Br?nsted Acid Organocatalyzed Three-Component Hydroamidation Reactions of Vinyl Ethers

Article abstract of DOI:10.1021/acs.joc.0c03017

Hydroamidation of carbon-carbon double bonds is an attractive strategy for installing nitrogen functionality into molecular scaffolds and, with it, increasing molecular complexity. To date, metal-based approaches have dominated this area of chemical synth

Full text of DOI:10.1021/acs.joc.0c03017

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Brønsted Acid Organocatalyzed Three-Component Hydroamidation
Reactions of Vinyl Ethers
Ivor Smajlagic, Brenden Carlson, and Travis Dudding*
Cite This: J. Org. Chem. 2021, 86, 4171−4181
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ABSTRACT: Hydroamidation of carbon−carbon double bonds is
an attractive strategy for installing nitrogen functionality into
molecular scaffolds and, with it, increasing molecular complexity.
To date, metal-based approaches have dominated this area of
chemical synthesis, despite the drawbacks of air and moisture
sensitivity, limited functional group tolerance, toxicity, and/or high
cost often associated with using metals. Here, in offering an
alternative solution, we disclose an operationally simple, metal-free,
one-pot, regioselective, multicomponent synthetic procedure for
the hydroamidation of carbon−carbon double bonds. This method features mild reaction conditions and utilizes isocyanides and
vinyl ethers for the rapid and modular synthesis of privileged α-oxygenated amide scaffolds. In unraveling the mechanistic
underpinning of this non-metal-based reactivity, we present kinetic solvent isotope effect studies, variable time normalization
analysis, and density functional theory computations offering insight into the mechanism of this multistep catalytic hydroamidation
process.
sustainability enabling productive harmony, stability, and
resilience to support present and future generations. To bypass
these drawbacks, catalytic methods for the formation of amides
and their selective installation into organic molecules have
attracted considerable attention. These methods include
oxidative amidation using amine precursors,10 hydrocarbamoy-
lation of alkenes/alkynes,11 oxidative coupling of α-bromo
nitroalkanes with amines,12 transamidation reactions,13 and
acylation of amines.14 These catalytic procedures, however, are
not free of limitations, as many are restricted by the use of
costly, toxic metals and harsh reaction conditions requiring
excessive heating and long reaction times.4,15 Moreover, the
metals used in the procedures may engage in nonspecific
coordination with synthesized amide bonds.11h A particularly
productive alternative, however, has been the use of either
boron-based catalysts or group(IV) metals to catalytically
induce direct amidation.16 Nonetheless, more environmentally
benign methods implementing organocatalytic conditions for
amide formationideally using low catalyst loadingsare
highly desirable.
INTRODUCTION
■
The selective introduction of amide functionality into organic
molecules is of the utmost importance, and transformations for
achieving this goal are of fundamental interest in organic
synthesis and paramount to the chemical and life science
industries.1,2 This significance spans from the manifold roles of
amides in Nature, where they are the centerpiece of proteins,
e.g., enzymes, in essence the fabric and working machinery of
living systems. With this, amides are found in numerous drug
scaffolds and biologically active compounds, including natural
products, heterocycles, polymers, and pharmaceutical drugs,
with nearly two-thirds of drug candidates containing this
privileged functionality.3 Notwithstanding, the efficient and
selective introduction of amides4 into organic molecules under
mild catalytic conditions that are tolerant of various functional
groups is a formidable challenge with practical limitations.
Traditional synthetic strategies toward amide formation rely
upon the condensation of carboxylic acids and their derivatives
with amines in the presence of stoichiometric amounts of
activating or coupling reagents. While tried and true, these
methods are at a disadvantage because of the use of toxic,
hazardous, and/or costly coupling reagents generating
equivalents of waste, thus complicating product isolation and
driving up costs.5 For instance, benzotriazole-based aminium
salts, such as HATU,6 HCTU,7 and HBTU,8 are considered as
class 1 explosives, showing autocatalytic decomposition,
difficult handling during transport and storage,9 and their use
results in stoichiometric equivalents of byproduct waste.
Though viable, the use of coupling reagents for amide
formation is subpar in terms of meeting the goal of global
By the same token, the advancement of novel modes of
catalysis enabling access to amides or, more broadly, less
Received: December 23, 2020
Published: February 24, 2021
https://dx.doi.org/10.1021/acs.joc.0c03017
© 2021 American Chemical Society
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explored or uncharted modes of bond construction is a
powerful way of increasing chemical space. On this front, the
use of isocyanides as linchpins for innovative modes of bond
formation has witnessed a renaissance over the past two
decades, owing to their rich, diverse, and ambiphilic reactivity
profiles.17,18 Isocyanide-based multicomponent reactions
(IMCRs),18 as one of the most efficient and operationally
simple methods, attest to this fact. This is clearly seen from
their use in diversity-oriented synthesis (DOS) and con-
struction of valuable molecules, such as heterocyclic cores in
natural products.19 Moreover, various Passerini,20 Ugi,21 and
related IMCR transformations are reported, many of which
proceed by reaction mechanisms relying upon Lewis acid
catalysis or organocatalysis.22 While these achievements are
impressive, an overarching feature of these reactivities is the
limited use of polar CX (X = O, N) bonds23−26 along with a
handful of examples of polar CC or CC bonds as the
electrophilic component.24e,27
In view of this current state, coupled with our interest in
oxocarbenium functionalization,28 the prospect of developing
an organocatalyzed hydroamidation reaction furnishing amide
products attracted our attention. As a point of departure for
this undertaking targeting unique catalytic reactivity for amide
formation, we turned to the blueprint of retrosynthetic analysis
to identify viable precursors (synthons) for accessing
distinctive bond connectivity. To this end, we arrived at the
transformation depicted in Figure 1A tracing back to the
tion reaction of carbon−carbon double bonds providing
synthetically relevant amide-containing compounds from
isocyanides and vinyl ethers under mild conditions with
regioselectivity. Critical to this work were mechanistic studies
including variable time normalization analysis (VTNA),29
kinetic solvent isotope effect (KSIE) experiments, and density
functional theory (DFT) calculations.
