Reductive Alkylation of Tertiary Lactams via Addition of Organocopper (RCu) Reagents to Thioiminium Ions

Article abstract of DOI:10.1021/acs.joc.7b02150

A simple procedure for the conversion of tertiary lactams to 2-monoalkylated cyclic amines is described. The reaction sequence involves conversion of a lactam to a thioiminium ion followed by reaction with an organocopper (RCu) reagent and final reduction with triacetoxyborohydride. The reaction is high yielding and shows an excellent functional group tolerance. Its utility is demonstrated by a rapid synthesis of indolizidine 167B. The excellent chemoselectivity of the process, where only monoalkylation products are formed, is rationalized by a mechanism involving the formation of a transient enamine.

Full text of DOI:10.1021/acs.joc.7b02150

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Article
Reductive Alkylation of Tertiary Lactams via Addition
of Organocopper (RCu) Reagents to Thioiminium Ions
Pierre Mateo, Joséphine Cinqualbre, Melinda Meyer Mojzes, Kurt Schenk, and Philippe Renaud
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02150 • Publication Date (Web): 21 Oct 2017
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Reductive Alkylation of Tertiary Lactams via Addition of Organocopper (RCu) Reagents to
Thioiminium Ions
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Pierre Mateo,† Joséphine E. Cinqualbre,† Melinda Meyer Mojzes,† Kurt Schenk,§ Philippe Renaud†*
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†University of Bern, Department of Chemistry and Biochemistry, Freiestrasse 3, 3012 Bern, Switzerland
§Ecole Polytechnique Fédérale de Lausanne, Laboratoire de Magnétisme Quantique, BSP 314, Rte de la
Sorge, CHꢀ1015 Lausanne, Switzerland
philippe.renaud@dcb.unibe.ch
Abstract
A simple procedure for the conversion of tertiary lactams to 2ꢀmonoalkylated cyclic amines is
described. The reaction sequence involves conversion of a lactam to a thioiminium ion followed by
reaction with an organocopper (RCu) reagent and final reduction with triacetoxyborohydride. The
reaction is high yielding and shows an excellent functional group tolerance. Its utility is demonstrated
by a rapid synthesis of indolizidine 167B. The excellent chemoselectivity of the process, only
monoalkylation products are formed, is rationalized by a mechanism involving the formation of a
transient enamine.
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Introduction
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Lactams are attractive building blocks for the preparation of a wide range of substituted Nꢀheterocycles.
For instance, addition of organometallic nucleophiles to the activated carbonyl of amides or lactams has
emerged as a useful tool for the preparation of 2ꢀmonoꢀ and 2,2ꢀdisubtituted cyclic amines.1ꢀ3 Tertiary
amides and lactams are quite poor electrophiles, however, their reactivity can be dramatically enhanced
by converting them into the corresponding trifluoromethanesulfonyloxyiminium ions.4ꢀ5 This approach
proved to be good for the preparation of 2ꢀmonoalkylated as well as unsymmetrical 2,2ꢀdialkylated
cyclic tertiary amines but significant amounts of side products arising from the bisꢀaddition of the
second nucleophile are usually observed in this reaction.6ꢀ7 In term of cost and experimental ease,
conversion of tertiary amides and lactams into thioiminium ions is more attractive. Our initial work on
the reaction of thioiminium ions with organometallic reagents has shown that moderately basic species
such as allylic and benzylic Grignard reagents as well as organocerium compounds react efficiently and
provide exclusively the gemꢀdisubstituted compounds (Scheme 1).8
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Scheme 1. Synthesis of gemꢀ2,2ꢀdisubstituted amines.
The preparation of monoalkylated products from thioiminium ions is more challenging. Takahata et al.
reported that sequential use of lithium acetylides and LiAlH4 afford product of monoalkylation (Scheme
2, eq. 2).9 Murai and coꢀworkers extended this method for the sequential addition of two different
nucleophiles to an in situ generated thioiminium salt.10ꢀ11 In these two approaches, the first nucleophile
has to be a lithium acetylide to avoid bisꢀalkylation processes. Klaver et al. reported an isolated example
where a thioiminium ion derived from a bicyclic amide reacts with an alkyl Grignard reagent to afford,
after treatment with NaBH3CN, the monoalkylated product when the reaction was run in
dichloromethane (Scheme 2, eq. 3).12 Amat et al. have reported the reaction of Gilman cuprates with a
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methylthioiminium ion derived from Nꢀalkylated 6ꢀmethylpiperidinꢀ2ꢀone.13 No product of bisꢀ
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alkylation was observed but reported yields were moderate (55%) (Scheme 2, eq. 4).
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Scheme 2. Preparation of monoalkylated amides from thioiminium ions.
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Herein, we report that clean and selective monoalkylation products can be obtained by treating
methylthioiminium ions successively with a simple organocopper reagent and sodium
triacetoxyborohydride.
