Generation and hydrolysis of N-acyloxazolinium salts allowing regiospecific acylation of chiral amino alcohols

Article abstract of DOI:10.1007/s10593-020-02707-3

[Figure not available: see fulltext.] In an attempt to form 2-alkylidene-1,3-oxazolidines, chiral 2-oxazolines have been N-alkylated and N-acylated. Two new N-methyloxazolinium salts have been prepared and characterized, but alkaline treatment resulted in

Full text of DOI:10.1007/s10593-020-02707-3

DOI 10.1007/s10593-020-02707-3
Chemistry of Heterocyclic Compounds 2020, 56(5), 611–614
Generation and hydrolysis of N-acyloxazolinium salts
allowing regiospecific acylation of chiral amino alcohols
R. Alan Aitken1*, Alexandra M. Z. Slawin1, Andrew Wilson1
1 EaStCHEM School of Chemistry, University of St Andrews,
North Haugh, St Andrews, Fife, KY16 9ST, United Kingdom;
e-mail: raa@st-and.ac.uk
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(5), 611–614
Submitted March 4, 2020
Accepted after revision April 27, 2020
In an attempt to form 2-alkylidene-1,3-oxazolidines, chiral 2-oxazolines have been N-alkylated and N-acylated. Two new N-methyl-
oxazolinium salts have been prepared and characterized, but alkaline treatment resulted in their decomposition. In contrast, attempts to
isolate three N-benzoyloxazolinium salts gave the products of their ring hydrolysis: unsymmetrically diacylated amino alcohols whose
structure was confirmed by X-ray diffraction in one case. Overall the method allows stepwise regiospecific N,O-diacylation of 2-amino
alcohols.
Keywords: amino alcohols, oxazolines, oxazolinium salts, acylation, hydrolysis.
We recently reported that the thermal isomerization of
2-benzylidene-1,3-dioxolane (1) to give γ-lactone 2
(Scheme 1), which was previously carried out by gas-phase
flow pyrolysis at atmospheric pressure,1 could be achieved
more efficiently using conditions of flash vacuum pyrolysis
(FVP).2 In the same paper, 1,3-oxathiolane derivatives
including the sulfone analog of dioxalane 1 were also
examined but in these cases the pyrolysis took a different
course.2 We were interested to examine the nitrogen
analogs 3 since, if these reacted in the same way as
dioxolane 1, they would give the more useful γ-lactams 4
with the added advantage that a stereogenic center at
position 4 in the starting oxazolidines would likely appear
with retention of configuration at C-5 atom in the product
and induce stereoselectivity at the newly formed C-3 center.
We envisaged that the required 2-alkylideneoxazolidines
7 could be prepared starting from the readily available
oxazolines 5 by N-alkylation to give salts 6 followed by
base treatment (Scheme 2). Literature precedent for this is
provided by sodium hydride treatment of 2,3,4,4-tetra-
methyloxazolinium iodide to give the 2-methylidene com-
pound,3 although it was noted to be extremely susceptible
to acid-catalyzed hydrolysis, a feature also observed for
similar N-methyloxazolinium salts in an earlier study.4
Scheme 2
Scheme 1
We started by converting two readily available chiral
oxazolines 5a and 5b, prepared by reaction of ethyl
acetimidate hydrochloride with (S)-phenylalaninol and
(S)-valinol, respectively,5 into the corresponding N-methyl-
oxazolinium salts 6a and 6b. Treatment with MeI in THF
at room temperature in the dark gave the required salts in
0009-3122/20/56(5)-0611©2020 Springer Science+Business Media, LLC
611

Chemistry of Heterocyclic Compounds 2020, 56(5), 611–614
Scheme 5
low to moderate yield as colorless crystals (Scheme 3). It was
noticeable that the more sterically hindered compound 5b
reacted more slowly to give a lower yield of salt 6b than
oxazoline 5a. These gave the expected HRMS and spectro-
scopic properties including significant movement to higher
chemical shift in the 1H NMR signals for the ring
hydrogens and 2-methyl group as compared to the starting
oxazolines. In the 13C NMR spectra, the most prominent
change was an increase in the chemical shift for the C-2
carbon from 164 ppm for oxazolines 5 to 176 ppm for
compounds 6.
