Neighboring group participation by sulfonamido nitrogen

Article abstract of DOI:10.1021/jo800952m

(Chemical Equation Presented) The ability of sulfonamido nitrogen to enter into neighboring group participation was established in two different reaction settings. The first was uncovered during the bromination of benzodiazocine 8 in dichloromethane at 0°

Full text of DOI:10.1021/jo800952m

Neighboring Group Participation by Sulfonamido Nitrogen
Nicolas Proust, Judith C. Gallucci, and Leo A. Paquette*
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
paquette.1@osu.edu
ReceiVed May 2, 2008
The ability of sulfonamido nitrogen to enter into neighboring group participation was established in two
different reaction settings. The first was uncovered during the bromination of benzodiazocine 8 in
dichloromethane at 0 °C, and the second during the base treatment of 15a en route to allene 18.
Introduction
functionalization reactions involving 8 were first accorded
attention. The involvement of 8 with such mild reagents as
hydrogen over palladium on charcoal, the borane-dimethyl
sulfide complex, m-chloroperbenzoic acid, and osmium tetrox-
ide/NMO was initially probed and found to give rise to
bissulfonamides 9-12, respectively, in good yields. Signifi-
cantly, no rearrangement of the heterocyclic framework was in
evidence with any of these reagents. When recourse was instead
made to bromination, however, the same straightforward
behavior was not encountered. This result foreshadowed the
unanticipated ability of the nitrogen atoms in 8 to engage in
neighboring group participation. This and related observations
constitute the subject matter of this report.
Doubly unsaturated bridgehead sultams exemplified by 1-3
have recently received attention as informative substrates for
their response to photochemical activation. The system defined
by 1 has been shown to experience isomerization to 4 (eq 1)
when irradiated under conditions of acetone sensitization.1
Noteworthy here is the adoption of a reaction pathway involving
unprecedented homolytic cleavage of the customarily robust
N-SO2 bond. This mechanistic option appears to hold some
generality as gauged by the conversion of 2 f 5 (eq 2) upon
direct irradiation.2 However this alternative pathway is not
followed by 3, which has the sulfonyl group located at the apex
position (eq 3). Instead, this dienyl sulfonamide experiences
inefficient conversion to exo-cyclobutene 6.3
Results and Discussion
The lack of any examples of related systems having a nitrogen
center at both bridgehead sites has led to an interest in acquiring
7.4 The development of a synthetic plan based upon the known
1,6-benzodiazocine 85 was therefore initiated. Preliminary
Bromination Results. The four reactions mentioned above
share in common a low electrophilic demand. This fact, when
coupled with a projected attenuated level of involvement
10.1021/jo800952m CCC: $40.75
Published on Web 07/17/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6279–6282 6279

Proust et al.
TABLE 1. Results of the Bromination of 8
entry
conditions
temp (°C)
results
1
2
3
4
5
Br2 (2.0 equiv)/CH2Cl2
Br2 (2.0 equiv)/CH2Cl2
liquid Br2
Br2 (2.0 equiv)/CH2Cl2
Br2 (2.0 equiv)/CH2Cl2 (1 g scale up)
rt
0
rt
-78
>95% yield, 3:1 ratio of 15a:16
>95% yield, 2.7:1 ratio of 15a:16
70% yield, only 16 observed + side products
80% yield, 7:1 ratio of 15a:16 some SM remaining
>95% yield, 6:1 ratio of 15a:16
-78 to 0
SCHEME 1. Proposed Mechanism for the Formation of 15a
and 16
materialize when the reaction temperature is lowered are
consistent with the enhanced direct involvement of 13 (Table
1, entries 4 and 5).
Analysis of the two possible stereoselective aziridinium ring
openings by Br- hold interest. The comparison involves the
formation of 16 (path d) and the cis-dibromide 15b (path c).
Although both routes seem to be reasonable, path c is considered
to be highly disfavored as implied by the total absence of 15b
from the reaction mixture (as confirmed by TLC analysis and
high field NMR of the crude products). In this light, preference
is given to aziridinium ring opening at the less hindered site to
give rise to 16 exclusively. The cisoid arrangement of the Br
and CH2Br functional groups in dibromide 16, which relative
configuration was corroborated by X-ray crystallography,
requires the involvement of 14.
Strikingly, 16 is the very dominant product when the
bromination is performed in liquid Br2 as the reaction medium
(Table 1, entry 3). Evidently, the 13 f 14 transition is facilitated
under these conditions, with collapse via path b materializing
subsequently.
