Efficient Synthesis of N-Sulfonyl β -Arylmethylalaninates from Serine via Ring Opening of N-Sulfonyl Aziridine-2-carboxylate

Article abstract of DOI:10.1080/00397911.2014.965328

We report the efficient synthesis of N-sulfonyl β-arylalanines methyl ester through regioselective ring opening of N-protected aziridines by variety of heteroaryl C-nucleophiles. We have optimized synthesis of N-protected aziridines with versatile protecting groups to afford 4a-c, 6a, and 6b with moderate to good yields using sulfuryl chloride, triethyl amine, and toluene at -50 °C. The present work reports on the studies related to electronic effect of nitrogen substituent on aziridination from the inexpensive starting material DL-serine. The present investigation also reports the efficient synthesis of N-sulfonyl β-arylmethylalaninates (7a-e and 8a-e) by regioselective nucleophilic ring opening of N-sulfonamido-protected aziridines using various aryl moieties such as C-nucleophiles and Lewis acids (InCl₃, FeCl₃, Cu(OTf)₂) as catalysts and some trials by ring opening using Grignard reagent. GRAPHICAL ABSTRACT.

Full text of DOI:10.1080/00397911.2014.965328

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An Efficient Synthesis of N-Sulphonyl β-
Arylmethylalaninates from Serine via Ring Opening of
N-Sulphonyl Aziridine-2 Carboxylate
Prashant Chaudhariac & Sanjay Barib
a Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical
Education and Research, Shirpur, Maharashtra, India
b Department of Pharmaceutical Chemistry, H. R. Patel Institute of Pharmaceutical
Education and Research, Shirpur, Maharashtra, India
c National Institute of Pharmaceutical Education and Research Kolkata, Kolkata, West
Bengal, India
Accepted author version posted online: 06 Oct 2014.
To cite this article: Prashant Chaudhari & Sanjay Bari (2014): An Efficient Synthesis of N-Sulphonyl β-Arylmethylalaninates
from Serine via Ring Opening of N-Sulphonyl Aziridine-2 Carboxylate, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2014.965328
To link to this article: http://dx.doi.org/10.1080/00397911.2014.965328
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AN EFFICIENT SYNTHESIS OF N-SULPHONYL β-
ARYLMETHYLALANINATES FROM SERINE VIA RING OPENING OF N-
SULPHONYL AZIRIDINE-2 CARBOXYLATE
Prashant Chaudhari1,3, Sanjay Bari2
1Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical
Education and Research, Shirpur, Maharashtra, India, 2Department of Pharmaceutical
Chemistry, H. R. Patel Institute of Pharmaceutical Education and Research, Shirpur,
Maharashtra, India, 3National Institute of Pharmaceutical Education and Research
Kolkata, Kolkata, West Bengal, India
Corresponding Author to P. Chaudhari: Department of Pharmaceutical Chemistry, R. C.
Patel Institute of Pharmaceutical Education and Research., Shirpur, Dist-.Dhule,
Maharashtra, 425 405, India. E-mail: prashantniperk@gmail.com
Abstract
We report the efficient synthesis of N-Sulphonyl β-arylalanines methyl ester through
regioselective ring opening of N-protected aziridines by variety of heteroaryl C-
nucleophiles. We have optimized synthesis of N-protected aziridines with versatile
protecting groups to afford (4a-c) and (6a-b) with moderate to high yields using
sulphuryl chloride, triethyl amine and Toluene at -50º C temp. Present work reports the
studies related to electronic effect of Nitrogen substituent on aiziridination from cheap
starting material DL-Serine. Present investigation also reports the efficient synthesis of
N-sulphonyl β-arylmethylalaninates (7a-e and 8a-e) by regioselective nucleophilic ring
opening of N-sulphonamido protected aziridines using various aryl moieties as C-
nucleophiles and Lewis acids (InCl3, FeCl3, Cu(OTf)2) as catalysts and some trials by
ring opening through Grignard reagent.
1

