Lewis Acid-Catalyzed Addition of Benzophenone Imine to Epoxides Enables the Selective Synthesis and Derivatization of Primary 1,2-Amino Alcohols

Article abstract of DOI:10.1021/acs.oprd.8b00133

Benzophenone imine was found to be an effective ammonia surrogate for the selective preparation of primary 1,2-amino alcohols from epoxides, including enantiopure epichlorohydrin, in the presence of catalytic Y(OTf)₃. High-throughput screening of 48 Lewis acids quickly identified Y(OTf)₃ as an effective mediator of the addition reaction under mild conditions. Following acidic hydrolysis, the primary amino alcohol salt is revealed and partitions into the aqueous solution, while the benzophenone byproduct is easily removed by simple extraction with ethyl acetate. These ammonium salts can be directly Boc-protected or further derivatized without isolation to form benzamides and sulfonamides under Schotten-Baumann-type conditions in up to 79% isolated yield over three steps. This methodology has been used to prepare key intermediates for the synthesis of PRMT5 inhibitors with high enantiopurity as well as numerous other amide and sulfonamide derivatives.

Full text of DOI:10.1021/acs.oprd.8b00133

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Lewis Acid Catalyzed Addition of Benzophenone Imine to Epoxides Enables
the Selective Synthesis and Derivatization of Primary 1,2-Amino Alcohols
John Jin Lim, and David C. Leitch
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00133 • Publication Date (Web): 27 Apr 2018
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Lewis Acid Catalyzed Addition of Benzophenone
Imine to Epoxides Enables the Selective Synthesis
and Derivatization of Primary 1,2-Amino Alcohols
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John Jin Lim*,† and David C. Leitch†
†Continuous Primary Group, API Chemistry, GlaxoSmithKline, King of Prussia PA.
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Table of Contents artwork.
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ABSTRACT. Benzophenone imine was found to be an effective ammonia surrogate to
selectively prepare primary 1,2-amino alcohols from epoxides, including enantiopure
epichlorohydrin, in the presence of catalytic Y(OTf)3. High-throughput screening of 48 Lewis
acids quickly identified Y(OTf)3 as an effective mediator of the addition reaction under mild
conditions. Following acidic hydrolysis, the primary amino alcohol salt is revealed and
partitions into the aqueous solution, while the benzophenone byproduct is easily removed by
simple extraction with ethyl acetate. These ammonium salts can be directly Boc-protected or
further derivatized without isolation to form benzamides and sulfonamides under Schotten-
Baumann type conditions in up to 79% isolated yield over three steps. This methodology has
been used to prepare key intermediates for the synthesis of PRMT5 inhibitors with high
enantiopurity, as well as numerous other amide and sulfonamide derivatives.
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Introduction.
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1,2-Amino alcohols are a well reviewed class of organic compounds with a variety of
pharmaceutical and industrial uses.1 Because of this importance, many synthetic methods have
been devised to access structurally diverse analogs. Classic routes to access primary 1,2-amino
alcohols proceed via either Strecker (cyanide)2 or Henry (nitromethane)3 additions to aldehydes,
followed by reduction. While there is a plethora of literature devoted to implementation of these
transformations, the need for toxic or high-energy reactants (cyanide sources and nitromethane,
respectively) can be a significant safety concern when working on larger scales. Amination of
epoxides is an attractive alternative strategy for the synthesis of 1,2-amino alcohols; however,
direct access to primary 1,2-amino alcohols from epoxides and ammonia often results in
overalkylation even with large excesses of NH3, as the primary amine product reacts further with
the epoxide electrophile.4 Use of an appropriately protected ammonia surrogate can circumvent
this overalkylation, but this often requires a subsequent and separate deprotection step.5
Addition of azide to an epoxide followed by reduction is a commonly employed strategy;6
however, safety concerns around the use of azide are even more severe than the aforementioned
Strecker or Henry routes. Finally, regardless of the synthetic strategy employed, the desired
primary amino alcohol products are often very water soluble and thus can be difficult to isolate,
typically requiring precipitation of an appropriate ammonium salt or fractional distillation.
As part of synthetic efforts toward a key amino alcohol intermediate (1) for oncology target 3,
a protein arginine methyltransferase-5 (PRMT5) inhibitor7, we sought to evaluate the use of
alternative ammonia surrogates able to react selectively with epoxides (Scheme 1). The
synthesis for 1 required the use of an expensive epoxide (a), yield loss due to overalkylation
(formation of c), large volumes of ethanolic ammonia at high temperature in a pressure vessel for
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the second step, and the use of chromatography for two isolations. A loss of stereochemical
purity was also observed in this sequence, giving 1 with only 86% enantiomeric excess. We
hoped to remedy these issues by developing a new synthesis that relied on reacting inexpensive,
enantiopure epichlorohydrin with an ammonia surrogate, and then directly reacting the addition
intermediate with tetrahydroisoquinoline (THQ, Scheme 2).
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Scheme 1. Reported synthesis of 3, using ammonia to prepare 1.7
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Scheme 2. Proposed synthesis of 1 via benzophenone imine addition to epichlorohydrin.
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The direct reaction of ammonia with epichlorohydrin is unknown in the literature, and would
likely result in a complex mixture of oligo/polymeric amine products. Use of a mono-protected
ammonia equivalent such as benzylamine poses the risk of overalkylation, either
intermolecularly with another equivalent of epoxide, or through cyclization to form an azetidine.8
In contrast, use of an ammonia-derived imine as a nucleophile would prevent overalkylation, and
provide an easy method to reveal the primary amine through hydrolysis. There are examples of
reacting epoxides with in-situ generated aldimine nucleophiles in the patent literature;9 however,
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ammonia-derived aldimine formation can be problematic due to low solubility of the imine itself,
and the competitive formation of oxazolidines via cyclization after addition to the epoxide.
