Mechanistic and Synthetic Implications of the Diol-Ritter Reaction: Unexpected Yet Reversible Pathways in the Regioselective Synthesis of Vicinal-Aminoalcohols

Article abstract of DOI:10.1021/acs.joc.8b02320

The Ritter reaction of 1,2-diolmonoesters with nitriles to 1-vic-amido-2-esters proceeds through dioxonium and nitrilium cation intermediates. To provide the basis for the reaction mechanism, novel forms of these cations were isolated, characterized, and studied by spectroscopic methods and single crystal X-ray analysis. Ground and transition state energies were determined both experimentally and theoretically. Taken together, these data suggest that the reaction proceeds via rapid formation of the dioxonium cation 9, followed by rate determining yet reversible ring opening by acetonitrile to the corresponding nitrilium cation 10 (computed ΔG^∞ = 24.7 kcal at 50 °C). Rapid, irreversible hydration of the latter affords the corresponding vic-acetamido ester. Controlled addition of H₂O to the dioxonium cation 9 in acetonitrile-d₃ results in near-quantitative production of deuterated acetamido ester 13a. Kinetics of this conversion (9 to 13a) are biphasic, and the slow phase is ascribed to either direct cation 9 attack by acetamide to form cation 16 via O-alkylation or by reversible ether formation. Deuterium labeling studies suggest O-alkylated cation 16 does not directly isomerize to N-alkylated cation 18; instead, it reverts to vic-amidoester 13a via the nitrilium pathway. Preliminary results indicate high regioselectivity for primary amide formation in the diol-Ritter sequence.

Full text of DOI:10.1021/acs.joc.8b02320

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Article
Mechanistic and Synthetic Implications of the Diol-
Ritter Reaction: Unexpected, Yet Reversible Pathways in
the Regioselective Synthesis of Vicinal-Aminoalcohols
Mark Ondari, Jerzy Klosin, Robert D.J. Froese, William R Kruper, Jason MacDonald,
Daniel J. Arriola, Bruce M. Bell, John Robert Briggs, and William J. Kruper
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02320 • Publication Date (Web): 14 Nov 2018
Downloaded from http://pubs.acs.org on November 15, 2018
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Mechanistic and Synthetic Implications of the Diol-Ritter
Reaction: Unexpected, Yet Reversible Pathways in the
Regioselective Synthesis of Vicinal-Aminoalcohols
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Mark Ondari,1 Jerzy Klosin,2 Robert, D. J. Froese,2 William R. Kruper,1 Jason
MacDonald,1 Dan J. Arriola,2 Bruce M. Bell,2 John R. Briggs,2 and William J. Kruper3*
1Corteva Agriscience, Agriculture Division of DowDupont, 1710 Building
Midland, MI, 48674
2 Corporate R&D, The Dow Chemical Company, 1776 building, Midland, MI 48674
3 Michigan State University, St Andrews, Midland MI, 48674
kruperw@msu.edu
Abstract:
The Ritter reaction of 1,2-diolmonoesters with nitriles to 1-vic-amido-2-esters proceeds
through dioxonium and nitrilium cation intermediates. To provide the basis for the reaction
mechanism, novel forms of these cations were isolated, characterized, and studied by
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spectroscopic methods and single crystal X-ray analysis. Ground and transition state
energies were determined both experimentally and theoretically. Taken together, this data
suggest that the reaction proceeds via rapid formation of the dioxonium cation 9, followed
by rate determining yet reversible ring opening by acetonitrile to the corresponding
nitrilium cation 10 (computed DG‡ = 24.7 kcal at 50 °C). Rapid, irreversible hydration of
the latter affords the corresponding vic-acetamido ester. Controlled addition of H2O to the
dioxonium cation 9 in acetonitrile-d3 results in near-quantitative production of deuterated
acetamido ester 13a. Kinetics of this conversion (9 to 13a) are biphasic and the slow phase
is ascribed to either direct cation 9 attack by acetamide to form cation 16 via O-alkylation
or by reversible ether formation. Deuterium labeling studies suggest O-alkylated cation 16
does not directly isomerize to N-alkylated cation 18, instead it reverts to vic-amidoester
13a via the nitrilium pathway. Preliminary results indicate high regioselectivity for primary
amide formation in the diol-Ritter sequence.
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Introduction:
Over the past two decades resurgence in chemical transformations based upon feedstocks
such as sugars, carbohydrates and seed oils as alternatives to traditional petrochemical
feedstocks has taken place with mixed commercial success.1 In particular, a variety of
mixed glycols are available as by-products from sucrose hydrolysis and hydrogenation as
well as fermentation. A temporary spike in biodiesel production has led to an ephemeral
surplus of glycerin, which industry has viewed as a convenient source of propylene glycol,
acrylic acid and epichlorohydrin.2 Vicinal diols available from fermentation and natural
sources or hydrolytic kinetic resolution of epoxides may offer the added benefit of
chirality.3
In our quest to produce epichlorohydrin (3) from glycerin via 1,3-dichloropropanol (2),
we previously studied the intimate steps of this catalytic and highly regioselective process
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(Scheme 1).4 The acid catalyzed hydrochlorination of glycerin proceeds through the
intermediacy of dioxonium cations, although other intermediates (protonated epoxides)
have been postulated.5 Given the higher regioselectivity of chloride attack in the ring
opening reaction of dioxonium cations such as 5 (Scheme 1) versus epoxides, we wondered
if other nucleophiles (e.g. acetonitrile) would give similar advantage.
