Design of thermally stable versions of the burgess reagent: Stability and reactivity study (1)

Article abstract of DOI:10.1021/jo100212n

Three new versions of the Burgess reagent were synthesized and their thermal stability investigated by NMR. The new reagents exhibited improved reactivity toward epoxides, diols, and vinyl oxiranes as compared with the original version.

Full text of DOI:10.1021/jo100212n

pubs.acs.org/joc
a report on the conversion of oxiranes to cis-fused cyclic
Design of Thermally Stable Versions of the Burgess
Reagent: Stability and Reactivity Study1
sulfamidates.5 Nicolaou reported the synthesis of sulfami-
dates6 by the reaction of the Burgess reagent with 1,2-diols or
epoxy alcohols and we have investigated mechanistic simila-
rities of the two pathways. In 2006 we reported the syn-
thesis of a chiral auxiliary version of the Burgess reagent
by reacting the chlorosulfonylisocyanate with (-)-menthol.7
Reactions of this version of the Burgess reagent with various
oxiranes allowed isolation of diastereomeric sulfamidates
that could be hydrolyzed to yield protected cis-1,2-amino
alcohols in both enatiomeric configurations following the
removal of the menthyl auxiliary. In addition, as the sulfa-
midates mimic the reactivity of cyclic sulfates, trans-1,2-
amino alcohols were obtained following the opening of the
sulfamidates with ammonium benzoate. Thus all isomers of
1,2-amino alcohols in both enantiomeric series became easily
accessible. A concise application of this protocol was ex-
pressed in the enantiodivergent formal total synthesis of (þ)-
and (-)-balanol.8 In addition, a serendipidous discovery
allowed for a high yield preparation of disulfides from thiols
by the action of the Burgess reagent.9 Details of the synthetic,
mechanistic, and computational studies, including modeling
by Density Functional Theory and suggestions of possible
transition states for the epoxide opening, were published in a
recent full paper.10 Herein we report the synthesis of new
versions of the Burgess reagent and their thermal stability
profile along with a comparison of their reactivity with the
original methyl carbamate compound.
During our studies of the reactivity of the Burgess reagent
with various cyclic and acyclic oxiranes we were disappointed
with rather modest yields of the sulfamidates. Furthermore,
we found that the reactions with epoxides led to cis-fused sulf-
amidates in a process that required 2 equiv of the Burgess
reagent, in analogy with Nicolaou’s observations of similar
requirements for the conversion of 1,2-diols to sulfamidates.
The nucleophilic opening of strained rings is energetically more
demanding than the relatively facile sulfonation of alcohols
that operates in the dehydration protocols or in the reactions
with 1,2-diols. We have observed that both the original Burgess
reagent 1 and its chiral auxiliary version 2 were not particularly
stable at the temperature of refluxing THF, conditions fre-
quently necessary for the nucleophilic opening of oxiranes. As
the yields of sulfamidates from oxiranes rarely exceeded 40%,
we set out to design several versions that would increase the
stability of either the anionic or the cationic portion of the
zwitterions. The new reagents shown in Figure 1 were easily
prepared from their components by the usual procedures (see
the Experimental Section for details).
Thomas A. Metcalf, Razvan Simionescu, and
Tomas Hudlicky*
Department of Chemistry and Centre for Biotechnology,
Brock University, 500 Glenridge Avenue, St. Catharines,
Ontario L2S 3A1, Canada
thudlicky@brocku.ca
Received February 10, 2010
Three new versions of the Burgess reagent were synthesized
and their thermal stability investigated by NMR. The new
reagents exhibited improved reactivity toward epoxides, diols,
and vinyl oxiranes as compared with the original version.
The Burgess reagent, discovered in 19682 and employed as
a mild dehydrating agent for primary and secondary alco-
hols, has recently come to focus in a variety of new reaction
schemes. Several reviews highlighting the reactive options of
this reagent were published3 and its use was featured in the
total syntheses of quite a few natural products.4 As recently
as a decade ago it was assumed that epoxides were inert to the
action of the Burgess reagent. However, in 2003 we published
(1) Presented in part at the 92nd CSC conference in Hamilton, ON, May
2009.