Benzophenone imine is a stable, inexpensive, readily available, and highly organic soluble
compound that is frequently used as an ammonia surrogate in Pd-catalyzed amination
chemistry;10-11 however, its use as a nucleophile in reactions with epoxides is almost completely
unexplored. To the best of our knowledge, there is a single report of benzophenone imine
addition to epoxides, using chiral scandium and indium bipyridine catalysts,12 though these
transformations require long reaction times (5 days) and use of the undesirable process solvent
DCM. Furthermore, the reaction scope was not explored beyond a few symmetric 1,2-
diarylepoxides, giving no indication of the degree of regioselectivity possible with non-
symmetric epoxides.
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Herein, we report that Lewis acids can effectively catalyze the regioselective addition of
benzophenone imine to a variety of substituted epoxides, including epichlorohydrin, with
Y(OTf)3 as the preferred catalyst. Simple hydrolysis of the intermediate alkylated imine and
extraction with organic solvent removes the benzophenone, giving an aqueous solution of the
desired primary amino alcohol as its ammonium salt; no overalkylated byproducts are observed.
These ammonium salts can then be directly acylated or sulfonylated using biphasic Schotten-
Baumann conditions to give an array of functionalized products in good yield over multiple steps
in a simple, rapid, and scalable protocol. Importantly, stereochemical purity is retained when
(S)-epichlorohydrin is employed in the synthesis of 2, providing an efficient route to access
homochiral primary amino alcohol derivatives from simple, inexpensive precursors.
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Results and Discussion.
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Based on the aforementioned report of Lewis acid catalyzed addition of benzophenone imine
to select 1,2-diarylepoxides,12 as well as reports of Lewis acid catalyzed addition of amines to
epoxides,13 we sought to identify an appropriate Lewis acid to effect the regioselective addition
of benzophenone imine to epichlorohydrin under mild conditions. In order to achieve this, we
designed a high-throughput screen drawn from our in-house catalyst library. This screen
included 48 Lewis acids (20 mol%) and 2 solvents (5 vol of acetonitrile or ethanol) for a total of
96 reactions, using benzophenone imine (22 ꢀmol) and racemic epichlorohydrin (20 ꢀmol); the
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plate was run for one hour at 50 C to form the racemic diphenylmethylene amino alcohol 4,
which was identified by HPLC analysis (Figure 1).
NH
O
OH
LA (20 mol%)
O
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N
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Cl
+
ACN or EtOH
1 h, 50 oC
(1 equiv)
Ph
(1.1 equiv)
4
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Figure 1. Selected results from Lewis acid screen with CH3CN as solvent, showing only those
reactions with >1% conversion (judged by LC area%). See Supporting Information for further
details.
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In EtOH, only La(OTf)3 showed >8% conversion to product 4, whereas all of the other
catalysts promoted hydrolysis of the benzophenone imine instead of alkylation. In CH3CN,
InCl3, La(OTf)3, Sc(OTf)3, ScCl3, VCl3, Y(OTf)3 and Yb(OTf)3 all showed 8-20% conversion,
and were therefore chosen for confirmation experiments on larger scale. In every case, the
addition occurs exclusively at the unhindered position of the epoxide, and no displacement of the
alkyl chloride was observed. In the absence of catalyst, benzophenone imine reacts very slowly
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with epichlorohydrin in CH3CN, giving <2% conversion to product after 20 hours at 65 C. A
second control experiment using 30 mol% triflic acid in the absence of yttrium showed no
conversion to 4, indicating that adventituous protons are likely not responsible for promoting the
epoxide activation. In our scale-up experiments, ScCl3 gave similar results as Y(OTf)3; however,
Y(OTf)3 has the added benefit of lower cost and wider availability.14 The lower conversions
observed in our screening panel compared to the higher conversions observed in scale-up
experiments were most likely due to order of addition. The screening panel contained pre-
weighed Lewis acids to which were added stock solutions of benzophenone imine followed by
epichlorohydrin. The Lewis acids thus had opportunity to hydrolyze the benzophenone imine
prior to the addition of epichlorohydrin. The procedure was refined so that the catalyst was added
last.
In addition to identifying several possible Lewis acid catalysts, our screening results indicated
a distinct solvent preference for CH3CN over EtOH. With Y(OTf)3 as the Lewis acid, we
evaluted several other aprotic solvents under otherwise identical conditions. The addition
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reaction performs well in a number of alternative solvents, including 2-MeTHF, TBME, iPrOAc,
toluene, and diethylcarbonate, though CH3CN did still provide the best results.14 Thus, Y(OTf)3
in CH3CN exhibits the best combination of short reaction time and minimal hydrolysis of the
benzophenone imine when reacting with epichlorohydrin, giving up to 80% conversion to 4 at 65
°C after only one hour. Notably, this catalyst/solvent combination is even able to perform at
room temperature (equation 1)
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With an improved catalyst/solvent system identified, we applied this strategy to the gram-scale
synthesis of enantioenriched intermediate 2 (Scheme 3). In Step 1, the catalyst loading could be
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reduced to 10 mol%, and the reaction run at 60 C for 2 h. The Step 1 solution output of (S)-4
can be telescoped directly into Step 2.1 by the addition of 2 M NaOH to form (S)-5 followed by
treatment with THQ in Step 2.2. The Step 2 solution output was then treated with 1 M HCl and
EtOAc to effect imine hydrolysis and separation of the benzophenone in Step 3. After 30
minutes, the amino alcohol 1 had partitioned exclusively into the aqueous phase while the
benzophenone protecting group remained in the organic phase. Following removal of the
organic phase, the acidic solution of 1 was basified with 2 M NaOH, and then added to a slurry
of the 6-chloropyrimidine-4-carbonyl chloride in 2-MeTHF to effect the amidation under
Schotten-Baumann conditions. Following purification, 2 was obtained in 25% isolated yield
(average 70% per transformation) and 95% enantiomeric excess, with no isolation of any
intermediates. This streamlined sequence can be conducted in a single day, does not require the
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use of pressure equipment, affords an equivalent yield to that previously reported for the multi-
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step route (Scheme 1), and achieves higher enantiopurity of 2 prior to any crystallization.
