Ammonia-free synthesis of 3-trifluoromethyl-3-phenyldiaziridine

Article abstract of DOI:10.1080/00397911.2017.1354026

An ammonia-free synthesis of 3-trifluoromethyl-3-phenyldiaziridine, an important intermediate in the synthesis of a widely used photolabel 3-trifluoromethyl-3-phenyldiazirine, is described. By avoiding the use of volatile, corrosive, and toxic anhydrous ammonia, the major hazard involved in the synthesis of this widely used photolabel is eliminated. Furthermore, this synthesis is convenient compared to the conventional route, since it is significantly less time consuming and, due to the absence of liquid ammonia, this method does not require the maintenance of low temperature for prolonged periods.

Full text of DOI:10.1080/00397911.2017.1354026

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Ammonia-Free Synthesis of 3-Trifluoromethyl-3-
phenyldiaziridine
Arun Babu Kumar & Roman Manetsch
To cite this article: Arun Babu Kumar & Roman Manetsch (2017): Ammonia-Free
Synthesis of 3-Trifluoromethyl-3-phenyldiaziridine, Synthetic Communications, DOI:
10.1080/00397911.2017.1354026
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1354026
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Date: 22 July 2017, At: 10:17

Ammonia-free synthesis of 3-trifluoromethyl-3-
phenyldiaziridine
Arun Babu Kumar
Department of Chemistry, University of South Florida, Tampa, FL, USA
Roman Manetsch
Department of Chemistry and Chemical Biology and Department of Pharmaceutical Sciences,
Northeastern University, Boston, MA, USA
Address correspondence to Roman Manetsch, Department of Chemistry and Chemical Biology
and Department of Pharmaceutical Sciences, Northeastern University, 102 Hurtig Hall, 360
Huntington Avenue, Boston, MA 02115, USA. Tele.: +1-617-373-6316, Fax: +1-617-373-8795.
E-mail: r.manetsch@neu.edu
ABSTRACT
An ammonia-free synthesis of 3-trifluoromethyl-3-phenyldiaziridine, an important
intermediate in the synthesis of a widely used photolabel 3-trifluoromethyl-3-phenyldiazirine, is
described. By avoiding the use of volatile, corrosive, and toxic anhydrous ammonia, the major
hazard involved in the synthesis of this widely used photolabel is eliminated. Furthermore, this
synthesis is convenient compared to the conventional route since it is significantly less time
1

consuming and, due to the absence of liquid ammonia this method does not require the
maintenance of low temperature for prolonged periods.
GRAPHICAL ABSTRACT
KEYWORD: diaziridine, diazirine, o-mesitylenesulfonyl hydroxylamine, photoaffinity label,
photolabel
Introduction
In photoaffinity labeling, 3-trifluoromethyl-3-phenyldiazirine 1 is one of the most
commonly used photoactivatable crosslinking groups.[1] In comparison to arylzide or
benzophenone labeling agents, diazirine 1 is the preferred photo-crosslinking moiety due to its
favorable physicochemical properties, improved chemical and thermal stability in the dark, short
UV irradiation time to generate the reactive carbene intermediate in high yields, predictable
carbene insertion reactivity, and the ability to be activated at a wavelength benign for
biomolecules.[1–3] Notably, the 3-trifluoromethyl-3-phenyldiazirine 1 is an important intermediate
for chemists and biochemists because in addition to its direct derivability as a photoaffinity
probe,[2] it can be easily converted to other widely used 3-trifluoromethyl-3-phenyldiazirine
precursors that could be derivatized under mild conditions to a variety of photoaffinity probes
(
Scheme 1).[2,4–8]
2

