Chemoselective hydrogenation reaction of unsaturated bonds in the presence of an o-nitrobenzenesulfonyl group

Article abstract of DOI:10.1021/ol4002448

Chemoselective hydrogenation of unsaturated compounds bearing an o-nitrobenzenesulfonyl (Ns)-amide moiety, affording the corresponding saturated compounds, was accomplished efficiently without loss of the nitro group by using the Pd/MS3A catalyst and a H₂ balloon. Partial hydrogenation of alkynes bearing an Ns group to corresponding cis alkenes was achieved with the combination of the Pd/BN catalyst and an additive (diethylenetriamine or acetic acid).

Full text of DOI:10.1021/ol4002448

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1306–1309
Chemoselective Hydrogenation Reaction
of Unsaturated Bonds in the Presence
of an o‑Nitrobenzenesulfonyl Group
Akinori Kawanishi,† Chiyako Miyamoto,† Yuki Yabe,‡ Makoto Inai,†
Tomohiro Asakawa,† Yoshitaka Hamashima,† Hironao Sajiki,‡ and Toshiyuki Kan*,†
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku,
Shizuoka, 422-8526, Japan, and Laboratory of Organic Chemistry,
Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan
kant@u-shizuoka-ken.ac.jp
Received January 28, 2013
ABSTRACT
Chemoselective hydrogenation of unsaturated compounds bearing an o-nitrobenzenesulfonyl (Ns)-amide moiety, affording the corresponding
saturated compounds, was accomplished efficiently without loss of the nitro group by using the Pd/MS3A catalyst and a H2 balloon. Partial
hydrogenation of alkynes bearing an Ns group to corresponding cis alkenes was achieved with the combination of the Pd/BN catalyst and an
additive (diethylenetriamine or acetic acid).
The development of synthetic methods for the obtention
of nitrogen-containing compounds has attracted much
attention, mainly because these compounds often possess
a variety of interesting biological activities. We have devel-
oped an efficient synthetic methodology for primary and
secondary amine synthesis by employing nitrobenzenesul-
fonamides (Ns-amides).1 This strategy enables selective
preparation of secondary amine synthesis from primary
amines, as shown in Scheme 1.2 In addition, the reactions
of Ns-NH2 and its derivatives, such as N-Boc-Ns-NH and
N-Cbz-Ns-NH, can produce protected primary amines
from the corresponding alcohols via the Mitsunobu reac-
tion (Method A) or from alkyl halides via conventional
alkylation reactions (Method B).3
Furthermore, the high alkylation ability of Ns-amides
permits the efficient construction of macrocyclic amines
without the need for high dilution conditions.1À4 Although
this strategy has great potential, there is a serious limita-
tion: commonly used heterogeneous Pd-catalyzed hydro-
genation conditions cannot be applied, because the nitro
group on the sulfonylbenzene ring, which is essential for
removal of the Ns group via a Meisenheimer complex,1,2
is considered to be highly sensitive to such conditions
(see Table 1, entries 1À5). During our synthetic studies
on natural products, we needed to achieve selective partial
hydrogenation of analkyne in the presenceof anNs group.
Therefore, we set out to develop a suitable reaction for
this purpose, anticipating that such a selective reduction
† University of Shizuoka.
(3) Fukuyama, T.; Cheung, M.; Kan, T. Synlett 1999, 1301.
(4) (a) Fujiwara, A.; Kan, T.; Fukuyama, T. Synlett 2000, 1667.
(b) Kan, T.; Kobayashi, H.; Fukuyama, T. Synlett 2002, 697. (c) Kurosawa,
W.;Kan, T.;Fukuyama, T.J. Am. Chem. Soc. 2003, 125, 8112. (d) Kaburagi,
Y.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2004, 126, 10246.
(e) Kita, Y.; Toma, T.; Kan, T.; Fukuyama, T. Org. Lett. 2008, 10, 3251.
(f) Toma, T.; Kita, Y.; Fukuyama, T. J. Am. Chem. Soc. 2010, 132, 10232.
(g) Iwasaki, K.; Kanno, R.; Morimoto, T.; Yamashita, T.; Yokoshima, S.;
Fukuyama, T. Angew. Chem., Int. Ed. 2012, 51, 9160.
‡ Gifu Pharmaceutical University.
(1) For a review on Ns chemistry: (a) Kan, T.; Fukuyama, T. J. Syn.
Org. Chem., Jpn. 2001, 59, 779. (b) Kan, T.; Fukuyama, T. Chem.
Commun. 2004, 353.
(2) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373. (b) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.;
Kan, T. Tetrahedron Lett. 1997, 38, 5831. (c) Kurosawa, W.; Kan, T.;
Fukuyama, T. Org. Synth. 2002, 79, 186.
r
10.1021/ol4002448
Published on Web 03/01/2013
2013 American Chemical Society

