Charge tags for most comprehensive ESI-MS monitoring of Morita-Baylis-Hillman (MBH)/aza-MBH reactions: Solid mechanistic view and the dualistic role of the charge tagged acrylate

Article abstract of DOI:10.1021/acs.joc.5b02651

Neutral and charge tagged reagents were used to investigate the mechanism of the classical Morita-Baylis-Hillman (MBH) reaction as well as its aza-version using mass spectrometry with electrospray ionization (ESI-MS). The use of an acrylate (activated alk

Full text of DOI:10.1021/acs.joc.5b02651

Article
pubs.acs.org/joc
Charge Tags for Most Comprehensive ESI-MS Monitoring of Morita−
Baylis−Hillman (MBH)/aza-MBH Reactions: Solid Mechanistic View
and the Dualistic Role of the Charge Tagged Acrylate
Renan Galaverna,*,† Nilton S. Camilo,‡ Marla N. Godoi,§ Fernando Coelho,*,‡ and Marcos N. Eberlin†
†ThoMSon Mass Spectrometry Laboratory, Institute of Chemistry, University of Campinas - UNICAMP, P.O. Box 6154, Zip Code
13083-970, Campinas, SP, Brazil
‡Laboratory of Synthesis of Natural Products and Drugs, Institute of Chemistry, University of Campinas - UNICAMP, P.O. Box 6154,
Zip Code 13083-970, Campinas, SP, Brazil
§Health Sciences Federal University of Porto Alegre - UFCSPA, Department of Pharmacoscience Sarmento Leite, Zip Code
90050-170, Porto Alegre, RS, Brazil
S
* Supporting Information
ABSTRACT: Neutral and charge tagged reagents were used to investigate
the mechanism of the classical Morita−Baylis−Hillman (MBH) reaction as
well as its aza-version using mass spectrometry with electrospray ionization
(ESI-MS). The use of an acrylate (activated alkene) with a methylimidazolium
ion as a charge tag eliminates the requirement for adding acids as ESI(+)
additives, which are normally used to favor protonation and therefore
detection of reaction partners (reagents, intermediates, and products) by
ESI(+)-MS. For both charge tagged reactions (MBH/aza-MBH), most
reactants, intermediates, and the final adducts were efficiently detected in the
form of abundant doubly and singly charged ions. Characterization of the
reactions partners was performed via both tandem mass spectrometry
(ESI(+)-MS/MS) and accurate m/z measurements. The charge tagged
reactions also showed faster conversion rates when compare to the neutral
reaction, indicating a dualistic role for the charge tagged acrylate. It acts as both the reagent and a cocatalyst due to the inherent
ionic-coordination nature of the methylimidazolium ion, which stabilizes the zwitterionic intermediates and reagents through
different types of coordination ion pairs. Hemiacetal intermediates for the rate-limiting proton transfer step were also intercepted
and characterized for both classical and aza-MBH charge tagged reactions.
Such mechanistic studies have, however, been most often
carried out using neutral reagents, but neutrals are undetectable
by MS. Ions from such reagents and their further intermediates
and products must therefore be formed in the reaction solution
and later transferred to the gas phase to be detected. This
requirement comes from the basic principles of ESI, which
serves simply as a way to “eject” solution ions directly to the gas
phase.1 In this context, basic or acidic additives such as formic
acid or ammonium hydroxide are normally used, providing a
charge for the reaction partners in order to turn them into an
ionic form that is suitable for ESI-MS detection.21 The effects
of such additives to the reaction outcome are, however, difficult
to determine and remain unknown. In view of this concern, the
use of such additives can be mostly avoided in two situations:
(i) when a metal-catalyzed reaction is performed, due the
charge associated to the metal when it coordinate with the
reaction partners and some examples are catalysis by Au, Cu,
Ag, Ir, Zr, Pd,5,7,9,10,14 or (ii) by using a charge tag, covalently
INTRODUCTION
■
Direct mass spectrometry (MS) monitoring of reaction
solutions via spray-based techniques such as electrospray
ionization (ESI-MS)1 has become a central protocol for
investigating reaction mechanisms and the actual intermediates
involved.2 ESI monitoring seems therefore to provide proper
snapshots of the actual ionic composition of the reaction
solution and has therefore unveiled many mechanistic details.