Results
nꢀButylation of the thioiminium ion 1, prepared in 87% yield from Nꢀbenzylpyrrolidinone, was
investigated first to optimize the reaction. A rapid screening of the conditions with the cuprate
Bu2Cu·LiI showed that a good 89% yield of 2a was obtained when 3 equivalents of the cuprate were
added at –30 °C (Table 1, entry 1). The corresponding higher order cyanocuprate led to a similar yield
(Table 1, entry 2). In order to enhance the atom efficiency of the process, the use of organocuprous
reagent BuCu (3 equiv) was tested. It afforded the desired product in 83% yield (Table 1, entry 3). To
our delight, by using Me2S as an additive (10 equiv), the monoalkylated product 2a was obtained in
95% yield (Table 1, entry 4). Me2S is known to solubilize copper iodide14 and to stabilize organocopper
reagents.15 Attempt to use a smaller excess of the organocuprous reagent (1.5 equiv) led to a clear drop
of the yield (Table 1, entry 5).
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Table 1. Optimization of the reaction conditions with the model compound 1.
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Yielda,b
Organocopper
nꢀBu2CuLi·LiI
nꢀBu2Cu(CN)Li2
nꢀBuCu·LiI
Equiv Additive
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3
–
89%
81%
83%
95%
66%
3
–
3
–
nꢀBuCu·LiI
3
Me2S
Me2S
nꢀBuCu·LiI
1.5
a) For practical convenience, a CH2Cl2 solution of the thioiminium ion 1 was added to the –78 °C
cooled organocopper solution in THF. Identical results were obtained when the cooled organocopper
reagent was added to a cooled solution of 1. b) Yields determined from the NMR of the crude product
using 1,4ꢀdimethoxybenzene as an internal standard. Yields refer to the sum of 2a and 2a·BH3 that are
formed as mixtures under these reaction conditions.
When the reaction was run with NaBH4 as a reducing agent, the tertiary amines were isolated as a
mixture of free amine and amine·BH3 complex. Since the complexes are less polar and easier to purify
than the free amines, addition of an excess of BH3·THF to the crude product was performed to furnish
the amine·BH3 complexes.16 nꢀBuCu and iꢀBuCu afforded the amine 2a and 2b as amine·BH3
complexes. Both complexes were obtained as single diastereoisomers and in high yields (Scheme 3).
The relative configuration of the 2b·BH3 complex has been unambiguously assigned by Xꢀray single
crystal structure analysis (Scheme 3).17
Scheme 3. Formation of the amine·borane complexes via reductive alkylation of the thioiminium ion 1
and Xꢀray single crystal structure of 2b·BH3 complex (20% probability ellipsoids).
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By using sodium triacetoxyborohydride (NaBH(OAc)3), the formation of the borane complex is
suppressed and the free amine is isolated. A simple filtration of the crude product over basic aluminum
oxide ensures the removal of inorganic byꢀproducts and affords the pure tertiary amines. The reaction
was performed with different substrates and various organocuprous species in order to evaluate the
scope and limitations of the process (Scheme 4).
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Scheme 4. Reaction of thioiminium ions 1, 3 and 4 with organocopper reagents.
Reaction of the 5ꢀmemberedꢀring thioiminium 1 with primary, secondary and tertiary alkylcopper
reagents gave, after reduction, the 2ꢀalkyl Nꢀbenzylpyrrolidines 2a, 2c–2e in 81–94% yield. In these
examples, the only sideꢀproduct detected in trace amount is the parent lactam that was easily separated
by chromatography. The reaction with PhCu·LiI gave mainly biphenyl. However, the desired amine 2e
was obtained in 89% yield when the reaction was run in THF only (no CH2Cl2) with NaBH4 as a
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hydride source. The piperidine derivative 3 obtained in 93% by thionation of Nꢀbenzylvalerolactam
followed by methylation with methyl iodide was examined next. The products 5a, 5c and 5e were
obtained in good yields (80–89%). Amine 5d (R = tertꢀbutyl) was obtained in lower yield (40%).
Finally, the 7ꢀmembered ring 6a was obtained in 73% yield from 4 demonstrating the generality of the
reaction.
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The reaction was further examined starting from substituted lactams 7–10 in order to test the
stereochemical outcome of the process as well as the functional group tolerance (Scheme 5). The four
thioiminiums 11–14 were prepared in >90% yield. The thioiminium 9 and 10 containing either an ester
or ketone moiety are easily prepared due to the remarkable chemoselectivity of the Lawesson's
reagent.18ꢀ20 Moreover, the four thioiminiums were converted into the 2,3ꢀ and 2,4ꢀdisubstituted
pyrrolidines 15–18 in 84–96% yield and good cis stereoselectivity. The relative configuration of the
products has been attributed based on n.O.e. difference spectra and by analogy to literature precedents.6ꢀ
7, 21ꢀ22 In case of 18, the corresponding substituted pyrrole sideꢀproduct 19 was also isolated.
Scheme 5. Diastereoselectivity and chemoselectivity of the reductive alkylation.