KEYWORDS: Aziridine; Arylalanine; Serine; Lewis acid; Sulphuryl chloride
INTRODUCTION
Aryl substituted alanines are found to be biologically active compounds against sickle-
cell anemia [1a] and epileptogenesis.[1b] Synthesis of arylalanine is reported, by
regioselective ring opening of chiral aziridines, which is prepared by asymmetric
synthesis of cis-aziridines from chiral N-benzylimines and ethyl diazoacetate (EDA)
using cobalt(II) as Lewis acid catalyst.[2a] Richard F.W. Jackson [2b] et al. synthesized β-
aryl alanines from β-iodoalanines and aryl iodides using bis(tri-o-tolylphosphine)
palladium dichloride as catalyst. Eva Medina [2c] et al. synthesized N-boc-β-methyl-β-aryl
alanines by regioselective ring-opening of enantiomerically pure N-Boc-aziridines. We
were interested in exploiting aziridines for the synthesis of arylalanines because ‘C-3’ of
aziridine provides prominent centre for nucleophilic attack if it is unsubstituted.[2d] The
inherent ring strain and presence of stereogenic carbons attached to nitrogen make the
aziridine a structure for the formation of enantioenriched 1,2-amino alcohols, 1,2-
diamines, 1,2-amino thiols, and remote secondary amines. [3a-d] Aziridines also explored
and found to be useful moiety in a solid-phase peptide synthesis (SPPS) technology. [4]
2

Serine is the most common starting material for synthesis of arylalanines. [5] Travins and
Etzkorn [6] reported synthesis of D-amino acids from L-Serine derived aziridine, but their
conversion involves redundant steps of reduction to L-Serinal and oxidation at final step
to afford D-amino acid. Here we wish to report synthesis of N-Sulphonyl methyl
arylalaninates via aziridination from DL-Serine molecule, without redox reaction. Our
synthetic plan was based upon protection-deprotection chemistry [7] of α-amino acids,
Serine in our case to yield an activated aziridine. On Serine 1 we protected, free carboxyl
terminal by methyl ester 2, then after free primary amino group by Trityl (Tr), Boc,
Chlorobenzyloxycarbonyl (Cbz) 3a-c, also tried for p-nitrobenzenesulfonyl (p-Ns)/(p-
Nosyl), p-toluene sulfonyl (p-Ts)/(p-Tosyl), then followed by Cyclization [8] to yield N-
substituted aziridines 4a-c. The regioselective ring opening reactions of aziridines by
hydrogen halides, water and other nucleophiles are studied extensively and well known
reactions. [9] We achieved this step by various heterocyclic aryl C-nucleophiles using
catalysts viz: Cu(Otf)2 [5], FeCl3, InCl3 [10], All compounds were characterized by LC-MS,
1
HRMS, H NMR and 13C NMR.
RESULT AND DISCUSSION
In order to carry out a cost effective and novel methodology towards affording final
arylalanines we did a retro-synthetic analysis (Fig.1).
DL-Serine 1 was selected as starting material, methyl esterification was done using
methanol and thionyl chloride, and this was stirred overnight.[11] In another method
reaction mixture was refluxed for 3 h. Product was confirmed by LC-MS. N-protection of
3

DL-serine methyl ester 2 was done with Trityl chloride (Triphenyl methyl chloride) 3a,
Boc (di-ter-butyl dicarbonate) 3b, Chlorobenzyloxycarbonyl (CBz) 3c, (Scheme 1)
products were confirmed by LC-MS, HRMS, 1H NMR and 13C NMR. Initially, before
carboxyl, N-protection tried but reactions were not successful, after protecting carboxyl
terminal, N-terminal of DL-serine was protected successfully. N-Tritylation of Methyl 2-
amino-3-hydroxypropanoate hydrochloride was initially quite difficult by method A but
done successfully by method B. N-tritylation was done by two methods; Method A
suggested by Marisa L. Blauvelt and Amy R. Howell [12] for unprotected carboxyl group
of Serine, using TMS (trimethyl silane) chloride, product 3a was formed but, method was
quite tedious and yield was not so promising (35 %). Method B suggested by Jack E.
Baldwin [13] et al. for serinate involves addition of chloroform; triethylamine and Trityl
chloride (yield 86 %). As compared to former method this is very fast and purification
was easy. During N-Boc protection 3b it was observed that Boc group gets de-protected
in acidic condition so care is taken to maintain alkaline pH. Compound 3c was prepared
successfully by two methods, in method A [14] compound 2 in water was treated with
magnesium oxide (MgO), CBZ-Cl in ether for 2-3 h. Product obtained successfully in
yield (68 %).While in Method B compound 2 in water was treated with sodium
bicarbonate, CBZ-Cl in ether and stirred overnight. After work up a major UV visible
spot was observed in TLC (BuOH: AA: H2O; 3:1:1), product was confirmed by LC-MS
further characterized by HRMS, 1H NMR and 13C NMR spectra. This procedure is time
consuming than former but higher yielding (82 %). Synthesis of activated aziridines
through N-protection by p-tosyl and p-nosyl was a easy approach for ring opening,
because aziridines needs to be activated, by keeping electron withdrawing group like (i.e.
4

