Substitution reactions of hindered cyclic sulfamidates

Article abstract of DOI:10.1055/s-2002-28509

Five- and six-membered cyclic sulfamidates, [1,2,3]-oxathiazolidineand [1,2,3]-oxathiazinane-2,2-dioxides, with the leaving group oxygen at sterically hindered centers were synthesized and treated with selected nucleophiles (azide, cyanide, fluoride, butylamine, sec-butylamine, tert-amylamine, and imidazole) in substitution reactions to demonstrate the general utility and limitations of these substrates. Substitutions adjacent to quaternary carbon centers were accomplished with relative ease. In contrast to the 4,4-dimethyl substituted 5-membered sulfamidate 1, which reacted with the entire set of nucleophiles, the more hindered 5-membered and 6-membered sulfamidates (7 and 6, respectively) reacted only with the first few of this set.

Full text of DOI:10.1055/s-2002-28509

PAPER
859
Substitution Reactions of Hindered Cyclic Sulfamidates
S
ubstitutio
e
nReaction
f
s
of
H
in
f
deredCy
r
clic Sul
e
a
University of Washington, Department of Radiology Imaging Research Laboratory, Rm NW041, Box 356004, 1959 NE Pacific St., Se-
attle, WA 98195, USA
b
University of Iowa PET, Imaging Center, Department of Radiology, 0911Z JPP, 200 Hawkins Drive, Iowa City, Iowa, 52242-1007, USA
Fax +1(319)3536512; E-mail: timothy-tewson@uiowa.edu
Received 18 March 2001; revised 6 March 2002
Abstract: Five- and six-membered cyclic sulfamidates, [1,2,3]-ox-
athiazolidine- and [1,2,3]-oxathiazinane-2,2-dioxides, with the
leaving group oxygen at sterically hindered centers were synthe-
sized and treated with selected nucleophiles (azide, cyanide, fluo-
ride, butylamine, sec-butylamine, tert-amylamine, and imidazole)
in substitution reactions to demonstrate the general utility and limi-
tations of these substrates. Substitutions adjacent to quaternary car-
bon centers were accomplished with relative ease. In contrast to the
4,4-dimethyl substituted 5-membered sulfamidate 1, which reacted
with the entire set of nucleophiles, the more hindered 5-membered
and 6-membered sulfamidates (7 and 6, respectively) reacted only
with the first few of this set.
Key words: nucleophilic additions, steric hindrance, amines, sub-
stituent effects, cyclic sulfamidates
Figure
nium tetroxide to afford 6 and 7 in 33 and 52% overall
yield, respectively.
Cyclic sulfamidates are reactive electrophiles and have
been useful in the conversion of amino alcohols to unique-
Sulfamidates 1, 6 and 7 were treated with selected nucleo-
philes (from the set of azide, cyanide, fluoride, buty-
lamine, sec-butylamine, tert-amylamine, and imidazole)
under a variety of conditions. After hydrolysis of the N
SO3 intermediates, the products were purified by chro-
matography or by recrystallization of their hydrochloride
salts.
6
ly substituted amines.1 Recently, the hindered cyclic
sulfamidate 1 was described in the synthesis of fluoro-
9
tert-butylamine.7 Compound 1 was highly reactive to-
ward fluoride, giving the expected substitution product at
a carbon center adjacent to a quaternary carbon, a substi-
tution analogous to a neopentyl substitution, which is
known to be difficult. We then became interested in prob-
ing the limitations of substitution reactions of 1 and even Sulfamidate 1 reacted readily with azide and cyanide to
more hindered sulfamidates (Figure) such as 6 and 7. Sul- yield 8 (70%) and 9 (59%), respectively (Scheme 1). The
famidate 6 incorporates a quarternary carbon center in a 6-
membered ring, and sulfamidate 7 incorporates tertiary
and quaternary carbon centers in a 5-membered ring. We
report here the results of our experiments with progres-
sively more hindered sulfamidates, 1, 6 and 7 in displace-
ment reactions with a set of useful nucleophiles and a
varied degree of steric bulk (e.g. azide, cyanide, fluoride,
imidazole, butyl-, sec-butyl, and tert-amyl amines). These
results will have implications for the usefulness of hin-
dered cyclic sulfamidates in the production of sterically
hindered amines.