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Scheme 1: Dioxonium cation intermediates during regioselective hydrochlorination of glycerin
Acid-catalyzed ring opening of epoxides by nitriles is well known for the synthesis of vic-
amidoalcohols6 and oxazolines.7 The far less common, ring-opening of dioxonium cations
by nitriles was first reported by Kubisa8, and the synthetic ramifications of this ring-
opening reaction were exploited by Hollingsworth who realized that the nitrilium cations
could be hydrated as a means of converting glycol monoesters to vicinal
acetamidoesters.9,10
Between these reports, little is known about the true mechanism of the reaction, the rate
determining step and the potential to convert diols directly to acetamidoalcohols through
cationic intermediates. Such an approach would allow diols to serve as proxies for cyclic
sulfate esters11 or higher energy epoxy intermediates.
Based upon experimental and computational modeling data, herein we propose a
mechanistic pathway for the Ritter reaction of diol monoesters to terminal 1-acetamido-2
esters. Such an understanding would have implications for regioselective synthesis of vic-
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1o-aminoalcohols some of which have already found utility in the synthesis of Taxol side
chains12, AZT agonists5 and the antibacterial agent Zyvox.13
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Results and Discussion:
9
To perform systematic stepwise studies of the reaction mechanism, dioxonium
intermediate 9 was synthesized by reacting chloroester 7 with SbCl5 in CH2Cl2 at ambient
or sub-ambient temperatures14 (Scheme 2). At the onset of the reaction a bright yellow
solution developed from which cation 9 slowly precipitated over time. This yellow color
is associated with the formation of a novel precursor cation 8 which was characterized by
NMR spectroscopy and single crystal X-ray analyses. Zwitterion 8 was obtained as highly
crystalline yellow-green solid in 87% yield by precipitation from CH2Cl2/hexane mixture
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at low temperature. Interestingly, chemical shifts of many resonances in H-NMR
spectrum of 8 are concentration-dependent suggestive of dynamic equilibrium between 7
and 8. To confirm this, an equimolar mixture of 7 and 8 was prepared in CD2Cl2. The 1H-
NMR spectrum shows a single set of new resonances with chemical shifts between those
of 7 and 8 clearly indicating fast equilibrium between the two species.
Scheme 2: Reaction of chloro ester 7 with SbCl5 to give kinetic (8) and thermodynamic (9)
cations
Zwitterion 8 is unstable at ambient temperature and undergoes rearrangement to
cation 9 in CD2Cl2 (t1/2 ~ 120 min at 25 °C). Unlike 8, cation 9 is extremely insoluble in
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CH2Cl2 and precipitates out as colorless plates from even very dilute solutions. It is not
clear whether 9 is formed by direct rearrangement of 8 or from the reaction of free
chloroester 7 and SbCl5.
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9
To understand energetics of these transformations, theoretical calculations15 were
performed at the G3MP2B3 or equivalent level of theory. The calculations include the
PCM solvation model (solvent: acetonitrile). The gas phase entropies were scaled by 0.6
to bring them more in-line with solution entropies and the free energies were determined
at 50 °C. Calculations were performed exclusively on the antimony-based counterion and
not any boron-based species. These theoretical calculations suggest that conversion of
cation 8 to cation 9 is exergonic (25 °C) by 2.6 kcal/mol (compared to the transformation
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¯
of 7 to 8) implying that there is a driving force for cyclization and the formation of SbCl6 .
The sp2 hybridization of the carbon in both cation 8 and 9 is apparent from C-O
bond distances, and bond angles in 9 are comparable to other analogous solid-state
structures.15 There is no evidence for any interaction between cation 9 and its counterion
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in the solid-state structure. Computationally, the coordination of SbCl6 to 9 to form a
contact ion pair is computed to be exergonic by 4.1 kcal/mol implying the counterion is
weakly coordinating.
Zwitterion 8 can be viewed as an extreme version of a contact ion pair and due to
its 1,3-dipolar nature, exhibits a higher field carbonium ion resonance (13C = 168 ppm),
versus the ion separated cation 9 (13C = 185 ppm). The molecular structure of zwitterion
8 is shown in Figure 1. The Sb-O bond length of 2.152 Å compares well to the computed
value of 2.197 Å and is similar to analogous bonds in structures containing an SbCl5 unit
coordinated to a carbonyl fragment.16 Comparison of important geometric parameters for
the computed vs. solid state structures for the three compounds determined
crystallographically indicates excellent agreement between the two methods.
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Figure 1: Molecular structures of 8 (left) and 9 (right). Thermal ellipsoids are shown at 50%
probability.
After isolating and characterizing these Ritter intermediates, ring-opening studies
of cation 9 to nitrilium 10 were then performed in acetonitrile-d3 solvent at different
temperatures (Scheme 3). Spectroscopically, nitrilium cation 10 exhibits strong quadrupole
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coupling between N and the nitrilium carbon (1:1:1 triplet with J = 47 Hz at 111 ppm,
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with additional two-bond C-D coupling) in its C-NMR spectrum, primarily due to the
linear (sp) hybridization of the adduct. Coupling to 14N is relatively uncommon and appears
to be restricted to species with highly symmetric electric fields at nitrogen, such as tetra-
alkylammonium salts17 and isonitriles,18 which leads to fast relaxation. The nitrilium
methylene (47 ppm) also shows coupling to 14N with 1J(C13-N14) = 7 Hz. These values are
comparable to those seen for N-isopropylacetonitrilium hexachloroantimonate:
CH3CNCH(CH3)2 (dC = 5.1 ppm, 1J(C13-N14) = 43 Hz); (CH3)2CHNCCH3 (dC = 54 ppm,
1J(C13-N14) = 3.5 Hz).19 Interestingly, even the remote C-3 methylene carbon of 10 still
shows a 2-bond coupling of about 1 Hz to 14N.
