Effect of sulfonyl protecting groups on the neighboring group participation ability of sulfonamido nitrogen

Full text of DOI:10.1021/jo900065q

SCHEME 1
Effect of Sulfonyl Protecting Groups on the
Neighboring Group Participation Ability of
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 January 12, 2009
of 3 to aziridinium ion 6 may also be operational (Scheme 1).
Presently, added insight into the electron movement available
to benzo-fused 1,4-diazocines related to 3 has been examined
from two perspectives.
In the first, the p-aryl substituents X in 8a-e were altered in
pairwise fashion with maintenance of molecular Cs symmetry.
The objective here was to learn if distribution of the isomeric
products related to 5 and 7 is altered as a function of the
electron-donating or electron-withdrawing nature of X in 8.
Adherence to a Hammett-type relationship would reflect the
relative importance of neighboring group participation in routes
a and b in Scheme 1. On the other hand, the presence of two
different substituents as in 8f and 8g sets the stage for direct
intramolecular competition involving the sulfonamide nitrogen
electron pairs.
The addition of elemental bromine dissolved in CH2Cl2 to
para-disubstituted benzodiazocines where X is the same (H,
CH3, Br, OMe, NO2) or a different substituent as X and Y
(CH3, Br; OMe, NO2) has been found to proceed in most
cases with competition between two pathways. While
conventional trans-1,2-addition operates predominantly, elec-
tron-releasing groups also foster a ring-contraction process
with ultimate 1,3-positioning of the pair of bromine atoms.
The observed regio- and stereoselectivities, confirmed where
necessary by X-ray crystallographic analysis, establish the
capability of sulfonamide nitrogen centers to engage in
neighboring group participation.
According to classical opinion, neighboring group participa-
tion is a phenomenon defined by three criteria: rate enhance-
ments, abnormal stereochemical outcomes, and the isolation of
isomeric products.1 While the capacity of ether, hydroxyl,
thioether, amino, and amido groups for nucleophilic involvement
in such processes has been extensively reported, examples of
comparable participation by the electron pair of sulfonamido
nitrogen centers are much less well documented. The conver-
sions of 1 to 22 and of 3 to 73 under bromination conditions
represent two uncommon examples. For 3, the initial generation
of bromonium ion 4 has been advanced in light of the
coformation of the trans vicinal dibromide 5. The possibility
exists, however, that the pathway involving the direct conversion
Preparative Considerations. In light of the prior report
detailing the successful disulfonylation of the o-phenylenedi-
amine (9) with tosyl chloride,4 comparable conditions were
evaluated for the close analogues. The protocol consisted of
the slow addition of a solution of the sulfonyl chloride in
pyridine to 9 in the same solvent at 0 °C. Unexpectedly, only
very low yields were realized. Recourse was therefore made to
the methodology developed by Massacret.5 Under these experi-
(1) Capon, B.; Mc Manus, S. P. Neighboring Group Participation; Plenum
Press: New York, 1976; Vol. 1.
(2) Paquette, L. A.; Kelly, J. F. J. Org. Chem. 1971, 36, 442.
(3) Proust, N.; Gallucci, J. C.; Paquette, L. A. J. Org. Chem. 2008, 73, 6279.
(4) (a) Van Otterlo, W. A. L.; Morgans, G. L.; Khanye, S. D.; Aderibigbe,
B. A.; Michael, J. P.; Billing, D. G. Tetrahedron Lett. 2004, 45, 9171. (b)
Acheson, R. M. J. Chem. Soc. 1956, 4731.
(5) Massacret, M.; Lhoste, P.; Sinou, D. Eur. J. Org. Chem. 1999, 129.
10.1021/jo900065q CCC: $40.75
Published on Web 03/10/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2897–2900 2897

SCHEME 2
scale experiments. For convenience, the subsequent quantitative
bromination studies were performed under standard conditions
with 5.0 equiv of Br2.
The 1H NMR spectra of 12b-g were expectedly very similar
to those of 12a, whose trans geometry had been previously
defined by X-ray crystallography.3 The cis relative configuration
of the Br and CH2Br substituents in 13b-g could be similarly
deduced by spectral comparison with 13a and three-dimensional
structure analysis.3 However, definition of the regiochemical
course of this ring contraction required independent verification
of the exact placement of the para substituents X and Y when
different (13f and 13g).
