A simple large-scale synthesis of Cbz-protected taurylsulfonyl azide

Article abstract of DOI:10.1055/s-0030-1261201

A simple and efficient method for the large-scale synthesis of Cbz-taurylsulfonyl azide is described. This sulfonyl azide is accessible from taurine using three or four synthetic steps. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1261201

2228
LETTER
A Simple Large-Scale Synthesis of Cbz-Protected Taurylsulfonyl Azide
L
arge-Scale Synth
r
esis of
C
w
bz-ProtectedTaur
i
ylsulf
o
n
nyl
A
zide J. Brouwer, Rob M. J. Liskamp*
Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science,
Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands
Fax +31(30)2536655; E-mail: R.M.J.Liskamp@uu.nl
Received 3 May 2011
O
O
Abstract: A simple and efficient method for the large-scale synthe-
sis of Cbz-taurylsulfonyl azide is described. This sulfonyl azide is
accessible from taurine using three or four synthetic steps.
S
HCl⋅H2N
N3
H
OH
N
N3
S
BOP, DiPEA, NMP
O
O
Key words: sulfonyl azide, sulfonyl chloride, large-scale synthesis,
chemoselectivity, sulfo-click reaction
O
O
O
R
HS
P
R
H
N
H
H
N
N
P
O
S
N
Sulfonyl azides have gained a lot of interest and impor-
tance in recent years, which is apparent from the large in-
crease of scientific papers concerning sulfonyl
azides.1,2,4,5,7 Our contribution has been the development
of the sulfo-click reaction, a new chemoselective reaction
between a sulfonyl azide (A) and a thioacid (Scheme 1).2
2,6-lutidine
DMF, 3–6 h
H
O
O
O
Scheme 2 Preparation of Kenner’s N-acyl sulfonamide linker
which taurylsulfonyl azide was first coupled to a carbox-
ylic acid resin (Scheme 2).7
Due to the recent increase of applications for sulfonyl
azides, there is a growing need for large amounts of them.
We herein describe a large-scale synthesis of Cbz-protect-
ed taurylsulfonyl azide, based on the previously reported
small-scale synthesis.4 The first step, Cbz-protection of
taurine, was originally performed by reaction with Cbz-
chloride and sodium hydroxide in a water–dioxane mix-
ture. For the large-scale reaction it proved advantageous
to discard the dioxane, decreasing the volume and simpli-
fying the workup. To this end, taurine (1) was Cbz-pro-
tected under Schotten–Baumann conditions on a 500
mmol scale using neat Cbz-chloride and aqueous NaOH
(Scheme 3).
O
O
R2
O
O
O
O
HS
R1
S
R1
S
N
N
R2
N
N3
DMF, 2,6-lutidine
3–6 h, r.t.
H
H
H
A
B
Scheme 1 Sulfo-click reaction of taurylsulfonyl azides with thio-
acids
Compared to the widely used azide-alkyne click reaction,3
the sulfo-click reaction has the great advantage that it is a
metal-free click reaction. The necessity of Cu catalysis
was a major impetus to develop alternatives that do not in-
clude Cu catalysis. In general the synthesis of the required
molecules is rather complicated. In contrast, synthesis of
the components for the sulfo-click reaction is extremely
simple and can be carried out conveniently on a large
scale as will be described here. Recently, we described the
synthesis and applications of aliphatic amino acid derived
sulfonyl azides, b-aminoethanesulfonyl azides (A).4
These were successfully applied in the sulfo-click reac-
tion for peptide ligation and for bioconjugation.2d,e The
Cbz-glycine derived sulfonyl azide, Cbz-protected tauryl-
sulfonyl azide (A, R1 = Cbz), was also used for surface
immobilization of biomolecules5 and for the preparation
of the N-acyl sulfonamide linker for solid-phase synthesis
(Kenner’s safety catch linker).6 An optimized protocol for
the loading efficiency of the N-acyl sulfonamide linker us-
ing the sulfo-click reaction was recently described, in
O
O
NaOH, H2O
CbzCl, r.t.
O
O
S
+
S
H3N
O–
CbzHN
ONa
1
2
COCl2, DMF
CH2Cl2, r.t.