9
The synthesis of 1 was described previously.7 The re-
maining sulfamidates were synthesized using similar con-
ditions by treating the corresponding N-benzyl amino
alcohols (2 and 3) with thionyl chloride to produce the sul-
famidites (4 and 5) which were then oxidized with ruthe-
Synthesis 2002, No. 7, 21 05 2002. Article Identifier:
1437-210X,E;2002,0,07,0859,0864,ftx,en;M00901SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
Scheme 1

860
J. J. Posakony, T J. Tewson
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previously described reaction of 1 with fluoride yielded
N-benzyl fluoro-tert-butylamine in 78% yield.8,9 Imida-
zole, in the presence of cesium carbonate, reacted with 1
to yield 10 after hydrolysis (72%); in contrast, triethyl-
amine did not promote this reaction. N-butyl-, sec-butyl-,
and even tert-amylamine reacted with 1 to yield the di-
aminopropanes 11 13, in 71, 70, and 41% yields, respec-
tively. However, the syntheses of 12 and 13 required
refluxing 1 in neat sec-butylamine and tert-amylamine for
3 days and 7 days, respectively. There was no indication
of other products in the synthesis of 12 and 13 and signif-
icant amounts of unreacted 1 were recovered.
The 6-membered 6 and 5-membered, hindered 7 under-
went substitution only with the less bulky nucleophiles of
the series (Scheme 2). Compound 6 reacted with sodium
azide and sodium cyanide in DMF at 100 °C to yield 14
and 15 in 52 and 44% yields, respectively. The reaction of
6 with TBAF yielded a small amount of 16 (9%), while
the reaction with neat butylamine to produce 17 (61%) re-
quired 8 days at reflux. No reaction was observed when a
solution of 6 was refluxed for ~2 days with sec-buty-
lamine. Compound 7 reacted with sodium azide and sodi-
um cyanide in DMF at ~100 °C to yield 18 and 19 in 68%
and 22% yields, respectively. However, only the elimina-
tion product 20 was isolated when 7 was treated with bu-
tylamine or TBAF.
Scheme 2
been obtained that would clearly demonstrate whether
these substrates react via direct substitution (SN2) or nu-
cleophilic capture (SN1) of a transient carbocation derived
from the cyclic sulfamidate. However, the fact that many
of these reactions proceed cleanly to a single product in
good yields suggests that a direct substitution is involved.
It is interesting that the fluoride ion (as TBAF), a small
nucleophile, afforded low yields with 6 and only the elim-
ination product with 7. Other factors, in addition to steric
restrictions limiting the substitution reaction are likely to
be involved. TBAF is known to be basic and induce elim-
inations with some substrates, including cyclic sulfami-
dates.10 Better results might be obtained using a less basic
source of fluoride, such as (triphenylsilyl)difluorosili-
cate;11 and the results of such experiments will be reported
elsewhere. HPLC analyses of the fluorination reaction of
6 (data not shown) indicated that several products are
formed with during the initial fluorination step. It is con-
ceivable that 6 also undergoes SN2 attack at the carbon ad-
jacent to nitrogen. Such a substitution would require the
sulfonamide as the leaving group, similar to the substitu-
tion reactions of N-sulfonyl aziridines.12 In addition, the
product of this substitution could itself be susceptible to
SN2 attack at the carbon adjacent to oxygen. Additional
displacement reactions and the fact that substitutions at
neopentyl centers are frequently accompanied by rear-
rangements could help explain the additional products ob-
served by HPLC.
In summary, the three hindered cyclic sulfamidates 1, 6
and 7 were synthesized using standard methodologies. An
investigation of these sulfamidates was performed by
treating these substrates with a set of useful nucleophiles
with varied degrees of steric bulk (azide, cyanide, imida-
zole (for 1 only), butylamine, sec-butylamine, and tert-
amylamine). Sulfamidate 1 reacted with all these nucleo-
philes in moderate to excellent yields at the carbon adja-
cent to the tertiary carbon. The more hindered 6 and 7
were more limited in their reactivity. Sulfamidate 6 under-
went substitution reactions with azide, cyanide, TBAF
and butylamine. Although 7 reacted with azide, and cya-
nide, it underwent elimination to produce 20 with treated
with TBAF and butylamine. These cyclic sulfamidates are
adequate substrates for preparing a variety of sterically
hindered amines.
Melting points were determined using an Electrothermal® melting
point apparatus and are uncorrected. Low resolution mass spec-
trometry was performed on a Micromass Quattro II Tandem Qua-
drupole Mass Spectrometer (electrospray ionization). High
resolution mass spectrometry was performed using a Micromass
70SEQ Tandem Hybrid Mass Spectrometer (FAB) or a PE Biosys-
SN2 displacements at neopentyl centers are typically very
slow and are often impractical as synthetic routes. The
high reactivity of these hindered substrates (1, 6 and 7)
must be due, in part, to the increased access to the reactive
carbon afforded by the ring structure of the cyclic sulfami-
date in comparison to acyclic substrates (e.g. with leaving
groups like iodide, tosylate, mesylate, triflate, etc.). In
contrast to 1, which reacted with some very hindered nu-
cleophiles, definite limits were encountered with the reac-
tivity of 6 and 7. The necessary kinetic data have not yet
teMS: Mariner electrospray (TOF) instrument. H- and 19F NMR
1
spectra were obtained with a GE Omega 300 MHz spectrometer.
