N-methylative aziridine ring opening and the synthesis of (S)-3-methylamino-3-[(R)-pyrrolidin-3-yl]propanenitrile

Article abstract of DOI:10.1016/j.tet.2017.08.043

The preparation of (S)-3-methylamino-3-[(R)-pyrrolidin-3-yl]propanenitrile (1), a key fragment of fluoroquinolone antibiotic PF-00951966 and others was achieved by N-methylative aziridine ring opening, addition of methyl group at the ring nitrogen, and ring-opening via a cyanide nucleophile in a single operation starting from bicyclic (R)-2-[(R)-pyrrolidine-3-yl]aziridine. The starting compound was elaborated from stereoselective conjugate addition of nitromethane to (R)-aziridine-2-yl acrylate followed by selective reduction without breaking the aziridine ring.

Full text of DOI:10.1016/j.tet.2017.08.043

Tetrahedron xxx (2017) 1e7
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N-methylative aziridine ring opening and the synthesis of (S)-3-
methylamino-3-[(R)-pyrrolidin-3-yl]propanenitrile
a
a
a
b,
**
, Hyun-Joon Ha a
, *
Jae-Hoon Jung , Seunghee Kim , Heesung Eum , Won Koo Lee
a
Department of Chemistry, Hankuk University of Foreign Studies, Yongin, Gyeonggi-do, 17035, Republic of Korea
Department of Chemistry, Sogang University, Seoul, 04107, Republic of Korea
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 May 2017
Received in revised form
The preparation of (S)-3-methylamino-3-[(R)-pyrrolidin-3-yl]propanenitrile (1), a key fragment of flu-
oroquinolone antibiotic PF-00951966 and others was achieved by N-methylative aziridine ring opening,
addition of methyl group at the ring nitrogen, and ring-opening via a cyanide nucleophile in a single
operation starting from bicyclic (R)-2-[(R)-pyrrolidine-3-yl]aziridine. The starting compound was elab-
orated from stereoselective conjugate addition of nitromethane to (R)-aziridine-2-yl acrylate followed by
selective reduction without breaking the aziridine ring.
12 August 2017
Accepted 21 August 2017
Available online xxx
©
2017 Elsevier Ltd. All rights reserved.
Keywords:
Aziridine
Ring opening
PF-00951966
Pyrrolidine
Conjugate addition
1. Introduction
(S)-3-methylamino-3-[(R)-pyrrolidin-3-yl]propanenitrile (1), a key
fragment of fluoroquinolone antibiotic PF-00951966 and others, as
5
Over the past few years we reported asymmetric syntheses of
shown in Fig. 1, via introduction of a methyl group to nitrogen and
nitrile at its b-position simultaneously.
We envisioned the synthesis of (S)-3-methylamino-3-[(R)-pyr-
rolidin-3-yl]propanenitrile (1) by taking advantage of the N-
methylative aziridine ring opening reaction and stereoselective
construction of a pyrrolidine ring as shown in Scheme 2. Once we
1
a
several bioactive compounds including hygroline, pseudohygro-
1
b,c
1e
1d
line, hygrine, tyroscherin,
selective N-methylative aziridine ring opening reactions (Scheme 1).
Non-activated’ aziridines (S) bearing electron-donating groups at
ephedrine, and MeBMT via regio-
‘
the ring nitrogen such as phenylethyl substituents were used in our
lab for the asymmetric synthesis of aforementioned compounds,
obtain b-methylamino nitrile compound 6 via N-methylative azir-
2
which are inert to most nucleophiles. This ‘non-activated’ aziridine
idine ring opening from 5, chemoselective debenzylation should
form the final product 1. Pyrrolidine ring 5 is expected to be derived
from sequential reductions of the nitro group in compound 3 to
amine without breaking the aziridine ring of the resulting lactam.
We expect compound 3 from 3-aziridin-2-yl acrylate 2, which is
easily accessible from chiral aziridine-2-carboxylate 9, through
stereoselective conjugate addition of nitromethane.
was activated prior to the nucleophilic ring opening with the assis-
tance of an electrophile-creating aziridinium ion or equivalents
3
thereof. One of the activating reagents is methyl trifluoromethane
sulfonate (MeOTf), which generates the N-methylaziridinium ion (I),
as shownin Scheme 1.1 AlthoughI is stable in the reaction medium,
it still reacts with various nucleophiles such as alkoxide, azide, cya-
e,4
1,3
nide, amine, carbon, and halide to form N-methylated cyclic- or
acyclic amino compounds via aziridine ring opening. The regio-
chemical outcomes of such a ring opening via either way a or b de-
pends on the substituent R at the C2 carbon of the aziridine ring,
2. Results and discussion
3
,4
The synthesis of (S)-3-methylamino-3-[(R)-pyrrolidin-3-yl]
propanenitrile (1) started from the conjugate addition of nitro-
methane from (E)-methyl 3-[(R)-1-((R)-1-phenylethyl)aziri-dine-
yielding either P
a
and/or P
b
.
We used this method to synthesize
2
-yl]acrylate 2 which could be prepared easily from aziridine-2-
*
Corresponding author.
* Corresponding author.
E-mail addresses: wonkoo@sogang.ac.kr (W.K. Lee), hjha@hufs.ac.kr (H.-J. Ha).