Discussion
Among the most important intermediates for the preparation of diazirine derivatized
photoaffinity probe 6 is 3-trifluoromethyl-3-phenyldiaziridine 5, which is synthesized from
trifluoromethyl phenyl ketone in a three step synthesis sequence (Scheme 2A).[9–11] At the heart of
this synthetic sequence is the use of anhydrous liquid ammonia for the conversion of O-sulfonyl
oxime 4 to diaziridine 5. Since this procedure involves the use of volatile, toxic, and corrosive
anhydrous liquid ammonia under very cold conditions (below -50 °C), the preparation of diazirine
6
requires a high degree of synthetic expertise. Although aliphatic diazirines have been synthesized
using ammonium hydroxide or methanolic ammonia in place of anhydrous liquid ammonia, 3-
trifluoromethyl-3-phenyldiazirine is not synthetically accessible using these milder ammonia
reagents due to the formation of stable hemiaminal adduct.[12,13] Herein we describe a
straightforward and operationally simple preparation of 3-trifluoromethyl-3-phenyldiaziridine 5 in
good yields without the need for liquid ammonia. To the best of our knowledge, an ammonia-free
synthesis of 3-trifluoromethyl-3-phenyldiazirine has not yet been reported.
The key conversion step for preparation of the three-membered diaziridine ring is the
nucleophilic attack of ammonia to O-sulfonyl oxime 4 forming O-sulfonyl hydroxylamine
intermediate 7 (Scheme 2B), which then spontaneously cyclizes in an intramolecular substitution
reaction between the amino group and the O-sulfonyl hydroxylamine moiety. We hypothesized
that the same intermediate 7 could readily be generated without the use of liquid ammonia by
reacting imine 8 with an O-sulfonyl hydroxylamine reagent. Conventionally, the reaction of an
aliphatic ketone with liquid ammonia and hydroxylamine-O-sulfonic acid has been reported to
yield the corresponding aliphatic diaziridine.[14,15] Nevertheless, the exact same approach starting
3

from trifluoromethyl phenyl ketone 5 and liquid ammonia failed in the generation of 3-
trifluoromethyl-3-phenyldiaziridine due to the formation of a stable hemiaminal adduct.[16,17]
Motivated by the work reported by Gosselin and coworkers for the preparation of
trifluoromethyl phenyl imines using lithium bis(trimethylsilyl)amide as an ammonia equivalent,[16]
we treated trifluoromethyl phenyl ketone 11 with lithium bis(trimethylsilyl)amide to give N-TMS-
ketimine 12 (Scheme 3), which was then subjected to solvolysis with methanol to provide imine
1
3 in good yields. Unfortunately, the use of hydroxylamine-O-sulfonic acid as the O-sulfonyl
hydroxylamine source did not yield the desired diaziridine product. We hypothesize that this poor
reactivity may be due to the reduced nucleophilicity of the amine function in hydroxylamine-O-
sulfonic acid, since it exists as a zwitterion. Thus, we decided to use an aromatic sulfonyl
hydroxylamine as O-sulfonyl hydroxylamine source. For this purpose, O-mesitylenesulfonyl
hydroxylamine was chosen over p-toluenesulfonyl hydroxylamine due to its higher stability in the
purified state, as the neat sample of p-toluenesulfonyl hydroxylamine deflagrates rapidly in the
pure state. The reaction of O-mesitylenesulfonyl hydroxylamine 10, that was synthesized
according to the methodology reported by Tamura and coworkers,[18] resulted in the formation of
the diaziridine 14 when treated with imine 13. Initially, when the reaction was worked-up and
concentrated without quenching the excess O-mesitylenesulfonyl hydroxylamine 10, it resulted in
the decomposition of diaziridine 14, possibly by reacting with the excess 10. Therefore, we decided
to add piperidine to the reaction mixture, just before the work-up, to quench the excess
O-mesitylenesulfonyl hydroxylamine 10 that was present. This resulted in the formation of
diaziridine 14 in reasonably good yield over three steps.
We noticed that this ammonia-free synthesis was significantly shorter than the
conventional 3-trifluoromethyl-3-phenyldiaziridine synthesis. In total, the three step conversion
4

