Solvent dependency of the yield of an N-monosubstituted diaziridine: A GC-MS study

Article abstract of DOI:10.1016/j.tetlet.2012.03.105

Due to the growing importance of diaziridines in the drug design and the increasing popularity of diazirines as carbene precursors, the solvent influence on the yield of an N-monosubstituted diaziridine has been studied. It was observed that data points w

Full text of DOI:10.1016/j.tetlet.2012.03.105

Tetrahedron Letters 53 (2012) 2822–2824
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Solvent dependency of the yield of an N-monosubstituted diaziridine: a
GC–MS study
⇑
Peter Billing, Udo H. Brinker
Institut für Organische Chemie, Universität Wien, Währinger Straße 38, A-1090 Wien, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
Due to the growing importance of diaziridines in the drug design and the increasing popularity of
diazirines as carbene precursors, the solvent influence on the yield of an N-monosubstituted diaziridine
has been studied. It was observed that data points within every solvent class are clustering and the yield
in general is the highest in apolar aprotic solvents.
Received 29 February 2012
Revised 21 March 2012
Accepted 26 March 2012
Available online 4 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Diaziridines
Solvent parameters
GC–MS
Optimization
Diaziridines without alkyl substituents on the nitrogen atoms
are fairly labile and reactive due to their strain, and the reactivity
is enhanced when the nitrogens are unsymmetrically substituted.
These facts make diaziridines powerful alkylating agents and such
compounds have therefore been tested as inhibitors of enzymes
precursors for the generation of carbenes for example in photo-
affinity labeling experiments.4f
Most C,C-disubstituted diaziridines4g are available only in poor
to moderate yields.5–10 This is often due to steric hindrance caused
by substituents and probably stereoelectronic factors that are not
known in detail. Thus, it is desirable to have a better understanding
of the reaction in general and the importance of the solvent used to
improve yields. Therefore, it seemed prudent to examine the sol-
vent influence on diaziridine synthesis with respect to the yield.
From the literature it is known that in general diaziridine syn-
theses with hydroxylamine-O-sulfonic acid (HOSA) have been per-
formed either in water,11a methanol,11b or pure liquid ammonia.11c
such as monoamine oxidase (MAO)1 and
a
-glycosidase2, respec-
tively. This could provide a medicinal treatment against psychic
disorders and diabetes mellitus type 2, respectively.
Moreover, diaziridines can be used in heterocyclic chemistry as
building blocks for the synthesis of hetero atom-containing five-
membered rings.3 Finally, oxidation of C,C-disubstituted dia-
ziridines provides easy access to diazirines,4 which are popular
NH2
O
N
3h, rt solvent
- H2O
+
3
1
2
TS
NH2
N
2
N
NH
2-
SO4
NH
NH
O
+
H2N
O
SO3H
2
SO3H
5
4
3
Figure 1. Proposed mechanism of formation of diaziridine 4.
⇑
Corresponding author. Tel.: +43 1 4277 52121.
E-mail address: udo.brinker@univie.ac.at (U.H. Brinker).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.105