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Scheme 3. Synthesis of 2 in a two-pot telescoped sequence.
While this method provides rapid access to gram-quantities of 2, we sought to further
investigate the suitability of this approach toward a more general synthesis of amino alcohol
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derivatives. Using racemic epichlorohydrin, we evaluated several points for isolation of key
intermediates to enable synthetic diversification (Scheme 4). Unfortunately, attempts to isolate 4
via chromatography did not give a pure product. We suspect that hydrolysis of the imine,
cyclization to the oxazolidine, and/or formation of the epoxide can occur during the
chromatographic separation; therefore, progressing 4 as a solution into the subsequent steps is
advisable. We were able to hydrolyze 4 to obtain amino alcohol 7 in 80% solution yield as its
HCl salt (Scheme 5); however, 7 was not further derivatized. In order to access an easily isolated
intermediate capable of diversification, we have prepared the Boc-protected analogue 6 in 41%
isolated yield by treating a basified solution of racemic 1 with Boc-carbonate.
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Scheme 4. Preparation and isolation of 6.
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Given the success observed with epichlorohydrin, we have further expanded the scope of the
Y(OTf)3 catalyzed addition of benzophenone imine to epoxides into a general two-pot, three-step
process as shown in Scheme 5. In Step 1, various epoxides can be reacted to form
benzophenone-protected amino alcohols of type d, which are then hydrolyzed and separated
from the benzophenone by extraction with EtOAc in Step 2. We have used this method to
generate amino alcohol salts 7-20; solution yields for these intermediates ranged from 56-87%
(determined using 40 mol% BHT as internal standard), except for compounds 18, 19, and 20.
The poor results for the synthesis of 18 and 19 are likely due to steric hindrance, while the
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epoxide used for 20 likely decomposed under the reaction conditions. In Step 3, the aqueous
solution of the ammonium salt is basified with either 2 M NaOH or Hunig’s base, followed by
the addition of 2-MeTHF and the desired electrophile. Amidation or sulfonylation is thus
effected under Schotten-Baumann conditions, generally reaching completion within 1-2 h. The
organic layer was separated and purified by chromatography to afford a variety of benzamides
and sulfonamides in up to 79% isolated yield over 3 steps (Scheme 5). The poor yield of 27 is
probably due to the high aqueous solubility of the product, especially given the high solution
yield of 14. While most of these examples were conducted on 100 mg scale to test the
methodology, we also performed several multi-gram runs to confirm the practicality of this
approach toward preparative synthesis. Compounds 31 and 32 were thus prepared using 1-2 g of
benzophenone imine as the input material in 20% and 28% isolated yield respectively. While the
isolated yields of the final products are modest in many cases, we note that each example was
prepared using the same general set of conditions over three steps; specific process optimization
for a desired product, particularly with respect to isolation, would undoubtedly result in higher
isolated yields.
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Scheme 5. General approach to derivatized 1,2-diamino alcohols from Y(OTf)3-catalyzed
addition of benzophenone imine to epoxides (reactions run using 100 mg of benzophenone imine
unless otherwise noted).
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The mass efficiency of the process can be improved by recovering the benzophenone
protecting group and eliminating chromatography, both of which would be desirable for larger
scale applications. The synthesis of compound 34 was chosen for a 10 g scale up demonstration,
and to assess the feasibility of benzophenone recovery and a simplified purification procedure.
o
In Step 1, an extra 0.4 equiv of the epoxide was charged after 2 h at 60 C followed by stirring
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for an additional hour at 60 oC. Following Step 2, the organic layer containing the benzophenone
protecting group was concentrated under reduced pressure, seeded with pure benzophenone, and
then filtered to afford 4.6 g (46%) of recovered benzophenone. Following Step 3, the organic
layer was washed with water to remove inorganic impurities. The organic layer was then
concentrated and recrystallized from MeOH to afford 6.6 g of 34 for an isolated yield of 41%
over three steps with no chromatographic purifications.
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Conclusions.
Benzophenone imine was found to be an effective ammonia surrogate for the selective
synthesis of primary 1,2-amino alcohols from epoxides, including epichlorohydrin. Several
Lewis acids are capable of promoting this reaction, with Y(OTf)3 identified as the best catalyst
from a panel of 48 different Lewis acids. The aqueous amino alcohol solutions generated after
imine hydrolysis are easily derivatized without the need for isolation. We have demonstrated
that this chemistry is amenable for both rapid small-scale analogue synthesis and multi-gram
scale-up without the need for chromatography. Importantly, we have shown that the
enantiopurity of the starting epoxide can be carried through these steps with little erosion, as in
the synthesis of 2. From a practicality standpoint, both benzophenone imine and Y(OTf)3 are air
stable and readily available from a variety of vendors at low cost. If desired, extraction of the
benzophenone byproduct provides an opportunity for recycling; we have demonstrated the
feasibility of this by simple crystallization of benzophenone on larger scale. Thus, this
operationally simple procedure should have broad applicability in the synthesis and
derivatization of primary amino alcohols from readily available precursor materials.
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Experimental Section.
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General information:
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All solvents and reagents were obtained from commercial sources and were used as they were
received. All reactions were carried out in oven-dried reaction vessels or glass vials. TLC
analysis was performed on silica gel TLC plates. Column chromatography was carried out on
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prepacked ISCO columns on Combiflash purification unit. H and 13C NMR spectra were
recorded on a 400 MHz spectrometer, and are reported as chemical shifts (δ) in parts per million
(ppm), and multiplicities are abbreviated as s= singlet, d = doublet, t = triplet, m = multiplet, b =
broad, dd = doublet of doublets, ddd = doublet of doublet of doublets. Residual solvent signals
were used as reference. HRMS (m/z) was measured using a LTQ Discovery Orbitrap (Thermo)
mass spectrometer equipped with a heated electrospray ionization (HESI) ion source. LRMS
(m/z) was measured using a Water Acquity SQD mass spectrometer on a Waters CSH column
(C18, 30mm x 2.1 mm, 1.7 µm particle size).