Approach to equilibrium kinetics were studied by 1H-NMR spectroscopy in 30 °C to 70 °C
temperature range from where rate constants were obtained. Figure 2 and Figure 3 show
representative examples of 1H-NMR array spectra and approach to equilibrium plot at 50
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°C, respectively. Table 1 includes rate constants obtained from H-NMR kinetics of 9 to
10 in this temperature range while Figure 4 is an Eyring plot of the kinetics at 30 °C.
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Scheme 3. Ring opening of cation 9 to nitrilium 10.
Figure 2. Arrayed 1H-NMR spectra for ring opening of cation 9 to nitrilium 10 at 50 °C
(total reaction time 6.5 hr). Resonances at d 5.48 belong to methylene protons of 9 whereas
peaks at d 4.53 and 4.70 belong to methylene protons of 10.
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Figure 3. Approach to equilibrium plot for ring opening of cation 9 (Blue) to nitrilium
cation 10 (Red) at 50 °C
-10.5
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y = -10956x + 21.333
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Figure 4. An Eyring plot for ring opening of cation 9 to nitrilium 10
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Table 1. Rate and equilibrium constants for ring opening of cation 9 to nitrilium 10.
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kf, rate const. (min-1)
Keq, (L/mol)
Temp (°C)
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0.00664 ± 0.00002
0.02157 ± 0.00003
0.06740 ± 0.00014
0.1964 ± 0.0003
0.4940 ± 0.0010
1.86 ± 0.04
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0.907 ± 0.005
0.740 ± 0.004
In contrast to Kubisa’s study8, our data show that bimolecular ring opening of
cation 9 to nitrilium ion 10 is reversible, nearly thermoneutral (initial concentration of
cation 9 = 44 X 10-2 M, Keq = 0.74 - 1.86 Lmol -1, 30 °C and 70 °C) and has a substantial
activation barrier (DG‡ = 23.1 kcal/mol, DH‡ = 21.7 kcal/mol. DS‡ = -0.00466 kcal/K, Eact
= 22.3 kcal/mol). Computational estimations of thermodynamic and kinetic parameters
(DG‡ = 24.7 kcal/mol, DGo = 1.9 kcal/mol) are in good agreement with the experimental
data. The kinetic analysis indicates a pseudo-first order half-life of about 10 min at 50 oC
for the ring opening reaction of 9 with acetonitrile.
Once formed, nitrilium 10 rapidly and irreversibly reacts with added water to form
acetamidoester 13 quantitatively. In contrast, when one equivalent of water was added to
cation 9 in acetonitrile, acetamidoester 13 was formed in 92% yield over the course of three
weeks at room temperature. Despite the sensitivity of cation 9 to water (ring opening to
ester 11), this step is reversible (Scheme 4), allowing for complete and irreversible
formation of 13 by equilibrium control.
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Scheme 4: Major equilibria established when 1 equiv. of water is added to cation 9 in
acetonitrile. A = SbCl6
Addition of one equivalent of water to cation 9 in dry solution of acetonitrile-d3,
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forms hydroxyester 11 (20% relative to 9) within 10 min as revealed by H-NMR. It is
probable that cation 9 is first hydrated to hemi-orthoester 12 which then undergoes rapid
and exothermic ring opening to hydroxyester 11.20 It would seem unusual that only such
limited ring opening to 11 would occur under these conditions; the implication is that ample
cation 9 is free to react with acetonitrile. Previous work by Plesnicar and co-workers
indicates that the breakdown of hemi-orthoester 12 to 11 is suspected to require Bronsted
acid assistance by at least 2 equivalents of water in the transition state, which may explain
why 80% of cation 9 remains intact.21,22 Dynamic conversion profiles (Figure 5) depict a
process wherein cation 9 consumption is fast for the first 80% of the reaction and is then
substantially retarded because of the competitive steady-state buildup of two (initially)
unknown intermediates derived from cation 9. Despite this rate change, the overall yield
to amidoester 13 is very high (92% isolated yield) at long reaction times (weeks).
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Ether 14
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Hydroxy ester 11
Amido ester 13a
Cation 16
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Figure 5: Reaction of cation 9 with one equivalent of H2O (50 °C) as monitored by 1H-500 MHz
1H-NMR in acetonitrile-d3. Note the monitor starts at about 50 mole% cation consumption. Rate
of cation 16 and ether 14 decomposition equal to rate of amidoester 13a formation in slow phase
of reaction.
Identifying minor competitive pathways from cation 9 proved to be challenging
due to their reversible nature. Nonetheless, a series of experiments were performed to
delineate these pathways. The first competitive element to this chemistry is reaction of
cation 9 by hydroxyester 11 to afford ether cation 14 which was isolated and characterized
as its free base 15 (Figure 5). This reaction was found to predominate only at early stages
of the reaction because the steady state concentration of 11 is high and its nucleophilicity
greatly exceeds that of acetonitrile. Despite initial formation of ether cation 14, it appears
that at long reaction times this side reaction is actually reversible.
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Scheme 5: Reversible ring-opening pathways (ether 14 and imidate adduct 16 formation)
responsible for rate suppression of amide 13a formation from cation 9 hydration in acetonitrile-d3
A = methanesulfonate or SbCl6; AcN = acetonitrile; Ac-NH2 = acetamide; R = Bz
After eliminating a variety of structural hypotheses, it was reasoned that acetamide
may play a role in further inhibiting the nitrilium pathway. Since water is eliminated during
cation 9 formation from ester 11, concomitant hydration of protonated or Lewis acid-
activated acetonitrile to form acetamide was suspected to be one of the competitive
pathways.23 To test this hypothesis, 1 equiv. of acetamide was added to cation 9 in
acetonitrile at room temperature which resulted in the formation of new cation 16,
ostensibly through direct ring opening attack in which the acetamide undergoes O-
alkylation (Scheme 5). Cation 16 is therefore a kinetic product which is rapidly formed
(within 10 min) at 30 oC from 9 (9→16 computed DG‡ = 20.2 kcal, DG°= -4.9 kcal/mol)
despite the excess of acetonitrile.
