A reversible safety-catch method for the hydrogenolysis of N-benzyl moieties

Article abstract of DOI:10.1016/j.tetlet.2004.09.118

The benzyl groups of β-hydroxy-N-benzyl sulfonamides are labile toward hydrogenolysis-unlike N-benzyl sulfonamides lacking the β-hydroxy moiety. We find that N-acyl-N-benzyl sulfonamides undergo hydrogenolysis under very mild conditions. Based upon these observations, we developed a reversible safety-catch method using tert-butoxycarbonyl moieties to activate N-benzyl sulfonamides toward hydrogenolysis. We also explored the utility of the safety-catch activation method for other nitrogen-based functionality such as N-benzyl carboxamides, imides, and related functionality.

Full text of DOI:10.1016/j.tetlet.2004.09.118

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8483–8487
A reversible safety-catch method for the hydrogenolysis of
N-benzyl moieties
David C. Johnson, II and Theodore S. Widlanski*
Department of Chemistry, Indiana University, Bloomington, IN 47405, USA
Received 9 August 2004; revised 15 September 2004; accepted 16 September 2004
Available online 5 October 2004
Abstract—The benzyl groups of b-hydroxy-N-benzyl sulfonamides are labile toward hydrogenolysis-unlike N-benzyl sulfonamides
lacking the b-hydroxy moiety. We find that N-acyl-N-benzyl sulfonamides undergo hydrogenolysis under very mild conditions.
Based upon these observations, we developed a reversible safety-catch method using tert-butoxycarbonyl moieties to activate N-
benzyl sulfonamides toward hydrogenolysis. We also explored the utility of the safety-catch activation method for other nitro-
gen-based functionality such as N-benzyl carboxamides, imides, and related functionality.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
There are an abundant number of molecules that
contain the sulfonamide moiety. Chiral auxiliaries,1
peptidomimetics,2 modified oligonucleotides,3 amine
synthons,4 and therapeutics5 illustrate diverse applica-
tions for the sulfonamide group. Although many meth-
ods exist for the synthesis and manipulation of the
sulfonamide functional group, there is a general dearth
of protecting groups6 for this functionality. In principle,
the benzyl group could serve as a useful protecting
group for sulfonamides, its deprotection could be
effected by hydrogenolysis—a process orthogonal to
conditions used for the removal of many other protect-
ing groups. Unfortunately, hydrogenolysis of N-benzyl
moieties—particularly N-benzyl sulfonamides—can be
quite problematic.7,8 We now present a general method
to facilitate hydrogenolysis of N-benzyl sulfonamides
using a reversible safety-catch modification. Further,
we explore the utility of the reversible safety-catch strat-
egy toward the hydrogenolysis of N-benzyl protecting
groups from sulfonamides and other similar nitrogen-
based functional groups.
N-Benzyl-ethanesulfonamide (1) undergoes no apprecia-
ble hydrogenolysis under atmospheric pressures of
hydrogen in the presence of PearlmanÕs catalyst.9 Such
stability might be attenuated through modification of
the sulfonamide nitrogen—similar to the safety-catch
strategies used in solid-phase peptide synthesis. Ellman
and co-workers10 and others11 have shown that alkyl-
ation of N-acyl sulfonamides increases the lability of
the acyl-functionality. However, alkylation of sulfon-
amide 1 does not activate the N-benzyl group toward
hydrogenolysis. Acylation of sulfonamide 1, however,
is an effective way to activate the benzyl group to affect
hydrogenolysis in good yield (83%) (Table 1). Although,
acylation is not the most useful activation strategy, as
N-acyl sulfonamides are very resistant to hydrolysis.12
Table 1. Hydrogenolysis of N-substituted-N-benzyl sulfonamides
conducted under an atmosphere of hydrogen
H2
O
O
O O
Pd(OH)2
S
R'
S
R'
N
R
N
R
EtOH
14 hrs.
R
R0
R
R0
(1)
(2)
(3)
Bn
Bn
Bn
H
(1)
(2)
(4)
Bn
Bn
H
H
(95%)
(94%)
(83%)a
CH3
Ac
CH3
Ac
Keywords: Sulfonamide; Amide; Protecting group; Benzyl; Safety
catch; Hydrogenolysis.
a No evidence was observed by NMR for reduction of the phenyl ring
in the recovered starting material.
