Observations on the modified wenker synthesis of aziridines and the development of a biphasic system

Article abstract of DOI:10.1021/jo302615g

A cheap and reliable process for the modified Wenker cyclization to afford aziridines has been achieved using biphasic conditions for a range of amino alcohol starting materials. A 100 mmol "one-pot" process has also been devised, and the enantiopurity of the starting amino alcohol is retained in the aziridine product.

Full text of DOI:10.1021/jo302615g

Note
pubs.acs.org/joc
Observations on the Modified Wenker Synthesis of Aziridines and
the Development of a Biphasic System
Benjamin R. Buckley,* Anish P. Patel, and K. G. U. Wijayantha*
Department of Chemistry, Loughborough University, Loughborough, Leicestershire, LE11 3TU, U.K.
S
* Supporting Information
ABSTRACT: A cheap and reliable process for the modified
Wenker cyclization to afford aziridines has been achieved using
biphasic conditions for a range of amino alcohol starting
materials. A 100 mmol “one-pot” process has also been
devised, and the enantiopurity of the starting amino alcohol is
retained in the aziridine product.
ring close to form the desired aziridine. This is an attractive
route due to the plethora of starting materials readily available
either through synthesis of amino alcohols or by direct
purchase from commercial suppliers. However, the harsh
reaction conditions employed in the original synthesis (treat-
ment with sulfuric acid and vacuum dehydration) have
precluded its use in some circumstances.
ziridines are important synthetic building blocks for the
Aconstruction of complex nitrogen-containing compounds
and are found in several natural products, for example the
mitomycins and azicemicins. The construction of the aziridine
ring system has been studied intensively over many decades,
and a host of approaches have been identified, some examples
of which are shown in Scheme 1.1,2
For example, Xu and co-workers have reported some
unexpected products that were obtained after treatment of
certain amino alcohols under conventional Wenker conditions,
in which vicinal amino alcohols in hot sulfuric acid readily
undergo elimination of water.3,4 In an improved process Xu and
co-workers have converted a range of amino alcohols, under
mild conditions, into their corresponding hydrogen sulfate salts
with chlorosulfonic acid; the sulfates were then cyclized in good
yield with sodium hydroxide or sodium carbonate (Scheme 2).5
Most approaches require the existence of a protecting group
at nitrogen, which is invariably a sulfonate group such as the
tosyl group. Approaches toward N−H aziridines are much less
frequent, and perhaps the most well-known of these is the
Wenker synthesis, in which an amino alcohol is first treated
with sulfuric acid and then in a subsequent step with base to
Scheme 1. Common Routes towards Aziridines
Scheme 2. Xu and Co-workers’ Route to Aziridines
In connection with a number of research programs in our
laboratory we required a mild, reliable, cheap, and scalable
synthesis of a range of N−H aziridines. There are a plethora of
reports in this area, and we were attracted to the Wenker and
related syntheses.6−9 Hence we initiated a program to prepare
the aziridines required using the mild conditions reported by
Received: November 30, 2012
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
Note
Xu and co-workers above. Synthesis of the hydrogen sulfate
adducts 1−6 from amino alcohols was straightforward and
proceeded in good to excellent yields, employing chlorosulfonic
acid in acetonitrile at 0 °C (Table 1).
Table 2. Attempted Synthesis of Aziridines under Aqueous
Conditions
a
a
Table 1. Synthesis of the Hydrogen Sulfate Adducts
b
entry
(aq.) NaOH concn (M)
ratio (amino alcohol 7/aziridine 8)
1
1
2
68:32
55:45
67:33
52:48
57:43
49:51
57:43
66:34
57:43
59:41
82:18
79:21
2
3
3
4
4
5
5
6
6
7
7
8
8
9
9
10
11
12
10
11
12
a
General conditions: 5 mmol of substrate, 6.0 M aq. NaOH/cosolvent
b
(1:1), Δ 18 h. Ratio evaluated from the 1H NMR spectrum by
integration of the benzylic C−H peak; isolated yields were typically
60−80%.