RESULTS AND DISCUSSION
■
At the outset of this study, the following queries of concern
materialized: Can we enable catalytic turnover? What Brønsted
acid(s) would be optimal? How might we minimize non-
productive byproduct formation, e.g., hydration of vinyl ethers
and/or isocyanides? In entertaining these questions, we
undertook preliminary studies investigating the reaction of
easy-to-handle p-toluenesulfonylmethyl isocyanide (1a) with
ethyl vinyl ether (2a) and H2O in the presence of readily
available Brønsted acids under several different experimental
conditions (Table 1).
These efforts commenced with a scan of different Brønsted
acids as potential catalysts under atmospheric conditions open
to air (Table 1, entries 1−7). Evident from this survey of acids
was that the use of mild acids, such as boric acid and benzoic
acid (BzOH), resulted in unreacted starting materials, whereas
highly acidic triflic acid (TfOH) led to extensive decom-
position of the isocyanide and vinyl ether reagents,30 ultimately
revealing ( )-10-camphorsulfonic acid (CSA) as a promising
lead. We then added stoichiometric amounts of H2O to the
reaction by syringe pump over the course of 4 h with
conversion monitored periodically up to 24 h (entries 8−11).
Gratifyingly, the addition of 3 equiv of H2O was found to be
optimal in terms of product formation, whereas larger amounts
of H2O (5 to 20 equiv) negatively impacted the reaction owing
to formation of formamide (4) and 1-ethoxyethanol (5a)
1
byproducts, as confirmed by H NMR analysis. Further, the
use of dichloromethane (DCM) or 1,2-dichloroethane (DCE)
as solvents resulted in slightly lower conversions to the desired
product, making tetrahydrofuran (THF) the solvent of choice
(entries 12−14). Next, the catalyst loading was sequentially
decreased resulting in significant product formation with
Brønsted acid CSA at 4 mol % catalyst loading (entries 15 and
16). It is worth noting that a control reaction employing the
optimized conditions in the absence of added H2O provided
minuscule amounts of product formation (entry 17). Lastly,
cooling the reaction resulted in a decrease in product
formation with a concomitant increase in byproducts (entries
18 and 19).
With a viable set of experimental conditions in hand, we
turned to VTNA to probe the mechanistic underpinnings of
this reaction. Notably, this approach has seen rampant growth
in the recent literature owing to its operational simplicity,
reliability, and amenability to metal- and metal-free cataly-
sis.29,31 The motivation for these analyses was two-fold: (1) to
gain fundamental mechanistic understanding of this novel
catalytic hydroamidation reaction, especially with respect to
the catalyst, and (2) to identify optimal experimental
conditions by pinpointing concentration dependences of
each respective reaction component.
Figure 1. Envisioned approach to access α-oxygenated amides.
disconnection of a carbenium- and amide acyl anion synthons;
the former derived from vinyl ether protonation, while the
latter arises from isocyanide and H2O synthetic equivalents.
Notably, in the forward direction, this novel mode of catalysis
shares hallmarks of IMCR Passerini-type reactivity allowing
atom-economical access to synthetically attractive α-oxy-
genated amides (Figure 1B). Moreover, this posited reactivity
would expand the scope of IMCR transformations beyond its
heavy reliance upon electrophilic carbonyl and alkene/alkyne
components by employing vinyl ethers.
Curious as to the mechanistic features of this putative
reactivity, and, with it, the goal of rendering a robust catalytic
method, we embarked upon the current study. In this interest,
our primary objective was to provide a comprehensive
mechanistic study with facets rooted in multicomponent
Passerini-type reactivity, ultimately leading to innovative
metal-free catalysis for amide formation. Along with this
advancement was exploration of the innate preferences of
ambiphilic isocyanide reactivity with vinyl ethers. Accordingly,
we present herein the successful development of a one-pot,
multicomponent, Brønsted acid organocatalyzed hydroamida-
Accordingly, the reaction of isocyanide 1a (limiting reagent)
and vinyl ether 2a model substrates, selected for their synthetic
utility32 and unobtrusive reactivity profile (i.e., less side
1
product formation), was monitored by H NMR until ∼50%
consumption of 1a was observed. Restricting the analyses to
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Table 1. Optimization of Reaction Conditions
e
entry
catalyst (mol %)
boric acid (30)
BzOH (30)
4-chlorophenoxyacetic acid (30)
3-nitrophthalic acid (30)
L-tartaric (30)
TfOH (30)
( )-CSA (30)
( )-CSA (30)
( )-CSA(30)
( )-CSA (30)
( )-CSA (30)
( )-CSA (30)
( )-CSA (30)
( )-CSA (30)
( )-CSA (10)
( )-CSA (4)
solvent
time (h)
H2O (equiv)
3a conversion (%)
a
1
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DCM
DCE
THF
THF
THF
THF
THF
24
24
24
24
24
24
24
24
24
24
24
2
2
2
3
5
5
5
5
0
0
a
a
a
a
a
a
b
b
2
3
4
5
6
7
8
9
i
<1
i
7
i
9
0
35 (10)
46 (16)
91 (64)
1
3
5
20
3
3
3
3
2.5
f
b
f
10
l1
55 (22)
b
f
29 (8)
c
f
12
13
14
15
16
17
18
19
93 (66)
85 (59)
84 (56)
89 (61)
c
f
c
f
c
f
cd
d
f
95 (67)
i
( )-CSA (4)
( )-CSA (4)
( )-CSA (4)
<3
c
c
,
d
d
,
,
g
2.5
2.5
62 (28)
32 (11)
,
h
a
Reaction conditions: isocyanide (1a) (1.0 mmol), ethyl vinyl ether (2a) (3.0 mmol), and Brønsted acid (30 mol %) in 0.5 mL of THF were
b
c
stirred for the indicated time. After addition of the aforementioned reactants, H2O was added over the course of 4 h via syringe pump. H2O (3.0
d
e
mmol) was added immediately. 1.2 mmol of 1a was used. Conversion involved monitoring the disappearance of the signal at 7.88 ppm for 1a and
appearance of the signals at 7.76 ppm for product 3a and 8.03 ppm for side product 4. Signal overlap between the hydroamidated product, e.g., 3a,
and side product 4 was observed at ∼7.76 ppm resulting in constructive interference. This was accounted for when determining product
f
conversion, and thus, product conversion was presented in the absence of inconsistencies. Isolated yields are reported in parentheses. Full
g
h
i
consumption of isocyanide (1a). Reaction was performed at 0 °C. Reaction was performed at −20 °C. Isolated yields could not be determined.