Procedure for synthesis of
2
(S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-
hydroxypropyl)pyrimidine-4-carboxamide.7
All reagent charges based on 1 equiv of benzophenone imine charged in Step 1.
Step 1: To a vial containing a magnetic stirbar were charged the following materials in this
order: CH3CN (10.0 mL, 5 vol), benzophenone imine (2.00 g, 1.94 mL, 11.0 mmol), (S)
epichlorohydrin (1.02 g, 0.86 mL, 11.0 mmol), and finally Y(OTf)3 (0.59 g, 1.10 mmol). The
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reaction vial was capped and placed on a heating block set for 60 C. The reaction mixture was
stirred for 2 hours.
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Step 2: The vial was removed from the heating block, allowed to cool to room temperature,
and then charged with 2.0 M NaOH (5.5 mL, 1.0 equiv). The vial was returned to heating block
and stirred for 1-2 min. THQ (1.17 g, 1.12 mL, 0.8 equiv) was then added, and the biphasic
mixture stirred at 60 oC for 3 h.
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Step 3: The reaction mixture was allowed to cool to room temperature, and then transferred to
a 125 mL Erlenmeyer flask. 2.0 M HCl (12.5 mL, 2.4 equiv) was added, followed by iPrOAc
(10.0 mL, 5 vol), ensuring the mixture is acidic to litmus (pH < 4). This biphasic mixture was
o
stirred vigorously for 30 min at 60 C. The mixture was then allowed to cool to room
temperature, the layers were separated using a separatory funnel, and the aqueous layer
transferred to a 100 mL flask.
Step 4: To the aqueous layer was charged 2.0 M NaOH (22.0 mL, 4.0 equiv), ensuring pH >
10. In a separate flask, 6-chloropyrimidine-4-carbonyl chloride (1.46 g, 0.75 equiv) was
suspended in 2-MeTHF (20.0 mL, 10 vol). This organic solution was added to the basified
aqueous amino alcohol solution. The biphasic reaction mixture was stirred vigorously at room
temperature for 2 h. Mixing was stopped, and the layers allowed to settle. The layers were
separated, the organic phase was concentrated under reduced pressure before directly loading the
material onto a silica gel column. Elution using a gradient of 0% to 100% EtOAc/hexanes
yielded 2 as a white solid (950 mg, 25% yield over 4 steps).
1H NMR (400 MHz, CDCl3) δ ppm 8.93 (s, 1 H), 8.53 (br. s. 1 H), 8.14 (d, J=0.78 Hz, 1 H), 7.08
- 7.23 (m, 3 H), 7.01 (d, J=6.26 Hz, 1 H), 4.52 (br. s. 1 H), 4.03 - 4.16 (m, 1 H), 3.87 (d, J=14.87
Hz, 1 H), 3.61 - 3.80 (m, 2 H), 3.45 - 3.58 (m, 1 H), 2.86 - 3.06 (m, 3 H), 2.75 - 2.86 (m, 1 H),
2.55 - 2.72 (m, 2 H)
LRMS (m/z) [M+H]+ : Found for C17H19ClN4O2: 347.2
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Procedure for synthesis of compound 6 (tert-butyl (3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-
hydroxypropyl)carbamate).
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Step 1: To a vial containing a magnetic stirbar were charged the following materials in this
order: CH3CN (10.0 mL, 5 vol), benzophenone imine (2.00 g, 1.94 mL, 11.0 mmol),
epichlorohydrin (racemic) (1.02 g, 0.86 mL, 11.0 mmol), and Y(OTf)3 (0.59 g, 1.10 mmol). The
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reaction vial was capped and placed on a heating block set for 60 C. The reaction mixture was
stirred for 2 hours. The presence of 4 was confirmed by HRMS; however, 4 was not isolated and
the Step 1 output was carried forward directly to Step 2.
HRMS (ESI) m/z [M+H]+: Calcd for C16H16ClNO: 274.0993; Found 274.0987.
Step 2.1: The vial was removed from the heating block, allowed to cool to room temperature,
and then charged with 2.0 M NaOH (5.5 mL, 1.0 equiv). The vial was returned to the heating
block and stirred for 1-2 min. The presence of 5 was confirmed by LRMS; however, 5 was not
isolated.
LRMS (m/z) [M+H]+: Found for C16H15NO: 238.1
Step 2.2: THQ (1.17 g, 1.12 mL, 0.8 equiv) was then added, and the biphasic mixture stirred
at 60 oC for 3 h.
Step 3: The reaction mixture was allowed to cool to room temperature before transferring to a
125 mL Erlenmeyer flask. 1 M HCl (25.0 mL, 2.4 equiv) and EtOAc (20.0 mL, 10 vol) were
o
charged, and the biphasic mixture stirred vigorously for 30 min at 60 C, ensuring the mixture is
acidic to litmus (pH < 4). The mixture was then allowed to cool to room temperature, the layers
were separated using a separatory funnel, and the aqueous layer transferred to a 100 mL flask.
