An improved process for the synthesis and isolation of (S)-N-(1- phenylettiyl)hydroxylamine

Article abstract of DOI:10.1021/op800230f

A three-step, single-solvent telescoped process amenable to the large-scale manufacture of (S)-N-(1-phenylethyl)hydroxylamine p-toluenesulfonic acid salt is reported. This synthetic protocol has been applied to the preparation of other chiral hydroxylamin

Full text of DOI:10.1021/op800230f

Organic Process Research & Development 2009, 13, 49–53
An Improved Process for the Synthesis and Isolation of
(S)-N-(1-Phenylethyl)hydroxylamine
Ian Patel, Neil A. Smith,* and Simon N. G. Tyler
AstraZeneca, Global Process R&D, AVlon Works, SeVern Road, Hallen, Bristol BS10 7ZE, U.K.
Scheme 1. Oxaziridine route to hydroxylamines
Abstract:
A three-step, single-solvent telescoped process amenable to the
large-scale manufacture of (S)-N-(1-phenylethyl)hydroxylamine
p-toluenesulfonic acid salt is reported. This synthetic protocol has
been applied to the preparation of other chiral hydroxylamines.
Introduction
The ability to access hydroxylamines continues to be
important,1 and the literature suggests several approaches to their
synthesis. The most straightforward, in principle, is the partial
oxidation of a primary amine, which has been best achieved
using Oxone on a silica or alumina support2 or with dimeth-
yldioxirane.3 The use of dibenzoyl peroxide has been reported
for the oxidation of primary4 and secondary5 amines, although
the reaction with primary amines also gives appreciable amounts
of the N-benzoylated derivative. A complementary approach
is the partial reduction of a nitro compound, such as the zinc-
mediated reduction of 2-methyl-2-nitropropane.6
An alternative strategy, designed to overcome the limitation
of over-reaction often encountered with more direct methods,
is to carry out a stepwise process. For example, the oxidation
of an imine to an oxaziridine may be carried out, whereupon
acid-catalyzed hydrolysis, sometimes Via isomerization to the
nitrone, then affords a hydroxylamine.7 A complication is that
where the carbon substituent on the oxaziridine ring is an alkyl,
rather than an aryl, group rearrangement to the amide product
is preferred.8 On the other hand, the oxidation of secondary
amines to nitrones has been effected using hydrogen pero-
xide-urea complex in the presence of sodium tungstate.9 These
reactions have largely been performed on symmetrical amines
where the regioselectivity of nitrone formation is not an issue,
although more recently non-symmetrical nitrones have been
prepared by this method.10
hydroxylamine, (S)-N-(1-phenylethyl)hydroxylamine. This ma-
terial would be required in multikilogram quantities, but despite
the interest in the synthesis of hydroxylamines, a viable, scalable
process still seems to be absent from the literature.11 The direct
oxidation of a primary amine appears impractical on a large
scale and is certainly not atom economical if it ultimately
requires the use of Oxone.12 The feasibility of the indirect
methods to furnish such a hydroxylamine, or more likely a salt
thereof, was thus explored, bearing in mind the necessity to
ensure chiral integrity and chemical stability.
Wovkulich has previously published a method for the
synthesis of our desired hydroxylamine and its isolation as the
oxalic acid salt.13 Starting from (S)-1-phenylethylamine (1a),
p-anisaldimine (2a) was prepared and oxidized to oxaziridine
(3a) with m-CPBA. Finally, cleavage with hydroxylamine
hydrochloride before treatment with oxalic acid furnished the
corresponding salt 4a in 69% overall yield (Scheme 1).
Presumably, salt formation protects the somewhat oxidation-
sensitive free base and allows for the isolation of a stable solid.
As part of our investigations into the synthesis of candidate
drug molecules for the treatment of osteoarthritis, one promising
strategy invoked the use of an enantiomerically pure chiral
Results and Discussion
We investigated this methodology and found that it worked
smoothly in our hands. Extending the scope to other electroni-
cally neutral substrates, such as (S)-1-(naphthalen-1-yl)ethy-
lamine (1b) and (S)-1-(naphthalen-2-yl)ethylamine (1c), gave
the requisite hydroxylamine products in 53% and 47% yields,
respectively. However, when an electron-rich substrate, (S)-1-
* Author for correspondence. E-mail: Neil.Smith1@astrazeneca.com.