Figure 2. VTNA experimental data with respect to isocyanide consumption for product formation. (A) Plot depicting mild catalyst deactivation.
(B) Normalized time scale plot displaying second-order in catalyst. (C−E) Plots revealing concentration dependences on substrates 1a, 2a, and
H2O indicating positive 1.5-order, negative first-order, and positive fifth-order, respectively.
this conversion range was required to diminish the effect of
inaccuracies arising from potential changes in reaction order.
To commence this kinetic investigation, we examined the
robustness of the catalyst by reducing the concentrations of
[1a]0, [2a]0, and [H2O]0 by 0.4 M, i.e., [1a]0 = 2.4 M, [2a]0 =
5.9 M, and [H2O]0 = 3.9 M to [1a]0 = 2.0 M, [2a]0 = 5.5 M,
and [H2O]0 = 3.5 M. In essence, this experiment allowed for
the comparison of the same reaction at different starting
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points. In addition, a third experiment was designed to mimic
the conditions of experiment 1 (standard conditions) at 45%
product conversion. Analysis of the data from these three
experiments revealed that product inhibition was an insignif-
icant process and mild catalyst deactivation was occurring
instead (Figure 2A). Further, based upon the normalized time
scale method31b taking side products into account, the reaction
was found to be second-order in catalyst (Figure 2B, see SI for
details). From this, two Brønsted acid catalysts in the rate-
determining step of the catalytic cycle of this hydroamidation
reaction are probable. By analogy, this is in line with the
findings from the research groups of Maeda20a and
Morokuma20c suggesting two molecules of acid catalyst are
involved in the rate-determining step of the Passerini reaction.
Next, the concentration dependency of each component of
this reaction was probed through a series of experiments. This
set of experiments was initiated by first delineating the order in
isocyanide, which we assigned through visual inspection a
positive 1.5-order dependence on [1a] consistent with an
accelerated reaction (faster rate) when higher initial substrate
concentrations were used (Figure 2C). Conversely, an increase
in [2a] led to a decrease in rate consistent with an, arguably,
negative first-order dependence in [2a], presumably arising
from the formation of a transient acetal involving catalyst CSA
and substrate 2a contributing to an unproductive off-cycle
equilibrium. Tied to the formation of this acetal was the
potential for further reaction with H2O affording side product
5a (Figure 2D). As a concluding study, we assessed the order
in H2O, which has profound implications toward side product
formation. Surfacing from this analysis was a positive order
concentration dependence on H2O, wherein we concluded that
a fifth-order assignment was reasonable upon visual inspection
(Figure 2e). From these kinetic studies, it is evident that a
complex balance of catalyst, isocyanide, vinyl ether and H2O is
required to obtain the desired hydroamidated products.
The generality of these kinetic trends was further probed by
additional VTNA studies employing a less reactive vinyl ether,
namely 3,4-dihydro-2H-pyran (DHP). Immediately evident
from these analyses were more complex reaction profiles with
higher populations of side products. Concurrent with these
observations were also minor deviations in concentration
dependences, though the overall trends remained consistent
with the former set of VTNA experiments (see th SI for
details).
Scheme 1. Deuterated Labeling Studies
differing modes of catalysis through inspection of the hydrated
side product. In theory, the latter would consist of both 5b′
and 5b′′ as a result of rapid reversible deuteration involving
the formation of an ion-pair intermediate from the reactants
(specific acid catalysis); see the SI for details. From this study,
compound 5′′ was not observed, thus supporting the role of
CSA as the active catalyst in mediating proton transfer.
Armed with this mechanistic insight, a tentative catalytic
cycle for the hydroamidation of 2a surfaced, wherein three
competing pathways presumably exist (Figure 3). One of these
was protonation of isocyanide by CSA with subsequent
trapping of nitrilium ion by sulfonate. Following this event,
formamide production concomitant with catalyst regeneration
is realized upon nucleophilic addition of H2O. Alternatively,
CSA-mediated protonation of ethyl vinyl ether provides a
CSA−vinyl ether adduct that may further undergo hydration to
furnish undesired side product 5a. This is a particularly
favorable process at high concentrations resulting in an off-
cycle unproductive equilibrium. In order to circumvent this
event, a lower concentration of vinyl ether is required from
which then two molecules of CSA interact, hence giving rise to
the second-order behavior in catalyst. The emerging hydrogen
bond (H-bond) catalyst network primes ethyl vinyl ether for
rate-limiting isocyanide addition, wherein the nitrilium is
trapped by the sulfonate. Finally, a joint effort between CSA
and H2O transpires with the latter serving a two-part function,
including generating the desired α-oxygenated amide product
and turning over the catalyst.
From this putative mechanistic interpretation, we turned to
DFT calculations at the ((IEFPCM)(THF))B3LYP/6-311+
+G(2d,p)//B3LYP/6-31+G(d,p) level using the Gaussian 09
program34 to gain further insight and corroborate our working
proposal for hydroamidation. In this effort, methanesulfonic
acid was used in place of CSA, while the remaining reaction
components included tert-butyl isocyanide and ethyl vinyl
ether. From these computational studies emerged the pathway
depicted in Figure 4. At the outset of the pathway,
intermediate IM1 reacts by concerted proton transfer
transition state (TS1) with C···H and C···O bond-forming
distances of 1.27 Å and 2.64 Å and a low Gibbs free energy
activation barrier (ΔG⧧) of 10.3 kcal mol−1. As a finer detail, it
is notable the concerted nature of TS1 contrasts with stepwise
proton transfer, as suggested in the catalytic cycle of Figure 3.
