Mechanistic and Synthetic Implications of the Diol-Ritter Reaction

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Mechanistic and Synthetic Implications of the DiolRitter 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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The Journal of Organic Chemistry

Mechanistic and Synthetic Implications of the Diol-Ritter Reaction: Unexpected, Yet Reversible Pathways in the Regioselective Synthesis of Vicinal-Aminoalcohols 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* 1

Corteva 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 [email protected] 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 1 ACS Paragon Plus Environment

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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.

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 2 ACS Paragon Plus Environment

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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.

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 vicamidoalcohols6 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 ringopening 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 vic3 ACS Paragon Plus Environment


1o-aminoalcohols some of which have already found utility in the synthesis of Taxol side chains12, AZT agonists5 and the antibacterial agent Zyvox.13 Results and Discussion: 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 at low temperature.

Interestingly, chemical shifts of many resonances in 1H-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 1HNMR 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 4 ACS Paragon Plus Environment

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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. 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 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 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 coupling between 14N and the nitrilium carbon (1:1:1 triplet with J = 47 Hz at 111 ppm, with additional two-bond C-D coupling) in its

13

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 tetraalkylammonium 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, 1

J(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 °C, respectively. Table 1 includes rate constants obtained from 1H-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.



1

mol fraction

0.8 0.6 0.4 0.2 0 0

50

100

150

200

250

300

350

400

450

Time (min) Figure 3. Approach to equilibrium plot for ring opening of cation 9 (Blue) to nitrilium cation 10 (Red) at 50 °C

-10.5 -11.5 Ln (k/T)

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-12.5 -13.5

y = -10956x + 21.333

-14.5 -15.5 0.0029

0.003

0.0031 1/T (K-1)

0.0032

0.0033

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. Temp (°C)

kf, rate const. (min-1)

Keq, (L/mol)

30

0.00664 ± 0.00002

1.86 ± 0.04

40

0.02157 ± 0.00003

1.45 ± 0.01 1.427658571

50

0.06740 ± 0.00014

1.11 ± 0.01 1.09517307

60

0.1964 ± 0.0003

70

0.4940 ± 0.0010

0.907 ± 0.005 cconstant const. 0.854722989 0.740 ± 0.004 0.702821985

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.



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, forms hydroxyester 11 (20% relative to 9) within 10 min as revealed by 1H-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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80 70 60 Cation 9 Relative mol %

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


50

Ether 14 Hydroxy ester 11

40

Amido ester 13a Cation 16

30 20 10 0 0

5

10

15

20

25

Time (hours)

Figure 5: Reaction of cation 9 with one equivalent of H2O (50 °C) as monitored by 1H-500 MHz 1 H-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.



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 acidactivated 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 Oalkylation (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. Spectroscopic characterization by

13

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 12 ACS Paragon Plus Environment

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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

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 exchange process as observed in the 1H-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



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). 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). 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 1and 2-N-subsituted oxazolines, respectively, by 1H-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-1oacetamido-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 (

Mechanistic and Synthetic Implications of the Diol-Ritter Reaction

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