Rhodium-Catalyzed Synthesis of Amides from Functionalized Blocked Isocyanates

Article abstract of DOI:10.1021/acscatal.9b02641

Isocyanates are useful building blocks for the synthesis of amides, although their widespread use has been limited by their high reactivity, which often results in poor functional group tolerance and a propensity to oligomerize. Herein, a rhodium-catalyzed synthesis of amides is described coupling boroxines with blocked (masked) isocyanates. The success of the reaction hinges on the ability to form both the isocyanate and the organorhodium intermediates in situ. Relying on masked isocyanate precursors and on the high reactivity of the organorhodium intermediate results in broad functional group tolerance, including protic nucleophilic groups such as amines, anilines, and alcohols.

Full text of DOI:10.1021/acscatal.9b02641

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Letter
Rhodium-Catalyzed Synthesis of Amides
from Functionalized Blocked Isocyanates
Joshua Derasp, and Andre Martin Beauchemin
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02641 • Publication Date (Web): 31 Jul 2019
Downloaded from pubs.acs.org on July 31, 2019
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Page 1 of 6
ACS Catalysis
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Rhodium-Catalyzed Synthesis of Amides from Functionalized
Blocked Isocyanates
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Joshua S. Derasp and André M. Beauchemin*
Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of
Ottawa, Ottawa, Ontario K1N 6N5, Canada
KEYWORDS. Rhodium, masked isocyanates, ambident/amphoteric reagents, chemoselectivity, in-situ deprotection
Benefits of Isocyanates
Commercial Availability
(>2,500 compounds)
O
A)
ABSTRACT: Isocyanates are useful building blocks for the
synthesis of amides, though their widespread use has been
limited by their high reactivity, which often results in poor
functional group tolerance and a propensity to oligomerize.
Herein, a rhodium-catalyzed synthesis of amides is described
coupling boroxines with blocked (masked) isocyanates. The
success of the reaction hinges on the ability to form both the
isocyanate and the organorhodium intermediates in situ.
Relying on masked isocyanate precursors and on the high
reactivity of the organorhodium intermediate results in broad
functional group tolerance, including protic nucleophilic
groups such as amines, anilines and alcohols.
HO
Li/XMg
R2
R2
Low cost / Ease of synthesis
O
O
R1
R1
C
N
R2
N
Catalyst
H
Limitations of Isocyanates
Low functional group tolerance
high toxicity
X
[M]
R2
R2
H
R2
or
or
[M]= B(OR)2,
X= Cl, Br,
I, OTs
Oligomerization

Sn(R)3, Si (OR)4
B)
C)
NH2
NH2
NH2
Nuc
O
[ArBO]3
Rh
-PhOH
O
O
+PhOH
E+
C
N
OPh
N
N
H
Ar
H
33 examples
Blocked Isocyanate
Amphoteric Isocyanate
B(OH)3
H
H+
R2
LnMn
R2
O
(HO)2B
R2
B
R1
N
BG
LnMn
BG
H
HBG
LnMn
HBG
OH
Reversible Isocyanate
Generation
O
A
R1
C
The ubiquitous presence of amides in biological systems and in
an array of useful products has led chemists to develop new
syntheses of this functional group.1 Innovations on this front
also have high relevance in drug discovery where amide
formation is amongst the most common processes in medicinal
chemistry.2 The low cost and broad commercial availability of
isocyanates make them attractive amide precursors.3-4 The
synthesis of amides from isocyanates has been known for over
a century, with the reaction of isocyanates with carboxylic
acids (Figure 1A).5 More recently, addition of nucleophiles
such as Grignard and organolithium reagents have been
reported, providing useful alternatives to traditional amide
bond formation.6 Milder catalytic alternatives have attracted
much interest with strategies including the directed metalation
of C-H bonds,7 reductive couplings,8 and redox neutral variants
employing organoboron or tin reagents.9 Despite these
advances, the use of isocyanates bearing critical functional
groups such as N-heterocycles, alcohols, amines, remain
exceedingly limited.10 Moreover, their propensity to
oligomerize, which can be exacerbated by metal catalysts or
common ligands,11 can result in major limitations or prevent
reaction development.6d,8d Lastly, their acute toxicity can have
serious consequences (pulmonary edema, sensitization,
death).12 Thus, we became interested in achieving transition
metal catalysis with safe, easily-handled isocyanate
equivalents. Herein we report a rhodium-catalyzed synthesis of
amides from functionalized masked isocyanate precursors and
boroxines that addresses these issues (Figure 1B), and
operates via the chemoselective reaction of a transiently
formed isocyanate with a catalytic rhodium aryl nucleophile
(Figure 1C).