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Step 4: To the aqueous layer was charged 2 M NaOH (11.0 mL, 2.0 equiv) and 2-MeTHF
(20.0 mL, 10 vol), ensuring pH > 10 by litmus. Boc-carbonate (3.60 g, 1.5 equiv) was charged
and the reaction mixture stirred vigorously overnight. Mixing was stopped, and the layers
allowed to settle. The layers were separated, and the organic phase was concentrated under
reduced pressure before directly loading the material onto a silica gel column. Elution using a
gradient of 0% to 90% TBME/hexanes yielded 6 as a clear oil (1.4 g, 41% yield over 4 steps)
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1H NMR (400 MHz, CDCl3) δ ppm 7.07 - 7.22 (m, 3 H), 6.98 - 7.07 (m, 1 H), 5.05 (br. s. 1 H),
4.96 (dd, J=6.06, 4.50 Hz, 1 H), 3.85 (d, J=14.87 Hz, 1 H), 3.62 (d, J=14.87 Hz, 1 H), 3.47 -
3.57 (m, 1 H), 3.41 (d, J=6.26 Hz, 1 H), 2.85 - 3.04 (m, 3 H), 2.69 - 2.85 (m, 2 H), 2.57 - 2.69
(m, 1 H), 2.49 - 2.57 (m, 1 H), 1.41 - 1.52 (m, 9 H)
13C NMR (101 MHz, CDCl3) δ ppm 156.43 (s, 1 C), 134.27 (s, 1 C), 134.04 (s, 1 C), 128.72 (s, 1
C), 126.53 (s, 1 C), 125.80 (s, 1 C), 125.69 (s, 1C), 71.31 (s, 1 C), 66.31 (s, 1 C), 60.76 (s, 1 C),
56.04 (s, 1 C), 51.12 (s, 1 C), 44.15 (s, 1 C), 29.08 (s, 1 C), 28.43 (s, 1 C)
HRMS (ESI) m/z [M+H]+: Calcd for C17H26N2O3: 307.2011; Found 307.2011.
General procedure for synthesis of benzamides 21-31. All reagent charges based on 1 equiv of
benzophenone imine charged in Step 1 (100 mg unless otherwise noted).
Step 1: To a vial containing a magnetic stirbar were charged the following materials in this
order: CH3CN (0.5 mL, 5 vol), benzophenone imine (100 mg, 1 equiv), epoxide (1 equiv), BHT
(48.6 mg, 40 mol %), and Y(OTf)3 (29.6 mg, 10 mol %). Note – BHT may be omitted if Step 1
o
will not be assayed. The reaction vial was capped and placed on a heating block set for 60 C.
The reaction mixture was stirred for 2 hours. If assaying Step 1, 5 uL of the reaction mixture
was then diluted in 1.0 mL of CH3CN and analyzed by HPLC.
Note – for Compounds 17 and 18, Step 1 was allowed to proceed for 20 h @ 60 oC.
Step 2: The reaction mixture was allowed to cool to room temperature. 1 M HCl (0.550 mL)
and EtOAc (0.5 mL, 5 vol) were charged, and the biphasic mixture stirred vigorously for 30 min
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at 60 oC, ensuring the mixture is acidic to litmus (pH < 4). The mixture was then allowed to cool
to room temperature, the layers were separated using a separatory funnel, and the aqueous layer
transferred to a vial containing a magnetic stirbar.
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Step 3: The aqueous layer was charged with either 2 M NaOH or Hunig’s base until basic to
litmus (usually 1 equiv based on benzophenone imine charge in Step 1) and 2-MeTHF (0.5 mL,
5 vol). To the resultant white slurry was charged benzoyl chloride (0.75 equiv based on
benzophenone imine charge in Step 1) and the mixture was stirred vigorously for 1-2 h @ 20-25
oC, at which point most of the solids have dissolved. The agitation was stopped and the layers
were allowed to separate. The aqueous layer was removed via pipet and the organic layer was
loaded directly onto a silica gel column and eluted using a gradient of EtOAc/hex to yield the
desired product, except Compound 30 – see below.
Compound 21 (N-(3,3,3-trifluoro-2-hydroxypropyl)benzamide)
29.4 mg collected as a white solid (40.8% over 3 steps).
1H NMR (400 MHz, CD3CN) δ ppm 7.81 - 7.90 (m, 2 H), 7.57 - 7.64 (m, 1 H), 7.46 - 7.57 (m, 2
H), 7.42 (br. s. 1 H), 4.88 (br. s. 1 H), 4.26 (br. s. 1 H), 3.78 (ddd, J=13.99, 5.97, 3.52 Hz, 1 H),
3.50 (ddd, J=13.99, 7.92, 5.87 Hz, 1 H)
13C NMR (101 MHz, CD3CN) δ ppm 168.89 (s, 1 C), 134.44 (s, 1 C), 132.31 (s, 1 C), 129.13 (s,
1 C), 127.69 (s, 1 C), 117.92 (s, 1 C), 69.52 (s, 1 C), 40.72 (s, 1 C)
HRMS (ESI) m/z [M+H]+: Calcd for C10H10F3NO2: 234.0736; Found 234.0734.
Compound 22 (methyl 3-benzamido-2-hydroxy-2-methylpropanoate)
47.4 mg collected as a light yellow oil (47.9% over 3 steps).
1H NMR (400 MHz, CDCl3) δ ppm 7.72 - 7.83 (m, 2 H), 7.49 - 7.56 (m, 1 H), 7.39 - 7.49 (m, 2
H), 6.66 (br. s. 1 H), 3.80 (s, 3 H), 2.32 - 2.53 (m, 2 H), 1.49 (s, 3 H)
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13C NMR (101 MHz, CDCl3) δ ppm 170.70 (s, 1 C), 168.17 (s, 1 C), 134.07 (s, 1 C), 131.73 (s, 1
C), 128.60 (s, 1 C), 127.04 (s, 1 C), 53.20 (s, 1 C), 47.64 (s, 1 C), 30.86 (s, 1 C), 23.62 (s, 1 C)
HMRS (ESI) m/z [M+H]+: Calcd for C12H15NO4: 238.0174; Found 238.1067
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Compound 23 (ethyl 3-benzamido-2-hydroxypropanoate)15
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45.0 mg collected as a white solid (45.0% over 3 steps).