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Spectroscopic characterization by C-NMR analysis suggested that cation 16 is
ring-opened and that both carbons of the ethylene glycol moiety bear oxygen rather than
oxygen and nitrogen. Notably, the imidate methylene carbon is downfield-shifted at 72.4
ppm and exhibits long range interaction to the methyl group (as revealed by HMBC
experiment), whereas the benzoate methylene carbon remains relatively unshifted (62.1
ppm). Unambiguous confirmation of cation 16 structure was afforded by its solid-state
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structure (Figure 6). Quenching cation 16 with aqueous base affords mainly free base
imidate 17, a well-known and relatively stable class of structures typically produced via
the Pinner reaction.24
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Figure 6. Molecular structure for 16. Thermal ellipsoids are shown at 50% probability.
When acetonitrile-d3 solution of pure 16 (CH3-containing acetamide) and one
equivalent of water is heated to 120 oC over the course of several hours, the isolated amide
(13a) is found to contain only deuterium label (CD3) (Scheme 5). Coincident with this
1
exchange process as observed in the H-NMR spectrum is the formation of CH3-labeled
acetamide and low, steady-state concentrations of cation 9. Thus, this data implies that at
high temperature acetamide cation 16 does not undergo O→N rearrangement to cation 18;
conversely, amide 13a evolves only from reversion of 16 to cation 9 followed by deuterated
(CD3) nitrile-mediated ring opening via the nitrilium pathway (see Scheme 4).
Computational studies suggest that cation 18 is the preferred thermodynamic cation in the
reaction with acetamide; however, the N-alkylation acetamide pathway from 9 has a sizable
barrier (9→18 computed DG‡ = 29.7 kcal/mol, DG° = -10.5 kcal/mol) versus nitrile ring
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opening of 9 (9→10 computed DG‡ = 24.7 kcal/mol, DG° = 1.9 kcal/mol) or O-alkylation
to 16 (9→10 computed DG‡ = 20.2 kcal, DG°= -4.9 kcal/mol).
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Under standard synthetic conditions where the nitrilium pathway prevails (9 to 11
through 10; see Scheme 4), a vic-hydroxyester is a typical starting material. Thus, it was
of interest to understand the actual rate-determining step in this sequence. Dioxonium
cations are thought to form rapidly at low temperature during intramolecular ether
formation from diol-orthoesters using catalytic BF3.25 In the Ritter-diol sequence, evidence
for nitrilium ion formation being rate-determining seems definitive and several-fold: 1)
High steady state concentrations of cation 9 (up to 20 mol%) can be immediately generated
from hydroxyester 7 in acetonitrile at -20 to 25 °C using excess methanesulfonic acid (Keq
= 6.5 ±0.3 x 10-3) or BF3, and cation 9 is relatively stable for hours at room temperature in
acetonitrile. Thus, the ground state energy of cation 9 is approximately 3 kcal higher than
that of ester 7 under typical preparative conditions and its kinetic formation is fast. 2)
Given the high activation barrier for nitrile-mediated ring opening (22.7 kcal/mol) and
observable low steady-state concentration of nitrilium cation 10 versus dioxonium cation
9 (observed at 10-100-fold concentration of 10), ring opening of 9 is strongly implicated
as rate determining. 3) When nitrilium cation 10 formation is maximized (circa 90%) by
heating cation 9 in anhydrous acetonitrile, quenching the medium with water (1 eq.) results
in immediate formation of amide 13a (fast and irreversible).
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The enhanced regioselectivity afforded in the hydrochlorination of glycerin which
is mediated by dioxonium cations suggests that ring opening by acetonitrile could have
similar advantage. On a preparative scale when glycerin-derived monoester 19 is subjected
to dry acetonitrile and sub-stoichiometric BF3 under reflux, amido-ester 20 is obtained in
82% yield with no detectable 2-amido regioisomer (Scheme 6). In contrast, BF3-mediated
Ritter reaction of epichlorohydrin using acetonitrile as solvent results in ~10:1 ratio of 1-
1
and 2-N-subsituted oxazolines, respectively, by H-NMR analysis (See supporting
information).26 The use of sub-stoichiometric BF3·Et2O commensurately lowers the yield
of product and this observation is consistent with computational data which suggest strong
and irreversible binding of catalyst to amide product 20.27
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Scheme 6: Synthetic scheme for the synthesis of amido-ester 20 from 19
The generality and optimization of the synthetic process will be reported elsewhere.28
Conclusions:
Terminal, vicinal diols can be converted to monoesters and transformed to vicinal-1o-
acetamido-2-benzoate esters. Preliminary results suggest that the diol monoester-Ritter
reaction is more regioselective for primary attack than the better-known epoxide-Ritter
reaction. Mechanistic studies suggest the rate-determining step is ring opening of the
cyclic dioxonium cation by acetonitrile and this step is reversible under anhydrous
conditions. The only irreversible step in the sequence appears to be hydration of nitrilium
cation which is exothermic by at least 15 kcal/mol. The stoichiometric need for catalyst is
explained by theoretical calculations suggesting an irreversible binding of Lewis acid (BF3)
to the acetamidoester.
