Formamides as Isocyanate Surrogates: A Mechanistically Driven Approach to the Development of Atom-Efficient, Selective Catalytic Syntheses of Ureas, Carbamates, and Heterocycles

Article abstract of DOI:10.1021/jacs.9b08942

Despite the hazardous nature of isocyanates, they remain key building blocks in bulk and fine chemical synthesis. By surrogating them with less potent and readily available formamide precursors, we herein demonstrate an alternative, mechanistic approach to selectively access a broad range of ureas, carbamates, and heterocycles via ruthenium-based pincer complex catalyzed acceptorless dehydrogenative coupling reactions. The design of these highly atom-efficient procedures was driven by the identification and characterization of the relevant organometallic complexes, uniquely exhibiting the trapping of an isocyanate intermediate. Density functional theory (DFT) calculations further contributed to shed light on the remarkably orchestrated chain of catalytic events, involving metal-ligand cooperation.

Full text of DOI:10.1021/jacs.9b08942

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Article
Formamides as Isocyanate Surrogates: A Mechanistically-
Driven Approach to the Development of Atom-Efficient, Selective
Catalytic Syntheses of Ureas, Carbamates and Heterocycles
Jeffrey Bruffaerts, Niklas von Wolff, Yael Diskin-Posner, Yehoshoa Ben-David, and David Milstein
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b08942 • Publication Date (Web): 18 Sep 2019
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Formamides as Isocyanate Surrogates: A Mechanistically-Driven
Approach to the Development of Atom-Efficient, Selective Catalytic
Syntheses of Ureas, Carbamates and Heterocycles
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†
Jeffrey Bruffaerts, Niklas von Wolff, Yael Diskin-Posner, Yehoshoa Ben-David, David Milstein*
Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel
Green Chemistry – Homogeneous Catalysis – Mechanistic Investigations – Computational Study – Pincer Complexes
ABSTRACT:
Despite the hazardous nature of isocyanates, they remain key building blocks in bulk and fine chemical synthesis. By surrogating
them with less potent and readily available formamide precursors, we herein demonstrate an alternative, mechanistic approach to selectively
access a broad range of ureas, carbamates and heterocycles via a ruthenium-based pincer complex catalyzed acceptorless dehydrogenative cou-
pling reactions. The design of these highly atom-efficient procedures was driven by the identification and characterization of the relevant or-
ganometallic complexes, uniquely exhibiting the trapping of an isocyanate intermediate. DFT calculations further contributed to shed light on
the remarkably orchestrated chain of catalytic events, involving metal-ligand cooperation.
inspired by Nature’s cooperative enzymatic systems, has shown
great promises in targeting covalent bond activation through active
ligand participation.10 This key feature enables, in some cases, to sig-
nificantly reduce covalent bond activation energies, thus enabling
new synthetically useful catalytic reactions. Complexes functioning
by metal-ligand cooperation have been especially useful in catalytic
acceptorless dehydrogenative coupling reactions, typically allowing
the α-functionalization of alcohols or amines through in situ for-
mation of aldehyde or imine intermediates, respectively.10-14 Advan-
tageously, such transformations catalytically generate these reactive
and sensitive intermediates while only releasing dihydrogen as by-
product. This approach has led to the development of highly atom-
efficient and straightforward transformations. The inherent ad-
vantages offered by this greener strategy prompted us to explore the
potential of substituting isocyanates by formamides, considerably
INTRODUCTION
Due to environmental and safety concerns, there is an urgent need
to render chemical synthesis not only more efficient, but also less
hazardous for humans and the biosphere.1 These efforts have led to:
(i) the banning of notoriously harmful chemicals while finding sus-
tainable alternatives;2 (ii) and to significantly reduce the amounts of
waste generated by fostering atom and step-efficient strategies.3-5
Although the environmental footprint of a given chemical process
may be continually optimized, surrogating a key but harmful chemi-
cal reagent generally appears more challenging. For instance, isocy-
anates belong to this class of essential though notoriously sensitive
and toxic compounds. Their industrial importance has continuously
grown over the century, as isocyanates are inevitable precursors of
urea and carbamate linkages found in polyurethanes, drugs, pesti-
cides, etc (Scheme 1, ). The most-produced isocyanate, methyli-
6
A
B
less noxious and more stable reagents (Scheme 1, ).
