Continuous-Flow Synthesis of 2 H -Azirines and Their Diastereoselective Transformation to Aziridines

Article abstract of DOI:10.1055/s-0035-1560391

Using continuous-flow techniques, a small collection of 2H-azirines was prepared from oxime precursors via mesylation and base-promoted cyclisation. The 2H-azirines were either isolated after in-line purification or derivatised into a selection of 2-subst

Full text of DOI:10.1055/s-0035-1560391

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©
Georg Thieme Verlag Stuttgart · New York
2016, 27, 159–163
159
letter
Synlett
M. Baumann, I. R. Baxendale
Letter
Continuous-Flow Synthesis of 2H-Azirines and Their Diastereose-
lective Transformation to Aziridines
Marcus Baumann*
Ian R. Baxendale
HO
Ar1
N
H
N
Nuc
Ar2
N
Ar1
Ar2
Ar1
Ar2
Nuc
Department of Chemistry, University of Durham, South Road,
Durham, DH1 3LE, UK
marcus.baumann@durham.ac.uk
MsCl
Nuc = H, CN, CF3
9 examples
dr >19:1, 71–92% yield
reactive 2H-azirine
intermediate
We dedicate the star of this paper to Prof. Steven V. Ley on the
th
occasion of his 70 birthday
Received: 27.11.2015
Accepted after revision: 30.11.2015
Published online: 01.12.2015
Current synthetic protocols towards 2H-azirines involve
time- and labour-intensive batch manipulations where
product instability results in decreased yield and the re-
quirement for extensive purification. In the past we have
successfully demonstrated several efficient flow processes
yielding selections of chiral and achiral heterocyclic archi-
tectures displaying various versatile functionalization sites.
We therefore aimed to harness the processing power of
flow chemistry to deliver a stream of 2H-azirines based on
an interrupted Neber rearrangement process. The interme-
diate 2H-azirines would be subsequently converted through
a second reaction step involving addition of various nucleo-
philes to furnish di- and trisubstituted aziridines.8
DOI: 10.1055/s-0035-1560391; Art ID: st-2015-d0920-l
Abstract Using continuous-flow techniques, a small collection of 2H-
azirines was prepared from oxime precursors via mesylation and base-
promoted cyclisation. The 2H-azirines were either isolated after in-line
purification or derivatised into a selection of 2-substituted aziridines
through a telescoped reaction sequence involving nitrile, trifluorometh-
yl, or hydride nucleophilic addition. Importantly, these 2-substituted
aziridines were produced with high cis diastereoselectivity providing ac-
cess to small chiral heterocyclic entities that hold promise for medicinal
chemistry programs because of their druglike features.
6
7
Key words flow synthesis, heterocycles, azirine, aziridine, microreac-
tor, monolith, in-line purification
We commenced our studies with the synthesis of differ-
ent substrates bearing a 4-pyridyl moiety adjacent to the
methylene carbon of the oxime motif that itself would be
2H-Azirines and their saturated aziridine counterparts
1
9
represent intriguing small heterocyclic components. Syn-
derived from the corresponding ketone precursor. It was
thesis of 2H-azirines commonly involves the photolysis of
quickly established that these ketone structures 3 could be
readily accessed through the addition of lithiated picolines
1 into nitriles 2 (Scheme 2, see Supporting Information for
full details). The desired oximes 4 were subsequently pre-
pared by condensation of the ketones 3 with hydroxyl-
amine hydrochloride under basic conditions.
2
vinyl azides or the Neber rearrangement of activated oxim-
3
es. Due to the inherently high ring strain of the 2H-azirine
structures, their conversion into aziridines through nucleo-
philic attack at the imine carbon is a very thermodynami-
cally favourable process accompanied by release of ~20
4
kcal/mol. In addition 2H-azirines readily undergo ring
opening into synthetically valuable nitrile ylide dipoles
O
NOH
NH2OH⋅HCl
NaOMe, MeOH
5
(Scheme 1).