6
carboxylate 9 via Wittig olefination. One carbon homologation
via stereoselective conjugate addition was the first task to build
*
http://dx.doi.org/10.1016/j.tet.2017.08.043
040-4020/© 2017 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Jung J-H, et al., N-methylative aziridine ring opening and the synthesis of (S)-3-methylamino-3-[(R)-
pyrrolidin-3-yl]propanenitrile, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.08.043

2
J.-H. Jung et al. / Tetrahedron xxx (2017) 1e7
Scheme 1. The mechanistic details of N-methylative aziridine ring opening reactions and the synthesis of MeBMT, ephedrine, hygroline, pseudo-hygroline, hygrine, and tyroscherin.
isomeric ratio of 69:31. Under neat conditions, the diastereomeric
ratio was 67:33 and the reaction yield was 74%. The reaction with
DBU as a base in CH
3
CN gave a moderate yield of 66% with a ratio of
N as a base did not yield any
6
4:36, while the same reaction with Et
3
product (entry 5, 6). When using Z-acrylate instead of the E-olefin
as starting material, the same reaction yielded the corresponding
product in nearly the same reaction yield and ratio as were
observed using the E-olefin (entry 7). We concluded from this result
that the conjugate addition of aziridine-2-yl acrylate is indepen-
dent of the stereochemistry of the starting substrate. When we
performed the reaction with (E)-methyl 3-[(R)-1-((R)-1-
phenylethyl)aziridine-2-yl]acrylate, the diastereomer of the previ-
ously used (E)-methyl 3-[(R)-1-((S)-1-phenylethyl)aziridine-2-yl]
acrylate, the reaction yield was nearly identical (entry 8). However,
no diastereomeric discrimination was observed, indicating that the
orientation of the nucleophile when approaching to the C1 position
of the side chain as a Michael acceptor is different than that of the
previous starting isomer. This difference in the diastereomeric ratio
is originated in the stereochemistry of a phenylethyl group
attached at the aziridine-ring nitrogen, which was observed in our
Fig. 1. The structure of PF-00951966 bearing (S)-3-methylamino-3-[(R)-pyrrolidin-3-
yl]propanenitrile (1).
pyrrolidine. We tried the addition of nitrile and malonate to yield
the addition product, but their diastereoselectivities were very
7
poor. Next, the addition of nitromethane was tried with tetra-n-
7
c
butylammonium fluoride as a base in THF (Table 1, entry 1). The
nitromethane adduct in THF was obtained at ease in 82% yield and
its diastereomeric ratio was 70:30, which is much better than those
of others, including nitrile and malonate additions. To improve the
diastereomeric ratio and reaction yield, we decided to screen sol-
vents including CH
action under neat conditions (entry 2e4). In CH
2
Cl
2
and 1,4-dioxane, and we also tried the re-
Cl , the reaction
8
previous study. After extensive investigations of reaction condi-
2
2
mixture was obtained with a ratio of 61:39 in 56% yield, which was
lower than that obtained in THF. The reaction in 1,4-dioxane gave
results similar to the reaction in THF with a yield of 78% and
tions, we found that the protocol for entry 1 yielded the best re-
sults. Two diastereomers obtained in this reaction were not
separable by flash column chromatography, but the
Scheme 2. Retrosynthetic analysis of (S)-3-methylamine-3-[(R)-pyrrolidin-3-yl]propanenitrile (1).
Please cite this article in press as: Jung J-H, et al., N-methylative aziridine ring opening and the synthesis of (S)-3-methylamino-3-[(R)-
pyrrolidin-3-yl]propanenitrile, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.08.043

J.-H. Jung et al. / Tetrahedron xxx (2017) 1e7
3
Table 1
conformations 2Z and 2E, we expected the addition of nitroate after
elimination of a proton by base to either re face for the erythro or si
face for the threo isomeric product. The addition reaction from
either conformers 2Z or 2E proceeded at the si face of the corre-
sponding (Z)- and (E)-acrylate, at which stage the hydrogen bond
between nitrogen on the aziridine ring and oxyanion of nitronate
a
Stereoselective conjugate addition of nitromethane to 3-aziridin-2-yl acrylate 2.
7
a
plays a key role as directing groups like TS in Fig. 2 to yield threo
product 3a.
To construct pyrrolidine ring compound 5, chemoselective
Entry
Substrateb
Basec
Solvent
THF
CH Cl
2 2
Dioxane
Neat
Ratio (3a:3b)d,e
Yieldf
reduction of the
We tried several different reductive methods, including CoCl
NaBH , NiCl /NaBH , Raney Ni/H , Zn/H NNH , Pd/C/H , Pd/C/Lin-
dlar's catalyst/H , and PtO
2
When reduced the nitro group with CoCl in the
g-aliphatic nitro group of the ester 3 was required.
1
2
3
4
5
6
7
8
E
E
E
E
E
E
Z
TBAF
TBAF
TBAF
TBAF
DBU
70:30
61:39
69:31
67:33
64:36
e
82%
56%
78%
74%
66%
N.R.
81%
79%
2
/
4
2
4
2
2
2
2
10
2
2 2
/H .
and NiCl
we observed multiple
CH
CH
3
CN
CN
2
10c,f
3
Et N
3
4
presence of NaBH (Table 2, entry 1, 2),
TBAF
TBAF
THF
THF
70:30
50:50
spots on the TLC plate, including small amounts of the desired
products in 16% and 32% yields, respectively. In aqueous medium,
(R/R)g
a
Reaction condition: CH
E and Z substrates are (E)- and (Z)-methyl 3-[(R)-1-((R)-1-phenylethyl)aziridin-
3
NO
2
(1.5 equiv.), Base (1.1 equiv.).
the reaction with Ni
NaBH , produced very small amounts of product (entry 3).
Raney Ni/H
B, prepared by reaction of Ni(OAc)
with
2
2
b
10a,11
4
2
-yl]acrylate.
10d,g
10e
c
2
, NaBH
4
,
and Zn/H
2
NNH
2
were also unable to
2
TBAF: TBAF$xH O.
d
The diastereomeric ratio of crude products was determined by 1
yield lactam 4. In 2012, we reported chemoselective reductions
H NMR
1
0b
(
400 MHz).
using a ‘mixed Pd catalyst’.
Due to the possibility of aziridine
e
10a
Compound 3a: (R)-methyl 4-nitro-3-((R)-1-((S)-1-phenylethyl) aziridin-2-yl)
butanoate, compound 3b: (R)-methyl 4-nitro-3-((R)-1-((S)-1-phenylethyl) aziridin-
ring-opening under hydrogen atmosphere with this ‘Pd’ catalyst,
we tried reduction with a 1:1 mixture of Pd/C and Lindlar's catalyst
under H gas, which yielded the reduced amine with small amount
2
of lactam (21% yield) without any aziridine ring-opened product
(entry 4). Next, we tried hydrogenation under atmospheric pres-
2
-yl)butanoate.
f
Isolated yield.
g
(E)-methyl 3-((R)-1-((R)-1-phenylethyl)aziridin-2-yl)acrylate as
a
starting
material.
