Expedient Synthesis of N-acyl anthranilamides and β-enamine amides by the Rh(III)-catalyzed amidation of aryl and vinyl C-H bonds with isocyanates

Article abstract of DOI:10.1021/ja203495c

A Rh(III)-catalyzed protocol for the amidation of anilide and enamide C-H bonds with isocyanates has been developed. This method provides direct and efficient syntheses of N-acyl anthranilamides, enamine amides, and pyrimidin-4-one heterocycles.

Full text of DOI:10.1021/ja203495c

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Expedient Synthesis of N-Acyl Anthranilamides and β-Enamine
Amides by the Rh(III)-Catalyzed Amidation of Aryl and Vinyl CÀH
Bonds with Isocyanates
Kevin D. Hesp,† Robert G. Bergman,*,‡ and Jonathan A. Ellman*,†
†Department of Chemistry, Yale University, New Haven, Connecticut, 06520 United States
‡Division of Chemical Sciences, Lawrence Berkeley National Laboratory, and Department of Chemistry, University of California - Berkeley,
Berkeley, California 94720, United States
S Supporting Information
b
from the corresponding anthranilic acids; however, this approach
ABSTRACT: A Rh(III)-catalyzed protocol for the amida-
tion of anilide and enamide CÀH bonds with isocyanates
has been developed. This method provides direct and
efficient syntheses of N-acyl anthranilamides, enamine
amides, and pyrimidin-4-one heterocycles.
is inherently restricted by the limited selection of commercially
available anthranilic acids.6 N-Acyl enamine amides obtained from
enamides and isocyanates are also useful intermediates because they
can readily be reduced to β-amino amides, which are present in
important drugs as well as β-peptides.7 Moreover, both N-acyl
anthranilamides and enamine amides are poised to undergo cyclode-
hydration reactions to provide quinazolinone and pyrimidinone frame-
works, which are also a common feature in approved drugs and drug
candidates.8 Herein we report the first examples of the coupling of
anilides and enamides with isocyanates to form amides. This unpre-
cedented method enables the efficient preparation of N-acyl anthrani-
lamides and enamine amides from readily available starting materials.
Our initial investigations focused on the identification of a
suitable catalyst and reaction conditions for the selective cou-
pling of phenyl isocyanate with the vinylic CÀH bond in N-acetyl
enamine 2a to afford the amidation product 3a.9,10 Although the
use of 2.5 mol % of [Cp*RhCl2]2 proved unsuccessful in
catalyzing this reaction (Table 1, entry 1), employing a mixture
of 2.5 mol % of [Cp*RhCl2]2 and either 10 mol % of AgSbF6 or
AgB(C6F5)4 in THF at 75 °C provided an excellent combined
yield of amidation products.11 However, the ratio of the desired
amidation product 3a to the cyclodehydrated pyrimidin-4-one 4a
remained low (Table 1, entries 2 and 3). Notably, comparable
catalyst activity was achieved through the use of the more
practical Rh(III) precursor [Cp*Rh(MeCN)3](SbF6)2,12 which
was used for all subsequent optimization (Table 1, entry 4).
When conducted in the absence of the Rh(III) catalyst, prefer-
ential reaction between the amide functionality of the substrate
and the isocyanate occurred, rather than the desired CÀC bond
formation (Table 1, entry 5). In addition, as shown in entries
6À8, a variety of acids and bases, as well as Lewis acids, did not
promote the desired reaction. Alternative solvents, such as
CH2Cl2 and tBuOH, provided good yields of the amidation
products 3a and 4a but did not improve the product ratios
(Table 1, entries 9 to 11). Variable substrate stoichiometries were
investigated; the highest yields were observed for reactions
employing 2 equiv of the enamide relative to phenyl isocyanate
(Table 1, entry 12).13 The selective formation of either 3a or 4a
was ultimately achieved by conducting the reaction at room
temperature or 105 °C, respectively (Table 1, entries 13 and 14).
ransition-metal catalyzed CÀH bond functionalization re-
T
actions have emerged as effective strategies for streamlining
chemical synthesis by avoiding tedious and costly substrate
preactivation steps. While the development of methods for the
functionalization of CÀH bonds with alkenes and alkynes has
been extensively investigated,1 the identification of related
procedures for additions across polar CÀN π-bonds has seen
considerably less progress.2 Given the ubiquity of amines in
bioactive molecules and drugs, the installment of nitrogen-based
functional groups into molecules through the direct addition of
CÀH bonds to unsaturated CÀN multiple bonds represents a
worthwhile pursuit with profound synthetic potential.