1H-chemical shifts are reported in ppm ( ) and 19F-chemical shifts
are referenced to CFCl3. Coupling constants are rounded to the
nearest 0.5 Hz. Elemental analyses were performed by Galbraith
Laboratories, Knoxville, TN. Prior to elemental analysis, samples
Synthesis 2002, No. 7, 859–864 ISSN 0039-7881 © Thieme Stuttgart · New York

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Substitution Reactions of Hindered Cyclic Sulfamidates
861
were dried under vacuum at 40 50 °C. Flash column chromatogra-
phy was performed using silica gel (Merck, grade 9385, 230 400
mesh). Analytical TLC and Rf values were determined using Anal-
tech GF silica gel plates (0.25 mm); preparative TLC was per-
formed using Analtech GF silica gel plates (1 mm). Unless
otherwise noted, reagents were purchased from Aldrich Chemical
Co. Solvents were ACS reagent grade or better. Unless otherwise
noted, anhyd solvents (Aldrich) were used as received except for
CH2Cl2 which was dried by storing over activated, crushed 4Å mo-
lecular sieves. Stable HCl salts were obtained by dissolving the
product in Et2O or Et2O–MeOH and bubbling HCl(g) through the so-
lution; the resulting precipitate was then collected and washed thor-
oughly with Et2O.
Anal. Calcd for C12H17NO2S: C, 60.22; H, 7.16; N, 5.85. Found: C,
60.33; H, 7.42; N, 5.85.
3-Benzyl-4,4,5-trimethyl-oxathiazolidine-2-oxide (5)
Compound 3 (0.3 g, 1.6 mmol) was used to produce crude 5, which
was purified by filtration through a pad of silica using CH2Cl2 ac-
etone, 20:1 to yield 0.25 g (63%) of an oil.
1H NMR (CDCl3): = [1.02 (s), 1.17 (s), 1.23 (s), and 1.34 (s); 6 H,
C(CH3)2], 1.35 and 1.44 (2 d, 3 H, J = 6.6 Hz, CH(CH3), 4.08 and
4.30 (2 d, 2 1 H, AB system, J = 14.4 Hz, benzyl H), 4.26 and
4.90 (2 q, 1 H, J = 6.6 Hz, CH(CH3) 7.26 7.42 (m, 5 H, phenyl
H).
MS: m/z = 240 (55, M + H), 176 (100).
3-(Benzylamino)-2,2-dimethyl-propan-1-ol (2)
Anal. Calcd for C12H17NO2S: C, 60.22; H, 7.16; N, 5.85. Found: C,
60.44; H, 7.43; N, 5.77.
A mixture of 3-amino-2,2-dimethyl-propan-1-ol (Lancaster Synthe-
sis, 3 g, 29 mmol) and benzaldehyde (3.1 mL, 30.5 mmol) in ben-
zene (50 mL) was refluxed for 4 h during which time H2O was
removed using a Dean Stark apparatus. The solvent was then re-
moved and the residual oil was dissolved in MeOH (40 mL). The
soln was then cooled to 0 °C and NaBH4 (1.67 g, 44 mmol) was add-
ed in 3 equal portions over several minutes. The mixture was stirred
for 2 h and then 6 N NaOH (7 mL) was added and the solvent evap-
orated. The residue was dissolved in H2O (30 mL) and extracted
with Et2O (4 15 mL). The organic phase was dried (Na2SO4) and
the solvent was removed. The product was crystallized by adding
heptane to the residual oil and stored at 10 °C to yield 4.6 g (82%)
of 2; mp 33.5 35.5 °C.
3-Benzyl-5,5-dimethyl-[1,2,3]-oxathiazinane-2,2-dioxide (6)
Compound 4 (0.5 g) was used to produce 6, which was purified by
filtration through silica gel using CH2Cl2 and subsequent recrystal-
lization from CH2Cl2 heptane to afford 0.38 g (71%); mp 61
62 °C; Rf 0.6 (CH2Cl2).
1H NMR (CD3CN): = 1.02 [s, 6 H, C(CH3)2], 2.97 (s, 2 H, ring
CH2), 4.28 and 4.30 (2 s, 2 2 H, benzyl and ring CH2), 7.28 7.32
(m, 5 H, phenyl H).
13C NMR (CDCl3): = 22.48, 31.65, 52.59, 58.71, 81.87, 128.11,
128.61, 128.66, 134.77.
The 1H NMR data are similar to those reported in the literature.13
MS: m/z = 278 (100, M + Na), 256 (5, M + H).
Anal. Calcd for C12H17NO3S: C, 56.44; H, 6.71; N, 5.48. Found: C,
56.44; H, 6.89; N, 5.35.
Anal. Calcd for C12H19NO: C, 74.57; H, 9.91; N, 7.24. Found: C,
74.56; H, 10.18; N, 7.52.
3-Benzyl-4,4,5-trimethyl-oxathiazolidine-2,2-dioxide (7)
Compound 5 (0.15 g, 0.63 mmol) was used to produce 7, which was
purified by filtration through a pad of silica gel using Et2O and sub-
sequent recrystallization from CH2Cl2 heptane to afford 0.134 g
(83%); mp 64 65 °C.
3-(Benzylamino)-3-methyl-butan-2-ol (3)
Compound 3 was synthesized from benzaldehyde and 3-amino-3-
methyl-butan-2-ol14 in 40% yield by the method used for the syn-
thesis of 2. The product was crystallized from heptane; mp 60.5
62.5 °C.
1H NMR (CDCl3): = 1.15 and 1.22 [s, 2 3 H, C(CH3)2], 1.41 (d,
3 H, J = 6.3 Hz, CHCH3), 4.16 and 4.36 (2 d, 2 1 H, AB system,
J = 15.9 Hz, benzyl H), 4.64 (q, 1 H, J = 6.3 Hz, CHCH3), 7.30
7.45 (m, 5 H, phenyl H).
1H NMR (CDCl3): = 1.04 and 1.17 [s, 2 3 H, C(CH3)2], 1.15 (d,
3 H, J = 6.3 Hz, CHCH3), 1.3 1.6 (br s 2 H, NH, OH), 3.60 (q, 1 H,
J = 6.3 Hz, CHCH3), 3.71 (s, 2 H, benzyl H), 7.25 7.40 (m, 5 H,
phenyl H).
13C NMR (CDCl3): = 13.67, 17.58, 23.73, 45.34, 65.35, 85.49,
127.93, 128.21, 128.59, 136.20.
MS: m/z = 194 (100, M + H).
Anal. Calcd for C12H19NO: C, 74.57; H, 9.91; N, 7.24. Found: C,
74.59; H, 10.11; N, 7.06.
MS: m/z = 256 (100, M + H).
Anal. Calcd for C12H17NO3S: C, 56.44; H, 6.71; N, 5.48. Found: C,
56.46; H, 6.83; N, 5.39.
Cyclic Sulfamidite and Sulfamidate; General Procedure
Sulfamidites 4 and 5 were synthesized by the same methodology
used to produce the N-benzyl sulfamidite precursor to 1, 3-benzyl-
4,4-dimethyl-[1,2,3]-oxathiazolidine-2-oxide, as described previ-
ously.8 Similarly, the previously described RuO4-oxidation condi-
tions were used to convert 4 and 5 to 6 and 7, respectively.
Sulfamidites 4 and 5 are mixtures of diasteromers and give complex
1H NMR spectra; their 13C NMR spectra were not obtained.
Substitution Reactions
The nucleophilic displacement reactions were carried out under a
variety of conditions. After solvent removal, the formed N SO3 in-
termediates were then hydrolyzed by treating with 20% H2SO4(aq)
Et2O (1:1, 20 mL/g of sulfamidate). The mixture was stirred for 2 h
at r.t. and then the organic phase, which contained unreacted start-
ing material, was separated from the aq phase. The aq phase was
then adjusted to pH = 10 12 using solid Na2CO3, the product was
extracted into Et2O and subsequently purified by column chroma-
tography or by recrystallization of its HCl salt. 13C NMR spectra
from the three nitriles are provided as representatives of the three
series of products.
3-Benzyl-5,5-dimethyl-[1,2,3]-oxathiazinane-2-oxide (4)
Compound 2 (2 g, 10.3 mmol) was used to produce 4. Purification
by repeated column chromatography (3 times; silica/CH2Cl2 ace-
tone, 50:1) yielded 1.18 g (47%) of 4 as a colorless oil; Rf 0.68.
1H NMR (CDCl3): = 0.81 and 1.16 [2 s, 2 3 H, C(CH3)2], [2.21
(dd, 1 H, J1 = 12 Hz, J2 = 2 Hz), 3.18 (d, 1 H, J = 12 Hz), 3.36 (dd,
1 H, J1 = 11.3 Hz, J2 = 2.4 Hz), and 4.49 (dd, 1 H, J1 = 11.0 Hz,
J2 = 0.5 Hz), ring CH2] 3.54 and 4.25 (2 d, 2 1 H, J = 14.1 Hz,
benzyl H), 7.28 7.34 (m, phenyl H).