*
Corresponding author. Tel./fax: +1 812 855 8300; e-mail:
twidlans@indiana.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.118

8484
D. C. Johnson, II, T. S. Widlanski / Tetrahedron Letters 45 (2004) 8483–8487
Table 2. Reversible Ôsafety-catchÕ deprotection of N-benzyl sulfonamides
Pd(OH)2
H2
Boc2O
TFA
R = Boc
R'= Bn
R = H
R = H
R'= H
R = Boc
R'= H
0
oC
R'= Bn
DMAP
O
S
O
R
(5)
(9)
(97%)
(6)
(98%)
(96%)
(7)
(96%)
(8)
N
R'
O
S
O
R
N
(99%)
(86%)
(10)
(11)
(97%)
(12)
R'
O
R
N
O
N
RO
R
O
(95%) for two steps
(13)
(14)
(15)
O
OTBS
S
N
O
R'
Therefore, we explored a means to reversibly activate N-
benzyl sulfonamides through carbamoylation.
Table 3. Yield for the deprotection of structurally diverse N-benzyl
protected sulfonamides using Pd(OH)2 in ethanol under an atmosphere
of hydrogen gas (22psi)
The tert-butoxycarbonyl (Boc) moiety effectively acti-
vates alkyl and aromatic N-benzyl sulfonamides toward
hydrogenolysis (Table 2). The resultant Boc-protected
sulfonamides are easily deprotected using acid to reveal
free sulfonamides. The three-step process (activation,
hydrogenolysis, and cleavage of the Boc group) can be
conducted in very high yield; the isolation of all interme-
diates being unnecessary. Unfortunately, the benzyloxy-
carbonyl (Cbz) moiety cannot be used as an activating
group, as it undergoes hydrogenolysis preferentially
with respect to the N-benzyl moiety.
Starting material (R = Bn)
% Yield
O
O
94
(17), R = H
O
H
N
R
S
O
O
HO
O
O
(16)
OH
O
S
N
O
H
92
(19), R = H
H
R
The safety-catch activation strategy is not the only means
to hydrogenolyze N-benzyl sulfonamides. Indeed, in a re-
cent study13 we hydrogenolyzed a N-benzyl sulfonamide
(Table 3, sugar 16) without activation; although, the
reaction conditions differed from those used with the
safety-catch method. However, our result seemed atypi-
cal because hydrogenolysis of the N-benzyl sulfonamide
was effected in ethanol (rather than acetic acid) at much
lower pressures (22psi as opposed to >700psi) than
previously reported for the hydrogenolysis of other
N-benzyl sulfonamides.7 Nonetheless, this result was
generally applicable to various sugars and steroids. Thus,
deprotection of several N-benzyl sulfonamide-containing
sugars and steroids was effected in high yield using the
aforementioned conditions (Table 3).
H
TBSO
O
(18)
OH
O
S
O
N
94
(21), R = H
H
R
H
H
O
H
(20)
H
87a
(23), R = H
H
H
H
HO
N
R
S
O
O
Many common functional groups are compatible with
the high pressure hydrogenolysis protocol. For example,
isopropylidene groups, aryl-silyl ethers, carboxylicesters,
tert-butyl carbonatesà as well as tert-butyl carbamatesà
(22)
O
S
H
R
O
OH
N
O
N
O
N
U
O
NH
O
NH
O
U =
O
O
Under the same conditions used for the safety-catch method:
N-benzyl-N-Cbz isopropylsulfonamide gives N-benzyl isopropylsul-
fonamide in 97% yield and N-benzyl-N-Cbz toluylsulfonamide gives
N-benzyl toluylsulfonamide in 93% yield.
49
(25), R = H
48
(26), R = Bn
(24)
a The alkene is reduced in the product.
à Data not shown.

D. C. Johnson, II, T. S. Widlanski / Tetrahedron Letters 45 (2004) 8483–8487
8485
O
an anionic transition state, thus promoting
hydrogenolysis.