acyl, sulfonyl, carbomyl) but 3d, 3e were unsuccessful (scheme 1), rather the product
which was formed in this trial was methyl 2-(4-methylphenylsulfonamido)acrylate 3x [13a]
(Table 1, entry 6). This product was easily isolable and confirmed by matching
characteristic spectra with similar notation observed by Jack E. Baldwin et al.[13b]
Similarly p-nosylation procedure yielded methyl 2-(4-nitrophenylsulfonamido) acrylate
3y [13c] (Table 1, entry 7).
Once N-protected methyl ester of DL-serine afforded, next target was to go for
cyclization to yield N-protected methyl 1-aziridine-2-carboxylate. After several trial we
got successful (cyclized) desired product by reaction on N-protected methyl ester of L-
Serine 3a, 3b, 3c (Scheme 1) with sulphuryl chloride, triethyl amine and Toluene at -50º
C temp for 2-3 h. This was done by analogous procedure reported by Kuyl-Yeheskiely et
al. [8] This reaction indicates that electron releasing ability of protecting group towards
nitrogen facilitates cyclization and electron withdrawing ability diminishes productivity
of cyclization. Tritylated methyl serinate yielded more cyclized product than CBz
protected methyl serinate (Fig.2).
To our anticipation behind usage of SO2Cl2 for Cyclization, key fact for aziridination was
that; free hydroxyl moiety of serine can easily attack on it and at the end SO3 liberated
forms a complex with triethyl amine. Proposed reaction mechanism is depicted (Fig.3).
Although 4a-c (Table 1, entry 8-10) were afforded successfully but could not be utilized
for further ring opening by desired Aryl moiety as nucleophiles, because these aziridines
5

needs to be activated by strong electron withdrawing group.
De-protection of aziridines was done using TFA (Trifluoro Acetic acid); compounds 4a-c
respectively was dissolved in solution of DCM: MeOH (1:1). Solution was cooled to the -
10º C and TFA was added slowly in an inert atmosphere. Reaction mixture was
maintained at -10º C for 3 h and the reaction was monitored by TLC, but to our
observation it was found that compounds 4a-c were forming salt with TFA. After
complete de-protection, on TLC status of compound 4a, it was also observed that, tritylH
was separated successfully (A UV light visible nonpolar spot) here, we confirmed de-
protection. During work up procedure after extraction with water combined aqueous layer
was treated with NaHCO3 until pH =10. After affording N-deprotected aziridine (5) with
very good yield (Table 1, entry 11).Immediately 6a and 6b (Table 1, entry 12 & 13) were
synthesized using activated potassium carbonate by reported protocol. [13]
Although sulfonamide-activated aziridines are regioselectively attacked at the least-
hindered carbon atom, to our anticipation powerful electron withdrawing group such as
p-nitrobenzenesulfonyl (p-Ns/p-nosyl) would activate aziridine ring for nucleophilic
attack more than electron releasing substituent on nitrogen, this was our rationale for
synthesis of 6a and 6b.
Nucleophilic attack by various aryl moieties as C-Nucleophile on unsubstituted C-3 of 6a
and 6b could be easy approach towards affording β-arylalanines. Nucleophilic ring
opening of aziridine ring using Grignard reagent (RMgCl) is reported. [15] The expected
6