H2O
N
D
O
LnMn
N
R1
R2
Key Transient Intermediates
C
O
O
LnMn
R1
C
R2
R1
N
R2
B
N
D
H
Figure 1. (A) Prior reports of isocyanates as amide building
blocks. (B) Current work using blocked isocyanates as amide
building block. (C) Prototypical catalytic cycle.
Blocked (masked) isocyanates are often bench stable solids
alleviating the hazards intrinsic to isocyanates. Moreover,
blocking groups regulate isocyanate concentration and
reactivity with in situ generation of the reactive isocyanate in a
controlled manner, proving
a powerful strategy during
polymerization reactions.13 This strategy was successfully
implemented by our group in new reactions of nitrogen- and
oxygen-substituted blocked isocyanates to mitigate the
oligomerization of these reactive species.14 Surprisingly, the
use of blocked isocyanates as amide precursors is rare.15
Moreover, their use in metal-catalyzed reactions is virtually
absent from the literature.11c,16,17 Intimations of the value of
such a strategy in transition metal catalysis are garnered from
Buchwald’s syntheses of complex ureas,16a,d in which the
desired reactivity relied on the masking of an isocyanate to
achieve the desired catalytic transformation. In contrast, a
catalytic amide synthesis from masked isocyanates demands
that two transient species present in low concentrations react
chemoselectively while avoiding common side reactions
(protodemetallation, homocoupling, etc.) (Figure 1C).
Moreover, potential blocking group interference with the
catalytic generation of the organometallic intermediate must
be avoided.
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Experiments began with masked isocyanate 1a possessing a
Table 1. Variation from Optimized Conditionsa,b
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8
phenol blocking group. Though phenol blocked isocyanates
undergo thermal deblocking generating the isocyanate around
120 C, base-promoted deblocking can occur at room
temperature.13 Boroxine 2a was chosen as the nucleophilic
partner due to the broad availability and low toxicity of
ogranoboron species. Unfortunately, reported conditions using
organoboron reagents and isocyanates failed to provide
product 3aa from blocked isocyanate 1a.9d-e,15h Gratifyingly,
after extensive catalyst surveying and optimization, mild
pTol
2a
1.6 equiv
"Ar-B"
O
[Rh(OH)(cod)]2 (1 mol%)
O
B
Et3N (1 eq.)
O
B
O
B
N
+
N
OPh
H
50 oC, THF (0.5 M)
H
pTol
O
pTol
Me
1a
3aa
O
Commonly observed
side products:
Me
Me
N
H
N
H
Homocoupling side
product
hydrolysis byproduct
Entry
Deviation from optimized conditions
none
Yield
89%
79%
0%
conditions using
1
mol% of commercially available
9
1
2
[Rh(OH)(cod)]2, 1 equiv of Et3N, at 50 C provided the desired
amide product 3aa in high yield (Table 1, entry 1).18 These
conditions allowed both the lowering of catalyst and boroxine
loadings relative to work on ‘free’ isocyanates.9d This is in stark
contrast to Mori’s work where stoichiometric phenol inhibited
a related reaction of ‘free’ isocyanates.9c Increasing the base
loading led to a lower yield, with more urea side product (entry
2). In contrast, a reaction without Et3N yielded mostly starting
material (entry 3). These results suggest precise control over
base-promoted isocyanate generation is necessary to form
amide 3aa efficiently. The formation of 3aa also occurred in the
absence of base at 120 C (thermal deblocking conditions, entry
4).13 In contrast, sluggish reactivity was observed at room
temperature even with increased catalyst loading and longer
reaction time (entry 5). A cationic rhodium catalyst displayed
similar reactivity (entry 7) though [Rh(OH)(cod)]2 proved
optimal due to its shorter reaction time and bench stability.