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Application of the developed method for the synthesis of (±)ꢀindolizidine 167B, a natural product
isolated from the skin of the frog Dendrobates speciosus,23,24ꢀ25 was examined next (Scheme 6).26ꢀ47
Reaction of the thioiminium 1 with the organocopper reagent derived from the protected bromoketone
20, easily prepared from commercial 4ꢀbromobutanoyl chloride in two steps,41, 48 afforded the desired 2ꢀ
substituted pyrrolidine 21 in 80% yield. Remarkably, the use of an organocopper species derived from
an organomagnesium reagent is fully compatible with our reaction sequence. The pyrrolidine 21 was
converted to (±)ꢀindolizidine 167B by Nꢀdebenzylation, hydrolysis of the dioxolane acetal and
intramolecular reductive amination. This sequence of reaction could be performed in a single operation
by running the hydrogenation under aqueous acidic condition (H2, Pd/C, aq. HCl in EtOH). The reaction
afforded the hydrochloride form of (±)ꢀindolizidine 167B (22·HCl) as a single diastereomer in 77%
yield.49 Starting from commercially available Nꢀbenzylpyrrolidinone, (±)ꢀindolizidine 167B was
synthesized in four step and 54% overall yield.
Scheme 6. Synthesis of (±)ꢀindolizidine 167B.
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Discussion
The highly selective monoalkylation process results from a delicate balance between the nucleophilic
character of the organocopper species and its basic character. A plausible mechanism for this
transformation is the reaction of the organocopper reagent with the thioiminium ion to afford the
intermediate iminium I that is deprotonated by a second equivalent of the organocopper species to
afford the enamine II. Finally, reduction of the enamine II by NaBH(OAc)3 affords the amine via the
transient iminium I (Scheme 7). Formation of enamine II prevents the formation of a gemꢀdisubstituted
product III. Interestingly, the less electrophilic thioiminium ion reacts efficiently with the organocopper
species while the iminium ion I is deprotonated by the same reagent. This may simply be a consequence
of the difference of their acidity (the thioiminium is expected to be less acidic) or of the complexation of
the organocopper species to the sulfur atom of the thioiminium ion (complex IV) that favors the
nucleophilic addition. An oxidative addition of the copper(I) species leading to a copper(III)
intermediate cannot be totally ruled out.
Scheme 7. Proposed mechanism.
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This mechanism involving an intermediate enamine II is supported by several experimental
observations: 1) The iminium ion 23 was prepared independently by Nꢀbenzylation of 5ꢀbutylꢀ3,4ꢀ
dihydroꢀ2Hꢀpyrrole. When treated with BuCu·LiI, it produces quantitatively the enamine exoꢀ24. 2)
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Reaction of the thioiminium 3 with BuCu·LiI followed by evaporation of the solvent afford the enamine
endoꢀ25. 3) When the thioiminium ion 1 is treated with BuCu·LiI followed by hydrolysis, a mixture of
the pyrrolidone 26 and the ring expanded ketone 27 resulting both from the oxidation of the enamine by
oxygen were isolated. A plausible mechanism for the formation of 26 and 27 is given in Scheme 8.
Interestingly, such oxidations of enamines have been reported but they require, when performed in the
absence of copper salts, the use of singlet oxygen.50ꢀ53 4) The reaction involving the thioiminium 14
(Scheme 5) afforded, beside the expected 18, a small amount of the pyrrole 19. The formation of this
product is expected to derive from the competitive isomerization of the enamine to an α,βꢀunsaturated
ketone (= dihydropyrrole) that cannot be reduced by NaB(OAc)3. This isomerization is followed by an
oxygen mediated aromatization of the dihydropyrrole either during the NaB(OAc)3H reduction step
(solvent not degassed) or during the workup procedure.
Scheme 8. Observations supporting the formation of an enamine intermediate.
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Conclusions
The reductive alkylation of lactams leading to 2ꢀmonoalkylated cyclic amines can be performed in two
steps via formation of a thioiminium salt followed by treatment successively with an organocopper
reagent and with sodium triacetoxyborohydride. This procedure shows an amazing functional group
tolerance and a high level of diastereocontrol. The highly selective monoalkylation results from the
formation of an intermediate enamine. Based on this mechanism, this reaction might be extended to
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polyfunctionalization of cyclic amines at position 2 using iminium chemistry and at position 3 using
enamine chemistry. Progress towards this goal will be reported soon.