mechanism was that the Grignard reagent will attack on C-3, less hindered site, to give a
desired opening. (Fig.4) (ArCH2MgX).
Grignard reagent (PhCH2MgCl) was prepared in lab using Benzyl chloride, Magnesium
chloride in THF. [16] Prepared reagent was confirmed by reactions with methyl vinyl
ketone (Scheme 2), this is perceived on the fact reported by Sandeep Modi [17] et al. that,
reaction of Grignard reagent takes place on enones system smoothly. This validation is
done by reacting copper (I) iodide with benzylmagnesium chloride at 0º C followed by
addition of methyl vinyl ketone. The expected attack of Grignard reagent was successful
to afford 5-phenylpentan-2-one. [17b]
This prepared Grignard reagent was stored at 0º C under argon atmosphere. Ring opening
through Grignard reagent (benzylmagnesium chloride) tried on 4a, 6b (Scheme 3). This
was perceived on the Baldwin and co-worker’s report, that nucleophilic ring opening by
RMgCl gives the desired C-3 attacked ring opening if bulky R group is taken as
nucleophile. But in our quest for ring opening, it was found that, no reaction took place to
obtain desired product from 4a, because 4a contains an electron releasing trityl
substitution on nitrogen so the ring opening reaction by Grignard nucleophile becomes
difficult, whilst 6b contains an electron withdrawing (p-nosyl) substituent on nitrogen,
reaction could fetch desired product but due to less hindered methyl ester group, reaction
with p-nosyl substituent on nitrogen gave a undesired products 6x. [18] Baldwin [15] et al.
in their report demonstrated that the desired ring opening, could be optimized by altering
the alkyl group of attacking moiety, we have observed that desired ring opening is also
7

affected by less hindered ester functionality of substrate molecule 4a and 6b in our case.
So from our study it can be deduced that, to afford desired aryl alanines through Grignard
nucleophile it’s necessary to protect carboxyl terminal of Serine with bulky group to
avoid attack on it. Instead, another approach was tried. 7a-e and 8a-e (Scheme 4) was
synthesized using different C-nucleophiles and different catalysts at good to higher yields
(Table 2).
Aryl C-nucleophile attack on expected C-3 was possible to afford desired compounds as
major product due to high electron withdrawing ability of p-nosyl and p-tosyl substituent
on nitrogen and high oxaphilic nature of select Lewis acids. In case of InCl3, 1-
Methylindole gave maximum 84 % yield compared to Cu(OTf)2 and FeCl3 (Table 2,
entry 1). Similar result was observed with p-nosylated aziridine. Attack by 1, 2-
dimethoxybenzene was more prominent compared to pyrrole, furan and thiofuran (Table
2, entry 5). Reactions with Cu(OTf)2 gave product with moderate yield compared to InCl3
and FeCl3.
EXPERIMENTAL
General Information
All reactions were conducted using oven-dried glassware under an atmosphere of
nitrogen (N2) or argon (Ar). All reagents used were of commercial grade and used
without further purification. Solvents were dried and distilled following the usual
protocols. Column chromatography was carried out using silica gel (100–200 mesh).
8

TLC was performed on aluminium-backed plates coated with Silica Gel 60 with F-254
indicator. The 1H NMR spectra were recorded with a 400 MHz and 13C NMR spectra
were recorded with a 100 MHz using CDCl3. DMSO-d6, 1H NMR chemical shifts are
expressed in parts per million (δ) relative to CDCl3 (δ = 7.26) and DMSO-d6 (δ = 2.49);
13C NMR chemical shifts are expressed in parts per million (δ) relative to the CDCl3 (δ
=77.0). High resolution mass spectra (HRMS) were obtained under positive electron
spray ionization (m/z values are given). Liquid chromatography Mass spectrometer (LC-
MS) spectra were obtained under positive electron spray ionization (m/z values are
given). Melting point of synthesized compound/s was uncorrected and determined by
capillary method.
General Procedure For Cyclization Of N-Protected Aziridines.
(3a/3b/3c) (8.3mmol) was stripped twice with dry dioxane. It was dissolved in dry
toluene (18 mL/ mmol) then triethyl amine (24.9mmol, 3 eq.) was added in inert
atmosphere. Temperature was cooled down to ,lomm 69.9( edirolhc lyruflus dna C°05ـ
1.2 eq.) was added slowly drop wise. Reaction mixture was allowed to warm at RT
slowly. pH of the reaction should be basic. Progress of reaction was monitored with TLC
in 5% to 10% EA/ Hex. Reaction mixture was diluted with ethyl acetate and washed with
brine twice. Organic part was dried over sodium sulphate and evaporated under reduced
pressure. On TLC compound was visible in UV light and also ninhydrin active.
Purification was done by column chromatography (silica G 100-200) product was eluted
using 1 to 10 % EA/ Hex as mobile phase.
9