Recently, we showed that [Cp*RhCl2]2/AgSbF6 mixtures are
capable of catalyzing the addition of 2-arylpyridines to N-Boc and
N-sulfonyl imines via CÀH functionalization to afford R-
branched amine products.2a,3 Building on this result, we focused
on expanding this reactivity to include the insertion of CÀH
bonds across isocyanates toward the synthesis of amides.4
Initially, we demonstrated the feasibility of this transformation
by successfully employing the 2-pyridyl directing group (eq 1),
but immediately refocused our efforts to the use of the N-acyl
amino directing group present in anilides and enamides for the
synthesis of N-acyl anthranilamides and enamine amides.
The atom-economical synthesis of N-acyl anthranilamides
from readily available anilides and isocyanates is of significant
practicalutilitygiventhat this structuralmotifis foundinnumerous
drugsand drug candidates.5 Anthranilamides are typically prepared
Received: April 15, 2011
Published: June 29, 2011
r
2011 American Chemical Society
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Table 1. Reaction Optimization
Table 2. Substrate Scopea
entry
catalyst
solvent
temp (°C)
yieldb
1
[Cp*RhCl2]2
[Cp*RhCl2]2, AgSbF6
THF
THF
75
75
75
75
75
75
75
75
75
75
75
75
rt
0
2c
3c
4
93 (1:8)
94 (1:3)
94 (1:3)
0
[Cp*RhCl2]2, AgB(C6F5)4 THF
[Cp*Rh(MeCN)3](SbF6)2 THF
5
À
AgSbF6
THF
THF
THF
THF
6d
7e
8e
9
0
AcOH or TFA
0
NEt3, K3PO4, or KO(tBu)
0
[Cp*Rh(MeCN)3](SbF6)2 CH2Cl2
[Cp*Rh(MeCN)3](SbF6)2 tBuOH
[Cp*Rh(MeCN)3](SbF6)2 toluene
[Cp*Rh(MeCN)3](SbF6)2 THF
[Cp*Rh(MeCN)3](SbF6)2 THF
[Cp*Rh(MeCN)3](SbF6)2 THF
85 (3:1)
75 (1:8)
30 (1:1)
78 (1:2)
96 (15:1)
99 (1:50)
10
11
12f
13
14
105
a Conditions: PhNCO:2a = 1:2, 0.05 mmol (0.1 mM) PhNCO scale, 5
mol % of Rh, 8 h. b Determined by 1H NMR relative to 2,6-dimethox-
ytoluene as an internal standard. Ratio of 3a:4a is indicated in par-
entheses. c Addition of 10 mol % of Ag salt. d 20 mol % of AgSbF6
employed. e 20 mol % of acid or base employed. f PhNCO:2a = 2:1.
Having defined a highly effective catalyst system and reaction
conditions for the selective amidation of N-acyl enamine 2a with
phenyl isocyanate, we sought to further explore the reaction
scope for other enamides and anilides with a broad range of
isocyanates (Table 2). In addition to employing phenyl isocya-
nate, the amidation of 2a with primary and secondary alkyl
isocyanate substrates provided amide products 3b and 3c in
excellent yields (96 and 84%, respectively) when employing 5
mol % of Rh in THF at room temperature. Addition of the
sterically demanding tertiary 1-adamantyl isocyanate was also
successful, albeit in a modest yield (3d; 40%). An isocyanate
derived from the readily available amino acid phenylalanine was
accommodated (3e; 65%) and served to highlight potential
opportunities for the incorporation of chiral components in
more complex synthesis. In addition to 2a, enamides derived
from 1-acetyl-cyclohexene and cyclohexanone were readily con-
verted to the amides 3f and 3g in good yields (80% and 76%,
respectively).
a Conditions: R3NCO:2 = 1:2, 0.25 mmol (0.25 mM) R3NCO scale, 5
mol % of Rh, 16 h; yields represent isolated material. b Reaction
conducted at 120 °C for 24 h. 1H NMR yield relative to 2,6-dimethox-
ytoluene. c Reaction conducted at 120 °C.