2
sure with a different catalyst consisting of PtO in ethanol solvent,
which gave the desired product 4 in 59% yield (entry 5). Under 5 bar
pressure, the desired product was obtained in 49% yield (entry 6).
When we changed solvent from EtOH to MeOH, the reaction rate
increased with an improved reaction yield of 62%. Attempts to in-
crease the reaction temperature from r.t. to 45 C and to the reflux
temperature lead to decreased yields (entry 7e9). The chemo-
stereoselectivity was determined by 1H NMR and/or HPLC. The
major isomer obtained from this threo 3a, where the stereochem-
1
13
istry was confirmed by comparing H and C NMR spectra of the
final products, (S)-3-(methylamino)-3-[(R)-pyrrolidin-3-yl]pro-
ꢀ
5
panenitrile (1) and of di-Cbz-protected amine 8 from literature.
2
selective nitro group reduction in the presence of a PtO catalyst
Previous work described stereoselective conjugate addition of
7
was therefore conducted at room temperature and yielded the
requisite lactam 4 without attacking the aziridine ring. After the
reaction was complete, we were able to acquire a major single
diastereomer by flash column chromatography. We were unable to
isolate the minor isomer.
nitromethane to enoates bearing chiral auxiliary on the g-position.
In 2010, our group reported the conjugate addition of alkylamines
9
to chiral 3-aziridin-2-yl acrylates.
The nucleophilic attack of an amine to the re face of 3-aziridin-2-
yl acrylate gives erythro product while avoiding steric hindrance of
the phenylethyl group at the ring nitrogen. Costa et al. also reported
erythro-selective Michael addition of nitromethane derivatives to
7
d
enoates prepared from D-(þ)-mannitol. In most cases the syn-
clinal approach of nitromethane nucleophile was favorable to yield
erythro-product. In contrast, our major product was the threo
compound 3a, which is different from previously reported re-
Table 2
Lactam formation through chemoselective reduction of
the ester 3.
g-aliphatic nitro group of
a
7
,9
sults.
MMFF) with commercial package Chem3D showed possible sta-
ble conformers 2Z and 2E from the corresponding (Z)- and (E)-ac-
Computational calculations using molecular mechanics
®
(
2
,6a
rylates as shown in Fig. 2. In our early study
of the nucleophilic
addition to aziridine-2-carboxaldehyde, erythro and threo isomers
were obtained from two different transition state models as Felkin-
Ahn's and chelation, respectively. From aforementioned stable
Entry
Reducing agent
20 mol% CoCl /NaBH
Solvent
MeOH
CH CN/H O
3 2
2
H O
MeOH
EtOH
EtOH
MeOH
MeOH
MeOH
Temp.
Yieldb
1
2
3
4
5
6
7
8
9
2
4
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
16%
32%
ꢁ5%
21%
59%
49%
62%
44%
15%
20 mol% NiCl /NaBH
10 mol% Ni B/NaBH
5 mol% Pd/C/Lindlar's catalyst/H
2
4
2
4
2
5 mol% PtO
5 mol% PtO
2
/H
/H
2
(1 bar)
(5 bar)
2
2
10 mol% PtO
10 mol% PtO
10 mol% PtO
2
2
2
/H
/H
/H
2
(1 bar)
(1 bar)
(1 bar)
r.t.
45
ꢀ
2
2
C
reflux
a
In this reaction, we utilized mixture of 3a and 3b with a ratio as 70:30 as a
Fig. 2. The possible stable conformation of (Z)- and (E)-3-aziridin-2-yl acrylates (2Z
and 2E) and the plausible transition state (TS) of the nitromethane conjugate addition.
starting material.
b
Isolated yield of 4 from the mixture of 3.
Please cite this article in press as: Jung J-H, et al., N-methylative aziridine ring opening and the synthesis of (S)-3-methylamino-3-[(R)-
pyrrolidin-3-yl]propanenitrile, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.08.043

4
J.-H. Jung et al. / Tetrahedron xxx (2017) 1e7
4
The lactam 4 was reduced by LiAlH followed by Boc-protection
to give N-Boc-protected pyrrolidine 5 in 82% yield in two steps
1
13
(
Scheme 3). Interestingly, the H and C NMR spectra of N-Boc-
pyrrolidin-3-yl aziridine 5 showed sets of split peaks with an
almost 1:1 ratio, possibly due to two different conformers. To
further investigate the presence of two conformers, we took NMR
ꢀ
spectra in DMSO-d
6
solvent at various temperatures, such as 25 C,
ꢀ ꢀ
4
5 C, and 60 C (Fig. 3A).
ꢀ
ꢀ
As the temperature was increased from 25 C to 45 C and to
0 C the split peaks from the two different conformers merged. At
ꢀ
ꢀ
6
6
0
C, all split peaks were merged into a single set of peaks that
matched to the compound 5 perfectly. This informed us the pres-
ence of two conformers of compound 5 with nearly the same
population. From the computational calculations using the molec-
ular mechanics method (MMFF) and optimization by DFT calcula-
tions (B3LYP, 3-21G), two different isoenergetic conformers 5a and
5
b were disclosed (Fig. 3B, SI-4).
After we obtained 3-(aziridine-2-yl)pyrrolidine 5, we applied
the “N-methylative aziridine ring opening reaction” as the key step,
i.e. introduction of a methyl group to the aziridine ring-nitrogen
and a nitrile nucleophile to its C3-position via concomitant azir-
idine ring opening in a single operation. This was successfully
achieved by treatment of the aziridine ring with MeOTf for N-
methylaziridinium ion formation in situ followed by the nitrile
attack at the C3-carbon of the aziridinium ion, which gave
b-
methylamino nitrile compound 6 in 94% yield with a regioisomeric
ratio of 97:3.
Next, we removed the
give the secondary methylamine as shown in the target product.