from the ketone 11 to the diaziridine 14 could be completed within 24 hours. In contrast, the
conventional synthesis (Scheme 2A) takes about 3 to 4 days depending on the reagents and
conditions used. In the conventional procedure, the multiple overnight steps involved and
purification required after each step are the leading factors that prolong the diaziridine synthesis.
In the ammonia-free synthesis, apart from the solvolysis by methanol, the other steps are rapid and
there is no intermediate purification required.
The 3-trifluoromethyl-3-phenyldiaziridine 14 obtained through the ammonia-free
synthesis was converted to the commonly used photolabel 1 through the conventional
silver(I)oxide oxidation followed by desilylation (Scheme 4).[2,10] As an alternative, the diaziridine
can also be oxidized to the corresponding diazirine utilizing iodine as the oxidant.[6]
We tried to extend this reaction to other trifluoromethyl phenyl ketones like trifluoromethyl
4
-methoxyphenyl ketone and trifluoromethyl 4-bromophenyl ketone but the desired diaziridine
was not formed in significant yield. We suspect that electron donating groups make the imine less
susceptible to the nucleophilic attack by O-mesitylenesulfonyl hydroxylamine 10. Nevertheless,
the proficiency of this method to synthesize the most commonly used diazirine photolabel 1 is very
significant. The useful precursors shown in Scheme 1, which are employed in integrating the
diazirine photolabel with complex molecules under mild conditions can be conveniently prepared
from the 3-trifluoromethyl-3-phenyldiazirine 1 (Scheme 1). However, the herein reported method
involves the use of reactive reagents like perchloric acid and O-(mesitylsulfonyl)hydroxylamine.
Specifically, perchloric acid exhibits strong oxidizing characteristics when it’s concentration
exceeds 72% by weight or when it is heated, nevertheless its use under the herein reported reaction
conditions are considered to be relatively safe. Although O-(mesitylsulfonyl)hydroxylamine (10)
is
a
highly reactive compound, there is no violent decomposition of O-
5

(mesitylsulfonyl)hydroxylamine reported thus far (see Supplementary Content section for safe
handling procedures).[19]
In conclusion, by creating the intermediate 7 without the use of ammonia we have
developed for the first time an ammonia-free method for the synthesis of 3-trifluoromethyl-3-
phenyldiaziridine 14, a vital intermediate in preparing diazirine based photolabels, in good yields.
Due to the elimination of toxic and corrosive anhydrous condensed ammonia, 3-trifluoromethyl-
3
-phenyldiaziridine 14 is now conveniently accessible to biologist and biochemists interested in
photolabeling with diazirines. In addition, by avoiding the use of volatile condensed ammonia
boiling point −33 °C) the need for maintaining very cold baths for prolonged periods for the
(
synthesis of the diaziridine has been eliminated. Using this novel ammonia-free method 3-
trifluoromethyl-3-phenyldiaziridine 14, the key synthetic precursor to diazirine 1, can be prepared
rapidly (24 hours instead of the conventional 3 to 4 days) from the trifluoromethyl phenyl ketone
1
1 in good yields.
Experimental Section
3
-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-3-(trifluoromethyl)diaziridine (14) To
[
4]
a solution of 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2,2,2-trifluoroethanone 11 (500
mg, 1.57 mmol) in anhydrous toluene (1.2 mL) at 0°C, a 1 M solution of lithium
bis(trimethylsilyl)amide in THF (1.7 mL, 1.70 mmol) was added and warmed to room temperature.
After stirring for 1 hour the reaction was extracted between water (with 10% brine) and ether.
Upon isolation of the ether layer, the water layer was further extracted with fresh portions of
diethyl ether 2 more times. The combined ether layer from the extraction was washed with fresh
portion of water. The resultant ether layer was dried with anhydrous sodium sulfate and
6

concentrated under reduced pressure. To this concentrate, methanol (1 mL) was added and stirred
for 18 hours at room temperature. The resultant solution was again concentrated under reduced
pressure and further dried with high vacuum pump. The concentrate thus obtained was dissolved
in anhydrous tetrahydrofuran (1 mL) and cooled to 0°C. To this cold solution, 10 (338 mg, 1.57
mmol), as a solution in anhydrous tetrahydrofuran (2 mL), was added slowly and stirred at 0°C for
1
hour. To the reaction mixture, piperidine (0.5 mL) was added dropwise and slowly warmed to
room temperature and let to stir for an additional 1 hour. Then the reaction mixture was extracted
between water and ether. Upon isolation of the ether layer, the water layer was further extracted
with fresh portion of diethyl ether 1 more time. The combined ether layer was dried with anhydrous
sodium sulfate and concentrated under reduced pressure. The resultant crude was purified by silica
flash column chromatography with 5% ethyl acetate in hexanes as the eluent to get 14 as colorless
1
liquid. H NMR (400 MHz, CDCl
3
) δ 7.58 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 4.77 (s,
1
3
2
1
H), 2.78 (br s, 1H), 2.21 (br s, 1H), 0.95 (s, 9H), 0.11 (s, 6H). C NMR (101 MHz, CDCl ) δ
3
1
9
43.9, 130.3, 128.1, 126.3, 123.7 (q, J = 278 Hz), 64.5, 58.1 (q, J = 35.9 Hz), 26.0, 18.5, -5.2. F
OSi + [M + H]+
NMR (376 MHz, CDCl
3
) δ -75.64. HRMS (ESI/TOF) m/z calcd for C15
H
24
F
3
N
2
3
33.1605, found 333.1604.
Supporting Information
Synthetic procedures for compounds 9, 10 and 1, general and safety information regarding
1
19
13
the experiments, copies of H, F and C NMR spectra. This material can be found online through
the “Supplementary Content” section of this article’s webpage.
References
[
1] Das, J. Chem. Rev. 2011, 111, 4405–4417.
7