LDA, THF, –78 °C
after 20 min
CN
r.t., 5 h
R
R
vinyl azide approach:
heat
N
3
4
1
N
N
2
N
R
N3
N
N
–
N2
vinyl nitrene
2H-azirine
nitrile ylide
NOH
NOH
NOH
Neber rearrangement:
LgO
N
O
N
2
H O
Me
F3C
MeO
R2
R2
R1
R1
R2
4a, 88%
4b, 80%
4c, 82%
R1
N
N
N
NH2
Scheme 2 Synthesis of oxime precusors 4a–c
Scheme 1 Synthetic approaches towards 2H-azirines
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Synlett
M. Baumann, I. R. Baxendale
Letter
Having gained rapid entry to quantities of the oxime
precursors we next turned our attention towards develop-
ing a flow process for their conversion into 2H-azirines and
related aziridines. To this end we configured a Vapourtec E-
series flow system so that a stream (stream A, Scheme 3)
containing the oxime substrate (4, 0.1 M MeCN) and tri-
ethylamine (1.2 equiv) was mixed at a T-piece with a sec-
ond stream containing methanesulfonyl chloride (0.12 M,
MeCN; stream B, Scheme 3) before entering a tubular con-
vection flow coil (CFC, 10 mL volume) maintained at 40 °C.
The resultant mesylated oxime would then enter a packed
glass column filled with silica-supported pyridine (2.5 g,
ethylamine hydrochloride generated presented a potential
risk of clogging of the narrow-bore tubing connectors. It
was found that although complete exclusion of triethyl-
amine still yielded the desired 2H-azirines, they existed as
their hydrochloride salts due to the embedded pyridyl moi-
ety. As these required base treatment, this approach was
not followed up further.
Next we explored the addition of various nucleophiles,
such as nitrile, trifluoromethyl, and hydride onto the 2H-
azirines 5. To this end we designed an extended process
that would merge the initial reaction stream containing the
2H-azirine product (ca. 0.05 M, MeCN) with an aqueous
10
1
.39 mmol/g functional loading ) as a base to promote dis-
solution of sodium cyanide (0.1 M, H O) in order to gener-
2
placement of the mesylate and thus formation of the de-
sired 2H-azirines via a 3-exo-trig cyclisation.
ate the corresponding nitrile derivatives (Scheme 4). After
passing through a second tubular reactor coil (10 mL) main-
tained at ambient temperature the desired nitrile product
was isolated after evaporation and aqueous extraction.
Pleasingly, it was quickly established that the desired ad-
ducts were formed not only in good yield but moreover
with excellent diastereoselectivity (dr >19:1).
HO
N
MeCN
MeCN
Py⋅SiO2
Ar2
Ar1
4
100 psi
N
+
Et3N
Ar1
Ar2
SiO2
2H-azirines 5
MsCl
10 mL CFC,
0 °C, 10 min
4
HO
N
Scheme 3 Flow set-up generating 2H-azirines 5
MeCN
MeCN
Py⋅SiO2
4-Py
Ar
4
N
+
Et3N
It was shown that this simple set-up was indeed suit-
able for delivering the desired 2H-azirine products 5 in a
mild and efficient flow sequence within an overall resi-
dence time of 20 minutes (16 minutes mesylation in CFC
Ar
4-Py
MsCl
SiO2
10 mL CFC,
0 °C, 10 min
4
2H-azirines 5
NOESY
100 psi
1
and 4 minutes cyclisation in the glass column). H NMR
H
H
spectroscopic analysis of the crude output indicated >85%
conversion of the oxime substrates to the 2H-azirine prod-
ucts. We therefore slightly modified the set-up to incorpo-
rate a small plug of silica gel (1 g) following the immobilised
pyridine base in order to trap the triethylamine hydrochlo-
ride salt formed in the process. This not only resulted in a
simple yet effective in-line purification, but also removed
coloured impurities from the product stream. The set-up
was used to rapidly generate a small selection of 2H-azirine
products as depicted in Figure 1.
H
R
N
N
10 mL CFC,
r.t., 5 min
NC
H
NaCN
0.1 M, H2O
6
6
a, R = CF3, 80%
b, R = Me, 71%
6c, R = OMe, 73%
Scheme 4 Continuous synthesis of aziridine-2-carbonitriles 6
Using NOESY NMR techniques it was shown that a cis
relationship between the two aryl rings existed as a result
of the nitrile approaching the azirine electrophile from the
sterically least hindered face. In addition, single-crystal X-
ray diffraction was used to confirm the stereochemical as-
signment (Figure 2).
N
N
N
N
F3C
5a, 77%
5b, 83%
N
N
MeO
5c, 87%
Figure 1 2H-Azirines 5a–c prepared in flow (isolated yields).