(1) For a recent summary, see: Walz, A. J.; Mo¨llmann, U.; Miller, M. J.
Org. Biomol. Chem. 2007, 5, 1621.
(2) Fields, J. D.; Kropp, P. J. J. Org. Chem. 2000, 65, 5937.
(3) Wittman, M. D.; Halcomb, R. L.; Danishefsky, S. J. J. Org. Chem.
1990, 55, 1981.
(4) Milewska, M. J.; Chimiak, A. Synthesis 1990, 233.
(5) Biloski, A. J.; Ganem, B. Synthesis 1983, 537.
(6) Zhang, Y.; Xu, G. Z. Naturforsch., B: Chem. Sci. 1989, 44, 1475.
(7) For an early example, see: Połon´ski, T.; Chimiak, A. Tetrahedron Lett.
1974, 28, 2453.
(11) For the description of a large-scale preparation of a nitrone Via the
oxidation of a secondary amine with m-CPBA, see: Stappers, F.;
Broeckx, R.; Leurs, S.; Van Den Bergh, L.; Agten, J.; Lambrechts,
A.; Van den Heuvel, D.; De Smaele, D. Org. Process. Res. DeV. 2002,
6, 911. It is interesting to note that this oxidation presumably goes
Via the intermediacy of a hydroxylamine.
(8) Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703.
(9) Heydari, A.; Aslanzadeh, S. AdV. Synth. Catal. 2005, 347, 1223.
(10) Cos¸kun, N.; Parlar, A. Synth. Commun. 2005, 35, 2445.
(12) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847.
(13) Wovkulich, P. M.; Uskokovicˇ, M. R. Tetrahedron 1985, 41, 3455.
10.1021/op800230f CCC: $40.75
Published on Web 12/03/2008
2009 American Chemical Society
Vol. 13, No. 1, 2009 / Organic Process Research & Development
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Scheme 2. Nitrone route to hydroxylamines
Scheme 3. Optimized route to
(S)-N-(1-phenylethyl)hydroxylamine
(4-methoxyphenyl)ethylamine (1d), was employed, the reaction
sequence failed to afford the desired product, resulting instead
in a number of unidentified degradants.
The alkylation reaction was originally carried out in aceto-
nitrile that was then evaporated in Vacuo and the residue
partitioned between saturated aq sodium bicarbonate, brine, and
chloroform. Changing to EtOAc meant that an aqueous work-
up could readily be performed without the need to swap
solvents. Whilst the reaction could in fact be carried out in a
biphasic mixture with saturated aq sodium bicarbonate, the
losses to the aqueous phase were significant due to the water
solubility of both the starting material and the secondary amine
product 5a. Incorporating just a small water wash of the EtOAc
solution post-reaction in order to dissolve the precipitated
Hu¨nig’s base hydrobromide proved effective in minimizing
losses.
The oxidation step with m-CPBA was formerly carried out
in methylene chloride. This has the advantage that the by-
product m-chlorobenzoic acid, m-CBA, is completely insoluble
in this solvent and can easily be removed by filtration. Changing
the reaction solvent to EtOAc had the disadvantage of increased
solubility of m-CBA. Consequently, m-CBA was therefore
removed in our modified process by washing with saturated aq
sodium bicarbonate. Using a stronger base, e.g. aq sodium
hydroxide, resulted in coloration of the organic phase due to
degradation of the intermediate nitrone 6a. It was found to be
imperative to remove all residual m-CBA as it interfered with
the crystallization of the hydroxylamine salt in the final step.
Any excess oxidant in the organic phase, as detected by starch/
iodide paper, was also removed into the basic aqueous phase,
which could then be treated with saturated aq sodium meta-
bisulfite as required prior to disposal.
Later work by Fukuyama also described the synthesis of our
desired compound (Scheme 2),14,15 again starting from (S)-1-
phenylethylamine (1a). Alkylation with bromoacetonitrile fur-
nished secondary amine 5a, to be used as the substrate for the
oxidation step. Crucially, the nitrile group controlled the
regioselectivity of the formation of nitrone 6a and mitigated
against racemization. Subsequent aminolysis using hydroxy-
lamine hydrochloride at elevated temperatures was required to
liberate the requisite chiral hydroxylamine, isolated again as
the oxalic acid salt 4a. Clearly, some of the problems evident
from other syntheses were addressed in this approach, and we
felt that it was a suitable starting point from which to develop
a process for large-scale production. Certainly, starting a
commercial manufacturing process with (S)-1-phenylethylamine
would be highly attractive, it being readily available in bulk
quantities at low cost and in high enantiomeric purity.