1. PhCOCl, Et3N
PhMe, 3 h
O
Ph
NH
Bn
Bn
O
O
2. Separation (H2O)
N
H
Me
Me
Me
Me
O
O
31%
O
5a
H
8a
1. PhCOCl, PhMe, 3 h
2. Separation (H2O)
O
Ph
NH
i-Pr
i-Pr
H
N
7%
O
5b
H
8b
Scheme 3
1. PhCOCl, PhMe, 72 h
2. Separation (H2O)
O
Ph
NH
Bn
Bn
H
O
N
Bn
31%
Bn
O
O
5c
H
8c
recently it has been mentioned under the trivial name
"saropeptate", together with a range of steroidal components,
as a constituent of Pupalia lappacea, a plant important in
Ayurvedic medicine.11
Unfortunately, treatment of salts 6a,b with NaH in dry
THF according to the literature method for the corres-
ponding 4,4-dimethyl compounds,3 led, after addition of
petroleum and removal of the resulting precipitate of NaI,
to solutions of compounds 7 that were too reactive to
handle by usual methods and polymerized. In order to
obtain less reactive and more easily handled 2-alkylidene-
3-benzoyl-1,3-oxazolidines 7', we decided first to obtain
N-benzoyloxazolinium salts 6' (Scheme 4) since these are a
well-known class of stable compounds6 and are reported to
undergo facile deprotonation using Et3N,7 although there
are a number of possible complicating side reactions of the
2-methylidene-1,3-oxazolidines in the presence of excess
acylating agent.8
The spectra of compound 8a showed excellent
agreement with the literature data.9 It was obtained in well-
formed crystals, and this provided a chance to confirm its
structure using X-ray diffraction (Fig. 1). As might be
expected, the presence of a secondary amide function leads
to hydrogen bonding and the crystal structure shows chains
of molecules formed by hydrogen bonding between the
amide carbonyl group and amide NH group (Fig. 2).
Having established that hydrolysis of the N-benzoyl-
oxazolidinium salts rather than any base-induced process
was involved in the formation of compound 8a, oxazolines
5b,c were subjected to reaction with PhCOCl in the
absence of Et3N and in each case the product recovered
after evaporation and trituration was the respective hydro-
lysis product 8b,c (Scheme 5). Both O-acetyl-N-benzoyl-
valinol (8b) and N-benzoyl-O-phenylacetylphenylalaninol (8c)
Scheme 4
Following the literature method,7 oxazoline 5a was
stirred in PhMe with 1 equiv of Et3N while 1 equiv of
PhCOCl was added dropwise. After 3 h, the solution was
filtered and evaporated to give, after trituration with Et2O
a solid that turned out to be hydrolysis product 8a
(Scheme 5).
It seems likely that the desired N-benzoyloxazolinium
salt 6' has been formed, but, rather than undergo deproto-
nation to form alkylidene compound 7', it has undergone
hydrolysis in the course of isolation to give O-acetyl-
N-benzoylphenylalaninol (8a). This compound was first
prepared and characterized spectroscopically in 1992,9 but
it was recorded in the literature some time earlier10 as a
derivative of N-benzoylphenylalaninol occurring as a
natural product in the leaves of Alangium lamarckii. More
Figure 1. Molecular structure of compound 8a with atoms repre-
sented by thermal vibration ellipsoids at the 50% probability
level.
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Chemistry of Heterocyclic Compounds 2020, 56(5), 611–614
(400 and 100 MHz, respectively), except that 13C NMR
spectra of compounds 6a and 8b were recorded on a Bruker
AVIII 500 spectrometer (125 MHz) in CDCl3; internal
standard TMS. The 13C signals were assigned with the help
of DEPTQ experiment. High-resolution mass spectra were
recorded on a Micromass LCT spectrometer with electro-
spray ionization. Melting points were determined using a
Gallenkamp 50 W melting point apparatus and are
uncorrected. THF was dried over sodium wire.