Figure 2 Relative stereochemistry of 6a as established by X-ray crystal-
lography
Additional experiments also revealed that other sol-
vents such as EtOAc or THF were also suitable for this trans-
formation. However, the diminished solubility of the tri-
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M. Baumann, I. R. Baxendale
Letter
One interesting feature of these aziridines bearing a ni-
trile substituent is their distinct red colour when in solid
form; whereas solutions possess an yellow-orange coloura-
tion. This is possibly indicative of a ‘push–pull’ interaction
between the electron-withdrawing nitrile group and the
electron-rich aziridine nitrogen atom. It was furthermore
found that these products slowly undergo decomposition
via a process likely to comprise a sequence of electrocyclic
ring opening of 6a and oxidative dimerization to generate
biscyanoimine species 7, the structure of which was con-
firmed by X-ray crystallography (Scheme 5).
HO
N
MeCN
MeCN
Py⋅SiO2
4
-Py
Ar
+
4
Et3N
N
Ar
4-Pyr
SiO2
MsCl
1
4
0 mL CFC,
2
H-azirines 5
0 °C, 10 min
fluoride monolith
H
100 psi
N
N
Ar
5
0 °C
F3C
H
10 mL CFC,
8
8
8
a, Ar = 4-F3CC6H4, 73%
b, Ar = 4-MeC6H4, 70%
c, Ar = 4-MeOC6H4, 81%
50 °C, 5 min
TMS-CF3
0.2 M THF)
(
Scheme 6 Telescoped flow approach towards trifluoromethylated
aziridines 8a–c
Pleasingly, this new set-up proved successful for the
telescoped synthesis of a small selection of trifluoromethyl-
ated aziridines starting from the corresponding oxime pre-
cursors. Importantly, all final products where isolated as
single diastereomers in good yield and high purity after col-
umn chromatography. In order to evaluate the relative ste-
reochemistry of our products we firstly turned to 2D NMR
techniques, specifically 1H- F HOESY experiments, con-
firming the expected cis relationship between the CF3
group and the adjacent proton. It was quickly established
that there was a cis correlation between these groups by the
observation of a through-space coupling at an estimated
spatial distance of ca. 2.7 Å compared to ca. 4.1 Å for the
trans diastereomer. Finally, a single-crystal X-ray structure
of compound 8a was secured and confirmed the assign-
ment unambiguously (Figure 3).
19
Scheme 5 Decomposition of 6a
Next, we decided to evaluate the viability of introducing
a trifluoromethyl group by reacting the azirine flow stream
with Ruppert’s reagent (TMSCF ) to yield the alternative tri-
fluoromethylaziridines as such fluorinated heterocyclic
structures are predisposed for potential applications in me-
dicinal chemistry programs. In order to achieve the syn-
thesis of these entities we decided to draw from our previ-
ous studies that had shown how flow chemical processing
offers a robust solution for safely and efficiently performing
3
11
12
fluorination reactions with various reagents such as DAST,
Ruppert’s reagent, and Selectfluor.13 Of particular benefit in
these studies was the successful development of a fluoride-
containing ion-exchange monolith that previously had al-
lowed us to activate TMSCF3 towards addition into alde-
hydes without requiring TBAF as a solution-phase reagent
that is often difficult to remove by chromatography. We
therefore prepared a monolithic reactor cartridge and load-
ed it with fluoride as previously reported. The crude 2H-
azirine flow stream was therefore mixed via a T-piece with
a stream containing Ruppert’s reagent (0.1 M, 2.0 equiv,
THF) before passing through the fluoride monolith main-
tained at 50 °C. A CFC reactor (10 mL volume, 50 °C) was
placed after the monolithic reactor to increase residence
time for the trifluoromethylation reaction. Finally, a 100 psi
back-pressure regulator was placed at the exit of the reactor
to maintain the system pressure, and the product was iso-
lated by direct evaporation of the output (Scheme 6).
Figure 3 Relative stereochemistry of 8a established by 2D NMR (1H-19F
HOESY, left) and X-ray crystallography (right)
Finally, we elected to study the conversion of in situ pre-
pared 2H-azirines into their corresponding aziridine deriv-
atives. In order to achieve this reduction, several options
were evaluated including flow-based hydrogenations with
13a
TM
14
the H-Cube system. In view of operational simplicity it
was, however, established that collecting the 2H-azirine
stream into a flask containing NaBH (1.5 equiv, 0.1 M THF)
4
would lead to the clean formation of the desired aziridine
products 9a–c that again were isolated as single diastereo-
mers. After aqueous workup and column chromatography
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M. Baumann, I. R. Baxendale
Letter
the relative stereochemistry of these entities was estab-
lished using NOESY NMR spectroscopy confirming the ex-
pected cis relationship (Figure 4).