Nonetheless, to employ the Fukuyama procedure as such
on scale presented several immediate concerns. Up to three
isolations, four different solvents (including the use of both
chloroform and methylene chloride), chromatography, and the
heating of hydroxylamine hydrochloride were all issues that
needed to be addressed.
Bretherick’s states that explosions have occurred when
heating hydroxylamine at atmospheric pressure and also when
distilling mixtures of hydroxylamine hydrochloride and sodium
hydroxide in methanol under reduced pressure.16 Accordingly,
the avoidance of heating hydroxylamine and its hydrochloride
was considered paramount to the safe running of the process
on scale.
Moreover, m-CPBA had always been added portionwise as
a solid to the reaction mixture, a procedure that would be
laborious and operationally problematic on a large scale.
Although the literature shows that methylene chloride is by far
the most common solvent for m-CPBA oxidations, no doubt
due to the ease of removal of m-CBA, the use of EtOAc is
also precedented.17 This facilitates the addition of an EtOAc
solution of m-CPBA to an EtOAc solution of the secondary
amine 5a in order to effect the oxidation to the desired nitrone
6a.
Choosing a common solvent suitable for each of the in-
dividual steps would readily ameliorate the issue of multiple
solvents. Such a solvent should be immiscible with water and
stable to the reaction conditions. Three solvents that passed these
criteria were immediately identified: methyl tert-butyl ether,
ethyl acetate, and butyl acetate. Each of the steps worked in all
three solvents, but the utilization of EtOAc gave the best results
in terms of consistent conversion and ease of work-up. As a
result, EtOAc became the solvent of choice (Scheme 3).
(14) Amano, A.; Fukuyama, T.; Kuboyama, T.; Tokuyama, H.; Yamashita,
T. Synthesis 2000, 1299.
This oxidation step is rather energetic, measured at 469 kJ
mol-1 in a Mettler Toledo RC1 calorimeter, which also indicated
(15) Fukuyama, T.; Kuboyama, T.; Tokuyama, H. Org. Synth. 2003, 80,
207.
(16) Urben, P. G., Ed.; Bretherick’s Handbook of ReactiVe Chemical
Hazards, 6th ed; Butterworth-Heinemann: Oxford, UK, 1999; Vol. 1,
pp 1662-1664.
(17) For an example of a process using m-CPBA in EtOAc for the oxidation
of a sulfide to a sulfoxide, see: Milacˇ, N. H.; Jereb, D. U.S. Patent
6,268,502, 2001.
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no accumulation of the oxidant and that the reaction was dose
controlled. Additional hazard testing showed that charging the
entire m-CPBA solution to the reaction in one dose would result
in an adiabatic temperature rise of ∼170 °C. Adding the
m-CPBA solution in four separate aliquots instead would give
individual predicted temperature rises of 58 °C, 46 °C, 38 °C,
and 32 °C, respectively, calculations which were supported by
experimental data (first dose 55.5 °C, second dose 42.5 °C).
With this degree of exothermicity, the reaction temperature
could be kept below the boiling point of the solvent. This
necessitated, however, some precautions on a larger scale to
ensure that the feed vessel contained no more than a quarter of
the total charge of m-CPBA in order to mitigate against dosing
all of the oxidant solution to the reactor at once, either by
accident or as a result of equipment failure.
Figure 1. Enantiomerically pure chiral hydroxylamines pre-
pared using the telescoped process outlined herein (overall
isolated yields in parentheses).
It should be noted that m-CPBA is supplied at ∼70% w/w
strength, the remainder being m-CBA and water for stabilization.