Novel kinetic 8 and thermodynamic 9 and 10 forms of these cations have been isolated and
characterized by spectroscopic methods and single crystal X-ray analysis and their relative
ground state energies have been determined by theoretical computations. These cations
can be observed by dynamic NMR spectroscopy during the conversion of diol-monoesters
to vic-acetamidoalkanoates. Although nitrilium cation 10 can be formed as the major
species (aprox 94%) under equilibrium conditions in dry acetonitrile starting from 9, its
steady-state concentration under preparative conditions is low (<0.5-1.0%). Controlled
addition of 1 equivalent of H2O to cation 9 in acetonitrile-d3 results in near-quantitative
production of amidoester 13a and the kinetics of this conversion are biphasic (fast and slow
phases). The competitive pathways which retard the reaction rate involve reversible ring
opening of cation 9 by diolmonoester or acetamide via an O-alkylation pathway. A
mechanistic pathway consistent with this behavior is presented.
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Experimental:
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Monoester 19 was prepared according to a previously reported method.29 All cations
preparations and stock solutions were prepared in a drybox under dry nitrogen.
Acetonitrile and CH2Cl2 were dried over 4A sieves and all other commercial reagents used
as received. All NMR spectra were obtained on a Varian 400 or 500 MHz instrument with
d1 = 60 s.
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Synthesis of zwitterionic cation 8: To chloroethanol benzoate ester 7 (Aldrich, 1.09g,
6.00 mmol,) was added 20 mL of CH2Cl2 (dried over 4Å sieves and N2 purged). SbCl5
(2.13 g, 6.81 mmol) was added to the stirred solution of 7 and the solution turned bright
yellow. The solution was immediately transferred to a freezer at -30 °C and golden yellow,
1
diffractable crystals of 8 (2.45g, 82%) were obtained after 16h: H-NMR (400 MHz,
acetonitrile-d3) δ 8.08 – 7.98 (m, 2H), 7.70 – 7.58 (m, 1H), 7.57 – 7.47 (m, 2H), 4.61 –
4.47 (m, 2H), 3.94 – 3.84 (m, 2H); 13C{1H} (101 MHz, acetonitrile-d3) δ 166.89, 134.31,
133.91, 130.34, 129.64, 65.58, 63.36. 1H-NMR (400 MHz, Methylene Chloride-d2) δ 8.42
– 8.34 (m, 2H), 7.94 – 7.82 (m, 1H), 7.72 – 7.60 (m, 2H), 5.25 – 5.18 (m, 2H), 4.07 – 3.99
(m, 2H). 13C{1H} (101 MHz, CD2Cl2) δ 174.2, 138.0, 133.3, 129.3, 125.7, 72.4, 41.3. No
exact mass observed. Anal. Calcd for C, 22.30; H, 2.08. Found: C, 22.10; H, 1.80
Synthesis of (2-phenyl-1,3-dioxolan-2-ylium hexachlorostibate(VI) (9): To
chloroethanol benzoate ester 7 (910 mg, 5.00 mmol, 99 area% GC purity) was added 20
mL of CH2Cl2 (dried over 4Å sieves and N2 purged). SbCl5 (1.78 g, 5.68 mmol) was added
to the stirred solution of 7 and the solution turned bright yellow white and small white
crystals began to precipitate within 10 min. This slurry was stirred 19h, then filtered
through a medium porosity frit, washed with 15 mL of CH2Cl2 and vacumn dried to give
2.11 g of dioxonium cation 9 in 87% yield. Crystals suitable for X-ray analysis were
obtained from the filtration liquor upon storage at -30 °C: 1H-NMR (500 MHz, acetonitrile-
d3) δ 8.31 – 8.22 (m, 2H), 8.15 – 8.02 (m, 1H), 7.86 – 7.67 (m, 2H), 5.43 (s, 4H). 13C{1H}
(126 MHz, acetonitrile-d3) δ 183.4, 142.0, 134.1, 131.4, 118.2 (acetonitrile), 76.6. HRMS
(ESI-QTOF) m/z: [M]+ Calcd for C9H9O2: 149.0597; found: 149.0599.
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NMR
Tube
Generation
of
(N-(2-(benzoyloxy)ethyl)ethan-1-aminium-d3
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hexachlorostibate(V)) (10): cation 9 (31mg) was dissolved in 355 mg of dry acetonitrile-
d3 and transferred to an NMR tube. The tube was heated for 45 min at 70 oC and 1H-NMR
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9
detected 92% conversion to nitrilium cation 10 at equilibrium: H-NMR (500 MHz,
acetonitrile-d3) δ 8.13 – 8.02 (m, 2), 7.73 – 7.62 (m, 1H), 7.60 – 7.48 (m, 2H), 4.74 – 4.60
(m, 2H), 4.50 (m, 2H).; 13C{1H} (126 MHz, acetonitrile-d3) δ 166.6, 134.7, 130.6, 130.2,
129.7, 111.3 (1:1:1: triplet JC-14N = 40Hz, linear nitrilium carbon). 60.6, 47.0 (1:1:1 triplet),
4.62 (Sextet, CD3); HRMS (ESI-QTOF) m/z: [M]+ Calcd for C11H9D3NO2 193.1051,
found: 193.1051
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Synthesis of 2-(acetamidoethyl)-1-benzoate 13 from 9: Cation 9 (967 mg, 2.00 mmol,)
was dissolved in 6 mL of 4A sieve dried acetonitrile and heated under nitrogen to 70 °C for
1 h. Water (500 uL) was added slowly via syringe with stirring and cooling in an ice bath
and the bulk of acetonitrile (5 mL) was removed. Water (5 mL) was added and the residue
was extracted with 3 X 5 mL portions of EtOAc. The organic phase was dried over MgSO4,
filtered and evaporated to give 400 mg of crude product (Rf = 0.25 EtOAc) as an oil which
was recrystallized from EtOAc to give 350 mg of white crystals (mp = 51-52°C) in 84%
1
overall yield. Single crystal X-ray analysis of 13 is included in SI: H-NMR (500 MHz,
CDCl3) δ 8.07 – 7.92 (m, 2H), 7.62 – 7.47 (m, 1H), 7.48 – 7.36 (m, 2H), 6.31 (broad s, 1H
13
amide), 4.45 – 4.28 (m, 2H), 3.61 (q, J = 5.6 Hz, 2H), 1.97 (s, 3H). C{1H} (126 MHz,
CDCl3) δ 170.5, 166.6, 133.1, 129.7, 129.5, 128.4, 63.6, 38.9, 23.1. Free base diester 15
(Rf= 0.82) (30 mg) was also isolated and its NMR spectra were consistent with a
commercial sample.