O
O
O
O
NaN3, H2O
acetone, r.t.
Cl
S
S
CbzN
R
N3
or SOCl2
40°C
CbzHN
3
4 (R = HC=O)
5 (R = H)
Scheme 3 Synthesis of Cbz-taurylsulfonyl azide
The resulting crude Cbz-taurine (2) was used without pu-
rification in the next step; conversion into Cbz-taurylsul-
fonyl chloride (3) by reaction with phosgene and DMF in
dichloromethane. This reaction could be easily scaled up
to 500 mmol with only slight modifications in the workup.
Originally, the reaction mixture was concentrated and di-
rectly purified using silica gel column chromatography.
To avoid column chromatography, the concentrated mix-
SYNLETT 2011, No. 15, pp 2228–2230
Advanced online publication: 30.08.2011
DOI: 10.1055/s-0030-1261201; Art ID: D13811ST
x
x
.x
x
.2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

LETTER
Large-Scale Synthesis of Cbz-Protected Taurylsulfonyl Azide
2229
(250 mL, 2.0 M), using two dropping funnels. After stirring vigor-
ously for 1 h at r.t., the mixture was washed with EtOAc (3 × 200
mL). The H2O layer was concentrated in vacuo, and the residue was
dried over P4O10 in a vacuum desiccator under reduced pressure,
yielding the crude sodium sulfonate 2 as a white solid (165 g). To a
cooled (ice/water bath) suspension of 2 in dry CH2Cl2 (650 mL) was
added a phosgene solution in toluene (470 mL, 20%, w/w) and dry
DMF (43 mL). After stirring for 1 h the cooling bath was removed,
and stirring was continued for 1 h. The solvents were evaporated,
and the residue was suspended in EtOAc (800 mL). Filtration over
Hyflo® followed by concentration in vacuo afforded the crude sul-
fonyl chloride 3 as a yellowish oil, which was directly dissolved in
acetone (1.0 L). This sulfonyl chloride solution was added dropwise
to a vigorously stirred solution of NaN3 (32.5 g, 500 mmol) in H2O
(1.0 L) in approximately 30 min, during which the color of the re-
ture was first extracted with ethyl acetate, to give, after fil-
tration and concentration, the crude sulfonyl chloride 3.
Addition of a solution of crude 3 to an aqueous solution of
sodium azide afforded Cbz-taurylsulfonyl azide (5). Un-
fortunately, it was found that varying amounts (0–10%) of
N-formylated sulfonyl azide 4 were formed in a number
of phosgene reactions, which had not been observed be-
fore in the small-scale reactions. The N-formylation is a
side reaction which can occur by reaction of the Cbz-pro-
tected amine with the Vilsmeyer–Haack complex8 gener-
ated from phosgene and DMF. Since the N-formylated
sulfonyl azide could not be removed by crystallization, a
deformylation reaction was performed by reaction of the
crude sulfonyl azide (5) with KHCO3, with water and ac- action mixture changed from yellowish to pink/orange. After stir-
etone as solvents.9 After 3 hours stirring at room temper-
ring overnight the acetone was evaporated in vacuo, and EtOAc (1.0
L) was added. After separation, the organic layer was washed with
a NaHCO3 solution (5%, w/w) and brine. Drying (Na2SO4) fol-
lowed by concentration in vacuo afforded the crude sulfonyl azide
(mixture of 4 and 5) which was directly dissolved in MeOH (2.0 L).
ature, Cbz-taurylsulfonyl azide (5) precipitated from the
reaction mixture and was obtained in high purity after fil-
tration in a very good overall yield of 71% (101 g) over
four steps.