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EXPERIMENTAL SECTION
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Materials and Method. For flash and simple column chromatography (FC and CC, respectively) silica
gel 60 Å (40–63 µm), neutral aluminum oxide (40–160 µm) and basic aluminum oxide (40–160 µm)
were used. TLC analyses were performed on silica gel 60 F254 and on neutral aluminum oxide N/UV254
analytical plates. The melting points (m.p.) are corrected. Infrared spectra were recorded neat on a FTꢀ
IR spectrometer equipped with a single reflection diamond ATR System and are reported in wave
1
numbers (cm–1). The H and 13C{1H} NMR spectra were recorded on a 300 MHz spectrometer (1H:
1
300.18 MHz, 13C: 75.48 MHz). 11B NMR and some H NMR spectra were recorded on 400 MHZ
spectrometer (1H: 400.12 MHz, 11B: 128.38 MHz). Chemical shifts are reported in units of δ (ppm)
using the internal standard residual signal of solvent. 1H NMR: CHCl3 δ = 7.26 ppm, C6H6 δ = 7.16 ppm
and CD2Cl2 δ = 5.32 ppm. 13C{1H} NMR: CDCl3 δ = 77.16 ppm, C6D6 δ = 128.06 ppm and CD2Cl2 δ =
1
54.0 ppm for spectra).54 B NMR: Et2OBF3 as an external standard (δ = 0 ppm). The following
abbreviations were used to describe the multiplicities: app (apparent), s (singlet), d (doublet), t (triplet),
q (quadruplet), quint (quintet), sext (sextet), sept (septuplet), m (multiplet), br (broad). Coupling
constants, J, are reported in Hz with a precision of one unit on the last digit. The number of carbon
atoms for each signal is indicated only when superior to 1. GCꢀMS analyses were performed on a
quadrupole mass analyzer using electron impact (70 eV) fitted with a 0.25 mm capillary column (20 m,
0.25 mm); gas carrier: He 1.4 mL/min; injector: 220°C split mode. HRMS analyses were recorded on a
hybrid quadrupole timeꢀofꢀflight mass spectrometer using positive electrospray ionization. Unless
otherwise stated, all reagents were obtained from commercial sources and used without further
purification. Solvents for reactions (THF, Et2O, CH2Cl2, benzene, toluene and CH3NO2) were filtered
over columns of dried alumina under a positive pressure of argon. Solvents for extractions and flash
column chromatography were of technical grade and were distilled prior to use. The solutions of
Grignard and organolithium reagents were titrated on a regular basis or just prior to use.55ꢀ58
Preparation of the thioiminium salts 1, 3 and 4
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1ꢀBenzylpyrrolidineꢀ2ꢀthione. Lawesson's reagent (9.9 g, 24.5 mmol) was added at rt to a solution of 1ꢀ
benzylpyrrolidinꢀ2ꢀone (8.0 mL, 48.5 mmol) in CH2Cl2 (100 mL). Vigorous stirring was maintained for
3ꢀ12 h (TLC monitoring). Filtration of the reaction mixture over neutral aluminium oxide (CH2Cl2)
afforded the thiolactam (8.80 g, 95% yield) as a colorless solid after concentration under reduced
pressure. M.p. 71–72 °C (lit.59 70–72 °C). Physical and spectral data in accordance with the literature.59
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1ꢀBenzylꢀ5ꢀmethylsulfanylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrolium iodide (1). Methyl iodide (1.8 mL, 29.2 mmol)
was added at rt to a solution of 1ꢀbenzylpyrrolidineꢀ2ꢀthione (4.30 g, 22.5 mmol) in THF (75 mL). The
flask was wrapped in aluminum foil and the reaction mixture was stirred at rt for 8ꢀ12 h (TLC
monitoring). Et2O was added and the suspension was cooled with an ice bath to ensure full precipitation
of the thioiminium. The supernatant was removed and the remaining solid was repeatedly washed with
Et2O. Drying under reduced pressure furnished 1 (6.86 g, 92% yield) as a pale brownish solid. Mp = 98ꢀ
99 °C (lit.8 94ꢀ95 °C). Physical and spectral data in accordance with the literature.8
1ꢀBenzylpiperidineꢀ2ꢀthione. Prepared from 1ꢀbenzylpiperidinꢀ2ꢀone (1.8 mL, 10.2 mmol) according to
the procedure for 1ꢀbenzylpyrrolidineꢀ2ꢀthione. The thiolactam (2.13 g, quantitative) was obtained as
colorless crystals. Mp = 69ꢀ71 °C (lit.59 68ꢀ69 °C). Physical and spectral data in accordance with the
literature.59ꢀ60
1ꢀBenzylꢀ6ꢀmethylsulfanylꢀ2,3,4,5ꢀtetrahydropyridinium iodide (3). Prepared from 1ꢀbenzylpiperidineꢀ
2ꢀthione (2.33 g, 11.3 mmol) according to the procedure for 1. The thioiminium 3 (3.67 g, 93% yield)
was obtained as a pale brownish solid. Mp = 116ꢀ118 °C (lit.8 103ꢀ106 °C). Physical and spectral data in
accordance with the literature.8