1. Methyl 1-Tritylaziridine-2-Carboxylate (4a)
Product isolated was off white solid, mp 130-132º C (lit [19]130-131º C), (88% yield). 1H
NMR 400 MHz in CDCl3, 1H (d, J=6.24, δ=1.40(, 1H (d, J=3.6, δ=1.87(, 3H (s, δ=3.7(,
4H (m, δ=7.09-7.03(, 5H (m, δ=7.22-7.17), 6H (d, J=7.44, δ=7.48(. 13C NMR, 100 MHz
in CDCl3 δ: 22.2 (-CH2 Aziridine), 37.3 (-CH Aziridine), 51.8 (-CH3), 85.0 (-C-Ph3), 126.2,
127.0, 129.2, 145.0 (-CH Aromatic), 171.2(-CO2-). LC-MS (ESI) m/z: 344.1 (MH+). Anal.
calcd. for C23H21NO2: C, 80.44; H, 6.16; N, 4.08; found: C, 80.37; H, 6.09; N,
4.17.HRMS (ESI) m/z: (MH+) calcd. for C23H21NO2: 344.1645; found: 344.1641.
2. 1-Tert-Butyl 2-Methyl Aziridine-1, 2-Dicarboxylate (4b)
Product isolated was brown oil (78% yield). 1H NMR, 400 MHz in CDCl3: 9H (s,
δ=1.42(, 2H (d, J=8.794, δ=2.10(, 1H (m, δ=3.32-3.27(, 3H (s, δ=3.78(. 13C NMR, 100
MHz in DMSO δ: 28.3 (-CH3Boc), 31.3 (-CH Aziridine), 37.2 (-CH2 Aziridine), 51.8 (-CH3),
79.8 (-C-CH3Boc), 154.2 (-CO2 Boc), 171.4 (-CO2-). LC-MS (ESI) m/z: 202.2 (MH+). Anal.
calcd. for C9H15NO4: C, 53.72; H, 7.51; N, 6.96; found: C, 53.79; H, 7.45; N,
6.88.HRMS (ESI) m/z: (MH+) calcd. for C9H15NO4: 202.1078; found: 202.1073.
3. 1-Benzyl 2-Methyl Aziridine-1, 2-Dicarboxylate (4c)
Product isolated was yellow oil (65 % yield). 1H NMR 400 MHz in CDCl3, 1H (m,
δ=1.92-1.86(, 1H (m, δ=2.14-2.09), 1H (t, J=4.318, δ=2.43(, 3H (s, δ=3.72(, 2H (m,
δ=7.73-7.67(, 1H (m, δ=7.81-7.86), 2H (d, J=4.673, δ=8.23(. 13C NMR, 100 MHz in
CDCl3 δ: 31.3 (-CH Aziridine), 37.2 (-CH2 Aziridine), 51.8 (-CH3), 67.3 (-CH2-OCBz), 127.1,
127.6, 128.9, 136.1 (-CH Aromatic CBz), 154.3 (-CO2 CBz), 171.4 (-CO2-). LC-MS (ESI) m/z:
10