We first attempted this debenzylation with a ‘Pd’ catalyst under H
atmosphere in MeOH, which was not successful. Performing hy-
drogenation with (Boc) O in the presence of Pd/C gave rise to two
a-methylbenzyl group at the nitrogen to
2
2
different products, di-Boc-protected compound 7 and tri-Boc-
protected compound 7′. In 2007, T. Maegawa et al. reported on
Pd/C(en) catalyzed chemoselective hydrogenation reactions in the
12
presence of aryl nitriles. Specifically, all reducible functional
groups were converted in THF, except for nitrile. Although our
compound includes aliphatic b-N-methylamino nitrile, we decided
to attempt Maegawa's conditions. We carried out the hydrogena-
tion reaction using 10 mol% Pd/C(en) as catalyst with 1.1 equiv. of
(
5
(
Boc)
6% yield with significant amount of nitrile reduced compound 7′
Table 3, entry 1). Next, we tried debenzylation under atmospheric
2
O at room temperature, which gave our desired product in
Fig. 3. (A) 1H and 13C NMR spectra of N-Boc pyrrolidine-3-yl aziridine 5 at 25, 45 and
60 C. (B) Two different isoenergetic conformers 5a and 5b.
ꢀ
pressure of hydrogen with 10 mol% Pd/C as catalyst (entry 2). All
starting material was consumed, with a higher reaction rate for
entry 1. Due to production of a significant amount of tri-Boc-
protected compound 7′, the yield of desired compound 7 was
relatively low. In order to avoid nitrile group reduction and to
improve the reaction yield of compound 7, we changed the amount
Table 3
Optimization of debenzylation with palladium catalyst.
Cat.a
(Boc)
O (equiv.)
Solvent (M)
Temp. ( C)
ꢀ
Yieldb (%)
Entry
2
1
2
3
4
5
Pd/C(en)
Pd/C
Pd/C
Pd/C
Pd/C
1.1
1.1
3.0
3.0
1.1
THF (0.15)
THF (0.15)
THF (0.15)
THF (0.15)
THF (0.30)
r.t.
r.t.
r.t.
45
r.t.
56
56
86
76
64
a
Scheme 3. Pyrrolidine formation and regioselective N-methylative aziridine ring
opening reaction.
Catalyst was used with 10 mol%.
Isolated yields of the compound 7.
b
Please cite this article in press as: Jung J-H, et al., N-methylative aziridine ring opening and the synthesis of (S)-3-methylamino-3-[(R)-
pyrrolidin-3-yl]propanenitrile, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.08.043

J.-H. Jung et al. / Tetrahedron xxx (2017) 1e7
5
of (Boc)
2
O. When 3.0 equiv. (Boc)
2
O were used, compound 7 was
carbon. The starting bicyclic compound used for the “N-methylative
aziridine ring opening” reaction in this synthesis was obtained via
stereoselective conjugate addition of nitromethane to (R)-azir-
idine-2-yl acrylate followed by selective reduction of nitro and
amide groups without breaking the aziridine ring. Selective
removal of the benzyl group at the nitrogen was also performed in
an efficient manner under atmospheric hydrogen.
ꢀ
obtained in 86% yield (entry 3). When performed at 45 C, the re-
action yielded slightly decreased amounts of compound 7 (entry 4).
When increasing the starting compound concentration in THF from
0
.15 M to 0.3 M, the yield dropped from 86% to 64% (entry 5). We
found that the best condition for chemoselective debenzylation
under atmospheric hydrogen was as in entry 3, carrying out the
reaction with 10 mol% of Pd/C catalyst and 3.0 equiv. of (Boc)
THF (0.15 M) at r.t..
2
O in
4. Experimental section
The final free amine 1 was obtained in quantitative yield by
removal of the Boc-protecting group with trifluoroacetic acid fol-
lowed by anion exchange column chromatography (Scheme 4). The
4.1. General
23
ꢀ
optical rotation [
different from the reported value of [
We therefore decided to convert compound 7 into another known
diCbz-protected amine 8 via a sequential reaction including diBoc-
deprotection from compound 7 and double protection of all amines
a
]
was þ29 (c 5.02 in CH
3
OH), which was
Chiral aziridine-2-carboxylates are available >98% ee as their
menthyl ester from Sigma-Aldrich as reagents and from Imagene
Co., Ltd. (http://www.imagene.co.kr/) in bulk quantities. Their
corresponding ethyl esters were also available either from trans-
esterification of menthyl ester or from Imagene Co., Ltd.. All re-
actions were carried out under an atmosphere of nitrogen in oven-
dried glassware with magnetic stirrer. Reactions were monitored
by thin layer chromatography (TLC) with 0.25 mm E. Merck pre-
coated silica gel plates (60 F254). Visualization was accomplished
with either UV light, or by immersion in solutions of ninhydrin, p-
anisaldehyde, or phosphomolybdic acid (PMA) followed by heating
on a hot plate for about 10 s. Purification of reaction products was
carried out by flash chromatography using Kieselgel 60 Art 9385
(230e400 mesh). 1H NMR and 13C NMR spectra were obtained
using Bruker AVANCE III HD (400 MHz) spectrometer. Data are
reported as (br ¼ broad, s ¼ singlet, d ¼ doublet, t ¼ triplet,
q ¼ quartet, p ¼ quintet, m ¼ multiplet). Coupling constants are
given in Hz. Ambiguous assignments were resolved on the basis of
standard one dimensional proton decoupling experiments. Optical
rotations were obtained using JASCO P-2000. Optical rotation data
2
3
ꢀ
5a
a]
þ2.4 (c 5.00 in CH
3
OH).
2
3
with Cbz. The optical rotation [
a
]
of the compound 8 was
3
), which was comparable to
ꢀ
measured to be þ24 (c 4.50 in CHCl
2
3
ꢀ
5a
the reported value of [
a
]
þ30.4 (c 5.00 in CHCl
3
).
2
3
Although there is discrepancy in [
a
]
values of compounds 1
1
13
and 8, all spectral data including H and C NMR were identical.