Our attention then turned to probing the role of nitrilium
intermediates in these CSA-catalyzed hydroamidation reac-
tions. In order to gain this insight, a kinetic solvent isotope
effect study (Scheme 1A) monitoring relative reaction rates by
NMR time-course analysis via tracking isocyanide consump-
tion (1a) in protium or deuterium oxide was performed that
resulted in a normal KSIE value (kH O/kD O = 1.7 at ∼50%
2
2
consumption of 1a). To confine this KSIE value to a sole effect
would be questionable as its magnitude encompasses multiple
small effects. Irrespective, we ascribe this observed normal
KSIE finding to the formation of a transient ion-pair derived
from the conjugate base of CSA and a nitrilium species, as
KSIE values >1 are anticipated for ion-forming reactions.33
Finally, to confirm the role of the active catalyst in this
reaction, namely Brønsted acid CSA, as opposed to hydronium
ion, a simplified system encompassing DHP, D2O and
deuterated CSA was investigated (Scheme 1B). From this
experiment, we hoped to distinguish between these two
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Figure 3. Tentative catalytic cycle based on experimental kinetic studies.
Next, in the presence of another molecule of catalyst and
isocyanide, intermediate IM3, via a tricomponent complex,
reacts by SN2-like transition state35 (TS2) with an activation
barrier of 19.5 kcal mol−1 to provide intermediate IM4. The
key features of this transition state includes a C···C bond-
making distance of 2.17 Å and a C···O bond-breaking distance
of 3.27 Å. Overall, this endergonic process involving two
molecules of catalyst is the rate-limiting step, thus corroborat-
ing our initial conjecture. What is more, the 5.2 kcal mol−1
difference in stability between intermediates IM2 and IM4 is
consistent with an irreversible process having a negative first-
order concentration dependence on the vinyl ether compo-
nent. Further, these computed results involving the inter-
mediacy of charged nitrilium species IM4 is in line with our
KSIE findings.
At this juncture, we rule out nitrilium trapping with another
equivalent of catalyst owing to transition state TS3C (C =
catalyst addition) (ΔG⧧ = 13.3 kcal mol−1) being more
energetically demanding. The product of this transition state
(intermediate IM5) is 14.3 kcal mol−1 less stable than
intermediate IM1 (blue line), and, thus, this pathway was
not further investigated. Alternatively, more feasible was
trapping of the incipient nitrilium species with H2O operating
through a concerted process. The activation barrier for this
event was found to be marginally lower (ΔG⧧ = 12.3 kcal
mol−1), relative to intermediate IM4, formed from transition
state TS3H (H = H2O) featuring C···O and O···H bond
forming distances of 1.94 Å and 1.60 Å, respectively. A distinct
feature of this transition state was a unique 10-membered H-
bond network priming H2O for nucleophilic addition and
concomitant proton transfer yielding IM7 residing 10.7 kcal
mol−1 below intermediate IM5 on the reaction coordinate.
Tautomerization of IM7 then furnishes product 3′, presumably
by a simple stepwise acid−base mechanism.36 The specific
details of this transformation were not further investigated as
tautomerization processes are a contentious subject inevitably
marred in ambiguity and, for that matter, not readily tractable
in computational investigations.
investigated (Figure 5). Various isocyanides (1a−c) and
endocyclic, exocylic, and short-chain vinyl ethers (2a−d)
reacted to furnish hydroamidated products (3a−3f) in low-to-
good yields (35−71%). Further, additional complex vinyl ether
products (3g−3l) were obtained using a slightly modified
procedure substituting water for alcohol. Long-chain vinyl
ethers provided products 3g−i in moderate yields (40−48%),
while more complex and bulky vinyl ether substrates afforded
products 3j and 3k in low-to-moderate yields (41% and 31%,
respectively), displaying the negative impact of sterics upon
product formation.
Comparatively, negligible differences in yield were observed
for more substituted vinyl ethers (3l, 41%). In probing other
reaction centers, the methodology was found to be unreactive
toward unactivated alkenes and alkynes.37 Moreover, in
demonstrating synthetic utility, we performed a multigram-
scale reaction that afforded compound 3a in 62% yield
(Scheme 2).
CONCLUSION
■
In closing, a Brønsted acid organocatalyzed hydroamidation of
vinyl ethers using readily available reagents in a one-pot, three-
component reaction has been developed. The strengths of this
protocol include operational simplicity, environmentally
benign reaction conditions, regioselectivity, and fast reaction
times. Detailed VTNA studies revealed concentration depend-
ences of reaction components as well as catalyst deactivation.
Further, kinetic solvent isotope effect studies supported the
presence of a nitrilium ion pair as a key intermediate in this
reaction. Corroborating these experimental findings were
computations offering insight into the mechanism of this
amide-forming reactivity from which isocyanide addition was
pinpointed as the rate-limiting step. Collectively, this work
provides an innovative strategy for accessing α-oxygenated
amide products that complement current metal-based
approaches.
EXPERIMENTAL SECTION
■
Having a firm understanding of the mechanism at hand, the
substrate scope of hydroamidation of vinyl ethers was then
Computational Methods. Quantum mechanical calculations
were performed using the Gaussian 09 software package.34 All
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Figure 4. Free energy profile for the CSA-mediated hydroamidation of vinyl ethers.
geometry optimizations were performed using the B3LYP functional38
with a 6-31+G(d,p) basis set. The optimized geometries were verified
as transition state structures (one imaginary frequency) or minima
(zero imaginary frequencies) by frequency calculations. Intrinsic
reaction coordinate (IRC) calculations39,40 were performed to
confirm that all transition state structures were linked to relevant
minima. The energies of the B3LYP/6-31+G(d,p)-optimized
structures were further refined by single-point calculations performed
at the B3LYP/6-311++G(2d,p) level of theory using the integral
equation formalism polarizable continuum model (IEFPCM) with the
default parameters of THF (ε = 7.43) to account for solvent.41 The
final reported Gibbs free energies are the summed thermal corrections
to the Gibbs free energies (temperature = 298.15 K) computed at the
lower (B3LYP/6-31+G(d,p)) level of theory and electronic energies
from single-point B3LYP/6-311++G(2d,p) calculations. The keyword
(integral = grid = ultrafine) was used for all calculations. The 3D
images of all optimized geometries were generated with CYLview,42
and GaussView43 was used to construct all structures prior to
optimization and to visualize the output from the Gaussian 09
calculations.
