Methylprenyl and prenyl protection for sulfonamides

Article abstract of DOI:10.1055/s-0034-1379428

2-Methylprenyl (MePre) is an efficient protection for sulfonamides. The acidic cleavage of this group leads to volatile by-products and the product can be obtained in high purity without additional purification. MePre group is resistant to Pd/C-catalysed hydrogenolysis at 1 atm, Suzuki-Miyaura reaction, Ni(0) catalysis conditions and oxidising reagents such as NIS and DDQ. The prenyl (Pre) group can also be used to protect sulfonamides in certain cases; however, the substrate scope is limited due to the side product formation.

Full text of DOI:10.1055/s-0034-1379428

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 183–186
letter
183
A. Nikitjuka et al.
Letter
Synlett
Methylprenyl and Prenyl Protection for Sulfonamides
O
Me
O
O
O
TFA (10–25 vol%)
Anna Nikitjuka
S
S
R1
R1
N
R2
Me
NH
R2
Aleksandra Nekrasova
Aigars Jirgensons*
CH2Cl2, r.t.
R3
R3 = Me; 13 examples, quantitative
3 = H; 4 examples, 72–89%
R
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
+
3
7
1
6
7
5
5
0
3
3
8
aigars@osi.lv
Dedicated to Dr. Valerjans Kauss on the occasion of his 60th birthday
Received: 12.09.2014
Accepted after revision: 18.10.2014
Published online: 14.11.2014
2-Methylprenyl (MePre) and prenyl (Pre) sulfonamides
1 and 2 can be obtained via several routes (Scheme 1,Table
1). Sulfonamides 4 prepared from sulfonyl chlorides 3 and
amines can be alkylated with prenyl bromides 5 and 6 (path
A). Sulfonamides 9 and 10 obtained from sulfonyl chlorides
3 and N-prenylamines 7 and 8 can be alkylated or arylated
(path B). N-(2-Methylprenyl)anilines 12 prepared via Pd-ca-
talysed hydroamination of dienes 1122 can be sulfonylated
with sulfonyl chlorides 3 (Path C).
DOI: 10.1055/s-0034-1379428; Art ID: st-2014-d0760-l
Abstract 2-Methylprenyl (MePre) is an efficient protection for sulfon-
amides. The acidic cleavage of this group leads to volatile by-products
and the product can be obtained in high purity without additional puri-
fication. MePre group is resistant to Pd/C-catalysed hydrogenolysis at 1
atm, Suzuki–Miyaura reaction, Ni(0) catalysis conditions and oxidising
reagents such as NIS and DDQ. The prenyl (Pre) group can also be used
to protect sulfonamides in certain cases; however, the substrate scope
is limited due to the side product formation.
MePreBr (5)
or PreBr (6)
O
O
O
O
R2NH2
S
R2
S
path A
path B
R1
Key words sulfonamides, protecting groups, allylation, cations, cleav-
age
R1
N
Cl
H
4
3
MePreNH2 (7)
or PreNH2 (8)
Sulfonamide substructure is often incorporated in phar-
macologically active agents.1,2 This functionality, due to the
relative acidity and nucleophilicity in the deprotonated
form, may often require protection during the synthesis of
complex compounds. Nevertheless, options for sulfonamide
protection are limited to a few groups such as tert-butyl,3–5
benzyl,6,7 diphenylmethyl,8 4-methoxybenzyl,9 2,4-dime-
thoxybenzyl,10 2,4,6-trimethoxybenzyl11 and allyl.12,13 Con-
sequently, there is a need to broaden the arsenal of sulfon-
amide protection with groups that are easily installed and
cleaved under mild conditions generating volatile by-prod-
uct(s). The prenyl-type protection has been used for alco-
hols,14–20 carboxylic acids14–16 and hydroxamic acids;21
however, to the best of our knowledge it has not been used
to protect sulfonamides. In this article, we report our inves-
tigations on the utility of prenyl and 2-methylprenyl as
acid-labile sulfonamide protecting groups (Figure 1).
Me
O
O
R2X
1, 2
S
R1
Me
N
H
R
9 R = Me
10 R = H
Me
Me
R1SO2Cl (3)
PhNH2
Ph
N
path C
Me
H
Me
Me
11
12
Scheme 1 Preparation of 2-methylprenyl- and prenyl-protected sul-
fonamides
Using the protected sulfonamides 1a and 2a as model
substrates, we found that the cleavage of MePre and Pre
groups can be achieved in acidic conditions (10 vol% TFA in
CH2Cl2).23 In the case of substrate 1a, addition of triethylsi-
lane as a cation scavenger was beneficial to achieve a clean
cleavage of the MePre group. The workup required only
evaporation of the reaction mixture to provide the product
with high purity. In turn, the deprotection of Pre analogue
2a in the presence of triethylsilane led to the formation of
N-isopentylsulfonamide as a side product resulting from
the Pre group reduction (ca 15%) along with the deprotect-
ed sulfonamide (Table 1, entry 2). In the absence of triethyl-
silane, a considerable amount of competing intramolecular
Friedel–Crafts reaction was observed (ca. 40% by NMR of
O
Me
O
S
R1
N
R2
1 R3 = Me
2 R3 = H
Me
R3
Figure 1 2-Methylprenyl (MePre)- and prenyl (Pre)-protected sulfon-
amides 1 and 2
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 183–186