socyanate (MIC), has been most (in)famously known since the
Bhopal disaster,7,8 tragically highlighting the hazards of stocking
large amounts of volatile and toxic chemicals. Besides improving
safety containments for such reagents, it would fundamentally be
safer to substitute them with less potent –though still inexpensive–
surrogates. To circumvent the direct usage of an isocyanate, an alter-
native approach consists in pre-activating amines or alcohols (typi-
cally with phosgene, or any other synthetic equivalent synthon). Yet,
on large scale, such two-step strategies may suffer from the toxicity
of phosgene (if employed) and the waste consequently generated
(as additional bases are usually required). Assessing the issues of
classical approaches to generate urea and carbamate bonds further
stresses the importance of developing greener selective alternatives.
In the context of the modern green(r)evolution in chemical synthe-
sis, the rise of catalysis has not only contributed to reduce the ener-
getic and environmental impact of reactions, but also to reveal novel
and unforeseen synthetic strategies.9 Specifically, the rational design
of increasingly capable and sophisticated transition-metal based ho-
mogeneous complexes has considerably enhanced the potential of
catalyzed reactions. For example, metal-ligand cooperation (MLC),
Interestingly, pioneering reports critically suggested the possibility
of catalytically generating isocyanates from N-arylformamides to ac-
cess ureas15 and carbamates16 using ruthenium-based complexes, alt-
hough yields and turn-over numbers were relatively modest. Only
recently, this transformation has further drawn attention through
the utilization of PNP-type pincer complexes based on ruthe-
nium17,18 and iron,19 although limited to amine nucleophiles and
without the possibility of surrogation of the notorious MIC. Dedi-
cated to further promote and exploit the full potential of this remark-
able and somewhat undervalued reaction, we developed an interest
in fundamentally understanding its mechanism, essential to poten-
tially address the current synthetic limitations. Indeed, the selectiv-
ity for the desired transformation can be drastically hampered by nu-
merous (catalyzed or uncatalyzed) side reactions. For instance, we
and others16-19 observed cases of (i) formamide decarbonylation, (ii)
transamidation / esterification, (iii) competitive dehydrogenative
C
pathways and (iv) urea scrambling (Scheme 1, ) leading to limited
substrate scope and selectivity. These numerous side reactions fur-
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ther highlight the remarkable challenge of finding the optimal exper-
potentially empower us to rationally enhance its scope, as well as
spark new opportunities.
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3
imental conditions to efficiently and selectively generate urea or car-
bamate moieties from formamides. To address the selectivity issues,
we anticipated that insight into the mechanistic events at play may
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Scheme 1. Approaches to access ureas and carbamates (X = leaving group, Alk = alkyl, Ar = aryl).
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RESULTS AND DISCUSSION
ation of isocyanic acid (HNCO) via the stoichiometric dehydro-
genative decomposition of formamide. Furthermore, the reaction of
We have been interested in the behavior of ruthenium(II) and man-
ganese(I) based pincer complexes (for a list of complexes assessed
in this study, see Fig. S1 in Supplementary Information) in the acti-
vation of covalent N-H bonds, such as in amines.20 At the outset, we
studied the possibility of N-H activation of formamide derivatives.