A general trend for the bromination reaction was observed,
as electron-withdrawing groups tended to decrease the amount
of rearranged dibromide generated during the reaction (Table
1, entries 1 and 2), whereas electron-donating groups showed
enhancement of the amount of rearranged dibromide (entries 4
and 5). As a result, the ratios of trans dibromides to rearranged
dibromides at the time of reaction completion were concluded
to be directly related to the nucleophilicity of the sulfonamide
nitrogens and, hence, to the nature of the para substituents in
the particular sulfonamide.
The two nonsymmetric substrates 8f and 8g were investigated
to shed added insight into this trend by way of intramolecular
competition. Diazocine 8f reacted with Br2 to give trans-
dibromide 12f as well as a mixture of two rearranged dibro-
mides, 13f and its regioisomer (X ) Br, Y ) CH3) in a 2:1
ratio, respectively. In contrast, diazocine 8g reacted with Br2 to
generate trans-dibromide 12g and the unique rearranged dibro-
mide 13g, whose structure could be determined by high-field
NMR analysis and X-ray crystallography (see the Supporting
Information for an ORTEP diagram of 13g).
In both cases (8f and 8g), we observed that the sulfonamido
nitrogen linked to the electron-donating group displayed en-
hanced nucleophilicity as demonstrated by the regioselectivity
of the rearrangement of the diazocine upon bromination. As a
consequence, we concluded that electron-withdrawing groups
reduce the nucleophilicity of the nitrogen, which in turn
decreases neighboring group participation of this nitrogen in
the bromination reaction. Conversely, electron-donating groups
enhance the nucleophilicity of the sulfonamide nitrogen, which
increase its neighboring group participation.
TABLE 1. Selectivity of the Dibromination Reaction
rearranged
trans-dibromides 12 (%) dibromides 13 (%)
entries
substrate 8
1
2
3
4
5
6
7
b, NO2/NO2
c, Br/Br
d, H/H
a, CH3/CH3
e, OMe/OMe
f, CH3/Br
>99
>97
73
82
64
trace
<3
27
18
36
68
81
32
19
g, NO2/MeO
mental conditions, 9 was dissolved in cold (0 °C) CH2Cl2 and
treated sequentially with pyridine (2.0 equiv) and the sulfonyl
chloride (2.0 equiv). The reaction mixture was then warmed to
rt where it was maintained until complete reaction was realized
(TLC analysis). The yields of 11 were in excess of 75% in all
cases.
Relevantly, the mixed derivatives 11f and 11g were prepared
in a single flask by the preliminary addition of 1 equiv of the
first sulfonyl chloride and subsequent introduction of an
equivalent of the second sulfonyl chloride after 4 h at rt (Scheme
2). For arrival at the benzodiazocines, the diprotected phe-
nylenediamines were dissolved in CH3CN, admixed with K2CO3
and cis-1,4-dichloro-2-butene, and heated at reflux overnight.6
Ultimate purification by flash chromatography on silica gel
afforded pure samples of 8a-g.
Formation of the Dibromides. The addition of elemental
bromine to the five symmetrically difunctionalized benzodia-
zocines 8a-e in CH2Cl2 at 0 °C to rt under standardized
conditions led quantitatively to the formation of 12a-e and
13a-e in the ratios compiled for entries 1-5 in Table 1. No
additional products were isolated, thereby demonstrating the
consistency of the chemical response of these medium-ring
heterocycles. When the observations were made that the more
electronically deactivated diazocines 8b and 8c did not proceed
to completion even after several days at rt, the decision was
made to employ an excess of the halogen in the preparative
Concurrently, we evaluated the influence of the para substit-
uents of the sulfonyl protecting group on the reactivity of the
double bond of the diazocines toward bromine. This was
1
achieved via high-field H NMR monitoring of the reaction
progress. Diazocines 8a-g were dissolved in CDCl3 at rt, placed
in NMR tubes, and treated with Br2 (5.0 equiv) in one portion.
