Ammonium formate-based one-pot reductive Heck reactions for the construction of cyclic sulfonamides

Article abstract of DOI:10.1016/j.tetlet.2017.10.053

A modified method is reported for the conversion of unsaturated sulfonamides into their cyclic saturated counterparts. This method utilises a single palladium catalyst for an intramolecular Heck reaction and subsequent transfer hydrogenation, which is ach

Full text of DOI:10.1016/j.tetlet.2017.10.053

Tetrahedron Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ammonium formate-based one-pot reductive Heck reactions for the
construction of cyclic sulfonamides
⇑
Aisha Khalifa, Lorna Conway, Kimberly Geoghegan, Paul Evans
Centre for Synthesis and Chemical Biology, School of Chemistry, University College Dublin, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
A modified method is reported for the conversion of unsaturated sulfonamides into their cyclic saturated
counterparts. This method utilises a single palladium catalyst for an intramolecular Heck reaction and
subsequent transfer hydrogenation, which is achieved in one-pot following the addition of ammonium
formate. Accordingly, a range of fourteen structural variations are reported and under optimal conditions
the adducts were generated in typically good to excellent yields. Notably, discrimination of differentially
substituted dienes can be accomplished in the case of compounds 28 and 29 and the process was only
observed to fail with the more sterically hindered precursor 32.
Received 4 September 2017
Revised 18 October 2017
Accepted 20 October 2017
Available online xxxx
Keywords:
Sultam
Hydrogen transfer
Regioselectivity
Chemoselectivity
Ring closing metathesis
Ó 2017 Published by Elsevier Ltd.
1
The Heck reaction is an important method for the formation of
carbon–carbon bonds and one that we have exploited in its
intramolecular guise for the synthesis of unsaturated cyclic sulfon-
amides (Scheme 1, 1 to 2),2 the ultimate aim being to study how
the sulfonamide motif behaved under reductive conditions. In rela-
tion to this we have demonstrated that under certain conditions
both the nitrogen-sulfur and carbon–sulfur bonds undergo cleav-
compounds containing an aryl substituted octahydroindole
skeleton, including mesembrine (Scheme 1).
Catalytic hydrogenation with hydrogen gas is a technology used
globally within the chemical industry and academic research labo-
ratories. However, the use of molecular hydrogen constitutes a
potential hazard and requires the use/installation of specialist
equipment for both its storage and usage. In this current study
we demonstrate that the hydrogen gas previously used for alkene
reduction can be effectively replaced with solid ammonium for-
3
age affording saturated N-heterocycles of the type 4. The 3-aryl
pyrrolidine skeleton 4 is prevalent in a range of naturally occurring
and/or pharmacologically interesting alkaloids (depicted in
Scheme 1). In order to achieve the key sulfonamide double reduc-
7
mate and that, using this safer and operationally simpler hydro-
4
gen-transfer protocol, higher yields of the corresponding adducts
are typically observed.
tion, the alkene (2), formed following the intramolecular Heck
reaction, must be first saturated (3). Initially this was performed
via a standard stop-go process, in which the reduction was accom-
As shown in Scheme 2, for bromide 5 the traditional stop-go,
two-pot Heck-hydrogenation process afforded 8, via alkene 7, in
and Pd/C.2a Subsequently, we demonstrated that
good yield over two-steps (Entry 1). In this case the palladium
2a
plished with H
this overall process (1 to 3) may be achieved in one-pot, using
2
loading for both steps can be reduced to 1 mol% without a
dramatically detrimental effect on the overall yield. Running the
Heck reaction and the hydrogenation in the same pot gave 8 in
5
the same palladium source, simply by introducing H
ing the Heck reaction.
2
gas follow-
6
4
Although the overall yields for this one-pot process are some-
what lower than those observed in the two-pot process, use of
the same catalyst for two different reactions and the requirement
for only one purification process make it attractive. Notably, in
the case of R = Me high levels of regioselectivity are encountered
for the generation of the congested quaternary all-carbon cen-
61% yield (Entry 2). In contrast to Entry 1, results in this case indi-
cate that the hydrogenation step only proceeds effectively if a
higher loading of Pd(OAc) is used – a finding which is likely to
2
be linked to the nature of the Pd-species present post-Heck
reaction.
Pleasingly, as shown in Entry 3, performing the Heck reaction
with N-sulfonyl dihydropyrrole 5 in an identical manner but then
adding ammonium formate (15 equiv.) generates 8 in comparable
yield to the hydrogen-based process as long as the mixture is
heated to approximately 65 °C (without heating no evidence of
2
d,e
tre
and this overall synthetic sequence provided entry to
⇑
Corresponding author.