Table 1. Catalytic Activity for the Selective Hydrogenation
Scheme 1. Conversion of Primary Amines to Secondary Amines
via the Ns Strategy
time
(h)
yielda
entry
catalyst (wt %)
(%)
b
1
2
3
4
5
6
7
8
5% Pd/C (10)
1
À
c
5% Lindlar (10)
5% PtO2/C (10)
3
À
c
1
À
c
5% Rh/C (10)
1
À
d
Wilkinson’s cat. (10)
0.5% Pd/MS3A (15)
0.5% Pd/MS3A (25)
0.5% Pd/MS3A (50)
1
À
22
12
2
80
85
86
a Isolated yield. b An inseparable mixture of alkane and reduced
aniline derivative was formed.8 c A reduced aniline derivative was
formed.8 d An inseparable mixture of alkane and alkene was formed.8
reaction would further enhance the synthetic utility of our
Ns-strategy.
Recently, one of the authors (H.S.) has developed
heterogeneous Pd-catalysts,5 such as Pd/MS3A5h,j and
Pd/BN (Pd/boron nitride),5i which are useful for chemo-
selective hydrogenation of unsaturated bonds without
decomposition of various reducible functional groups
including N-Cbz, O-benzyl, nitro, and azide groups.
Therefore, we speculated that such Pd catalysts would be
suitable for the desired selective hydrogenation of unsatu-
rated compounds bearing an Ns group, even though the
nitro group is activated by the neighboring sulfonylamide
group. Herein, we report the chemoselective hydrogena-
tionof unsaturatedbonds linked toanNs-amidemoietyby
using a Pd/MS3A or Pd/BN catalyst system.
To establish appropriate reaction conditions, we exam-
ined the hydrogenation of N-methyl-N-propargyl Ns-
amide (8a), which was readily prepared by the alkylation
reaction of N-methyl Ns-amide (7)3 with propargyl bro-
mide (Table 1). While reactions with 5% Pd/C, Lindlar’s
catalyst6 [Pd/CaCO3 poisoned with Pb(OAc)2], PtO2, 5%
Rh/C, and Wilkinson’s catalyst [RhCl(PPh3)3]7 gave an
inseparable mixture resulting from the undesired reduction
of the nitro group (entries 1À5),8 we found that the
reaction of Ns-amide 8awithH2 (delivered from a balloon)
and Pd/MS3A (15 wt %) in MeOH for 22 h proceeded
smoothly to give the corresponding saturated alkane 9a in
80% yield (entry 3). In this reaction, no appreciable
reduction of the nitro group was observed. Increasing the
amount of Pd/MS3A from 15 to 25 wt % resulted in faster
conversion, affording 9a in 85% yield after 12 h (entry 4).
With 50 wt % of the Pd/MS3A catalyst, the reaction was
completed in only 2 h, and 9a was obtained in 86% yield.
With optimized conditions in hand, we examined the
generality of this reaction using several alkyne or
alkene substrates bearing Ns-amide. As shown in Table 2,
chemoselective conversions to the corresponding alkanes
were accomplished without any loss of the nitro group in
the Ns-amide. This method was applicable to a variety of
terminal alkynes 8aÀ8f (entries 1À6) as well as internal
alkynes 8gÀ8l (entries 7À12), with excellent yields. Fur-
thermore, internal alkenes 8mÀ8o (entries 13À15) were
also reduced cleanly to the corresponding alkanes 9dÀ9f
with 0.5% Pd/MS3A (100 wt %) over 10À15 h in excellent
yields. In these reactions, an acidic Ns-amide proton did
not inhibit the reaction (entries 3, 6, 9, and 12).
(5) (a) Sajiki, H.; Hirota, K. Tetrahedron 1998, 54, 13981. (b) Hattori,
K.; Sajiki, H.; Hirota, K. Tetrahedron 2001, 57, 2109. (c) Ikawa, T.;
Sajiki, H.; Hirota, K. Tetrahedron 2005, 61, 2217. (d) Mori, A.;
Miyakawa, Y.; Ohashi, E.; Haga, T.; Maegawa, T.; Sajiki, H. Org. Lett.
2006, 8, 3279. (e) Sajiki, H.; Mori, S.; Ohkubo, T.; Ikawa, T.; Kume, A.;
Maegawa, T.; Monguchi, Y. Chem.;Eur. J. 2008, 14, 5109. (f) Mori, A.;
Mizusaki, T.; Kawase, M.; Maegawa, T.; Monguchi, Y.; Takao, S.;
Takagi, Y.; Sajiki, H. Adv. Synth. Catal. 2008, 350, 406. (g) Mori, S.;
Ohkubo, T.; Ikawa, T.; Kume, A.; Maegawa, T.; Monguchi, Y.; Sajiki,
H. J. Mol. Catal. A: Chem. 2009, 307, 77. (h) Maegawa, T.; Takahashi,
T.; Yoshimura, M.; Suzuka, H.; Monguchi, Y.; Sajiki, H. Adv. Synth.
Catal. 2009, 351, 2091. (i) Yabe, Y.; Yamada, T.; Nagata, S.; Sawama,
Y.; Monguchi, Y.; Sajiki, H. Adv. Synth. Catal. 2012, 354, 1264.
(j) Takahashi, T.; Yoshimura, M.; Suzuka, H.; Maegawa, T.; Sawama,
Y.; Monguchi, Y.; Sajiki, H. Tetrahedron 2012, 68, 8293.
Notably, removal of the PMB protecting group was not
observed (entries 2, 5, 8, 11, and 14).9
Next, we turned our attention to selective partial hydro-
genation of alkynes bearing Ns-amide to the correspond-
ing cis-alkenes. While Lindlar’s catalyst6 has been the
catalyst of choice for this transformation, the reaction of
nitrobenzene compounds containing alkynes is difficult to
perform without reduction of the nitro group (see also
(6) (a) Lindlar, H. Helv. Chim. Acta 1952, 35, 446. (b) Lindlar, H.;
Dubuis, R. Org. Synth. Coll. Vol. 5, 1973, 880.
(7) (a) Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G.
J. Chem. Soc. A 1966, 1711. (b) Harmon, R. E.; Gupta, S. K.; Brown,
D. J. Chem. Rev. 1973, 73, 21.
(8) Hydrogenation reactions of 8a with these catalysts in other
solvents (n-hexane, THF, EtOAc) were also investigated. For details,
see Supporting Information.
(9) Hydrogenation reactions of N-Boc-N-propargyl Ns-amide and
N-Cbz-N-propargyl Ns-amide were also investigated. However, these
reactions failed to give the desired alkanes. Thus, hydrogenation of
N-Boc-N-propargyl Ns-amide did not occur and the starting material
was recovered. In the case of N-Cbz-N-propargyl Ns-amide, the Cbz
group was removed without hydrogenation of the alkyne.
Org. Lett., Vol. 15, No. 6, 2013
1307