Base-Promoted Elimination Studies. As forecasted by the
generic response of vicinal medium-ring dibromides to dehydro-
halogenations,6,7 all attempts to effect the conversion of 15a to
the corresponding diene with fluoride ion sources led to
degradation or no indication of reaction.4 Recourse to other bases
such as t-BuOK, NaOH, DBU, Et3N, or pyridine proved to be
equally problematic over broad temperature ranges. Ultimately
uncovered was the successful reaction with silazide bases in
THF, most especially the sodium derivative NaHMDS (Table
2).
The first equivalent of NaHMDS was expected to result in
abstraction of the proton from the most acidic bromine-
substituted carbon in 15a to generate vinyl bromide 19 (Scheme
2). This intermediate would then find it possible to experience
1,4-elimination of the NTs leaving group by involving a second
deprotonation as depicted in the transformation of 19 to 20.
Quenching by a proton source would then deliver 17 whose
structural features were confirmed by crystallographic means
(for ORTEP diagram, see Supporting Information).
The additional data derived from 15a indicate that the first
equivalent of NaHMDS may also proceed competitively to
attack the other side of the eight-membered ring with generation
of the neutral 1,6-benzoadiazocine 21 (Scheme 3). The distribu-
tion of functional groups in 21 is such as to enable the operation
of transannular neighboring group participation eventually
leading to formation of the tricyclic ammonium intermediate
22. A second equivalent of the base can then abstract the vinylic
expected for the sulfonamide functionality, should be met with
an absence of neighboring group involvement as has been noted.
At issue is whether processes involving higher electron demand
would trigger a unique capacity for nitrogen atom participation.
The bromination of 8 reveals that its sulfonamide nitrogens do
respond positively to the formation of bromonium ion 13
(Scheme 1).
The addition of elemental bromine to 8 dissolved in dichlo-
romethane at 0 °C to room temperature led quantitatively to
the formation of 15a and 16 in a ratio of approximately 3 to 1
(Table 1, entries 1 and 2). X-ray crystallographic analysis of
the vicinal dibromide confirmed the trans arrangement of the
two halogens in a C2-symmetric setting (see Supporting
Information for ORTEP diagrams of 15a and 16). We postulate
that 15a arises from the classical anti dibromination of alkenes
involving the precursor bromonium intermediate 13 (path a).
In contrast, 16 is most likely derived from aziridinium ion 14
(path b). The latter highly strained intermediate could have been
generated by way of two mechanistic routes. The first originates
from 8 by nucleophilic attack of a tosyl nitrogen at an sp2
carbon, thereby assisting electrophilic addition of bromine across
the double bond (dotted path). Alternatively, stereoselective
nucleophilic opening of the bromonium ion by the tosyl nitrogen
may operate (path b). It is presently not possible to differentiate
between these two pathways. The heightened levels of 15a that
(1) Paquette, L. A.; Barton, W. R. S.; Gallucci, J. C. Org. Lett. 2004, 6,
1313.
(2) Paquette, L. A.; Dura, R. D.; Fosnaugh, N.; Stepanian, M. J. Org. Chem.
2006, 71, 8438.
(3) Preston, A. J.; Gallucci, J. C.; Paquette, L. A. J. Org. Chem. 2006, 91,
6573.
(4) Proust, N. Ph.D. Thesis, The Ohio State University, 2008.
(5) (a) Grasso, S.; Zappala, M.; Chimirri, A. Heterocycles 1987, 26, 2477.
(b) Proust, N.; Preston, A. J.; Paquette, L. A. Heterocycles 2009, 77.
(6) King, P. F.; Paquette, L. A. Synthesis 1977, 279.
(7) Dura, R. D.; Paquette, A. L. Synthesis 2006, 2837.
6280 J. Org. Chem. Vol. 73, No. 16, 2008

Neighboring Group Participation by Sulfonamido Nitrogen
TABLE 2. Dehydrobromination of 15aa
entry
base/solvent
temp (°C)
equiv of base
inverse additionb
addition time
product ratio 17:18
total yield (%)
6
7
8
9
10
11
12
13
14
15
16
NaHMDS/THF
NaHMDS/THF
NaHMDS/THF
NaHMDS/THF
NaHMDS/THF
NaHMDS/THF
NaHMDS/THF
NaHMDS/THF
KHMDS/THF
LHMDS/THF
DBU/MeCN
-78
-78
-78
-78
-78
-78
-40
0
1.0
2.0
2.0
3.0
5.0
2.0
2.0
2.0
2.0
2.0
2.0
no
no
yes
no
no
no
no
no
no
no
no
6 min
8 min
20 min
12 min
20 min
15 s
8 min
10 min
8 min
9 min
5 min
2:1
4:1
3:1
4:1
2.1:1
3:1
3:1
1.3:1
3:1
4:1
43
71
54
80
66
60
58
45
60
56
-78
-78
0 to rt
NR
a Reactions performed on 100 mg (0.6 mmol) of 15a in 5 mL of solvent. b Dibromide 15a was added to a solution of base in THF at -78 °C.