E-mail address: paul.evans@ucd.ie (P. Evans).
https://doi.org/10.1016/j.tetlet.2017.10.053
040-4039/Ó 2017 Published by Elsevier Ltd.
0
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2
A. Khalifa et al. / Tetrahedron Letters xxx (2017) xxx–xxx
R
This failure stems directly from the reduced reactivity of the C
(sp )–Cl bond in the oxidative addition step of the Heck reaction,
R
2
Br
S
(
1) Pd(0)
R'
R'
under our reaction conditions. Related to this we have shown that
chlorides like 6 may be effectively used in this type of intramolec-
ular Heck reaction when Buchwald’s BrettPhos is used as the
R'
N
N
S
O
1
2
2
O
2
2
e
ligand. Thus, we investigated whether under these conditions
chloride 6 could be used to prepare 8 by introducing ammonium
formate to the post-Heck reaction mixture (Entry 6). This was
achieved to a degree, however, both the hydrogenation and the
Heck reactions did not reach completion and consequently, in
(
2) H2
R
R
Li, NH
3
R'
N
N
H
S
addition to 8,
a
mixture of compounds were present
O
2
4
3
necessitating a difficult purification.
Following identification of the optimal reaction conditions dis-
cussed above a range of 2-bromo-substituted, unsaturated sulfon-
amide Heck reaction precursors were prepared and studied in their
OMe
3
H C
MeO
CH3
HO
9
respective one-pot reductive Heck reactions. The substrates orig-
NCH
3
inate from the corresponding 2-bromo substituted benzenesul-
fonyl chlorides. The non-commercially available substituted 2-
bromobenzenesulfonyl chlorides used in this study were either
prepared by electrophilic aromatic substitution (chlorosulfonic
N
H
N
(−)-aphanorphine
O
CH
(+)-bicifadine
H
3
(
−)-mesembrine
2
a,g
acid),
or from
a
Meerwein’s diazotisation/Cu(I)-SOCl
2
1
0
Scheme 1. One-pot intramolecular Heck reaction-reduction sequence for the
synthesis of saturated cyclic sulfonamides 3 and their subsequent double reduction
to 3-aryl pyrrolidines 4.
sequence. As shown in Scheme 3, N-sulfonyl dihydropyrroles 9
to 14 were converted into the corresponding saturated cyclic sul-
fonamides 15 to 20. The yields obtained for adducts 15 to 17
demonstrate that under the optimal conditions, electron releasing
oxygen substituents are well-tolerated. The 4-chloro substituent in
substrate 13 was predominantly preserved over the course of the
reaction and 19 was isolated in reasonable yield (67%). Compound
X
(
a)
(b)
N
N
N
S
S
S
8
2
, the product of hydrogen-chloride exchange, was also isolated in
0% yield following purification from this particular reaction.
As anticipated, 4-nitro substituted dihydropyrrole 14 under-
O
O
2
O
2
2
5
6
: X = Br
: X = Cl
7
8
Yield 8a
went both the expected reductive Heck process but also nitro
reduction generating compound 20 (R = NH ). Additional unidenti-
Entry
X
Cond.
2
(
a) Pd(OAc)2 (10 mol%), PPh3 (20 mol%),
CO , DMF, 110 °C, 15 h; (b) Pd/C (10 mol%),
(1 atm), EtOH, rt, 15 h
Pd(OAc)2 (10 mol%), PPh3 (20 mol%), K CO ,
DMF, 110 °C, 15 h; then H2 (1 atm), rt, 12 h
fied products are present in the crude reaction mixture, serving to
reduce the yield of 20. As a comparison, using hydrogen gas at
room temperature, rather than ammonium formate at 80 °C, the
1b Br
2c Br
K
2
81%
61%
45%
3
H
2
2
3
2
nitro group was largely preserved, and 21 (R = NO ) was isolated
in 43% yield. These complementary outcomes demonstrate that
functional group selectivity may be achieved using the two
methods.
Pd(OAc)2 (10 mol%), PPh3 (20 mol%),
3
4
Br
Br
Cl
K
2
CO
15 equiv.), 65 °C, 15 h
Pd(OAc)2 (10 mol%), PPh3 (20 mol%),
CO , DMF, 110 °C, 15 h; then NH HCO
55 equiv.), 80 °C, 15 h
Pd(OAc)2 (10 mol%), PPh3 (20 mol%),
CO , DMF, 110 °C, 15 h; then NH HCO
55 equiv.), 80 °C, 15 h
Pd(OAc)2 (10 mol%), BrettPhos (10 mol%),
Cl K CO , DMF, 110 °C, 15 h; then NH HCO
3
, DMF, 110 °C, 15 h; then NH
4
HCO
2
(
3
-Methyl substituted dihydropyrroles 22 to 24, in which addi-
tional steric functionality is introduced into the alkene, were next
studied (Scheme 4). As expected, based on our previous work,2
high levels of regioselectivity in the Heck reaction were observed
and good yields of the adducts 25 to 27 were obtained after
purification by flash column chromatography. Notably, in these
examples, better yields of the saturated cyclic sulfonamides were
K
2
91%
3
4
2
d,e
(
0%d
5
6
K
2
3
4
2
(
obtained than the corresponding processes using H
parentheses).