Table 2. Scope of Terminal or Internal Unsaturated Ns-Amides
Table 3. Partial Reduction of Terminal Alkynes Bearing
Ns-Amide
a Isolated yield. b The reaction was carried out using 25 wt % of 0.3%
Pd/BN and 1.0 equiv of DETA. c The reaction was carried out using
20 wt % of 0.3% Pd/BN and 5.0 equiv of AcOH. d The reaction was
carried out using 100 wt % of 0.3% Pd/BN and 5.0 equiv of AcOH. e The
reaction was carried out using 50 wt % of 0.3% Pd/BN and 5.0 equiv of
AcOH in EtOH/THF = 10/1.
a Isolated yield. b The reaction was carried out using 50 wt % of 0.5%
Pd/MS3A. c The reaction was carried out using 100 wt % of 0.5%
Pd/MS3A. d MeOH/THF = 10/1 was used.
Table 1, entry 2).10 However, our previous study indicated
that the target transformation would be possible with the
Pd/BN-diethylenetriamine (DETA) system.5i As shown in
Table 3, the same alkynes used in Table 2 were tested using
Pd/BN-DETA as a catalyst. As we had hoped, selective
reduction of terminal alkynes 8aÀ8f proceeded smoothly,
leaving the nitro group intact, affording 10aÀ10f in ex-
cellent yield. However, reaction of the internal alkynes
8gÀ8l was accompanied by concomitant reduction of
the nitro group under the same reaction conditions.11 To
overcome this problem, we examined the effect of addi-
tives. After numerous attempts, selective partial hydroge-
nation of internal alkynes was finally achieved by changing
the additive from DETA to acetic acid (AcOH). As shown
in entries 7À9, selective reduction of methyl-substituted
alkynes 8gÀ8i was accomplished by using 20 wt % of 0.3%
Pd/BN and 5.0 equiv of AcOH, and the desired cis-alkenes
were obtained in high yields. Even in the case of bulkier
n-propyl-substituted alkynes 8jÀ8l, the partial reduc-
tion proceeded smoothly to provide the corresponding
alkenes 10jÀ10l in excellent yields, albeit with 100 wt %
of catalyst.12 Since the undesired Pd/BN-catalyzed reduc-
tion of nitro groups is assumed to be a result of the Lewis
acidic affinity of Pd metal on Pd/BN for the nitro group,
this result can be rationalized by assuming that addition of
AcOH as a mild acid reduces the affinity, thereby effec-
tively suppressing the reduction of the nitro group.
Finally, we investigated recycling of the Pd-catalyst.
The catalyst was easily recovered by simple filtration and
rinsing with MeOH. As shown in Table 4, Pd/MS3A could
be reused at least three times, generating 9c with similar
chemical yields (85À94%), although the reaction time
tended to become longer as the number of runs was
increased.
In conclusion, we have demonstrated the chemoselective
hydrogenation of unsaturated bonds with Pd/MS3A in
compounds bearing an Ns group, which is sensitive to
reducing conditions. Moreover, partial hydrogenation of
(10) Hydrogenation reactions of 8a with Lindlar’s catalyst in other
solvents (n-hexane, THF, EtOAc) were also investigated. However,
these reactions failed to give 10a. For details, see Supporting
Information.
(11) In this case, selective partial reduction occurred to afford cis
olefin and the saturated product was not formed. However, separation
from aniline derivatives formed by the undesired reduction of the nitro
group was difficult.
(12) Interestingly, Pd/BN-AcOH was not applicable to terminal
alkynes 8aÀ8f. The reaction of these substrates gave the corresponding
alkanes 9aÀ9f. Although the reason for this is not clear, we speculate
that AcOH is a weaker catalyst poison than DETA for more sterically
less accessible terminal alkynes.
1308
Org. Lett., Vol. 15, No. 6, 2013