General Information. Materials were obtained from commercial
suppliers and were used without further purification unless otherwise
specified. All solvents were of technical grade and used without
further purification. Unless otherwise stated, all reactions were
performed under ambient conditions. Flash column chromatography
was performed on neutral Brockmann I grade aluminum oxide.
Reactions were monitored by nuclear magnetic resonance (NMR)
with a Bruker DPX-300 spectrometer (1H 300 MHz, 13C 75.5 MHz)
in CDCl3. The observed chemical shifts are reported as δ-values
(ppm) relative to tetramethylsilane (TMS). Coupling constants (J)
are recorded in hertz. Multiplicities are reported as follows: s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd
(doublet of doublets), dt (doublet of triplets), td (triplet of doublets),
br (broad singlet). Mass spectra were obtained on an MSI/Kratos
concept IS mass spectrometer. Vinyl ethers were prepared according
to literature procedures44 and the spectra match accordingly.
General Procedure using H2O as Proton Source. To a stirred
solution of vinyl ether (3.0 mmol) and isocyanide (1.2 mmol) in THF
(0.5 mL) were quickly added CSA (4 mol %) and distilled water (3.0
mmol), respectively. The solution was stirred at room temperature
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Figure 5. Substrate scope using varying conditions denoted as either “[a]” involving water or as “[b]” involving alcohol; see the Supporting
Information for details. [c] indicates the diastereomeric ratio (dr) of compound 3i is 1:1. The yields provided are reported as isolated yields after
flash chromatography.
N-Benzyltetrahydro-2H-pyran-2-carboxamide (3c): (0.092 g,
35%), pink solid; mp 63−65 °C (hexanes/EtOAc = 3:1); H NMR
Scheme 2. Multi-Gram-Scale Reaction
1
(300 MHz, CDCl3, 25 °C) δ = 1.41−1.50 (m, 3H), 1.55−1.58 (m,
3H), 1.92−1.95 (m, 1H), 2.17−2.22 (dd, J = 12.6, 3.0 Hz, 1H),
3.45−3.53 (m, 1H), 3.83−3.87 (dd, J = 11.1, 2.4 Hz, 1H), 4.00−4.05
(dd, J = 10.5, 2.1 Hz, 1H), 4.47−4.49 (d, J = 5.7 Hz, 2H), 6.88 (br,
1H), 7.28−7.38 (m, 5H); 13C{1H} NMR (75.5 MHz, CDCl3, 25 °C)
δ = 23.2, 25.6, 29.3, 42.8, 68.3, 127.4, 127.8, 128.7, 138.2, 171.9;
HRMS (EI-DFS) m/z [M + H]+ Calcd for C13H17NO2 219.1259;
Found 219.1258.
N-(Tosylmethyl)tetrahydro-2H-pyran-2-carboxamide (3d):
(0.153 g, 43%), white solid; mp 89−91 °C (hexanes/EtOAc =
until full consumption of isocyanide was observed via TLC. The
reaction was quenched with 1 M HCl, separated with DCM, and
concentrated. After removal of solvent, the crude material was
subjected to flash column chromatography to furnish the product.
Alternative Procedure using Alcohol as Proton Source. To a
stirred solution of vinyl ether (3.0 mmol) and isocyanide (1.2 mmol)
in THF (0.5 mL) were quickly added CSA (30 mol %) and alcohol
(12.0 mmol), respectively. The solution was stirred at room
temperature until full consumption of isocyanide was observed via
TLC. The reaction was quenched with 1 M HCl, separated with
DCM and concentrated. After removal of solvent, the crude material
was subjected to flash column chromatography to furnish the product.
Characterization Data. 2-Ethoxy-N-(tosylmethyl)propanamide
(3a): (0.230 g, 67%), yellow solid; mp 71−73 °C (hexanes/EtOAc =
1
1:1); H NMR (300 MHz, CDCl3, 25 °C) δ = 1.54 (br, 4H), 1.84−
1.88 (d, J = 10.5 Hz, 2H), 2.45 (s, 3H), 3.43−3.51 (m, 1H), 3.64−
3.87 (dd, J = 11.7, 2.1 Hz, 1H), 4.05−4.09 (d, J = 12.0 Hz, 1H),
4.58−4.77 (m, 2H), 7.34−7.37 (d, J = 8.1 Hz, 2H), 7.79−7.81 (d, J =
8.4 Hz, 2H); 13C{1H} NMR (75.5 MHz, CDCl3, 25 °C) δ = 21.7,
22.9, 25.5, 28.8, 29.7, 59.5, 68.3, 128.9, 129.8, 133.8, 145.8, 171.5;
HRMS (EI-DFS) m/z [M + H]+ Calcd for C14H20NO4S 298.1113;
Found 298.1110.
N-(Tosylmethyl)tetrahydro-2H-furan-2-carboxamide (3e): (0.241
1
g, 71%), white solid; mp 131−133 °C (DCM/EtOAc = 9:1); H
NMR (300 MHz, CDCl3, 25 °C) δ = 1.73−1.93 (m, 3H), 2.11−2.20
(m, 1H), 2.45 (s, 3H), 3.83−3.99 (m, 2H), 4.19−4.23 (dd, J = 8.3,
4.8 Hz, 1H), 4.53−4.60 (dd, J = 14.0, 6.6 Hz, 1H), 4.76−4.83 (dd, J =
14.0, 7.4 Hz, 1H), 7.34−7.37 (d, J = 8.0 Hz, 2H), 7.44 (br, 1H),
7.77−7.80 (d, J = 8.3 Hz, 2H); 13C{1H} NMR (75.5 MHz, CDCl3, 25
°C) δ = 21.7, 25.4, 30.0, 59.6, 69.6, 77.9, 128.9, 129.9, 133.8, 145.5,
172.9; HRMS (EI-DFS) m/z [M + H]+ Calcd for C13H17NO4S
283.0878; Found 283.0870.