1-Azido-2-benzylamino-2-methylpropane (8)
Compound 1 (0.1 g, 0.4 mmol) and NaN3 (39 mg, 0.6 mmol) were
added to anhyd DMF (1 mL); the mixture was stirred overnight at
r.t. and then refluxed for 1 h to complete the reaction (TLC). The
MS: m/z = 262 (65, M + Na), 240 (25, M + H), 176 (100).
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J. J. Posakony, T J. Tewson
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solvent was evaporated and the residual product was hydrolyzed to
[s, 2 H, C(CH3)2CH2], 2.56 (t, 2 H, J = 7.0 Hz, butyl CH2NH), 3.66
yield 72 mg (88%) of crude 8.
(s, 2 H, benzyl H), 7.20 7.40 (m, 5 H, phenyl H).
1H NMR (CD3CN): = 1.14 [s, 6 H, C(CH3)2], 3.29 (s, 2 H, CH2N3),
3.72 (s, 2 H, benzyl H), 7.22 7.41 (m, 5 H, phenyl H).
MS: m/z = 235.2 (100, M + H), 162.1 (30, M + H – C4H11N), 128.1
(35).
MS: m/z = 205.2 (100, M + H).
8 HCl
A sample (64 mg) was converted to its HCl salt and purified recrys-
tallization from MeOH EtOAc to yield 64 mg (71%).
11 2HCl
The product was converted to its HCl salt and then purified by re-
crystallization from MeOH EtOAc to afford 59 mg (70%); mp
179 183 °C (dec.).
Mp 216 219.5 °C.
Anal. Calcd for C15H28Cl2N2: C, 58.62; H, 9.18; N, 9.11. Found: C,
58.51; H, 9.35; N, 9.03.
Anal. Calcd for C11H17ClN4: C, 54.88; H, 7.12; N, 23.26. Found: C,
54.89; H, 7.18; N, 23.12.
N1-(sec-Butyl)-N2-benzyl-2-methylpropane-1,2-diamine (12)
A soln of 1 (0.20 g, 0.83 mmol) in sec-butylamine (10 mL) was
stirred and refluxed for 3 d. TLC showed that some material re-
mained. After solvent removal the residue was hydrolyzed; 47 mg
(23%) of 1 was recovered and 0.175 g of crude 12 was isolated.
3-Benzylamino-3-methyl-butyronitrile (9)
Compound 1 (0.1 g, 0.4 mmol) and NaCN (29 mg, 0.6 mmol) were
dissolved in anhyd DMF (1 mL) and the mixture was stirred for 24
h at r.t. After solvent evaporation and subsequent hydrolysis, 69 mg
of crude 9 was isolated as an oil.
1H NMR (CD3CN): = 1.26 [s, 6 H, C(CH3)2], 1.45 (br s 1 H, NH),
2.58 (s, 2 H, CH2CN), 3.73 (s, 2 H, benzyl H), 7.25 7.41 (m, 5 H,
phenyl H).
MS: m/z = 235.1 (80, M + H), 162 (100, M + H – C4H11N).
1H NMR (CD3CN): = 0.88 (t, J = 7.5 Hz, 3 H, butyl CH2CH3),
0.99 (d, J = 6.3 Hz, 3 H, butyl CHCH3), 1.08 [s, 6 H, C(CH3)2],
1.25 1.5 (m, 2 H, butyl CH2), 2.0 (br s NH), overlapping signals
[2.45 (m, butyl CH), 2.44 and 2.54 (2 d, AB system, J = 11.4 Hz,
benzyl H); 3 H], 3.65 [s, 2 H, C(CH3)2CH2N], 7.2 7.35 (m, 5 H,
phenyl H).
13C NMR (DMSO-d6): = 24.36, 27.61, 32.45, 54.24, 118.19,
129.76, 130.20, 130.95, 131.27.
MS: m/z = 211.2 (15, M + Na), 189.2 (100, M + H).
9 HCl
The product was converted to its HCl salt; yield was 0.173 g (70%)
of 12 2HCl. Recrystallization attempts using MeOH Et2O, CH2Cl2
or EtOAc were unsuccessful. 12 2HCl
A sample (42 mg) was converted to its HCl salt to yield 32 mg
(59%); mp 255 256 °C (dec.).
Anal. Calcd for C15H28Cl2N2: C, 58.62; H, 9.18; N, 9.11. Found: C,
58.24; H, 9.45; N, 8.92.
Anal. Calcd for C12H17ClN2: C, 64.13; H, 7.63; N, 12.46. Found: C,
63.90; H, 7.77; N, 12.28.
N1-(tert-Amyl)-N2-benzyl-2-methylpropane-1,2-diamine (13)
Compound 1 (0.20 g, 0.83 mmol) was added to tert-amylamine (10
mL,) and the mixture was stirred and refluxed for 7 d. TLC showed
some remaining starting material. After solvent removal and hy-
drolysis, 0.118 g (59%) of unreacted 1 was recovered.