(6) (a) Malhas, R. N.; Ibrahim, Y. A. Synthesis 2006, 3261. (b) Proust, N.;
Preston, A.; Paquette, L. A. Heterocycles 2009, 77, 163.
2898 J. Org. Chem. Vol. 74, No. 7, 2009

TABLE 2. Reactivity of the Double Bond
1,4-dichloro-2-butene (1.0 equiv) in acetonitrile (100 mL) over
K2CO3 (5.0 equiv) was heated at reflux for 24 h. At the end of this
period, the reaction mixture was cooled to rt, filtered, and freed of
solvent under reduced pressure. The resulting pale yellow solid was
purified over silica gel by flash chromatography (CH2Cl2/EtOAc,
98:2) to provide the desired diazocine as a white powder.
entries
substrate 8
completion time (min)
1/time (min-1
)
1
2
3
4
5
6
7
b, NO2/NO2
c, Br/Br
d, H/H
a, Me/Me
e, OMe/OMe
f, CH3/Br
g, NO2/MeO
1020
520
165
75
75
555
600
9.8
19.2
60.6
133.3
133.3
18.0
1
p-Br/p-CH3 derivative 8f: 1.55 g, 70%; mp 197-199 °C; H
NMR (CDCl3, 400 MHz) δ 7.69-7.66 (m, 6H), 7.40-7.10 (m,
6H), 5.67-5.60 (m, 2H), 4.36 (d, J ) 6.0 Hz, 2H), 4.19 (d, J )
4.8 Hz, 2H), 2.46 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 144.0,
137.6, 136.3, 135.7, 132.4, 132.3, 129.9, 129.8, 129.7, 129.3, 129.2,
128.4, 128.2, 128.1, 127.9, 127.7, 48.4, 47.1, 21.6; HRMS (ES)
calcd for [C23H21BrN2O4S2 + Na]+ 556.9999, found 556.9979.
p-NO2/p-MeO derivative 8g: 0.76 g, 68%; mp 213.8-214.7
16.7
The NMR tubes were then loaded into a 400 MHz NMR
spectrometer, and spectra of the reaction mixtures were collected
until completion of the reaction was established. Each substrate
was noted to require a different time to reach complete reaction
(Table 2). Concluded from these data is the fact that electron-
withdrawing groups (such as NO2 or Br) on the sulfonyl
protecting group appreciably decrease the reactivity of the
double bond of the diazocine (entries 1, 2, 6, and 7). On the
other hand, electron-donating groups (such as CH3 or MeO)
dramatically increase the reactivity of the double bond of the
diazocine as demonstrated by the shorter time needed to bring
about complete conversion to products (entries 4 and 5). These
observations highlight the long-range inductive effect of para
substituents of the sulfonyl protecting groups on the electronic
profile of the diazocine double bond.
1
°C; H NMR (CDCl3, 400 MHz) δ 8.34 (m, 2H), 8.02 (m, 2H),
7.63 (m, 2H), 7.58 (m, 1H), 7.31 (m, 1H), 7.18 (m, 1H), 6.98 (m,
2H), 6.83 (m, 1H), 5.70-5.64 (m, 2H), 5.60-5.55 (m, 2H), 4.58
(d, J ) 7.6 Hz, 2H), 4.07 (dd, J ) 4.8, 0.8 Hz, 2H), 3.9 (s, 3H);
13C NMR (CDCl3, 100 MHz) δ 163.3, 150.3, 143.9, 136.9, 135.3,
130.5, 130.2, 130.1, 129.6, 128.7, 128.0, 127.7, 126.6, 124.3, 114.3,
55.7, 49.4, 46.3; HRMS (ES) calcd for [C23H21N3O7S2 + Na]+
538.0713, found 538.0722.
General Method for Dibromination with a Large Excess
of Br2. 3,4-Dibromo-1,6-bis(X-4-sulfonyl)-1,2,3,4,5,6-hexahy-
drobenzo[b] [1,4]diazocine and 3-bromo-2-bromomethyl-1,5-
bis(X-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine
(X ) NO2, Br, H, CH3, MeO). In a 50 mL flask was loaded
diazocine 8 (100 mg, 2.14 mmol) dissolved in CH2Cl2 (5 mL) at
rt. The resulting mixture was cooled to 0 °C in an ice bath when
Br2 (10.0 equiv) was added dropwise. Each reaction mixture was
slowly warmed and maintained at rt until completion was reached
(reactions were followed by TLC analysis, CH2Cl2). 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 an off-white
solid. The solid was analyzed by 1H NMR and shown to consist of
the normal trans-dibromide 12 and the rearranged dibromides 13,
which could be separated by chromatography on silica gel using
CH2Cl2 as the eluent.
