in very clean reactions and
high yields (5aÀd). For more hindered amines, such as the
adamantylamine (4e) the yield decreaseddramatically. The
reaction workedwellfor the benzylamine, giving5fingood
To investigate the mechanism of the reaction, we ran
additional experiments for the cross-coupling of methanol
with cyclohexylamine. First of all, we confirmed that the
reaction works equally well with the isolated catalyst 3 as
with the catalyst formed in situ, precluding the possibility
that traces of base could catalyze the reaction. In fact,
when we ran the reaction with an excess of base, the yield
decreased dramatically. To test the importance of the
cyclohexyl substituent in the NHC ligand, we replaced
ICy with other NHCs, such as IPr or IMes, but we
obtained a lower conversion (below 15%). Reaction with
the ruthenium precursor in the absence of any NHC
(19) Downie, I. M.; Earle, M. J.; Heaney, H.; Shuhaibar, K. F.
Tetrahedron 1993, 49, 4015.
(20) Han, Y.; Cai, L. Tetrahedron Lett. 1997, 38, 5423.
(21) Olah, G. A.; Ohannesian, L.; Arvanaghi, M. Chem. Rev. 1987,
87, 671.
(22) For the synthesis of N-formamides from methanol and amines
under aerobic/oxidative conditions, see: (a) Tumma, H.; Nagaraju, N.;
Reddy, K. V. J. Mol. Catal. A: Chem. 2009, 320, 121. (b) Ishida, T.;
Haruta, M. ChemSusChem 2009, 2, 538. (c) Preedasuriyachai, P.;
Kitahara, H.; Chavasiri, W.; Sakurai, H. Chem. Lett. 2010, 39, 1174.
(23) Afagh, N. A.; Yudin, A. K. Angew. Chem. 2010, 122, 270.
Angew. Chem., Int. Ed. 2010, 49, 262.
(24) For more details on the optimization reactions, see Supporting
Information.
Org. Lett., Vol. XX, No. XX, XXXX
C

resulted in decomposition of starting materials only.25
Interestingly, when methanol was replaced with parafor-
maldehyde, only traces of product 5a were observed. In
addition, when the standard reaction was run in the
presence of 1 equiv of additional aldehyde (decanal), again
only traces of product 5a were obtained, and only products
derived from the aldol condensation of decanal or addition
of the amine to the decanal were observed. These experi-
ments suggest that during the course of the standard
reaction free aldehyde is either not present or present only
at very low concentrations.
regenerating the methoxide species (V) (Scheme 4). Cur-
rently we do not know the exact structure of the complex
formed in the presence of methanol and are unable to
provide a more detailed mechanism at this point. Also, the
active involvement of the cyclohexyl ring of the NHC
ligand (leading to the intermediate formation of chelate/
pincer rings) cannot be excluded at present.
Scheme 4. Proposed Mechanism for the N-Formylationa
Finally, we investigated the order of events during the
catalytic cycle by NMR experiments. We found that
already the addition of MeOH at 125 °C to a solution of
complex3 causes a significant changeinthe structure ofthe
complex and the same NMR signals are observed in a
reaction under standard conditions, indicating that the
same species is formed. Due to the sensitivity of the species
formed and the complexity of the NMR spectrum, the
newly formed species could not be defined. Still, some
conclusions can be drawn: First, it is apparent that the
NHC isstill coordinatedtothe metal center, whichfitswith
the observation that without an NHC no reaction occurs.
Second, the methallyl groups of complex 3 are no longer
coordinatedto the metal center. Up tonow the fate ofthese
methallyl groups was unknown. Either they are proton-
ated by MeOH, resulting in the formation of a methoxide
complex and the release of isobutene, or they could under-
go a rearrangement to a different ligand structure such as
trimethylenemethane.26 We suggest that the formation of a
methoxide complex is likely, in which free coordination
sites could be reversibly occupied by methanol or the
amine, maintaining an octahedral coordination geometry
of the RuII. In agreement with our results and in analogy to
Madsen’s detailed investigation of the amidation of alco-
hols by NHC-Ru complexes, we think that the catalytic
cycle starts from a methoxide complex and proceeds via
β-hydride elimination of the methoxide (I), addition of the
amine to the coordinated formaldehyde (II), extrusion of
hydrogen (III), and a second β-hydride elimination of the
hemiaminal complex, which forms the formamide (IV).27
The coordinated formamide could be exchanged by a
methanol molecule, and extrusion of hydrogen is
a [Ru] = ICy2L1L2nRu(II) complex; L1 = anionic ligand (e.g., meth-
oxide); L2 = neutral ligand (e.g., MeOH, HNR2); R1,R2 = alkyl, H.
In conclusion, we have developed a homogeneous cata-
lyzed dehydrogenation of methanol in a synthetically
valuable cross-coupling reaction with amines to form
N-formamides. This finding, together with experimenta-
tion leading to a better mechanistic understanding, should
open the door to the conversion of methanol into key
building blocks in a green and sustainable manner.
Acknowledgment. We thank Dr. Klaus Bergander and
€
Bernhard Beiring (both WWU Munster) for experimental
support and fruitful discussions. Generous financial sup-
port by the Deutsche Forschungsgemeinschaft (SFB 858)
is gratefully acknowledged. The research of F.G. has also
been supported by the Alfried Krupp Prize for Young
University Teachers of the Alfried Krupp von Bohlen und
Halbach Foundation.
(25) In our hands, the dehydrogenative activation of methanol to
render the corresponding formamide 5a did not give any product using
the NHC-ruthenium catalyst reported by Madsen and co-workers for
the amide formation by dehydrogenative coupling of higher alcohols
and amines, under the conditions reported by them (ref 18b). Using their
catalytic system, under the standard conditions of Scheme 3, provided 5a
in 7% yield.
(26) Wesselbaum, S.; Stein, T.; Klankermayer, J.; Leitner, W. Angew.
Chem. 2012, 124, 7617. Angew. Chem., Int. Ed. 2012, 51, 7499.
(27) Makarov, I. S.; Fristup, P.; Madsen, R. Chem.;Eur. J. 2012, 18,
15683.
Supporting Information Available. Experimental pro-
cedures, spectral data, optimization tables, and prepara-
tion of complex 3. This material is available free of charge
via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX