Ring opening of cyclic sulfamidates with bromophenyl metal reagents: Complementarity of sulfamidates and aziridines

Article abstract of DOI:10.1016/j.tetlet.2011.07.123

Bromophenyl magnesium reagents generated via a Knochel type magnesium-halogen exchange of aryl iodides undergo regioselective ring opening of cyclic primary and secondary N-Boc sulfamidates in good to excellent yields. With secondary sulfamidates the reaction proceeds with clean inversion of the stereochemistry. This protocol complements the ring opening of aziridines with bromophenyl metal reagents and extends its scope to secondary substrates.

Full text of DOI:10.1016/j.tetlet.2011.07.123

Tetrahedron Letters 52 (2011) 5229–5233
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Tetrahedron Letters
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Ring opening of cyclic sulfamidates with bromophenyl metal reagents:
complementarity of sulfamidates and aziridines
⇑
Paul Hebeisen , Urs Weiss, André Alker, Andreas Staempfli
F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, CH-4070 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Bromophenyl magnesium reagents generated via a Knochel type magnesium–halogen exchange of aryl
iodides undergo regioselective ring opening of cyclic primary and secondary N-Boc sulfamidates in good
to excellent yields. With secondary sulfamidates the reaction proceeds with clean inversion of the stereo-
chemistry. This protocol complements the ring opening of aziridines with bromophenyl metal reagents
and extends its scope to secondary substrates.
Received 10 June 2011
Revised 22 July 2011
Accepted 27 July 2011
Available online 12 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cyclic sulfamidate
Aziridine
Regioselectivity
Stereoselectivity
Knochel Grignard
Early papers on the ring opening of cyclic sulfam(id)ates with a
variety of nucleophiles made specific mention of the complemen-
tarity with aziridines.1a–c In a recent paper ring opening reactions
of aziridines with ortho-bromophenyl metal reagents as a means
to access pharmacologically interesting indolines were reported2
(Scheme 1). The present work allows a comparison of N-Boc aziri-
dines and N-Boc sulfamidates as electrophiles and provides evi-
dence for the superiority of analogous ring opening reactions of
cyclic sulfamidates with respect to regiochemical control and sim-
plicity of the reaction conditions.
During a program directed toward selective 5HT2c receptor ago-
nists3a,b we were confronted with the problem of introducing a chi-
ral 2-amino-propyl moiety4 at the 3-position of an indole. Ring
opening of aziridines was expected to be a straight forward way to
affect the desired transformation. Aryl lithium, aryl magnesium ha-
lide, aryl zinc halide and aryl organocuprate reagents have all been
used in the ring opening of aziridines.5a–d Our attempts to open a
variety of differently N-protected aziridines (N-tosyl, N-Boc, N-ben-
zyl) with the indole lithium reagent obtained from iodine metal ex-
change of an iodoindole were unsuccessful (Scheme 2). Neither
addition of copper(I)salts such as copper(I)iodide or copper(I)bro-
mide-dimethylsulfide complex nor addition of Lewis acids such as
borontrifluoride etherate improved the conversion.
propylated derivative was formed in an excellent 86% yield
(Scheme 2).3a While this protocol allowed rapid and efficient ac-
cess to the desired serotoninergic compounds its restriction to pri-
mary sulfamidates and the necessity to operate at low
temperatures limited practicality and versatility.
Reaction of commercial phenyllithum with sulfamidate 2b at
À78 °C required a ca twofold excess for complete consumption of
2b and resulted in a 53% yield of the ring opened product accom-
panied by 32% of the des-Boc analog resulting from competing at-
tack of the lithio species at the Boc carbonyl. With this result we
felt encouraged to study ring opening reactions of cyclic sulfami-
dates with the aim to develop a general practical method for the
synthesis of b-phenylethylamines allowing regio and stereocon-
trolled introduction of substituents both at the 1 and the 2-posi-
tion. (Scheme 3).
Substituted b-phenylethylamines represent an important class
of pharmacologically active compounds.6 They can also serve as
intermediates to a wide variety of equally interesting derivatives
such as indolines.7a–d Ortho-bromophenyl analogs in particular
are well established precursors for indolines.2
Ring opening of mono substituted N-Boc-aziridines works well
with ortho-bromophenyl lithium at À78 °C in the presence of
borontrifluoride etherate and proceeds regioselectivly with attack
at the less hindered side. Reactions with phenylzinc, phenylmagne-
sium chloride or corresponding organocuprate reagents were less
satisfactory in terms of reaction times and excess of reagent neces-
sary for full conversion of the employed aziridines.
When N-Boc-sulfamidate 2b was reacted with lithioindole, ob-
tained at À78 °C by iodine lithium exchange, the desired 2-amino-
The ease of preparation and the much higher stability of
arylmagnesium halide reagents especially in the presence of
⇑
Corresponding author.
E-mail address: paul.hebeisen@roche.com (P. Hebeisen).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.123

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P. Hebeisen et al. / Tetrahedron Letters 52 (2011) 5229–5233
R
M
N
PG
R
Pd or Cu
R
HN
N
Br
PG
Br
PG
Scheme 1. Synthesis of indolines via ring opening of aziridines.
I
O
N
O
N
O
nBuLi
O
THF, -78ºC
Li
Pg
N
S
O
O
NHBoc
NHPg
O
2b
O
O
-78ºC to r.t.
aqu. citric acid
86%
N
N
N
Scheme 2. Reaction of N-protected aziridines and N-Boc sulfamidates with 3-lithioindoles.
O
O
O
N
O
S
R2
O
R1
O
I
M
R2
R1 2a-g
HN
O
R3
R3
R3
Scheme 3. General synthesis of 1- or 2-monosubstituted b-phenylethylamines via ring opening of sulfamidates.
Table 1
Yields and selected properties of N-Boc sulfamidates
O
S+
O
O
N
1)NaIO4 1.5-2eq
RuO2 1mol%
CH2Cl2 0-r.t.
O
O
O
R2
SOCl2 1.8eq
imidazole 6eq
S
H
N
O
N
O
O
O
HO
1a-g
CH2Cl2 0-5ºC 2h
thenwash with
water and brine
2)aqu. Na ascorbate
RuO2 removal by
filtration over silica
R1
O
R2
R1
R2
R1
2a-g
Entry
Chirality
R1
R2
Yield (%)
ee11 (%)
Mp (°C)
Lit.
2a
2b
2c
2d
2e
2f
—
R
S
S
R
S
H
H
H
H
CH3
CH3
H
72
88
88
84
84
71
83
—
117–118
121–122
122–123
115–117
117–118
CH3
CH3
H
H
COOEt
100
100
99.2
99.7
n.d.
n.d.
120–12112
2g
S
CH2OTBDMS
H

P. Hebeisen et al. / Tetrahedron Letters 52 (2011) 5229–5233
5231
ortho-halo substituents, however, would make them the preferred
organometal species provided their reactivity being sufficient.
For instance ortho-bromophenyl magnesium halides can be
generated at À15 °C and undergo copper(I) promoted 1,4-addition
to enones at temperatures as high as 0 °C.8a,b
For the synthesis of more elaborated b-phenylethylamines
especially such as the ones carrying additional bromine substitu-
ents we investigated ring opening of cyclic N-Boc-sulfamidates
by aryl magnesium halides.
diethyl ether in which the reactions looked cleaner than in tetrahy-
drofuran. After hydrolysis of the reaction mixture with 10% aque-
ous citric acid the target compounds 3a, 3b, 3c, 4c, 5c, and 6c
were obtained by crystallization from heptane or by short path dis-
tillation (in case of low melting or oily products) in analytically and
optically pure form in yields ranging from 65 to 83% at a 5 mmol
scale14 (Table 2). Similar ring opening reactions of N-Boc aziridines
provide comparable yields but require the phenyllithium reagent
and activation by borontrifluoride etherate, rather than the Grig-
nard reagent, and operation at cryogenic À78 °C.2
The synthesis of cyclic N-Boc sulfamidates9a,b is well established
and involves the reaction of N-Boc protected amino alcohols with
thionylchloride in the presence of a suitable base followed by
Sharpless oxidation of the formed sulfamidites. We have developed
a convenient modified protocol which also addresses removal of
toxic ruthenium tetroxide produced during Sharpless oxidation10
(Table 1).
As the starting iodoaryl compounds as well as their des iodo
analogs were easily separable from the reaction mixture by our
standard workup procedure we usually used them in a twofold
As sulfamidates are well known to undergo ring opening with a
variety of nucleophiles including halides we sought to generate the
Grignard reagent with the least nuleophilic halide possible. A Kno-
chel8a type halogen metal exchange of iodo-bromobenzenes with
isopropylmagnesium chloride in diethyl ether proceeded rapidly
at À15 °C. When sulfamidate 2b was added to this mixture it
was rapidly consumed predominantly with the formation of the
desired ring opened product. Addition of 1 mol % of copper(I) io-
dide improved the conversion with respect to suppression of un-
wanted side products resulting from competitive opening of the
sulfamidate by the halide counter anion.13
Although primary sulfamidates 2a, 2b and 2c reacted even at
À78 °C the outcome with respect to yield and stereochemical pur-
ity did not differ to reactions carried out at non cryogenic À15 °C.
At this temperature all reaction components were freely soluble in
Figure 1. X-ray crystal structure compound 7.
Table 2
b-Phenylethylamines derived from ring opening of cyclic sulfamidates
O
O
O
S
O
N
O
iPrMgCl (1.15-2eq)
R2
diethylether
I
MgCl
H
2a-g
-10 - -15ºC 0.5h
O
N
R2
R1
R3
1mol% Cu(I)I
-15ºC, 2-18h
O
R1
R3
1.1-2 eq
R3
R2
H
N
O
Entry
Chirality
Yield (%t)
ee15 (%)
Mp (°C)
R3
O
R1
R1
H
CH3
CH3
H
H
CH3
H
CH3
H
CH3
H
COOEt
CH2OTBDMS
R2
R3
3a
3b
3c
3d
3e
4c
4e
5c
5e
6c
6e
6f
H
H
H
m-CF3
—
R
S
S
R
S
R
S
R
S
R
S
R
82b
78a
75a
87b
85b
83a
75b
70a
62b
65a
62a
43c
89c
—
100
54–56
84–85
84–85
39–40
40–41
94–95
Oil
108–109
Oil
98–99
57–59
m-CF3
m-CF3
m-CF3
m-CF3
o-Br
99.7
99.2
99.3
100
99.6
100
>97.9
>98.7
>99.6
n.d.
CH3
CH3
H
CH3
H
CH3
H
CH3
H
o-Br
m-Br
m-Br
p-Br
p-Br
o-Br
6g
H
o-Br
n.d.
a
b
c
Crystallization.
Distillation.
Chromatography.

5232
P. Hebeisen et al. / Tetrahedron Letters 52 (2011) 5229–5233
O
O
O
O
O
N
N
H
O
N
H
O
MgX
CF3
S
i, v
Br
O
CuI cat.
83%
3e
2e
CF3
7
CF3
Scheme 4. Stereochemical course of reactions with secondary sulfamidates. Reagents: (i) 2.26 N hydrochloric acid in ethyl acetate; (v) 4-bromobenzoylchloride, Hünig’s base.
excess. However using only slight excess (1.1 equiv) of the iodoaryl
starting material did not reduce the yield significantly (Table 2, en-
try 6g).
In comparison ring opening reactions with corresponding mono
substituted N-Boc aziridines require the more reactive but less sta-
ble bromoaryllithium reagents in combination with a Lewis acid
and are typically carried out at À78 °C. They occur exclusively at
the less hindered side and thus provide access exclusively to
2-substituted phenylethylamines. Pyrimidine-2-sulfonyl (pymisyl)
protected aziridines have recently been shown to ring open effi-
ciently upon reaction with organocuprates offering benefits over
N-Boc aziridines with respect to reactivity. While synthetic acces-
sibility of N-Boc-aziridines and N-Boc-sulfamidates is comparable
the latter are superior with respect to regiochemical control as well
as reactivity in reactions with aryl Grignard reagents.
Having access to the isomeric enantiomerically pure secondary
sulfamidates 2d and 2e from an earlier program we submitted
them to the same reaction conditions. Again good conversions
(62–87%) this time to b-substituted phenylethylamines 3d, 3e,
4e, 5e, and 6e were observed. This substitution pattern has not
been accessible by analogous ring opening reactions of N-Boc azir-
idines due to their propensity to open from the less hindered side.
In contrast to analogous ring opening reactions of primary sulfam-
idates no significant conversion was observed below ca. À40 °C.
The ring opening of secondary sulfamidates 2d and 2e with
nucleophiles such as indoles has been shown to proceed with
inversion.16 Copper(I) mediated ring opening reactions of the sec-
ondary cyclic sulfamidates 2d and 2e with phenylmagnesium chlo-
ride reagents (Table 2, entries 3d, 3e, 4e, 5e, 6e) also proceed with
inversion as evidenced by the X-ray single crystal analysis (Fig. 1)
of a crystalline derivative 7 obtained from phenylethlamine 3e by
N-Boc deprotection and acylation with 4-bromobenzoyl chloride
(Scheme 4).17
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.123.
References and notes
1. (a) Alker, D.; Doyle, K. J.; Harwood, L. M.; McGregor, A. Tetrahedron: Asymmetry
1990, 1, 877–880; (b) Baldwin, J. E.; Spivey, A. C.; Schofield, C. J. Tetrahedron:
Asymmetry 1990, 1, 881–884; (c) White, G. J.; Garst, M. E. J. Org. Chem. 1991, 56,
3177–3178.
2. Michaelis, D. J.; Dineen, T. A. Tetrahedron Lett. 2009, 50, 1920–1923.
3. (a) Adams, D.; Benardeau, A.; Bickerdike, M. J.; Bentley, J. M.; Bissantz, C.;
Bourson, A.; Cliffe, I. A.; Hebeisen, P.; Kennett, G. A.; Knight, A. R.; Malcolm, C.
S.; Mizrahi, J.; Plancher, J.-M.; Richter, H.; Roever, S.; Taylor, S.; Vickers, S. P.
Chimia 2004, 58, 613–620; (b) Bentley, J. M.; Bickerdike, M. J.; Hebeisen, P.;
Kennett, G. A.; Lightowler, S.; Mattei, P.; Mizrahi, J.; Morley, T. J.; Plancher, J.-
M.; Richter, H.; Roever, S.; Taylor, S.; Vickers, S. P.; (F. Hoffmann-La Roche A.-G.,
Switz.; Vernalis Research Limited).WO 2002051844.
Having established conditions for efficient ring opening of sim-
ple methyl substituted primary and secondary N-Boc sulfamidates
we next explored sulfamidates carrying extra functionality such as
carboxylate and silyloxymethyl substituents.
Starting from L-serine esters sulfamidates 2f and 2g were ob-
tained via, also commercially available, intermediates 1f and 1g
by a standard sequence of reactions in excellent overall yield as
crystalline white powders.
Reaction of ethoxycarbonyl substituted 2f with o-bromophenyl-
magnesium chloride under the above described conditions
provided an unsatisfactory 40% yield of carboxyl substituted o-
bromophenylethylamine presumably due to competing attack at
the ester group (Table 2, entry 6f). During their elegant synthesis
of Reinieramycin Zhu et al. used ring opening of t-butylester
substituted N-Boc aziridine with an o-methoxy stabilized aryl Grig-
nard with good success18 which suggests that this aziridine might
also be better compatible o-bromophenylmagnesium chloride than
N-Boc sulfamidate 2f. Silyloxymethyl substituted sulfamidate 2g
gave an excellent 89% yield of the desired product (Table 2, entry
6g) this time after chromatography. Similar ring opening of a cor-
responding silyloxymethyl substituted aziridine was reported in
comparable 79% yield again using a phenyllithium reagent with
activation by borontrifluoride etherate at À78 °C.
4. Adams, D. R.; Bentley, J. M.; Roffey, J. R. A.; Hamlyn, R. J.; Gaur, S.; Duncton, M.
A. J.; Davidson, J. E. P.; Bickerdike, M. J.; Cliffe, I. A.; Mansell, H. L. WO
2000012510, 2000, 54.
5. (a) McCoull, W.; Davis, F. A. Synthesis 2000, 1347–1365; (b) Hu, X. E.
Tetrahedron 2004, 60, 2701–2743; (c) Pineschi, M. Eur. J. Org. Chem. 2006,
4979–4988; (d) Bornholdt, J.; Felding, J.; Clausen, R. P.; Kristensen, J. L. Chem.
Eur. J. 2010, 16, 12474–12480.
6. Bentley, K. W. Nat. Prod. Rep. 2006, 23, 444–463.
7. (a) Bermudez, J.; Dabbs, S.; Joiner, K. A.; King, F. D. J. Med. Chem. 1990, 33, 1929–
1932; (b) Hlasta, D. J.; Luttinger, D.; Perrone, M. H.; Silbernagel, M. J.; Ward, S.
J.; Haubrich, D. R. J. Med. Chem. 1987, 30, 1555–1562; (c) Deboves, H. J. C.;
Hunter, C.; Jackson, R. F. W. J. Chem. Soc., Perkin Trans. 1 2002, 733–736; (d) Yu,
Y.; Ostresh, J. M.; Houghten, R. A. Tetrahedron Lett. 2003, 44, 2569–2572.
8. (a) Boymond, L.; Rottlander, M.; Cahiez, G.; Knochel, P. Angew. Chem., Int. Ed.
1998, 37, 1701–1703; (b) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004,
43, 3333–3336.
9. (a) Melendez, R. E.; Lubell, W. D. Tetrahedron 2003, 59, 2581–2616; (b) Bower, J.
F.; Rujirawanich, J.; Gallagher, T. Org. Biomol. Chem. 2010, 8, 1505–1519.
10. Modified general protocol for the synthesis of N-Boc cyclic sulfamidates: To a
solution of imidazole (41.2 g, 0.60 mol, 6.00 equiv) in dichloromethane
(400 mL) was added at 0 °C a solution of thionyl chloride (21.41 g, 0.18 mol,
13.06 ml, 1.8 equiv) in dichloromethane (130 ml) during 15 min. The reaction
mixture was then stirred at ambient temperature for 1 h and then cooled to
The extension of this chemistry to heteroaryl metal reagents
and secondary silyoxymethyl substituted sulfamidates as well as
application to the synthesis of pharmacologically interesting aza-
indolines19 will be reported in due course.
À10 °C. To the resulting suspension was added a solution of N-Boc-
D-alalinol
(17.52 g, 0.10 mol) in 200 ml dichloromethane during 30 min at À10 °C and the
mixture was then stirred at ambient temperature for 2 h. To the resulting
suspension was added water (800 ml) and the mixture was stirred at ambient
temperature for 10 min. The phases were separated and the organic phase was
washed with 10% aqueous citric acid (500 ml) and half concentrated brine
(500 ml) and dried over magnesium sulfate. The solids were removed by
filtration and washed with ca 50 ml dichloromethane. The combined filtrates
were mixed with a 10% aqueous sodium meta periodate solution (500 ml) and
cooled to 0 °C. To the well stirred mixture was added ruthenium dioxide
In conclusion we have demonstrated that cyclic primary and
secondary N-Boc-sulfamidates undergo efficient copper(I) pro-
moted ring opening reactions with bromoarylmagnesium chlorides
obtained from Knochel type iodo metal exchange at convenient
temperatures (À15 °C) thus giving access to optically pure 1- and
2-monosubstituted b-(bromophenyl)-ethylamines in good to
excellent yields.

P. Hebeisen et al. / Tetrahedron Letters 52 (2011) 5229–5233
5233
hydrate (0.90 g, 0.0060 mol 0.01 equiv) and the mixture was stirred at 0 °C for
2 h and at ambient temperature for 2 h. The phases were separated and the
organic phase washed with a 10% aqueous sodium ascorbate solution (100 ml).
The phases were separated and the organic phase was filtered over silica gel
(300 g). The product was eluted with heptane/ethyl acetate = 2: 1. The product
fractions were combined and concentrated until crystallization occurred. The
solid was collected by filtration, washed with heptane and dried to constant
weight under high vacuum to yield 2b (20.1 g, 86%) as white crystals melting at
121–122 °C.
the residue was purified by kugelrohr distillation (0.4 m bar, 105 °C) or by
crystallization from heptane to furnish products (Table 2, entries 4–6b and c)
in 62–83% yield.
15. Chiral LC on a Chiralcel-ODH, 25 cm  4.6 mm, DB075 mobile phase A: heptan
B: heptan+ 5% ethanol+ 5% isopropanol+ 0.01 M NH4Ac
16. Roever, S.; Adams, D. R.; Benardeau, A.; Bentley, J. M.; Bickerdike, M. J.;
Bourson, A.; Cliffe, I. A.; Coassolo, P.; Davidson, J. E. P.; Dourish, C. T.; Hebeisen,
P.; Kennett, G. A.; Knight, A. R.; Malcolm, C. S.; Mattei, P.; Misra, A.; Mizrahi, J.;
Muller, M.; Porter, R. H. P.; Richter, H.; Taylor, S.; Vickers, S. P. Bioorg. Med.
Chem. Lett. 2005, 15, 3604–3608.
11. Chiral LC on a Chiralcel-ODH, 25 cm  4.6 mm, DB075 mobile phase A: heptan
B: heptan+ 5% ethanol+ 5% isopropanol+ 0.01 M NH4Ac
17. A single crystal of compound 7 (0.8 Â 0.03 Â 0.03 mm) was mounted in a loop
12. Posakony, J. J.; Grierson, J. R.; Tewson, T. J. J. Org. Chem. 2002, 67, 5164–5169.
13. When 10 mol % of copper(I)iodide was employed the yields did not improve
and the product of competitive ring opening of the sulfamidate with iodide
became detectable.
and cooled to 89 K in a nitrogen stream. Data were collected at the swiss light
source beamline X10SA using
a MAR CCD225 detector with synchrotron
radiation (0.7 Å) and data processed with the program XDS. The crystal
structure was solved and refined with ShelXTL (Bruker AXS, Karlsruhe). The
absolute configuration of the molecule was determined to be R based on
refinement of the Flack absolute structure parameter (Flack 1983). The low
standard deviation (0.008) of the Flack parameter (0.036) indicated a reliable
determination of the absolute structure. Flack, H.D. Acta Crystallogr., Sect. A
1983, 39, 876–881.
14. General protocol for ring opening of sulfamidates with bromophenyl magnesium
chlorides: To a 2 M solution of isopropylmagnesium chloride in diethyl ether
(5 ml; 0.010 mol) was added drop wise at À12 °C the corresponding bromo-
iodobenzene (2.83 g; 0.010 mol; 2 equiv) and the mixture was stirred at À12 °C
for 2 h. To the resulting mixture was added cuprous(I) iodide (0.020 g;
0.10 mmol; 0.01 equiv) and the mixture was stirred at À12 °C for 0.5 h. The
resulting mixture was added via syringe to a suspension of the corresponding
sulfamidate (2b or 2c) (1.19 g 0.0050 mol; 1 equiv) in 10 ml diethyl ether at
À12 °C and the mixture was stirred at this temperature for 2 h. To the resulting
solution was added drop wise a 10% aqueous solution of citric acid (10 ml) and
the mixture was stirred at room temperature for 2 h. The phases were
separated, the organic phase was concentrated under aspirator vacuum and
18. Wu, Y.-C.; Zhu, J. Org. Lett. 2009, 11, 5558–5561.
19. Richter, H. G. F.; Adams, D. R.; Benardeau, A.; Bickerdike, M. J.; Bentley, J. M.;
Blench, T. J.; Cliffe, I. A.; Dourish, C.; Hebeisen, P.; Kennett, G. A.; Knight, A. R.;
Malcolm, C. S.; Mattei, P.; Misra, A.; Mizrahi, J.; Monck, N. J. T.; Plancher, J. M.;
Roever, S.; Roffey, J. R. A.; Taylor, S.; Vickers, S. P. Bioorg. Med. Chem. Lett. 2006,
16, 1207–1211.