Considering the utility of the Ns-strategy as well as
alkene-containing compounds, as exemplified by the olefin
metathesis reaction13 and MizorokiÀHeck reaction,14 the
reaction we report here should be a powerful tool for the
synthesis of nitrogen-containing compounds. Further ap-
plications of the present methodology are under intensive
investigation in our laboratory.
Table 4. Recycling of the Pd/MS3A Catalyst
Acknowledgment. The authors thank Professor Tohru
Fukuyama (Graduate School of Pharmaceutical Sciences,
Nagoya University), who developed the Ns-group, for his
encouragement. This work was financially supported by a
Grant-in-Aid for Scientific Research on Priority Areas
12045232 from the Ministry of Education, Culture, Sports,
Science and Technology (MEXT) of Japan.
run
time (h)
yield (%)a
1
2
3
2
3
8
94
89
85
a Isolated yield.
alkynes bearing Ns-amide to the corresponding cis-alkenes
was also achieved by using either Pd/BN-DETA or
Pd/BN-AcOH without loss of the nitro group. To our knowl-
edge, this is the first example of selective hydrogenation of
unsaturated bonds while leaving an Ns group intact.
Supporting Information Available. Experimental pro-
cedures and analytical data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971,
44, 581. (b) Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320.
(c) Heck, R. F. Org. React. 1982, 27, 345. (d) de Meijere, A.; Meyer,
F. E., Jr. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379. (e) Beletskaya,
I. P.; Cheprakov, A. B. Chem. Rev. 2000, 100, 3009. (f) Dounay, A. B.;
Overman, L. E. Chem. Rev. 2003, 103, 2945. (g) Link, J. T. Org. React.
2003, 103, 2945.
€
(13) The recent reviews on olefin metathesis reaction: (a) Furstner,
A. Angew. Chem., Int. Ed. 2000, 39, 3012. (b) Trnka, T. M.; Grubbs,
R. H. Acc. Chem. Res. 2001, 34, 18. (c) Connon, S. J.; Blechert, S. Angew.
Chem., Int. Ed. 2003, 42, 1900. (d) Schrock, R. R.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2003, 42, 4592. (e) McReynolds, M. D.; Dougherty, J. M.;
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2004, 60, 7117. (g) Nicolaou, K. C.; Bulger, P. G.;Sarlah, D.Angew. Chem.,
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The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
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