[
[
[
2] Kumar, A. B.; Tipton, J. D.; Manetsch, R. Chem. Commun. 2016, 52, 2729–2732.
3] Hashimoto, M.; Hatanaka, Y. European J. Org. Chem. 2008, 2008, 2513–2523.
4] Fishwick, C. W. G.; Sanderson, J. M.; Findlay, J. B. C. Tetrahedron Lett. 1994, 35, 4611–
4
614.
5] Ambroise, Y.; Pillon, F.; Mioskowski, C.; Valleix, A.; Rousseau, B. European J. Org. Chem.
001, 2001, 3961–3964.
[
2
[
[
6] Song, Z.; Zhang, Q. Org. Lett. 2009, 11, 4882–4885.
7] Nakashima, H.; Hashimoto, M.; Sadakane, Y.; Tomohiro, T.; Hatanaka, Y. J. Am. Chem. Soc.
2
006, 128, 15092–15093.
[
[
[
[
8] Weber, T.; Brunner, J. J. Am. Chem. Soc. 1995, 117, 3084–3095.
9] Brunner, J.; Senn, H.; Richards, F. M. J. Biol. Chem. 1980, 255, 3313–3318.
10] Kumar, A. B.; Anderson, J. M.; Manetsch, R. Org. Biomol. Chem. 2011, 9, 6284–6292.
11] Wang, L.; Murai, Y.; Yoshida, T.; Ishida, A.; Masuda, K.; Sakihama, Y.; Hashidoko, Y.;
Hatanaka, Y.; Hashimoto, M. Org. Lett. 2015, 17, 616–619.
[
12] Lehmann, J.; Steck, J.; Weiser, W.; Boos, W.; Wrissenberg, S. Carbohydr. Res. 1988, 113–
1
20.
[
[
[
[
13] Schmitz, E.; Ohme, R. Org. Synth. 1965, 83.
14] Church, R. F. R.; Kende, A. S.; Weiss, M. J. J. Am. Chem. Soc. 1965, 87, 2665–2671.
15] Schmitz, E.; Ohme, R. Chem. Ber. 1961, 94, 2166–2173.
16] Gosselin, F.; O’Shea, P. D.; Roy, S.; Reamer, R.; Chen, C.-Y.; Volante, R. P. Org. Lett. 2005,
7
, 355–358.
[
[
17] Barney, C. L.; Huber, E. V.; McCarthy, J. R. Tetrahedron Lett. 1990, 31, 5547–5550.
18] Tamura, Y.; Minamikawa, J.; Sumoto, K.; Fujii, S.; Ikeda, M. J. Org. Chem. 1973, 38, 1239–
1
241.
[
19] Mendiola, J.; Rincón, J. A.; Mateos, C.; Soriano, J. F.; de Frutos, O. S.; Niemeier, J. K.; Davis,
E. M. Org. Process Res. Dev. 2009, 13(2), 263–267.
8

Scheme 1. Synthetic routes for the making various photolabeling handles and precursors from
the diazirine 1.
9

Scheme 2. (A) Conventional synthesis of 3-trifluoromethyl-3-phenyldiazirine 6 from
trifluoromethyl phenyl ketone (B) Mechanistic representation of alternate ammonia-free route for
diaziridine synthesis by common intermediate hypothesis.
1
0

Scheme 3. Ammonia-free synthetic route for 3-trifluoromethyl-3-phenyldiaziridine.
1
1

Scheme 4. Synthesis of photolabel 1 from diaziridine 14 through conventional methods.
1
2