2-(acetamidoethyl)-1-benzoate (acetamido-d3) 13a: (31 mg 9 at 95% conversion to 10)
in 700 mg of acetonitrile-d3 was treated with 1 mL of distilled water. The solution was
extracted with 2 X 3 mL of CH2Cl2 and the combined extract was dried with MgSO4 and
evaporated to give a white film. The solid was dissolved in 1 mL of boiling EtOAc and
cooled to give 9 mg of white crystals of deuterated amide 13a in 74% yield: Rf = 0.25
1
(EtOAc); H-NMR (500 MHz, acetone-d6) δ 8.03 (d, J = 7.6 Hz, 2H), 7.65 (t, J = 7.4 Hz,
1H), 7.52 (t, J = 7.7 Hz, 1H), 4.48 (t, J = 5.3 Hz, 2H), 3.83 (t, J = 5.3 Hz, 2H); 13C{1H}
(126 MHz, acetone-d6) δ 174.7, 166.7, 134.1, 131.1, 130.3, 129.4, 63.6, 40.7. HRMS (ESI-
QTOF) m/z: [M+H]+ Calcd for C11H11D3NO3 211.1157; found: 211.1161.
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Reaction of cation 9 with acetamide to cation 16: Cation 9 (966 mg, 2.00 mmol) was
suspended in 15 mL of CH2Cl2 with stirring and acetamide (122 mg, 2.02 mmol) was added
o
o
8
9
to effect dissolution (25 C). The clear solution was stored in the freezer at -30 C for
several days to give 16 (820 mg, 1.51 mmol) as diffractible, colorless crystals in 76% yield.
1H-NMR (400 MHz, acetonitrile-d3) δ 9.28 (broad s, 1H), 8.79 (broad s, 1H), 8.05 (d, J =
7.5 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.53(t, J = 7.5 Hz, 2H), 4.67 (m, 4H), 2.43 (s, 3H).
13C{1H} (126 MHz, acetonitrile-d3) δ 180.1, 166.7, 134.4, 130.4, 130.3, 129.5, 118.1, 72.5,
62.1, 20.0.
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1-Acetamido-3-(chloropropanyl)-2-benzoate 20 from monoester 19: Ester 19 (429 mg,
2.00 mmol, 97% area GC purity) was dissolved in 4 mL of 4A sieve dried acetonitrile in a
conical Wheaton vial under N2 purge, using a Teflon pressure cap. BF3 etherate (140 mg,
approx 1 eq) was added via syringe and the reaction was stirred in the sealed vial at 70 oC
for 20 hr. Workup consisted of dissolving solution (light yellow) in 4 mL of water and
extracting with 2 X 4 mL portions of EtOAc. The organic phase was dried over MgSO4,
filtered and evaporated to give crude colorless 11 as an oil. Crude 11 was purified by flash
chromatography using CH2Cl2 to give a colorless oil (419 mg, 1.64 mmol) in 82% yield:
Rf = 0.56 EtOAc; 1H-NMR (500 MHz, CDCl3) δ 8.11 – 7.97 (m, 2H), 7.58 (ddd, J = 8.4,
1.2, 0.6 Hz, 1H), 7.52 – 7.37 (m, 2H), 6.03 (s, 1H), 5.33 (pentet, J = 6.8, 1H), 3.90 – 3.48
(m, 4H), 1.96 (s, 3H). 13C{1H} (126 MHz, CDCl3) δ 170.5, 166.0, 133.5, 129.8, 129.3,
128.5, 72.5, 43.7, 40.8, 23.1. 193.1. HRMS (ESI-QTOF) m/z: [M+H]+ Calcd for
(C12H15ClNO3 ) 256.0735; found: 256.0747.
X-ray data measurement. X-ray intensity data were collected on a Bruker SMART
diffractometer using MoKα radiation (λ = 0.71073 Å) and an APEXII CCD area detector.
Raw data frames were read by program SAINT31 and integrated using 3D profiling
algorithms. The resulting data were reduced to produce hkl reflections and their intensities
and estimated standard deviations. The data were corrected for Lorentz and polarization
effects and multi-scan absorption corrections were applied. The structure was solved
(SHELXS-97) and refined (SHELXL-2013) using full-matrix least-squares refinement.
The non-H atoms were refined with anisotropic thermal parameters and H atoms were
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calculated in idealized positions and refined riding on their parent atoms. The refinement
was carried out using F2 rather than F values. R1 is calculated to provide a reference to the
conventional R value, but its function is not minimized.
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Supporting Information:
All NMR data including kinetic and equilibrium measurements for cation 9 and nitrilium
ion 10 as well as all new compounds are reported in supporting information section. Details
of computational and experimental methods for kinetic and thermodynamic measurements
and crystallographic parameters for 8, 9, 13, 16 are included here (xxx pages).