(S)-4-Benzyl-2-methyloxazoline (5a) and (S)-4-iso-
propyl-2-methyloxazoline (5b) were prepared from ethyl
acetimidate hydrochloride by respective reaction with
(S)-phenylalaninol and (S)-valinol as previously reported,5
while (S)-2,4-dibenzyloxazoline 5c was similarly pre-
pared,13 using ethyl 2-phenylacetimidate hydrochloride14
and (S)-phenylalaninol.
Figure 2. Hydrogen bonding pattern in crystal structure of com-
pound 8a viewed perpendicular to the a axis (hydrogen bond
N(2)–H(2)···O(1): bond lengths N(2)–H(2) 0.98(5) Å, H(2)···O(1)
1.94(5) Å, N(2)···O(1) 2.870(7) Å; bond angle 157(6)°).
are apparently new compounds and gave spectroscopic data
in good agreement with the proposed structures and with that
of compound 8a. 2-Benzyloxazoline 5c took much longer to
react than 2-methyloxazolines 5a,b, presumably due to the
electron-withdrawing phenyl group making it less nucleo-
philic.
Although it has clearly been arrived at by accident rather
than design, the overall formation of the selectively diacylated
amino alcohols 8a–c starting from 2-amino alcohols is a
rather useful transformation. Recent studies have proposed
various catalysts to bring about enzyme-like selectivity in
such reactions.12 In this case, the general method for
overall conversion of an amino acid-derived chiral 2-amino
alcohol into diacylated derivative 8 involves formation of
oxazoline 5 with the ultimate O-substituent at position 2,
N-acylation with the ultimate N-substituent, and hydrolytic
isolation to give product 8 (Scheme 6).
(S)-4-Benzyl-2,3-dimethyl-4,5-dihydrooxazol-3-ium
iodide (6a). A solution of oxazoline 5a (2.0 g, 11.4 mmol)
in dry THF (2.5 ml) was stirred at room temperature while
MeI (0.87 ml, 1.99 g, 14 mmol) was added, and the
resulting mixture was stirred in the dark for 15 h. The
resulting solid was filtered off and dried. Yield 1.65 g
(47%), colorless crystals, mp 176–178°C. IR spectrum, ν, cm–1:
1668, 1483, 1279, 1033, 984, 758, 704. 1H NMR spectrum,
δ, ppm (J, Hz): 2.59 (3H, s, 2-CH3); 3.20 (1H, dd, J = 14.4,
J = 7.6) and 3.35 (1H, dd, J = 14.4, J = 4.8, PhCH2); 3.51
(3H, s, 3-CH3); 4.68 (1H, dd, J = 9.0, J = 6.4, OCH2); 5.08–
5.16 (1H, m, 4-CH); 5.19 (1H, dd, J = 10.3, J = 9.0,
OCH2); 7.23–7.27 (2H, m, H Ph); 7.30–7.41 (3H, m, H Ph).
13C NMR spectrum, δ, ppm: 15.3 (2-CH3); 34.5 (3-CH3);
36.3 (PhCH2); 64.6 (4-CH); 75.4 (CH2O); 128.1 (CH Ph);
129.1 (2CH Ph); 129.4 (2CH Ph); 133.0 (C Ph); 176.7
(C-2). Found, m/z: 190.1224 [M–I]+. C12H16NO. Calcu-
lated, m/z: 190.1226.
