Asymmetric synthesis of 2-heteroaryl cyclic amines: Total synthesis of (-)-anabasine

Article abstract of DOI:10.1002/ejoc.201402202

A new and concise method for the synthesis of enantioenriched 2-heteroaryl cyclic amines was developed through an intramolecular chirality transfer. The influence of the nature of both ring size and heteroaryl moiety was investigated. The versatility of this reaction was demonstrated by the enantioselective synthesis of (-)-anabasine. Copyright

Full text of DOI:10.1002/ejoc.201402202

Job/Unit: O42202
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Date: 28-05-14 19:11:56
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FULL PAPER
DOI: 10.1002/ejoc.201402202
Asymmetric Synthesis of 2-Heteroaryl Cyclic Amines: Total Synthesis of
(–)-Anabasine
Romain Sallio,[a] Stéphane Lebrun,[a] Nicolas Gigant,[b] Isabelle Gillaizeau,*[b] and
Eric Deniau*[a]
Keywords: Synthetic methods / Asymmetric synthesis / Chiral auxiliaries / Cross-coupling / Amines
A new and concise method for the synthesis of enantioen-
riched 2-heteroaryl cyclic amines was developed through an
intramolecular chirality transfer. The influence of the nature
of both ring size and heteroaryl moiety was investigated. The
versatility of this reaction was demonstrated by the enantio-
selective synthesis of (–)-anabasine.
Introduction
Simple cyclic amines, namely piperidines and pyrrolid-
ines, have been a target for many synthetic chemists because
these ring systems are a common entity in many alkaloid
natural products. They can also be regarded as privileged
structures owing to their frequent appearance in multifari-
ous bioactive substances.[1] Thus no fewer than 33 pyrroli-
dine or piperidine derivatives were on the list of top 200
prescription drugs in 2010 in the US market.[2] In particu-
lar, simple enantiopure 2-heteroaryl cyclic amines have be-
come attractive scaffolds in medicinal chemistry. They exhi-
bit significant biological activities and have been recently
employed in the design of new pharmacophores with poten-
tial therapeutic applications. Representative examples are
shown in Figure 1. For instance, this scaffold is present in
natural product (–)-anabasine I, which is found in Tree To-
bacco (Nicotiana glauca) and has been reported as a nico-
tinic acetylcholine agonist.[3] In addition, benzimidazole II
is considered as a PARP-1 inhibitor,[4] whereas benzofuran
derivative III displays high affinity for a4b2 nAChR.[5]
Azepane framework IV has been recently reported as a
prophylactic or therapeutic agent against cancer.[6]
Figure 1. Examples of pharmacologically active 2-heteroaryl cyclic
amines.
sponding saturated cyclic amines,[2] asymmetric hydrogen-
ation[8] or allylboration[9] of cyclic imines, addition to pyrid-
inium salts bearing a chiral auxiliary,[10] and catalyzed
asymmetric addition of diethylzinc to imines.[11] Thus, syn-
thesis of enantiopure 2-substituted piperidine derivatives
still constitutes an area of current interest and alternative
methods are currently the object of intensive synthetic en-
deavors. The present study was carried out in connection
with our on-going project on the development of efficient
methodologies to generate original collections of new nitro-
gen-containing molecules.[12]
Existing approaches for synthesizing cyclic amines with
stereogenic centers at the C2 position are generally based
on one of the following processes as the key step: ring-clos-
ing metathesis of disubstituted branches linked to a chiral
amine,[7] asymmetric direct α-functionalization of the corre-
Results and Discussion
Our conceptually new synthetic methodology, which is
depicted in retrosynthetic Scheme 1, is mainly based on the
[a] Université Lille Nord de France, ENSCL, E.A. 4478 Chimie asymmetric reduction of endocyclic enehydrazide 5 and 6
bearing a (S)-methylprolinol chiral auxiliary (SMP).[13]
Moléculaire et Formulation, Cité Scientifique,
59652 Villeneuve d’Ascq Cedex, France
Such precursors can be easily obtained from imide 7 and 8
through a palladium-catalyzed cross-coupling reaction.[14]
The chiral SMP auxiliary has previously been used by En-
ders in the area of hydrazine and hydrazide chemistry and
has proven to be more advantageous than the α-meth-
ylbenzyl group in related systems.[15] Recently, we have also
reported the successful asymmetric reduction of endocyclic
E-mail: Eric.Deniau@univ-lille1.fr
http://www.univ-lille1.fr
[b] Institut de Chimie Organique et Analytique, UMR 7311 CNRS,
Université d’Orléans,
Rue de Chartres, 45067 Orléans Cedex 2, France
E-mail: isabelle.gillaizeau@univ-orleans.fr
http://www.univ-orleans.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402202.
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R. Sallio, S. Lebrun, N. Gigant, I. Gillaizeau, E. Deniau
FULL PAPER
enamides in high yields and good stereoselectivity.[16] Fi-
nally, concomitant reductive N–N bond cleavage and ulti-
mate reduction of the lactam carbonyl functionality (3 and
4) should provide desired chiral cyclic amine 1 and 2.
Scheme 1. Retrosynthesis analysis for the preparation of chiral en-
antioenriched 2-heteroarylated cyclic amines.
The synthetic route, depicted in Scheme 2, required the
preliminary elaboration of chiral imides 7 and 8, which were
easily prepared by condensation of the corresponding cyclic
anhydrides and (S)-aminomethylprolinol.[17] We assumed
that these cyclic imides would possess the appropriate func-
tionality required for the connection of an additional het-
eroaryl unit through a palladium-mediated Suzuki–Mi-
yaura cross-coupling reaction.[18] Since the pioneering work
of Oshima et al.,[19] several groups have used constitution-
ally diverse enol phosphates in a variety of cross-coupling
reactions.[20] Once installation of the stereocontrolling agent
had been achieved, resulting chiral imides 7 and 8 were al-
lowed to react with potassium bis(trimethylsilyl)amide
(KHMDS) in the presence of diphenylchlorophosphate in
Scheme 2. Synthesis of 2-heteroaryl cyclic amines.
Our first attempt, performed with the six-membered ring
THF to give mono vinyl phosphates 9 and 10, which were models linked in C-2 with benzofuran entity 5a, indole de-
used in the next step without further purification. Desired rivative 5b and furan entity 5c, delivered lactam intermedi-
enehydrazides 5 and 6 were obtained in good yields over ates 3a–3c in high yield and good diastereoselectivity
1
two steps by applying traditional Stille or Suzuki–Miyaura (Table 1). The two diastereoisomers were detectable by H
coupling conditions. Stille coupling was performed with the NMR spectrometry. Isomer S was the main isomer ob-
appropriate tin reagents in the presence of catalytic tained, probably because the hydrogen source can preferen-
Pd(PPh3)4 and LiCl in THF at reflux temperatures. The Su- tially attack from the most sterically free face.[16] Most
zuki–Miyaura reaction was achieved by using boronic acids interestingly, the seven-member ring bearing indole and di-
in combination with a catalytic amount of PdCl2(PPh3)2, benzofuran group 6b and 6d afforded reduced compound
aqueous Na2CO3 and some drops of ethanol in THF heated 3b and 3d in good yield as a single pure diastereoisomer.
1
to reflux. With a reliable route to these enehydrazides in No trace of the second isomer was detected by H NMR
hand, studies addressing the enantioselective preparation of spectrometry (deϾ96% after chromatographic treatment),
2-substituted piperidines and azepines 1 and 2 were initi- that demonstrates the high selectivity in the reduction of
ated. For this purpose we first envisaged adopting a pre- unsaturated compounds 6b and 6d. Finally, reductive N–N
viously reported procedure,[21] which consists of treatment bond cleavage with a BH3·THF complex[22] was ac-
of enehydrazides 5 and 6 with trifluoroacetic acid and then complished through the concomitant reduction of the
with triethylsilane in sequence. Unfortunately no significant lactam carbonyl moiety to conclude the synthesis and this
results could be obtained following this procedure. To obvi- operation afforded desired enantioenriched 2-heteroaryl cy-
ate the lack of reactivity of our models toward hydride me- clic amines 1a–1c and 2b and 2d.
diated reductions, we then envisaged reducing the ene-
With this feasible methodology in hand we then turned
hydrazide endocyclic double bond through a catalytic asym- our attention to the total synthesis of exemplary representa-
metric hydrogenation in the presence of Pd/C and ammo- tive natural product (S)-(–)-anabasine 1e, which belongs to
nium formate[16] (Scheme 2).
the large group of piperidine alkaloids containing a 3-pyr-
2
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Asymmetric Synthesis of 2-Heteroaryl Cyclic Amines
Table 1. Yields of intermediates 5, 6 and 3, 4 and of the 2-heteroaryl cyclic amines 1, 2.
[a] Isolated yields after purification by column chromatography. [b] Determined by 1H NMR spectroscopy. [c] Correlated to the value of
corresponding lactams 3 and 4 assuming that the deprotection takes place without detectable racemization.[22]
idyl substituent in the 2-position of the piperidine ring. Al-
though structurally not very complex, only a limited
number of stereocontrolled total syntheses of this natural
product have been reported.[23] According to the previously
described procedure, we first planned to synthesize enehyd-
razide precursor 5e equipped with a pyridin-3-yl unit from
parent chiral imide 7 (Scheme 3).
Scheme 3. Attempts towards the synthesis of chiral enehydrazide 5e.
Somewhat disappointingly, imide 7 was not amenable to
the cross-coupling reaction conditions likely to give access
to required 6-hetarylated compound 5e even after consider-
able experimentation with various catalysts, bases and sol-
vents (Table 2).
Table 2. Conditions for the cross-coupling reaction.
Entry
M
Catalyst
Base or additive Solvent
1
2
3
4
5
B(OH)2
B(OH)2
B(OH)2
B(OH)2
SnBu3
Pd(PPh3)4
Na2CO3
Na2CO3
Cs2CO3
K3PO4
LiCl
THF, H2O
DME, H2O
DMF
dioxane
THF
Scheme 4. Total synthesis of (–)-anabasine.
PdCl2(PPh3)2
PdCl2(PPh3)2
Pd(PPh3)4
Following a procedure reported by Occhiato et al.,[24a]
Pd(PPh3)4
the conversion of vinyl phosphate 9 into the corresponding
One can reasonably assume that this failure is attribut- boronate was first realized by the Pd-catalyzed coupling
able to the lack of reactivity of electron-poor boronic acids with commercial bis(pinacolato)diboron. The best protocol
towards Suzuki–Miyaura and Stille cross-coupling reac- was made use of Pd(PPh3)4 as a catalyst with finely pow-
tions. Consequently, we decided to adopt an alternative dered Ba(OH)2 as base in anhydrous DMF at 90 °C. The
strategy for the installation of the pyridine-3-yl unit de- reaction was complete within 5 h and furnished aminovinyl
picted in Scheme 4, which is based upon an umpolung of boronate 11, which was used without further purification
the phosphate electrophile by α-borylation.[24]
in the next step. Heterocyclic boronate 11 was then success-
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R. Sallio, S. Lebrun, N. Gigant, I. Gillaizeau, E. Deniau
FULL PAPER
pyrrolidine[25] (3.91 g, 0.03 mol) and commercial glutaric anhydride
(3.42 g, 0.03 mol) or adipic anhydride[26] (3.84 g, 0.03 mol).
fully engaged in a Suzuki–Miyaura cross-coupling reaction
to furnish targeted enehydrazide 5e. Catalytic hydrogena-
tion with Pd on C with ammonium formate proceeded
uneventfully to provide an excellent yield of corresponding
cyclic hydrazide (S,S)-3e. NMR spectroscopic investigations
after chromatographic separation indicated the presence of
a single diastereomer, thus confirming the high level of dia-
stereoselectivity observed in the catalytic hydrogenation of
unsaturated compound 5e. Treatment with borane–THF
complex of (S,S)-3e effected reductive N–N bond cleavage
with the concomitant reduction of the lactam carbonyl
group to afford targeted natural product 1e (Scheme 4). The
absolute configuration of the stereogenic center was con-
firmed to be (S) from the sign of the specific rotation of 1e,
and the enantiopurity of our synthetic (S)-(–)-anabasine 1e
was clearly established from the optical rotation and spec-
troscopic data that matched with those reported for the nat-
ural product.[23b]
(S)-1-[2-(Methoxymethyl)pyrrolidin-1-yl]azepane-2,7-dione
Yield 5.62 g, 78% as a colorless oil. Rf = 0.35 (EtOAc/PE, 7:3).
[α]2D0 = –37.3 (c = 1.50, CHCl ). IR (diamond-ATR, neat): ν
(8):
=
max
˜
3
1
1682 (C=O), 1126 (C–O) cm–1. H NMR (300 MHz, CDCl3): δ =
1.51–1.57 (m, 1 H, CH2), 1.66–1.99 (m, 8 H, 4ϫCH2), 2.53–2.65
(m, 4 H, 2ϫCH2), 3.12–3.29 (m, 7 H), 3.58–3.67 (m, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 20.3 (CH2), 20.7 (CH2), 22.6
(CH2), 27.2 (CH2), 35.4 (CH2), 36.1 (CH2), 51.3 (CH2), 58.7
(CH3O), 59.8 (CH), 77.1 (CH2), 174.2 (CO), 176.5 (CO) ppm. MS
(IS): m/z = 241.0 [M + H]+, 263.0 [M + Na]+. HRMS (ESI): calcd.
for C12H21N2O3 [M + H]+ 241.1546; found 214.1542.
General Procedure for the Suzuki–Miyaura Cross-Coupling and the
Preparation of Enehydrazides 5a, 5c and 6d: To a solution of imide
7 and 8 (2 mmol) and diphenylphosphoryl chloride (0.62 mL,
3 mmol) in anhydrous THF (30 mL) cooled to –78 °C and under
nitrogen atmosphere, was added dropwise whilst stirring a solution
of KHMDS (6 mL, 0.5 m in toluene, 3 mmol). After 30 min at
–78 °C, water (20 mL) was added and the resulting mixture was
extracted with Et2O (2ϫ 50 mL) and dried with MgSO4. Evapora-
tion of the solvent under vacuum yielded 9 and 10 as a yellow oil,
which were directly used for the next coupling step.
Conclusions
To a stirred solution of crude 9 and 10 (2 mmol) in THF (20 mL)
maintained under a nitrogen atmosphere, were added 2 m aqueous
Na2CO3 solution (2 mL, 4 mmol), Pd(PPh3)4 (120 mg, 5 mol-%)
and the appropriate aromatic boronic acid (3 mmol). The mixture
was stirred for 2 h at reflux temperatures, and was then diluted with
water (2 mL) and extracted with Et2O (3ϫ 50 mL). The combined
organic layers were dried with MgSO4, concentrated under vacuum
and purified by flash column chromatography with EtOAc/PE as
eluent to afford enhydrazides 5a, 5c and 6d.
In conclusion, a new strategy has been developed and
successfully employed for the asymmetric synthesis of a
variety of 2-heteroaryl cyclic amines. The key step is based
upon the diastereoselective reduction of enehydrazides
equipped with Enders chiral auxiliary. In addition, this pro-
tocol shows great flexibility regarding ring size and het-
eroaryl groups. The utility of our synthetic protocol is illus-
trated by the total synthesis of (S)-(–)-anabasine, an alka-
loid extracted from Nicotiana glauca. The extension of this
approach to other scaffolds is in progress in our laboratory.
(S)-6-(Benzofuran-2-yl)-1-[2-(methoxymethyl)pyrrolidin-1-yl]-3,4-di-
hydropyridin-2(1H)-one (5a): Yield 352 mg, 54% as a yellow oil. Rf
= 0.57 (EtOAc/PE, 3:7). [α]2D0 = –57.2 (c = 0.10, CHCl3). IR (dia-
mond-ATR, neat):
ν
= 2873 (CH), 1682 (C=O), 1452
˜
max
(C=C) cm–1. H NMR (400 MHz, CDCl3): δ = 1.38–1.45 (m, 1 H,
CH2), 1.64–1.72 (m, 1 H, CH2), 1.95–2.01 (m, 1 H, CH2), 2.03–209
(m, 1 H, CH2), 2.31–2.40 (m, 1 H, CH2), 2.45–2.50 (m, 1 H, CH2),
2.53–2.61 (m, 2 H, CH2), 3.12–3.18 (m, 1 H, CH2), 3.14 (s, 3 H,
OCH3), 3.17–3.21 (m, 1 H, CH2), 3.29–3.36 (m, 1 H, CH2), 3.59
(q, J = 8.0 Hz, 1 H, CH2), 3.87 (qt, J = 6.5 Hz, 1 H, CH), 5.88 (q,
J = 3.2 Hz, 1 H, CH=), 6.92 (s, 1 H, ArH), 7.18–7.28 (m, 2 H,
ArH), 7.43 (d, J = 8.1 Hz, 1 H, ArH), 7.56 (d, J = 7.2 Hz, 1 H,
Harom) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.9 (CH2), 23.0
(CH2), 28.0 (CH2), 33.5 (CH2), 51.7 (CH2), 58.9 (OCH3), 60.7
(CH), 76.5 (CH2), 105.4 (CH), 109.4 (CH=), 111.0 (CH), 121.3
(CH), 122.9 (CH), 124.6 (CH), 128.9 (C), 136.9 (C), 151.3 (C),
154.3 (C), 169.4 (CO) ppm. MS (IS): m/z = 327.0 [M + H]+, 349.0
[M + Na]+. HRMS (ESI): calcd. for C19H23N2O3 [M + H]+
327.1702; found 327.1710.
1
Experimental Section
General: The reactions were performed with dried glassware under
an atmosphere of dry argon. Dimethyl sulfoxide was distilled from
molecular sieves (4 Å), CH2Cl2 was dried by heating to reflux over
CaH2 and then distilled, and toluene was distilled from sodium.
Reactions were monitored by thin layer chromatography (TLC) by
using Sorbent Technologies 0–20 mm silica gel 60 Å plates. TLC
spots were viewed under ultraviolet light and by heating the plate
after treatment with an appropriate revelatory agent (KMnO4,
phosphomolybdic acid). Purifications by column chromatography
were performed with Sorbent Technologies 32–63 μm silica gel
(60 Å). NMR Spectra were recorded with a Bruker AM 300 MHz
or 400 MHz spectrometers. Chemical shifts are given in ppm (δ)
and referenced to the internal solvent signal or to tetramethylsilane
used as an internal standard. Multiplicities are declared as follows:
s (singlet), br. s (broad singlet), d (doublet), t (triplet), quint (quin-
tuplet), sept (septet), dd (doublet of doublet), ddd (doublet of
doublet of doublet), dt (doublet of triplet), ABq (ABq system), m
(multiplet). IR absorption spectra were obtained with a Nicolet 380
FTIR. Optical rotations were recorded with a Perkin–Elmer 343.
Melting points were obtained with a Reichert-Thermopan appara-
tus. HRMS were recorded with a Maxis Bruker 4G instrument.
(S)-6-(Furan-2-yl)-1-[2-(methoxymethyl)pyrrolidin-1-yl]-3,4-dihy-
dropyridin-2(1H)-one (5c): Yield 270 mg, 49% as a colorless oil. Rf
= 0.73 (EtOAc/PE, 5:5). [α]2D0 = –59.7 (c = 1.81, CHCl3). IR (dia-
mond-ATR, neat): ν
= 2970 (CH), 2885 (CH), 1666 (C=O),
˜
max
1465 (C=C), 1087 (C–O) cm–1. H NMR (300 MHz, CDCl3): δ =
1.41–1.51 (m, 1 H, CH2), 1.61–1.74 (m, 1 H, CH2), 1.90–2.14 (m,
2 H, CH2), 2.20–2.31 (m, 1 H, CH2), 2.36–2.59 (m, 3 H, CH2),
3.06–3.20 (m, 6 H), 3.50–3.58 (q, J = 8 Hz, 1 H), 3.79–3.87 (m, 1
H), 5.61–5.64 (m, 1 H, CH=), 6.36–6.38 (m, 1 H, ArH), 6.52–6.53
(m, 1 H, ArH), 7.36 (m, 1 H, ArH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 19.5 (CH2), 22.8 (CH2), 27.8 (CH2), 33.3 (CH2), 51.3
1
General Procedure for the Preparation of Cyclic Hydrazimides 7 and
8: Cyclic hydrazimides 7 and 8 were prepared according to a re-
ported procedure[16] starting from (S)-1-Amino-2-(methoxymethyl)-
4
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Asymmetric Synthesis of 2-Heteroaryl Cyclic Amines
(CH2), 58.7 (CH3O), 60.3 (CH), 76.2 (CH2), 106.7 (CH), 108.8 were added LiCl (255 mg, 6 mmol), Pd(PPh3)4 (114 mg, 5 mol-%)
(CH), 110.8 (CH), 136.6 (C), 141.5 (CH), 149.0 (C), 169.5 and tributyl(5-methoxy-1H-indol-2-yl)tin (1.31 g, 3 mmol). The
(CO) ppm. MS (IS): m/z = 277.0 [M + H]+, 299.0 [M + Na]+.
HRMS (ESI): calcd. for C15H21N2O3 [M + H]+ 277.1546; found
277.1545.
mixture was stirred for 16 h at reflux temperatures, and then it was
diluted with water (2 mL) and extracted with EtOAc (3ϫ 40 mL).
The combined organic layers were dried with MgSO4, concentrated
under vacuum and purified by flash column chromatography with
EtOAc/PE (3:7) as eluent to afford enhydrazide 5b and 6b.