184
A. Nikitjuka et al.
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Table 1 Proteolytic Deprotection of Sulfonamides 1 and 2a
Entry
Deprotection substrate (synthesis path)
PG
Reaction time, yield
O
N
O
1
2
S
1a (C)
2a (A)
MePre
Pre
20 min, quantitative
60 min,72%b
PG
PG
4-MeC6H4
Ph
O
O
3
4
S
1b (A)
2b (A)
MePre
Pre
45 min, quantitative
12 h, 76%b
N
4-MeC6H4
4-BnOC6H4
O
N
O
S
PG
5
1c (A)
MePre
60 min, quantitative.
4-MeC6H4
4-MeOC6H4
O
N
O
S
PG
6
7
1d (B)
2d (B)
MePre
Pre
45 min, quantitative
60 min, 78%b
4-MeC6H4
O
O
60 min, quantitativec
60 min, mixture of products
S
PG
8
9
1e (B)
2e (B)
MePre
Pre
N
4-MeC6H4
O
O
10
11
1f (B)
2f (B)
MePre
Pre
90 min, quantitativec
90 min, mixture of products
S
PG
N
4-MeC6H4
Bn
O
O
12
13
1g (B)
2g (B)
MePre
Pre
60 min, quantitative
12 h, mixture of products
S
PG
PG
N
H
4-MeC6H4
O
N
O
S
14
1h (A)
MePre
12 h, mixture of productsd
4-MeC6H4
t-Bu
O
O
15
16
1i (C)
2i (A)
MePre
Pre
20 min, quantitative
60 min, 89%b
S
PG
N
4-MeOC6H4
Ph
O
N
O
17
18
1j (A)
2j (A)
MePre
Pre
12 h, quantitative
12 h, mixture of products
S
PG
O
n-Bu
Bn
O
S
PG
12 h, 92%b,c
N
19
1k (A)
MePre
Ph
N
O
O
S
PG
N
N
20
21
1l (A)
MePre
MePre
60 min, 91%b
90 min, 94%b,c
Ph
S
O
N
O
S
PG
1m (A)
3-BrC6H4
Bn
a Reaction conditions: TFA (10 vol%), triethylsilane (6 equiv), CH2Cl2 if not stated otherwise.
b Isolation of the product was achieved by flash chromatography.
c Amount of TFA used in CH2Cl2 was 25 vol%.
d The main components were the product of MePre group cleavage and primary sulfonamide (1:1); increasing the reaction time led to primary sulfonamide
formation (full conversion was observed after 72 h).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 183–186