1-(2-Benzylamino-2-methyl-propyl)-imidazole (10)
A mixture of 1 (0.2 g, 0.83 mmol), imidazole (0.565 g, 8.3 mmol)
and Cs2CO3 (1.3 g, 4 mmol) in anhyd DMF (5 mL) was heated to
100 °C with stirring for 30 min. The solvent was removed and the
mixture was hydrolyzed. Purification of crude 10 by column chro-
matography (silica/CH2Cl2 MeOH, 20:1; Rf 0.41) and conversion
to its HCl salt in MeOH Et2O afforded 0.202 g (72%) of a white
powder. Attempts to recrystallize 10 2HCl from MeOH EtOAc or
MeOH Et2O were unsuccessful.
Crude 13
1H NMR (CDCl3): = 0.83 (t, J = 7.5 Hz, 3 H, amyl CH2CH3), 1.00
(s, 6 H, amyl CH3), 1.11 [s, 6 H, HNC(CH3)2], 1.1 (br s 2 H, NH)
1.38 (q, J = 7.5 Hz, 2 H, amyl CH2CH3), 2.44 [s, 2 H, C(CH3)2CH2],
3.66 (s, 2 H, benzyl H), 7.25 7.41 (m, 5 H, phenyl H).
10 2HCl
MS: m/z = 249.1 (75, M + H), 162 (100, M + H – C5H13N).
1H NMR (DMSO-d6): = 1.47 [s, 6 H, C(CH3)2], 4.24 (s, 2 H, ben-
zyl H), 4.77 [s, 2 H, CH2N(imidazole)], 7.4 (m, 3 H, phenyl H), 7.7
[m, 3 H, phenyl and 4 (or 5)-imidazolyl H), 7.85 (t, 1 H, 5 (or 4)-
imidazolyl H], 9.31 (s, 1 H, 2-imidazolyl H), 9.80 10.0 (br s, 1.5 H,
NH).
13C NMR (DMSO-d6): = 20.94, 44.64, 53.21, 58.77, 119.70,
123.60, 128.44, 128.71, 128.81, 130.32, 132.16.
The product was converted to its HCl salt (0.103 g, 41%), which
could not be recrystallized.
13 2HCl
Mp 216 218.5 °C.
Anal. Calcd for C16H30Cl2N2: C, 59.80; H, 9.41; N, 8.71. Found: C,
59.14; H, 9.67; N, 8.50.
MS: m/z = 230.0 (35, M + H), 162 (100, M + H –C3H4N2).
Anal. Calcd for C14H19N3 2(HCl) 2.25(H2O): C, 49.06; H, 7.50; N,
12.25. Found: C, 49.10; H, 7.63; N, 12.42.
1-Azido-3-benzylamino-2,2-dimethylpropane (14)
A stirred mixture of 6 (0.3 g, 1.2 mmol) and NaN3 (0.115 g, 1.8
mmol) in anhyd DMF (3 mL) was heated for 3 h at 100 °C. The sol-
vent was evaporated under reduced pressure, the residual product
was hydrolyzed and crude 14 (0.18 g) was isolated as an oil.
1H NMR (CDCl3): = 0.91 [s, 6 H, C(CH3)2], 1.3 (br s 1 H, NH),
2.43 (s, 2 H, propyl HNCH2), 3.21 (s, 2 H, CH2N3), 3.78 (s, 2 H,
benzyl H), 7.25 7.40 (br m, 5 H, phenyl H).
N1-Butyl-N2-benzyl-2-methylpropane-1,2-diamine (11)
A soln of 1 (0.1 g, 0.4 mmol) and butylamine (0.4 mL, 4mmol) in
anhyd CH3CN (1 mL) was refluxed and stirred for 6.5 h. Some start-
ing material remained, thus additional butylamine (0.4 mL) and
CH3CN (0.5 mL) were added and refluxing was continued for 18 h.
The mixture was cooled to r.t., an unidentified precipitate was fil-
tered off, then the solvent was evaporated and the mixture hydro-
lyzed to yield 77 mg (82%) of crude 11 as an oil.
MS: m/z = 219.2 (M + H, 100).
The crude product was converted to its HCl salt and recrystallized
1H NMR (CD3CN): = 0.92 (t, 3 H, J = 7.2 Hz, butyl CH3), 1.09 [s,
from MeOH EtOAc to yield 0.156 g (52%) of 14 HCl.
6 H, C(CH3)2], 1.3 1.45 [m, 5 H, butyl CH3(CH2)2 and NH], 2.48
Mp 174.5 179 °C.