A solution of KHCO3 (12.6 g, 125 mmol) in H2O (1.5 L) was added,
and the mixture was stirred at r.t. During the reaction, the sulfonyl
azide 5 precipitated from the reaction mixture. After 3 h stirring, ad-
ditional H2O (1.5 L) was added, and the mixture was filtered. The
solid residue was dried over phosphorus pentoxide under reduced
pressure to yield Cbz-taurylsulfonyl azide (5) as a colorless crystal-
We envisaged that the use of thionyl chloride instead of
phosgene could be a less toxic and cheaper alternative for
the conversion of the sodium sulfonate 2 into sulfonyl
chloride 3. It was also expected that by using thionyl chlo-
ride we could prevent N-formylation, and thereby omit
1
line solid (101 g, 71% overall yield from taurine); mp 85 °C. H
one reaction step. To this end, 500 mmol sodium sulfonate NMR (300 MHz, CDCl3): d = 3.51 (m, 2 H, CH2SO2), 3.66 (m, 2 H,
NCH2), 5.10 (s, 2 H, CH2Ph), 5.56 (br s, 1 H, NH), 7.33 (s, 5 H,
2 was treated with thionyl chloride, as reagent and sol-
vent. Due to the lower reactivity of thionyl chloride, com-
pared to phosgene/DMF, the reaction was slower and an
elevated temperature (40 °C) combined with a longer re-
ArCH). 13C NMR (75 MHz, CDCl3): d = 35.6 (NCH2), 55.0
(CH2SO2), 67.0 (OCH2Ph), 128.0, 128.2, 128.5, 135.9 (ArC), 156.1
[C=O (Cbz)]. IR (KBr): 2151 (s) cm–1.
action time (20 h) was necessary. Reaction of the crude
sulfonyl chloride with sodium azide afforded Cbz-tauryl-
sulfonyl azide (5) in a reasonable yield of 50% (71.5 g).
Although this yield was clearly lower than the yield from
the phosgene route, it is an attractive alternative. The syn-
thesis contains one reaction step less, and thionyl chloride
is less toxic and much cheaper than phosgene. Character-
ization data of both Cbz-taurylsulfonyl azides (5) from
both large-scale synthetic routes were found to be identi-
cal to previous data obtained after small-scale synthesis.
Cbz-Tau-N3 (5) (Thionyl Chloride Route)
The synthesis route using SOCl2 differs from the phosgene route as
follows: After drying the crude sulfonate 2 over P4O10, it was added
portionwise to SOCl2 (500 mL). The mixture was stirred for 20 h at
40 °C, after which it was concentrated in vacuo. After co-evapora-
tion with CHCl3 (3 × 200 mL), the residue was suspended in EtOAc
(800 mL), and workup was carried out similarly to the workup of
the phosgene reaction. After the reaction with NaN3, the crude sul-
fonyl azide 5 was purified by re-crystallization from EtOH–H2O.
Cbz-taurylsulfonyl azide (5) was obtained as a colorless crystalline
solid (71.5 g, 50% overall yield from taurine); mp 81 °C. 1H NMR
(300 MHz, CDCl3): d = 3.53 (m, 2 H, CH2SO2), 3.69 (m, 2 H,
NCH2), 5.11 (s, 2 H, CH2Ph), 5.46 (br s, 1 H, NH), 7.34 (s, 5 H,
ArCH). 13C NMR (75 MHz, CDCl3): d = 35.7 (NCH2), 55.1
(CH2SO2), 67.2 (OCH2Ph), 128.1, 128.3, 128.5, 135.9 (ArC), 156.2
[C=O (Cbz)]. IR (KBr): 2151 (s) cm–1.
In conclusion, we have developed two efficient synthesis
routes for the large-scale synthesis of Cbz-taurylsulfonyl
azide (5). The key step in both routes, conversion of the
sodium sulfonate to the sulfonyl chloride was achieved
using either thionyl chloride or phosgene. The phosgene
route gave the highest overall yield (71%), but contains
one synthetic step more. The thionyl chloride route gave a
lower yield (50%), but has the advantage that thionyl
chloride is less toxic and is much cheaper. We expect that
the convenient access of large amounts of Cbz-taurylsul-
fonyl azide (5) will stimulate the use of the sulfo-click re-
action and its application in the use of the safety-catch
linker strategy.
Acknowledgment
We thank Steffen van der Wal for helpful discussions.
References
(1) (a) Chen, Z.; Zheng, D.; Wu, J. Org. Lett. 2011, 13, 848.
(b) Song, W.; Lei, M.; Shen, Y.; Cai, S.; Lu, W.; Lu, P.;
Wang, Y. Adv. Org. Synth. Catal. 2010, 352, 2432.