Indeed, upon reaction with the dearomatized pincer complex
1
with N-methyl- or N-benzylformamide similarly yielded, respec-
3
4
tively, complexes and in solution at room temperature. Upon
heating, these complexes also liberated H2 and were interconverted
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8
into the novel isocyanate complexes and , respectively, featuring
new covalent C-C bonds between the pincer ligand and the isocya-
nate moiety, and a hydrogen bond to a formamide molecule
121
(PNP*)RuH(CO) complex
(Scheme 2), rapid N-H activation
7
(Scheme 2). Complex was crystallographically characterized (Fig-
took place, quantitatively providing ruthenium amido complexes in
ure 1, middle). The crystallographically characterized isocyanate
2-5
2
solution ( ). Remarkably, the formamido complex was unstable
at higher temperatures (100°C), releasing hydrogen in an acceptor-
less fashion, while yielding a novel, crystallographically character-
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8
complex (Figure 1, right), same as except for the hydrogen
bonded benzylformamide, was prepared by addition of benzyl isocy-
1
9
anate to . Addition of H2 (2at) to in the presence of excess benzyl
6
ized (Figure 1, left) Ru-isocyanate complex ( ). We are unaware of
previous reports on isocyanate metal complexes accessed from
formamides. This unprecedented result suggested the in situ gener-
8
isocyanate led to isocyante hydrogenation and formation of , con-
firming the structural features of complex , as well as the regioselec-
8
tivity of its binding (covalent binding of the metal complex through
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1
the C=N bond of the isocyanate moiety). (Scheme 2). This C-C co-
valent binding was further corroborated by NMR, IR and HRMS
dimethylformamide (DMF) did not react with even at elevated
temperatures, ruling out a direct oxidative insertion of the formyl C-
H bond to the metal complex. These initial findings indicate dihy-
drogen abstraction through metal-ligand cooperation, similarly to
the reaction with alcohols (vide infra Scheme 5 and 6).22
1
2
3
4
5
analyses (see Supporting Information). Interestingly, complex ,
1
formed by the reaction of N-methylacetamide with , did not lead
upon heating in solution to any dehydrogenation event. Also, N,N’-
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Scheme 2. Stoichiometric experiments and reactivity towards formamides and isocyanates (
bath temperatures).
NR = no reaction, specified temperatures are
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Figure 1. X-ray crystal structures of compounds
Selected bond distances (Å) and angles (deg) for
O(2)-C(25) 1.2197(16), C(24)-Ru(1)-N(1) 175.09(4), P(2)-Ru(1)-P(1) 158.270(10), N(2)-Ru(1)-H 175.2(7), C(25)-N(2)-Ru(1) 151.64(10),
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,
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and
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(thermal ellipsoids drawn at the 50% probability level, C-H bonds are omitted for clarity).
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: Ru(1)-H 1.512(17), Ru(1)-N(1) 2.1518(9), Ru(1)-N(2) 2.2164(11), N(2)-C(25) 1.1503(17),
N(2)-C(25)-O(2) 178.52(15). For : Ru(1)-H 1.51(2), Ru(1)-N(1) 2.1233(11), Ru(1)-N(2) 2.2548(11), N(2)-C(25) 1.3210(18), O(2)-C(25)
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1.2547(17), C(7)-C(25) 1.5494(19), C(24)-Ru(1)-N(1) 177.28(6), P(1)-Ru(1)-P(2) 161.444(13), N(2)-Ru(1)-H 164.3(8). For : Ru(1)-H
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1.505(17), Ru(1)-N(1) 2.1170(10), Ru(1)-N(2) 2.2980(10), N(2)-C(23) 1.3253(15), C(1)-C(23) 1.5512(16), O(1)-C(23) 1.2526(14), P(2)-
Ru(1)-P(1) 157.245(11), N(2)-Ru(1)-H 163.5(6), C(31)-Ru(1)-N(1) 176.61(4), O(1)-C(23)-N(2) 128.05(11).
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Based on these experiments, we then turned our attention to devise
optimal catalytic protocols. Gratifyingly, in the presence of catalytic
amounts of complex , monosubstituted formamides could indeed
fully surrogating MIC. Our optimization efforts were primarily con-
cerned by the selectivity of this reaction to prevent urea scrambling,
which is especially observed at higher temperatures (>120°C). Ad-
ditionally, the catalytic coupling of secondary amines was also effi-
cient though exclusively triggered at higher temperatures (typically
135°C). Several experimental observations such as the unsuccessful
coupling of various less nucleophilic (e.g. aniline) and/or bulkier
amines (e.g. diisopropylamine, even in the presence of the isopropyl
1
be efficiently and selectively coupled with a large variety of nucleo-
philes (Scheme 3), including amines, alcohols and aminoalcohols
(Scheme 4), exclusively releasing dihydrogen as by-product in an ac-
ceptorless fashion. For instance, primary amines were coupled with
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10a-d
N-benzylformamide (
10e-m
) or N-methylformamide (
) at
1
version of catalyst ) revealed the acute chemoselectivity of complex
100°C in 1,2-diethoxyethane as the solvent of choice in the presence
1
1
of 0.5 mol% of under additive-free conditions. To the best of our
towards different nucleophilic reagents (see Supplementary Infor-
knowledge, the latter represent the first examples of accessing me-
thyl ureas via the dehydrogenation of formamides, hence success-
mation).