1H NMR (400 MHz, CDCl3) δ ppm 7.73 - 7.88 (m, 2 H), 7.51 - 7.59 (m, 1 H), 7.39 - 7.51 (m, 2
H), 6.67 (br. s., 1 H), 4.41 (dd, J=5.48, 3.91 Hz, 1 H), 4.29 (q, J=7.30 Hz, 2 H), 3.76 - 3.95 (m, 2
H), 1.32 (t, J=7.04 Hz, 3 H)
LRMS (m/z) [M+H]+: Found for C12H15NO4: 238.1
Compound 24 (N-(2-hydroxy-3-methoxypropyl)benzamide)
28.6 mg collected as a white solid (34.2% over 3 steps).
1H NMR (400 MHz, CDCl3) δ ppm 7.69 - 7.79 (m, 2 H), 7.43 - 7.51 (m, 1 H), 7.31 - 7.43 (m, 2
H), 6.67 (br. s. 1 H), 3.86 - 4.01 (m, 1 H), 3.67 (ddd, J=14.09, 6.26, 3.52 Hz, 1 H), 3.37 - 3.49
(m, 2 H), 3.26 - 3.37 (m, 4 H)
13C NMR (101 MHz, CDCl3) δ ppm 168.38 (s, 1 C), 134.17 (s, 1 C), 131.66 (s, 1 C), 128.61 (s, 1
C), 127.00 (s, 1 C), 69.66 (s, 1 C), 59.27 (s, 1 C), 43.01 (s, 1 C)
HMRS (ESI) m/z [M+H]+: Calcd for C11H15NO3: 210.1125; Found 210.1123
Compound 25 (N-(2-hydroxy-2-phenylethyl)benzamide)16
13.2 mg collected as a white solid (13.9% over 3 steps).
1H NMR (400 MHz, CDCl3) δ ppm 7.79 - 7.90 (m, 2 H), 7.51 - 7.60 (m, 1 H), 7.44 - 7.51 (m, 2
H), 7.37 - 7.44 (m, 3 H), 7.31 - 7.37 (m, 1 H), 6.87 (b, 1H), 5.25 - 5.41 (m, 1 H), 4.05 (br. s. 2
H)
LRMS (m/z) [M+H]+: Found for C15H15NO2: 242.2
Compound 26 (N-(2-hydroxybutyl)benzamide)16
63.9 mg collected as a white solid (73.0% over 3 steps).
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1H NMR (400 MHz, CDCl3) δ ppm 7.75 - 7.86 (m, 2 H), 7.49 - 7.58 (m, 1 H), 7.35 - 7.49 (m, 2
H), 6.76 (br. s. 1 H), 3.64 - 3.85 (m, 2 H), 3.23 - 3.41 (m, 1 H), 1.45 - 1.65 (m, 2 H), 0.91 - 1.08
(m, 3 H)
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LRMS (m/z) [M+H]+: Found for C11H15NO2: 194.1
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Compound 27 (N-(2,3-dihydroxypropyl)benzamide)17
3.2 mg collected as a white solid (4.5% over 3 steps).
1H NMR (400 MHz, CDCl3) δ ppm 7.75 - 7.88 (m, 2 H), 7.52 - 7.61 (m, 1 H), 7.41 - 7.52 (m, 2
H), 7.41 - 7.52 (m, 2 H), 6.65 (br. s. 1 H), 3.92 (d, J=4.70 Hz, 1 H), 3.56 - 3.79 (m, 3 H), 2.96
(br. s. 2 H)
LRMS (m/z) [M+H]+: Found for C10H13NO3: 196.0
Compound 28 (N-(2-hydroxy-3-phenylpropyl)benzamide)
79.1 mg collected as a white solid (79.0% over 3 steps)
1H NMR (400 MHz, CDCl3) δ ppm 7.63 - 7.77 (m, 2 H), 7.40 - 7.49 (m, 1 H), 7.33 - 7.40 (m, 2
H), 7.23 - 7.33 (m, 2 H), 7.12 - 7.22 (m, 3 H), 6.51 (br. s. 1 H), 3.96 - 4.08 (m, 1 H), 3.65 - 3.82
(m, 1 H), 3.33 (ddd, J=13.99, 7.73, 4.89 Hz, 1 H), 2.83 (dd, J=13.69, 5.48 Hz, 1 H), 2.73 (dd,
J=13.69, 8.22 Hz, 1 H)
13C NMR (101 MHz, CDCl3) δ ppm 168.37 (s, 1 C), 137.55 (s, 1 C), 131.63 (s, 1 C), 129.40 (s, 1
C), 128.76 (s, 1 C), 128.60 (s, 1 C), 127.00 (s, 1 C), 126.76 (s, 1 C), 60.44 (s, 1 C), 45.45 (s, 1
C), 41.63 (s, 1 C)
HMRS (ESI) m/z [M+H]+: Calcd for C16H17NO2: 256.1332; Found 256.1328
Compound 29 (N-(2-hydroxy-3-phenoxypropyl)benzamide)
61.2 mg collected as a white solid (50.3% over 3 steps).
1H NMR (400 MHz, CDCl3) δ ppm 7.76 - 7.89 (m, 2 H), 7.53 - 7.59 (m, 1 H), 7.42 - 7.53 (m, 2
H), 7.26 - 7.37 (m, 2 H), 7.00 (tt, J=7.34, 1.08 Hz, 1 H), 6.89 - 6.97 (m, 2 H), 6.74 (br. s. 1 H),
4.20 - 4.35 (m, 1 H), 4.04 (qd, J=9.19, 5.67 Hz, 2 H), 3.79 - 3.95 (m, 1 H), 3.66 (ddd, J=14.09,
6.65, 5.48 Hz, 1 H)
13C NMR (101 MHz, CDCl3) δ ppm 168.91 (s, 1 C), 158.28 (s, 1 C), 133.90 (s, 1 C), 131.85 (s, 1
C), 129.63 (s, 1 C), 128.70 (s, 1 C), 127.04 (s, 1 C), 121.38 (s, 1 C), 114.52 (s, 1 C), 69.85 (s, 1
C), 69.39 (s, 1 C), 43.18 (s, 1 C)
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HMRS (ESI) m/z [M+H]+: Calcd for C16H17NO3: 272.1281; Found 272.1276
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Compound 30 (racemic N-((1S,2R)-2-hydroxy-1,2-diphenylethyl)benzamide)
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32.3 mg collected as a white solid (precipitated out of solution, 54.4% over 3 steps).