Table 3. Cosolvent Optimization for the Synthesis of
a
Aziridines
b
c
entry
cosolvent
ratio (amino alcohol 7/aziridine 8)
yield
nd
a
General conditions: Amino alcohol (10 mmol), MeCN (75 mL), 0
b
1
2
3
4
5
6
7
none
16:84
5:95
°C, chlorosulfonic acid (10 mmol), 3.5 h. Isolated yield.
toluene
EtOAc
THF
85%
d
<5:<5
19:81
50:50
<5:<5
<5:<5
nd
However, in our hands the synthesis of the cyclized aziridines
proved troublesome; for example, when using the hydrogen
sulfate adduct 1 the sole product produced when employing
aqueous 6.2 M NaOH or saturated aqueous Na2CO3 at room
temperature was phenylglycinol 7. Increasing the reaction
temperature to 70 °C under the 6.2 M NaOH conditions
resulted in a 1:1 mixture of phenylglycinol 7 to aziridine 8,
which could be further improved, by heating under reflux, to an
84:16 ratio in favor of the aziridine 8. We found that a screen of
the NaOH concentration only served to increase the ratio of
amino alcohol produced (for example, 12 M afforded a 79:21
ratio in favor of the amino alcohol; see Table 2).
In an attempt to increase the ratio toward an acceptable and
reproducible level of aziridine we opted to add a cosolvent to
the reaction; a screen shown in Table 3 shows that the use of
toluene under biphasic conditions provides the optimal ratio of
aziridine product, and an isolated yield of 85% was consistently
observed.
Having optimized the conditions for aziridine synthesis from
phenyl glycinol hydrogen sulfate we then went on to apply
these conditions over a range of substrates for aromatic,
aliphatic, and spirocyclic aziridine formation (Table 4). Good
to excellent yields were obtained. However, we encountered
problems with several substrates due to their volatility; hence
we opted to isolate these as the corresponding tosylate, with
yields over the two steps varying from 55 to 65%.
nd
nd
i-PrOH
MeCN
acetone
d
nd
d
nd
a
General conditions: 5 mmol of substrate, 6.0 M aq. NaOH/cosolvent
b
(1:1), Δ 18 h. Ratio evaluated from the 1H NMR spectrum by
c
integration of the benzylic C−H peak. Isolated yield after
d
1
chromatography. Complex mixture observed by H NMR spectros-
copy.
(58 mmol); gratifyingly we observed an 80% yield of aziridine.
We also carried out the process with enantioenriched starting
material and observed complete retention of stereochemical
information in the aziridine product (98% ee, Scheme 3).
As the initial sulfate salt was prepared in acetonitrile, filtered,
and then resuspended in toluene before addition of the sodium
hydroxide, we were intrigued to find out if the process could be
converted to a “one pot” protocol. We therefore dissolved 100
mmol of N-benzylethanolamine in toluene, cooled the solution
to 0 °C, and added the chlorosulfonic acid; immediate
precipitation of the salt ensued, and after 2 h we directly
added sodium hydroxide (6 M) and brought the reaction to
reflux. After 18 h the reaction was worked up in the usual
manner, and we obtained a 62% yield of the desired aziridine
after chromatography (Scheme 4).
In order to test the robustness of the procedure we carried
out the cyclization of the phenyl glycinol salt 1 on a larger scale
In conclusion we have developed a reliable and cheap
approach to simple aziridines under biphasic conditions. We are
B
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Note
a
Table 4. Aziridine Synthesis
EXPERIMENTAL SECTION
■
General Experimental. All infrared thin film spectra were
acquired using sodium chloride plates. All H and 13C NMR spectra
1
were measured at 400.13 and 100.62 MHz. The solvent used for NMR
spectroscopy was CDCl3 (unless stated otherwise) using TMS
(tetramethylsilane) as the internal reference. Chemical shifts are
given in parts per million (ppm), and J values are given in Hertz (Hz).
All mass spectra were recorded by an orbitrap HRMS with an ion max
source and ESI probe. Melting points are uncorrected. All chromato-
graphic manipulations used silica gel as the adsorbent. Reactions were
monitored using thin layer chromatography (TLC) on aluminum
backed plates. TLC was visualized by UV radiation at a wavelength of
254 nm, or stained by exposure to an ethanolic solution of
phosphomolybdic acid (acidified with concentrated sulfuric acid),
followed by charring where appropriate. Purification by column
chromatography used silica adsorbent. Reaction solvents were
obtained commercially dry and were used without further purification.
The enantiomeric excess was determined by chiral HPLC. A Eurocel
01 (manufactured by Knauer, Chiracel OD equivalent) column was
used for the determination of an enantiomeric excess of the
nonracemic styrene aziridine reaction on an HPLC instrument, with
the ultraviolet absorption detector set at 254 nm, attached to a data
station.
Representative Procedure for the Formation of the Amino-
sulfate Salts. Amino alcohol (10 mmol) was dissolved in acetonitrile
(75 mL), and the reaction mixture was cooled to 0 °C followed by the
dropwise addition of chlorosulfonic acid (1.17 g, 0.66 mL, 10 mmol).