1
3:1); H NMR (300 MHz, CDCl3, 25 °C): δ = 1.26−1.32 (m, 6H),
2.45 (s, 3H), 3.41−3.61 (m, 2H), 3.70−3.77 (dd, J = 13.5, 6.6 Hz,
1H), 4.63−4.77 (m, 2H), 7.34−7.37 (d, J = 8.1 Hz, 2H), 7.78−7.81
(d, J = 8.1 Hz, 2H); 13C{1H} NMR (75.5 MHz, CDCl3, 25 °C) δ =
15.3, 18.2, 21.7, 59.6, 65.6, 75.9, 128.9, 129.9, 133.8, 145.4, 173.0;
HRMS (EI-DFS) m/z [M + H]+ Calcd for C13H19NO4S 285.1035;
Found 285.1027.
2-(Cyclohexyloxy)-N-(tosylmethyl)propanamide (3f): (0.236 g,
1
58%), yellow solid; mp 93−95 °C (DCM/EtOAc = 9:1); H NMR
N-Cyclohexyltetrahydro-2H-pyran-2-carboxamide (3b):45 (0.174
g, 69%), white solid; mp 69−71 °C (hexanes/EtOAc = 3:1); 1H
NMR (300 MHz, CDCl3, 25 °C) δ = 1.12−1.28 (m, 4H), 1.32−1.42
(m, 3H), 1.53−1.58 (m, 3H), 1.64 (br, 2H), 1.70−1.76 (dt, J = 12.9,
2.8 Hz, 2H), 1.90−1.93 (m, 3H), 2.13−2.17 (d, J = 13.2 Hz, 1H),
3.45−3.53 (td, J = 10.4, 3.7 Hz, 1H), 3.73−3.79 (m, 2H), 4.03−4.05
(dt, J = 11.0, 1.9 Hz, 1H), 6.45 (br, 1H); 13C{1H} NMR (75.5 MHz,
CDCl3, 25 °C) δ = 23.2, 24.9, 25.6, 25.7, 29.3, 33.1, 33.1, 47.4, 68.3;
HRMS (CI-DFS) m/z [M + H]+ Calcd for C12H22NO2 212.1651;
Found 212.1647.
(300 MHz, CDCl3, 25 °C) δ = 1.17−1.20 (d, J = 6.8 Hz, 3H), 1.23−
1.34 (m, 6H), 1.71−1.87 (m, 4H), 2.45 (s, 3H), 3.24−3.30 (m, 1H),
3.81−3.88 (q, J = 6.9 Hz, 1H), 4.62−4.78 (m, 2H), 7.33−7.36 (d, J =
8.1 Hz, 2H), 7.40−7.45 (t, J = 6.6 Hz, 1H), 7.78−7.80 (d, J = 8.4 Hz,
2H); 13C{1H} NMR (75.5 MHz, CDCl3, 25 °C) δ = 19.1, 21.7, 23.9,
24.1, 25.50, 32.5, 59.5, 73.3, 128.9, 129.8, 133.7, 145.4, 173.6; HRMS
(EI-DFS) m/z [M + H]+ Calcd for C17H25NO4S 339.1504; Found
339.1499.
2-Butoxy-N-(tosylmethyl)propanamide (3g): (0.169 g, 45%),
yellow solid; mp 109−111 °C (DCM/EtOAc = 9:1); 1H NMR
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(300 MHz, CDCl3, 25 °C) δ = 0.95−0.99 (t, J = 7.3 Hz, 3H), 1.18−
1.21 (d, J = 6.9 Hz, 3H), 1.27−1.45 (m, 4H), 1.58−1.66 (m, 4H),
2.45 (s, 3H), 3.37−3.52 (m, 2H), 3.68−3.75 (m, 1H), 4.63−4.77 (m,
2H), 7.34−7.37 (d, J = 7.8 Hz, 2H), 7.78−7.81 (d, J = 8.1, 2H);
13C{1H} NMR (75.5 MHz, CDCl3, 25 °C) δ = 13.8, 18.1, 19.3, 21.7,
29.7, 31.78, 59.5, 70.0, 76.0, 128.9, 129.8, 133.8, 145.4, 173.0; HRMS
(EI-DFS) m/z [M + H]+ Calcd for C15H23NO4S 313.1348; Found
313.1339.
conditions”, was charged with vinyl ether (2a or 2b) (5.9 M) to which
was diluted in 1.0 mL of THF. Next, p-toluenesulfonylmethyl
isocyanide (1a) (2.4 M) was added to the stirring solution. Following
this, CSA (4 mol %; 0.095 M) and distilled H2O (3.9 M) were quickly
added, respectively. The next experiment followed the same protocol;
however, with a consistent reduction in the initial concentrations of
substrates by 0.4 M, i.e., 2a = 5.5 M, 1a = 2.0 M, and H2O = 3.5 M.
The third experiment was performed utilizing the conditions from
experiment 2 with product added (3a or 3b = 0.9 M). All reactions
were allowed to stir for ∼2 h. The reaction progress was determined
by 1H NMR (CDCl3) spectroscopy analyses of aliquots taken
periodically. Conversion involved monitoring the disappearance of the
signal at 7.88 ppm for 1a and appearance of the signals ∼7.76 ppm for
products 3a or 3b and 8.03 ppm for side product 4. Note: Signal
overlap between the hydroamidated product, e.g., 3a and side product
4 was observed ∼7.76 ppm resulting in constructive interference. This
was accounted for when determining product conversion, and thus,
product conversion was presented in the absence of inconsistencies.