1
Banholzer, W.; Jones, M.; Watson, K. How Might Biofuels Impact the Chemical Industry
Chemical Engineering Progress 2008, 104, S7-S14.
2
Pagliaro, M.; Rossi, M. The Future of Glycerin: New Uses for a Versatile Raw Material. RSC
Green Chemistry Series, Cambridge, 2008, pp 32-64.
3
Kumar, P.; Gupta, P. An Efficient Total Synthesis of Decarestrictine. Synlett, 2009, 9, 1367-
1382.
4
Bell, B. M.; Briggs, J. R.; Campbell, R. M.; Chambers, S. M.; Gaarenstroom, P.D.; Hippler, J.
G.; Hook, B. D.; Kearns,K.; Kenny, J. M.; Kruper, W. J. Glycerin as a Renewable Feedstock
for Epichlorohydrin Production. The GTE Process. Clean: Soil, Air, Water, 2008, 36, 657-661.
5
a) Tesser, R.; Santacesaria, E. ; Di Serio, G.; Casale, L.; Verde, D. New Process for Producing
Epichlorohydrin via Glycerol Chlorination. Ind. Eng. Chem. Res. 2010, 49, 964-970. b)
Tesser, R.; Santacesaria, E.; Di Serio, G.; Di Nuzzi, G.; Fiandra, V. Kinetics of Glycerol
Chlorination with Hydrochloric Acid:ꢀA New Route to α,γ-Dichlorohydrin. Ind. Eng. Chem.
Res. 2007, 46, 6456.
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Concellon, J. M.; Ramon Suarez, J.; del Solar, C. V. Total Selective Synthesis of Enantiopure
O1-Acyl-3-aminoalkane-1,2-diols by Ring Opening of Aminoepoxides with Carboxylic Acids.
J. Org. Chem. 2005, 70, 7447-7450.
a) Garcia Ruano, J. L.; Garcia Paredes, C. Tetrahedron Lett. 2000, 41, 5357-5361. b)
Umezawa, J.; Takahashi, O.; Furuhashi, K.; Nohira, H. Synthesis of Optically Active
Oxazolines from Optically Active Epoxides. Tetrahedron Asymmetry 1994, 5, 491-498. c)
Wohl, R.; Cannie, J. Stereochemistry of 2-Oxazolenes from Epoxides. J. Org. Chem. 1973, 38,
1787-1790.
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Kubisa, P. Ion Association and Free Ion Formation Effects on the Proton NMR Parameters of
1,3-Dioxolan-2-Ylium Salts In The Polymerization Of 1,3-Dioxolane. Bull L’Academie
Polanais Des Sciences 1978, 25, 627-33.
a) For diol-assisted Ritter: Song, X; Hollingsworth R. 1,3-Dioxonium Cation Facilitated
Ritter-Type Reaction Facile Synthesis Of Protected Aminopolyols. Tetrahedron Lett, 2006,
229, 332-336. b) For glycosyl isooxazolines via a Ritter-like reaction of b-
hydroxyoxocarbenium ion attack by nitriles, see: Jimenez Blanco, J. L.; Rubio, E. M.; Ortiz
Mellet, C.; Garcia Fernandez, J. M. Synthesis of Sugar Oxazolines by Intramolecular Ritter-
Like Reaction of D-Fructose Precursors. Synlett 2004, 12, 2230-2232.
10
11
For benzylic diols in Ritter reaction see: Davies, I. W.; Senayake, C. H.; Larsen, R.D.;
Verhoven, T. R.; Reider, P. J. “Application Of A Ritter-Type Reaction to the Synthesis of
Chiral Indane-Derived C2-Symmetric Bis(Oxazolines). Tetrahedron Lett. 1996, 37, 813-814.
Gao, Y.; Sharpless, K. B. Vicinal Diol Cyclic Sulfates. Like Epoxides Only More Reactive. J.
Am. Chem. Soc. 1988, 110, 7538 -7539.
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Feske, B. D.; Kaluzna, I. A.; Stewart, J. D. Enantiodivergent, Biocatalytic Routes to Both
Taxol Side Chain Antipodes. J. Org. Chem. 2005, 70, 9654-9657.
Perrault, W. R.; Pearlman, B. A.; Godrej, D. B.; Jeganathan, A.; Yamagat, K.; Chen, J. J.; Lu,
C. V; Herrinton, P. M.; Gadwood, R. C.; Chan, L.; Lyster, M. A.; Maloney, M. T.; Moeslein,
J. A.; Greene, M. L.; Barbachyn, M. R. The Synthesis of N-Aryl-5(S)-aminomethyl-2-
oxazolidinone Antibacterials and Derivatives in One Step from Aryl Carbamates. Org.
Process Res. Dev. 2003, 7, 533-546.
14
For a similar approach to 3 using glycol diesters, see: Paulson, H.; Behre, H. Darstellung von
acyloxonium-Salzen von 1,2-Diolen und 1,3-Diolen. Chem. Ber. 1971, 104, 1264-1280.
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a) Childs, R. F.; Orgias, R. M.; Lock, C. J. L.; Mahendran, M. The Structures of Dioxolan-2-
Ylium Cations; Carbon-Oxygen Bond Distances in Acetoxonium Ions. Can. J. Chem. 1993,
71, 2084-2089. b) Childs, R. F.; Kang, G. J.; Wank, T. A.; Frampton, C. S. Structural Studies
on Dioxan-2-Ylium Ions; Intramolecular Attack of an Oxygen Atom on a Carbenium Ion
Centre. Can. J. Chem. 1994, 72, 2084-2089. When stored at -30 oC, zwitterion 8 is stable
indefinitely. In the solid state, diffractible crystals of 2 (yellow) slowly convert to amorphous
9 (white) at room temperature over a 1year period.
