Highly Chemoselective O-Ethylation of N-Boc Amino Alcohols Using Phase Transfer Catalysis

Article abstract of DOI:10.1021/op500242k

A practical, highly selective O-ethylation method of N-Boc amino alcohols under phase-transfer catalyzed conditions is described. The O-ethylation was accomplished in heptanes or toluene using 50% aqueous sodium hydroxide as the base in the presence of a phase-transfer catalyst, tetrabutylammonium chloride. This method exclusively afforded the O-ethylated products in good yields.

Full text of DOI:10.1021/op500242k

Communication
pubs.acs.org/OPRD
Highly Chemoselective O‑Ethylation of N‑Boc Amino Alcohols Using
Phase Transfer Catalysis
Yugang Liu,* Lech Ciszewski, Lichun Shen, and Mahavir Prashad
Chemical and Analytical Development, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936,
United States
Scheme 1
ABSTRACT: A practical, highly selective O-ethylation
method of N-Boc amino alcohols under phase-transfer
catalyzed conditions is described. The O-ethylation was
accomplished in heptanes or toluene using 50% aqueous
sodium hydroxide as the base in the presence of a phase-
transfer catalyst, tetrabutylammonium chloride. This method
exclusively afforded the O-ethylated products in good yields.
INTRODUCTION
■
Etherification is one of the basic transformations in organic
chemistry. In spite of the many advances in organic chemistry
since the discovery of the Williamson reaction, it is still the
best general method for the preparation of unsymmetrical or
symmetrical ethers.1 In our effort to synthesize an active pharma-
ceutical ingredient, we needed to prepare the ethyl ether of
N-Boc-D-leucinol (1). The traditional method involving
deprotonation of the hydroxyl group using sodium hydride
followed by reaction with diethyl sulfate gave a mixture of
O-ethylated 1a and N,O-diethylated 1b products with poor
selectivity, apparently due to the insufficient difference of the pKa
between the NH and the OH groups in the presence of a strong
base (Scheme 1). Reactions with poor selectivity pose significant
challenges in scale-up due to the fact that isolation of the desired
isomer is not always straightforward, especially when the desired
isomer is an oil which often has to be purified by column
chromatography. It is of great interest that a highly selective
method is used in such cases to provide crude product with
sufficient purity, so that it can be carried directly to the next step
without further purification. Quite surprisingly, methods for
highly selective ethylation of N-Boc protected amino alcohols
do not exist in the literature, even though poorly selective
O-alkylation of unprotected amino alcohol was known.2 In this
communication, we wish to report a highly chemoselective
O-ethylation of N-Boc amino alcohols under phase-transfer
catalysis.
Scheme 2
We investigated the ethylation of N-Boc-D-leucinol (1) in
heptanes using 50% aqueous NaOH as the base and diethyl
sulfate as the alkylating agent in the presence of 1.5 mol % of
tetrabutylammonium chloride (TBAC). Under these PTC con-
ditions, the desired isomer 1a was formed exclusively, and the
isolated yield was 70−75%. These new conditions (method A)
are far superior when compared with the reaction using NaH in
DMF (method B), where a mixture of O-ethylated isomers 1a
and bisethylated product 1b was formed in a weight ratio of
65/35. To test the scope of this O-ethylation method under
PTC, a variety of N-Boc amino alcohols were subjected to these
conditions, which involved the addition of Et2SO4 to a biphasic
mixture of substrate solution heptanes or toluene and 50%
NaOH solution, in the presence of TBAC. The selection of
heptanes or toluene as the solvent was based on the solubility of
the substrate in each solvent and did not affect the outcome of
the ethylation reaction (Scheme 2).
RESULTS AND DISCUSSION
■
Variants of the Williamson reaction using phase-transfer catalysis
(PTC) have also been known for decades, including conditions
that allow selective formation of mono ether from diols or triols.3
In continuation of our interest in the application of PTC in the
pharmaceutical industry,4 and due to the fact that poor selec-
tivity was observed above with NaH/DMF conditions which also
posed significant safety hazard,5 we reasoned that under PTC