Scheme 6
(S)-4-Isopropyl-2,3-dimethyl-4,5-dihydrooxazol-3-ium
iodide (6b). A solution of oxazoline 5b (1.40 g, 11.0 mmol)
in dry THF (2.5 ml) was stirred at room temperature while
MeI (0.87 ml, 1.99 g, 14 mmol) was added, and the
resulting mixture was stirred in the dark for 72 h. The
resulting solid was filtered off and dried. Yield 0.69 g
(23%), colorless crystals, mp 143–144°C. IR spectrum, ν, cm–1:
1675, 1483, 1276, 1039, 987, 925, 830. 1H NMR spectrum,
δ, ppm (J, Hz): 0.95 (3H, d, J = 6.9, CHCH3); 1.02 (3H, d,
J = 6.9, CHCH3); 2.28–2.37 (1H, m, CH(CH3)2); 2.65 (3H,
s, 2-CH3); 3.44 (3H, s, 3-CH3); 4.62 (1H, dd, J = 9.2,
J = 6.8, OCH2); 4.70–4.80 (1H, m, 4-CH); 5.27 (1H, dd,
J = 11.0, J = 9.2, OCH2). 13C NMR spectrum, δ, ppm: 14.9
(CHCH3); 15.1 (CHCH3); 17.9 (2-CH3); 26.5 (CH(CH3)2); 34.0
(3-CH3); 68.6 (4-CH); 72.0 (CH2O); 176.8 (C-2). Found, m/z:
142.1223 [M–I]+. C8H16NO. Calculated, m/z: 142.1226.
(S)-2-Benzoylamino-3-phenylpropyl acetate (8a). A solu-
tion of oxazoline 5a (0.35 g, 2 mmol) and Et3N (0.33 ml,
0.25 g, 2.4 mmol) in dry PhMe (60 ml) was stirred at room
temperature while PhCOCl (0.23 ml, 0.28 g, 2 mmol) was
added dropwise. After stirring for 3 h, the reaction mixture was
filtered and the filtrate was evaporated. The residue was
triturated with Et2O to give the solid product. Yield 0.18 g
(31%), colorless crystals, mp 124–126°C (mp 125–127°C9).
1H NMR spectrum, δ, ppm (J, Hz): 2.10 (3H, s, COCH3);
Thus, in contrast to N-methyloxazolinium salts which
were easily prepared and isolated, the N-benzoyl-
oxazolinium salts proved to be much more reactive and
could not be isolated as such. However, the isolation of
their hydrolysis products in low to moderate yield does
form the basis of a useful overall synthetic transformation.
Experimental
IR spectra were recorded using the ATR technique on a
1
Shimadzu IR Affinity 1S instrument. H and 13C NMR
spectra were recorded on a Bruker AV400 spectrometer
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Chemistry of Heterocyclic Compounds 2020, 56(5), 611–614
2.91 (1H, dd, J = 13.6, J = 8.0) and 3.06 (1H, dd, J = 13.6,
(CH2Ph); 41.5 (CH2Ph); 50.2 (CHN); 64.8 (CH2O); 126.8
(3CH Ph); 127.3 (CH Ph); 128.5 (2CH Ph); 128.7 (4CH Ph);
129.2 (2CH Ph); 129.3 (2CH Ph); 131.6 (CH Ph); 133.8
(C Ph); 134.1 (C Ph); 136.8 (C Ph); 166.8 (NCO); 171.7
(OCO). Found, m/z: 374.1745 [M+H]+. C24H24NO3. Calcu-
lated, m/z: 374.1751.
X-ray diffraction study of compound 8a. Data were
collected on a Rigaku XtaLAB P200 system using graphite-
monochromated CuKa radiation (λ 1.54187 Å). Crystal
data: C18H19NO3, M 297.35, colorless needles; crystal
dimensions 0.12 × 0.01 × 0.01 mm; orthorhombic, space
group P212121; a 5.0182(4), b 16.208(3), c 19.498(3) Å;
V 1585.9(4) Å3; Z 4; Dcalc 1.245 g·cm–3; T 125 K; R 0.1219;
wR 0.3082 for 1890 reflections with I > 2σ(I) and 203
variables. The complete crystallographic information on
compound 8a has been deposited at the Cambridge
Crystallographic Data Center (deposit CCDC 1861267).