Representative Procedure for Determining the Order in
Catalyst. Using the “standard conditions” data obtained from the
experiments involving catalyst deactivation, two additional independ-
ent reactions were conducted in 4 dram vials charged with vinyl ether
(2a or 2b) (5.9 M) which were diluted in 1.0 mL of THF. Next, p-
toluenesulfonylmethyl isocyanide (1a) (2.4 M) was added to the
stirring solutions. Following this, CSA (1, 10, or 20 mol %; 0.024,
0.24, or 0.48 M, respectively) and distilled H2O (3.9 M) were quickly
added, respectively. The reactions were allowed to stir for ∼2 h.
2-(Octyloxy)-N-(tosylmethyl)propanamide (3h): (0.213 g, 48%),
1
colorless oil (DCM/EtOAc = 9:1); H NMR (300 MHz, CDCl3, 25
°C) δ = 0.89−0.94 (m, 3H), 1.18−1.21 (d, J = 6.6 Hz, 3H), 1.28−
1.39 (m, 10H), 1.57−1.63 (m, 2H), 2.45 (s, 3H), 3.36−3.53 (m, 2H),
3.68−3.75 (m, 1H), 4.62−4.78 (m, 2H), 7.34−7.37 (d, J = 8.1 Hz,
2H), 7.78−7.81 (d, J = 8.4 Hz, 2H); 13C{1H} NMR (75.5 MHz,
CDCl3, 25 °C) δ = 14.1, 18.1, 21.7, 22.6, 26.1, 29.2, 29.4, 29.7, 31.8,
59.5, 70.4, 76.0, 128.9, 129.8, 133.8, 145.4, 173.0; HRMS (FAB-DFS)
m/z [M + Na]+ Calcd for C19H31NO4NaS 392.1866; Found
392.1866.
2-((3,7-Dimethyloct-6-en-1-yl)oxy)-N-(tosylmethyl)propanamide
1
(3i): (0.190 g, 40%), pale white oil (DCM/EtOAc = 9:1); H NMR
(300 MHz, CDCl3, 25 °C) δ = 0.83−0.89 (q, J = 6.6 Hz, 4H), 1.10−
1.19 (m, 2H), 1.25−1.51 (m, 5H), 1.60−1.69 (m, 9H), 1.95−2.00
(m, 2H), 2.45 (s, 3H), 3.63−3.69 (m, 1H), 4.04−4.10 (m, 1H),
5.06−5.08 (m, 1H), 7.34−7.36 (d, J = 8.1 Hz, 2H), 7.60−7.62 (d, J =
8.1 Hz, 2H); 13C{1H} NMR (75.5 MHz, CDCl3, 25 °C) δ = 17.6,
19.2, 21.5, 25.3, 25.3, 25.7, 29.2, 36.6, 36.9, 36.9, 62.8, 62.9, 77.2,
124.5, 125.2, 129.7, 131.3, 141.9, 142.6; LRMS (ESI-ion trap) m/z
[M + CH3]+ Calcd for C22H35NO4S 409.2287; Found 409.21. Note:
This compound could not be reported using HRMS owing to
difficulties in ionization and the absence of peaks strong enough for an
accurate high-resolution mass measurement.
1
Reaction progress was determined by H NMR (CDCl3) spectros-
copy analyses of aliquots taken periodically. Conversion involved
monitoring the disappearance of the signal at 7.88 ppm for 1a and
appearance of the signals ∼7.76 ppm for products 3a or 3b and 8.03
ppm for side product 4.
2-Isobutoxy-N-(tosylmethyl)propanamide (3j): (0.154 g, 41%),
1
Representative Procedure for Determining the Reaction
Order Dependence of Substrate, e.g., Isocyanide Depend-
ency. Using the “standard conditions” data obtained from the
experiments involving catalyst deactivation, two additional independ-
ent reactions were conducted in 4 dram vials charged with vinyl ether
(2a or 2b) (5.9 M) to which were diluted in 1.0 mL of THF. Next, p-
toluenesulfonylmethyl isocyanide (1a) (1.8- or 1.4 M) was added to
the stirring solutions. Following this, CSA (4 mol %; 0.095 M) and
distilled H2O (3.9 M) were quickly added, respectively. The reactions
were allowed to stir for ∼2 h. Reaction progress was determined by
1H NMR (CDCl3) spectroscopy analyses of aliquots taken periodi-
cally. Conversion involved monitoring the disappearance of the signal
at 7.88 ppm for 1a and appearance of the signals ∼7.76 ppm for
products 3a or 3b and 8.03 ppm for side product 4. Note: Reaction
order dependencies for vinyl ether and H2O were determined in a
similar fashion by using the data from the “standard conditions”
reactions followed by additional experiments with varying concen-
trations of the respective substrate.
colorless oil (DCM/EtOAc = 9:1); H NMR (300 MHz, CDCl3, 25
°C) δ = 0.97−0.99 (d, J = 4.5 Hz, 6H), 1.19−1.22 (d, J = 6.6 Hz,
3H), 1.60 (s, 1H), 1.84−1.97 (m, 1H), 3.16−3.30 (m, 2H), 3.68−
3.75 (q, J = 6.9, 1H), 4.69−4.72 (dd, J = 6.9, 3.3 Hz), 7.34−7.37 (d, J
= 8.1 Hz, 2H), 7.79−7.81 (d, J = 8.1 Hz, 2H); 13C{1H} NMR (75.5
MHz, CDCl3, 25 °C) δ = 17.9, 19.2, 19.3, 21.7, 28.5, 59.5, 76.2, 128.9,
129.9, 133.8, 145.4, 172.9; HRMS (FAB-DFS) m/z [M + Na]+ Calcd
for C15H23NO4NaS 336.1240; Found 336.1256.