H
N
H
H
N
H
O
N
Pd(OH)2
S
Bn
H
H2 (22 psi)
O
O
H2N
OH
S
Bn
O
O
To test the possible involvement of an intramolecular H-
bond, b-hydroxy sulfonamide 32, and b-methoxy sulfon-
amide 34 were subjected to identical reaction conditions.
Hydrogenolysis of the benzyl group occurs for both the
hydroxy-containing (86%) and methoxy-containing
(61%) molecules (Table 5). These data negate the
involvement of an internal H-bond. However, H-bond-
ing could still be involved, as the reactions were
conducted in protic solvent. Therefore, to test the possi-
bility of intermolecular H-bonding, hydrogenolysis was
conducted in ethyl acetate—an aprotic solvent. Again,
hydrogenolysis of the benzyl group occurs for both the
hydroxy-containing (89%) and methoxy-containing
(99%) molecules. Collectively, these data mitigate against
the involvement of H-bonding as the determining factor
responsible for the hydrogenolysis of b-hydroxy-N-ben-
zyl sulfonamides. Another possibility for the facility of
hydrogeno- lysis of b-hydroxy-containing sulfonamides
is that the hydroxyl group assists in chelation between
reactive species. The same possibility may occur for the
N-acylated sulfonamides, as the carbonyl oxygen may
participate in chelation between reactive species.
OH
EtOH
(84%)
(27)
(28)
Figure 1. Fmoc-protected amines are preferentially cleaved under the
reaction conditions. The resultant amine presumably deactivates the
catalyst; thereby, leaving the N-benzyl sulfonamide intact.
Table 4. N-Benzyl sulfonamides lacking a b-hydroxy moiety hydro-
genolyze in poor yield
Pd(OH)2
H2 (22 psi)
O
O
O O
S
Ph
S
R
N
R
NH2
EtOH
H
R
% Recovered
R
% Product
(1)
(5)
(9)
Et
82a
87a
79
(29)
(30)
(31)
Et
i-Pr
16
7
i-Pr
Tol
Tol
9
a Recovered starting materials contained a mixture of the phenyl-form
and the reduced cyclohexyl-form of the benzyl protecting group.
are stable to the deprotection conditions. Though many
functional groups are stable, alkenes are reduced (Table
3, steroid 22 and nucleoside 24). Interestingly, in the
presence of an Fmoc-protected amine, hydrogenolysis
of the N-benzyl sulfonamide moiety does not occur; in-
stead, preferential deprotection of the Fmoc group oc-
curs (Fig. 1). Amines inhibit the hydrogenolysis of the
benzyl moiety from heteroatoms (e.g., oxygen)14 pre-
sumably by formation of a complex15 between the amine
and the palladium catalyst, thereby deactivating the cat-
alyst. Thus, facile hydrogenolysis of the Fmoc-amine
subsequently inhibits hydrogenolysis of the N-benzyl
sulfonamide.
N-Benzyl sulfonamides are not the only N-benzyl func-
tionality that is very difficult to hydrogenolyze; N-
Benzyl carboxamides are also notoriously difficult to
hydrogenolyze.6 Indeed, attempted hydrogenolysis of
N-benzyl-propanamide and N-benzyl-benzamide failed
using PearlmanÕs catalyst under atmospheric pressures
of hydrogen gas.– Similarly, use of the Boc-safety-catch
activation method also failed to effect appreciable
hydrogenolysis of the N-benzyl moiety, even after pro-
longed reaction times.k However, use of the safety-catch
method at elevated temperature (55°C) led to the reac-
tion of N-benzyl-N-Boc-benzamide (36); giving both
N-Boc-benzylamine (37) and N-Boc-cyclohexylmethyl-
amine in 81% total yield.** Similarly, the aromatic imide
N-acetyl-N-benzyl-benzamide gives a mixture of N-benzyl-
acetamide and N-cyclohexylmethyl acetamide in 80% to-
tal yield. These products could arise by two different
pathways, as illustrated in Figure 2.