Both copper and palladium catalysts yielded no detectable
product (e.g. entry 8). Finally, control reactions lacking the
rhodium catalyst yielded no detectable product (entries 9-10).
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3 equiv of Et3N
3
No Et3N
4
70%
44%
0%
No Et3N at 120 C
Room temperaturec
[Rh(Cl)(cod)]2
5
6
d
7
[Rh(MeCN)2(cod)]BF4
89%
0%
f
8
Cu(OAc)2e or Pd(OAc)2/PPh3
9
0%
No catalyst, no Et3N at 120 C
10
No catalyst
0%
aConditions: 1a (0.2 mmol), 2a (1.6 equiv “Ar-B”), catalyst (1
mol%), Et3N (0.2 mmol), THF (0.5 M), 50 C. 1H NMR yield
determined using 1,3,5-trimethoxybenzene as internal
standard. b[RBO]3:RB(OH)2 = 1:2.1 see SI. c2.5 mol% catalyst. d2
mol% catalyst. e2 equiv. fPd(OAc)2 (5 mol%), PPh3 (20 mol%).
Table 2. Rhodium-Catalyzed Amide Synthesis Using Masked Isocyanates: Reaction Scope
O
Ar
O
Ar
O
"Conc. Conditions"
[Rh(OH)(cod)]2 (1 mol%)
Et3N (1 eq.)
B
B
R
R
2a-k
1.5-1.6
equiv "Ar-B"
+
N
Ar
O
O
N
OPh
H
B
H
50 oC, THF (0.5 M)
1a-o
3aa-ak
Ar
(a) Masked Isocyanate Scopea
O
OMe
OMe
O
Br
MeO
O
O
O
O
O
O
N
H
MeO
N
Cl
N
N
N
N
H
H
H
H
H
Me
Me
3d 83%b
3ea 85%b
3fa 71%b
Me
Me
O
Me
Me
3aa 86%
3ba 83%
3ca 80%
Me
Me
Me
Me
O
O
i-Pr
O
OMe
O
O
O
O
O
Me
O
Me
Bn
t-Bu
N
B
N
H
Me
N
H
N
N
H
N
H
Ph
N
H
O
H
H
Me
Me
i-Pr
Me
Me
Me
Me
Me
Me
Cl
Me
3ga 83%b
3ia 40%b
3ja 79%
3xa 85%k
3la 81%
3ka 73%b
3ha 59%b,d
O
"dilute conditions"
[Rh(OH)(cod)]2 (2.5 mol%)
Et3N (1 eq.)