P. Billing, U. H. Brinker / Tetrahedron Letters 53 (2012) 2822–2824
2823
(1), benzylamine (2), and HOSA, which was performed similar to
the procedure of Schmitz and Ohme.11k,12
The reason for this decision was based on the fact that the yield
of the corresponding C,C-disubstituted diaziridine, 1,2-diazaspi-
ro[2,7]decane, with 22% is quite low.5 Thus, any improvement or
worsening of this yield should easily be detected. In order to cover
important solvent properties, five different solvents of the follow-
ing solvent classes (aprotic apolar, aprotic dipolar, and protic dipo-
lar) were used: pentane (nPen), hexane (nHex), dichloromethane
(DCM), cyclohexane (cHex), toluene (Tol), acetonitrile (MeCN),
diethyl ether (Et2O), tetrahydrofuran (THF), methyl tert-butyl ether
(TBME), ethyl acetate (EA), methanol (MeOH), ethanol (EtOH), iso-
propyl alcohol (iPrOH), 1-butanol (nBuOH), 1,4-butanediol
(nBu(OH)2).
For the determination of yields, a GC–MS calibration curve with
xylene as internal standard was made. For this purpose one reac-
tion batch was worked up, the content of diaziridine 4 was deter-
mined via 1H NMR with dimethyl malonate as internal standard
and the crude product was used for the construction of the GC–
MS calibration curve. In order to verify the yields of all other
reaction batches, the diaziridine content from each reaction mix-
ture was determined by using this curve.
β
Figure 2. Calibration curve plot showing the dependency of the GC–MS ratio
according to the mass concentration of 4.
Figure 2 demonstrates the linear dependency between the GC–
MS ratio (rGC–MS) and the diaziridine concentration. With a value of
0.982 the regression coefficient R2 is quite satisfactory. Further-
more, the confidence intervals (CI) at a confidence level of 95%
are given.
In order to find out how diaziridine yields depend on the sol-
vent used, yields were assigned for four solvent parameters: the
relative dielectric constant (erel
)
13, the dipole moment (
l
)
13, the
) (calcu-
eluting power (E0)14, and the calculated polarizability (c
a
lated with ChemSketch 12.0). No correlation could be observed be-
tween any of those solvent parameters and the calculated yields.
One of these correlations is depicted in Figure 3. All other correla-
tions are given in the Supplementary data (see Figs. 4–6). The val-
ues for the data points are given in Table 1.
It turns out that none of the solvent parameters used is able to
describe the obtained yields by its own. However, from Table 1 it is
obvious that the experimentally observed diaziridine yield is the
highest in apolar aprotic solvents. With a yield of 42% it is at its
maximum in cHex and Tol, which is an enormous improvement
compared to the usually used solvent MeOH, where the yield
amounts to 3.1% only (Table 1). No literature data for the yield of
4 in MeOH as solvent is available.
Figure 3. Correlation of eluting power versus yield.
The synthesis of diaziridines was reported by three research
groups between 1959 and 1961.11 All these groups carried out
the reactions in methanol–ammonia solutions. In 1961 Schmitz
and Ohme made diaziridines commercially available.11k
As for the mechanism of diaziridine generation these three re-
search groups invoked the intermediate formation of an imine,
which is nucleophilically attacked by HOSA. Thereby an aminal is
formed, which eliminates the very good leaving group hydrogen
sulfate via an intramolecular nucleophilic substitution reaction fol-
lowed by a proton elimination step (Fig. 1).
In conclusion, for diaziridine formation from ketones, benzyl-
amine, and HOSA it is recommended to apply apolar aprotic sol-
1-Benzyl-1,2-diazaspiro[2.7]decane (4) was used as model diaz-
iridine (Fig. 1). It is obtained from the reaction of cyclooctanone
Table 1
Solvents used, their parameters,13,14 and experimentally observed GC–MS ratios
13
Entry
Solvent
14E0
ca
(Å3)
l13 (D)
e
rel
rGC–MS
Yielda (%)
1
2
3
4
5
6
7
8
nPen
nHex
DCM
cHex
Tol
MeCN
Et2O
THF
0.00
0.01
0.42
0.04
0.29
0.65
0.38
0.45
—
0.58
0.95
0.88
0.82
0.77
0.42
10.0
11.8
6.49
11.0
12.3
4.45
8.85
7.95
10.7
8.86
3.26
5.09
6.91
8.77
11.0
0.00
0.00
1.55
0.00
0.429
3.44
1.30
1.75
—
1.88
1.70
1.70
1.66
1.75
3.98
1.84
1.88
8.93
2.02
2.38
37.5
4.34
7.60
4.50
6.00
32.2
24.5
19.9
17.5
31.5
0.692
0.677
0.192
0.927
0.905
0.039
0.538
0.458
0.139
0.127
0.309
0.613
0.135
0.335
0.039
34 0.2
34 0.2
17 0.2
42 0.2
42 0.2
12 0.2
30 0.2
26 0.2
15 0.2
15 0.2
3.1 0.03
5.3 0.03
2.4 0.03
3.6 0.03
2.0 0.03
9
TBME
EA
10
11
12
13
14
15
MeOH
EtOH
iPrOH
nBuOH
nBu(OH)2
a
Yields were calculated from the calibration curve of Figure 2. Measurement uncertainties were calculated via Gaussian’s propagation of uncertainty.