Synthesis 2002, No. 7, 859–864 ISSN 0039-7881 © Thieme Stuttgart · New York

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Substitution Reactions of Hindered Cyclic Sulfamidates
863
Anal. Calcd for C12H19ClN4: C, 56.57; H, 7.52; N, 21.98. Found: C,
56.29; H, 7.68; N, 21.66.
2-Azido-3-benzylamino-3-methylbutane (18)
A soln of 7 (0.1 g, 0.4 mmol) and NaN3 (40 mg, 0.62 mmol) in an-
hyd DMF was heated to 110 °C for 15 min. After solvent evapora-
tion and hydrolysis of the residual product, crude 18 (70 mg) was
isolated as an oil.
1H NMR (CDCl3): = 1.14 and 1.16 [2 s, 6 H, C(CH3)2], 1.34 (d,
3 H, J = 6.6 Hz, CHCH3), 1.45 (br s 1 H, NH), 3.61 (q, 1 H, J = 6.6
Hz,CHN3), 3.71 and 3.77 (2 d, 2 1 H, AB system, J = 12 Hz,
benzyl H), 7.25 7.40 (m, 5 H, phenyl H).
A small amount of 6 (50 mg) was recovered from the reaction.
4-Benzylamino-3,3-dimethylbutyronitrile (15)
A stirred mixture of 6 (0.3 g, 1.2 mmol) and NaCN (92 mg, 1.9
mmol) in anhyd DMF (3 mL) was heated at 100 °C for 3 h. The sol-
vent was evaporated under reduced pressure and the residual prod-
uct was hydrolyzed; 0.125 g of crude 15 was isolated as an oil.
1H NMR (CDCl3): = 1.04 [s, 6 H, C(CH3)2], 1.4 (br s 1 H, NH),
2.38 (s, 2 H, propyl HNCH2), 2.49 (s, 2 H, CH2CN), 3.80 (s, 2 H,
benzyl H), 7.25 7.40 (m, 5 H, phenyl H).
MS: m/z = 219 (100, M + H), 148 (50).
After conversion to its HCl salt, the product was recrystallized from
MeOH EtOAc to yield 68 mg (68%).
MS: m/z = 203.2 (M + H, 100).
18 HCl
The product was converted to its HCl salt and recrystallized from
MeOH EtOAc to yield 0.123 g (44%).
Mp 154 156.5 °C.
Anal. Calcd for C12H19ClN4 0.25 H2O: C, 55.59; H, 7.58; N, 21.60.
Found: C, 55.76; H, 7.70; N, 21.53.
15 HCl
Mp 151 153.5 °C.
3-Benzylamino-2,3-dimethylbutyronitrile (19)
13C NMR (DMSO-d6):
118.20, 128.54, 128.91, 130.41, 131.27.
= 24.40, 27.65, 32.47, 50.72, 54.18,
A soln of 7 (0.1 g, 0.4 mmol) and NaCN in anhyd DMF (1.5 mL)
was heated to 100 °C for 3 h. After evaporating the solvent under
reduced pressure and applying the standard hydrolysis procedure,
crude 19 (26 mg) was isolated as an oil. A small amount of 7 (35
mg) was recovered from the reaction. 19:
Anal. Calcd for C13H19ClN2: C, 65.39; H, 8.02; N, 11.73. Found: C,
65.18; H, 8.14; N, 11.59.
A small amount of 6 (25 mg) was recovered from the reaction.
1H NMR (CDCl3): = 1.24 and 1.30 [2 s, 6 H, C(CH3)2], 1.32 (d,
3 H, J = 7.2 Hz, CHCH3), 2.80 (q, 1 H, J = 7.2 Hz, CHCN), 3.64 and
3.76 (2 d, 2 1 H, AB system, J = 12.3 Hz, benzyl H), 7.25 7.40
(m, 5 H, phenyl H).
3-Benzylamino-1-fluoro-2,2-dimethylpropane (16)
A stirred mixture of 6 (0.10 g, 0.39 mmol) and TBAF (0.8 mmol) in
CH3CN (5 mL) was refluxed for 3 h; no starting material remained
(TLC). After hydrolysis, 16 was isolated as an oil.
1H NMR (CDCl3): = 0.93 [d, 6 H, JHF = 1.8 Hz, C(CH3)2], 2.48 (d,
2 H, JHF = 1.8 Hz, propyl HNCH2), 3.79 (s, 2 H, benzyl H), 4.20 (d,
2 H, J = 48 Hz, CH2F), 7.25 7.35 (m, 5 H, phenyl H).
MS: m/z = 203.2 (M + H, 100), 176.1 (M+, 10).
A sample was converted to its HCl salt and recrystallized from
MeOH EtOAc to yield 32 mg (22%).