Scheme 3. Scope of the catalytic dehydrogenative coupling of monosubstituted formamides with nucleophiles.
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Except if noted otherwise, all yields are reported as isolated yields after column chromatography purification.
a
: 1 mmol scale, 0.5 mol% catalytic
: 0.5
d
: 0.5 mmol scale, 1 mol% catalytic loading, mesitylene (0.5 mL), 145°C,
loading, 1,2-diethoxyethane (0.5 mL), 100°C, 12-20h. : 1 mmol scale, 0.5 mol% catalytic loading, 1,2-diethoxyethane (0.5 mL), 135°C, 4-18h.
b c
mmol scale, 1 mol% catalytic loading, mesitylene (0.5 mL), 125°C, 36-48h.
36-48h.
The coupling of alcohols with monosubstituted formamides proved
more challenging, especially as Ru(II) and Fe(II) pincer complexes
easily promote competitive alcohol dehydrogenative pathways, lim-
iting the substrate scope to amine nucleophiles.16-19 We discovered
that the choice of the ligand was essential, as complex was the only
1
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catalyst in our toolbox capable of allowing the selective formation of
carbamates (Scheme 3, ligand effects, path A), by favoring the dehy-
drogenation of formamides over that of the primary alcohol
(Scheme 3, ligand effects, path B) (see also Supplementary Infor-
mation). Indeed, primary alcohols could successfully be coupled
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11a b e-g
, , ) with monosubstituted formamides in closed systems at
(
1
125°C using 1 mol% of . We also noted a strong influence of the
electronic effects on the resulting carbamate yield. Thus, more elec-
trophilic N-arylformamides afforded higher yields of the corre-
11b c
sponding carbamates, whereas N-alkylformamides ( , ) failed to
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undergo a similar reaction, even at higher temperatures or in the
presence of other catalysts. Nonetheless, this methodology could be
extended to the coupling of secondary alcohols at 145°C, albeit in
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11h-m
typically moderate yields (
). Moreover, during our investiga-
10h 10p 10v 11j
and ), ter-
tion, functional groups such as ethers (
,
,
10r 10c
10s
and
10k
) were shown to be tolerated under our reaction conditions.
Also, the catalyst did not lead to any scrambling of any potentially
10i 11l 11m
tiary amines ( ), silanes ( ), olefins ( ), unprotected alco-
10w 11a-m 10f 10u 11b 11e-h
), cyclobu-
hols (
and
10i
), halides (
,
,
10j
tanes ( ), pyridines ( ), thiophenes ( ) and hydrazines
10d
(
sensitive during the synthesis of compounds
,
and
).
In the specific case of amino alcohols (Scheme 4, R’=Alk), a subse-
quent imido bond- forming reaction23 was triggered following the
urea synthesis, leading to the synthesis of the 5- membered ring hy-
12a, 12b
dantoin derivatives (
12f-h
) and the 6-membered ring
and
12d
dihydrouracil (
12i
and ) derivatives. The exceptional temporal
selectivity24 of this unprecedented transformation led us to access
these heterocycles in moderate to excellent overall yields, conse-
quently releasing three equivalents ofH2. Although this conceptually
new approach could not be extended at this stage to bulkier amino-
All reactions were carried out on a 1 mmol scale (1:1 equivalents) in 1,2-
diethoxyethane (0.5 mL) with 0.5 mol% of in closed systems. All yields
1
are reported as isolated yields after column chromatography purifica-
tion.