to 4a is facilitated by the rhodium catalyst rather than being solely
thermally induced.16
Literature methods are available for the efficient cyclodehy-
dration of N-acyl anthranilamides and enamine amides to
quinazolinone and pyrimidinones, respectively.14 However, we
postulated that by conducting the Rh(III)-catalyzed reaction at
high temperature, both the isocyanate coupling and cyclization
might be accomplished in a single step. Indeed, heating enamides
2a (R = Ph) and 2b (R = tBu) with phenyl isocyanate at 105 °C in
the presence of 5 mol % of [Cp*Rh(MeCN)3](SbF6)2 directly
provided the corresponding pyrimidin-4-ones 4a and 4b in
The substrate scope was extended further to include anilides
providing direct access to anthranilamide derivatives from readily
available anilines and isocyanates (Table 2). Although the
reaction did not proceed at room temperature, good yields were
obtained at 75 °C (3hÀ3t). Consistent with the substrate scope
for enamides (3aÀ3g), primary, secondary, and tertiary alkyl
isocyanates all readily coupled with acetanilide (3iÀ3t). Signifi-
cantly, more bulky alternative anilide acyl groups, such as iPr and
iBu, provided good yields of anthranilamides 3k and 3l (77% and
72%, respectively). Electron-rich or -poor acetanilides featur-
ing meta- or para-substitution gave the desired anthranilamide
1
excellent yields (eq 2).15 When monitored by H NMR, the
initial enamine amide products (3) are formed along with the
heterocycles (4) at early conversion. Notably, heating the isolated
amide 3a in the absence of [Cp*Rh(MeCN)3](SbF6)2 resulted in
negligible conversion to 4a, suggesting that cyclodehydration of 3a
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products with good to excellent yields (3mÀ3p; 44À97%).
Moreover, meta-substituted acetanilides exclusively provided
the less substituted anthranilamide products (3o and 3p). N-
acylamino substituted nitrogen and oxygen heterocycles were
also evaluated and yielded anthranilimides that incorporate
indole (3s) and benzofuran (3t) functionality, with two regioi-
someric products obtained for the substituted benzofuran sub-
strate (3t).
The product regiochemistry observed for the isocyanate
additions to aromatic substrates is most consistent with a Rh-
mediated CÀH cleavage step directed by a Lewis basic group
instead of a more traditional electrophilic aromatic substitution
mechanism. Specifically, ortho-functionalization rather than
meta-substitution is observed for 2-phenylpyridine, and exclusive
ortho-substitution, as opposed to ortho-/para-product mixtures,
is observed for anilides.
To provide preliminary insight into the reaction mechanism
for the Rh(III)-catalyzed addition of isocyanates to acetanilides,
deuterium kinetic isotope effects (DKIE) were also investigated.
When a competition reaction was conducted with an equimolar
ratio of deuterio- and protio-acetanilide, a g2-fold product ratio
favoring the protio-derived product was observed at early con-
version (eq 3).13 However, when acetanilide-d5 was subjected to
the standard reaction conditions, modest deuterium exchange
was observed at the ortho-positions of both the unreacted anilide
(21% H) and the product N-acyl anthranilamide (18% H) (eq 4),
thus complicating the interpretation of the data presented in eq 3.
The DKIE was therefore also evaluated for the reaction of phenyl
isocyanate with N-cyclohexenyl acetamide 2b and the analogous
deuterated enamide 2b-d3. Indeed, a comparison of the initial
rates of enamine amide product formation at early conversions
revealed a DKIE of 2.2 (eq 5).13 Importantly, no background H/
D exchange was observed for unreacted 2b-d3 under these
reaction conditions. Although elucidation of the rate law for
the reaction is necessary to interpret this result properly, a
primary isotope effect is consistent with rate-limiting CÀH bond
activation rather than direct π-bond addition to the isocyanate
electrophile.17 We plan to carry out a more thorough kinetic
examination of the reaction to confirm this inference.
’ ASSOCIATED CONTENT
S
Supporting Information. Full experimental details and
b
characterization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
rbergman@berkeley.edu; jonathan.ellman@yale.edu
’ ACKNOWLEDGMENT
This work was supported by the NIH Grant GM069559 (to J.
A.E.) and by the Director, Office of Energy Research, Office of
Basic Energy Science, Chemical Sciences Division, U.S. Depart-
ment of Energy under Contract DE-AC02-05CH11231 (to R.G.
B.). K.D.H. is grateful to the National Sciences and Engineering
Research Council of Canada (NSERC) for a postdoctoral
fellowship.
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literature, and access to ongoing clinical trials, applications, and usage:
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In summary, we have identified [Cp*Rh(MeCN)3](SbF6)2 as
an effective catalyst for the addition of anilide and enamide CÀH
bonds across a broad range of isocyanates to afford valuable
N-acyl anthranilamides and enamine amides. Studies are ongoing
to better understand the reaction mechanism as well as to apply
the method to natural product and drug synthesis.
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N-cyclohexyl amides obtained from alkyl isocyanates.
(16) The cyclodehydration of isolated 3a to 4a was achieved in an
1
80% H NMR yield (relative to 2,6-dimethoxytoluene) when treated
with 5 mol % [Cp*Rh(MeCN)3](SbF6)2 in THF at 105 °C for 16 h.
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