(3) (a) O’Brien, C. Chem. Rev. 1964, 64, 81. (b) Neber, P. W.; v.
Friedolsheim, A. Ann. 1926, 449, 109. (c) Neber, P. W.; Uber, A.
Ann. 1928, 467, 52. (d) Hatch, M. J.; Cram, D. J. J. Am. Chem. Soc.
1953, 75, 38.
(
4) Pearson, W. H.; Lian, B. W. In Comprehensive Heterocyclic Chem-
istry II; Vol. 1a; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.,
Eds.; Pergamon Press: Oxford, 1996, 1–60.
NOESY
H
H
N
N
H
H
(5) (a) Escolano, C.; Duque, M. D.; Vazquez, S. Curr. Org. Chem. 2007,
1
1, 741. (b) Padwa, A.; Carlsen, H. J. Nitrile Ylides and Nitrenes
N
N
F3C
H H
from 2H-Azirines, In Reactive Intermediates; Vol. 2;
Abramovitch, R. A., Ed.; Plenum Press: New York/London, 1982,
55–121.
9
a, 89%
9b, 92%
H
N
(6) (a) Baumann, M.; Baxendale, I. R.; Ley, S. V. Synlett 2010, 749.
(b) Baumann, M.; Baxendale, I. R.; Kirschning, A.; Ley, S. V.;
N
MeO
Wegner, J. Heterocycles 2010, 82, 1297. (c) Baumann, M.;
Baxendale, I. R.; Kuratli, C.; Ley, S. V.; Martin, R. E.; Schneider, J.
ACS Comb. Sci. 2011, 13, 405. (d) Battilocchio, C.; Baumann, M.;
Baxendale, I. R.; Biava, M.; Kitching, M. O.; Ley, S. V.; Martin, R.
E.; Ohnmacht, S. A.; Tappin, N. D. C. Synthesis 2012, 44, 635.
7) (a) Baumann, M.; Rodriguez-Garcia, A. M.; Baxendale, I. R. Org.
Biomol. Chem. 2015, 13, 4231. (b) Baumann, M.; Baxendale, I. R.;
Ley, S. V.; Smith, C. D.; Tranmer, G. K. Org. Lett. 2006, 8, 5231.
(c) Smith, C. J.; Iglesias-Siguenza, J.; Baxendale, I. R.; Ley, S. V.
Org. Biomol. Chem. 2007, 5, 2758. (d) Baxendale, I. R.; Ley, S. V.;
Mansfield, A. C.; Smith, C. D. Angew. Chem. Int. Ed. 2009, 48,
9c, 90%
Figure 4 Disubstituted aziridines 9a–c prepared in flow
In summary, we have developed a simple, yet robust
flow process generating a selection of 2H-azirines from
(
15
readily accessible oxime precursors. The value of these
species was furthermore demonstrated through a selection
of telescoped reaction sequences showcasing the rapid for-
mation of a number of aziridine derivatives accomplished
by reaction with hydride, trifluoromethyl, and nitrile nucle-
ophiles. Importantly, these structures were obtained in
high yield and with exclusive cis diastereoselectivity pre-
senting opportunities towards further exploitation of this
versatile methodology.
4017. (e) Guetzoyan, L.; Nikbin, N.; Baxendale, I. R.; Ley, S. V.
Chem. Sci. 2013, 4, 764.
(
8) (a) Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247. (b) Dahanukar,
V. H.; Zavialov, I. A. Curr. Opin. Drug Discovery Dev. 2002, 5, 918.
9) Venturoni, F.; Nikbin, B.; Ley, S. V.; Baxendale, I. R. Org. Biomol.
Chem. 2010, 8, 1798.
(
(
(
(
(
(
10) Silica-supported pyridine (Py·SiO ) was purchased from Silicy-
2
cle (Quebec, Canada). Particle size: 40–63 μm, loading: 1.39
mmol/g.
11) Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and
Applications; Petrov, V. A., Ed.; John Wiley and Sons: Hoboken,
Acknowledgment
We gratefully acknowledge financial support from the Royal Society
(to MB and IRB). Furthermore we are grateful to Dr Dmitry Yufit and
2
009.
12) (a) Baumann, M.; Baxendale, I. R.; Ley, S. V. Synlett 2008, 2111.
b) Gustafsson, T.; Gilmoure, R.; Seeberger, P. H. Chem. Commun.
008, 3022.
Dr Andrei Batsanov (both Department of Chemistry, University of
Durham) for solving the X-ray crystal structures and Dr Juan A. Aguilar
(
2
(Department of Chemistry, University of Durham) for assistance with
HOESY NMR experiments.