1ꢀBenzylazepaneꢀ2ꢀthione. Prepared from 1ꢀbenzylazepaneꢀ2ꢀone61 (6.35 g, 31.2 mmol) according to the
procedure for 1ꢀbenzylpyrrolidineꢀ2ꢀthione. The thiolactam (6.76 g, 99% yield) was obtained as a
colorless solid. Mp = 71ꢀ72 °C (lit.62 76 °C). Physical and spectral data in accordance with the
literature.62
1ꢀBenzylꢀ7ꢀmethylsulfanylꢀ3,4,5,6ꢀtetrahydroꢀ2Hꢀazepinium iodide (4). Prepared from 1ꢀbenzylazepaneꢀ
2ꢀthione (6.64 g, 30.3 mmol) according to the procedure for 1, with CH3NO2 instead of THF. The
thioiminium 4 (9.37 g, 94% yield) was obtained as a yellow solid. Mp = 111–112 °C (lit.8 124 °C,
decomposition). Physical and spectral data in accordance with the literature.8
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Preparation of the amineꢀborane complexes 2a·BH3 and 2b·BH3
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1ꢀBenzylꢀ2ꢀbutylpyrrolidinium trihydroborate (2a·BH3). Me2S (0.40 mL, 5.45 mmol) was added to a
suspension of CuI (333 mg, 1.75 mmol) in THF (5 mL) at rt. The colorless solution obtained was cooled
with a dryꢀice/acetone bath and the suitable organometallic lithium or magnesium derivative was added
dropwise (1.60 mmol). The temperature was maintained below –65 °C during the addition. The
resulting suspension was allowed to warm up to –20/–15 °C and was immediately cooled back to –78
°C. 1ꢀBenzylꢀ5ꢀmethylsulfanylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrolium iodide 1 (199 mg, 0.60 mmol) was then
added as a CH2Cl2 solution (4 mL). The stirring was maintained at –35/–30 °C for 0.5 h. An iceꢀbrine
bath was put in place and the stirring maintained for an additional 0.5 h. NaBH4 (57mg, 1.51 mmol) was
then added neat and allowed to react for 5 min at rt. Sat. aq. NH4Cl was added, followed by EtOAc,
H2O and solid Na2CO3. The mixture was allowed to decant and filtered over a pad of Celite. The
aqueous phase was separated and extracted with EtOAc. The combined organic layers were dried over
Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in THF (5
mL), and BH3·THF was added (0.5 mL, 1 M in THF) at 0 °C. The solution was allowed to warm gently
to rt over a 45 min period. After concentration under reduced pressure, FC (silica gel, pentane/CH2Cl2
1:1) afforded the pure amineꢀborane 2a·BH3 (125 mg, 90% yield) as a colorless solid. Mp = 86ꢀ87 °C.
1H NMR (300 MHz, CDCl3) δ 7.41ꢀ7.36 (m, 3H), 7.31ꢀ7.25 (m, 2H), 4.12 (A part of an AB system, J =
13.8 Hz, 1H), 4.06 (B part of an AB system, J = 13.8 Hz, 1H), 3.06 (ddd, J = 9.8, 8.4, 1.4 Hz, 1H), 2.74
(app q, J = 9.9 Hz, 1H), 2.58 (ddd, J = 18.7, 10.2, 3.5 Hz, 1H), 2.18ꢀ2.02 (m, 1H), 1.99ꢀ1.79 (m, 5H),
1.64ꢀ1.51 (m, 1H), 1.49ꢀ1.09 (m, 6H), 0.96 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 132.7
(2C), 131.2, 128.9, 128.4 (2C), 65.9, 62.5, 59.1, 29.6, 29.5, 27.8, 23.0, 19.7, 14.2. IR (cm–1): 2376,
2337, 1174, 1146. HRMS calcd. for C15H26BNNa [M+Na]+: 254.2056, found: 254.2051.
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1ꢀBenzylꢀ2ꢀisobutylpyrrolidinium trihydroborate (2b·BH3). Prepared from the 1ꢀbenzylꢀ5ꢀ
methylsulfanylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrolium iodide 1 (200 mg, 0.60 mmol) according to the procedure for
2a·BH3. FC (silica gel, pentane/EtOAc 97:3) afforded the complex 2b·BH3 as a colorless solid (125 mg,
90% yield). Suitable crystals for Xꢀray single crystal structure analysis were obtained by
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recrystallization from a mixture of ethyl acetate and pentane. Mp = 113ꢀ114 °C. H NMR (300 MHz,
CDCl3) δ 7.40ꢀ7.26 (m, 5H), 4.12 (A part of an AB system, J = 13.8 Hz, 1H), 4.03 (B part of an AB
system, J = 13.8 Hz, 1H), 3.07 (ddd, J = 9.8, 8.4, 1.4 Hz, 1H), 2.81ꢀ2.62 (m, 2H), 2.20ꢀ2.00 (m, 1H),
2.00ꢀ1.81 (m, 3H), 1.74ꢀ1.48 (m, 3H), 1.01 (d, J = 6.4 Hz, 3H), 0.91 (d, J = 6.4 Hz, 3H). 13C{1H} NMR
(75 MHz, CDCl3) δ 132.8 (2C), 131.2, 129.0, 128.4 (2C), 64.4, 62.5, 59.2, 38.3, 27.8, 26.4, 24.5, 21.7,
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19.8. 11B NMR (128 MHz, CDCl3) δ ꢀ14.7. IR (cm–1): 2371, 2330, 1173, 1069. HRMS calcd. for
C15H26BNNa [M+Na]+: 254.2056, found: 254.2051.
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1ꢀBenzylꢀ2ꢀbutylpyrrolidine (2a). Me2S (0.40 mL, 5.45 mmol) was added to a suspension of CuI (333
mg, 1.75 mmol) in THF (5 mL), at rt. The colorless solution obtained was cooled with a dryꢀice/acetone
bath and the suitable organometallic lithium or magnesium derivative was added dropwise (1.70 mmol).