We conclude that there is no diastereomer in the reaction product
with different stereochemistry at both stereocenters, S at the N-
methylamino substituent and R at the pyrrolidine attachment.
Furthermore, the configuration S at the N-methylamino part pre-
determined in (2S)-aziridine-2-carboxylate (>98% ee). It is
implausible for the stereocenter of this N-methylamino part to
become racemized during our synthetic pathway. We therefore
conclude that our synthetic material has the right configuration in
(
S)-3-(methylamino)-3-[(R)-pyrrolidin-3-yl]propanenitrile (1), in
13
more than 98% ee.
was reported as follows: [
vent). High resolution mass spectra were recorded on a AB Sciex
800 Plus MALDI TOFTM (2,5-dihydroxybenzoic acid (DHB) matrix
a
]20 (concentration c ¼ g/100 mL, sol-
3
. Conclusion
4
was used to prepare sample for MS. Data was obtained in the
reflector positive mode with internal standards for calibration).
Preparation of (S)-3-methylamino-3-[(R)-pyrrolidin-3-yl]pro-
panenitrile (1), a key fragment of fluoroquinolone antibiotic PF-
0951966 and others, was successfully achieved by N-methylative
0
4.2. Procedure of synthesis for (S)-3-methylamino-3-[(R)-
aziridine ring opening, addition of a methyl group to the ring ni-
trogen, and ring-opening via a nitrile nucleophile in a single
operation from starting bicyclic (R)-2-[(R)-pyrrolidine-3-yl]azir-
idine. This example showed that the “N-methylative aziridine ring
opening” reaction is an efficient synthetic method to introduce
methyl groups at the nitrogen and functionality to the aziridine
pyrrolidin-3-yl]propanenitrile (1)
4.2.1. Methyl 4-nitro-3-((R)-1-((S)-1-phenylethyl) aziridin-2-yl)
butanoate (3)
To a solution of (E)-methyl 3-((R)-1-((S)-1-phenylethyl) azir-
idin-2-yl)acrylate (2) (1.52 g, 6.59 mmol) in THF (22 mL) was added
tetrabutylammonium fluoride hydrate (172 mg, 0.659 mmol) and
nitromethane (538 mL, 9.882 mmol) at room temperature. After
the mixture was stirred for 4 h, the mixture was diluted with EtOAc
(
H
30 mL) and then the mixture was washed with std. NH
O (30 mL ꢂ 2) and brine. The organic layers were dried with
anhydrous MgSO , filtered and concentrated in vacuo. The mixture
was purified by silica gel flash column chromatography (1:
4
Cl (20 mL),
2
4
3
¼ EtOAc: Hex). The desired product 3 (2.35 g, 82%) as a bright
yellow oil was obtained.
1
3
H NMR (400 MHz, CDCl ): d 7.41e7.23 (5H, m, major and mi-
nor), 4.70 (2H, d, J ¼ 5.9 Hz, minor), 4.59 (2H, d, J ¼ 6.6 Hz, minor),
3
(
(
.73 (3H, s, major), 2.68 (1H, ddd, J ¼ 24.4,16.9, 6.3 Hz, major), 2.56
2H, d, J ¼ 6.7 Hz, major), 2.48 (2H, d, J ¼ 6.5 Hz, minor), 2.52e2.36
1H, m, NO CH CH in minor), 2.52e2.36 (1H, m, PhCH(CH ) in
2
2
3
major and minor), 1.73 (1H, ddd, J ¼ 7.9, 6.3, 3.3 Hz, major and
minor), 1.61 (1H, d, J ¼ 3.2 Hz, major), 1.60 (1H, d, J ¼ 3.3 Hz,
minor), 1.42 (3H, d, J ¼ 6.6 Hz, major), 1.39 (3H, d, J ¼ 6.6 Hz,
13
minor), 1.36 ppm (1H, t, J ¼ 6.4 Hz, major and minor); C NMR
3
(100 MHz, CDCl ): d 171.7, 144.2, 128.5, 127.3, 126.8, 77.4, 77.0, 76.5,
Scheme 4. Synthesis of (S)-3-(methylamino)-3-[(R)-pyrrolidin-3-yl]propanenitrile (1).
69.6, 69.5, 52.0, 40.1, 40.0, 37.6, 37.1, 34.1, 33.7, 33.1, 32.7, 23.5 ppm;
Please cite this article in press as: Jung J-H, et al., N-methylative aziridine ring opening and the synthesis of (S)-3-methylamino-3-[(R)-
pyrrolidin-3-yl]propanenitrile, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.08.043

6
J.-H. Jung et al. / Tetrahedron xxx (2017) 1e7
þ
þ Hþ,
]20 þ22 (c 1.53 in CHCl
ꢀ
); 1H NMR (400 MHz, DMSO-d
,
3 6
HRMS-MALDI (m/z): [M þ H] calcd for C15
H
20
N
2
O
4
[
a
ꢀ
2
93.1496; found, 293.1495.
60 C):
d
7.34e7.21 (5H, m), 3.79 (1H, q, J ¼ 6.5 Hz), 3.42 (2H, ddd,
J ¼ 10.8, 8.4, 2.6 Hz), 3.19 (3H, m), 2.60 (2H, ddd, J ¼ 22.3, 17.4,
5.6 Hz), 2.44 (1H, dd, J ¼ 16.7, 9.0 Hz), 2.09 (1H, s), 1.95 (1H, m), 1.61
4
.2.2. (R)-4-((R)-1-((S)-1-phenylethyl)aziridin-2-yl)pyrrolidin-2-
13
one (4)
To a solution of methyl 4-nitro-3-((R)-1-((S)-1-phenylethyl)
aziridin-2-yl)butanoate (3) (174 mg, 0.595 mmol) in CH OH (6 mL)
was added platinum oxide (13 mg, 0.060 mmol) at room temper-
ature. The solution was stirred for 48 h under atmospheric pressure
(1H, m), 1.42 (9H, s), 1.29 ppm (3H, d, J ¼ 6.7 Hz); C NMR
6
(100 MHz, DMSO-d ): d 153.4,145.9,128.4,128.3,126.8,126.7,120.0,
3
78.1, 78.0, 61.3, 61.0, 57.2, 56.9, 50.0, 45.8, 45.4, 41.3, 40.5, 32.8, 32.7,
þ
29.2, 28.2, 22.0, 21.7, 15.0, 14.8 ppm; HRMS-MALDI (m/z): [M þ Na]
þ
calcd for C21
H
31
N
3
O
2
þ Na , 380.2308; found, 380.2310.
of H
vacuo. The crude product was purified by silica gel flash column
chromatography (1: 19 ¼ CH OH: CH Cl ). The desired product 4
85 mg, 62%) as a white solid was obtained.