After effectively removing the water, the EtOAc solution of
m-CPBA was investigated by DSC, which showed an exotherm
onset at 105 °C. Invoking the 100 °C rule, the solution was
added at 5 °C. This addition temperature was investigated
further with an ARC measurement, which showed that the
solution would be stable at 5 °C for several days.18
As indicated previously, an alternative procedure for the
cleavage of nitrone 6a was essential, as the heating of
hydroxylamine hydrochloride to 60 °C was considered hazard-
ous for a large-scale manufacture. One distinct advantage that
hydroxylaminolysis did provide, however, was that the by-
product NC-CHdNOH was water soluble and could thus
easily be removed, albeit in a two-stage process. The reaction
was performed in methanol and followed by a methylene
chloride/water work-up. The methylene chloride solution of the
sensitive free hydroxylamine was then evaporated in Vacuo and
the residue redissolved in methanol before precipitation of the
desired product as the salt 4a on addition of methanolic oxalic
acid.
The continued use of EtOAc as the reaction solvent nicely
obviated this rather convoluted end to the synthesis. Using
p-toluenesulfonic acid monohydrate to function as both a
catalyst for a formal hydrolysis through reaction of the adventi-
tious water19 in the EtOAc solution and then also to provide
the counterion of the isolated salt made for an extremely
expedient route to the requisite chiral hydroxylamine as the
stable20 p-toluenesulfonic acid salt 7a in an overall strength-
corrected yield of 71% for the three-step process (Scheme 3).
One issue that did require some attention was the disposal
of the formal by-product from this modified hydrolytic cleavage
of nitrone 6a, namely formyl cyanide, since this presented the
potential for the liberation of hydrogen cyanide. Dra¨ger tube
analysis of the headspace during the hydrolysis indicated up to
2.5 ppm of HCN was present during the reaction, diminishing
to 0 ppm after 45 minutes. An adequate nitrogen sweep and
suitable scrubbing of the exhaust gas was therefore imperative.
In addition it was crucial that after isolation of the product by
filtration, the mother liquor was treated with 2 M aq potassium
carbonate to keep the pH above 9. This ensured that any cyanide
was retained in the aqueous phase.
Confirmation of the preservation of stereochemical integrity
throughout this synthetic sequence was attained through deri-
vatisation of hydroxylamine 7a to the N-benzoyl compound and
analysis by chiral HPLC against a racemic standard, wherein
>99% ee was always found. As expected, the nature of the
counterion proved to have no bearing on the intended down-
stream use of this building block, and the p-toluenesulfonic acid
salt performed as effectively as the oxalic acid salt in subsequent
chemistry.
The synthetic procedure outlined above has been shown to
be readily applicable to other chiral primary amine starting
materials displaying a variety of steric and electronic charac-
teristics, although the process conditions for the synthesis of
the corresponding hydroxylamine derivatives have not been
optimized (Figure 1).
Gratifyingly, where the oxaziridine approach had failed, (S)-
1-(4-methoxyphenyl)ethylamine (1d) was successfully con-
verted into the desired hydroxylamine salt 7d. Conversely,
whilst (S)-1-(naphthalen-1-yl)ethylamine (1b) had been con-
verted to the corresponding hydroxylamine Via the oxaziridine
route, our process to the hydroxylamine p-toluenesulfonic acid
salt (7b) failed. Interestingly, (S)-1-(naphthalen-2-yl)ethylamine
(1c) could be transformed into the corresponding hydroxylamine
salt 4c or 7c by either the oxaziridine or nitrone route,
respectively. In contrast, modifying the R-alkyl substituent of
the starting amine did not prove problematic, and smooth
conversion to the expected hydroxylamine could be achieved,
as exemplified by the ethyl analogue 7e and the tethered indane
derivative 7f. Taken together these results suggest that the
presence of an ortho substituent may present some limitation
to this protocol. The steps to the intermediate nitrone were
typically uneventful regardless of the aryl group, but the final
hydrolysis failed in the case of 7b, and the yield in the case of
7f was low.
(18) For use of m-CPBA as a solution in EtOH and associated discussion,
see: Prasad, J. S.; Vu, T.; Totleben, M. J.; Crispino, G. A.; Kacsur,
D. J.; Swaminathan, S.; Thornton, J. E.; Fritz, A.; Singh, A. K. Org.
Process Res. DeV. 2003, 7, 821.
Conclusion
A scalable process for the synthesis of (S)-N-(1-phenyleth-
yl)hydroxylamine from readily available (S)-R-methylbenzy-
lamine and its isolation as the stable p-toluenesulfonic acid salt
(19) Bentley, P. H.; Brooks, G. Tetrahedron Lett. 1976, 41, 3735.
(20) Proton and carbon NMR analysis after 5 years storage at room
temperature showed no discernable degradation.