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1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (d, J=9.39 Hz, 1 H), 7.58 - 7.69 (m, 2 H), 7.33 -
7.52 (m, 6 H), 7.23 - 7.33 (m, 4 H), 7.12 - 7.23 (m, 2 H), 5.48 (d, J=5.48 Hz, 1 H), 5.12 (t,
J=9.00 Hz, 1 H), 4.92 (dd, J=8.41, 5.28 Hz, 1 H)
13C NMR (101 MHz, DMSO-d6) δ ppm 165.68 (s, 1 C), 144.15 (s, 1 C), 141.91 (s, 1 C), 135.07
(s, 1 C), 131.51 (s, 1 C), 128.86 (s, 1 C), 128.60 (s, 1 C), 128.10 (s, 1 C), 128.02 (s, 1 C), 127.64
(s, 1 C), 127.48 (s, 1 C), 127.37 (s, 1 C), 127.12 (s, 1 C), 75.02 (s, 1 C), 59.53 (s, 1 C)
HMRS (ESI) m/z [M+H]+: Calcd for C21H19NO2: 318.1489; Found 318.1483
Compound 31 (N-((2R,3S)-3-hydroxybutan-2-yl)benzamide)18
211 mg collected as a white solid (19.8% over 3 steps, 1.0 g of benzophenone imine charged in
Step 1)
1H NMR (400 MHz, CDCl3) δ ppm 7.76 - 7.87 (m, 2 H), 7.53 - 7.60 (m, 1 H), 7.40 - 7.53 (m, 3
H), 6.36 (br. s., 1 H), 4.26 (ddd, J=7.83, 6.85, 2.93 Hz, 1 H), 4.02 (td, J=6.06, 2.74 Hz, 1 H),
2.62 (d, J=5.48 Hz, 1 H), 1.16 - 1.33 (m, 6 H)
LRMS (m/z) [M+H]+: Found for C11H15NO2:194.0
General procedure for synthesis of sulfonamides 32-37. All reagent charges based on 1 equiv
of benzophenone imine charged in Step 1 (100 mg unless otherwise noted).
Step 1: To a vial containing a magnetic stirbar were charged the following materials in this
order: CH3CN (0.5 mL, 5 vol), benzophenone imine (100 mg, 1 equiv), epoxide (1 equiv), BHT
(48.6 mg, 40 mol %), and Y(OTf)3 (29.6 mg, 10 mol %). Note – BHT may be omitted if Step 1
o
will not be assayed. The reaction vial was capped and placed in a heating block set for 60 C.
The reaction mixture was stirred for 2 hours.
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Step 2: The reaction mixture was allowed to cool to room. 1 M HCl (0.550 mL) and EtOAc
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(0.5 mL, 5 vol) were charged, and the biphasic mixture stirred vigorously for 30 min at 60 C,
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ensuring the mixture is acidic to litmus (pH < 4). The mixture was then allowed to cool to room
temperature, the layers were separated using a separatory funnel, and the aqueous layer
transferred to a vial containing a magnetic stirbar.
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Step 3: The aqueous layer was charged with either 2 M NaOH or Hunig’s base until basic to
litmus (usually 1 equiv based on benzophenone imine charge in Step 1) and 2-MeTHF (0.5 mL,
5 vol). To the resultant white slurry was charged sulfonyl chloride (0.75 equiv based on
benzophenone imine charge in Step 1) and the mixture was stirred vigorously for 1-2 h @ 20-25
oC, at which point most of the solids have dissolved. The agitation was stopped and the layers
allowed to separate. The aqueous layer was removed via pipet and the organic layer was loaded
directly onto a silica gel column and eluted using a gradient of EtOAc/hex to yield the desired
product.
Compound 32 (2-chloro-N-(2-hydroxybutyl)pyridine-3-sulfonamide)19
828 mg collected as a clear oil (28.0% over 3 steps, 2 g of benzophenone imine charged in Step
1).