Experimental data gleaned from 1H NMR monitoring of the
bromination of substrates 8a-g have led us to conclude that
substituents para to the sulfonyl protecting groups have a marked
influence on both the nucleophilicity of the sulfonamide
nitrogens and the reactivity of the double bond of the diazocines.
Electron-withdrawing groups greatly decrease the reactivity of
the diazocine double bond as well as the nucleophilicity of the
sulfonamido nitrogens. Electron-donating groups exhibit the
opposite effect and lead to shorter reaction times and enhanced
amounts of rearranged dibromides.
1
p-MeO Derivatives. 12e: mp 192-195 °C; H NMR (CDCl3,
Experimental Section
400 MHz) δ 7.87-7.83 (m, 4H), 7.31 (s, 4H), 7.03-6.99 (m, 4H),
4.24-4.21 (m, 2H), 4.08-4.01 (m, 4H), 3.88 (s, 6H); 13C NMR
(CDCl3, 100 MHz) δ 163.5, 136.8, 130.6, 130.2, 129.6, 129.1,
114.4, 55.7, 54.8, 51.5; HRMS (ES) calcd for [C24H24Br2N2O6S2
+ Na]+ 682.9315, found 682.9281.
General Method for the Preparation of the Diprotected
o-Phenylenediamines. To an ice-cold solution of o-phenylenedi-
amine (2.00 g, 18.5 mmol, 1.0 equiv) and pyridine (2.0 equiv) in
CH2Cl2 (50 mL) was added portionwise the desired sulfonyl
chloride (2.0 equiv). The reaction mixture was warmed and
maintained at rt until completion of the reaction (TLC analysis).
Water (50 mL) was next introduced, causing the product to
precipitate. (When no precipitation was observed, the products were
extracted into CH2Cl2. The CH2Cl2 layer was dried and evaporated
to give a residue, which was recrystallized from ethanol.) The
reaction mixture was filtered and the cake was washed with H2O.
The orange-red solid so obtained was recrystallized from EtOH to
afford a pale yellow to white crystalline product.
13e: mp 118-120 °C; 1H NMR (CDCl3, 400 MHz) δ 7.94-7.91
(m, 2H), 7.88-7.84 (m, 2H), 7.54 (d, J ) 8 Hz, 1H), 7.44-7.38
(m, 2H), 7.33-7.31 (m, 1H), 7.06-7.00 (m, 4H), 4.68-4.63
(m,1H), 4.39 (dd, J ) 15.2, 3.6 Hz, 1H), 4.32 (dt, J ) 12.0, 4.0
Hz, 1H), 3.90 (m, 6H), 3.83 (dd, J ) 11.2, 2.4 Hz, 1H), 3.04 (dd,
J ) 14.8, 12.4 Hz, 1H), 2.50 (t, J ) 11.6 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ 163.5, 163.4, 138.9, 132.2, 131.7, 131.2,
131.0, 130.3, 130.2, 129.5, 128.9, 128.3, 114.6, 114.2, 60.7, 55.7,
55.6, 48.7, 48.1, 26.7; HRMS (ES) calcd for [C24H24Br2N2O6S2 +
Na]+ 682.9315, found 682.9292.