(2) (a) Atkins, G. M.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744.
(b) Burgess, E. M.; Penton, H. R.; Taylor, E. A. J. Am. Chem. Soc. 1970, 92,
5224. (c) Atkins, G. M.; Burgess, E. M. J. Am. Chem. Soc. 1972, 94, 6135.
(d) Burgess, E. M.; Penton, H. R.; Taylor, E. A. J. Org. Chem. 1973, 38, 26.
(3) Reviews of applications: (a) Santra, S. Synlett 2009, 852. (b) Nicolaou,
K. C.; Snyder, S. A.; Longbottom, D. A.; Nalbandian, A. Z.; Huang, X.
Chem.;Eur. J. 2004, 10, 5581. (c) Khapli, S.; Dey, S.; Mal, D. J. Ind. Inst. Sci.
2001, 81, 461. (d) Burckhardt, S. Synlett 2000, 559. (e) Lamberth, C. J. Prakt.
Chem. 2000, 342, 518. (f)Taibe, P.; Mobashery, S. In Encyclopedia of Reagents in
Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, UK, 1995; Vol. 5,
p 3345.
(4) Use in natural product synthesis: (a) Cedrene: Rigby, J. H.; Kirova-Snover,
M. Tetrahedron Lett. 1997, 38, 8153. (b) Narciclasine: Rigby, J. H.; Mateo, M. E.
J. Am. Chem. Soc. 1997, 119, 12655. (c) Taxol: Holton, R. A.; Kim, H. B.; Sonoza,
C.; Liang, F.; Biediger, R. J.; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.;
Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K. K.;
Gentile, L. N.; Liu, J. H. J. Am. Chem. Soc. 1994,116, 1599. (d) Efrotomycin: Dolle,
R. E.; Nicolaou, K. C. J. Am. Chem. Soc. 1985, 107, 1691. (e) Pravastatin:
Daniewski, A. R.; Wovkulich, P. M.; Uskokovic, M. R. J. Org. Chem. 1992, 57,
7133. (f) Balanol: see ref 8.
To determine the thermal stability of the reagents we chose
to follow their decomposition in THF-d8 at 50 °C and at
reflux by monitoring the content of the sample by 13C NMR.
(7) Leisch, H.; Saxon, R.; Sullivan, B.; Hudlicky, T. Synlett 2006,
445–449.
(5) Rinner, U.; Adams, D. R.; dos Santos, M. L.; Hudlicky, T. Synlett
2003, 1247–1252.
(8) Sullivan, B.; Gilmet, J.; Leisch, H.; Hudlicky, T. J. Nat. Prod. 2008,
71, 346–350.
(9) Banfield, S. C.; Omori, A. T.; Leisch, H.; Hudlicky, T. J. Org. Chem.
2007, 72, 4989–4992.
(10) Leisch, H.; Sullivan, B.; Fonovic, B.; Dudding, T.; Hudlicky, T. Eur.
J. Org. Chem. 2009, 2806–2819.
(6) (a) Nicolaou, K. C.; Snyder, S. A.; Nalbandian, A. Z.; Longbottom,
D. A. J. Am. Chem. Soc. 2004, 126, 6234. (b) Nicolaou, K. C.; Huang, X.;
Snyder, S. A.; Rao, P. B.; Bella, M.; Reddy, M. V. Angew. Chem., Int. Ed.
2002, 41, 834. (c) Nicolaou, K. C.; Longbottom, D. A.; Snyder, S. A.;
Nalbandian, A. Z.; Huang, X. Angew. Chem., Int. Ed. 2002, 41, 3866.
DOI: 10.1021/jo100212n
r
Published on Web 04/16/2010
J. Org. Chem. 2010, 75, 3447–3450 3447
2010 American Chemical Society

Metcalf et al.
JOCNote
FIGURE 1. New versions of the Burgess reagent.