2
(values in
2
3
4
2
53%
(
55 equiv.), 80 °C, 15 h
aIsolated yields following purification by flash column chromatography; bTwo-pot
from ref. 2a; cOne-pot process using H from ref. 6; d6 was recovered (72%)
Building upon this selectivity and efficiency we were also inter-
ested to study how dienes 28 and 29, prepared by enyne metathe-
2
2
h
sis, would behave. It is worth mentioning that intermolecular
Heck processes with 1,3-dienes are known to occur at the
Scheme 2. Optimisation of the one-pot Heck-hydrogen transfer reaction for the
formation of cyclic sulfonamide 8.
1
1
terminal, rather than internal, positions. In contrast to these
intermolecular examples, compounds 28 and 29 generated par-
tially saturated cyclic sulfonamides 30 and 31 in good yield
(Scheme 5). This outcome is of interest and was not anticipated
since the yields obtained demonstrate that high levels of regiose-
lectivity for carbon–carbon bond formation in the intramolecular
Heck reaction and chemoselectivity in the reduction of the endo-
cyclic alkene over the exocyclic iso-propenyl group, have taken
place. As shown, X-ray crystallography confirmed this outcome
hydrogen transfer was observed and 7 was isolated). Further opti-
misation indicated that if the hydrogen transfer process was con-
ducted with a larger excess of ammonium formate (55 equiv.)
8
and at 80 °C excellent yields of 8 were obtained (Entry 4).
Next the use of aryl chloride 6 was considered. Aryl chlorides
are attractive substrates for this type of chemistry since they tend
to be cheaper and have a lower molecular weight than the corre-
sponding bromides and iodides. Unfortunately, this protocol does
not transfer directly to chloride 6 and, under the conditions identi-
fied in Entry 4, only starting material 6 was recovered (Entry 5).
9
for compound 30.
Finally, we investigated N-sulfonyl hexahydroindole 32, which
2
d
was an intermediate in our synthesis of mesembrane. Using the
previously published Heck-hydrogenation process with hydrogen
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A. Khalifa et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
(
1) Pd(OAc)2 (10 mol%),
PPh3 (20 mol%), K CO ,
2
3
R
Br
S
R
DMF, 110 °C, 15 h
N
N
R'
(2) NH HCO2 (55 equiv.),
R'
S
4
O
O
2
80 °C, 18 h
2
6
1
5: R = R' = OMe, 85% (H : 52%)
2
9
1
1
1
1
1
: R = R' = OMe
0: R = R' = OCH
1: R = OMe, R' = H
2: R = H, R' OMe
3: R = Cl, R' = H
4: R = NO2, R' = H
1
6: R = R' = OCH O, 87%
O
2
2
17: R = OMe, R' = H, 87%
1
1
2
2
8: R = H, R' OMe, 92%
9: R = Cl, R' = H, 67% (8: 20%)
0: R = NH , R' = H, 65%
2
1: R = NO , R' = H, 43% (H )
2
2
Scheme 3. Synthesis of benzo-substituted cyclic sulfonamides 15–21 using the one-pot Heck-hydrogen transfer protocol.
(
1) Pd(OAc)2 (10 mol%),
Me PPh3 (20 mol%),
K CO , DMF, 110 °C, 15 h
Me
R
Br
R
2
3
N
N
R'
S
(2) NH
80 °C, 15 h
4
HCO
2
(55 equiv.),
R'
S
O
O
2
2
25: R = R' = H, 93% (67%)6
2
2: R = R' = H
2
3: R = R' = OMe
4: R = OMe, R' = H
6: R = R' = OMe, 70% (58%)6
2
2
2
7: R = OMe, R' = H, R'' = Me, 92%
Scheme 4. Synthesis of substituted cyclic sulfonamides 25–27 using the one-pot Heck-hydrogen transfer protocol (values in parentheses, yields for the corresponding
process conducted with H
2
, see Ref. 6).