(c) Krisnamoorthy, K.; Begley, T. P. J. Am. Chem. Soc.
2010, 132, 11608. (d) Xu, X.; Ge, Z.; Cheng, D.; Ma, L.; Lu,
C.; Zhang, Q.; Yao, N.; Li, X. Org. Lett. 2010, 12, 897.
(e) Raghuraman, G. K.; Schuh, K.; Prucker, O.; Ruhe, J.
Langmuir 2010, 26, 796. (f) Cho, S. H.; Hwang, S. J.;
Chang, S. Org. Synth. 2008, 85, 131. (g) Kim, J.-G.; Jang,
Cbz-Tau-N3 (5) (Phosgene Route)
Taurine (62.6 g, 500 mmol) was dissolved in aq NaOH (250 mL, 2.0
M) using a large magnetic oval stirring bar. To this solution were si-
multaneously added CbzCl (78.5 mL, 550 mmol) and aq NaOH
Synlett 2011, No. 15, 2228–2230 © Thieme Stuttgart · New York

2230
A. J. Brouwer, R. M. J. Liskamp
LETTER
(3) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org.
D. O. Synlett 2008, 2885. (h) Hu, X.; Sun, J.; Wang, H.-G.;
Manetsch, R. J. Am. Chem. Soc. 2008, 130, 13820.
(i) Wang, F.; Fu, H.; Jiang, Y.; Zhao, Y. Adv. Synth. Catal.
2008, 350, 1830. (j) Raushel, J.; Pitram, S. M.; Fokin, V. V.
Org. Lett. 2008, 10, 3385. (k) Mandal, S.; Gauniyal, H. M.;
Pramanik, K.; Mukhopadhyay, B. J. Org. Chem. 2007, 72,
9753.
Chem. 2002, 67, 3057. (b) Rostovtsev, V. V.; Green, L. G.;
Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002,
41, 2596.
(4) Brouwer, A. J.; Merkx, R.; Dabrowska, K.; Rijkers, D. T. S.;
Liskamp, R. M. J. Synthesis 2006, 455.
(5) Govindaraju, T.; Jonkheijm, P.; Gogolin, L.; Becker, C. F.
W.; Niemeyer, C. M.; Waldmann, H. Chem. Commun. 2008,
32, 3723.
(6) Kenner, G. W.; McDermott, J. R.; Sheppard, R. C. Chem.
Commun. 1971, 636.
(7) Merkx, R.; van Haren, M. J.; Rijkers, D. T. S.; Liskamp, R.
M. J. J. Org. Chem. 2007, 72, 4574.
(8) (a) Vilsmeier, A.; Haack, A. Ber. Dtsch. Chem. Ges. 1927,
60, 119. (b) Maheas, M.-R. Bull. Soc. Chim. Fr. 1962, 1989.
(9) Beumer, R.; Bubert, C.; Cabrele, C.; Vielhauer, O.; Pietzsch,
M.; Reiser, O. J. Org. Chem. 2000, 65, 8960.
(2) (a) Shangguan, N.; Katukojvala, S.; Greenberg, R.;
Williams, L. J. J. Am. Chem. Soc. 2003, 125, 7754.
(b) Barlett, K. N.; Kolakowski, R. V.; Katukojvala, S.;
Williams, L. J. Org. Lett. 2006, 8, 823. (c) Kolakowski, R.
V.; Shangguan, N.; Sauers, R. R.; Williams, L. J. J. Am.
Chem. Soc. 2006, 128, 5695. (d) Merkx, R.; Brouwer, A. J.;
Rijkers, D. T. S.; Liskamp, R. M. J. Org. Lett. 2005, 7, 1125.
(e) Yim, C.-B.; Dijkgraaf, I.; Merkx, R.; Versluis, C.; Eek,
A.; Mulder, G. E.; Rijkers, D. T. S.; Boerman, O. C.;
Liskamp, R. M. J. J. Med. Chem. 2010, 53, 3944.
(f) Rijkers, D. T. S.; Merkx, R.; Yim, C.-B.; Brouwer, A. J.;
Liskamp, R. M. J. J. Pept. Sci. 2010, 16, 1.
Synlett 2011, No. 15, 2228–2230 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.