Although there have been concerns about interferences caused
by the ESI source conditions, which can be tuned to accelerate
reactions rates,3,4 no exceptional changes in such rates or the
detection of unusual intermediates have been reported if
conventional ESI parameters are used.2,5 In this context,
important organic reactions have been investigated by ESI-MS
monitoring and some examples of these are dynamic kinetic
resolution (DKR),6 Pesci decarboxylation,7 [2 + 2 + 2]-
cycloaddition,8 Heck and Heck-type reactions,9 propene
polymerization,10 dephosphorylation,11 olefin metathesis,12
homogeneous catalysis reactions,5 Pauson−Khand reaction,13
Stille reaction,14 hydro- and dehydrogenative silylation,15
Mannich reaction,16 and MBH/aza-MBH reactions.17−20
Received: November 19, 2015
Published: December 23, 2015
© 2015 American Chemical Society
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Scheme 1. General Scope of MBH/aza-MBH Reactions
Scheme 2. MBH Mechanism Based on the McQuade and Aggarwal Proposals
bonded to the reactants of a reaction to be monitored by ESI-
MS, called a charge tagged reagent.5,22−25 The use of charge
tags seems, however, more appropriate for ESI reaction
monitoring since it, in principle, guarantees that all possible
intermediates involving the charge tagged reactant would have
an inherent charge to facilitate the detection by MS. The charge
tagging approach has, therefore, been increasingly and
successfully employed in several ESI mechanistic investigations.
For instance, reactions between the acetate anion bearing an
imidazolium ion as the charge tag and M(OAc)2 complexes
(where M = Ni, Cu, and Pd; in situ reaction) to form members
of a new class of charge tagged metal complexes were efficiently
performed and monitored by ESI-MS.26 Later, the catalytic
performance of such palladium complexes was tested in Heck
and Suzuki cross-coupling reactions, often with superior activity
and yields as compared with Pd(OAc)2.26 The charge tag
strategy was also used to monitor Ugi four-component
condensations.25 Hantzsch and Mannich reactions also had
their mechanisms studied via charge tagged reagents.27
Recently, we reported comprehensive ESI-MS monitoring
using charge tagged reagents to study the multicomponent
Hantzsch reaction.28 As before, the use of charge tagged
reagents allowed reaction monitoring under real reaction
conditions without the requirement for ESI additives. But in
this study, the charge tag was placed on either, or both, of the
two key reactants, that is, an aldehyde and a dicarbonyl
compound. The strategy indeed facilitated the interception and
characterization of most important intermediates allowing the
proposal of a detailed mechanistic scheme for the Hantzsch
reaction.28
The MBH reaction process with materials which are
commercially available, displays high atom economy, their
adducts are flexible and multifunctional, and the reaction
involves a nucleophilic organocatalytic system without serious
environmental impacts. The reaction conditions are also mild
and can occur with high regio- and chemoselectivity.29 MBH
adducts are therefore formed when three partners are reacting:
an electrophile 1 (aldehyde or imine), an activated alkene 2,
and a Lewis basic catalyst (most often tertiary amines) (Scheme
1).
Most fundamental steps of the MBH reaction have been
described mainly by Morita,30 and later by Hillman and
Baylis,31 and the initial mechanistic approach has been
described by Hoffmann and Rabe32 and Hill and Isaacs.33
Fine MBH mechanistic details such as those operating during
asymmetric induction were later proposed by Aggarwal34 and
McQuade.35 For the mechanism therefore, the first reaction
step is believed to involve a 1,4-Michael addition of the catalyst
4 (tertiary amine) to the α,β-unsaturated carbonyl compounds
containing electron-withdrawing groups 5, which generate the
enolate product 6, that is, the first zwitterionic intermediate. In
step II, the aldol product (second zwitterionic intermediate 8)
is formed after aldolic addition of 6 to the aldehyde 7. In the
last and key proton transfer step, two mechanisms, as proposed
by Aggarwal and co-workers34 and McQuade and co-workers,35
are still debated (Scheme 2). According to McQuade, a second
aldehyde molecule is added to the aldol product in order to
form the hemiacetal intermediate 9. Now, the proton transfer
involves a six-membered cyclic transition state, and the catalyst
is eliminated to form the adduct 10 (step IIIa). This step was
initially attributed as the rate-determining step (RDS) and is
also able to explain the dioxanone byproduct 11 formed when
X is a good leaving group.35 However, Aggarwal showed
Among the carbon−carbon bond-forming reactions, the
Morita−Baylis−Hillman (MBH) and its aza-MBH version have
been widely studied and have shown high synthetic utility.29
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through supporting theoretical calculations and kinetic studies
that when the MBH-adduct concentration builds up, the aldol
addition step II becomes the RDS (Scheme 2). In this way,
autocatalysis of the proton-transfer step then takes place and
now protic species (adduct or solvents) by a hydrogen bond
can lead to the intermediate 12, which increases the rate
conversion due to its participation in the proton transfer step
(step IIIb). This rationale explains the autocatalytic MBH
adduct effect.34
Most recently, Plata and Singleton re-evaluated the MBH
mechanism by NMR and theoretical calculations and then
proposed a new mechanism for the MBH elimination step.36 In
this new proposal, the elimination step can be thought of as a
simple acid−base exchange. They proposed that the proton
shuttle process as suggested by Aggarwal should be abandoned
and replaced by a simple acid−base model, in which no cyclic
intermediate is involved due the different bond lengths
(Scheme 3).