(S)-7-(Dibenzo[b,d]furan-4-yl)-1-[2-(methoxymethyl)pyrrolidin-1-yl]-
1,3,4,5-tetrahydroazepin-2-one (6d): Yield 562 mg, 72% as a yellow
oil. Rf = 0.41 (EtOAc/PE, 3:7). [α]2D0 = –76.6 (c = 1.84, CHCl3). IR
(S)-6-(5-Methoxy-1H-indol-2-yl)-1-[(2-methoxymethyl)pyrrolidin-1-
yl]-3,4-dihydro-1H-pyridin-2-one (5b): Yield 405 mg, 57% as a col-
orless oil. Rf = 0.23 (EtOAc/PE, 3:7). [α]2D0 = –27.9 (c = 0.10,
(diamond-ATR, neat): ν
= 2868 (CH), 1673 (C=O), 1454
˜
max
1
(C=C), 1108 (C–O) cm–1. H NMR (300 MHz, CDCl3): δ = 1.33–
1.44 (m, 2 H, CH2), 1.81–1.89 (m, 1 H, CH2), 2.05–2.17 (m, 2 H,
CH2), 2.26–2.65 (m, 5 H, CH2), 2.74–2.92 (m, 2 H), 3.11–3.15 (m,
4 H), 3.41–3.49 (m, 1 H), 3.84 (br. s, 1 H), 6.02 (t, J = 7.5 Hz, 1
H, CH=), 7.30–7.47 (m, 4 H, ArH), 7.54–7.56 (m, 1 H, ArH), 7.87–
7.95 (m, 2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.5
(CH2), 24.1 (CH2), 28.7 (CH2), 30.8 (CH2), 34.8 (CH2), 51.7 (CH2),
58.8 (CH3O), 62.4 (CH), 76.0 (CH2), 111.8 (CH), 120.1 (CH), 120.7
(CH), 121.4 (CH), 122.6 (CH), 122.9 (CH), 123.1 (C), 124.1 (C),
124.4 (C), 127.2 (CH), 127.3 (CH), 141.5 (C), 153.5 (C), 155.9 (C),
174.2 (CO) ppm. MS (IS): m/z = 391.0 [M + H]+, 413.0 [M +
Na]+. HRMS (ESI): calcd. for C24H27N2O3 [M + H]+ 391.2015;
found 391.2009.
CHCl ). IR (diamond-ATR, neat): ν
= 3295 (NH), 2941 (CH),
˜
3
max
2876 (CH), 1680 (C=O), 1486 (C=C) cm–1. 1H NMR (400 MHz,
CDCl3): δ = 1.65–1.71 (m, 1 H, CH2), 1.79–1.94 (m, 2 H, CH2),
2.12–2.18 (m, 1 H, CH2), 2.28–2.39 (m, 2 H, CH2), 2.59–2.68 (m,
2 H, CH2), 2.82 (td, J = 7.4, 4.0 Hz, 1 H, CH2), 3.33 (q, J = 8.0 Hz,
1 H, CH), 3.39 (dd, J = 10.1, 3.2 Hz, 1 H, CH), 3.44 (s, 3 H,
OCH3), 3.55 (dd, J = 10.0, 2.3 Hz, 1 H, CH2), 3.85 (s, 3 H, OCH3),
4.07–4.12 (m, 1 H, CH), 5.63 (q, J = 3.8 Hz, 1 H, CH=), 6.51 (d,
J = 1.5 Hz, 1 H, ArH), 6.83 (dd, J = 8.8, 2.4 Hz, 1 H, ArH), 7.04
(d, J = 2.2 Hz, 1 H, ArH), 7.22 (d, J = 8.8 Hz, 1 H, ArH), 10.9
(br. s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.3
(CH2), 23.7 (CH2), 26.9 (CH2), 33.6 (CH2), 51.7 (CH2), 56.1
(OCH3), 58.9 (OCH3), 60.5 (CH), 74.0 (CH2), 101.8 (CH), 102.1
(CH), 108.8 (CH=), 112.0 (CH), 112.7 (CH), 127.8 (C), 132.1 (C),
134.2 (C), 137.0 (C), 154.2 (C), 170.0 (CO) ppm. MS (IS): m/z =
356.0 [M + H]+. HRMS (ESI): calcd. for C20H26N3O3 [M + H]+
356.1965; found 356.1971.
General Procedure for the Stille Cross-Coupling and the Preparation
of Enhydrazides 5b, 6b: Synthesis of the organic tin compound [tri-
butyl(5-methoxy-1H-indol-2-yl)tin]: To a solution of 5-methoxy-
1H-indole (12.20 g, 83.0 mmol) in dry THF (30 mL) at –78 °C was
added nBuLi (1.6 m, 56.9 mL, 91.0 mmol) over a 15 min period.
The reaction mixture was warmed to room temperature, stirred for
1 h and then re-cooled to –78 °C. Benzenesulfonyl chloride
(11.6 mL, 91.0 mmol) was added and the reaction mixture was
warmed to room temperature and stirred for 16 h. Saturated so-
dium hydrogen carbonate solution (50 mL) was added and the mix-
ture extracted with diethyl ether (2ϫ50 mL). The combined or-
ganic extracts were washed with brine (2ϫ50 mL), dried (MgSO4),
and concentrated in vacuo. Crystallization from hexane/Et2O (2:1)
afforded 5-methoxy-(1-phenylsulfonyl)-1H-indole (19.06 g, 80%).
(S)-7-(5-Methoxy-1H-indol-2-yl)-1-[2-(methoxymethyl)pyrrolidin-1-
yl]-1,3,4,5-tetrahydroazepin-2-one (6b): Yield 494 mg, 67 % as a
brown film. Rf = 0.27 (EtOAc/PE, 3:7). [α]2D0 = –39.1 (c = 0.10,
CHCl ). IR (diamond-ATR, neat): ν
= 3303 (NH), 2946 (CH),
˜
3
max
1
2866 (CH), 1670 (C=O), 1450 (C=C), 1113 (C–O) cm–1. H NMR
(400 MHz, CDCl3): δ = 1.52–1.59 (m, 1 H, CH2), 1.67–1.75 (m, 1
H, CH2), 1.90–1.97 (m, 1 H, CH2), 2.08–2.15 (m, 1 H, CH2), 2.18–
2.26 (m, 2 H, CH2), 2.31–2.36 (m, 2 H, CH2), 2.46–2.55 (m, 2 H,
CH2), 3.13–3.20 (m, 1 H, CH2), 3.32–3.41 (m, 6 H, CH, CH2 and
OCH3), 3.85 (s, 3 H, OCH3), 4.22 (br., 1 H, CH), 6.14 (t, J =
7.7 Hz, 1 H, CH=), 6.55 (s, 1 H, ArH), 6.82 (dd, J = 8.8, 2.4 Hz,
1 H, ArH), 7.05 (s, 1 H, ArH), 7.23 (d, J = 8.8 Hz, 1 H, ArH),
10.01 (s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.0
(CH2), 24.2 (CH2), 27.8 (CH2), 30.1 (CH2), 34.9 (CH2), 52.1 (CH2),
56.1 (OCH3), 59.0 (OCH3), 60.2 (CH), 76.0 (CH2), 100.4 (CH),
102.0 (CH), 112.0 (CH), 112.5 (CH), 120.5 (CH=), 128.6 (CH),
130.1 (CH), 131.6 (CH), 136.4 (CH), 154.4 (CH), 175.4 (CO) ppm.
MS (IS): m/z = 370.0 [M + H]+. HRMS (ESI): calcd. for
C21H28N3O3 [M + H]+ 370.2121; found 370.2119.
