Efficient synthesis of N-nosyl-protected 3-azabicyclo[4.3.0]nonen-8-one by an aniline- and nitrobenzene-mediated Pauson–Khand cyclization

Article abstract of DOI:10.1080/00397911.2017.1337151

The intramolecular Pauson–Khand cyclization in the presence of both aniline and nitrobenzene was used to improve the construction of N-nitrobenzenesulfonyl-protected 3-azabicyclo[4.3.0]nonane skeletons. We found that aniline enhanced the cyclization and t

Full text of DOI:10.1080/00397911.2017.1337151

Synthetic Communications
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Efficient synthesis of N-nosyl-protected 3-
azabicyclo[4.3.0]nonen-8-one by an aniline- and
nitrobenzene-mediated Pauson–Khand cyclization
Kyosuke Kaneda , Ryuki Taira & Tsubasa Fukuzawa
To cite this article: Kyosuke Kaneda , Ryuki Taira & Tsubasa Fukuzawa (2017): Efficient synthesis
of N-nosyl-protected 3-azabicyclo[4.3.0]nonen-8-one by an aniline- and nitrobenzene-mediated
Pauson–Khand cyclization, Synthetic Communications, DOI: 10.1080/00397911.2017.1337151
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1337151
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Date: 24 July 2017, At: 04:53

SYNTHETIC COMMUNICATIONS®
https://doi.org/10.1080/00397911.2017.1337151
Efficient synthesis of N-nosyl-protected 3-azabicyclo[4.3.0]
nonen-8-one by an aniline- and nitrobenzene-mediated
Pauson–Khand cyclization
Kyosuke Kaneda , Ryuki Taira, and Tsubasa Fukuzawa
Medicinal Chemistry Department, Hokkaido Pharmaceutical University School of Pharmacy, Sapporo,
Hokkaido, Japan
ABSTRACT
ARTICLE HISTORY
Received 9 April 2017
The intramolecular Pauson–Khand cyclization in the presence of both
aniline and nitrobenzene was used to improve the construction
of N-nitrobenzenesulfonyl-protected 3-azabicyclo[4.3.0]nonane
skeletons. We found that aniline enhanced the cyclization and that
nitrobenzene prevents the concurrent reduction in this process. This
combination of mediators allows for the efficient synthesis of
bioactive azabicyclic nonane-type alkaloids and the use of milder
deprotection conditions in the synthetic route.
KEYWORDS
Aromatic amine;
aza-bicyclononane;
nitrobenzenesulfonyl
protecting group;
Pauson–Khand reaction
GRAPHICAL ABSTRACT
Introduction
3-Azabicyclo[4.3.0]nonane, or cyclopenta[c]piperidine, is a common structural motif in
bioactive alkaloids, such as nakadomarin A (1),[1] incarvillateine (2),[2] skytanthine
(3),[3] and tecomanine (4)[4] (Figure 1).
The Pauson–Khand reaction (PKR) is a key step in the synthesis of these alkaloids,[5]
providing a reliable single-step method of assembling the cyclopentenone from an alkene,
an alkyne, and carbon monoxide through a cobalt–carbonyl complex (Scheme 1).[6] For
example, the intramolecular PKR allows effective construction of the bicyclic skeleton of
6 from the corresponding enyne-arylsulfonamide precursor 5. The p-toluenesulfonyl
(Ts) nitrogen-protecting group is commonly used because of its chemical stability and
ease of handling. However, the removal of Ts group requires the use of harsh reaction con-
ditions, which are often problematic.[7] Thus, we used the nitrobenzenesulfonyl (nosyl, Ns)
CONTACT Kyosuke Kaneda
kaneda@hokuyakudai.ac.jp
Hokkaido Pharmaceutical University School of Pharmacy,
7-15-4-1 Maeda, Teine, Sapporo, Hokkaido 0068590, Japan.
Color versions of one or more of the figures in this article can be found online at www.tandfonline.com/lsyc.
Supplemental data (detailed procedures and characterization data, including NMR spectra, for new compounds) can be
accessed on the publisher’s website.
© 2017 Taylor & Francis