Figure 1. Charge tagged benzaldehyde and acrylate used in the MBH
reaction ESI(+)-MS monitoring.
First, the classical MBH reaction was monitored using the
charge tagged benzaldehyde 7 with a neutral acrylate (ethyl
acrylate 5b), 1,4-diazabicyclo[2.2.2]octane (DABCO, 4a) as
the catalyst, and acetonitrile (ACN) as the solvent. Despite
many attempts to optimize the reaction as well as ESI(+)-MS
conditions, the spectra (as an example see Figure S13,
Supporting Information, p S9) for the classical MBH reaction
were quite noisy. Furthermore, only the enolate product (first
intermediate, 6, Scheme 2) and the final MBH adduct were
detected. Other intermediates, such as the aldol product
(second intermediate 8, Scheme 2) and the hemiacetal (9)
were not detected at all. Probably, the failure to detect the aldol
product was due to the high proximity of its two positive
charges. This repulsive factor would be even worse for the
hemiacetal due to its three positive charge centers (Scheme S1,
Supporting Information, p S10). The use of the charge tagged
acrylate 5a with the neutral aldehyde (4-nitrobenzaldehyde)
provided, however, very clean ESI(+) mass spectra detecting
most of the expected charge tagged intermediates in high
abundances. The charge tagged acrylate 5a was therefore
employed for the ESI(+)-MS monitoring of both the MBH/
aza-MBH reactions.
Scheme 3. Proton Transfer Step To Form the MBH Adduct
As Proposed by Plata and Singleton36
For reaction monitoring therefore, the classical MBH
reaction involved 5a and 4-nitrobenzaldehyde (7a), DABCO
(4a) as the catalyst, and ACN as the solvent. For the aza-MBH
reaction, just the aldehyde 7a was replaced by N-(4-
methoxybenzylidene)-4-methyl-benzenesulfonamide (7b). For
the corresponding “neutral” MBH/aza-MBH reactions, 5a was
replaced by ethyl acrylate (5b) (Scheme 4).
For monitoring, aliquots from the reaction solution were
continuously taken, diluted, and then subjected to the ESI(+)-
MS analysis (see Experimental Section). Figure 2 shows the
ESI(+)-MS for both the neutral and charge tagged MBH/aza-
MBH reactions at 60 min. This reaction time was selected since
at 60 min the most illustrative set of intermediates were
intercepted.
Note that, for both the neutral MBH/aza-MBH reactions
(Figure 2A/B bottom), the most predominant species in the
spectra after 60 min is 4a, which is [DABCO + H]+ of m/z 113.
This ion predominates due to facile protonation of such a basic
catalyst (pKaH 8).39 Few other intermediates such as the enolate
and aldol products (6b of m/z 213, 8b of m/z 364, and 8d of
m/z 502, A/B bottom) are also detected at low abundances.
But unlike, the use of the charge tagged acrylate 5a of m/z 195
offers instead a very detailed view of the reaction with the
efficient interception (Figure 2A/B top) of several, if not all,
key intermediates (6a of m/z 154, 8a of m/z 229, 8c of m/z
298, 9c of m/z 443, and 9c2 of m/z 587) as well as the final
adducts (10a of m/z 346 and 10c of m/z 484). This initial
ESI(+)-MS monitoring using both neutral and charge tagged
reagents proved therefore to be an efficient and sensitive
strategy to obtain most intermediates of the MBH/aza-MBH
reactions. For instance, the enolate products 6a and 6b (first
intermediate) were unequivocally intercepted. Using theoretical
calculations, NMR experiments, and kinetics estimations, Plata
Using ESI(+)-MS monitoring, we have been systematically
evaluating most mechanistic aspects of the MBH/aza-MBH
reactions, intercepting and characterizing several of their key
reaction intermediates.17 We have also investigated the
cocatalyst role of ionic liquids18 and its dualistic nature,19
that is, the operation of both Aggarwal and McQuade routes,
and have also used a charge tagged to facilitate the detection of
the intermediates.20
We report herein the use of the charge tag strategy to
comprehensively investigate the mechanisms of the classical
MBH reaction as well as its aza-version. Charge tags for both
the aldehyde and the activated alkene were employed, and the
cocatalyst action of the charge tagged reagents was also
evaluated. A comparison between the neutral MBH/aza-MBH
reactions (employing only neutral reagents) and the charge
tagged reactions was also performed. Although a simplistic
mechanistic view of MBH reactions has been recently
proposed, based on theoretical calculations and NMR
monitoring,36 the comprehensive results herein reported
using selective and highly sensitive ESI-(+)MS monitoring
and the charge tag strategy allowed us to intercept
intermediates that seem to be undetectable by NMR.