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7a has been developed by judicious selection of solvent,
reagents and conditions. Anhydrous conditions were not
required and allowed the use of reagent grade solvent through-
out. The process has been proven in a large-scale laboratory
manufacturing campaign, where the potential hazards were
managed in a controlled manner, to deliver 4.5 kg of material
in excellent quality.21 Furthermore, this synthetic method has
been shown to have applicability to the preparation of other
chiral hydroxylamines.
to leave the product as a colorless solid. The product was dried
in Vacuo at 40 °C (85.6 g, 71% overall yield). Mp 126-128
°C. FT-IR 2838, 1161, 1033, 1006 cm-1. 1H NMR (400 MHz,
CD3OD) δ 1.66 (d, J ) 6.9 Hz, 3H), 2.35 (s, 3H), 4.50 (q, J )
6.9 Hz, 1H), 7.22 (d, J ) 7.9 Hz, 2H), 7.41-7.48 (m, 5H),
7.69 (d, J ) 8.2 Hz, 2H). 13C NMR (100 MHz, CD3OD) δ
16.1, 21.4, 63.0, 127.0, 129.5, 129.9, 130.3, 131.0, 135.7, 141.8,
143.4. HRMS (CI-TOF) m/z [M + H]+ calcd for C8H12NO
138.0919, found 138.0859. Enantioselectivity was determined
after conversion to the corresponding N-benzoylhydroxylamine
and found to be >99% ee by chiral HPLC (DAICEL CHIRAL-
PAK AS, 25 cm × 4.6 mm, isopropanol/hexane 40:60, 1.0 mL/
min, 30 °C, λ 254 nm, tR 9.18 min [R], 18.22 min [S]).
The following compounds were synthesized using the
appropriate procedure as described above for compounds 5a,
6a, and 7a.
(S)-2-[1-(Naphthalen-1-yl)ethylamino]acetonitrile (5b): 1H
NMR (400 MHz, CDCl3) δ 1.50 (d, J ) 6.7 Hz, 3H), 1.73 (s,
1H), 3.32 (d, J ) 17.7 Hz, 1H), 3.57 (d, J ) 17.7 Hz, 1H),
4.84 (q, J ) 6.5 Hz, 1H), 7.42-7.53 (m, 3H), 7.62 (d, J ) 6.9
Hz, 1H), 7.75 (d, J ) 8.2 Hz, 1H), 7.85 (d, J ) 7.9 Hz, 1H),
8.27 (d, J ) 8.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 23.1,
35.2, 53.0, 118.1, 122.9, 123.5, 125.6, 125.7, 126.1, 128.0,
129.0, 131.2, 134.1, 138.4.
Experimental Section
All reagents and solvents were used without further purifica-
tion or drying. Solutions of m-CPBA in EtOAc were made
without heating to aid dissolution and used immediately. Any
unused m-CPBA solution was treated with saturated aq sodium
metabisulfite solution before disposal. NMR spectra were
obtained in CDCl3, CD3OD, or DMSO-d6 on a Varian Inova
400 MHz spectrometer. All 1H spectra are relative to the TMS
signal and 13C spectra to the relevant solvent peak. IR spectra
were recorded on a Perkin Elmer Spectrum One FT-IR. Mass
spectroscopy was performed on a Waters Micromass GCT.
(S)-2-(1-Phenylethylamino)acetonitrile (5a). (S)-R-Meth-
ylbenzylamine (50 mL, 0.39 mol) and Hu¨nig’s base (75.8 mL,
0.43 mol) were dissolved in ethyl acetate (250 mL), and the
solution was heated to 40 °C. Bromoacetonitrile (30.6 mL, 0.43
mol) was added over 2 h. At the end of the addition, an ethyl
acetate (25 mL) line wash was added, whereupon the reaction
mixture was stirred for an additional 3 h. The suspension was
then cooled to 20 °C and washed with water (75 mL) to afford
an ethyl acetate solution of 5a. 1H NMR (400 MHz, CDCl3) δ
1.38 (d, J ) 6.7 Hz, 3H), 3.24 (d, J ) 17.4 Hz, 1H), 3.54 (d,
J ) 17.4 Hz, 1H), 4.01 (q, J ) 6.5 Hz, 1H), 7.25-7.34 (m,
5H). 13C NMR (100 MHz, CDCl3) δ 23.9, 35.0, 56.8, 117.8,
126.9, 127.7, 128.7, 142.9.