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K. KANEDA ET AL.
Figure 1. Bioactive alkaloids containing 3-azabicyclo[4.3.0]nonane skeletons.
group,[8] which is more easily removed through a Meisenheimer complex than Ts in the
PKR.[5c]
We encountered low conversion yields in our attempts to use the PKR to synthesize 8
from the Ns-protected enyne-precursor 7 (Scheme 2) as well as generation of the undesired
aminoarene 9.[5c] In contrast, the enyne-aminoarene 10 could be converted to 9 in 56%
yield under the same reaction conditions. These results indicate that the substituents on
the aromatic ring affected the PKR process.
In 1997, the Sugihara and Yamaguchi group reported that amine additives, in particular
cyclohexylamine, enhance the PKR and proposed a mechanism involving the labilization of
a cobalt–carbonyl complex.[9] However, the effect of intramolecular aromatic amines on
the PKR is unknown. In this communication, we report the results of our investigation
of PKR in the presence of aromatic amino- and nitro-functional groups to improve the
yield of the important compound, N-Ns 3-azabicyclo[4.3.0]nonen-8-one (8).
Results and discussion
The precursors for the PKR were prepared from the corresponding N-propargylic arylsul-
fonamides (11–15)[10] in one or two steps (Scheme 3).
A Mitsunobu reaction[11] using a combination of the arylsulfonamide (11–15), but-3-
en-1-ol, dimethoxyethyl azodicarboxylate,[12] and triphenylphosphine (PPh3) provided
the N-butenylated compounds (7, 16–19) in 63–99% yield. The subsequent reduction of
nitro group was performed using the Fe/NH4Cl/EtOH/H2O protocol[13] to give the
aminoarene products (10, 20–22) in 77–93% yield.
Scheme 1. Construction of azabicyclic framework through PKR. Note: PKR, Pauson–Khand reaction.

SYNTHETIC COMMUNICATIONS®
3
Scheme 2. Preliminary study of PKR. Note: PKR, Pauson–Khand reaction.
The general PKR procedure was as follows: the enyne substrate was dissolved in 1,2-
dichloroethane (DCE) (0.05 mol/L solution) at room temperature under an argon
atmosphere, and dicobalt octacarbonyl [Co2(CO)8] (1.05 equiv.) was added to the solution.
After stirring for 2 h to generate the cobalt–alkyne complex in situ, the mixture was heated
to 60 °C and stirred for 24 h. The reaction mixture was then filtered once and the filtrate
was concentrated under reduced pressure. The residue was purified by silica gel column
chromatography using a mixture of hexane and EtOAc to isolate the bicyclic product.
The results of PKR with the enyne substrates 10, 16, and 20–22 are summarized in Table 1.
N-Butenyl N-propargyl benzenesulfonamide (16) was used as a control to assess the
PKR, resulting in a 57% yield of the bicyclic compound 23 (Table 1, entry 1). The
ortho-amino group in benzenesulfonamide 10 gave 9 in 56% yield under the same con-
dition (Table 1, entry 2). The substrates with amine groups in the meta- and para-positions
gave 24 and 25 in yields of 32 and 34%, respectively (Table 1, entries 3 and 4). In addition,
substrate 22, with ortho- and para-substituted diaminoarene, was converted to 26 in 30%
yield (Table 1, entry 5).
Thus, the substrates with ortho-substituted NH2 groups showed enhanced yields of the
PKR product compared to those substituted in the meta or para positions. We suggest that
an intramolecular coordination of the amino group to the cobalt moiety (TS1) during the
ring formation process (10 to 9 in Scheme 4) could be responsible for these enhanced
yields, in accordance with the previous proposal by Sugihara and Yamaguchi groups.[9]
Scheme 3. Preparation of various enyne-arylsulfonamides.