To a solution of 5-methoxy-(1-phenylsulfonyl)-1H-indole (6.14 g,
21.4 mmol) in dry THF (10 mL) at –78 °C was added a solution of
lithium diisopropylamide in THF/hexanes (1.0 m, 22.5 mL,
22.5 mmol). The reaction mixture was stirred at –78 °C for 30 min,
then at 0 °C for 30 min, then re-cooled to –78 °C. Tri-n-butyltin
chloride (5.79 mL, 21.4 mmol) was added and the reaction mixture
stirred at –78 °C for 1 h, then at 0 °C for 1 h. Saturated ammonium
chloride solution (20 mL) was added and the mixture extracted
with diethyl ether (3ϫ15 mL). The combined organic extracts were
washed with water (2ϫ20 mL), dried (MgSO4), and concentrated
in vacuo. Column chromatography (EtOAc/PE, 1:99) yielded 2-
tri-n-butylstannyl-5-methoxy-(1-phenylsulfonyl)-1H-indole (5.30 g,
43%) as a colorless oil.
General Procedure for the Preparation of Cyclic Hydrazides 3 and
4: A suspension of compound 5 and 6 (0.5 mmol) in MeOH
(10 mL) was stirred with activated Pd/C (10%, 20 mg) and a solu-
tion of HCO2NH4 (315 mg, 5 mmol) in distilled water (2 mL) was
then added. The reaction mixture was heated to reflux for 4 h, fil-
tered through CeliteTM and diluted with water. Extraction with
CH2Cl2 (3ϫ 20 mL), drying over MgSO4 and concentration under
vacuum left an oily product, which was purified by chromatography
on silica gel with EtOAc/EP (6:4) as eluent to give 3 and 4.
2-Tri-n-butylstannyl-5-methoxy-(1-phenylsulfonyl)-1H-indole
(4.00 g, 6.94 mmol) was dissolved in a mixture of dry THF (30 mL)
and dry MeOH (30 mL) under argon at –30 °C. To this solution
was added disodium hydrogen phosphate (2.16 g, 15.26 mmol) fol-
lowed by Na(Hg) amalgam (5–6%; 3.40 g, 15.26 mmol) and the
resulting mixture was stirred 2 h at 0 °C before filtration through
Celite. After addition of water, the aqueous layer was extracted
with EtOAc and the combined organic extracts were washed with
brine, dried with MgSO4, filtered and concentrated. The tributyl(5-
methoxy-1H-indol-2-yl)tin (yellow oil, 2.21 g, 73%) was used for
the next step without further purification.
(S)-6-(Benzofuran-2-yl)-1-[(S)-2-(methoxymethyl)pyrrolidin-1-yl]-
piperidin-2-one (3a): Yield 144 mg, 88% as a colorless oil. Rf = 0.23
(EtOAc/PE, 5:5). [α]2D0 = –83.4 (c = 0.10, CHCl3). IR (diamond-
ATR, neat): ν
= 2949 (CH), 2872 (CH), 1651 (C=O), 1453
˜
max
(C=C), 1011 (C–O) cm–1. H NMR (400 MHz, CDCl3): δ = 1.53–
1.58 (m, 1 H, CH2), 1.65–1.90 (m, 3 H, CH and CH2), 2.01–2.08
(m, 1 H, CH2), 2.15–2.25 (m, 3 H, CH and CH2), 2.40–2.64 (m, 4
1
To a stirred solution of crude vinyl phosphates 9 and 10 (2 mmol)
in anhydrous THF (40 mL) maintained under nitrogen atmosphere,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O42202
/KAP1
Date: 28-05-14 19:11:56
Pages: 9
R. Sallio, S. Lebrun, N. Gigant, I. Gillaizeau, E. Deniau
FULL PAPER
H, 2ϫCH2), 2.77 (br. s, 3 H, OCH3), 3.16–3.24 (m, 2 H, CH2), 3.70
(br., 1 H, CH), 4.83 (t, J = 4.3 Hz, 1 H, CH), 6.62 (s, 1 H, CH), 1-yl]azepan-2-one (4d): Yield 168 mg, 86% as a colorless oil. Rf =
7.20–7.27 (m, 2 H, ArH), 7.46 (d, J = 8.0 Hz, 1 H, ArH), 7.54 (d,
0.25 (EtOAc/PE, 5:5). [α]2D0 = –24.6 (c = 1.49, CHCl3). IR (dia-
J = 7.0 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = mond-ATR, neat): ν
= 2970 (CH), 2901 (CH), 1651 (C=O),
(S)-7-(Dibenzo[b,d]furan-4-yl)-1-[(S)-2-(methoxymethyl)pyrrolidin-
˜
max
1
18.2 (CH2), 23.2 (CH2), 27.8 (CH2), 29.9 (CH2), 33.9 (CH2), 51.0
(CH2), 58.6 (OCH3), 60.1 (CH), 60.7 (CH), 75.5 (CH2), 104.9 (CH), 1.34–1.59 (m, 3 H, CH2), 1.65–1.90 (m, 4 H, CH2), 2.01–2.10 (m,
1404 (C=C), 1057 (C–O) cm–1. H NMR (300 MHz, CDCl3): δ =
111.4 (CH), 121.0 (CH), 123.1 (CH), 124.3 (CH), 128.3 (C), 154.7
(C), 157.8 (C), 169.7 (CO) ppm. MS (IS): m/z = 329.0 [M + H]+,
351.0 [M + Na]+. HRMS (ESI): calcd. for C19H25N2O3 [M + H]+
329.1859; found 329.1851.
1 H, CH2), 2.23–2.32 (m, 1 H, CH2), 2.60–2.64 (m, 2 H, CH2),
2.77–2.81 (m, 1 H), 2.92–3.04 (m, 3 H), 3.23 (s, 3 H, OCH3), 3.58–
3.61 (m, 1 H), 3.86 (br. s, 1 H), 5.52–5.56 (m, 1 H, NCH), 7.31–
7.39 (m, 3 H, ArH), 7.44–7.50 (t, J = 9 Hz, 1 H, ArH), 7.57–7.60
(d, J = 9 Hz, 1 H, ArH), 7.87–7.90 (d, J = 9 Hz, 1 H, ArH), 7.95–
7.98 (d, J = 9 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ
= 22.9 (CH2), 23.3 (CH2), 25.0 (CH2), 27.3 (CH2), 32.1 (CH2), 37.4
(CH2), 51.5 (CH2), 58.9 (CH3O), 60.8 (CH), 65.8 (CH), 76.4 (CH2),
111.7 (CH), 119.5 (CH), 120.7 (CH), 122.6 (CH), 122.9 (CH), 124.1
(C), 124.4 (C), 125.2 (C), 125.9 (CH), 127.2 (CH), 153.2 (C), 155.9
(C), 174.1 (CO) ppm. MS (IS): m/z = 393.0 [M + H]+, 414.0 [M +
Na]+. HRMS (ESI): calcd. for C24H29N2O3 [M + H]+ 393.2172;
found 393.2169.