RESULTS AND DISCUSSION
■
The imidazolium ion has been shown to offer one of the most
efficient charge tags to monitor reaction mechanisms by
ESI(+)-MS.37,38 In this way, we used an acrylate with a
methylimidazolium ion (5a) and an alternate charge tag
(ammonium ion) for the benzaldehyde (7) in the MBH
ESI(+)-MS monitoring (Figure 1).
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Scheme 4. Mechanistic Proposal to the MBH/aza-MBH Reactions
and Singleton were, however, unable to detect or theoretically
find such species.36
(DABCO + N-tosyl imine + H)+. ESI(+)-MS monitoring
showed us that this species reverts to the starting material as
the reaction proceeds. Lastly, the ion of m/z 601 was assigned
as N-tosyl imine dimer sodium adduct [(N-tosyl imine)2 +
Na]+.
Note in Figure 2A for the classical MBH reactions that the
enolate and the aldol products (first and second intermediates)
were intercepted in both neutral and charge tagged reactions
(6a and 8a, 6b and 8b, respectively). Note also that the final
adduct 10a could be intercepted only using the charge tagged
strategy.
Interestingly, for the charge tagged reactions, such efficient
detection of the doubly charged intermediates of m/z 154 (6a),
229 (8a), 298 (8c), 443 (9c), and 587 (9c2) from steps I, II,
and III (Scheme 4) seems to have been facilitated during the
ESI process. Considering the electrostatic models used to
describe the ionization via ESI, that is, the charge residue model
(CRM) and the ion evaporation model (IEM),1 doubly charged
species should indeed display higher ESI ionization and
consequently MS detectabilities as compared to singly charged
ions. This more efficient ion ejection would arise from doubled
electrostatic repulsion occurring within ESI droplets as well as
much greater preference for the doubly charged species to
occupy the surface of the shrinking droplets.40 This superior
and nearly overall detectability of intermediates highlights
another important aspect of the charge tag strategy for
mechanistic studies that may facilitate the detection of transient
intermediates which could be, for instance, undetectable by
NMR.
In Figure 2B, for the aza-MBH reactions, the aza-enolate and
aza-aldol products (first and second intermediates) were also
detected in both the charge tagged and neutral reactions, that is,
6a/8c and 6b/8d, respectively. For the charge tagged reaction,
two additional and key doubly charge intermediates 9c and 9c2
were also very efficiently intercepted. ESI(+)-MS/MS and
ultrahigh resolution experiments allowed us to assign 9c and
9c2 as hemiacetal intermediates, which are analogous to those
described by McQuade35 (Figure S17, Supporting Information,
p S12). These intermediates likely have an important role in the
proton transfer step due to participation of a six-membered
cyclic transition state, which returns the catalyst 4a to the
catalytic cycle and leads to the final adduct (Scheme 4). The
ESI(+)-MS monitoring failed to detect the autocatalytic
intermediate described by Aggarwal, which also agrees with
recent theoretical evaluations20 and with the Plata and
Singleton proposal.36
To demonstrate the possibility of nearly continuous ESI(+)-
MS monitoring, Figures 3 and 4 summarize the monitoring
data by showing a temporal profile for the neutral and charge
tagged MBH/aza-MBH reactions up to completion. Beginning
with the classical MBH reactions, note that, for the neutral
reaction (Figure 3A), the DABCO catalyst (4a) is always
detected as a major ion and a significant appearance of the
Figure 2B shows the interception of additional ions such as
those of m/z 328, 402, and 601. The ion of m/z 328 was
assigned to the N-tosyl imine potassium adduct, that is, (N-
tosyl imine + K)+, whereas that of m/z 402 likely results from
nucleophilic attack of DABCO to the N-tosyl imine, that is
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Figure 2. ESI(+)-MS of the MBH/aza-MBH reactions solutions at 60 min: (a) classical MBH reaction using the charge tagged acrylate 5a (top) and
ethyl acrylate 5b (bottom); (b) aza-MBH reaction using 5a (top) and 5b (bottom).
enolate product (first intermediate 6b) and a low abundance of
the aldol product (second intermediate 8b) can be monitored
by ESI(+)-MS (10 min up to 21 h). These intermediates (6b
and 8b) have an expected increase and then a decrease in their
abundances, leading to the adduct. At 21 h, the catalyst 4a is
again intercepted and only traces of the enolate and aldol
products were detected. The final adduct was not detected at
all. This failure to detect the adduct is likely due to the release
of DABCO in the last step leading to an MBH adduct with no
basic sites for protonation and subsequent detection (Scheme
4). Note that, in contrast, for the charge tagged reaction (Figure
3B), the reactant 5a, the enolate and aldol products 6a and 8a,
and the final adduct 10a were all intercepted at high
abundances. Initially (10 min), the charge tagged acrylate 5a
is the predominant ion in the spectrum (Figure 3B), but after 1
h and up to 4 h, the spectra are dominated by the enolate and
aldol products (6a and 8a) and the MBH adduct (10a). At the
end of the monitoring (12 h), the MBH adduct 10a greatly
predominates. Note that the singly charged protonated
DABCO catalyst 4a is rarely detected during the whole
reaction period.