236.2 (MH+). Anal. calcd. for C12H13NO4: C, 61.27; H, 5.57; N, 5.95; found: C, 61.29; H,
5.49; N, 5.90. HRMS (ESI) m/z: (MH+) calcd. for C12H13NO4: 236.2437; found:
236.2435.
Typical Procedure For Synthesis Of N-P-Tosyl Β-Arylmethylalaninates (7a-E) And
N-P-Nosyl Β-Arylmethylalaninates (8a-E).
A mixture of compound (6a) (50mg, 0.196mmoles) or (6b) (50 mg, 0.174 mmoles) and
various aryl moieties (1.5 eq) (as nucleophiles) in 1 mL CH2Cl2 or CHCl3 added in tightly
capped test tube (seal tube) followed by addition of various catalyst at suitable
temperature finally mixed with 2-5 mL of CH2Cl2 and reacted in a same tightly capped
test tube for overnight (12 h).Reactions were monitored by TLC. After confirmation of
new spot, crude mixtures were analyzed for LC-MS and products were confirmed by m/z
obtained. The reaction mixture was diluted with 5mL water and extracted with EtOAc
and washed with brine. The extract was dried over anhydrous Na2SO4 and concentrated
in vacuo. The residue was purified by flash chromatography on silica gel 2:8 EA/Hex as
mobile phase. All the isolated final compounds were confirmed by HRMS, 1H NMR and
13C NMR spectra.
CONCLUSION
Finally our report on findings regarding electronic effect essential for two processes,
cyclization of –N and –O protected serine to afford aziridines and regioselective ring
opening of it, enables to understand that for ring formation Nitrogen of DL-Serine should
be protected with electron releasing group, whilst for ring opening it must be with
11

electron withdrawing group. For activated aziridines, sulphonamido protected aziridines
(p-tosyl/p-nosyl) was found successful moieties to achieve desired β-aryl methyl
alaninate. p-tosyl/p-nosyl substituent on aziridines not only exerts electron withdrawing
effect which facilitate nucleophilic attack at less hindered carbon but also it enhances the
oxaphilic utility of Lewis acids such as InCl3, FeCl3 and Cu(OTf)2 to afford high yielding
β-aryl alanines methyl ester.
SUPPORTING INFORMATION
Full experimental detail, 1H and 13C NMR spectral data, LC-MS, and HRMS data, for
this article can be accessed on the publisher’s website.
ACKNOWLEDGEMENT
Authors are grateful to Mr. Pavan Payghan for his valuable suggestion while preparing
the manuscript.
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13. (a) Procedure for methyl 2-(4-methylphenylsulfonamido)acrylate 3X: methyl 2-
Blauvelt, M. L.; Howell, A. R. Synthesis of epi-Oxetin via a Serine-Derived 2-
amino-3-hydroxypropanoate 2 (19.04mmol) was added in a solution of p-
toluenesulphonyl chloride (38.08 mmol) in triethylamine (47.6 mmol) at 0º C. Then
reaction mixture was allowed to stir at RT under inert atmosphere for overnight. The
triethylamine was removed under reduced pressure and the residual crude mixture was
dissolved in EtOAc (60 ml) washed with acetic acid (25 mL) and water (60 mL).The
14

organic part was dried over sodium sulphate, filtered and purified by comlumn
chromatography by using 10-30 % EA : Hexane as mobile phase. Product isolated as
white solid mp 90-94º C. (lit [13b] mp 93-94º C). Product confirmed by LC-MS (ESI): m/z:
256.06 (MH+). 1H NMR and 13C NMR spectra were in agreement with lit [13b]; (b)
Baldwin, J. E.; Spivey, A. C.; Schofield, C. J.; Sweeney J. B. Amino Acid Synthesis via
Ring Opening of N-Sulphonyl Aziridine-2-Carboxylate Esters with Organometallic
Reagents. Tetrahedron. 1993, 49, 6309–6330; (c) Procedure for methyl 2-(4-
nitrophenylsulfonamido) acrylate 3y: methyl 2-amino-3-hydroxypropanoate 2
(19.04mmol) was added in a solution of p-nitrobenzenesulphonyl chloride (38.08 mmol)
in triethylamine (47.6 mmol) at 0º C. Then reaction mixture was allowed to stir at RT
under inert atmosphere for overnight. The triethylamine was removed under reduced
pressure and the residual crude mixture was dissolved in EtOAc (60 ml) washed with
acetic acid (25 mL) and water (60 mL).The organic part was dried over sodium sulphate,
filtered and purified by column chromatography by using 10-30 % EA : Hexane as
mobile phase. Product isolated as brown oil. 1H NMR, 400 MHz in CDCl3: 3H (s,
δ=3.78(, 2H (d, J=10.64, δ=5.20(, 2H (m, δ=8.10-8.16(, 2H (m, δ=8.42-8.36). 13C NMR,
100 MHz in CDCl3 δ: 52.1 (-CH3 ester), 103.7 (-C=CH2), 124.2, 128.2, 146.9, 149.8 (-CH
Aromatic) 154.3 (-CH2=C) 165.2 (-CO2-). LC-MS (ESI) m/z: 287.05 (MH+).
14.
15.
Harold, K.; Houston, T. U. S. Patent 5,773,475 A1, 1998.
Baldwin, J. E.; Adlington, R. M.; O'Neil, I. A.; Schofield, C.; Spivey, A.
C.; Sweeney, J. B. The ring opening of aziridine-2-carboxylate esters with organometallic
reagents. J. Chem. Soc., Chem. Commun. 1989, 1852–1854.
15