The temperature was maintained below –65 °C during the addition. The resulting suspension was
allowed to warm up to –20/–15 °C and was immediately cooled back to –78 °C. The thioiminium (0.60
mmol) was then added as a CH2Cl2 solution (4 mL). The stirring was maintained at –35/–30 °C for 0.5
h. An iceꢀbrine bath was put in place and the stirring maintained for an additional 0.5 h. Na(AcO)3BH
(360 mg, 1.70 mmol) was then added neat and allowed to react for 1 h at rt. Sat. aq. NH4Cl was added,
followed by EtOAc, H2O and solid Na2CO3. The mixture was allowed to decant and filtered over a pad
of Celite. The aqueous phase was separated and extracted with EtOAc. The combined organic layers
were dried over Na2SO4, filtered and concentrated under reduced pressure to furnish the crude product.
Filtration with CH2Cl2 over basic aluminum oxide afforded the pure substituted amine 2a (114 mg, 88%
yield) as a colorless oil after concentration under reduced pressure. Physical and spectral data in
accordance with the literature.7
1ꢀBenzylꢀ2ꢀisopropylpyrrolidine (2c). Prepared from the 1ꢀbenzylꢀ5ꢀmethylsulfanylꢀ3,4ꢀdihydroꢀ2Hꢀ
pyrrolium iodide 1 (199 mg, 0.60 mmol) according to the procedure for 2a. The amine 2c (114 mg, 94%
yield) was obtained as a colorless oil. Physical and spectral data in accordance with the literature.63
1ꢀBenzylꢀ2ꢀ(tertꢀbutyl)pyrrolidine (2d). Prepared from the 1ꢀbenzylꢀ5ꢀmethylsulfanylꢀ3,4ꢀdihydroꢀ2Hꢀ
pyrrolium iodide 1 (333 mg, 1.00 mmol) according to the procedure for 2a. The amine 2d (176 mg, 81%
yield) was obtained as a colorless oil after filtration over neutral aluminum oxide (pentane/EtOAc 96:4).
1H NMR (300 MHz, CDCl3) δ 7.42ꢀ7.18 (m, 5H), 4.07 (A part of an AB system, J = 14.0 Hz, 1H), 3.49
(B part of an AB system, J = 14.0 Hz, 1H), 2.90ꢀ2.78 (m, 1H), 2.53 (dd, J = 9.1, 4.2 Hz, 1H), 2.29 (app
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dt, J = 9.7, 6.9 Hz, 1H), 1.88ꢀ1.74 (m, 1H), 1.72ꢀ1.58 (m, 3H), 0.92 (s, 9H). C{1H} NMR (75 MHz,
CDCl3) δ 141.8, 128.24 (2C), 128.17 (2C), 126.6, 73.5, 63.4, 55.7, 36.2, 27.9, 27.0 (3C), 25.4. IR (cm–
1): 3026, 1495, 1452, 1028, 733, 696. EIꢀMS, m/z (%): 202 (2), 160 (95), 91 (100), 89 (2), 70 (2), 68 (2),
65 (13). HRMS calcd. for C15H24N [M+H]+: 218.1903, found: 218.1896.
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1ꢀBenzylꢀ2ꢀphenylpyrrolidine (2e). To CuI (334 mg, 1.75 mmol) in Et2O (7 mL) were added Me2S (1.0
mL, 13.6 mmol) and THF (3 mL). PhMgBr (2.4 mL, 0.7 M in THF) was added dropwise at –78 °C. The
resulting yellow suspension was allowed to warm up to –7 °C and was cooled back to –78 °C. 1ꢀBenzylꢀ
5ꢀmethylsulfanylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrolium iodide 1 (200 mg, 0.60 mmol) was added neat, followed by
2 mL of THF. The stirring was maintained at –35/–30 °C for 0.5 h. An iceꢀbrine bath was put in place
and the stirring maintained for an additional 0.5 h. NaBH4 (70 mg, 1.85 mmol) was added neat and
allowed to react for 5 min at rt. Sat. aq. NH4Cl was added, followed by EtOAc, H2O and solid Na2CO3.
The mixture was allowed to decant and filtered over a pad of Celite. The aqueous phase was separated
and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and
concentrated under reduced pressure. Acidꢀbase extraction afforded 2e as a colorless oil that crystallized
on standing (127 mg, 89% yield). Mp = 41ꢀ42 °C (lit.64 44ꢀ45 °C). Physical and spectral data in
accordance with the literature.64ꢀ65
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1ꢀBenzylꢀ2ꢀbutylpiperidine (5a). Prepared from the 1ꢀbenzylꢀ6ꢀmethylsulfanylꢀ2,3,4,5ꢀtetrahydro
pyridinium iodide 3 (339 mg, 0.98 mmol) according to the procedure for 2a. The amine 5a (216 mg,
1
96% yield) was obtained as a paleꢀorange liquid. H NMR (300 MHz, CDCl3) δ 7.38 ꢀ7.20 (m, 5H),
3.98 (A part of an AB system, J = 13.4 Hz, 1H), 3.22 (B part of an AB system, J = 13.4 Hz, 1H), 2.81ꢀ
2.64 (m, 1H), 2.35ꢀ2.18 (m, 1H), 2.10ꢀ1.93 (m, 1H), 1.75ꢀ1.17 (m, 12H), 0.91 (t, J = 6.9 Hz, 3H).