Another interesting and key intermediate was detected in the
beginning stage of the charge tagged reaction. This
intermediate was characterized as the hemiacetal (9a) described
by McQuade (Figure S21, Supporting Information, p S14).
This initial and short time period detection corroborates with
theoretical calculations reported by Aggarwal that showed that
the action of such an intermediate occurs mainly up to ca. 20%
adduct conversion for the classical MBH reactions.34
Both the neutral and charge tagged aza-MBH reactions were
also monitored until its completion (Figure 4). The monitoring
of the aza-MBH reactions showed similar trends to those
obtained for the classical reaction. For the neutral aza-MBH
reaction (Figure 4A), again the overall preference was for the
detection of the protonated DABCO catalyst 4a. The reactant
N-tosyl imine in the form of a sodium adduct (7b2) was also
detected as well as the aza-enolate and aza-aldol products (6b
and 8d). At the beginning, 10 min, the catalyst 4a, N-tosyl
imine 7b2, and the aza-enolate and aza-aldol products (6b and
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The data from Figures 3B and 4B are also summarized via
the plots of Figure 5, which allows us to follow the relative
changes in abundance for the charge tagged reactions including
reagents, intermediates, and final adducts as a function of
reaction time. Note the much higher conversion rate for the
classical MBH since even at t = 0 the final adduct is already
detected as one of the most abundant ions whereas for the aza-
MBH it becomes a major ion only after 10 h. For the classical
reaction a nearly constant contribution is seen for the catalyst
ion, i.e., protonated DABCO (4a). There is a decrease for 4a
during the course of the reaction but a return to the original
abundance as the reaction comes to its end. For the hemiacetal
intermediates, a major difference is noted between the aza and
classical MBH reactions. For the aza-MBH reaction, both
hemiacetal intermediates (9c and 9c2) are detected as quite
abundant ions during the whole reaction period with a normal
up and down pattern. On the other hand, the short detection
time of the hemiacetal for the classical MBH charge tagged
reaction was not enough to set via plot in Figure 5.
Another key feature for the charge tagged reactions was the
conversion rate. The total reaction time for the charge tagged
reactions (Figures 3 and 4) was substantially lower than that for
the corresponding neutral reactions. For the classical MBH
reaction, a more dramatic (ca. 50%) decrease was observed,
from 21 to 12 h. For the aza-MBH reaction, a decrease of ca.
30% was observed, that is, from 30 to 22 h. We have showed
that imidazolium ionic liquids (IL) act as a cocatalyst for the
MBH reactions, and supramolecular species formed by
coordination of neutral reagents, adducts, and the protonated
forms of zwitterionic intermediates with cations and anions of
ionic liquids have been characterized by ESI(+)-MS.18 The
interception of these supramolecular species indicated the IL
cocatalyst’s role, which acts in the mechanism to activate both
electrophiles (aldehyde and activated alkene) toward nucleo-
philic attack and/or to stabilize the zwitterionic intermediates
that constitute the main MBH intermediates. Based on these
findings, the cocatalyst action of the methylimidazolium ion for
the acrylate 5a could be rationalized as contributing in the
mechanism steps as shown in Scheme S2 in Supporting
Information, p S10.
Figure 3. Temporal ESI(+)-MS monitoring for the classical MBH
reaction using (a) ethyl acrylate 5b (top) and (b) acrylate tagged 5a
(bottom).
8d) are already intercepted. From 2 h up to 20 h, there is an
increase and then a decrease in their abundances, as expected,
in order to form the aza-adduct. After 30 h, the catalyst 4a and
traces of the intermediates 6b and 8d and sodiated N-tosyl
imine 7b2 are detected. The aza-adduct with no basic sites, in
the neutral reaction, was again not detected at all.