13) (a) Baumann, M.; Baxendale, I. R.; Martin, L. J.; Ley, S. V. Tetrahe-
dron 2009, 65, 6611. (b) Amii, H.; Nagaki, A.; Yoshida, J.-I. Beil-
stein J. Org. Chem. 2013, 9, 2793.
Supporting Information
14) For selected examples highlighting hydrogenation reactions via
TM
the H-Cube system, please see: (a) Saaby, S.; Knudsen, K. R.;
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560391.
Ladlow, M.; Ley, S. V. Chem. Commun. 2005, 2909.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
(b) Franckevicius, V.; Knudsen, K. R.; Ladlow, M.; Longbottom,
D. A.; Ley, S. V. Synlett 2006, 889. (c) Baumann, M.; Baxendale, I.
R.; Hornung, C. H.; Ley, S. V.; Rojo, M. V.; Roper, K. A. Molecules
References and Notes
2014, 19, 9736; see also ref. 6a.
(
15) Typical Flow Procedure for the Synthesis of 2H-Azirines
Using a Vapourtec E-Series flow system, two streams containing
the oxime substrate (4, 0.1 M MeCN, 1.0 equiv; stream A) and
(
1) (a) Klebnikov, A. F.; Novikov, M. S. Tetrahedron 2013, 69, 3363.
b) Bergmeier, S. C.; Lapinsky, D. J. Prog. Heterocycl. Chem. 2009,
1, 69. (c) Palacios, F.; Ochoa de Retana, A. M.; de Marigorta, E.
M.; de los Santos, J. M. Org. Prep. Proced. Int. 2002, 34, 219.
d) Palacios, F.; Ochoa de Retana, A. M.; de Marigorta, E. M.; de
(
2
Et N (1.2 equiv; 0.3 mL/min; stream A) and MsCl (0.12 M MeCN,
3
1.2 equiv; 0.3 mL/min; stream B) were mixed in a T-piece prior
(
to entering a tubular flow coil (10 mL volume, 40 °C) in which
the mesylation occurred. The exiting flow stream was then
directed into an Omnifit glass column (10 mm i.d., 150 mm
length) filled with silica supported pyridine (2.5 g, 1.39
mmol/g loading) and silica gel (1 g) that was maintained at
ambient temperature. After exiting this column the crude reac-
tion mixture passed a backpressure regulator (100 psi) before
being collected. Final purification could be achieved via silica
los Santos, J. M. Eur. J. Org. Chem. 2001, 2401. (e) Padwa, A. Adv.
Heterocycl. Chem. 2010, 99, 1.
2) (a) Cludius-Brandt, S.; Kupracz, L.; Kirschning, A. Beilstein J. Org.
Chem. 2013, 9, 1745. (b) Bou-Hamdan, F. R.; Levesque, F.;
O’Brien, A. G.; Seeberger, P. H. Beilstein J. Org. Chem. 2011, 7,
(
10
1124.
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M. Baumann, I. R. Baxendale
Letter
column chromatography (20–50% EtOAc–hexanes) yielding the
(101 MHz, CDCl ): δ = 161.9 (C), 149.5 (2 CH), 149.4 (C), 135.1
3
desired 2H-aziridines typically in high yield as yellow oils.
(C, q, J = 23 Hz), 130.3 (2 CH), 126.4 (2 CH, q, J = 4 Hz), 126.3 (C),
19
4-{3-[4-(Trifluoromethyl)phenyl]-2H-azirin-2-yl}pyridine
123.3 (CF , q, J = 271 Hz), 120.9 (2 CH), 33.6 (CH). F NMR (376
3
(
5a)
MHz, CDCl ): δ = –63.3 . IR (neat): ν = 1602 , 1413 , 1322 , 1168 ,
1126 , 1065 , 1017 , 851 cm . LC–MS (ESI-TOF): m/z = 263.1
3
1
–1
Yield 201 mg (0.77 mmol, 77%); yellow oil. H NMR (400 MHz,
CDCl ): δ = 8.47 (2 H, d, J = 8.0 Hz), 7.97 (2 H, d, J = 8.0 Hz), 7.79
[M + H]. HRMS (ESI-TOF): m/z calcd for C14H10N F : 263.0796;
found: 263.0792 (Δ 0.4 mDa).
3
2 3
13
(2 H, d, J = 8.0 Hz), 7.02 (2 H, d, J = 8.0 Hz), 3.29 (1 H, s). C NMR
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 159–163