SCHEME 2. Proposed Mechanism for the Formation of 17
neighboring group participation in electron-demanding trans-
formations. This capability has been displayed in two processes
involving a dibromination and a dehydrobromination reaction.
These unprecedented results may well open future discussions
regarding the nucleophilicity and basicity of sulfonamide
protected nitrogens.
Experimental Section
1,6-Bis(toluene-4-sulfonyl)-1,2,5,6-tetrahydrobenzo[b][1,4]di-
azocine (8). A solution of N,N′-ditosyl-1,2-diaminobenzene (25 g,
60.1 mmol) and cis-1,4-dichloro-2-butene (6.37 mL, 1.0 equiv) in
acetonitrile (1500 mL) over K2CO3 (41.6 g, 5.0 equiv) was heated
to reflux for 24 h. At the end of that period, the reaction mixture
was cooled down to room temperature, filtered, and freed of solvent
under reduced pressure. The resulting pale yellow solid was purified
over silica gel by flash chromatography using CH2Cl2/EtOAc (98:
2) to provide 8 as a white powder (21.1 g, 75%), mp 215-216 °C
(lit.8 mp 204 °C); 1H NMR (CDCl3, 250 MHz) δ 7.67 (d, J ) 8.4
Hz, 4H), 7.32-7.22 m, 8H), 5.61 (t, J ) 4.0 Hz, 2H), 4.23 (d, J )
4.8 Hz, 4H), 2.44 (s, 6H).
SCHEME 3. Proposed Mechanism for the Formation of 18
1,6-Bis(toluene-4-sulfonyl)-1,2,3,4,5,6-hexahydrobenzo[b][1,4]-
diazocine (9). In a high pressure hydrogenator were loaded 8 (10
mg, 0.02 mmol), MeOH (3 mL), CH2Cl2 (1 mL), and Pd/C (10%
wet, 2 mg). The reactor was purged with N2, closed, and placed
under 600 psi of H2. The reaction mixture was maintained overnight
with stirring. The reaction mixture was filtered over a pad of Celite
and evaporated to leave 9 as a white solid (8.4 mg, 83%), mp
222-225 °C (lit.9 mp 219 °C); H NMR (CDCl3, 250 MHz) δ
1
7.86 (d, J ) 8.3 Hz, 4H), 7.23 (d, J ) 8.3 Hz, 4H), 7.24-7.09 (m,
4H), 3.28-3.27 (m, 4H), 2.34 (s, 6H), 1.33 (m, 4H).
proton to generate allene 18, which structure was also cor-
roborated by crystallographic means; see Supporting Informa-
tion. It is worth noting that under no set of conditions examined
was the formation of diene 23 observed.
1,6-Bis(toluene-4-sulfonyl)-1,2,3,4,5,6-hexahydrobenzo[b][1,4]-
diazocin-3-ol (10). To a solution of 8 (1.0 g, 2.1 mmol) and THF
(50 mL) was added BH3 ·THF (1M, 6.4 mL, 3.0 equiv) at 0 °C.
The reaction mixture was warmed to room temperature and stirred
for 5 h. The reaction mixture was then quenched with NaOH and
H2O2 at 0 °C and extracted with CH2Cl2. The organic layer was
separated, dried over Na2SO4, and evaporated under reduced
pressure to afford 10 as an off-white foam. The alcohol was purified
by flash chromatography on silica gel using CH2Cl2/MeOH (98:2)
to provide 10 as a white solid (0.68 g, 65%), mp 200-202 °C; 1H
NMR (CDCl3, 400 MHz) δ 8.01 (d, J ) 8.25 Hz, 2H), 7.93 (d, J
) 8.25 Hz, 2H), 7.44-7.29 (m, 6H), 7.27-7.23 (m, 1H), 7.21-7.18
Conclusion
In our efforts directed toward the synthesis of the benzodia-
zocine ring system having sulfur at the apex position, we have
discovered the latent potential of sulfonamido nitrogens for
(8) Kleinpeter, E.; Gaebler, M.; Schroth, W. Monatsh. Chem. 1988, 119,
233.