For the charge tagged reaction (Figure 4B), the formation of
doubly charged intermediates such as aza-enolate product 8c
and the hemiacetal intermediates 9c and 9c2 as well as for the
singly charged aza-adduct 10c was highly beneficial for efficient
ESI. Again for the intermediates, there is an expected increase
and decrease in the abundances of 8c, 9c, and 9c2, which form
the aza-adduct 10c. The notable exception was for the first
intermediate 6a in the charge tagged reaction, which was
detected with low abundance. Since the charge tag methyl-
imidazolium ion should normalize all ionization efficiencies, the
low abundance of the doubly charged aza-enolate 6a suggests a
faster conversion rate for the first intermediate of the aza-MBH
reaction using acrylate tagged 5a. After 22 h, the final aza-
adduct represents the major ion with only traces of the acrylate
tagged 5a, aza-aldol product 8c, and the hemiacetal 9c and 9c2
(Figure 4B).
A most notable feature therefore for the ESI(+)-MS
monitoring of the charge tagged MBH/aza-MBH reactions
was the interception of the doubly charged hemiacetal
intermediates. Their proper characterization via accurate mass
measurements and ESI(+)-MS/MS experiments could there-
fore be performed. For the neutral reaction, such intermediates
remained undetectable even when using a molar excess of
either N-tosyl imine or 4-nitrobenzaldehyde.
To demonstrate this intrinsic high conversion rate due to the
cocatalyst effect of the charge tagged 5a, we monitored the
charge tagged reactions by HPLC-ESI-MS as well as the neutral
reaction by TLC until their completion. Table 1 summarizes
the results and confirms the dual role of the charge tagged
acrylate 5a.
CONCLUSIONS
■
The use of a charge tagged acrylate 5a allowed comprehensive
ESI(+)-MS monitoring of both MBH/aza-MBH reactions.
Most reagents, intermediates, and MBH adducts could be
efficiently and directly transferred by ESI from the reaction
solutions to the gas phase for proper ultrahigh resolution and
tandem MS characterization. Superior detectability was
promoted by the formation of doubly charged species. The
hemiacetal interception for both MBH/aza-MBH agrees with
our previous reports indicating the formation of this
intermediate.19 The dual cocatalyst role of the charge tagged
acrylate 5a was also demonstrated. A detailed temporal
monitoring of the reactions was also possible which allowed
for the observation of the rising and fading of all reaction
partners for the successive reaction steps.
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Figure 4. Temporal ESI(+)-MS monitoring of aza-MBH reaction using (a) ethyl acrylate 5b (top) and (b) acrylate tagged 5a (bottom).
Figure 5. Temporal monitoring for both the charge tagged MBH/aza-MBH reactions.
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Table 1. Cocatalyst Role of the Charge Tagged Acrylate 5a for the MBH/aza-MBH Reactions
a
b
Determined by HPLC-ESI-MS. Determined by TLC.
166.0 ppm. HRMS (ESI, m/z): calculated for C10H15N2O2+ 195.1128;
found 195.1127.
EXPERIMENTAL SECTION
■
General Methods. All reactions were carried out under air, in a
Experimental Data for Compounds of Table 1. 3-[3-({2-
[Hydroxy(4-nitrophenyl)methyl]prop-2-enoyl}oxy)propyl]-1-methyl-
1H-imidazol-3-ium Bromide (10a, entry 1). In a round-bottom flask
of 10 mL containing a magnetic stirrer were mixed acrylate 5a (0.21 g,
0.5 mmol, 1 equiv), 4-nitrobenzaldehyde (0.151 g, 1 mmol, 2 equiv),
and DABCO (0.034 g, 0.6 mmol, 0.6 equiv) in acetonitrile (500 μL).
The reaction evolution was monitored with a UPLC−MS instrument
using a Hypersil Gold C18 column, and the mobile phase employed
was a mixture of water/acetonitrile 50:50 v/v. After completion (12 h),
solvent was removed and the residue was dissolved in water (2 mL)
and extracted with ethyl acetate (5 × 5 mL). The organic layers were
combined and dried over Na2SO4, and the solvent was removed under
reduced pressure. Afterward, the residue was kept under a high
vacuum for 3 h to afford the corresponding MBH adduct 10a as a
round-bottom flask with magnetic stirring, unless otherwise noted.
Commercially available reagents and solvents were used without
further purification. 1H and 13C NMR spectra were recorded on a 250
MHz instrument. Chemical shifts (δ) are given in parts per million.
The following abbreviations were used to designate chemical shift
multiplicities: s = singlet, d = doublet, dd = doublet of doublets, t =
triplet, q = quartet, quint. = quintuplet, m = multiplet. High-resolution
mass spectra data were recorded on a 7.2T LTQ-FT Ultra mass
spectrometer.