2
. The mixture was filtered and the filtrate was concentrated in
4.2.5. (R)-tert-Butyl 3-((S)-1-((tert-butoxycarbonyl) (methyl)
amino)-2-cyanoethyl)pyrrole-dine-1-carboxylate (7)
To solution of (R)-tert-butyl 3-((S)-2-cyano-1-(methyl((S)-1-
phenylethyl)amino)ethyl) pyrrolidine-1-carboxylate (6) (190 mg,
0.530 mmol) in THF was added 10% Pd/C (29 mg, 0.027 mmol) and
di-tert-butyl dicarbonate (347 mg, 1.591 mmol) at room tempera-
3
2
2
(
ꢀ
20
ꢀ
); 1H NMR (400 MHz,
3
Mp 119.1 C; [
a
]
ꢃ56 (c 1.24 in CHCl
CDCl ):
3
d
7.39e7.23 (5H, m), 6.12 (1H, brs), 3.58 (1H, dd, J ¼ 9.3,
7
.4 Hz), 3.38 (1H, dd, J ¼ 9.6, 5.2 Hz), 2.47 (1H, dd, J ¼ 15.9, 8.0 Hz),
2
(
.28 (2H, m),1.63 (1H, td, J ¼ 6.8, 3.4 Hz),1.55 (1H, d, J ¼ 3.4 Hz),1.41
2
ture. The mixture was stirred under H gas (balloon). After con-
13
3H, d, J ¼ 6.6 Hz), 1.34 ppm (1H, d, J ¼ 6.3 Hz); C NMR (100 MHz,
version was completed, the reaction mixture was filtered on the
celite pad. The mixture was purified by flash column chromatog-
raphy (1: 3 ¼ EtOAc: Hex). The desired product 7 (161 mg, 86%) as a
viscous colorless liquid was obtained.
3
CDCl ): d 177.9, 144.3, 128.5, 127.2, 126.9, 69.5, 46.3, 42.7, 37.8, 34.5,
3
C
2.4, 23.6 ppm; HRMS-MALDI (m/z): [M þ Na]þ calcd for
þ
H
14 18
N
2
O þ Na , 253.1311; found, 253.1311.
2
0
ꢀ
); 1H NMR (400 MHz, DMSO-d
[
a
]
þ28 (c 1.11 in CHCl
3
6
,
ꢀ
4
.2.3. (R)-tert-butyl 3-((R)-1-((S)-1-phenylethyl) aziridin-2-yl)
60 C):
d
4.12 (1H, brs), 3.40 (1H, ddd, J ¼ 11.3, 8.2, 3.3 Hz), 3.26 (1H,
pyrrolidine-1-carboxylate (5)
dd, J ¼ 10.6, 7.6 Hz), 3.19 (1H, dd, J ¼ 17.5, 8.9 Hz), 2.85 (3H, m), 2.74
(3H, s), 2.43 (1H, dd, J ¼ 15.3, 7.7 Hz), 1.89 (1H, m), 1.60 (1H, m), 1.43
To a solution of (R)-4-((R)-1-((S)-1-phenylethyl)aziridin-2-yl)
pyrrolidin-2-one (4) (2.83 g, 12.30 mmol) in THF (123 mL) was
added lithium aluminum hydride (1.17 g, 30.76 mmol) at 0 C. After
min, the solution was warmed to room temperature and stirred
for 10 min followed by was refluxed for 1 h. The mixture was
13
ꢀ
(9H, s), 1.39 ppm (9H, s); C NMR (100 MHz, DMSO-d , 60 C):
6
ꢀ
d
154.7, 154.3, 153.1, 117.9, 79.1, 78.0, 54.7, 48.4, 45.1, 27.9, 27.7,
18.9 ppm; HRMS-MALDI (m/z): [M
þ
5
þ
Na]
calcd for
þ
C
18
H
31
N
3
O
4
þ Na , 376.2207; found, 376.2207.
quenched with 10% KOH solution (15 mL) and then dried with
anhydrous MgSO
4
. The mixture was filtered on the celite pad and
4.2.6. (R)-Benzyl 3-((S)-1-(((benzyloxy)carbonyl) (methyl)amino)-
concentrated in vacuo. The obtained compound was used in next
step without purification. The obtained compound was diluted in
2-cyanoethyl)pyrrolidine-1-carboxylate (8)
To
ycarbonyl)(methyl)amino)-2-cyanoethyl)pyrrolidine-1-
carboxylate (7) (116 mg, 0.328 mmol) in CH Cl (4 mL) was added
trifluoroacetic acid (0.250 mL, 3.276 mmol) at room temperature.