(S)-N-(Cyanomethylene)-1-phenylethylamine Oxide (6a).
The ethyl acetate solution of 5a was cooled to 0 °C, and a
freshly prepared solution of m-CPBA (210.4 g, 0.85 mol) in
ethyl acetate (250 mL) was added, keeping the internal
temperature below 5 °C, typically over 2 h. At the end of the
addition, an ethyl acetate (50 mL) line wash was added and
the temperature increased to 20 °C. The reaction mixture was
washed with saturated aq sodium bicarbonate (3 × 250 mL)
and brine (250 mL) to afford an ethyl acetate solution of 6a.
1H NMR (400 MHz, CDCl3) δ 1.82 (d, J ) 6.9 Hz, 3H), 5.20
(q, J ) 6.8 Hz, 1H), 6.73 (s, 1H), 7.37-7.45 (m, 5H). 13C NMR
(100 MHz, CDCl3) δ 18.9, 76.3, 112.2, 127.3, 128.9, 129.2,
129.7, 136.2.
(S)-N-(Cyanomethylene)-1-(naphthalen-1-yl)ethylamine
1
oxide (6b): H NMR (400 MHz, CDCl3) δ 2.01 (d, J ) 6.9
Hz, 3H), 5.92 (q, J ) 6.9 Hz, 1H), 6.47 (s, 1H), 7.49-7.61
(m, 3H), 7.69 (d, J ) 7.2 Hz, 1H), 7.89-7.93 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 19.2, 73.5, 106.5, 112.4, 121.9,
125.3, 126.6, 127.8, 129.4, 130.1, 130.9, 133.7, 133.9, 129.8.
(S)-2-[1-(Naphthalen-2-yl)ethylamino]acetonitrile (5c): 1H
NMR (400 MHz, CDCl3) δ 1.42 (d, J ) 6.7 Hz, 3H), 1.71 (s,
1H), 3.20 (d, J ) 17.4 Hz, 1H), 3.51 (d, J ) 17.7 Hz, 1H),
4.15 (q, J ) 6.5 Hz, 1H), 7.42-7.48 (m, 3H), 7.77-7.83 (m,
4H). 13C NMR (100 MHz, CDCl3) δ 23.9, 35.1, 56.9, 117.9,
124.6, 125.9, 126.1, 126.3, 127.7, 127.8, 128.7, 133.2, 133.4,
140.3.
(S)-N-(Cyanomethylene)-1-(naphthalen-2-yl)ethylamine
1
oxide (6c): H NMR (400 MHz, CDCl3) δ 1.88 (d, J ) 6.9
Hz, 3H), 5.34 (q, J ) 6.8 Hz, 1H), 6.78 (s, 1H), 7.46-7.53
(m, 3H), 7.82-7.87 (m, 4H). 13C NMR (100 MHz, CDCl3) δ
19.0, 76.5, 106.3, 112.4, 124.2, 126.9, 127.1, 127.2, 127.8,
128.2, 129.2, 133.0, 133.6 (2C).
(S)-2-[1-(Naphthalen-2-yl)ethyl]hydroxylamine p-toluene-
sulfonic acid salt (7c): mp 137-138 °C. FT-IR 2804, 1196,
1159, 1123, 1035, 1010 cm-1. 1H NMR (400 MHz, CD3OD)
δ 1.76 (d, J ) 6.9 Hz, 3H), 2.32 (s, 3H), 4.71 (q, J ) 6.9 Hz,
1H), 7.18 (d, J ) 7.9 Hz, 2H), 7.50-7.58 (m, 3H), 7.70 (d, J
) 8.2 Hz, 2H), 7.86-7.94 (m, 3H), 8.00 (s, 1H). 13C NMR
(100 MHz, CD3OD) δ 21.3, 63.0, 126.0, 126.9, 127.8, 128.2,
128.7, 129.3, 129.4, 129.8, 130.1, 132.8,134.5, 135.1, 141.8,
143.3. HRMS (CI-TOF) m/z [M + H]+ calcd for C12H14NO
188.1075, found 188.1067.