The resulting heterogeneous solution was stirred constantly at room
temperature for 3.5 h. The reaction mixture was then filtered under
vacuum, followed by washing with ethyl acetate and diethyl ether. The
filter cake was dried in air under vacuum and then transferred to an
RBF and placed under high vacuum to afford the aminosulfate salt as a
colorless solid.
2-Ammonio-2-phenylethyl Sulfate 1.10 Colorless solid (1.76 g,
81%), mp 245−246 °C (lit.10 247 °C); 1H NMR (400 MHz, CDCl3)
4.30−4.32 (m, 2H), 4.65−4.69 (m, 1H), 7.38−7.43 (m, 5H) ppm; 13C
NMR (100 MHz, CDCl3) 54.0, 68.7, 127.2, 129.3, 129.8, 132.4 ppm;
IR (CH2Cl2) 998, 1161, 1227, 1252, 1458, 1620, 2943 cm−1; HRMS
(ESI) calcd for C8H11NO4S (M+Na) 240.0306, found 240.0295.
2-Ammonio-3-phenylpropyl Sulfate 2.11 Colorless solid (2.08 g,
90%), mp 266−272 °C (lit.11 265−270 °C); H NMR (400 MHz,
1
a
General conditions: Substrate (5 mmol), 6.0 M aq. NaOH/toluene
CDCl3, Me4Si) 2.90−3.02 (m, 2H), 3.74−3.80 (m, 1H), 3.99 (dd, J =
5.9, 11.4 Hz, 1H), 4.16 (dd, J = 3.1, 11.4 Hz, 1H), 7.24−7.36 (m, 5H)
ppm; 13C NMR (100 MHz, CDCl3, Me4Si) 33.7, 51.1, 65.6, 126.8,
128.3, 128.6, 134.0 ppm; IR (CH2Cl2) 1008, 1170, 1224, 1247, 1457,
1610, 2992 cm−1; HRMS (ESI) calcd for C9H13NO4S (M+Na)
254.0463, found 254.0451.
b
(1:1), Δ 18 h. Isolated yield after chromatography; yield in
parentheses is from a 58 mmol reaction. Average yield over three
individual runs. Reaction conditions: (i) Substrate (5 mmol), 6.0 M
aq. NaOH/toluene (1:1), Δ 18 h; (ii) p-tolsulfonyl chloride (5 mmol),
Et3N (5 mmol) 12 h.
c
d
2-Ammonio-4-methylpentyl Sulfate 3. Colorless solid (1.38 g,
Scheme 3. Retention of Stereochemical Information after the
Cyclization Process
70%), mp 287−288 °C. Anal. Calcd for C6H15NO4S: C, 36.5; H, 7.7;
1
N, 7.1. Found: C, 36.3; H, 7.5; N, 7.0. H NMR (400 MHz, CDCl3)
0.86 (d, J = 6.6 Hz, 6H) 1.42−1.53 (m, 2H), 1.60−1.65 (m, 1H),
3.55−3.61 (m, 1H), 4.02 (d, J = 6.6, 11.6 Hz, 1H), 4.20 (d, J = 3.2,
11.6 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) 21.2, 21.6, 23.7
37.3, 49.2, 67.4 ppm; IR (CH2Cl2) 1004, 1167, 1228, 1259, 1608
cm−1; HRMS (ESI) calcd for C6H15NO4S (M+Na) 220.0619, found
220.0610.
2-(Benzylammonio)ethyl Sulfate 4.12 Colorless solid (1.73 g,
75%), mp 245−247 °C (lit.12 244−246 °C); H NMR (400 MHz,
1
Scheme 4. The “One-Pot” Process
CDCl3) 3.36−3.38 (m, 2H), 4.25−4.28 (m, 4H), 7.44 (s, 5H) ppm;
13C NMR (100 MHz, CDCl3) 45.9, 51.0, 63.4, 129.3, 129.7, 129.9,
130.4 ppm; IR (CH2Cl2) 1028, 1192, 1214, 1251, 1457, 1613, 3003
cm−1; HRMS (ESI) calcd for C9H13NO4S (M+Na) 254.0463, found
254.0449.