1H NMR (400 MHz, CDCl3) δ ppm 8.60 (dd, J=4.70, 1.96 Hz, 1 H), 8.43 (dd, J=7.82, 1.56 Hz, 1
H), 7.47 (dd, J=7.63, 4.89 Hz, 1 H), 5.68 (br. s. 1 H), 3.59 - 3.74 (m, 1 H), 3.15 (ddd, J=12.91,
7.04, 3.13 Hz, 1 H), 2.85 (ddd, J=12.91, 8.02, 4.89 Hz, 1 H), 2.03 (d, J=3.91 Hz, 1 H), 1.41 -
1.55 (m, 2 H), 0.93 (t, J=7.43 Hz, 3 H)
LRMS (m/z) [M+H]+: Found for C9H13ClN2O3S: 265.1
Compound 33 (N-(2-hydroxy-3-phenylpropyl)benzenesulfonamide)
49 mg collected as a white solid (32.2% over 3 steps)
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1H NMR (400 MHz, CDCl3) δ ppm 7.81 - 7.93 (m, 2 H), 7.60 - 7.68 (m, 1 H), 7.49 - 7.60 (m, 2
H), 7.30 - 7.39 (m, 2 H), 7.21 - 7.30 (m, 1 H), 7.10 - 7.21 (m, 2 H), 4.87 - 5.05 (m, 1 H), 3.95
(dd, J=7.63, 3.33 Hz, 1 H), 3.20 (ddd, J=12.91, 7.43, 3.13 Hz, 1 H), 2.92 (ddd, J=12.72, 7.63,
5.09 Hz, 1 H), 2.81 (dd, J=13.69, 4.70 Hz, 1 H), 2.70 (dd, J=13.69, 8.61 Hz, 1 H),1.97 (d, J=3.52
Hz, 1 H)
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13C NMR (101 MHz, CDCl3) δ ppm 136.90 (s, 1 C), 132.79 (s, 1 C), 129.32 (s, 1 C), 129.22 (s, 1
C), 128.84 (s, 1 C), 127.06 (s, 1 C), 126.95 (s, 1 C), 71.23 (s, 1 C), 47.98 (s, 1 C), 41.14 (s, 1 C)
HMRS (ESI) m/z [M+H]+: Calcd for C15H17NO3S: 292.1002; Found 292.0998
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Compound 34 (N-(2-hydroxy-3-phenylpropyl)-4-methylbenzenesulfonamide)20
6.6 g collected as a white solid (41.0% over 3 steps, 10 g benzophenone imine charged in Step 1)
1H NMR (400 MHz, CDCl3) δ ppm 7.70 - 7.80 (m, 2 H), 7.31 - 7.39 (m, 3 H), 7.22 - 7.31 (m, 2
H), 7.11 - 7.21 (m, 2 H), 4.90 (br. s. 1 H), 3.86 - 4.00 (m, 1 H), 3.09 - 3.24 (m, 1 H), 2.85 - 2.97
(m, 1 H), 2.80 (dd, J=13.69, 4.70 Hz, 1 H), 2.70 (dd, J=13.69, 8.61 Hz, 1 H), 2.46 (s, 3 H)
LRMS (m/z) [M+H]+: Found for C16H19NO3S: 306.2
Compound 35 (N-(2-hydroxy-3-phenylpropyl)-1-phenylmethanesulfonamide)
74 mg collected as a white solid (18.5% over 3 steps)
1H NMR (400 MHz, CDCl3) δ ppm 7.29 - 7.39 (m, 4 H), 7.22 - 7.29 (m, 2 H), 7.13 - 7.22 (m, 2
H), 7.02 - 7.13 (m, 2 H), 4.62 (br. s. 1 H), 4.21 (s, 2 H), 3.71 - 3.86 (m, 1 H), 3.02 (dd, J=7.04,
3.13 Hz, 1 H), 2.87 (dd, J=8.02, 4.89 Hz, 1 H), 2.67 (dd, J=13.69, 4.70 Hz, 1 H), 2.58 (dd,
J=13.69, 8.61 Hz, 1 H)
13C NMR (101 MHz, CDCl3) δ ppm 136.92 (s, 1 C), 130.67 (s, 1 C), 129.33 (s, 1 C), 129.25 (s, 1
C), 128.89 (s, 1 C), 128.84 (s, 1 C), 126.95 (s, 1 C), 71.76 (s, 1 C), 58.99 (s, 1 C), 48.56 (s, 1 C),
41.03 (s, 1 C)
HMRS (ESI) m/z [M+H]+: Calcd for C16H19NO3S: 306.1158; Found 306.1152
Compound 36 (5-chloro-N-(2-hydroxy-3-phenylpropyl)thiophene-2-sulfonamide)
155 mg collected as a white solid (35.7% over 3 steps)
1H NMR (400 MHz, CDCl3) δ ppm 7.30 (d, J=3.91 Hz, 1 H), 7.23 - 7.28 (m, 2 H), 7.14 - 7.23
(m, 1 H), 7.05 - 7.14 (m, 2 H), 6.85 (d, J=3.91 Hz, 1 H), 5.13 (br. s.1 H), 3.78 - 3.98 (m, 1 H),
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3.09 - 3.24 (m, 1 H), 2.92 (dd, J=8.22, 3.91 Hz, 1 H), 2.74 (dd, J=13.69, 5.09 Hz, 1 H), 2.63 (dd,
J=13.69, 8.22 Hz, 1 H)
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13C NMR (101 MHz, CDCl3) δ ppm 137.38 (s, 1 C), 136.71 (s, 1 C), 131.61 (s, 1 C), 129.33 (s, 1
C), 128.90 (s, 1 C), 127.06 (s, 1 C), 126.84 (s, 1 C), 71.11 (s, 1 C), 48.13 (s, 1 C), 41.18 (s, 1 C)
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HMRS (ESI) m/z [M+H]+: Calcd for C13H14ClNO3S2: 332.0176; Found 332.0173
Compound 37 (N-(2-hydroxy-3-phenylpropyl)methanesulfonamide)
53 mg collected as a white solid (17.6% over 3 steps)
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1H NMR (400 MHz, CDCl3) δ ppm 7.31 - 7.39 (m, 2 H), 7.17 - 7.31 (m, 3 H), 5.17 (br. s. 1 H),
3.92 - 4.05 (m, 1 H), 3.25 - 3.39 (m, 1 H), 3.02 - 3.15 (m, 1 H), 2.91 - 3.02 (m, 3 H), 2.69 - 2.88
(m, 2 H)
13C NMR (101 MHz, CDCl3) δ ppm 133.26 (s, 1 C), 129.78 (s, 1 C), 129.35 (s, 1 C), 128.90 (s, 1
C), 71.55 (s, 1 C), 48.11 (s, 1 C), 41.18 (s, 1 C), 40.38 (s, 1 C)
HMRS (ESI) m/z [M+H]+: Calcd for C10H15NO3S: 230.0845; Found 230.0844
ASSOCIATED CONTENT
Supporting Information. Table of Lewis acid screening data, solution yield determinations, and
characterization data for all isolated compounds. This material is available free of charge via the
internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* john-jin.x.lim@gsk.com.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
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The authors thank Qunying Dai and Dr. Kelsey VanGelder for their assistance in high-
throughput screening, Kavitha Jakka for analytical method development, and Mike Morris and
David Thornton for HRMS determination.
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