FIGURE 3. Decomposition of Burgess reagents as a function of
time at 78 °C.
version 4. The increased stability of reagent 5 does not offer
additional advantages in its reactivity, at least in the cases
involving the oxiranes. The reaction of the Burgess reagents 3
and 5 with 1,2-styrene diol did not produce the sulfamidates
under the reaction conditions used for the other reagents.
Only bis-sulfonation was observed and this would be con-
sistent with the mechanism proposed by Nicolaou and tested
by our group for the formation of sulfamidates from diols.
The inductive effect of the trifluoromethyl group decreases
the nucleophilicity of the carbamate anion in both reagents
containing this group and hence the rate of displacement to
form the sulfamidates is greatly reduced in the intermediates
such as 15. The isolation of the protected diamine 12 from the
reaction of the menthyl Burgess reagent 2 with styrene diol
was surprising. However, its formation may be rationalized
by invoking the bis-sulfonated intermediate 16, which, for
steric reasons, may not undergo the intramolecular displace-
ment at the benzylic position to yield the expected sulf-
amidate of type 8. Instead the alternate, less sterically demand-
ing, process may yield sulfamidate 17, whose further displacement
at the benzylic position with the carbamate anion (generated upon
the departure of the second equivalent of the Burgess reagent from
16) provides the protected diamine 12, as shown.
FIGURE 2. Decomposition of Burgess reagents as a function of
time at 50 °C.
A timed series of 13C{1H} NMR spectra were recorded for
each reagent. For each spectrum the peak area of the
carbamate 13C signal (around 157 ppm) was determined by
direct integration and calibration against solvent 13C signal
corresponding to THF-d8 at 64.6 ppm. The magnitude of the
carbamate 13C signal in the first spectrum was set at 100%.
The results are shown in Figures 2 and 3 and are compared
with those obtained for the original Burgess reagent as well
as its menthyl chiral auxiliary version. [The plots shown are
the actual decays with percent content illustrated on the left.]
We were surprised how unstable both the original Burgess
reagent 1 and its chiral auxiliary version 2 were at higher temp-
erature. The half-life of 1 and 2 at 50 °C is 216 and 198 min,
respectively. At reflux, the corresponding half-lives are even
shorter, determined at 19 min for 1 and 13 min for 2. The Burgess
reagent as well as the menthyl chiral auxiliary version completely
decompose in less than an hour at 78 °C. These observations
explain why the yields of sulfamidates from oxiranes were
modest, in contrast to the yields reported for sulfamidate produc-
tion from 1,2-diols. Major improvements in stability were noticed
with the new reagents 3,4,and5, as shown in Figures 2 and 3. The
reagents derived from N-methylpiperidine are essentially com-
pletely stable even at refluxing temperatures for 3 h or more. The
reactivity of the new reagents was examined for simple dehydra-
tion as well as nucleophilic opening of oxiranes and the synthesis
of sulfamidates from 1,2-styrene diol, as shown in Figure 4. The
results are compared in terms of yields to those obtained with the
original Burgess reagent 1 and the chiral auxiliary version 2.
From the results in Figure 4 it is clear that the best
compromise between stability and reactivity is attained with
either trifluoroethyl version 3 or the N-methyl piperidine
The suggested mechanism for the conversion of styrene diol
to 12 is in agreement with the results reported by Burgess in
1973 on the conversion of cyclohexanol and benzyl alcohol to
the corresponding N-hexyl- and N-benzylcarbamates by SN2
displacement of the sulfonylated intermediates such as 16.11
(11) Burgess, E. M.; Penton, H. R.; Taylor, E. A. J. Org. Chem. 1973, 38,
26–31.
3448 J. Org. Chem. Vol. 75, No. 10, 2010

Metcalf et al.
JOCNote
FIGURE 4. Reactivity trends of the new Burgess reagents in dehydration, reactions with oxiranes, and with styrene diol. The reactions were
carried out in refluxing THF at ∼80 °C.
The full assignment of structures was performed by 2D HSQC
and 2D COSY NMR spectroscopy for all compounds and is
shown for all H- and C-atoms in the Supporting Information.
For the assignment of 12 2D HMBC NMR spectroscopy was
also performed.