12c
12e
alcohols ( ) or larger heterocycles ( ), it uniquely demon-
strates the unforeseen potential to devise cascade catalytic transfor-
mations triggered by formamide dehydrogenation. The current
route using formamide dehydrogenative coupling with aminoalco-
hols may provide an alternative access to core heterocyclic structures
of high therapeutic significance; hydantoins25 (generally featured in
anticonvulsant active ingredients) and uracils26 being frequently en-
countered motifs in drugs.
1
In all the aforementioned cases using catalyst , it must be stressed
that free isocyanates were not detected during the course of these
1
reactions. Given the acute chemoselectivity of complex towards
both coupling partners and the absence of observed free isocyanates
in solution, a metal-ligand cooperative dehydrogenative coupling
mode is indicated (see Scheme 6).
In addition to the insights provided by the stoichiometric control ex-
periments, DFT calculations (see Supporting Information for de-
tails) were carried out to further understand the chain of events of
these highly-controlled coupling reactions. In agreement with the
stoichiometric experiments (see Scheme 2), we can simplify the re-
action scheme into two main steps: formamide dehydrogenation
Scheme 4. Catalytic dehydrogenative coupling of N-alkylforma-
mides with amino alcohols leading to the formation of heterocy-
clic adducts 12.
A
B
(Scheme 5, ) and urea bond formation (Scheme 5, ). In qualita-
tive agreement with the experiments, N-H activation by MLC to
Ia
Ib
form intermediates and , and H-abstraction to form transient
TS1 TS3
isocyanate, are readily achieved (
elimination). Hydrogen release from the dihydride species might
TS4
be facilitated through H-bonding (
and
, not via β-hydride
III
ǂ
-1 27,28
, ΔG = 33.8 kcal.mol ).
Free isocyanates might be avoided through reversible C-C bond for-
V
TS5
B
, Scheme 5, , see also Scheme 2,
mation with the ligand ( via
7
1
complex ). Indeed, the coupling of free isocyanate with after H2-
loss is downhill in energy by around 15 kcal.mol-1. Importantly, this
V
formation of (experimentally observed), which can be viewed as a
“tamed isocyanate”, decreases the electrophilic character of the cen-
tral isocyanate carbon atom (compared to free methylisocyanate,
C
Scheme 5, ) possibly preventing uncontrolled side-reactions. It
V
also represents the resting state of the catalytic cycles as species is
relatively inert towards nucleophile attack (e.g. benzyl amine,
and Scheme 5, ). In the presence of a nucleophile, the O-coordi-
nated intermediate
TS6
C
IVb
undergoes metal-ligand cooperative urea
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ǂ
-1
C
acidic metal center (see also Scheme 5, ). The benzylic ligand po-
TS7b
bond formation (
, ΔG = 32.1 kcal.mol ). Indeed, the ligand
1
2
3
sition is then acidic enough to re-protonate the urea-nitrogen, thus
C=C double bond is well positioned to deprotonate the incoming
nucleophile, while the heterocumulene is activated by the Lewis
TS8
releasing the product (
).
4
5
6
Scheme 5. DFT calculations of the catalytic coupling of N-methylformamide with benzylamine at the ωB97X-V/def2-TZVP//M06-L
GD3/def2-SVP/W06 level of theory.
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Values correspond to Gibbs free energies in toluene (SMD model) at 298 K in kcal.mol-1 with respect to the starting complex (0.0 kcal.mol-1). Values
1
in brackets are gas phase Gibbs free energies. DFT-structures with C-H hydrogens, omitted for clarity, are given for key structures and transition states.
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(A) Reaction potential energy surface for the dehydrogenation of N-methylformamide, (B) subsequent urea bond formation, (C) calculated NBO
charges on the central carbon atom of different isocyanate moieties and (D) Energies of key transition state TS7b for different substrate nucleophiles.