2-Ammonio-3,3-dimethylbutyl Sulfate 5. Colorless solid (1.68 g,
97%), mp 278−280 °C. Anal. Calcd for C6H15NO4S: C, 36.5; H, 7.7;
1
N, 7.1. Found: C, 36.6; H, 7.5; N, 6.9. H NMR (400 MHz, CDCl3)
0.98 (s, 9H), 3.31 (dd, J = 3.3, 8.8 Hz, 1H), 4.08 (dd, J = 8.8, 11.4 Hz,
1H), 4.30 (dd, J = 3.3, 11.4, 1H) ppm; 13C NMR (100 MHz, CDCl3)
25.3, 31.7, 59.3, 65.8 ppm; IR (CH2Cl2) 1009, 1180, 1219, 1246, 1611
now applying this system to a range of aziridines for use in
future research areas.
C
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The Journal of Organic Chemistry
Note
cm−1; HRMS (ESI) calcd for C6H15NO4S (M+Na) 220.0619, found
220.0609.
(1-Ammoniocyclopentyl)methyl Sulfate 6. Colorless solid (1.42 g,
acid (11.7 g, 6.6 mL, 100 mmol). The resulting heterogeneous
solution was stirred constantly at room temperature for 2 h. NaOH
(300 mL, aq. 6 M) was added, and the resulting biphasic solution was
heated under reflux for 18 h with constant stirring. On completion the
organic phase was separated and the aqueous phase was extracted with
ethyl acetate (3 × 50 mL). The organics were combined, dried over
MgSO4, and evaporated under reduced pressure to afford a pale yellow
oil. Purification by column chromatography on silica gel afforded the
aziridine 11 as a colorless oil (8.25 g, 62%).
73%), mp 258−260 °C. Anal. Calcd for C6H13NO4S: C, 36.9; H, 6.7;
1
N, 7.2. Found: C, 36.8; H, 6.7; N, 7.1. H NMR (400 MHz, CDCl3)
1.67−1.79 (m, 6H), 1.86−1.93 (m, 2H), 4.04 (m, 2H); 13C NMR
(100 MHz, CDCl3) 23.8, 33.4, 63.3, 70.6; IR (CH2Cl2) 999, 1108,
1207, 1246, 1634 cm−1; HRMS (ESI) calcd for C6H13NO4S (M+Na)
218.0463, found 218.0451.
General Procedure for the Cyclization To Form Aziridines.
N-H Aziridines. Aminosulfate salt (5.0 mmol) was dissolved in NaOH
(40 mL, aq. 6 M) followed by the addition of toluene (40 mL). The
resulting biphasic solution was heated under reflux for 18 h with
constant stirring. On completion the organic phase was extracted with
ethyl acetate, dried over MgSO4, and evaporated under reduced
pressure, followed by purification by column chromatography on silica
gel, affording the aziridine as a colorless oil.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of all 1H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: b.r.buckley@lboro.ac.uk; u.wijayantha@lboro.ac.uk.
Notes
■
N-Ts Aziridines. Aminosulfate salt (5.0 mmol) was dissolved in
NaOH (40 mL, aq. 6 M) followed by the addition of toluene (40 mL).
The resulting biphasic solution was heated under reflux for 18 h with
constant stirring. On completion the organic phase was extracted with
ethyl acetate, dried over MgSO4, and evaporated under reduced
pressure, followed by addition of p-toluenesulfonyl chloride (0.95 g,
5.0 mmol) and triethylamine (0.51 g/0.70 mL, 5.0 mmol). The
resulting reaction mixture was stirred at room temperature for 12 h.
On completion the reaction mixture was washed with water, extracted,
dried over MgSO4, and evaporated under reduced pressure followed
by purification by column chromatography on silica, affording the
aziridine as a colorless solid or oil.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
B.R.B. and K.G.U.W. would like to thank Research Councils
UK for RCUK fellowships and Loughborough University for
funding a PhD studentship (to A.P.P.). B.R.B. would also like
to thank Eli Lilly Co. for an equipment donation grant.
2-Phenylaziridine 8.13 Colorless oil (0.51 g, 80%); H NMR (400
1
REFERENCES
■
MHz, CDCl3) 1.83 (d, J = 3.2 Hz, 1H), 2.24 (d, J = 6.0 Hz, 1H),
3.04−3.06 (m, 1H), 7.25−7.36 (m, 5H) ppm; 13C NMR (100 MHz,
CDCl3) 29.3, 32.1, 125.7, 127.1, 128.5, 140.5 ppm; HRMS (ESI) calcd
For C8H9N (M+H) 120.0808, found 120.0807.
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(12) Tomalia, D. A.; Falk, J. C. J. Heterocycl. Chem. 1972, 9, 891.
(13) Mison, P.; Chaabouni, R.; Diab, Y.; Martino, R.; Lopez, A.;
Lattes, A.; Wehrli, F. W.; Wirthlin, T. Org. Magn. Reson. 1976, 8, 79.