2824
P. Billing, U. H. Brinker / Tetrahedron Letters 53 (2012) 2822–2824
6. (a) Kupfer, R.; Rosenberg, M. G.; Brinker, U. H. Tetrahedron Lett. 1996, 37, 6647–
6648; (b) Krois, D.; Brinker, U. H. Synthesis 2001, 379–381.
7. Zhao, X.; Wu, G.; Yan, C.; Lu, K.; Li, H.; Zhang, Y.; Wang, J. Org. Lett. 2010, 12,
5580–5583.
vents such as cyclohexane and toluene. Use of such solvents in the
reaction to prepare diaziridine 4 clearly leads to superior results,
when compared to reactions in water, methanol, or pure liquid
ammonia as was suggested originally.11a–c
ˇ
8. Mieusset, J.-L.; Bespokoev, A.; Pacar, M.; Abraham, M.; Arion, V. B.; Brinker, U.
H. J. Org. Chem. 2008, 73, 6551–6558.
9. Shustov, G. V.; Varlamov, S. V.; Rauk, A.; Kostyanovskii, R. G. J. Am. Chem. Soc.
1990, 112, 3403–3408.
10. Isaev, S. D.; Karpenko, N. F.; Kolyada, G. G.; Novikov, S. S.; Yurchenko, A. G. Zh.
Org. Khim. 1978, 14, 767–772.
11. (a) Schmitz, E.; Ohme, R. Org. Synth. 1965, 45, 83–86; (b) Bond, M. R.; Zhang, H.;
Vu, P. D.; Kohler, J. J. Nat. Protoc. 2009, 4, 1044–1063; (c) Sasnovsk, G.; Lukszo, J.
Z. Naturforsch. B 1983, 38B, 884–894; (d) Abendroth, H. J.; Heinrich, G. Angew.
Chem. 1959, 71, 283–284; (e) Ger. Pat. 1082889 (1960).; (f) Chem. Abstr. 1961,
55, 16930.; (g) Paulsen, S.R. Belg. Pat. 588352 (1959).; (h) Schmitz, E. Angew.
Chem. 1959, 71, 127; (i) Schmitz, E.; Ohme, R. Tetrahedron Lett. 1961, 612–614;
(j) Paulsen, S. R.; Huck, G. Chem. Ber. 1961, 94, 968–975; (k) Schmitz, E.; Ohme,
R. Chem. Ber. 1961, 94, 2166–2173.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
03.105.
References and notes
1. Paget, C. J.; Davis, C. S. J. Med. Chem. 1964, 7, 626–628.
12. General procedure for the preparation of 4: 1.00 mol equiv of cyclooctanone (1)
was dissolved in dry solvent at ambient temperature to yield a concentration of
about 0.5 M. 3.15 mol equiv of benzylamine (2) were added and the resulting
turbid solution was stirred for 3.5 h. After that 1.05 mol equiv of HOSA were
2. Kapferer, P.; Birault, V.; Poisson, J.-F.; Vasella, A. Helv. Chim. Acta 2003, 86,
2210–2227.
3. (a) Carboni, B.; Toupet, L.; Carrié, R. Tetrahedron 1987, 43, 2293–2302; (b)
El’natanov, Y. I.; Kostyanovskii, R. G. Seriya Khimicheskaya 1988, 1858–1862; (c)
Bin Mohamed, M.; Parrick, J. Org. Prep. Proced. Int. 1981, 13, 371–374.
4. (a) Church, R. F. R.; Kende, A. S.; Weiss, M. J. J. Am. Chem. Soc. 1965, 87, 2665–
2671; (b) Church, R. F. R.; Weiss, M. J. J. Org. Chem. 1970, 35, 2465–2471; (c)
Frey, H. M. Pure Appl. Chem. 1964, 9, 527–538; (d) Shustov, G. V.; Tavakalyan, N.
B.; Pleshkova, A. P.; Kostyanovskii, R. G. Khim. Geterotsikl. Soedin. 1981, 810–
815; (e) Liu, M. T. H. Chemistry of Diazirines; CRC: Boca Raton, 1987; (f)
Dubinski, L.; Krom, B. P.; Meijler, M. M. Bioorg. Med. Chem. 2012, 20, 554–570;
(g) Alvarez-Builla, J.; Vaquero, J. J.; Barluenga, J. In Modern Heterocyclic
Chemistry; Wiley-VCH: Weinheim, 2011; Vol. 1, pp. 117–122.
added at once. After 10 min, 9
Gilson pipette and added to a solution consisting of 900
standard solution (0.25 mg/mL of xylene in EA) and 91
into a GC–MS vial.
l
L of the reaction mixture were taken up with a
L internal GC–MS
L of pure EA placed
l
l
For the determination of the NMR yields, the reaction mixture was filtered,
evaporated on rotary evaporator and small weighted amount of the
a
a
remaining oil was mixed with a small weighted amount of the internal NMR
standard (diethyl malonate) and the resulting mixture was dissolved in CDCl3.
13. Zschunke, A. Molekülstruktur; Spektrum Akademischer: Heidelberg, 1993.
14. Elbert, W. C.; Stanley, T. W. Chem. Anal. 1965, 54, 68–69.
5. Bradley, G. F.; Evans, W. B. L.; Stevens, I. D. R. J. Chem. Soc., Perkin Trans. 2 1977,
1214–1220.