conditions the reactivity difference of the hydroxyl group and
the BocNH group might be sufficient enough to allow pref-
erential deprotonation of the hydroxyl group for its ethylation.
Received: July 24, 2014
Published: August 21, 2014
© 2014 American Chemical Society
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Communication
d
Table 1. Comparison of O-ethylation of N-Boc amino alcohols using methods A and B
a
b
Isolated yield; a/b for Method A was 100/0 in all cases, ratio determination methods are described in footnotes b and c. Weight ratio of isolated
c
d
products obtained from silica gel chromatography (heptanes/ethyl acetate, 4:1 to 2:1). Ratio of peak areas in HPLC at 254 nm. Conditions:
Method A: 3.75 mmol of Et2SO4 was added to a mixture of 2.5 mmol of substrate, 0.0375 mmol of TBAC, 3 mL of heptanes, and 6.5 mmol of
NaOH (50 wt % aq. solution) at 20 °C; Method B: 3.75 mmol of NaH (60 wt % in mineral oil) was added to the solution of 2.5 mmol of substrate
in 3 mL of anhydrous DMF at 0 °C followed by the addition of 3.75 mmol of Et2SO4. The reaction was allowed to warm to 20 °C.
In all cases using the PTC conditions, the selectivity was
complete for the desired ethyl ether. The experimental results are
summarized in Table 1 (for comparison, results using method B
are also included). Ethylation of N-Boc amino alcohols 2−8
using method A gave exclusively O-ethylated compound 2a−8a
in 70−90% yield, whereas a mixture of O-ethylated and
bisethylated products were obtained in the weight ratios as
indicated in Table 1 when method B was used.6 Either heptanes
or toluene could be used as the solvent without any impact on the
selectivity. Safety tests of the reaction mixture of the PTC pro-
cedure did not show much appreciable exotherm below 150 °C.
The ethylation of N-Boc-D-leucinol (1) using method A was
scaled up to 53.8 kg in one batch, affording the desired
O-ethylated product in 75% yield, same as obtained in the lab.
As one example of a methylation, the methylation of N-Boc-D-
α-phenylglycinol (7) was successfully carried out with dimethyl
sulfate using method A, and the reaction again produced only the
O-methylated product in 85% isolated yield.
Interestingly, when we tried to expend the scope of the
reaction using activated alkyl halides such as benzyl chloride, we
observed the formation of a mixture of products.
In summary, we demonstrated that the selective O-ethylation
of a wide range of N-Boc amino alcohols was effectively accomplished
in heptanes or toluene using aqueous solution of NaOH in the
presence of a phase-transfer catalyst and scaled the preparation of
one compound to 54 kg.
EXPERIMENTAL SECTION
■
1
The crude product was sufficiently pure based on H NMR
(R)-tert-Butyl-(1-ethoxy-4-methylpentan-2-yl)carbamate
(1a). To a mixture of N-Boc-D-leucinol (1, 53.80 kg, 247.50 mol)
and tetrabutylammonium chloride (1.03 kg, 3.71 mol) in heptanes
(300 L) and 50% aq NaOH (51.4 kg, 643 mol) was added Et2SO4
(57.2 kg, 371.20 mol) over a period of 1 h while maintaining the
internal temperature at 20−35 °C. The mixture was cooled to 20 °C
over 30 min and stirred at this temperature for 14 h until TLC
analysis. It was hydrolyzed directly using 6 N HCl in isopropanol
to give the HCl salt of O-ethyl-D-leucinol as a crystalline material
which was isolated by filtration in 99% yield. The purity assay of
the HCl salt was 98.7% based on quantitative 1H NMR analysis.
For lab scale reactions, the products were isolated by silica gel
column purifications. The product purities ranged from 97 to 99%.
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(heptanes−EtOAc = 2:1) indicated completion of the reaction.
Aqueous NH4OH solution (29 wt %, 19 L) was added, and the
reaction mixture was stirred at 20−25 °C for 16 h. The organic
layer was separated and washed with water (2 × 75 L). It was
then concentrated under reduced pressure (90−30 mmHg) at
35−40 °C to afford 1a in heptanes (∼150 L, contains 45.6 kg of
pure 2a, 75% yield) which was used directly in the next step.
Analytical data of a purified sample were consistent with those
reported in the literature.6
AUTHOR INFORMATION
Corresponding Author
*E-mail: yugang.liu@novartis.com.
■
Notes
The authors declare no competing financial interest.
REFERENCES
■
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