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K. KANEDA ET AL.
Table 1. PKR of enyne-substrates.
Entry
Substrate
Product yield (%)
=
1
2
3
4
5
16, R H
23 (57)
9 (56)
24 (32)
25 (34)
26 (30)
10, R ¼ o-NH2
20, R ¼ m-NH2
21, R ¼ p-NH2
22, R ¼ o,p-2NH2
PKR, Pauson–Khand reaction.
Scheme 4. Possible mechanism through transition state (TS1).
We next investigated the ability of aniline and its derivatives to exert an intermolecular
effect during the PKR of 16, and the results are summarized in Table 2.
The addition of 1 equiv. of aniline increased the yield of PKR from 57 to 82% (Table 2,
entry 6). We varied the amount of aniline from 0.1 to 10 equiv., which showed that the
addition of excess aniline resulted in further yield improvements, with 10 equiv. providing
an almost quantitative conversion (Table 2, entries 7–9). The addition of N-methylaniline
and N,N-dimethylaniline had no effect on the yield (Table 2, entries 10 and 11). A primary
aromatic amine (aniline) additive provided the greatest yield improvement compared to
secondary or tertiary amines, and adding either a stoichiometric or excess amounts of
the amine each provided an effective yield increase.
Table 2. PKR of 16 with aminoarene additives.
Entry
Additive (equiv.)
Yield of 23 (%)
6
Aniline (1)
82
51
81
96
62
51
7
Aniline (0.1)
8
9
10
11
Aniline (3)
Aniline (10)
N-methylaniline (1)
N,N-dimethylaniline (1)
PKR, Pauson–Khand reaction.

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Table 3. PKR of enyne-nitroarene with the addition of aniline and nitrobenzene.
Entry
Substrate
Additive (equiv.)
Product nitro/amino yields (%)
12
13
14
15
16
17
7, o-NO2
Aniline (1)
8/9 (16/34)
8/9 (21/5)
7, o-NO2
Nitrobenzene (10)
7, o-NO2
Aniline (10) þ nitrobenzene (10)
Aniline (10) þ nitrobenzene (10)
Aniline (10) þ nitrobenzene (10)
Aniline (10) þ nitrobenzene (20)
8/9 (50/8)
17, m-NO2
18, p-NO2
19, o,p-2NO2
27/24 (54/trace)
28/25 (55/trace)
29/26 (43/trace)
PKR, Pauson–Khand reaction.
Finally, the PKR of nitroarene substrates 7 and 17–19 was investigated and the results
are summarized in Table 3.
The PKR of 7 in the presence of 1 equiv. of aniline resulted in the formation of both the
nitro- and amino-bicyclic compounds (8/9), which were obtained in a ∼1:2 ratio (Table 3,
entry 12) with a total yield of 50%. Although the mechanism by which the nitro group is
reduced during the PKR is unclear,[14] the addition of 10 equiv. of nitrobenzene as a
sacrificial reagent was found to prevent the formation of aminoarene 9 (Table 3, entry 13).
Thus, the PKR of 7 in the presence of 10 equiv. of both aniline and nitrobenzene improved
the ratio in which the nitro and amino products were formed (Table 3, entry 14). This
protocol was found to be applicable to a range of other nitroarenes (17–19), which gave
bicyclic nitro products (27–29) in moderate yield (Table 3, entries 15–17).
Conclusion
We investigated the effect of aromatic amine groups on the PKR and found that the use of
a primary aromatic amine as an additive provided increased yield. Furthermore, we found
that the use of an excess of both aniline and nitrobenzene could improve the efficiency of
PKR-based synthesis of N-Ns azabicyclic compound 8. These results allow the syntheses of
bioactive alkaloids and related compounds to be carried out using milder deprotection
conditions. Further optimization of the solvent, concentration, temperature, and reaction
time of the PKR is currently being investigated in our group.
Experimental
Representative procedures and selected characterization data are as follows:
Mitsunobu reaction (11 to 16, Scheme 3)
Dimethoxyethyl azodicarboxylate (95% purity, 456 mg, 1.85 mmol) was added to a mixture
of N-propargyl benzenesulfonamide 11 (300 mg, 1.54 mmol), but-3-en-1-ol (0.15 mL, 1.69
mmol), and PPh3 (485 mg, 1.85 mmol) in anhydrous THF (8 mL) under an argon atmos-
phere at room temperature. After stirring for 24 h at room temperature, the solution was
evaporated under reduced pressure. The residue was dissolved in H2O (8 mL) and Et2O