Procedure for Preparing 1-[3-(Acryloyloxy)propyl]-3-
methylimidazolium Bromide (5a). In a sealed tube of 100 mL
containing a magnetic stirrer were added 1-methylimidazole (328 mg,
4 mmol), 3-bromo-1-propanol (690 mg, 5 mmol), and dry acetonitrile
(10 mL). The reaction mixture was refluxed at 90 °C for 24 h and
monitored by thin layer chromatography (TLC). After cooling at
room temperature, solvent was removed and the residue was dissolved
in water (2 mL) and extracted with ethyl acetate (5 × 5 mL). The
organic layers were combined and dried over Na2SO4, and the solvent
was removed under reduced pressure. Afterward, the residue was kept
under a high vacuum line for 3 h. Colorless viscous liquid, 98% yield
(884 mg, 3.9 mmol). Spectroscopic data: 1-(3-Hydroxypropyl)-3-
1
yellow viscous liquid, 60% yield (255 mg, 0.6 mmol). H NMR (250
MHz, CD3OD) δ 2.21 (quint., J = 6.6 Hz, 2H); 3.92 (s, 3H); 4.17 (t, J
= 6.0 Hz, 2H); 4.24 (t, J = 7.0 Hz, 2H); 5.68 (s, 1H); 6.08 (s, 1H);
6.37 (s, 1H); 7.61 (m, 4H); 8.19 (d, 2H). 13C NMR (62.5 MHz,
CD3OD) δ 28.7; 31.3; 35.1; 61.0; 62.4; 70.8; 122.3; 123.0; 123.6;
125.4; 127.7; 142.5; 147.3; 149.9; 166.9. HRMS (ESI, m/z): calculated
+
for C17H20N3O5 346.1397; found 346.1404.
Ethyl 2-[Hydroxy(4-nitrophenyl)methyl]prop-2-enoate (10b,
entry 2). In a round-bottom flask of 10 mL containing a magnetic
stirrer were mixed ethyl acrylate (54 μL, 0.5 mmol, 1 equiv), 4-
nitrobenzaldehyde (0.151 g, 1 mmol, 2 equiv), and DABCO (0.034 g,
0.6 mmol, 0.6 equiv) in acetonitrile (500 μL). The reaction was stirred
for 21 h at room temperature, and its evolution was monitored by thin
layer chromatography (TLC). After completion, the solvent was
removed and the residue was purified by flash column chromatography
(SiO2, gradient: Hex; 9/1 Hex/AcOEt; 8/2 Hex/AcOEt) to give MBH
1
methylimidazolium bromide, H NMR (250 MHz, CD3OD) δ 2.05
(quint, J = 6.7 Hz, 2H); 3.56 (t, J = 6 Hz, 2H); 3.91 (s, 3H); 3.92 (s,
1H); 4.31 (t, J = 6 Hz, 2H); 7.55 (s, 1H) 7.62 (s, 1H) 8.94 ppm (s,
1H). 13C NMR (62.5 MHz, D2O) δ 31.7; 35.8; 46.6; 58.0; 122.4;
123.7; 136.2 ppm. HRMS (ESI, m/z): calculated for C7H13N2O+
141.1022; found 141.1024.
Subsequently, in order to prepare the tagged acrylate (5a), in a
round-bottom flask of 25 mL, 1-(3-hydroxypropyl)-3-methyl-
imidazolium bromide (alcohol tagged) (141 mg, 1 mmol) was
mixed with acryloyl chloride (108 mg, 1.2 mmol). The reaction
mixture was kept at room temperature for 4 h. After its completion,
the reaction medium was concentrated under reduced pressure and
the residue was dissolved in water (2 mL) and extracted with ethyl
acetate (5 × 5 mL). The organic layers were combined and dried over
Na2SO4, and the solvent was removed under reduced pressure.
Afterward, the residue was kept under a high vacuum line for 3 h.
Colorless viscous liquid, 98% yield (0.269 mg, 0.98 mmol).
Spectroscopic data: 1-Methyl-3-[3-(prop-2-enoyloxy)propyl]-1H-imi-
dazol-3-ium bromide (5a), 1H NMR (250 MHz, CD3OD) δ 1.88
(quint, J = 6.7 Hz, 2H); 3.94 (s, 3H); 4.24 (t, J = 6 Hz, 2H); 4.37 (t, J
= 6 Hz, 2H); 5.93−5.88 (dd, J = 1.6 and 10.3 Hz, 1H); 6.17−6.10 (dd,
J = 10.3 and 17.2 Hz, 1H); 6.41−6.34 (dd, J = 1.6 and 17.2 Hz, 1H)
7.60 (s, 1H) 7.69 (s, 1H) 9.03 ppm (s, 1H). 13C NMR (62.5 MHz,
CD3OD) δ 28.9; 35.3; 46.7; 60.9; 122.4; 123.7; 127.8; 130.7; 136.8;
1
adduct 10b as a pale yellow oil (113 mg, 0.45 mmol, 90%). H NMR
(250 MHz, CD3OD) δ 1.25 (t, J = 7.1 Hz, 3H); 3.42 (s, 1H); 4.14 (q,
J = 7.1 Hz, 2H); 5.61 (s, 1H); 5.85 (s, 1H); 6.38 (s, 1H); 7.56 (d, J =
8.7 Hz, 2H); 8.18 (d, J = 8.6 Hz, 2H). 13C NMR (62.5 MHz,
CD3OD), δ 14.0; 61.3; 72.7; 123.5; 127.0; 127.3; 141.2; 147.4; 148.7;
+
166.0. HRMS (ESI, m/z) calculated for C12H13NNaO5 274.0686;
found: 274.0679.