N
O
O
O
O
Tolp
O
pTol
MeO
B
B
N
R
R
N
H
N
H
2a-k
3.3 equiv
"Ar-B"
N
+
N
N
OPh
O
O
H
H
OMe
H
B
50 oC, THF (0.1 M)
Me
Me
Me
1p-v
Me
3oa 76%b,c
3pa-3va
Me
3na 67%b,e
3ma 73%
(b) Boronic Acid Scope
pTol
(c) Amphoteric Masked Isocyanate Scopei
PhHN
O
Me
H2N
O
O
O
O
O
N
H
N
H
N
H
H2N
N
H
N
H
N
H
Me
3ad 67%b,f
Me
Me
Me
3pa 84%
3qa 83%
3ra 85%
Me
Me
3ab 81%f
3ac 86%b,d
HO
OH
O
HO
O
O
O
O
O
OMe
N
H
N
H
N
H
N
N
H
N
H
H
Me
Me
CO2Me
3sa 89%
3ta 93%
3ua 82%
OMe
CN
3ag 71%g
3ae 74%d
3af 84%b,d
CO2Me
O
O
O
O
O
HN
O
O
HN
HN
HN
F
Me
N
S
N
H
HN
N
H
N
N
CO2Me
3va 72%j
H
H
Me
O
N
F
CO2Me
3vva Dimer
3ah 78%d
3ai 80%b,d
3aj 75%b,d
3ak 79%h
aConditions: 1 (0.6 mmol), 2a (1.6 equiv “Ar-B”, see footnote b, Table 1), [Rh]2 (1 mol%), Et3N (0.6 mmol), THF (0.5 M), 50 C; isolated
yields. b[Rh]2 2.5 mol%. c3.3 equiv “Ar-B”. d0.3 mmol [RBO]3. e5.4 equiv “Ar-B”, 120 C. f0.9 mmol RB(OH)2. g[Rh]2 0.5 mol%. h0.6 mmol
[RBO]3, [Rh]2 2.5 mol%, 80 C. iConditions: 1 (0.6 mmol), 2a (3.3 equiv “Ar-B”), [Rh]2 (2.5 mol%), Et3N (0.6 mmol), THF (0.1 M), 50
C; isolated yields. jAt 80 °C. kAt 100 °C.
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With optimized conditions, the scope of blocked isocyanate
Finally, efforts were directed at gaining insight on the
reaction mechanism using the variable time normalization
analysis (VTNA) developed by Burés (Table 3).22 Under
‘concentrated conditions’ employed for substrates in Table 2a-
b, a 0th order dependence in 1w and a 0.75 order dependence
in catalyst was observed. Taken together, these results support
a rate limiting transmetallation, in line with facile base-
mediated isocyanate unmasking (formation of B, Figure 1).23
Moreover, the 0.75 order in catalyst suggest the presence of an
equilibrium with an inactive dimeric species, analogous to
related rhodium catalyzed additions onto enone
electrophiles.24 Given the need for alternative reaction
conditions to achieve efficient product formation with
ambiphilic isocyanates (Table 2c), we speculated a potential
change in rate determining step. In fact, VTNA revealed a 0th
order dependence in catalyst and a 0.6 order in 1w. Taken
together, these results support a rate determining isocyanate
unmasking under the ‘dilute conditions’ (formation of D, Figure
1). Moreover, the 0.6 order in 1w suggests the presence of an
H-bonded dimer in solution.25 Despite the increased loading of
catalyst and organoboron reagent in the latter conditions, their
concentration were halved overall as a result of the dilution of
the reaction media. Consequently, the rate of transmetallation
would be expected to decrease slightly under these conditions.
However, the 5-fold dilution of the base and masked isocyanate
1w under ‘dilute conditions’ has a much more pronounced
effect on the rate of base mediated isocyanate unmasking,
resulting in the change in rate limiting step. Thus, the
successful amidation of ambiphilic isocyanate hinged on the
ability to control the rate of isocyanate release. These results
are expected to have broad implications for further
developments towards functional group tolerant isocyanate
based transformations.
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reagents was investigated (Table 2a). The model reaction on
0.6 mmol scale provided the desired product 3aa in 86%
isolated yield. Both electron-donating (3ba) and electron-
withdrawing (3ca) groups were tolerated on the isocyanate
precursor. To our delight, ketones (3da) and aryl halides (3ea-
3fa) were compatible with the reaction. Sterically hindered
substrates also provided the desired products in excellent to
moderate yields (3ga-3ha). Conceptually this provides a
catalytic alternative to Bode’s synthesis of sterically
hindered/electronically deactivated amides from isocyanates
using Grignard nucleophiles.6b Despite the tendency for boron
species to equilibrate in situ,19 a boronic acid pinacol ester
bearing starting material provided the desired product 3ia,
albeit in modest yield. Pleasingly, a benzylamine-derived
blocked isocyanate was a competent reaction partner despite
the decreased deblocking rate of aliphatic masked isocyanates
compared to their aromatic counterparts (3ja).13 Methyl amide
3ka was also formed in good yield, thus providing a safe
alternative to the use of methyl isocyanate.12 An amino acid
derivative and a precursor containing an acetal also formed the
desired products efficiently (3la-3ma). The readily
epimerizable stereocenter in the former was not conserved
under the reaction conditions. Gratifyingly, given the typically
problematic Lewis basic motif,10a-b product 3na could be
formed using higher temperatures and loadings of the
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organoboron reagent and rhodium.18,20 In contrast,
a
heterocyclic substrate with attenuated Lewis basicity provided
product 3oa under milder conditions.