6
K. KANEDA ET AL.
(8 mL) and the mixture was stirred for 10 min. The Et2O was separated from H2O layer,
washed with brine, and dried with MgSO4. The dried solution was filtered, and the filtrate
was evaporated under reduced pressure. The resulting residue was purified by silica gel col-
umn chromatography by eluting with hexane:EtOAc (3:1) to give 16 (244 mg, 63% yield) as
1
a colorless oil; H NMR (600 MHz, CDCl3) d 7.84 (d, J ¼ 7.6 Hz, 2H), 7.56 (t, J ¼ 7.6 Hz,
1H), 7.49 (dd, J ¼ 7.6, 7.6 Hz, 2H), 5.76 (ddt, J ¼ 6.9, 10.3, 17.2 Hz, 1H), 5.11 (d, J ¼ 17.2 Hz,
1H), 5.06 (d, J ¼ 10.3 Hz, 1H), 4.15 (s, 2H), 3.28 (t, J ¼ 7.6 Hz, 2H), 2.34 (dt, J ¼ 6.9, 7.6 Hz,
2H), 1.99 (s, 1H); 13C NMR (150 MHz, CDCl3) d 139.0, 134.5, 132.8, 128.9, 127.7, 117.4,
76.5, 73.8, 45.8, 36.5, 32.3; IR (neat, cmÀ 1): 3290, 1447, 1348, 1332, 1161; HR-MS (CI):
m/z [M]þ calcd for C13H15NO2S: 249.0823; found, 249.0802.
Reduction of nitroarene (18 to 21, Scheme 3)
Iron powder (95% purity, 2.16 g, 36.7 mmol) was added to a mixture of the nitroarene 18
(1.08 g, 3.67 mmol) and NH4Cl (1.98 g, 36.7 mmol) in EtOH (36.5 mL) and H2O (36.5 mL)
at room temperature. After stirring for 72 h at room temperature, the mixture was filtered
through a celite pad. The organic solvents were removed from the filtrate under reduced
pressure. The remaining H2O layer was extracted with EtOAc (36.5 mL � 2) and the com-
bined EtOAc fractions were washed with brine and dried with MgSO4. The solution was
then filtered and the filtrate was evaporated under reduced pressure. The resulting residue
was purified by silica gel column chromatography by eluting with hexane:EtOAc (3:1) to
1
give 21 (0.88 g, 90% yield) as a white solid; mp 63–65 °C; H NMR (600 MHz, CDCl3) d
7.58 (d, J ¼ 8.9 Hz, 2H), 6.65 (d, J ¼ 8.9 Hz, 2H), 5.75 (ddt, J ¼ 6.9, 10.3, 17.2 Hz, 1H),
5.09 (d, J ¼ 17.2 Hz, 1H), 5.04 (d, J ¼ 10.3 Hz, 1H), 4.12 (br s, 2H), 4.09 (d, J ¼ 2.8 Hz,
2H), 3.22 (t, J ¼ 7.2 Hz, 2H), 2.32 (dt, J ¼ 6.9, 7.2 Hz, 2H), 2.04 (t, J ¼ 2.8 Hz, 1H); 13C
NMR (150 MHz, CDCl3) d 150.7, 134.8, 129.9, 127.1, 117.2, 114.0, 77.0, 73.7, 45.8, 36.4,
32.3; IR (neat, cmÀ 1): 3463, 3369, 3268, 1663, 1596, 1504, 1433, 1336, 1303, 1139, 1122;
HR-MS (CI): m/z [MþH]þ calcd for C13H17N2O2S: 265.1011; found, 265.1009.
Pauson–Khand reaction (7 to 8/9, Table 3, entry 14)
Co2(CO)8 (95% purity, 50.0 mg, 0.125 mmol) was added to a solution of 7 (35.0 mg, 0.119
mmol) in anhydrous 1,2-DCE (2.40 mL) under an argon atmosphere at room temperature.
After stirring for 2 h at room temperature, thin layer chromatography (TLC) analysis
confirmed the generation of a di-cobalt–alkyne complex (Rf ¼ 0.45 in hexane:EtOAc
1:1). Aniline (0.108 mL, 1.19 mmol) and nitrobenzene (0.122 mL, 1.19 mmol) were then
added to the complex and the mixture was heated to 60 °C in an oil bath. After stirring
for 24 h at 60 °C, the mixture was cooled to room temperature and filtered through a celite
pad. The filtrate was added to HCl (1 M, 5 mL) and stirred for 10 min. The organic layer
was separated from the aqueous layer, washed with H2O (5 mL) and brine, and dried with
MgSO4. The solution was then filtered and the solvent was removed from the filtrate under
reduced pressure. The resulting residue was purified by silica gel column chromatography
by eluting with hexane:EtOAc (1:2) to give 9 (2.8 mg, 8% yield) as a pale yellow oil, or with
hexane:EtOAc (0:1) to give 8 (19.3 mg, 50% yield) as a colorless oil.
Compound 8: 1H NMR (600 MHz, CDCl3) d 8.03 (d, J ¼ 7.6 Hz, 1H), 7.76–7.67 (m, 2H),
7.64 (d, J ¼ 7.6 Hz, 1H), 6.03 (s, 1H), 4.79 (d, J ¼ 14.4 Hz, 1H), 4.00 (d, J ¼ 11.7 Hz, 1H),