After 2 h, reaction mixture was quenched with CH OH (2 mL). The
solution was concentrated in vacuo. Obtained mixture was diluted
in EtOAc/H O (1: 1, 4 mL) followed by K CO (271 mg, 1.966 mmol)
a
solution of (R)-tert-butyl 3-((S)-1-((tert-butox-
EtOH (41 mL) followed by (Boc)
2
O (3.76 g, 17.22 mmol) was added
to solution. The reaction mixture was stirred for 6 h. The EtOH was
2
2
removed in vacuo and then the mixture was diluted in CH
2
Cl
Cl
2
(
(
50 mL). The reaction mixture was extracted with CH
50 mL ꢂ 2) and H
, filtered and concentrated in vacuo. The mixture was
2
2
3
2
O (50 mL). Combined organic layer was dried
with MgSO
4
2
2
3
purified by silica gel flash column chromatography (1: 3 ¼ EtOAc:
Hex). The desired product 5 (3.25 g, 85% in 2 steps) as a colorless
liquid was obtained.
was added to solution at room temperature. After 30 min, benzyl
chloroformate (0.140 mL, 0.983 mmol) was added to solution at
0 C and the mixture was stirred for 1 h. The reaction mixture was
ꢀ
2
0
ꢀ
); 1H NMR (400 MHz, DMSO-d
[
a
]
ꢃ39 (c 1.02 in CHCl
3
6
,
extracted with EtOAc (20 mL ꢂ 2). Combined organic layer was
ꢀ
6
0 C):
d
7.36e7.20 (5H, m), 3.39 (2H, m), 3.20 (2H, m), 2.47 (1H, q,
4
dried with anhydrous MgSO , filtered and concentrated in vacuo.
J ¼ 6.5 Hz), 1.71 (1H, m), 1.57 (1H, td, J ¼ 6.5, 3.4 Hz), 1.43e1.41 (1H,
The crude compound was purified by silica gel flash column chro-
matography (1: 1 ¼ EtOAc: Hex). The desired product 8 (115 mg,
83%), as a clear viscous oil, was obtained.
m), 1.42 (9H, s), 1.31 (3H, d, J ¼ 6.5 Hz), 1.23 ppm (1H, d, J ¼ 6.4 Hz);
13
6
C NMR (100 MHz, DMSO-d ): d 153.6,144.8,128.1,126.7, 78.1, 68.2,
2
3
ꢀ
14
]23 þ30.4ꢀ (c 5.00 in
4
9.1, 48.9, 45.4, 45.0, 40.9, 40.5, 32.0, 29.0, 28.2, 28.1, 23.3 ppm;
[
a
]
þ24 (c 4.50 in CHCl
3
)
(lit. [5a], [
a
þ
þ
1
HRMS-MALDI (m/z): [M þ H] calcd for C19
H
28
N
2
O
2
þ H , 317.2224;
CHCl
3
)); H NMR (400 MHz, CDCl
3
): d 7.35 (10H, m), 5.15 (2H, s),
found, 317.2213.
5.13 (2H, s), 4.08 (1H, brs), 3.71e3.49 (2H, m), 3.40 (1H, dd, J ¼ 17.3,
1
0.3 Hz), 3.10 (1H, m), 2.96 (1H, brs), 2.80e2.52 (3H, m), 2.02 (1H,
13
4.2.4. (R)-tert-Butyl 3-((S)-2-cyano-1-(methyl((S)-1-phenylethyl)
3
m), 1.65 ppm (1H, m); C NMR (100 MHz, CDCl ): d 156.1, 154.7,
amino)ethyl)pyrrolidine-1-carboxylate (6)
136.9, 136.3, 128.7, 128.6, 128.3, 128.2, 128.1, 128.0, 127.9, 117.3, 68.2,
To a solution of (R)-tert-butyl 3-((R)-1-((S)-1-phenylethyl)azir-
idin-2-yl)pyrrolidine-1-carboxylate (5) (430 mg, 1.358 mmol) in
67.8, 67.0, 49.7, 49.2, 46.3, 45.9, 40.9, 40.0, 29.9, 29.1, 20.9,
þ
20.5 ppm; HRMS-MALDI (m/z): [M
þ
Na]
calcd for
þ
CH
3
CN (14 mL) was added methyl trifluoromethanesulfonate
C H
24 27
N
3
O
4
þ Na , 444.1894; found, 444.1895.
ꢀ
(
(
0.163 mL, 1.493 mmol) at 0 C. After 5e10 min, sodium cyanide
113 mg, 2.715 mmol) was added to the solution and then the so-
4.2.7. (S)-3-(Methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile
lution was allowed to be warmed to room temperature. The
mixture was extracted with CH Cl
(30 mL ꢂ 2). The combined
organic layers were dried with anhydrous MgSO , filtered on the
celite pad and concentrated in vacuo. The crude compound was
purified by flash column chromatography (1: 9 ¼ EtOAc: Hex). The
desired product 6 (434 mg, 91% as a viscous colorless liquid was
obtained.
(1)
2
2
To
ycarbonyl)(methyl)amino)-2-cyanoethyl)pyrrolidine-1-
carboxylate (7) (896 mg, 2.535 mmol) in CH Cl (25 mL) was added
trifluoroacetic acid (2.91 mL, 38.029 mmol) at room temperature.
After 2 h, reaction mixture was quenched with CH OH (10 mL). The
solution was concentrated in vacuo. Recrystallization was
a
solution of (R)-tert-butyl 3-((S)-1-((tert-butox-
4
2
2
3
Please cite this article in press as: Jung J-H, et al., N-methylative aziridine ring opening and the synthesis of (S)-3-methylamino-3-[(R)-
pyrrolidin-3-yl]propanenitrile, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.08.043

J.-H. Jung et al. / Tetrahedron xxx (2017) 1e7
7
performed with CH
Obtained solid was diluted in H
2
Cl
2
followed by the white solid was filtered.
O and then anion-exchange col-
(e) Kim Y, Ha HJ, Yun SY, Lee WK. Chem Commun. 2008:4363e4365.
2
3
4
. Ha HJ, Jung JH, Lee WK. Asian J Org Chem. 2014;3:1020e1035.
2
. Stankovi ꢀc S, D’hooghe M, Catak S, et al. Chem Soc Rev. 2012;41:643e665.
®
15
umn chromatography (Amberlite IRA-410 chloride form) was
conducted. Combined aqueous solution was concentrated in vacuo.
The desired product 1 (381 mg, 98%), as a colorless oil, was
obtained.
ꢀ
. (a) D’hooghe M, Catak S, Stankovic S, et al. Eur J Org Chem. 2010:4920e4931;
(b) Yun SY, Catak S, Lee WK, et al. Chem Commun. 2009:2508e2510.