To test the generality of the reaction conditions associ-
ated with hydrogenolysis of b-hydroxy-containing sul-
fonamides, we subjected several simple N-benzyl
sulfonamides lacking the b-hydroxy-group to the depro-
tection conditions. As expected, hydrogenolysis of sim-
ple N-benzyl sulfonamides proceeds in poor yield
(Table 4). This result suggests that hydrogenolysis of
N-benzyl sulfonamides, without use of the safety-catch
protocol, seems dependent upon the presence of the b-
hydroxy moiety.
To test the operative pathway, N-benzyl-N-Boc-m-
methyl benzamide (40) was subjected to the reaction
conditions. Quenching the hydrogenolysis early leads
to exclusive formation of N-Boc-benzylamine (37)
(47%) with recovery of unreacted starting material
(39%) possible (Fig. 3). Additionally, hydrogenolysis
of N-Boc-benzamide (38) under the same reaction con-
ditions gives benzamide (36%) and starting material
(35%). These data support regioselective acyl-cleavage
of the aromatic amide bond and support pathway a of
Van Bekkum and co-workers,16 as well as McQuillin
and co-workers,17 have reported kinetic data that is con-
sistent with an anionic transition state for hydrogenoly-
sis. An increase in anionic character in the transition
state is also supported by competition experiments re-
ported by Baltzly and Buck.§, The b-hydroxy moiety
18
may form an intramolecular H-bond to stabilize such
– N-Benzyl-propanamide was recovered in 97% yield and N-benzyl
benzamide was quantitatively recovered.
k After 4days, N-benzyl-N-Boc-propanamide was recovered in 81%
yield, and N-benzyl-N-Boc-benzamide was recovered in 68% yield.
** N-Benzyl-N-Boc-propanamide (and the reduced cyclohexyl-form)
was recovered in 95% combined yield from the same reaction
conditions used with the benzamide species.
§ Baltzly and Buck report a competition experiment where bis-benzyl
diamines are hydrogenolyzed in acidic medium. Benzyl groups are
found to hydrogenolyze in preference to q-substituted benzyl groups
bearing electron-donating substituents.

8486
D. C. Johnson, II, T. S. Widlanski / Tetrahedron Letters 45 (2004) 8483–8487
Table 5. Hydrogenolysis of N-benzyl sulfonamides containing b-oxy
functionality occurs in both protic and aprotic solvents
nately, this activation strategy cannot be extended to
similar functionality such as alkylcarboxamides, arylcar-
boxamides, or arylimide functionality. The N-benzyl
moiety of an alkylcarboxamide does not undergo hydro-
genolysis under the reaction conditions tested and aryl-
carboxamides and alkylcarboxamides decompose in an
undesirable fashion.
Pd(OH)2
H2 (22 psi)
O
O
O O
S
Ph
S
RO
N
RO
NH2
H
R
% Recovered Solvent
R
H
% Product
86
(32)
(34) Me 36a
(32)
9a
(34) Me
H
13a
EtOH
(33)
(35) Me 61
(33) 89
(35) Me 99
H
EtOAc
H
4. Experimental procedures
—
a Recovered starting materials contained a mixture of the phenyl-form
and the reduced cyclohexyl-form of the benzyl protecting group.
4.1. General procedure for the synthesis of Boc-activated
N-benzyl sulfonamides
Di-tert-butyl dicarbonate (1.5equiv) was slowly added
to an ice-cold 0.45M THF solution of N-benzyl sulfon-
amide (1equiv). DMAP (0.1equiv) was then added and
the reaction stirred overnight at rt. All volatiles were re-
moved with a rotary evaporator and the desired com-
pound isolated by silica gel chromatography using the
solvent system indicated.
O
O
O
a
Ph
N
OtBu
Ph
N
H
OtBu
Ph
(37)
(36)
b
[Red]
4.1.1. N-Benzyl N-(tert-butoxycarbonyl) iso-propylsul-
fonamide (6). Quantities: sulfonamide
5 (500mg,
O
O
OH O
2.344mmol), Boc2O (0.81mL, 3.516mmol), DMAP
(28mg, 0.2344mmol). Eluent = 2:1 hexanes:Et2O gives
6 (712mg, 2.272mmol) as a solid. Yield = 97%.