In conclusion, we have shown that the stability as well as
the reactivity of the original Burgess reagent can be improved
by addressing the electronic quality of both portions of the
zwitterion. The best results in terms of yield improvements
were achieved with reagent 4.
chlorosulfonylcarbamate, was precipitated with cold hexanes as
white crystals, 10.25 g (42 mmol, 92%); mp 80-82 °C (C6H6);
1H NMR (CDCl3, 300 MHz) δ 8.44 (m, 1H), 4.66 (q, J = 7.9 Hz,
2H); 13C NMR1483.9, 1396.8, 1166.0 cm-1; LRMS (FABþ
NBA matrix) m/z 242, 149 (18.9), 99 (41.3), 73 (25.9), 59 (80.8), 49
(100.0); HRMS calcd for C3H4ClNF3O4 241.9423, found 241.9496.
2,2,2-Trifluoroethyl chlorosulfonylcarbamate (2.0 g, 8.3 mmol)
in 50 mL of dry THF was added dropwise to triethylamine
(2.90 mL, 20.75 mmol) in 20 mL of dry THF in an ice bath, then
the reaction mixture was stirred for 2 h. Triethylammonium chloride
was filtered and the solvent removed in vacuo. The product (3) was
recrystallized twice from dry THF, 1.91 g (6.2 mmol, 75%); mp
77-79 °C (THF); 1H NMR (CDCl3, 300 MHz) δ 4.45 (dq, J =
8.6, 3.7 Hz, 2H) 3.46 (dq, J = 7.3, 2.9 Hz, 6H) 1.41 (dt, J = 7.2,
3.7 Hz, 9H); 13C NMR (THF-d8, 150 MHz) δ 155.4, 123.8 (q, J =
277.4 Hz), 60.1 (q, J = 35.8 Hz), 50.6, 8.5; IR (KBr) v 3167.6,
2986.1, 2931.6, 2676.8, 2637.9, 2107.9, 1750.3, 1691.2 cm-1;LRMS
(FAB þ NBA matrix) m/z 307, 239 (30.8), 102 (100.0), 86 (20.0);
HRMS calcd for C9H17F3N2O4S 306.0851, found 307.0930 (Mþ þ H).
N-Methyl-N-{[(methyloxycarbonyl)amino]sulfonyl}piperidin-
aminium, Inner Salt (4). Methyl chlorosulfonylcarbamate (6.83 g,
39 mmol) in benzene (30 mL) was added dropwise to N-methyl-
piperidine in benzene (20 mL) at 0 °C. The reaction mixture was
stirred for an additional 2 h. After removal of N-methylpiperidinium
Experimental Section
General. All reactions were performed in flame-dried glass-
ware under argon atmosphere. THF and benzene were freshly
distilled from sodium/benzophenone. All Burgess reagents were
recrystallized twice from dry THF prior to use.
N,N-Diethyl-N-{[(2,2,2-trifluoroethyloxycarbonyl)amino]sulfonyl}-
ethanaminium, Inner Salt (3). 2,2,2-Trifluoroethanol (3.36 mL,
46 mmol) in dry benzene (10 mL) was added dropwise to chloro-
sulfonyl isocyanate (4.0 mL, 46 mmol) in 15 mL of dry benzene
at room temperature. When the addition was complete, the reac-
tion mixture was stirred for 30 min. The product, 2,2,2-trifluoroethyl
J. Org. Chem. Vol. 75, No. 10, 2010 3449

Metcalf et al.
JOCNote
ꢀ
for C9H13F3NO5S 304.0467, found 304.0512. Anal. Calcd for
ꢀ
C9H12F3NO5S: C 35.65, H 3.99. Found: C 35.74, H 3.98.
chloride by filtration, the solvent was removed in vacuo. The
product was recrystallized twice from dry THF to yield 4, 6.6 g
(28mmol,71%);mp87-90 °C(THF);1HNMR(CDCl3,300MHz)
δ 3.72 (s, 3H), 3.60 (m, 2H), 3.45 (m, 2H), 3.14 (s, 3H), 1.50-2.00
(m, 6H); 13C NMR (CDCl3, 75 MHz) δ 158.2, 76.6, 54.7, 53.3,
40.1, 21.6, 20.6; IR (KBr) v 3206.4, 2951.4, 2869.3, 2686.4, 2110.2,
1704.5, 1470.7 cm-1; LRMS (FAB þ NBA matrix) m/z 237, 205
(34.3), 100 (100.0), 70 (11.2).