(S)-7-(5-Methoxy-1H-indol-2-yl)-1-[(S)-2-(methoxymethyl)pyrrol-
idin-1-yl]azepan-2-one (3b): Yield 168 mg, 94% as a yellow oil. Rf
= 0.28 (EtOAc/PE, 9:1). [α]2D0 = –38.1 (c = 0.10, CHCl3). IR (dia-
mond-ATR, neat): ν
= 3270 (NH), 2929 (CH), 1629 (C=O),
˜
max
1
1442 (C=C), 1089 (C–O) cm–1. H NMR (250 MHz, CDCl3): δ =
1.43–1.50 (m, 1 H, CH2), 1.65–2.01 (m, 4 H, 2ϫCH2), 2.09–2.18
(m, 2 H, 2ϫCH), 2.23–2.29 (m, 1 H, CH2), 2.34–2.50 (m, 2 H, H3),
2.86–2.98 (m, 1 H, CH2), 3.01 (dd, J = 10.0, 4.0 Hz, 1 H, CH2),
3.22 (s, 3 H, OCH3), 3.26–2.35 (m, 2 H, CH2), 3.84 (s, 3 H, OCH3),
4.10–4.15 (m, 1 H, CH), 4.88 (t, J = 5.0 Hz, 1 H, CH), 6.31 (s, 1
H, ArH), 6.81 (dd, J = 8.7, 2.3 Hz, 1 H, Harom), 7.04 (d, J = 2.2 Hz,
1 H, ArH), 7.23 (d, J = 8.8 Hz, 1 H, ArH), 9.57 (br. s, 1 H,
NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.6 (CH2), 23.3
(CH2), 27.5 (CH2), 30.7 (CH2), 33.9 (CH2), 51.4 (CH2), 56.1
(OCH3), 59.0 (OCH3), 59.5 (CH), 60.0 (CH), 76.4 (CH2), 99.9
(CH), 102.2 (CH), 111.9 (CH), 112.0 (CH), 128.9 (C), 131.5 (C),
140.4 (C), 154.3 (C), 171.0 (CO) ppm. MS (IS): m/z = 358.0 [M +
H]+, 380.0 [M + Na]+. HRMS (ESI): calcd. for C20H28N3O3 [M +
H]+ 358.2121; found 358.2125.
General Procedure for Synthesis of Heteroaryl Cyclic Amines 1 and
2: A solution of borane–THF complex (1.0 m solution in THF,
5 mL, 5 mmol) was added at 0 °C to a stirred solution of 3 and 4
(0.25 mmol) in THF (10 mL). The solution was stirred at room
temperature for 15 min and then heated to reflux for 24 h. After
the mixture was cooled in an ice-bath, 10% aqueous NaOH
(10 mL) was added and the mixture was briefly stirred (5 min). The
mixture was extracted with Et2O (3ϫ10 mL). The combined ex-
tracts were washed with brine, dried with MgSO4 and concentrated
under reduced pressure. The crude residue was purified by flash
column chromatography on silica gel (acetone/MeOH, 9:1) to give
1 and 2.
(S)-6-(Furan-2-yl)-1-[(S)-2-(methoxymethyl)pyrrolidin-1-yl]piper-
idin-2-one (3c): Yield 118 mg, 85% as a colorless oil. Rf = 0.35
(EtOAc/PE, 5:5). [α]2D0 = –36.2 (c = 1.59, CHCl3). IR (diamond-
(S)-2-(Benzofuran-2-yl)piperidine (1a): Yield 40 mg, 80% as a yel-
low film. Rf = 0.18 (acetone/MeOH, 9:1). [α]2D0 = –22.2 (c = 0.51,
ATR, neat): ν
= 2962 (CH), 2877 (CH), 1651 (C=O), 1396
˜
max
CHCl ). IR (diamond-ATR, neat): ν
= 3301 (NH), 2929 (CH),
1
˜
(C=C), 1111 (C–O) cm–1. H NMR (300 MHz, CDCl3): δ = 1.47–
1.65 (m, 3 H, CH2), 1.70–1.82 (m, 1 H, CH2), 1.87–2.01 (m, 3 H,
CH2), 2.06–2.12 (m, 1 H, CH2), 2.27–2.52 (m, 4 H, CH2), 3.04–
3.11 (m, 5 H), 3.57–3.68 (m, 1 H), 4.60–4.63 (t, J = 4.5 Hz, 1 H,
NCH), 6.14–6.18 (m, 1 H, ArH), 6.28–6.30 (m, 1 H, ArH), 7.32–
7.40 (m, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.9
(CH2), 23.3 (CH2), 27.7 (CH2), 29.9 (CH2), 33.6 (CH2), 50.7 (CH2),
58.3 (CH3O), 59.6 (CH), 60.5 (CH), 75.3 (CH2), 107.8 (CH), 110.1
(CH), 141.7 (CH), 154.8 (C), 169.2 (CO) ppm. MS (IS): m/z = 279.0
[M + H]+, 301.0 [M + Na]+. HRMS (ESI): calcd. for C15H23N2O3
[M + H]+ 279.1702; found 279.1695.
3
max
2854 (CH), 1554 (C=C), 1253 (C–O) cm–1. 1H NMR (250 MHz,
CDCl3): δ = 1.67–2.16 (m, 5 H, 2ϫCH2 and NH), 2.33–2.40 (m, 2
H, CH2), 2.82 (t, J = 10.4 Hz, 1 H, CH2), 3.19 (d, J = 11.6 Hz, 1
H, CH2), 3.91 (d, J = 8.1 Hz, 1 H, CH), 6.57 (s, 1 H, ArH), 7.18–
7.23 (m, 2 H, ArH), 7.44–7.49 (m, 1 H, ArH), 7.52–7.58 (m, 1 H,
ArH) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 24.4 (CH2), 26.0
(CH2), 31.1 (CH2), 46.9 (CH2), 55.1 (CH), 101.8 (CH), 111.3 (CH),
121.0 (CH), 122.8 (CH), 123.9 (CH), 128.5 (C), 154.8 (C), 160.2
(C) ppm. MS (IS): m/z = 202.0 [M + H]+. HRMS (ESI): calcd. for
C13H16NO [M + H]+ 202.1229; found 202.1236.
(S)-5-Methoxy-2-piperidin-2-yl-1H-indole (1b): Yield 50 mg, 87% as
a yellow oil. Rf = 0.11 (acetone/MeOH, 9:1). [α]2D0 = –9.5 (c = 0.10,
(S)-7-(5-Methoxy-1H-indol-2-yl)-1-[(S)-2-(methoxymethyl)pyrrol-
idin-1-yl]azepan-2-one (4b): Yield 156 mg, 84% as a brown solid,
m.p. 89–91 °C. Rf = 0.54 (EtOAc/PE, 6:4). [α]2D0 = –42.9 (c = 0.11,
CHCl ). IR (diamond-ATR, neat): ν
= 3234 (NH), 2929 (CH),
˜
3
max
1
1589 (C=C), 1487 (C=C), 1454 (C=C) cm–1. H NMR (400 MHz,
CDCl3): δ = 1.47–1.65 (m, 4 H, CH, CH2 and NH), 1.91–2.08 (m,
3 H, CH and CH2), 2.69–2.75 (m, 1 H, CH2), 2.97–3.06 (m, 1 H,
CH2), 3.81 (s, 3 H, OCH3), 4.00 (d, J = 10.2 Hz, 1 H, CH), 6.33
(s, 1 H, ArH), 6.81 (dd, J = 8.8, 2.4 Hz, 1 H, ArH), 6.96 (d, J =
1.8 Hz, 1 H, ArH), 7.22 (d, J = 8.8 Hz, 1 H, ArH), 6.65 (br. s, 1
H, NH) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 23.3 (CH2), 23.8
(CH2), 29.9 (CH2), 45.5 (CH2), 54.7 (CH), 56.6 (OCH3), 100.9
(CH), 102.4 (CH), 112.2 (CH), 112.9 (CH), 128.2 (C), 131.6 (C),
137.3 (C), 154.4 (C) ppm. MS (IS): m/z = 231.0 [M + H]+. HRMS
(ESI): calcd. for C14H19N2O [M + H]+ 231.1491; found 231.1492.