(9) Stetter, H. Chem. Ber. 1953, 86, 197.
J. Org. Chem. Vol. 73, No. 16, 2008 6281

Proust et al.
(m, 1H), 3.78-3.67 (m, 3H), 3.34-3.31 (m, 1H), 3.23-3.18 (m,
1H), 2.46 (s, 6H), 2.42-2.38 (m, 1H), 1.75-1.70 (m, 1H),
1.40-1.32 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 144.1, 144.0,
141.3, 139.0, 136.9, 136.0, 130.0, 129.9, 129.8, 129.7, 129.4, 128.8,
128.6, 128.2, 68.1, 59.3, 48.1, 31.8, 21.61, 21.59; ES HRMS m/z
(M + Na)+ calcd 509.1175, obsd 509.1149.
13C NMR (CDCl3, 100 MHz) δ 144.3, 144.1, 138.8, 137.1, 136.9,
132.3, 131.0, 130.0, 129.9, 129.7, 129.5, 128.7, 128.4, 128.1, 127.9,
60.7, 48.8, 48.1, 26.7, 21.6. ES HRMS m/z (M + Na)+ calcd
650.9423, obsd 650.9395.
N-(2-Bromobuta-1,3-dienyl)-N,N′-di(toluene-4-sulfonyl)benzene-
1,2-diamine (17) and 2-Propa-1,2-dienyl-1,3-bis(toluene-4-sulfonyl)-
2,3-dihydro-1H-benzoimidazole (18). Into a dry 25 mL flask,
dibromide 15a (100 mg, 0.16 mmol) and THF (5 mL) were loaded
at room temperature. The reaction mixture was cooled to -78 °C
under N2, and then NaHMDS (0.5 M in THF, 0.64 mL, 2.0 equiv)
was added dropwise very slowly. The colorless reaction mixture
was maintained at -78 °C for 2 h and quenched by the addition of
5 mL of water at -78 °C. The temporarily frozen reaction mixture
was warmed until stirring was possible (0 °C), and then CH2Cl2
was added (30 mL). The separated aqueous layer was extracted
again with 10 mL of CH2Cl2. The organic layers were then
combined, washed with brine, dried over Na2SO4, and evaporated
under reduced pressure to give a pale yellow foam, which was
immediately taken back in the minimum amount of CH2Cl2 and
loaded on a column of silica gel for purification using CH2Cl2.
Compounds 17 and 18 were obtained as white crystalline solids.
The overall yield was 71% with a 4:1 ratio of 17:18.
1,6-Bis(toluene-4-sulfonyl)-1,2,3,4,5,6-hexahydrobenzo[b][1,4]-
diazocine-3,4-diol (12). In a 25 mL flask, the diazocine 8 (0.25 g,
0.53 mmol), NMO (87 mg, 0.64 mmol), THF (10 mL) and H2O (1
mL) were added at room temperature. OsO4 (50 g/l solution, 0.2
equiv) was then added in one portion. The reaction mixture was
maintained overnight at room temperature. Five minutes after the
end of the addition of OsO4, the reaction mixture turned progres-
sively pink to red to black. Na2SO3 was introduced to the mix to
trap the osmium residues. The reaction mixture was filtered, the
solvent was evaporated under reduced pressure, and the residue
was taken back into CH2Cl2, washed with water and brine, dried,
and evaporated. The residue was purified on silica gel using
EtOAc-hexanes (2:1) to afford 12 as a white crystalline solid (0.22
1
g, 82%), mp ∼220 °C (decomp observed ∼200 °C); H NMR
(CDCl3, 400 MHz) δ 7.97 (d, J ) 8.0 Hz, 4H), 7.40 (d, J ) 6.0
Hz, 4H), 7.39-7.37 (m, 2H), 7.29-7.26 (m, 2H), 3.92 (dd, J )
7.6, 13.6 Hz, 2H), 3.61-3.63 (m, 2H), 3.27 (dd, J ) 3.3, 13.6 Hz,
2H), 2.56 (d, J ) 9.6 Hz, 2H), 2.49 (s, 6H); 13C NMR (CDCl3,
100 MHz) δ 144.3, 140.1, 136.0, 130.1, 129.9, 128.8, 128.5, 73.4,
54.6, 21.6; ES HRMS m/z (M + Na)+ calcd 525.1124, obsd
525.1125.