16.
Benkeser, R. A.; Snyder D. C. Mechanism of the reaction between
benzylmagnesium chloride and carbonyl compounds: A detailed study with
formaldehyde. J. Org. Chem. 1982, 47, 1243–1249.
17.
(a) Modi, S. P.; Gardner, J. O.; Milowsky, A.; Wierzba , M.; Forgione, L.; Mazur,
P.; Solo, A. J.; Duax, W. L.; Galdecki, Z. Conjugate addition of Grignard reagents to
enones and dienones. J. Org. Chem. 1989, 54, 2317–2321; (b) General procedure for
synthesis of 5-phenylpentan-2-one: CuCl (0.137 mmol, 0.097eq) was cooled at 0º C for
10 min under argon atmosphere, to this Grignard reagent (benzylmagnesium chloride)
(2.82 mmol, 2.09eq) was added slowly and allowed to stir for 10 min at 0º C. Methyl
vinyl ketone (1.14mmol) in THF (0.4ml/mmol) was added. Reaction mix was allowed to
stir for overnight. Reaction mix was diluted with ethyl acetate (10 mL) and washed with
ammonium chloride sol (2 × 4 mL), brine (4 mL). Organic layer was dried over sodium
sulphate and evaporated under reduced pressure. TLC was monitored in 10 % EA/Hex As
mobile phase. Purification was done by column chromatography (silica G 100-200)
product was eluted using 2 to 4 % ethyl acetate/ hexane as mobile phase. Product isolated
as colourless semisolid, ( yield 85 %) 1H NMR, 400 MHz in CDCl3, 2H (m, δ=1.84-
1.79(, 3H (s, δ=2.12(, 2H (m, δ=2.42-2.37(, 2H (dd, J=9.4, 4.4 Hz, δ=2.62(, 3H (m,
δ=7.30-7.25(, 2H (m, δ=7.44-7.39). 13C NMR, 100 MHz in CDCl3 δ: 22.8 (-CH2), 37.3 (-
CH2), 29.6 (-CH3), 45.2 (-CH2), 126.1, 128.3, 129.2, 143.1 (-CH aromatic), 208.6 (-CO-
CH3). LC-MS (ESI) m/z: 163.1 (MH+).
18.
General Procedure for synthesis of 1-(1-((4-nitrophenyl)sulfonyl)aziridin-2-yl)-2-
phenylethanol 6x: CuCl (0.137 mmol, 0.097eq) was cooled at 0º C for 10 min under
argon atmosphere, to this Grignard reagent (benzylmagnesium chloride) (2.82 mmol,
16