1
p-Br/p-CH3 derivative 11f: 7.0 g, 79%; mp 200-201 °C; H
1
NMR (acetone-d6, 400 MHz) δ 7.49-7.39 (m, 6H), 7.11-7.08 (m,
2H), 7.03-6.81 (m, 4H), 2.27 (s, 3H); 13C NMR (acetone-d6, 100
MHz) δ 144.4, 137.7, 134.9, 132.2, 131.2, 130.0, 129.7, 129.1,
128.3, 127.8, 127.6, 127.3, 126.5, 125.7, 21.6; HRMS (ES) calcd
for [C19H17BrN2O4S2 + Na]+ 504.9682, found 504.9685.
p-NO2/p-MeO Derivatives. 12g: mp 170-171 °C; H NMR
(CDCl3, 400 MHz) δ 8.37 (dd, J ) 2.0, 7.2 Hz, 2H), 8.14 (dd, J )
2.0, 7.3 Hz, 2H), 7.78 (dd, J ) 2.0, 7.2 Hz, 2H), 7.59 (dd, J ) 1.2,
8.4 Hz, 1H), 7.41 (dt, J ) 1.2, 7.6 Hz), 7.35 (dt, J ) 1.2, 7.6 Hz,
1H), 7.03 (dd, J ) 2.1, 7.0 Hz, 2H), 6.98 (dd, J ) 1.2, 7.6 Hz,
1H), 4.62-4.59 (m, 1H), 4.35 (dd, J ) 5.6, 14.4 Hz, 1H), 4.28-4.24
(m, 1H), 4.06-3.96 (m, 2H), 3.91 (s, 3H), 3.87-3.85 (m, 1H);
13C NMR (CDCl3, 100 MHz) δ 163.6, 150.5, 150.4, 144.1, 137.8,
130.9, 130.4, 129.9, 129.8, 129.7, 129.0, 124.4, 114.5, 60.4, 55.7,
55.1, 21.0, 14.2; HRMS (ES) calcd for [C23H21Br2N3O7S2 + Na]+
697.9060, found 697.9078.
p-NO2/p-MeO derivative 11g: 6.6 g, 60%; mp 204-205 °C;
1H NMR (acetone-d6, 400 MHz) δ 8.56 (br s, 1H), 8.38 (m, 2H),
7.97 (m, 2H), 7.58 (m, 2H), 7.27-6.91 (m, 6H), 3.85 (s, 3H); 13
C
NMR (acetone-d6, 100 MHz) δ 163.5, 150.5, 144.6, 131.3, 130.9,
129.9, 129.5, 128.9, 127.9, 127.5, 127.3, 126.4, 126.1, 126.0, 124.4,
124.3, 114.2, 55.3; HRMS (ES) calcd for [C19H17N3O7S2 + Na]+
486.0400, found 486.0386.
13g: mp 218-220 °C dec; 1H NMR (CDCl3, 400 MHz) δ
8.36-8.35 (m, 2H), 8.07-8.04 (m, 2H), 7.82-7.78 (m, 2H), 7.68
(d, J ) 7.6 Hz, 1H), 7.48-7.44 (m, 1H), 7.40-7.38 (m, 1H),
General Method for the Preparation of the Diazocines. A
solution of the N,N′-disulfonyl-1,2-diaminobenzene (1.0 g) and cis-
J. Org. Chem. Vol. 74, No. 7, 2009 2899

7.02-6.99 (m, 2H), 4,74-4.70 (m, 1H), 4.43-4.36 (m, 2H), 3.90
(s, 3H), 3.79-3.76 (m, 1H), 3.15 (dd, J ) 12.4, 15.6, 1H), 2.43 (t,
J ) 11.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 163.6, 150.5,
145.0. 137.6, 133.5, 132.8, 131.2, 130.7, 130.3, 130.0, 129.7, 129.3,
124.8, 114.3, 60.4, 55.7, 49.0, 47.5, 26.4; HRMS (ES) calcd for
[C23H21Br2N3O7S2 + Na]+ 697.9060, found 697.9087.
Quantitative Bromination Studies. Each experiment was
performed under standardized conditions with 5 equiv of bromine
dissolved in CH2Cl2 in the temperature range 0 °C to rt. The product
distributions (see Table 1) were determined after workup with the
NMR data provided above as reference.
Acknowledgment. We thank The Ohio State University for
partial financial support and Dr. Jeanette Krause of the
University of Cincinnati for the crystallographic data collection.
Supporting Information Available: Experimental data,
details of the X-ray crystallographic analysis of 13f, and copies
of the 1H and 13C NMR spectra of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.
org.
JO900065Q
2900 J. Org. Chem. Vol. 74, No. 7, 2009