. (a) Lall MS, Hoge G, Tran TP, et al. J Org Chem. 2012;77:4732e4739;
5
(
b) Murphy ST, Case HL, Ellsworth E, et al. Bioorg Med Chem Lett. 2007;17:
150e2155;
(c) Domagala JM, Hagen SE, Joannides T, et al. J Med Chem. 1993;36:871e882.
6. (a) Lee WK, Ha HJ. Aldrichm Acta. 2003;36:57e63;
b) Lee BK, Kim MS, Hahm HS, Kim DS, Lee WK, Ha HJ. Tetrahedron. 2006;62:
393e8397.
7. (a) Kumar MG, Mali SM, Gopi HN. Org Biomol Chem. 2013;11:803e813;
b) Domingos JLO, Lima EC, Dias AG, Costa PRR. Tetrahedron Asymmetry.
2004;15:2313e2314;
c) Pinto AC, Freitas CBL, Dias AG, et al. Tetrahedron Asymmetry. 2002;13:
1025e1031;
d) Costa JS, Dias AG, Anholeto AL, Monteiro MD, Patrocinio VL, Costa PRR. J Org
Chem. 1997;62:4002e4006;
e) Plummer JS, Emery LA, Stier MA, Suto MJ. Tetrahedron Lett. 1993;34,
2
2
3
ꢀ
OH)14 (lit. [5a], [
OD):
]23 þ2.4 (c 5.00 in
ꢀ
[
a]
þ29 (c 5.02 in CH
3
a
1
CH
3
OH)); H NMR (400 MHz, CD
3
d
3.18 (1H, dd, J ¼ 11.3,
(
8
7
.8 Hz), 3.01 (1H, m), 2.93 (1H, ddd, J ¼ 11.1, 8.3, 7.5 Hz), 2.79 (1H, td,
J ¼ 6.8, 2.9 Hz), 2.70 (1H, m), 2.63 (2H, ddd, J ¼ 19.4, 11.6, 4.4 Hz),
.41 (3H, s), 2.26 (1H, dd, J ¼ 17.3, 8.9 Hz), 2.00 (1H, m), 1.50 ppm
(
2
13
(
6
1H, ddd, J ¼ 17.5, 12.4, 8.6 Hz); C NMR (100 MHz, CDCl
3
): d 119.3,
(
0.7, 50.7, 47.1, 44.9, 33.6, 30.5, 21.2 ppm; HRMS-MALDI (m/z): [M þ
þ
þ
(
Na] calcd for C
8
H
15
N
3
þ Na , 176.1158; found, 176.1155.
(
Acknowledgements
7529e2532.
8
9
1
. Han SM, Ma SH, Ha HJ, Lee WK. Tetrahedron. 2008;64:11110e11114.
. Yoon DH, Ha HJ, Kim BC, Lee WK. Tetrahedron Lett. 2010;51:2181e2183.
This work supported by the National Research Foundation of
Korea (NRF-2012M3A7B4049645 and 2014R1A5A1011165 with
Centre for New Directions in Organic Synthesis). In addition many
thanks go to Mr. S. Y. Na for his help to prepare (R)-2-(methyl-
amino)-2-((R)-pyrrolidin-3-yl)ethanol bishydrochloride.
0. (a) Zeynizadeh B, Zabihzadeh M. J Iran Chem Soc. 2015;12:1221e1226;
b) Ji MK, Yoon DH, Ha HJ, Kang P, Lee WK. Bull Korean Chem Soc. 2012;33:
2853e2854;
(
(
(
c) Setamdideh D, Khezri B, Mollapour M. Orient J Chem. 2011;27:991e996;
d) Pogorli ꢀc I, Firela-Litvi ꢀc M, Merka ꢁs S, Ljubi ꢀc G, Cepanec I, Litvi ꢀc M. J Mol Catal
A Chem. 2007;274:202e207;
(e) Gowda S, Gowda DC. Indian J Chem Sect B. 2003;42B:180e183;
(f) Beccalli EM, Gelmi ML, Marchesini A. Tetrahedron. 1998;54:6909e6918;
(g) Osby JO, Ganem B. Tetrahedron Lett. 1985;26:6413e6416.
Appendix A. Supplementary data
1
1
1. (a) Lloyd DH, Nichols DE. J Org Chem. 1986;51:4294e4295;
(b) Brown CA, Ahuja VK. J Org Chem. 1973;38:2226e2230;
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2017.08.043.
(
(
c) Brown CA, Brown HC. J Am Chem Soc. 1963;85:1003e1005;
d) Brown HC, Brown CA. J Am Chem Soc. 1963;85:1005e1006.
2. Maegawa T, Fujita Y, Sakurai A, et al. Chem Pharm Bull. 2007;55:837e839.
References
13. We elaborated (R)-2-(methylamino)-2-((R)-pyrrolidin-3-yl)ethanol bishydro-
chloride (Figure SI-8) by N-methylative aziridine ring opening with oxygen
2
3
1
. (a) Lee J, Lee JE, Ha HJ, Son SI, Lee WK. Tetrahedron Lett. 2015;56:856e858;
b) Yoon DH, Ji MK, Ha HJ, Park J, Kang P, Lee WK. Bull Korean Chem Soc.
013;34:1899e1902;
nucleophile which gave [
a
]
¼ þ6.0 (c 1.00 in H
2
O) matched with the reported
O) in the reference 5a.
23
(
2
value [
a
]
¼ þ6 (c 5.00 in H
2
14. Specific rotation values were measured at least 3 times from each batch.
15. The Amberite IRA-410 chloride form resin was substituted with hydroxide by
®
(
(
c) Yoon DH, Kang P, Lee WK, Kim Y, Ha HJ. Org Lett. 2012;14:429e431;
d) Kim Y, Yoon DH, Ha HJ, Kang KY, Lee WK. Tetrahedron Lett. 2011;52:
10% KOH.
5918e5920;
Please cite this article in press as: Jung J-H, et al., N-methylative aziridine ring opening and the synthesis of (S)-3-methylamino-3-[(R)-
pyrrolidin-3-yl]propanenitrile, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.08.043