C12
C12
(
1) Pd(OAc) (10 mol%),
2
PPh (20 mol%),
K CO , DMF, 110 °C, 15 h
C13
C13
3
R
R
Br
R
R
C11
C11
2
3
C4
C4
C5
C5
C7
C7
N
N
C9
C9
S
(2) NH
80 °C, 15 h
4
HCO
2
(55 equiv.),
S
C6
C6
C3
C3
O
O
2
C8
8
C10
C10
2
C
C
2
2
C1
C1
2
8: R = H
9: R = OMe
3
0: R = H, 90%
1: R = OMe, 67%
N1
N1
S1
1
2
3
O2
O2
O1
O1
Scheme 5. Synthesis of substituted cyclic sulfonamides 30 and 31 using the one-pot Heck-hydrogen transfer protocol. Single crystal X-ray structure of iso-propenyl
containing sulfonamide 30 (ellipsoids shown at 50% probability).
gas a 43% yield of 34 has been obtained.6 However, several
attempts to replicate this result with ammonium formate led only
to the formation of traces of 34. The main product for this reaction
proved to be intermediate alkene 33 resulting from a regioselective
intramolecular Heck reaction (Scheme 6).
We reason that the failure of the hydrogenation stems from the
alkene being too sterically encumbered which is evident from the
X-ray crystal structure of 33 (see ESI). This failure, and also the
selectivity encountered with dienes 28 and 29, demonstrates that
sterically hindered alkenes are more difficult to reduce under the
In summary, we have reported that a range of intramolecular
Heck reactions to form cyclic sulfonamides can be telescoped with
a hydrogen transfer reaction upon the addition of ammonium for-
mate. Reactions were performed on scales ranging from 0.1 to 5.5
mmol and employ the same palladium source in two distinct reac-
tions, which typically generate the saturated products in high iso-
lated yields. Additionally, it should be noted that the use of
ammonium formate as the hydrogen source is operationally easy
and avoids the direct use of hydrogen gas and the potential hazards
associated with its use. Further studies, employing these adducts in
our double reduction chemistry, are underway.
reported Pd-NH
4
HCO
2
conditions.
(
1) Pd(OAc)2 (10 mol%),
PPh3 (20 mol%),
K CO , DMF, 110 °C, 15 h MeO
MeO
MeO
Br
MeO
MeO
2
3
H
H
N
N
(
2) NH CHO (55 equiv.),
N
S
4
2
MeO
S
S
O
80 °C, 15 h
O
O
32
2
2
2
33, 91%
6
3
4, trace (43%)
Scheme 6. Attempted synthesis of substituted cyclic sulfonamides 34 using the one-pot Heck-hydrogen transfer protocol (value in parentheses, yield for the corresponding
process conducted with H , see Ref. 6).
2
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4
A. Khalifa et al. / Tetrahedron Letters xxx (2017) xxx–xxx
(
(
(
e) Geoghegan K, Evans P, Rozas I, Alkorta I. Chem Eur J. 2012;18:13379;
f) Geoghegan K, Evans P. J Org Chem. 2013;78:3410;
g) Geoghegan K, Smullen S, Evans P. J Org Chem. 2013;78:10443;
Acknowledgements
We thank the Libyan Government, Department of Cultural
Affairs and Al-Mergib University, Al-Khums, Libya for the provision
of a postgraduate scholarship (AK) and the National University of
Ireland for an NUI Travelling Studentship (KG). We also thank Dr.
Helge Müller-Bunz for X-ray crystallography and Noel Clinton for
the preparation of compound 14.
(h) Keeley A, McCauley S, Evans P. Tetrahedron. 2016;72:2552.
3. For a review on the synthesis of N-heterocycles see: Vo C-VT, Bode JW. J Org
Chem. 2014;79:2809.
4
.
(a) Xu F, Murry JA, Simmons B, et al. Org Lett. 2006;8:3885;
b) . For a recent mesembrine review, see:Krstenansky JLJ. Ethnopharmacology.
2017;195:10;
c) Tamura O, Yanagimachi T, Ishibashi H. Tetrahedron Asymmetry.
003;14:3033.
For review concerning multifunctional catalysts for tandem/telescoped
(
(
2
5
.
.
a
processes see: Felpin F-X, Fouquet E. ChemSusChem. 2008;1:718.
Geoghegan K, Kelleher S, Evans P. J Org Chem. 2011;76:2187. Direct reductive
Heck reactions are only feasible in certain cases due to rapid b-hydride
elimination, which typically precludes interception of the carbopalladated
intermediate.
Supplementary data
6
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2017.10.053.
7.
Weiner H, Zaidman B, Sasson Y. Int J Hydrogen Energy. 1989;14:365;
.
For reviews concerning the use of hydrogen transfer agents including formic
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