13C{1H} NMR (75 MHz, CDCl3) δ 140.1, 129.0 (2C), 128.2 (2C), 126.6, 60.9, 57.7, 51.8, 31.6, 30.4,
27.8, 25.3, 23.9, 23.3, 14.3. IR (cm–1): 3026, 1495, 1452, 1028, 731, 696. EIꢀMS, m/z (%): 174 (99), 132
(2), 104 (2), 91 (100), 89 (2), 82 (5), 65 (9). HRMS calcd. for C16H26N [M+H]+: 232.2060, found:
232.2064.
1ꢀBenzylꢀ2ꢀisopropylpiperidine (5c). Prepared from the 1ꢀbenzylꢀ6ꢀmethylsulfanylꢀ2,3,4,5ꢀ
tetrahydropyridinium iodide 3 (348 mg, 1.00 mmol) according to the procedure for 2a. The amine 5c
(174 mg, 80% yield) was obtained as a paleꢀyellow solid. Physical and spectral data in accordance with
the literature.63
1H NMR (300 MHz, CDCl3) δ 7.35 ꢀ7.18 (m, 5H), 4.11 (A part of an AB system, J = 13.5 Hz, 1H), 3.08
(B part of an AB system, J = 13.5 Hz, 1H), 2.86ꢀ2.79 (m, 1H), 2.26 (septd, J = 6.8, 1.7 Hz, 1H), 2.05ꢀ
1.90 (m, 2H), 1.76ꢀ1.71 (m, 1H), 1.64ꢀ1.56 (m, 1H), 1.50ꢀ1.21 (m, 4H), 0.94 (d, J = 2.4 Hz, 3H), 0.93
(d, J = 2.4 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 140.5, 128.9 (2C), 128.2 (2C), 126.6, 66.6, 56.7,
52.8, 27.7, 24.9, 24.7, 23.6, 20.3, 16.2.
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1ꢀBenzylꢀ2ꢀ(tertꢀbutyl)piperidine (5d). Prepared from the 1ꢀbenzylꢀ6ꢀmethylsulfanylꢀ2,3,4,5ꢀ
tetrahydropyridinium iodide 3 (345 mg, 0.99 mmol) according to the procedure for 2a. The amine 5d
(91 mg, 40% yield) was obtained as a colorless liquid. CC (neutral aluminum oxide, pentane/EtOAc
98:2 then 90:10). 1H NMR (300 MHz, CDCl3) δ 7.42 ꢀ7.37 (m, 2H), 7.34 ꢀ7.27 (m, 2H), 7.25 ꢀ7.18 (m,
1H), 3.91 (A part of an AB system, J = 13.6 Hz, 1H), 3.75 (B part of an AB system, J = 13.6 Hz, 1H),
2.76ꢀ2.68 (m, 1H), 2.50 (app dt, J = 14.2, 5.1 Hz, 1H), 2.41ꢀ2.36 (m, 1H), 1.89ꢀ1.76 (m, 1H), 1.59ꢀ1.38
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(m, 5H), 0.98 (s, 9H). C{1H} NMR (75 MHz, CDCl3) δ 141.3, 128.6 (2C), 128.3 (2C), 126.7, 70.3,
56.9, 45.3, 36.1, 27.8 (3C), 22.4, 20.8, 18.0. IR (cm–1): 3026, 1494, 1451, 1018, 730, 696. EIꢀMS, m/z
(%): 216 (7), 174 (98), 91 (100), 82 (12), 65 (19), 55 (16). HRMS calcd. for C16H26N [M+H]+:
232.2060, found: 232.2057.