N-Methyl-N-{[(2,2,2-trifluoroethyloxycarbonyl) amino]sulfonyl}-
piperidinaminium, Inner Salt (5). 2,2,2-Trifluoroethyl chlorosulfonyl-
carbamate (4.0 g, 17 mmol) in 30 mL of dry THF was added
dropwise to N-methylpiperidine (3.80 g, 38 mmol) in 20 mL of dry
THF at 0 °C. The reaction mixture was stirred for 2 h. N-Methylpiper-
idinium chloride was removed by filtration and the solvent was
removed in vacuo. The product was recrystallized twice from dry
THF to yield 5, 2.4 g (7.9 mmol, 48%); mp 79-81 °C (THF); 1H
NMR (CDCl3, 300 MHz) δ 4.48 (q, J = 8.5 Hz, 2H), 3.63 (m, 2H),
3.45 (m, 2H), 3.15 (s, 3H), 1.82-1.99 (m, 6H); 13C NMR (CDCl3,
150 MHz) δ 156.1, 123.2 (q, J = 277.8 Hz), 61.7 (q, J = 36.0 Hz),
54.8, 40.2, 21.4, 20.6; IR (KBr) v 3425.3, 2964.1, 2872.7, 2716.4,
2127.0, 1712.9, 1470.3 cm-1; LRMS (FAB þ NBA matrix) m/z
305, 205 (26.7), 137 (3.9), 100 (100.00); HRMS calcd for C9H15-
F3N2O4S 305.0783, found 305.0764.
Methyl cis-Tetrahydro-3H-1,2,3-benzoxathiazole-3-carboxy-
late 2,2-Dioxide (7). Eluent hexanes-ethyl acetate, 4:1; Rf 0.42
(2:1 hexanes-ethyl acetate); mp 145-147 °C (EtOAc); 1H
NMR (CDCl3, 600 MHz) δ 6.12 (m, 1H), 5.81 (d, 10.32 Hz,
1H), 5.21 (s, 1H), 4.80 (s, 1H), 3.93 (s, 3H), 2.35 (m, 1H), 2.30 (m,
1H), 2.15 (m, 1H), 1.92 (m, 1H); 13C NMR (CDCl3, 150 MHz)
δ 150.5, 131.6, 120.7, 77.8, 55.5, 54.6, 24.0, 18.5; IR (KBr) v
3438.9, 3010.2, 2963.5, 2853.3, 2544.9, 1725.9 cm-1; LRMS
(FAB þ NBA matrix) m/z 234, 214 (13.5), 156 (27.4), 79 (40.3);
HRMS calcd for C8H11NO4S 233.0358, found 234.0394 (Mþ þ
H). Anal. Calcd for C8H11NO5S: C 41.20, H 4.75. Found: C
41.32, H 4.75.
2,2,2-Trifluoroethyl cis-Tetrahydro-3H-1,2,3-benzoxathiazole-
3-carboxylate 2,2-Dioxide (14). Eluent hexanes-ethyl acetate, 2:1;
Rf 0.46 (2:1 hexanes-ethyl acetate); mp 70-72 °C (EtOAc);
1H NMR (CDCl3, 300 MHz) δ 6.15 (m, 1H), 5.79 (d, J = 10.2 Hz,
1H), 5.24 (s, 1H), 4.85 (s, 1H), 4.65 (m, 2H), 2.29 (m, 2H), 2.09 (m,
1H), 1.85 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 148.6, 132.3,
122.3 (q, J = 277.7 Hz), 120.1, 78.1, 62.5 (q, J = 37.6 Hz), 55.7,
27.1, 23.9, 18.5; IR (KBr) v 3492.1, 3044.8, 2982.3, 2933.8, 2853.8,
1766.9 cm-1; LRMS (EI) m/z 301, 221 (33.5), 220 (18.4), 216
(14.2), 120 (21.5), 94 (30.0), 78 (100.0); HRMS calcd for C9H10-
F3NO5S 301.0232, found 301.0229. Anal. Calcd for C9H10-
F3NO5S: C 35.88, H 3.35. Found: C 35.98, H 3.24.