185
A. Nikitjuka et al.
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Synlett
crude product). Moreover, a longer reaction time was need-
ed to achieve the complete conversion of Pre-protected sul-
fonamide 2a compared to MePre analogue 1a. The in-
creased lability of MePre group in sulfonamides 1 can be
explained by the small positive carbenium ion stabilising
effect of the 2-methyl substituent.24
The substrate scope for MePre deprotection in sulfon-
amides 1 appeared to be quite broad. In the case of most ex-
amples studied, cleavage of the MePre group was efficiently
achieved. An exception was N-t-Bu-substituted sulfon-
amide 1h where the deprotection was accompanied by
cleavage of the t-Bu group (Table 1, entry 14). For Pre pro-
tection the substrate scope was apparently limited: the
cleavage of protecting group in sulfonamides 2 was accom-
panied by side product formation. Only in the case of sul-
fonamide 2i did deprotection provide the desired product
in high yield (Table 1, entry 15).
The stability of the prenyl-type sulfonamide protection
was studied under various conditions used for the cleavage
of other protecting groups. Selective O-debenzylation was
achieved in the MePre-protected sulfonamide 1b under cat-
alytic hydrogenation conditions at 1 atm of H2 (Table 2, en-
try 1). Notably, these conditions led to a complete satura-
tion of the Pre group in the substrate 2b (Table 2, entry 2).
At the increased pressure, saturation of MePre group also
took place in the substrate 1b (Table 2, entry 3). The MePre-
protected sulfonamide 1c was resistant to NIS and DDQ (Ta-
ble 2, entries 4 and 5). The allyl group could be selectively
cleaved from sulfonamide 1d under the conditions of Ni(0)
catalysis13 in the presence of MePre group (Table 2, entry 6).
Strong Lewis acids such as BCl3 promoted the cleavage of
MePre group together with Bn and t-Bu groups in sub-
strates 1b and 1h leading to primary sulfonamides in a very
high yield (Table 2, entries 7 and 8).
The stability of the MePre group under the Suzuki–
Miyaura coupling conditions was demonstrated in the syn-
thesis of biphenyl intermediate 13 from protected bro-
mophenylsulfonamide 1m (Scheme 2). The MePre group
was also stable at the stage of catalytic nitro group reduc-
tion in compound 13 to give the aniline intermediate 14. Fi-
nally, the cleavage of the MePre group provided unprotect-
ed sulfonamide 15.
Table 2 Stability Studies of MePre and Pre-Protected Sulfonamides 1
and 2
En- Com-
try pound
Conditions
Results (yield of product)a
1b
2b
1
2
Pd/C, H2 (1atm),
EtOAc
selective O-debenzylation (84%)
O-debenzylation and saturation of
Pre group
3
1b
Pd/C, H2 (6 atm),
EtOAc
O-debenzylation and saturation of
MePre group
4
5
1c
1c
NIS, CH2Cl2, r.t.
stable
stable
DDQ, CH2Cl2, H2O,
reflux
6
1d
DIBAL-H, cat.
(dppp)NiCl2, tolu-
ene, r.t.
selective allyl group cleavage (89%)
7
8
1b
1h
BCl3 (1.5 equiv),
CH2Cl2, r.t.
MePre and Bn cleavage (98%)
BCl3 (1.1 equiv),
CH2Cl2, r.t.
MePre and t-Bu cleavage (99%)
a Isolated yield.
In summary, we have demonstrated that the MePre
group can be used as an acid-labile protection for sulfon-
amides. The acid-promoted cleavage of this protecting
group leads to volatile by-products and the product can be
obtained in high purity after evaporation of the reaction
mixture. MePre group is resistant to Pd/C-catalysed hydrog-
enolysis at 1 atm, Suzuki–Miyaura reaction, Ni(0) catalysis
conditions, and oxidising reagents such as NIS and DDQ.
The Pre group can also be used to protect sulfonamides;
however, formation of side products is observed in many
cases and the substrate scope is limited.
Acknowledgment
Funding from EU FP7, programme Health, project NABARSI (Grant
agreement no: 601725) is gratefully acknowledged.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379428. Included are synthetic
procedures for compounds 1a–m, 2a–j, 3, 9, 10, 12 and 13–15, their
spectroscopic characterisation as well as NMR spectra of compounds
1a–g, 1i–j and 13–15.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
O
O
O
S
O
O
O
O
O
S
Bn
Bn
S
Bn
Bn
N
TFA
EtSiH
3-(NO2)C6H4B(OH)2
cat. Pd(PPh3)4, Cs2CO3
S
N
N
N
Pd/C, H2 (1 atm)
H
MePre
MePre
MePre
THF, reflux
85% (brsm)
EtOAc, r.t.
84%
CH2Cl2, r.t.
99%
Br
1m
NO2
13
NH2
14
NH2
15
Scheme 2 Stability of MePre in Suzuki–Miyaura coupling and in the reduction of the nitro group
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 183–186

186
A. Nikitjuka et al.
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References and Notes
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