(S)-2-[1-(4-Methoxyphenyl)ethylamino]acetonitrile (5d):
mp 64-65 °C. 1H NMR (400 MHz, CDCl3) δ 1.36 (d, J ) 6.4
Hz, 3H), 3.24 (d, J ) 17.7 Hz, 1H), 3.54 (d, J ) 17.4 Hz, 1H),
3.80 (s, 3H), 3.98 (q, J ) 6.5 Hz, 1H), 6.88 (d, J ) 8.7 Hz,
(S)-N-(1-Phenylethyl)hydroxylamine p-Toluenesulfonic
Acid Salt (7a). The ethyl acetate solution of 6a was heated to
40 °C, p-toluenesulfonic acid monohydrate (74.5 g, 0.39 mol)
and further ethyl acetate (50 mL) were added, and the reaction
mixture was stirred for 3 h [CAUTION: Potential release of
HCN in headspace; ensure adequate ventilation!]. Seed was
added, if required, at the end of the hold period, and the reaction
mixture was ramp cooled to 0 °C over 3 h. The hydroxylamine
salt was isolated by filtration and washed with EtOAc (50 ml)
(21) Patel, I.; Smith, N.; Tyler, S. N. G. PCT Int. Appl. WO 2008/029090,
2008.
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2H), 7.26 (d, J ) 8.7 Hz, 2H). 13C NMR (100 MHz, CDCl3)
δ 23.9, 34.9, 55.3, 56.1, 114.1, 117.8, 128.0, 134.8, 159.1.
(S)-N-(Cyanomethylene)-1-(4-methoxyphenyl)ethy-
lamine oxide (6d): 1H NMR (400 MHz, CDCl3) δ 1.78 (d, J
) 6.9 Hz, 3H), 3.81 (s, 3H), 5.17 (q, J ) 6.9 Hz, 1H), 6.76 (s,
1H), 3.60 (s, 2H), 4.36 (t, J ) 6.0 Hz, 1H), 7.17-7.26 (m,
3H), 7.30 (d, J ) 6.9 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ 30.4, 33.2, 35.2, 62.3, 118.5, 124.1, 125.0, 126.5, 128.1, 143.4,
143.8.
(S)-N-(Cyanomethylene)-2,3-dihydro-1H-inden-1-
amine oxide (6f): 1H NMR (400 MHz, CDCl3) δ 2.50-2.60
(m, 2H), 2.92-2.99 (m, 1H), 3.15-3.23 (m, 1H), 5.48-5.51
(m, 1H), 6.65 (s, 1H), 7.26-7.42 (m, 4H). 13C NMR (100 MHz,
CDCl3) δ 30.7, 31.5, 81.9, 106.0, 112.4, 125.2, 125.7, 127.5,
130.5, 136.7, 145.9.
(S)-N-(2,3-Dihydro-1H-inden-1-yl)hydroxylamine p-tolu-
enesulfonic acid salt (7f): mp 137-139 °C. FT-IR 2983, 1123,
1034 1009 cm-1. 1H NMR (400 MHz, DMSO-d6) δ 2.18-2.25
(m, 1H), 2.27 (s, 3H), 2.33-2.43 (m, 1H), 2.83-2.90 (m, 1H),
3.03-3.11 (m, 1H), 4.85-4.88 (m, 1H), 7.12 (d, J ) 7.9 Hz,
2H), 7.24-7.38 (m, 2H), 7.49 (d, J ) 8.2 Hz, 2H), 7.56 (d, J
) 7.7 Hz, 1H), 10.88 (br s, 1H), 11.36 (br s, 2H). 13C NMR
(100 MHz, DMSO-d6) δ 20.8, 26.1, 29.9, 52.9, 125.0, 125.5,
126.4, 126.6, 128.2, 129.8, 135.3, 138.0, 145.1, 145.5. HRMS
(CI-TOF) m/z [M + H]+ calcd for C9H12NO 150.0919, found
150.0869.
1H), 6.92 (d, J ) 8.7 Hz, 2H), 7.35 (d, J ) 8.7 Hz, 2H). 13
C
NMR (100 MHz, CDCl3) δ 18.9, 55.4, 63.2, 105.8, 112.5,
114.2, 114.5, 128.1, 129.0.