Bis((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl) 1-Phenylethane-
1,2-diyldicarbamate (12). Rf 0.75 (1:1 hexanes-ethyl acetate); mp
173-75 °C (EtOAc); 1H NMR (CDCl3, 300 MHz) δ 7.36 (m, 2H),
7.29 (m, 3H), 5.72 (m, 1H), 4.82 (m, 2H), 4.56 (m, 2H), 3.52 (s, 2H),
2.01 (m, 4H), 1.69 (m, 5H), 1.51 (s, 3H), 1.32 (m, 2H), 0.75-1.20
(m, 24H);13CNMR (CDCl3, 150 MHz) δ128.7, 127.7, 126.3, 75.0,
74.8, 56.4, 47.3, 41.4, 34.3, 31.4, 26.3, 23.5, 22.0, 20.9, 16.4; IR
(KBr) v 1015.2, 1148.8, 1291.1, 1455.0, 1533.1, 1685.8, 2956.1,
3364.2 cm-1; LRMS (FAB þ NBA matrix) m/z, 501(11.3), 319
(22.1), 225 (24.3), 181 (69.9), 120 (38.0), 83 (100.0); HRMS calcd for
ꢀ
C30H49N2O4 501.3692, found 501.3691. Anal. Calcd for C30H48N2O4:
C 71.96, H 9.66, N 5.59. Found: C 71.70, H 9.78, N 5.60.
Acknowledgment. The authors are grateful to the follow-
ing agencies for support of this work: the Natural Sciences
and Engineering Research Council (NSERC, Discovery
Grant and Idea to Innovation programs), Canada Research
Chairs program, Canada Foundation for Innovation (CFI),
Ontario Partnership for Innovation and Commercialization
(OPIC), Ontario Innovation Trust (OIT), Research Corporation,
Noramco, Inc., TDC Research, Inc., TDC Research Foundation,
and Brock University.
2,2,2-Trifluoroethyl cis-Hexahydro-3H-1,2,3-benzoxathiazole-
3-carboxylate 2,2-Dioxide (13). Eluent hexanes-ethyl acetate, 2:1;
1
Rf 0.45 (2:1 hexanes-ethyl acetate); mp 83-85 °C (EtOAc); H
NMR (CDCl3, 600 MHz) δ 5.07 (d, J = 3.1 Hz, 1H), 4.69 (m, 1H),
4.61 (m, 1H), 4.27 (m, 1H), 2.38 (m, 1H), 2.33 (m, 1H), 1.90 (m,
Supporting Information Available: NMR data collection
protocol, procedure for decomposition study of Burgess re-
agents at 50 and 78 °C, general procedures for dehydration of
1,2,3,4-tetrahydro-1-naphthol and for reactions with oxiranes
and diols, and 1H and 13C NMR spectra of new Burgess reagents
and sulfamidates. This material is available free of charge via the
Internet at http://pubs.acs.org.
1H), 1.81 (m, 2H), 1.69 (m, 1H), 1.55 (m, 1H), 1.27 (m, 1H); 13
C
NMR (CDCl3, 150 MHz) δ 148.3, 122.3 (q, J = 278.8 Hz), 80.0,
62.5 (q, J= 37.6 Hz), 58.4, 27.1, 26.9, 21.8, 18.8; IR (KBr) v3031.7,
2947.2, 2871.5, 1755.5, 1623.1 cm-1; LRMS (FAB þ NBA matrix)
m/z 304, 258 (5.5), 224 (43.3), 136 (30.7), 81 (100.0); HRMS calcd
3450 J. Org. Chem. Vol. 75, No. 10, 2010