3-[3-({2-({[(4-Methanesulfonylphenyl)methyl]amino}(4-methoxy-
phenyl)methyl)prop-2-enoyl}oxy)propyl]-1-methyl-1H-imidazol-3-
ium Bromide (10c, entry 3). In a round-bottom flask of 10 mL
containing a magnetic stirrer were mixed acrylate 5a (0.137 g, 0.5
mmol, 1 equiv), N-(4-methoxybenzylidene)-4-methyl-benzenesulfon-
amide (0.289 g, 1 mmol, 2 equiv), and DABCO (0.034 g, 0.6 mmol,
0.6 equiv) in acetonitrile (500 μL). The reaction was monitored with a
UPLC−MS instrument using a Hypersil Gold C18 column, and the
mobile phase employed was a mixture of water/acetonitrile 50:50 v/v.
After completion (22 h), solvent was removed and the residue
1096
DOI: 10.1021/acs.joc.5b02651
J. Org. Chem. 2016, 81, 1089−1098

The Journal of Organic Chemistry
Article
obtained was dissolved in water (2 mL). Then, the aqueous phase was
extracted with ethyl acetate (5 × 5 mL). The organic layers were
combined and dried over Na2SO4, and the solvent was removed under
reduced pressure. Afterward, the residue was kept under high vacuum
for 3 h to furnish aza-MBH adduct 10c, as an orange viscous oil in
AUTHOR INFORMATION
Corresponding Authors
*E-mail: renan.galaverna@iqm.unicamp.br.
*E-mail: coelho@iqm.unicamp.br.
Notes
■
1
55% yield (158 mg, 0.28 mmol). H NMR (250 MHz, CD3OD) δ
2.34 (quint, J = 6.5 Hz, 3H); 2.52 (s, 3H); 3.85 (s, 3H); 4.06 (s, 3H);
4.32 (m, J = 7.1 Hz, 4H); 5.49 (s, 1H); 5.91 (s, 1H); 6.40 (s, 1H);
6.85 (d, J = 8.8 Hz, 2H); 7.06 (d, J = 8.6 Hz, 2H); 7.37 (d, J = 8.0 Hz,
2H); 7.71 (m, J = 7.8 Hz, 4H); 9.03 (s, 1H). 13C NMR (62.5 MHz,
CD3OD), δ 20.0; 28.7; 35.2; 54.4; 57.0; 61.1; 113.4; 122.2; 123.6;
126.1; 126.7; 128.4; 128.9; 129.0; 129.5; 130.3; 138.1; 140.9; 143.1;
159.2; 165.6. HRMS (ESI, m/z) calculated for C25H30N3O5S+
484.1901; found: 484.1893.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors are grateful to Fundaca
■
̧
o de Amparo a
̃
̀
Pesquisa do
Estado de Sao Paulo (Fapesp) for research fund (Nos. 2013/
̃
10449-5 and 2012/10701-3) and CNPq for research fellow-
ships (F.C. and M.N.E.).
Ethyl 2-[(4-Methoxyphenyl)(4-methylbenzenesulfonamido)-
methyl]prop-2-enoate (10d, entry 4). In a round-bottom flask of
10 mL containing a magnetic stirrer were mixed ethyl acrylate (54 μL,
0.5 mmol, 1 equiv), N-(4-methoxybenzylidene)-4-methyl-benzene-
sulfonamide (0.289 g, 1 mmol, 2 equiv), and DABCO (0.034 g, 0.6
mmol, 0.6 equiv) in acetonitrile (500 μL). The reaction was stirred for
30 h at room temperature, and its evolution was followed by thin layer
chromatography (TLC). After completion, the solvent was removed
under reduced pressure and the residue was purified on silica gel by
flash column chromatography (SiO2, gradient: Hex; 9/1 Hex/AcOEt;
8/2 Hex/AcOEt) to furnish the aza-MBH adduct 10d, as a pale yellow
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02651.
ESI(+)-MS/MS and mass measurements data for the
MBH/aza-MBH reactions; NMR spectra (PDF)
1097
DOI: 10.1021/acs.joc.5b02651
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