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Although the reaction was computed to be only slightly exergonic
(ΔG = -1.9 kcal.mol-1), the experimentally observed insolubility of
the urea product might act as an additional driving force. Im-
portantly, this mechanism also qualitatively accounts for the ob-
served order of reactivity of the different nucleophiles (Scheme 5,
In conclusion, we report a general and isocyanate-free alternative ap-
proach to access valuable unsymmetrical ureas including methyl
ureas (avoiding the notorious methylisocyanate), carbamates and
the heterocycles hydantoins and dihydrouracils in good yields and
excellent selectivities (Scheme 3). Despite the numerous competi-
tive pathways (Scheme 1, C), it was demonstrated that various
monosubstituted formamides could be employed as versatile surro-
gates to isocyanates in generally atom-economical and efficient de-
hydrogenative coupling reactions. Control experiments, including
isolation of key relevant novel complexes (Scheme 2) and DFT stud-
ies (Scheme 5) provided critical and unique insights of the mecha-
nisms involved, highlighting the critical ligand’s cooperative role.
Advantageously, the singular mode of action of complex 1 allows to
minimize uncontrolled side-reactions (Scheme 6). Isocyanate-or-
ganometallic adducts obtained by dehydrogenation were observed
via this approach for the first time (Schemes 2, 6-8), providing struc-
tural information on catalytic intermediates (Scheme 6, IV and V).
Remarkably, complex 1 also enabled the unprecedented subsequent
cascade transformation leading to valuable hydantoin- and dihy-
drouracil- derivatives (Scheme 4) with an excellent temporal selec-
tivity between the formamide and alcohol dehydrogenation key
events. Ultimately, we hope that the fundamental understanding of
the catalytic events in play may spark interest in the implementation
of such catalytic generation of isocyanates into organic synthesis. We
also hope that this work illustrates the need, as well as the opportu-
nities, in seeking surrogates for commonly used hazardous chemicals
to establish safer and greener synthetic transformations.
D
V
). In order to confirm the resting state character of , we per-
7
formed catalytic reactions using complex as the catalyst in the pres-
ence of N-benzylformamide and benzylamine, which showed good
activity although at slightly higher temperature (130 °C, see SI for
additional details). This is in qualitative agreement with the com-
puted mechanism and highlights the reversible nature of the resting
state.
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Scheme 6. General plausible mechanism (dotted boxes indicate
experimentally identified complexes).
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is available free
of charge via the Internet at http://pubs.acs.org.”
Experimental details of synthetic procedures, NMR spectra,
X-ray data, and computational details (PDF
Crystallographic data for and
CIF
)
6
,
7
9
(
)
AUTHOR INFORMATION
Corresponding Author
* david.milstein@weizmann.ac.il
Present Address
† Laboratoire d’Electrochimie Moléculaire, UMR CNRS
7591, Université Paris Diderot, Sorbonne Paris Cité, 15 rue
Jean-Antoine de Baïf, F-75205 Paris Cedex 13, France
Both our experimental and theoretical studies emphasize the pivotal
1
role of MLC of the pincer ligand of by aromatization-dearomatiza-
tion29 on the catalytic activity in almost all fundamental events. In
summary, we suggest the following general catalytic mechanism
(Scheme 6): (i) rapid N-H activation via MLC of the formamide by
Notes
The authors declare no competing interests.
1
I
affords the Ru-amido complexes , (ii) followed by a hydride ab-
III
straction, formally a disproportionation reaction, yielding
presumably , (iii) rapid C-C bond activation equilibrium results
in adduct as the resting state of this catalytic system; (iv) nucleo-
philic coupling of yields , this event presumably being the rate
determining step; (v) eventually, the catalyst ( ) is concomitantly
and
ACKNOWLEDGMENT
IV
This research was supported by the European Research Council (ERC
AdG 692775). D. M. holds the Israel Matz Professorial Chair of Organic
Chemistry. J. B. is thankful to the Feinberg graduate school for a post-
doctoral fellowship. N. v. W is supported by the Foreign Postdoctoral
Fellowship Program of the Israel Academy of Sciences and Humanities.
V
IV VI
1
regenerated either through the extrusion of the corresponding urea
10
11
) or carbamate ( ), and hydrogen release from the dihydride
(
III
.
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