CHCl ). IR (diamond-ATR, neat): ν
= 3270 (NH), 2929 (CH),
˜
3
max
1
1629 (C=O), 1442 (C=C), 1089 (C–O) cm–1. H NMR (250 MHz,
CDCl3): δ = 1.34–1.96 (m, 11 H, CH and 5ϫCH2), 2.46–2.55 (m,
1 H, CH2), 3.07 (td, J = 7.6, 2.8 Hz, 1 H, CH2), 3.31–3.45 (m, 2
H, 2ϫCH), 3.51–3.60 (m, 4 H, CH2 and OCH3), 3.79 (s, 3 H,
OCH3), 4.20–4.28 (m, 1 H, CH), 5.16–5.25 (m, 1 H, CH), 6.28 (s,
1 H, ArH), 6.84 (dd, J = 8.7, 2.5 Hz, 1 H, ArH), 7.06 (d, J =
2.4 Hz, 1 H, ArH), 7.24 (d, J = 2.8 Hz, 1 H, ArH), 10.38 (s, 1 H,
NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.8 (CH2), 23.8
(CH2), 25.2 (CH2), 27.4 (CH2), 31.5 (CH2), 37.0 (CH2), 53.1 (CH2),
56.1 (OCH3), 58.9 (OCH3), 60.5 (CH), 63.6 (CH), 78.3 (CH2), 99.9
(CH), 102.2 (CH), 111.7 (CH), 111.8 (CH), 128.9 (C), 131.9 (C), (S)-2-(Furan-2-yl)piperidine (1c): Yield 26 mg, 69% as a colorless
138.4 (C), 154.1 (C), 175.0 (CO) ppm. MS (IS): m/z = 372.0 [M +
H]+, 394.0 [M + Na]+. HRMS (ESI): calcd. for C21H29N3O3 [M +
H]+ 372.2278; found 372.2286.
oil. Rf = 0.2 (acetone/MeOH, 9:1). [α]2D0 = –4.1 (c = 0.73, CHCl3).
IR (diamond-ATR, neat): ν = 3302 (NH), 2970 (CH), 2903
˜
max
(CH), 1396 (C=C) cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.45–
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42202
/KAP1
Date: 28-05-14 19:11:56
Pages: 9
Asymmetric Synthesis of 2-Heteroaryl Cyclic Amines
1.95 (m, 6 H, CH2), 2.78–2.86 (m, 1 H, CH2), 3.17–3.24 (m, 1 H,
CHCl ). IR (diamond-ATR, neat): νmax = 2890 (CH), 1674 (C=O),
˜
3
1
CH2), 3.89–3.94 (m, 1 H, NCH), 3.97 (br. s, 1 H, NH), 6.28–6.35 1350 (C=C), 1103 (C–O) cm–1. H NMR (300 MHz, CDCl3): δ =
(m, 2 H, ArH), 7.35–7.40 (m, 1 H, ArH) ppm. 13C NMR (75 MHz,
1.21–1.31 (m, 1 H, CH2), 1.46–1.57 (m, 1 H, CH2), 1.90–2.05 (m,
CDCl3): δ = 23.6 (CH2), 24.5 (CH2), 29.6 (CH2), 45.8 (CH2), 53.9 2 H, CH2), 2.24–2.73 (m, 4 H, CH2), 2.87–3.05 (m, 3 H), 3.18 (s,
(CH), 106.1 (CH), 110.3 (CH), 141.9 (CH), 154.7 (C) ppm. HRMS 3 H), 3.48–3.55 (q, J = 7 Hz, 1 H), 3.76–3.84 (m, 1 H), 5.22–5.25
(ESI): calcd. for C9H14NO [M + H]+ 152.1072; found 152.1069.
(m, 1 H, CH=), 7.24–7.28 (m, 1 H, ArH), 7.60–7.64 (m, 1 H, ArH),
8.52–8.55 (m, 2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ =
19.8 (CH2), 22.9 (CH2), 27.9 (CH2), 33.8 (CH2), 52.1 (CH2), 58.7
(CH3O), 60.7 (CH), 76.0 (CH2), 108.4 (CH), 122.3 (CH), 133.2 (C),
135.3 (CH), 143.6 (C), 148.6 (CH), 148.9 (CH), 169.4 (CO) ppm.
HRMS (ESI): calcd. for C16H22N3O2 [M + H]+ 288.1703; found
288.1700.
(S)-2-Azepan-2-yl-5-methoxy-1H-indole (2b): Yield 50 mg, 82% as
a yellow film. Rf = 0.13 (acetone/MeOH, 9:1). [α]2D0 = –25.7 (c =
0.15, CHCl ). IR (diamond-ATR, neat): ν
= 3233 (NH), 2925
˜
3
max
(CH), 2854 (CH), 1588 (C=C), 1487 (C=C), 1456 (C=C) cm–1. H
NMR (250 MHz, CDCl3): δ = 1.66–1.91 (m, 5 H, 2ϫCH2 and
NH), 2.17–2.27 (m, 4 H, 2ϫCH2), 2.95–3.01 (m, 2 H, CH2), 3.80
(s, 3 H, OCH3), 4.27 (d, J = 4.7 Hz, 1 H, CH), 6.34 (s, 1 H, ArH),
6.79 (dd, J = 8.8, 2.4 Hz, 1 H, ArH), 6.96 (d, J = 2.3 Hz, 1 H,
ArH), (d, J = 8.7 Hz, 1 H, ArH), 9.75 (br. s, 1 H, NH) ppm. 13C
NMR (62.5 MHz, CDCl3): δ = 27.2 (CH2), 27.5 (CH2), 33.1 (CH2),
45.4 (CH2), 56.0 (CH2), 56.3 (OCH3), 63.1 (CH), 100.8 (CH), 102.3
(CH), 112.2 (CH), 112.7 (CH), 127.2 (C), 133.1 (C), 138.1 (C),
155.7 (C) ppm. MS (IS): m/z = 245.0 [M + H]+. HRMS (ESI):
calcd. for C15H21N2O [M + H]+ 245.1648; found 245.1652.
1
Synthesis of Cyclic Hydrazide 3e: A suspension of compound 5e
(100 mg, 0.35 mmol) in MeOH (10 mL) was stirred with activated
Pd/C (10 %, 20 mg) and a solution of HCO2NH4 (220 mg,
3.5 mmol) in distilled water (2 mL) was then added. The reaction
mixture was heated to reflux for 5 h, filtered through CeliteTM and
diluted with water. Extraction with CH2Cl2 (3ϫ 20 mL), drying
over MgSO4 and concentration under vacuum left an oily product,
which was purified by chromatography on silica gel with acetone/
petroleum ether (5:5) as eluent to give 3e (78 mg, 77%) as a color-
less oil.