The effect of different organoboron reagents on the
transformation was then surveyed (Table 2b). A variety of
boroxines were competent reaction partners including
sterically hindered (3ac-3ad), electron-rich (3ae), electron-
deficient (3af-3ag), halide-containing (3ah), and heterocyclic
Table 3: Results of kinetic studies
reagents (3ai-3aj). Remarkably,
a pyridyl boroxine was
compatible with the reaction, though modified conditions were
necessary (3ak).20 It is noteworthy that catalyst loadings as
low as 0.5 mol% were possible in some cases (3ag).
F
p-Tol
F
O
[Rh(OH)(cod)]2
Et3N
O
B
2a
O
B
O
B
+
N
N
OPh
H
50 oC, THF
H
p-Tol
O
p-Tol
1w
3wa
Me
It was hypothesized that this catalytic system could be used
with blocked isocyanates containing nucleophilic motifs. The
blocking group would allow access to amphoteric (ambident)
reagents which are typically beyond the reach of standard
isocyanate chemistry. Moreover, stringent control over the
isocyanate concentration imparted by the blocking group
would allow high chemoselectivity for the transient
organometallic catalyst to outcompete stoichiometric
nucleophiles. Gratifyingly, lowering the concentration and
increasing the boroxine/catalyst loading18 resulted in efficient
Conditions
1w
Catalyst
Proposed rate-
order
order
0.75
0
determining step
transmetallation
deblocking
Table 2a-b
Table 2c
0
0.6
In conclusion, a robust catalytic synthesis of functionalized
amides has been developed relying on blocked isocyanate
precursors. Mechanistic studies suggested that reaction
optimization led to conditions with different rate determining
steps which proved vital to achieve the desired transformation
with amphoteric isocyanates. This work provides a rare
example of the use of blocked isocyanates in transition metal
catalysis, highlighting the broad functional group tolerance
possible and the use of otherwise ‘impossible’ isocyanates, and
enabling their application in complex settings typically beyond
the reach of normal isocyanates.
amide formation with
a variety of amphoteric masked
isocyanates (Table 2c). Aniline derivatives produced the
desired products in high yields (3pa-3ra). A phenolic motif was
also tolerated. Alcohols (3ta) were compatible, even in cases
where a rapid intramolecular cyclization may be expected
(3ua). Finally, the reaction could also be achieved with an
unprotected (N-H) tryptophan derivative with minimal loss of
the stereochemical information.21 Interestingly, when the
reaction was performed at 50 °C, competitive dimer formation
occurred (3vva). This was alleviated by increasing the reaction
temperature to 80 °C (3va).21 In addition, variation on the
structure of the blocking group allowed the reaction to be
compatible with primary and secondary amines (see
Supporting Information). Overall, the blocking group strategy
enabled the high degree of chemoselectivity required to
achieve product formation from amphoteric isocyanates.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
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Heterocyclic Thioquinazolinones through Serial Microreactions with
Optimization
data,
experimental
procedures,
Two Organolithium Intermediates. Angew. Chem. Int. Ed. 2015, 54,
1877−1880. (e) Kerr, W. J.; Williams, J.; Leach, S.; Lindsay, D. A Practical
and General Amidation Method from Isocyanates Enabled by Flow
Technology. Angew. Chem. Int. Ed. 2018, 57, 12126−12130.