19 HCl
19F NMR (CDCl3):
= 225.83 (tm, J = 48 Hz).
Mp 192.5–195 °C.
13C NMR (DMSO-d6): =12.89, 20.23, 22.06, 32.23, 44.78, 59.56,
120.41, 128.42, 138.84, 130.66, 131.82.
MS: m/z = 196 (100, M + H).
The product was converted to its HCl salt (16 mg, 18%). Recrystal-
lization from MeOH EtOAc afforded 8 mg (~9%).
Anal. Calcd for C13H19ClN2 0.33 H2O: C, 63.79; H, 8.03; N, 11.44.
Found: C, 63.70; H, 8.32; N, 11.06.
16 HCl
Mp 222 225 °C dec.
Benzyl-(1,1-dimethyl-allyl)-amine (20)
Anal. Calcd for C12H19ClFN: C, 62.19; H, 8.26; N, 6.04. Found: C,
62.19; H, 8.40; N, 5.98.
A soln of 7 (0.05 g, 0.20 mmol) in butylamine (5 mL) was refluxed
for 3 d. The standard hydrolysis procedure was applied and unreact-
ed 7 (5 mg) and crude 20 were recovered. Crude 20 was purified by
preparative TLC (silica/CH2Cl2 acetone, 1:1; Rf 0.38) to yield
0.015 g (44%) of an oil. Compound 20 was unstable at r.t. over a pe-
riod of 2–3 weeks, yielding a mixture of products (TLC).
N1-Butyl-N3-benzyl-2,2-dimethylpropane-1,3-diamine (17)
A soln of 6 (0.3 g) in butylamine (10 mL) and the mixture was re-
fluxed for 8 d. After solvent removal and hydrolysis, crude 17 (0.19
g) was isolated as an oil. A small amount of 6 (35 mg) was recov-
ered from the reaction.
1H NMR (CDCl3): = 0.93 (overlapping s and t, 9 H, J = 6.6 Hz,
C(CH3)2 and butyl CH3), [1.36 (m) and 1.45 (m,) over a broad hump
MS: m/z = 176 (30, M + H), 108 (100).
The reaction of 7 (20 mg) with TBAF (1.5 equiv) in CD3CN (1 mL)
was monitored by 1H NMR. After 1 h at 80 °C, approximately 50%
of 7 was consumed and the sole product was an elimination product
by integration. Workup of a sample of this reaction using the stan-
dard hydrolyis conditions afforded 20 (yield not determined).
(6 H), butyl CH2 and NH], 2.45 and 2.46 [2
s, 4 H,
CH2C(CH3)2CH2], 2.58 (t, 2 H, J = 7.5 Hz, butyl CH2NH), 3.80 (s,
2 H, benzyl H), 7.25 7.34 (m, 5 H, phenyl H).
1H NMR (CDCl3): = 1.25 [s, 6 H, C(CH3)2], 3.46 (s, 2 H, benzyl
H), 5.10 and 5.11 (overlapping d, 2 H, J1 = 10.5 Hz, J2 = 17.4 Hz,
vinyl CH2), 5.85 (dd, 1 H, J1 = 10.2 Hz, J2 = 17.7 Hz, vinyl CH),
7.22–7.35 (m, 5 H, phenyl H).
MS: m/z = 249.2 (100).
This was converted to its HCl salt and recrystallized from MeOH
EtOAc to yield 0.213 g (61%).
17 HCl
HRMS: m/z calcd for C12H18N (M + 1), 176.14392; found,
176.14367.
Mp 240 242.5 °C.
Anal. Calcd for C16H30Cl2N2: C, 59.80; H, 9.41; N, 8.71. Found: C,
59.69; H, 9.65; N, 8.73.
Synthesis 2002, No. 7, 859–864 ISSN 0039-7881 © Thieme Stuttgart · New York

864
J. J. Posakony, T J. Tewson
PAPER
(6) Lohray, B. B.; Bhushan, V. In Advances in Heterocyclic
Chemistry, Vol. 68; Katritzky, A. R., Ed.; Academic Press:
San Diego, 1997, 89.
(7) Posakony, J. J.; Tewson, T. J. J. Labelled Compd.
Radiopharm. 1999, 42, S527.
Acknowledgement
We would like to thank Dr. John Grierson for many useful discus-
sions and the National Institutes of Health for funding: Grants
HL60221 and HL36728.
(8) Posakony, J. J.; Tewson, T. J. Synthesis 2002, 766.
(9) Ok, D.; Fisher, M. H.; Wyvratt, M. J.; Meinke, P. T.
Tetrahedron Lett. 1999, 40, 3831.
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Synthesis 2002, No. 7, 859–864 ISSN 0039-7881 © Thieme Stuttgart · New York