[Red]
Ph
N
H
OtBu
Ph
N
OtBu
H
(39)
(38)
1H NMR (400MHz, CDCl3): d = 7.39 (d, J = 7.4Hz,
2H), 7.34–7.24 (m, 3H), 4.82 (s, 2H), 4.01 (sept,
J = 6.9Hz, 1H), 1.47 (s, 9H), 1.31 (d, J = 6.9Hz, 6H);
13C NMR (100MHz, CDCl3): d = 152.00, 137.65,
128.55, 128.16, 127.70, 84.69, 54.54, 50.02, 28.14,
16.25; IR (film): m = 3089, 3070, 3031, 2981, 2938,
2879, 1726, 1497, 1456, 1371, 1349, 1254, 1136,
1058cmꢀ1; HRMS (CI) m/z calcd for C15H24NO4S
(MH+): 314.14206, found 314.14215.
Figure 2. Two possible pathways to form N-Boc-benzylamine from N-
benzyl-N-Boc-benzamide in the presence of Pd(OH)2 in ethanol at
55°C under an atmosphere of hydrogen.
O
O
O
H2
Pd(OH)2
N
H
OtBu
N
OtBu
+
40
EtOH, 55 o
Premature
Quench
C
39%
47%
(37)
(40)
4.2. General procedure for the hydrogenolysis of
N-activated N-benzyl sulfonamides
Figure 3. Regioselective reduction of aromatic amide bonds occurs for
aryl-N-carboxyl-carboxamides.
PearlmanÕs catalyst (10mg/100mg sulfonamide) was sus-
pended in a 0.35M EtOH solution of the appropriate N-
activated sulfonamide. The heterogeneous mixture was
stirred overnight under an atmosphere of hydrogen gas
(balloon). The mixture was then filtered through a 1in.
cake of Celite 545 with EtOH. All volatiles were re-
moved with a rotary evaporator and the desired com-
pound isolated by silica gel chromatography using the
solvent system indicated.
Figure 2. Furthermore, these results are in agreement with
a report by Ragnarsson et al.19 who observe a decrease in
the reduction potential (i.e., increase in lability) of aro-
matic amide bonds when incorporated into carboxamide
functionality—such as N-carboxyl-carboxamide 36.
3. Conclusions
4.2.1. N-(tert-Butoxycarbonyl) iso-propylsulfonamide
(7). Quantities: sulfonamide 6 (160mg, 0.5105mmol),
PearlmanÕs (16mg). Eluent = 1:1 Et2O:hexanes gives 7
(112mg, 0.5016mmol) as a solid. Yield = 98%.
N-Benzyl sulfonamides are resistant to hydrogenolysis.
Yet, acylation or carbamoylation of N-benzyl sulfon-
amides facilitates hydrogenolysis of the benzyl moiety.
Based upon these observations, we have introduced
the tert-butoxycarbonyl (Boc) moiety as a reversible
activation (i.e., safety-catch) method to facilitate hydro-
genolysis of both alkyl and aryl-N-benzyl sulfonamides.
Through reversible carbamoylation of N-benzyl pro-
tected sulfonamides using the tert-butoxycarbonyl
(Boc) moiety, we have introduced a new protecting
strategy for the sulfonamide functionality. Unfortu-
1H NMR (400MHz, CDCl3): d = 3.72 (sept, J = 7.0Hz,
1H), 1.47 (s, 9H), 1.40 (d, J = 6.9Hz, 6H); 13C NMR
(100MHz, CDCl3): d = 150.17, 84.24, 53.68, 28.08,
16.19; IR (film): m = 3590, 3241, 2983, 2940, 2880,
1742, 1435, 1371, 1340, 1243, 1163, 1135, 1061cmꢀ1
;
HRMS (CI) m/z calcd for C8H18NO4S (MH+):
224.09511, found 224.09584.

D. C. Johnson, II, T. S. Widlanski / Tetrahedron Letters 45 (2004) 8483–8487
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.
tetlet.2004.09.118. Experimental procedures and spectral
data (1H, 13C, MS, IR) for all compounds synthesized in
this study. The supplementary data is available online
with the paper in ScienceDirect.
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