(S)-N-[1-(4-Methoxyphenyl)ethyl]hydroxylamine p-tolu-
enesulfonic acid salt (7d): mp 139-141 °C. FT-IR 2710, 1183,
1031, 1005 cm-1. 1H NMR (400 MHz, DMSO-d6) δ 1.50 (d,
J ) 6.7 Hz, 3H), 2.27 (s, 3H), 3.74 (s, 3H), 4.42 (q, J ) 6.8
Hz, 1H), 6.96 (d, J ) 8.7 Hz, 2H), 7.12 (d, J ) 7.7 Hz, 2H),
7.39 (d, J ) 8.7 Hz, 2H), 7.49 (d, J ) 8.2 Hz, 2H), 10.73 (br
s, 1H), 11.22 (br s, 2H). 13C NMR (100 MHz, DMSO-d6) δ
15.9, 20.8, 55.2, 59.8, 114.0, 125.5, 126.8, 128.2, 129.8, 138.0,
145.1, 159.8. HRMS (CI-TOF) m/z [M + H]+ calcd for
C9H14NO2 168.1025, found 168.0977.
1
(S)-2-(1-Phenylpropylamino)acetonitrile (5e): H NMR
(400 MHz, CDCl3) δ 0.83 (t, J ) 7.4 Hz, 3H), 1.79-1.62 (m,
3H), 3.20 (d, J ) 17.7 Hz, 1H), 3.54 (d, J ) 17.7 Hz, 1H),
3.74 (dd, J ) 7.7, 6.2 Hz, 1H), 7.36-7.25 (m, 5H). 13C NMR
(100 MHz, CDCl3) δ 10.5, 30.7, 35.0, 63.4, 117.9, 127.6 (2C),
127.7, 128.6 (2C), 141.2.
(S)-N-(Cyanomethylene)-1-phenylpropylamine oxide (6e):
1H NMR (400 MHz, CDCl3) δ 0.94 (t, J ) 7.3 Hz, 3H),
2.07-1.96 (m, 1H), 2.46-2.35 (m, 1H), 4.93 (dd, J ) 8.5, 6.4
Hz, 1H), 6.92 (s, 1H), 7.39-7.36 (m, 3H), 7.45-7.40 (m, 2H).
13C NMR (100 MHz, CDCl3) δ 10.6, 26.2, 82.6, 106.4, 112.4,
127.6, 129.0, 129.6, 135.5.
Acknowledgment
We are grateful to Dolors Terricabras, David Hose, and
David Sharratt for useful discussions during the development
of this work, to David Hoile for process engineering input, and
to Neil Weston for the process safety assessments. Lee Timms
deserves special mention for running the large-scale lab
manufacturing campaign. We also thank Ian Botham for many
years of inspiration.
(S)-N-(1-Phenylpropyl)hydroxylamine p-toluenesulfonic
acid salt (7e): mp ) 166 °C. FT-IR 2845, 1161, 1126, 1034,
1005 cm-1. 1H NMR (400 MHz, DMSO-d6) δ 0.82 (t, J ) 7.7
Hz, 3H), 2.03-1.92 (m, 1H), 2.28-2.18 (m, 1H), 2.35 (s, 3H),
4.25 (dd, J ) 11.0, 4.6 Hz, 1H), 7.23 (d, J ) 7.9 Hz, 2H),
7.46-7.42 (m, 5H), 7.72 (d, J ) 8.2 Hz, 2H). 13C NMR (100
MHz, DMSO-d6) δ 9.1, 20.2, 22.6, 67.8, 125.8, 128.7, 128.8,
129.1, 129.8, 132.8, 140.7, 142.2. HRMS (CI-TOF) m/z [M +
H]+ calcd for C9H14NO 152.1075, found 152.1055.
Supporting Information Available
1
1H, H-1H COSY, and 13C NMR spectra for compounds
5a-f, 6a-f, and 7a,c-f; IR spectra for compounds 7a,c-f;
MS data for compounds 7a,c-f; chiral HPLC chromatograms
for 7a. This material is available free of charge Via the Internet
at http://pubs.acs.org.
(S)-2-(2,3-Dihydro-1H-inden-1-ylamino)acetonitrile (5f):
1H NMR (400 MHz, CDCl3) δ 1.58 (s, 1H), 1.80-1.88 (m,
1H), 2.37-2.46 (m, 1H), 2.78-2.86 (m, 1H), 2.99-3.06 (m,
Received for review September 19, 2008.
OP800230F
Vol. 13, No. 1, 2009 / Organic Process Research & Development
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