1
For 17: mp 120-127 °C (turned brown at 80 °C); H NMR
(CDCl3, 400 MHz) δ 7.82 (s, 1H), 7.79 (d, J ) 8.3 Hz, 2H), 7.64
(dd, J ) 1.3, 8.3 Hz, 1H), 7.41 (d, J ) 8.3 Hz, 2H), 7.27 (d, J )
8.0 Hz, 2H), 7.22 (d, J ) 8.0 Hz, 2H), 6.82 (td, J ) 1.3, 8.0 Hz,
1H), 6.69 (d, J ) 0.8 Hz, 1H), 6.26 (dd, J ) 1.3, 8.0 Hz, 1H),
5.82-5.93 (ddd, J ) 1.0, 10.5, 16.0 Hz, 1H), 5.42 (d, J ) 16.0
Hz, 1H), 5.03-5.09 (dt, J ) 1.3, 10.5 Hz, 1H), 2.44 (s, 3H), 2.38
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 145.5, 144.1, 136.7, 136.1,
132.3, 130.0, 129.9, 129.8, 129.7, 128.7, 128.3, 128.2, 127.7, 127.4,
124.5, 122.3, 121.0, 119.7, 21.7, 21.6; ES HRMS m/z (M + Na)+
calcd 571.0162, obsd 571.0158.
3,4-Dibromo-1,6-bis(toluene-4-sulfonyl)-1,2,3,4,5,6-
hexahydrobenzo[b][1,4]diazocine (15a) and 3-Bromo-2-bromom-
ethyl-1,5-bis(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-
benzo[b][1,4]diazepine (16). In a 50 mL flask, 8 (1.0 g, 2.14 mmol)
and CH2Cl2 (20 mL) were loaded at room temperature. The resulting
mixture was cooled to -78 °C in an acetone/dry ice bath, and then
bromine (2.0 equiv) was added dropwise. The reaction mixture was
slowly warmed and maintained at 0 °C for 1 h. Saturated aqueous
NaHSO3 solution was added to quench the excess bromine, CH2Cl2
and water were added, and the CH2Cl2 layer was separated, dried,
and evaporated under reduced pressure to afford a white solid in
For 18: mp 115-116 °C; 1H NMR (CDCl3, 400 MHz) δ 7.5 (d,
J ) 10.8 Hz, 4H), 7.33-7.37 (m, 2H), 7.1 (d, J ) 12.8 Hz, 4H),
7.01-7.05 (m, 2H), 6.41 (dt, J ) 2.8, 9.2 Hz, 1H), 5.30 (q, J )
10.4 Hz, 1H), 4.92 (dd, J ) 3.2, 10.4 Hz, 2H), 2.37 (s, 6H); 13C
NMR (CDCl3, 100 MHz) δ 208.7, 144.5, 134.8, 132.1, 129.8, 127.5,
125.1, 116.0, 91.0, 79.8, 77.5, 21.7; ES HRMS m/z (M + Na)+
calcd 489.0919, obsd 489.0904.
1
95% overall yield. The solid was analyzed by H NMR and was
shown to consiste of 15a and 16 in a 6:1 ratio. The mixture could
be separated on silica gel using CH2Cl2 as the eluent.
For 15a: mp 222-223 °C (degradation observed ∼210 °C); 1H
NMR (CDCl3, 500 MHz) δ 7.81 (d, J ) 8.5 Hz, 4H), 7.37 (d, J )
8.5 Hz, 4H), 7.35-7.28 (m, 4H), 4.24 (d, J ) 14.0 Hz, 2H),
4.11-4.02 (m, 4H), 2.47 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ
144.3, 136.6, 135.7, 129.8, 129.6, 129.1, 128.4, 54.7, 51.5, 21.6;
ES HRMS m/z (M + Na)+ calcd 650.9417, obsd 650.9416.
Acknowledgment. We thank The Ohio State University for
partial financial support.
Supporting Information Available: Details of the X-ray
crystallographic analyses of 15a, 16, 17 and 18 in CIF format
1
and the H and 13C NMR spectra for all compounds. This
1
For 16: mp 225-226 °C; H NMR (CDCl3, 500 MHz) δ 7.86
material is available free of charge via the Internet at
http://pubs.acs.org.
(d, J ) 8.0 Hz, 2H), 7.80 (d, J ) 8.4 Hz, 2H), 7.52-7.30 (m, 8H),
4.70-4.67 (m, 1H), 4.42-4.33 (m, 2H), 3.83 (dd, J ) 2.5, 11.5
Hz, 1H), 3.07-3.02 (m, 1H), 2.51-2.48 (m, 1H), 2.46 (s, 6H);
JO800952M
6282 J. Org. Chem. Vol. 73, No. 16, 2008