J = 5.8, CH2Ph); 4.14 (1H, dd, J = 11.6, J = 3.8) and 4.23
(1H, dd, J = 11.6, J = 6.0, CH2O); 4.60–4.70 (1H, m,
CHN); 6.41 (1H, br. d, J = 8.0, NH); 7.20–7.30 (2H, m,
H Ph); 7.30–7.34 (3H, m, H Ph); 7.40–7.45 (2H, m, H Ph);
7.48–7.52 (1H, m, H Ph); 7.70–7.73 (2H, m, H Ph).
13C NMR spectrum, δ, ppm: 20.9 (CH3); 37.5 (CH2Ph);
50.3 (CHN); 64.8 (CH2O); 126.8 (3CH Ph); 128.6 (2CH Ph);
128.7 (2CH Ph); 129.3 (2CH Ph); 131.6 (CH Ph); 134.3
(C Ph); 136.9 (C Ph); 167.0 (NCO); 171.5 (OCO). Both
1H and 13C NMR spectra showed excellent agreement with
literature data.9
(S)-2-Benzoylamino-3-methylbutyl acetate (8b). A solu-
tion of oxazoline 5b (0.51 g, 4 mmol) in dry PhMe (120 ml)
was stirred at room temperature while PhCOCl (0.46 ml,
0.56 g, 4 mmol) was added dropwise. After stirring for 3 h,
the reaction mixture was evaporated and the residue was
triturated with Et2O to afford the title compound. Yield
77 mg (7%), colorless crystals, mp 74–76°C. H NMR
Supplementary information file containing 1H and
13C NMR spectra of all synthesized compounds is available
at the journal website http://link.springer.com/journal/10593.
1
spectrum, δ, ppm (J, Hz): 1.02 (6H, d, J = 6.8, CH(CH3)2);
1.95 (1H, octet, J = 6.8, CH(CH3)2); 2.06 (3H, s, COCH3); 4.15
(1H, dd, J = 11.6, J = 3.6, CH2O); 4.20–4.30 (1H, m,
CHNH); 4.39 (1H, dd, J = 11.6, J = 6.6, CH2O); 6.24 (1H,
br. d, J = 8.4, NH); 7.40–7.60 (3H, m, H Ph); 7.70–7.80
(2H, m, H Ph). 13C NMR spectrum, δ, ppm: 18.7 (CH3);
19.3 (CH3); 20.9 (COCH3); 29.8 (CH(CH3)2); 54.0 (CHN);
64.5 (CH2O); 126.8 (2CH Ph); 128.6 (2CH Ph); 131.5 (CH
Ph); 134.6 (C Ph); 167.3 (NCO); 171.4 (OCO). Found, m/z:
250.1449 [M+H]+. C14H20NO3. Calculated, m/z: 250.1438.
(S)-2-Benzoylamino-3-phenylpropyl phenylacetate (8c).
A solution of oxazoline 5c (1.50 g, 6 mmol) in dry PhMe
(80 ml) was stirred at room temperature while PhCOCl
(0.69 ml, 0.84 g, 6 mmol) was added dropwise. After
stirring for 72 h, the mixture was evaporated and the
residue was triturated with Et2O to afford the title
compound. Yield 0.73 g (31%), colorless crystals, mp 122–
123°C. IR spectrum, ν, cm–1: 3292, 1720, 1638, 1537,
1263, 1152, 1011, 694. 1H NMR spectrum, δ, ppm (J, Hz):
2.79 (1H, dd, J = 13.6, J = 8.2) and 2.96 (1H, dd, J = 13.6,
J = 5.8, CH2Ph); 3.67 (2H, s, COCH2Ph); 4.16 (1H, dd,
J = 11.2, J = 4.0) and 4.21 (1H, dd, J = 11.2, J = 5.6,
CH2O); 4.55–4.65 (1H, m, CHN); 6.19 (1H, br. d, J = 8.4,
NH); 7.15 (2H, d, J = 8.0, H Ph); 7.20–7.35 (8H, m, H Ph);
7.41 (2H, t, J = 8.0, H Ph); 7.50 (1H, t, J = 7.0, H Ph); 7.60
(2H, d, J = 7.2, H Ph). 13C NMR spectrum, δ, ppm: 37.4
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