1
2
3
4
5
6
7
8
characterization data, kinetic data and discussion, NMR
spectra.
AUTHOR INFORMATION
Corresponding Author
(7) (a) Kuninobu, Y.; Tokunaga, Y.; Kawata, A.; Takai, K. Insertion of
Polar and Nonpolar Unsaturated Molecules into Carbon-Rhenium
Bonds Generated by C-H Bond Activation: Synthesis of Phthalimidine
and Indene Derivatives. J. Am. Chem. Soc. 2006, 128, 202−209. (b) Hesp,
K. D.; Bergman, R. G.; Ellman, J. A. Expedient Synthesis of N-Acyl
Anthranilamides and -Enamine Amides by the Rh(III)-Catalyzed
Amidation of Aryl and Vinyl C-H bonds with Isocyanates. J. Am. Chem.
Soc. 2011, 133, 11430−11433. (c) Li, J.; Ackermann, L. Cobalt(III)-
Catalyzed Aryl and Alkenyl C-H Aminocarbonylation with Isocyanates
and Acyl Azides. Angew. Chem. Int. Ed. 2015, 54, 8551−8554. (d) Liu,
W.; Bang, J.; Zhang, Y.; Ackermann, L. Manganese(I)-Catalyzed C-H
Aminocarbonylation of Heteroarenes. Angew. Chem. Int. Ed. 2015, 54,
14137−14140. (e) Zeng, R.; Chen, P.-H.; Dong, G. Efficient
Benzimidazolidinone Synthesis via Rhodium-Catalyzed Double-
Decarbonylative C-C Activation/Cycloaddition between Isatins and
Isocyanates. ACS Catal. 2016, 6, 969−973.
(8) (a) Hsieh, J.-C.; Cheng, C.-H. Nickel-Catalyzed Coupling Of
Isocyanates with 1,3-Iodoesters and Halobenzenes: a Novel Method for
the Synthesis of Imide and Amide Derivatives. Chem. Commun. 2005,
4554−4556. (b) Correa, A.; Martin, R. Ni-Catalyzed Direct Reductive
Amidation via C-O Bond Cleavage. J. Am. Chem. Soc. 2014, 136,
7253−7256. (c) Wang, X.; Nakajima, M.; Serrano, E.; Martin, R. Alkyl
Bromides as Mild Hydride Sources in Ni-Catalyzed Hydroamidation of
Alkynes with Isocyanates. J. Am. Chem. Soc. 2016, 138, 15531−11534.
(d) Serrano, E.; Martin, R. Nickel-Catalyzed Reductive Amidation of
Unactivated Alkyl Bromides. Angew. Chem. Int. Ed. 2016, 55,
11207−11211.
*Email: andre.beauchemin@uottawa.ca
ORCID
André M. Beauchemin: 0000-0003066706215
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Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the University of Ottawa and NSERC for the generous
financial support. J.S.D. thanks NSERC for a PDS-D scholarship.
We thank D. Brzezinski (University of Ottawa) for the
preparation of compound 3xa.
REFERENCES
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(18) See supporting information for full optimization, details and
control experiments.
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(20) (a) Albrecht, F.; Sowada, O.; Fistikci, M.; Boysen, M. M. K.
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(21) A 3% loss of enantiomeric excess was observed under the
reaction conditions.
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(23) This is in stark contrast to the mechanistic proposal of Zhang,15h
who reported reactions of t-butyl carbamates under different
conditions ([Rh(cod)Cl]2, KF as additive, dioxane, 100 °C). The reagents
used herein fail to provide amides under these conditions, and the
procedures display significantly different reaction scope. While
warranting further investigation, the difference in leaving group ability
and basicity / role of the additive could result in two productive
pathways operating with different carbamate precursors.
(24) Kina, A.; Iwamura, H.; Hayashi, T. A Kinetic Study on Rh/Binap-
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