SYNTHETIC COMMUNICATIONS®
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3.72 (d, J ¼ 14.4 Hz, 1H), 3.03 (ddd, J ¼ 2.1, 12.4, 13.1 Hz, 1H), 2.81–2.73 (m, 1H), 2.62
(dd, J ¼ 6.2, 19.3 Hz, 1H), 2.20–2.13 (m, 1H), 2.04 (d, J ¼ 18.6 Hz, 1H), 1.54–1.45 (m,
1H); 13C NMR (150 MHz, CDCl3) d 207.1, 171.7, 148.2, 134.1, 131.9, 131.8, 131.1, 129.1,
124.4, 47.2, 45.7, 41.5, 39.4, 32.8; IR (thin film, cmÀ 1): 1705, 1633, 1541, 1356, 1163;
HR-MS (EI): m/z [M]þ calcd for C14H14N2O5S: 322.0623; found, 322.0624.
1
Compound 9: H NMR (600 MHz, CDCl3) d 7.58 (d, J ¼ 8.3 Hz, 1H), 7.31 (dd, J ¼ 6.9,
8.3 Hz, 1H), 6.76 (dd, J ¼ 6.9, 8.3 Hz, 1H), 6.72 (d, J ¼ 8.3 Hz, 1H), 5.98 (s, 1H), 5.03 (s,
2H), 4.72 (d, J ¼ 13.8 Hz, 1H), 3.98–3.93 (m, 1H), 3.44 (d, J ¼ 13.8 Hz, 1H), 2.75 (dd, J ¼
12.4, 12.4 Hz, 1H), 2.69–2.63 (m, 1H), 2.58 (dd, J ¼ 6.9, 18.6 Hz, 1H), 2.14–2.07 (m, 1H),
1.99 (d, J ¼ 18.6 Hz, 1H), 1.50–1.42 (m, 1H); 13C NMR (150 MHz, CDCl3) d 207.3, 172.4,
146.4, 134.7, 130.4, 129.1, 117.9, 117.8, 117.6, 47.4, 45.7, 41.5, 39.4, 32.2; IR (thin film,
cmÀ 1): 3475, 3370, 1702, 1618, 1483, 1452, 1322, 1140; HR-MS (CI): m/z [MþH]þ calcd
for C14H17N2O3S: 293.0960; found, 293.0930.
Acknowledgments
We gratefully acknowledge Professor Tsubuki and Dr. Kasai of Hoshi University, Japan, and Mr. Hirose
of Hokkaido University, Japan, for their kind assistance with the mass spectrometry analyses.
ORCID
Kyosuke Kaneda
http://orcid.org/0000-0003-2415-2685
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