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a) Chevrier, B.; Le Carpentier, J. M.; Weiss, R. Synthesis of Two Crystalline Species of the
Friedel-Crafts Intermediate Antimony Pentachloride-p-Toluoyl Chloride. Crystal Structures of
the Donor-Acceptor Complex and of the Ionic Salt. J. Am. Chem. Soc. 1972, 94, 5718-5723. b)
Laube, T.; Stilz, H. U. Crystal Structure of the Complex 5-Phenyladamantan-2-one-
Pentachloroantimony. Hyperconjugative Effects in an Activated Ketone. J. Am. Chem. Soc.
1987, 109, 5876-5878. c) Laube, T.; Hollenstein, S. Crystal Structures of Two Activated
Cyclohexanones with Opposite Pyramidalizations of the Carbonyl Groups. J. Am. Chem. Soc.
1992, 114, 8812-8817.
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Bullock, E.; Tuck, D. G.; and Woodhouse, E. J. Unusual Spin-Spin Couplings In Nuclear
Magnetic Resonance Spectra Of Alkyl Ammonium Salts. J. Chem. Phys., 1963, 38, 2318.
Kuntz, I. D.; Schleyer. P. von R.; and Allerhand, A. Long-Range N14-H1 Nuclear-Resonance
Coupling in Isonitriles. J. Chem. Phys., 1961, 35, 1533.
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Jochims, J. C.; Abu-El-Halawa, R.; Jibril, I.; and Huttner, G. Metal Complexes of Cyanamides
and Their Alkylation to Cyanamidium Salts. A General Synthesis of Highly Substituted Ureas,
Isoureas, and Guanidines. Chem. Ber. 1984, 117, 1900.
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a) Ahmad, M.; Bergstrom, R.G.; Cashen, M.J.; Chiang, Y.; Kresge, A.J.; McClelland, R.A.
Ortho Ester Hydrolysis: Direct Evidence for a Three-Stage Reaction Mechanism. J. Am.
Chem. Soc. 1979, 110, 2669-2677. b) Conversely, under strong acid (magic acid) conditions
hydroxyester 7 cyclization to cation 9 is fast: Burt, R. A.; Chambers, C. A.; Y. Chiang;
Hillock, C.S; Kresge, A. J.; Larson, J. W. Heats of Formation of 1,3-Dioxolenium Ions from
Ortho Ester Precursors in Sulfuric Acid Solution: Methyl vs. Phenyl Substitution at the Pro-
Acyl Carbon Atom. J. Org. Chem. 1984, 49, 2622-2624.
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Tuttle, T.; Cerkovnik, J.; Plesnicar, B.; Cremer, D. Hemiortho Esters and Hydrotrioxides as
the Primary Products in the Low-Temperature Ozonation of Cyclic Acetals: An Experimental
and Theoretical Investigation. J. Am. Chem. Soc. 2004, 126, 16094-16104.
Capon, B.; Ghosh, A.K. Tetrahedral intermediates. 2. The Detection of Hemiorthoesters In
The Hydration of Ketene Acetals and the Mechanism of their Breakdown. J. Am. Chem.
Soc. 1981, 103, 1765-1768.
Axhausen, J.; Ritter, C.; Lux, K.; Kornath, A. The Protonation of Acetamide and
Thioacetamide in Super-acidic Solutions: Crystal Structures of [H3CC(OH)NH2]+AsF6- and
[H3CC(SH)NH2]+AsF6. Z. Anorg. Allg. Chem. 2013, 639, 65-72.
a) Ghosez, L.; Bayard, Ph.; Nsimyumukiza, P.; Gouveneur, V.; Sainte, F.; Beaudegnies, R.;
Rivera, M.; Frisque-Hesbain, A.-M.; Wynants, C. 2-Aza-1,3-Dienes: Methods of Synthesis
and Stereochemical Studies. Tetrahedron 1995, 51, 11021-11042. For related chemistry see:
b) Hitzler, M. G.; Lutz, M. Shrestha-Dawada, P. B.; Jochims, J. C. On the Reaction of
Nitrilium Salts with Secondary Carboxamides. Liebigs Ann. 1996, 247-257. c) Darbeau, R.
W.; White, E. H.; Nunez, N.; Coit, B.; Daigle, M. Reaction of Essentially Free Benzyl Cations
with Acetonitrile; Synthesis of Ethanimidic Carboxylic Anhydrides and Unsymmetrical
Diacylamines J. Org. Chem. 2000, 65, 1115-1120.
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In this report 10% BF3 catalyst is tolerant of methanol liberation from orthoester starting
material: Zheng, T.; Narayan, R.S.; Schoemaker, J. M.; Borhan. B. One-Pot Regio- and
Stereoselective Cyclization of 1,2,n-Triols J. Am. Chem. Soc. 2005, 127, 6946-6947.
Using the prep disclosed in this reference: Fodatar, U.; Becu, C.; Borremans, F.A.M.;
Anteunis, J. O. Synthetic and Conformational Aspects of trimethylammonium-Methyl
Substituted 2-Oxazolines as Potential Cholinergics Tetrahedron, 1978, 34, 3537-3543.
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Addition of BF3·Et2O to pure 20 results in substantial down-field shift of amido proton and
amide carbonyl resonances.
In addition to acetamide, residual chloride or benzoic acid detracts immensely from yield.
These impurities have ring-opening propensity greater than 1000 X acetonitrile.
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Khalafi-Nezhad, A.; Soltani Rad, M.N.; Khoshnood, A. An Efficient Method for the
Chemoselective Preparation of Benzoylated 1,2-Diols from Epoxides. Synthesis, 2003, 2552-
2558.
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