(14) El-Abadelah, M. M.; Sabri, S. S.; Jarrar, A. A.; Zarga, M. H. A. J.
Chem. Soc., Perkin Trans. 1 1979, 2881.
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(17) Kawamura, K.; Fukuzawa, H.; Hayashi, M. Org. Lett. 2008, 10,
3509.
2-Benzylaziridine 9.14 Colorless oil (0.57 g, 85%); H NMR (400
1
MHz, CDCl3) 1.46 (d, J = 3.6 Hz, 1H), 1.83 (d, J = 4.7 Hz, 1H),
2.19−2.25 (m, 1H), 2.66 (dd, J = 6.0, 14.6 Hz, 1H), 2.81 (dd, J = 6.0,
14.6 Hz, 1H), 7.21−7.33 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3)
24.8, 31.00, 40.0 126.4, 128.5, 128.8, 139.2 ppm; HRMS (ESI) calcd
For C9H11N (M+H) 134.0970, found 134.0980.
2-iso-Butyl-1-tosylaziridine 10.15 Colorless oil (0.76 g, 60%); H
1
NMR (400 MHz, CDCl3) 0.88 (dd, J = 2.1, 4.7 Hz, 6H), 1.28−1.40
(m, 2H), 1.57−1.6 (m, 1H), 2.02 (d, J = 4.7 Hz, 1H), 2.45 (s, 3H),
2.63 (d, J = 7.1 Hz, 1H), 2.76−2.82 (m, 1H), 7.34 (d, J = 8.5 Hz, 2H)
ppm; 13C NMR (100 MHz, CDCl3) 21.7, 21.9, 22.8, 26.8, 34.1, 39.1,
40.4, 128.0, 129.6, 135.3, 144.4 ppm; IR (CH2Cl2) 2958, 1494, 1376,
1365, 1184 cm−1; HRMS (ESI) calcd. For C13H19NO2S (M+Na)
276.1034, found 276.1021.
1-Benzylaziridine 11.16 Colorless oil (0.40 g, 60%); 1H NMR (400
MHz, CDCl3) 1.28 (t, J = 2.4 Hz, 2H), 1.83 (t, J = 2.4 Hz, 2H), 3.39
(s, 2H), 7.24−737 (m, 5H); 13C NMR (100 MHz, CDCl3) 27.6, 65.3,
127.0, 128.0, 128.4, 139.3 ppm; IR (CH2Cl2) 1358, 1496, 3031 cm−1;
HRMS (ESI) calcd for C9H11N (M+H) 134.0970, found 134.0963.
2-tert-Butyl-1-tosylaziridine 12.17 Colorless solid (0.82 g, 65%),
mp 58−60 °C (lit.17 58.5−59.2 °C); H NMR (400 MHz, CDCl3)
1
0.79 (s, 9H), 2.17 (d, J = 4.5 Hz, 1H), 2.44 (s, 3H), 2.49−2.57 (m,
2H), 7.33 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H) ppm; 13C NMR
(100 MHz, CDCl3) 21.6, 26.2, 30.1, 30.3, 48.9, 128.2, 129.6, 135.2,
144.4 ppm; IR (CH2Cl2) 2958, 1598, 1368, 1322, 1185 cm−1; HRMS
(ESI) calcd for C13H19NO2S (M+Na) 276.1034, found 276.1020.
2-Cyclopentyl-1-tosylaziridine 13. Colorless solid (0.82 g, 65%),
1
mp 77−79 °C (lit. 82−83 °C); H NMR (400 MHz, CDCl3) 1.66−
1.91 (m, 6H), 2.17−2.27 (m, 2H), 2.43 (s, 3H), 2.55 (s, 2H), 7.32 (d,
J = 8.3 Hz, 2H), 7.83 (d, J = 8.3 Hz, 2H) ppm; 13C NMR (100 MHz,
CDCl3) 21.6, 25.6, 32.3, 40.7, 56.7, 127.5, 129.5, 137.5, 143.9 ppm; IR
(CH2Cl2) 2960, 1599, 1364, 1319, 1184 cm−1; HRMS (ESI) calcd for
C13H17NO2S (M+Na) 274.0878, found 274.0866.
The One-Pot Protocol. N-Benzylethanolamine (15.2 g, 100 mmol)
was dissolved in toluene (300 mL), and the reaction mixture was
cooled to 0 °C followed by the dropwise addition of chlorosulfonic
D
dx.doi.org/10.1021/jo302615g | J. Org. Chem. XXXX, XXX, XXX−XXX