2-(tert-Pentyloxy)-N-(tosylmethyl)propanamide (3k): (0.122 g,
1
31%), white solid; mp 85−87 °C (DCM/EtOAc = 9:1); H NMR
(300 MHz, CDCl3, 25 °C) δ = 0.90−0.95 (t, J = 7.5 Hz, 3H), 1.14 (s,
6H), 1.15−1.17 (d, J = 6.9 Hz, 3H), 1.48−1.57 (m, 2H), 2.45 (s,
3H), 3.90−3.97 (q, J = 6.6 Hz, 1H), 4.69−4.71 (d, J = 6.6 Hz, 2H),
7.34−7.37 (d, J = 8.1 Hz, 2H), 7.42−7.46 (t, J = 6.3 Hz, 1H), 7.79−
7.81 (d, J = 8.1 Hz, 2H); 13C{1H} NMR (75.5 MHz, CDCl3, 25 °C) δ
= 8.6, 21.1, 21.7, 25.0, 34.1, 59.6, 76.6, 77.0, 77.2, 77.4, 128.8, 129.8,
134.0, 145.4, 174.5; HRMS (CI-DFS) m/z [M + H]+ Calcd for
C16H26NO4S 328.1583; Found 328.1576.
Procedure for Determining the Kinetic Solvent Isotope
Effect. Two independent reactions were conducted in NMR tubes,
maintaining similar concentrations as established in the round-bottom
flask. On this front, ethyl vinyl ether (2a) (2.1 mmol), p-
toluenesulfonylmethyl isocyanide (1a) (0.84 mmol), CSA (4 mol
%), and (D)H2O (2.1 mmol) were quickly added to 0.35 mL of THF
in a 4 dram vial. The respective mixture was allowed to sit for 2 min
prior to transfer to the NMR tube. Conversion was tracked over a
period of ∼90 min with data being collected periodically. This
involved monitoring the rate of isocyanide consumption. Once the
reactions reached ∼50% isocyanide consumption, the respective rate
constants were estimated from each plot by employing Bruker’s
Dynamics Center program. From these rate constants, a normal KSIE
(1.7) was observed using the following equation:
2-Ethoxy-2-methyl-N-(tosylmethyl)propanamide (3l): (0.147 g,
41%), colorless oil. (DCM/EtOAc = 9:1); 1H NMR (300 MHz,
CDCl3, 25 °C) δ = 1.21 (s, 6H), 1.22−1.27 (t, J = 6.9 Hz, 3H), 2.44
(s, 3H), 3.39−3.46 (q, J = 6.9 Hz, 2H), 4.68−4.71 (d, J = 6.9 Hz,
2H), 7.33−7.36 (d, J = 8.1 Hz, 2H), 7.44−7.49 (t, J = 6.3 Hz, 1H),
7.78−7.81 (d, J = 8.4 Hz, 2H); 13C{1H} NMR (75.5 MHz, CDCl3, 25
°C) δ = 15.9, 21.7, 23.4, 23.7, 58.7, 59.9, 78.1, 128.9, 129.8, 133.9,
145.3, 175.3; HRMS (FAB-DFS) m/z [M + Na]+ Calcd for
C14H21NO4NaS 322.1089; Found 322.1084.
N-(4-Methylbenzenesulfonylmethyl)formamide (4):46 (0.02 g,
1
7%), white solid; mp 106−108 °C (DCM/EtOAc = 9:1); H NMR
(300 MHz, CDCl3, 25 °C) δ = 1.54 (br, 4H), 1.84−1.88 (d, J = 10.5
Hz, 2H), 2.47 (s, 3H); 4.71−4.74 (d, J = 6.9 Hz, 2H), 6.67 (br, 1H),
7.37−7.40 (d, J = 8.1 Hz, 1H), 7.80−7.83 (d, J = 8.1 Hz, 2H), 8.11 (s,
1H); 13C{1H} NMR (75.5 MHz, CDCl3, 25 °C) δ = 21.8, 58.7, 128.8,
130.1, 133.5, 145.8, 160.0; HRMS (EI-DFS) m/z [M + H]+ Calcd for
C9H11NO3S 213.0460; Found 213.0457.
k
/k
H2O D2O
Procedure for Addition of D2O to DHP in the Presence of
Deuterated CSA. To initiate this study, CSA (0.2 g, 0.86 mmol) was
dissolved in 0.78 mL of D2O (43 mmol) and stirred for 1 h at room
temperature in a 4 dram vial. Next, the solution was concentrated in
Representative Procedure for Determining Product Inhib-
ition or Catalyst Deactivation. Three independent reactions were
conducted in 4 dram vials. The first reaction, coined as “standard
4178
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vacuo and the process repeated once more. The deuterium content of
the catalyst was verified with HRMS (EI-DFS) measurements: HRMS
(EI-DFS) m/z [M + H]+ Calcd for C10H15DO4S 233.0832; Found
233.0827 and 234.0892.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c03017.
■
sı
Kinetic and experimental methods, computational data,
and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
Travis Dudding − Department of Chemistry, Brock University,
St. Catharines, ON L2S 3A1, Canada; orcid.org/0000-
0002-2239-0818; Email: tdudding@brocku.ca
■
Authors
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Solid-Phase Peptide Synthesis with HCTU. Chim. Oggi. 2002, 20,
37−42. (b) Hood, C. A.; Fuentes, G.; Patel, H.; Page, K.; Menakuru,
M.; Park, J. H. Fast Conventional Fmoc Solid-Phase Peptide Synthesis
with HCTU. J. Pept. Sci. 2008, 14, 97−101.
Ivor Smajlagic − Department of Chemistry, Brock University,
St. Catharines, ON L2S 3A1, Canada
Brenden Carlson − Department of Chemistry, Brock
University, St. Catharines, ON L2S 3A1, Canada
(8) (a) Speicher, A.; Klaus, T.; Eicher, T. O-(1-Benzotriazolyl)-
N,N,N’,N’-tetramethyluronium Hexafluorophosphat (HBTU) und O-
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Lalithamba, H. S.; Narendra, N.; Hemantha, H. P. New and Simple
Synthesis of Acid Azides, Ureas and Carbamates from Carboxylic
Acids: Application of Peptide Coupling Agents EDC and HBTU. Org.
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c03017
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
T.D. acknowledges financial support from the Natural Science
and Engineering Research Council (NSERC) Discovery Grant
(2019-04205). I.S. acknowledges QEII-GSST for funding.
Computations were carried out using facilities at SHARCNET
(Shared Hierarchical Academic Research Computing Network:
www.sharcnet.ca) and Compute/Calcul Canada.
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