(S)-2-(Dibenzo[b,d]furan-4-yl)azepane (2d): Yield 52 mg, 79% as a
colorless oil. Rf = 0.21 (acetone/MeOH, 9:1). [α]2D0 = –18.9 (c =
0.26, CHCl ). IR (diamond-ATR, neat): ν
= 3308 (NH), 2978
˜
3
max
(S)-1-[(S)-2-(Methoxymethyl)pyrrolidin-1-yl]-6-(pyridin-3-yl)piper-
idin-2-one (3e): Yield 78 mg, 77% as a colorless oil. Rf = 0.52 (acet-
one/PE, 5:5). [α]2D0 = –32.1(c = 1.08, CHCl3). IR (diamond-ATR,
(CH), 2901 (CH), 1404 (C=C) cm–1. 1H NMR (300 MHz, CDCl3):
δ = 1.63–1.93 (m, 6 H, CH2), 2.03–2.14 (m, 2 H, CH2), 2.98–3.06
(m, 1 H, CH2), 3.21–3.29 (m, 1 H, CH2), 4.37 (br. s, 1 H, NH),
4.49–4.53 (m, 1 H, NCH), 7.27–7.36 (m, 2 H, ArH), 7.43–7.48 (t,
J = 7.5 Hz, 1 H, ArH), 7.53–7.60 (m, 2 H, ArH), 7.81–7.83 (d, J
= 6 Hz, 1 H, ArH), 7.92–7.94 (d, J = 6 Hz, 1 H, ArH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 26.3 (CH2), 26.7 (CH2), 29.6 (CH2),
36.4 (CH2), 47.7 (CH2), 58.2 (CH), 111.7 (CH), 119.4 (CH), 120.7
(CH), 122.7 (CH), 123.1 (CH), 124.2 (C), 124.3 (C), 124.6 (CH),
125.5 (C), 127.1 (CH), 153.0 (C), 155.9 (C) ppm. HRMS (ESI):
calcd. for C18H20NO [M + H]+ 266.1542; found 266.1549.
neat): ν
= 2877 (CH), 1651 (C=O), 1396 (C=C), 1097 (C–
˜
max
O) cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.49–1.95 (m, 6 H,
CH2), 2.04–2.63 (m, 6 H, CH2), 2.99–3.16 (m, 5 H), 3.63 (br. s, 1
H), 4.71–4.74 (t, J = 4.5 Hz, 1 H, NCH), 7.28–7.34 (m, 1 H, ArH),
7.58–7.62 (m, 1 H, ArH), 8.54–8.58 (m, 2 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 17.1 (CH2), 23.3 (CH2), 27.6 (CH2), 31.9
(CH2), 33.6 (CH2), 50.9 (CH2), 58.6 (CH3O), 60.6 (CH), 60.7 (CH),
75.4 (CH2), 123.1 (CH), 134.9 (CH), 138.1 (C), 148.8 (CH), 149.2
(CH), 169.7 (CO) ppm. HRMS (ESI): calcd. for C16H24N3O2 [M
+ H]+ 290.1859; found 290.1865.
General Procedure for Synthesis of Heterocyclic Boronate 11: Inter-
mediate vinyl phosphate 9 (916 mg, 2 mmol) was dissolved in anhy-
drous dimethylformamide (20 mL) in a two-necked flask under a
nitrogen atmosphere. To the solution were added, in the following
order, bis(pinacolato)diboron (762 mg, 3 mmol), (Ph3P)2PdCl2
(42 mg, 0.06 mmol), Ph3P (32 mg, 0.12 mmol), and Ba(OH)2
(513 mg, 3 mmol). The mixture was heated with an oil bath to
90 °C and left whilst stirring for 5 h, after which time the reaction
was complete (by TLC). After cooling to room temperature, the
mixture was diluted with Et2O (60 mL) and washed with water
(3ϫ40 mL). The organic phase was dried with MgSO4, filtered,
and concentrated to give boronate 11 (672 mg) as a yellow oil,
which was used in the next step without further purification.
Synthesis of (S)-Anabasine (1e): A solution of borane–THF com-
plex (1.0 m solution in THF, 5 mL, 5 mmol) was added at 0 °C to
a stirred solution of 3e (72 mg, 0.25 mmol) in THF (10 mL). The
solution was stirred at room temperature for 15 min and then
heated to reflux for 24 h. After the mixture was cooled in an ice-
bath, 10% aqueous NaOH (10 mL) was added and the mixture
was briefly stirred (5 min). The mixture was extracted with Et2O
(3ϫ10 mL). The combined extracts were washed with brine, dried
with MgSO4 and concentrated under reduced pressure. The crude
residue was purified by flash column chromatography on silica gel
with CH2Cl2/MeOH (3:1) as eluent to give (S)-anabasine 1e.
(S)-3-(Piperidin-2-yl)pyridine (1e): Yield 26 mg, 64% as a yellow oil.
Rf = 0.23 (CH2Cl2/MeOH, 3:1). [α]2D0 = –79.2 (c = 0.8, MeOH);
ref.[23b] [α]2D0 = –80 (c = 0.91, MeOH). Analytical and spectroscopic
data were in agreement with those reported for the natural prod-
uct.[23b]
Synthesis of Enehydrazide 5e: Pd(OAc)2 (45 mg, 0.2 mmol), Ph3P
(105 mg, 0.4 mmol), and the crude boronate 11 (672 mg, 2 mmol)
were dissolved in anhydrous dioxane (15 mL) in a Schlenk flask
under a nitrogen atmosphere. To the solution was added 3-bromo-
pyridine (474 mg, 3 mmol), followed by K3PO4, H2O (921 mg,
4 mmol), and the resulting mixture was heated at 100 °C. After 4 h,
the reaction was complete (by TLC) and the mixture was diluted
with Et2O (15 mL) and washed with water (20 mL). The organic
phase was dried with Na2SO4, filtered, and concentrated. The
crude oil was purified by column chromatography with acetone/
petroleum ether (6:4) as eluent, to afford pure 5e (321 mg, 56%) as
a white solid.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H NMR and 13C NMR spectra for all new com-
pounds.
Acknowledgments
(S)-1-[2-(Methoxymethyl)pyrrolidin-1-yl]-6-(pyridin-3-yl)-3,4-dihy-
dropyridin-2(1H)-one (5e): Yield 321 mg, 56% as a white solid, m.p.
126–127 °C. Rf = 0.70 (acetone/PE, 6:4). [α]2D0 = –116.7 (c = 0.37,
The French Ministère de l’Enseignement Supérieur et de la Recher-
che is gratefully acknowledged for Ph.D. Fellowships (to R. S. and
N. G.). Ms. M. Dubois (CMF) is thanked for technical assistance.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O42202
/KAP1
Date: 28-05-14 19:11:56
Pages: 9
R. Sallio, S. Lebrun, N. Gigant, I. Gillaizeau, E. Deniau
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Received: March 5, 2014
Published Online: ᭿
8
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42202
/KAP1
Date: 28-05-14 19:11:56
Pages: 9
Asymmetric Synthesis of 2-Heteroaryl Cyclic Amines
Cyclic Amines
An asymmetric synthesis of a variety of 2-
heteroaryl cyclic amines through a (S)-
aminomethylprolinol chiral pool strategy is
described. This route was applied for the to-
tal synthesis of (–)-anabasine.
R. Sallio, S. Lebrun, N. Gigant,
I. Gillaizeau,* E. Deniau* .................. 1–9
Asymmetric Synthesis of 2-Heteroaryl Cy-
clic Amines: Total Synthesis of (–)-Ana-
basine
Keywords: Synthetic methods / Asymmetric
synthesis / Chiral auxiliaries / Cross-cou-
pling / Amines
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9