2.09eq) was added slowly and allowed to stir for 10 min at 0º C. Compound (6b) (2.86
mmol) in THF (0.4mL/mmol) was added. Reaction mix was allowed to stir for overnight.
Reaction mix was diluted with ethyl acetate (10 mL) and washed with ammonium
chloride sol (2 × 4 mL), brine (4 mL). Organic layer was dried over sodium sulphate and
evaporated under reduced pressure. TLC was monitored in 10 % EA/Hex as mobile
phase. Purification was done by column chromatography (silica G 100-200); product was
eluted using 2 to 6 % ethyl acetate/ hexane as mobile phase. 1H NMR, 400 MHz in
CDCl3, 1H (m, δ=1.46-1.41(, 2H (m, δ=1.71-1.66(, 1H (m, δ=2.62-2.57(, 1H (m, δ=2.86-
2.81(, 3H (m, δ=7.32-7.27(, 3H (m, δ=7.41-7.35(, 2H (m, δ=8.18-8.13 (, 2H (m, δ=8.42-
8.36 ). 13C NMR, 100 MHz in CDCl3 δ: 35.2 (-CH2 Aziridine), 38.4 (-CH Aziridine), 38.8 (-
CH2-Ph), 78.8 (-CH-OH), 124.3, 126.1, 128.1, 128.5, 128.8, 138.8, 150.2, 151.5 (-CH
Aromatic). LC-MS (ESI) m/z: 349.2 (MH+).
19.
Kato, S.; Harada, H.; Morie, T. Efficient synthesis of (6R)-6-amino-1-methyl-4-
(3-methylbenzyl)- hexahydro-1H-1,4-diazepine from methyl (2R)- and (2S)-1-benzyloxy
carbonyl aziridine-2-carboxylates. J. Chem. Soc., Perkin Trans. 1 1997, 3219–3226.
17

Table 1. Synthesis of Protected Aziridnes.
Entry Product Gr
Conditions
Ph3CCl,TEA,CHCl3
TempºC/Time Yielda (%)
1.
2.
3.
4.
5.
6.
7.
8.
9.
3a
3b
3c
3d
3e
3x
3y
4a
4b
Ph3CCl
Boc
CBz
0oC, 1-2 h
RT, 2-3 h
RT, 12 h
86
76
72
Boc anhydride, TEA, DCM
Benzylchloroformate, MgO, ether.
Acetone:H2O,TsCl,DIPEA
p-nitrobenzenesulfonyl-Cl in EtOAc
Acetone:H2O,TsCl,DIPEA
p-nitrobenzenesulfonyl-Cl in EtOAc
p-Tosyl
p-Nosyl
-----------
-----------
Cyclization SO2Cl2,TEA,Toluene
Cyclization SO2Cl2,TEA,Toluene
Cyclization SO2Cl2,TEA,Toluene
De-protect TFA, MeOH:DCM
RT, 12 h
Undesired
Undesired
0oC,12 h
RT,12 h
34
38
88
78
65
82
80
84
0oC,12 h
-50oC, 2-3 h
-50oC, 2-3 h
-50oC, 2-3 h
-10oC, 3 h
RT, 12 h
10. 4c
11.
5
12. 6a
13. 6b
p-Tosyl
p-Nosyl
DCM, p-TsCl, K2CO3
DCM, p-NsCl, K2CO3
RT, 12 h
aIsolated yield.
18

Table 2. Regioselective ring opening of activated aziridines with Aryl C-Nucleophile to
afford β-arylalanines.
Entry
ArH (1.5 eq.)
Product yield (%)
(7a-e)
Product yield
(%)
Gr = p-Ts
(8a-e)
Gr = p-Ns
88a, 65b, 72c
82a, 55b, 68c
72a, 48b, 42c
62a, 50b, 52c
88a, 76b, 62c
1
2
3
4
5
1-Methylindole
pyrrole
84a, 58b, 66c
72a, 56b, 62c
64a, 42b, 46c
60a, 56b, 52c
furan
thiofuran
1,2-dimethoxybenzene 77a, 72b, 54c
aInCl3 (0.4 eq.), DRY CH2Cl2, overnight.
bCu(OTf)2 (0.4 eq.), 78º C, CHCl3, 2 h.
cFeCl3 (0.2 eq.), RT, DRY CH2Cl2, overnight.
19

Scheme 1. Synthesis of N-substituted aziridines
20

Scheme 2. Preparation & Validation of Grignard reagent
21

Scheme 3. Trial for Nucleophilic ring opening of p-Ns/Tr substitutes aziridine
22

Scheme 4. Synthesis of N-sulphonyl β-arylmethylalaninates
23

Figure 1. Retrosynthetic analysis to afford desired compounds
24

Figure 2. Cyclization of various N-Substituted DL-Serinate to afford aziridines
25

Figure 3. Proposed Mechanism of aziridination using sulphuryl chloride
26

Figure 4. Paucibility of attack through Grignard reagent
27