1ꢀBenzylꢀ2ꢀphenylpiperidine (5e). To CuI (556 mg, 2.92 mmol) in Et2O (8 mL) were added Me2S (1.5
mL, 20.4 mmol) and THF (4 mL). PhMgBr (2.9 mL, 1.0 M in THF) was added dropwise at –78 °C. The
resulting yellow suspension was allowed to warm up to –7 °C and was cooled back to –78 °C. 1ꢀBenzylꢀ
6ꢀmethylsulfanylꢀ2,3,4,5ꢀtetrahydropyridinium iodide 3 (338 mg, 0.97 mmol) was added neat, followed
by 3 mL of THF. The stirring was maintained at –35/–30 °C for 0.5 h. An iceꢀbrine bath was put in
place and the stirring maintained for an additional 0.5 h. NaBH4 (115 mg, 2.89 mmol) was added neat
and allowed to react for 5 min at rt. Sat. aq. NH4Cl was added, followed by EtOAc, H2O and solid
Na2CO3. The mixture was allowed to decant and filtered over a pad of Celite. The aqueous phase was
separated and extracted with EtOAc. Acidꢀbase extraction of the combined organic layers afforded the
crude amine that crystallized upon trituration with EtOH to give 5e (199 mg, 81% yield). M.p. = 89ꢀ90
°C (lit.64 90ꢀ91 °C, EtOH/H2O). Physical and spectral data in accordance with the literature.64, 66ꢀ67
1ꢀBenzylꢀ2ꢀbutylazepane (6a). Prepared from the 1ꢀbenzylꢀ7ꢀmethylsulfanylꢀ3,4,5,6ꢀtetrahydroꢀ2Hꢀ
azepinium iodide 4 (361 mg, 1.00 mmol) according to the procedure for 2a. The amine 6a (178 mg,
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73% yield) was obtained as a paleꢀyellow liquid. H NMR (300 MHz, CDCl3) δ 7.39 ꢀ7.17 (m, 5H),
3.78 (A part of an AB system, J = 14.1 Hz, 1H), 3.68 (B part of an AB system, J = 14.1 Hz, 1H), 2.81
(A part of an ABXY system, J = 14.6, 6.0, 4.2 Hz, 1H), 2.76ꢀ2.65 (m, 1H), 2.58 (B part of an ABXY
system, J = 14.6, 7.1, 3.8 Hz, 1H), 1.85ꢀ1.72 (m, 1H), 1.71ꢀ1.41 (m, 8H), 1.41ꢀ1.22 (m, 5H), 0.89 (t, J =
7.0 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 141.5, 128.7 (2C), 128.2 (2C), 126.6, 62.6, 55.2, 49.8,
34.3, 33.4, 29.5, 28.6, 27.3, 26.1, 23.1, 14.4. IR (cm–1): 3025, 1451, 1028, 728, 695. EIꢀMS, m/z (%):
216 (4), 188 (100), 160 (6), 154 (13), 132 (4), 96 (11), 91 (92), 65 (9). HRMS calcd. for C17H28N
[M+H]+: 246.2216, found: 246.2213.
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Preparation of the substituted lactams 7ꢀ10
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1ꢀBenzylꢀ3ꢀ(tertꢀbutyldimethylsilyloxy)pyrrolidinꢀ2ꢀone (7). To 1ꢀbenzylꢀ3ꢀhydroxypyrrolidinꢀ2ꢀone68
(0.57 g, 2.98 mmol) in DMF were successively added imidazole (0.29 g, 4.26 mmol), DMAP (10 mg,
0.08 mmol), and TBDMSCl (0.62 g, 3.91 mmol). The stirring was then maintained overnight at rt. The
reaction mixture was diluted with ethyl acetate (a colorless precipitate formed) and poured into a
separatory funnel with brine. The organic layer was further washed, once with water and twice with
brine, dried over Na2SO4, filtered and concentrated under reduced pressure to furnish the crude lactam.
FC (silica gel, pentane/EtOAc 80:20) afforded 7 (0.88 g, 97% yield) as a colorless liquid. 1H NMR (300
MHz, CDCl3) δ 7.35ꢀ7.22 (m, 5H), 4.44 (s, 2H), 4.35 (app t, J = 7.6 Hz, 1H), 3.24 (ddd, J = 9.6, 8.8, 3.2
Hz, 1H), 3.09 (app dt, J = 9.6, 7.4 Hz, 1H), 2.28 (dddd, J = 12.7, 7.6, 7.4, 3.2 Hz, 1H), 1.89 (dddd, J =
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12.7, 8.8, 7.6, 7.4 Hz, 1H), 0.93 (s, 9H), 0.19 (s, 3H), 0.17 (s, 3H). C{1H} NMR (75 MHz, CDCl3) δ
173.1, 136.1, 128.5 (2C), 128.0 (2C), 127.5, 71.0, 46.8, 42.6, 29.1, 25.7 (3C), 18.2, ꢀ4.5, ꢀ5.1. IR (cm–1):
1699, 1254, 1143. EIꢀMS, m/z (%): 290 (10), 248 (100), 156 (3), 101 (3), 91 (74), 73 (10), 65 (9).
HRMS calcd. for C17H28NO2Si [M+H]+: 306.1884, found: 306.1884.
1ꢀBenzylꢀ4ꢀ[(tertꢀbutyldiphenylsilyloxy)methyl]pyrrolidinꢀ2ꢀone
(8).
To
1ꢀbenzylꢀ4ꢀ
(hydroxymethyl)pyrrolidinꢀ2ꢀone69 (1.50 g, 7.31 mmol) in DMF were successively added imidazole
(0.75 g, 11.0 mmol) and (tꢀBu)Ph2SiCl (2.2 mL, 8.60 mmol). The stirring was then maintained
overnight at rt. The reaction mixture was diluted with EtOAc, washed twice with water, dried over
Na2SO4, filtered and concentrated under reduced pressure to furnish the crude lactam. FC (silica gel,
pentane then pentane/EtOAc 1:1) afforded 8 (2.99 g, 92% yield) as a colorless oil. 1H NMR (300 MHz,
CDCl3) δ 7.62ꢀ7.54 (m, 4H), 7.47ꢀ7.18 (m, 11H), 4.44 (A part of an AB system, J = 14.7 Hz, 1H), 4.41
(B part of an AB system, J = 14.7 Hz, 1H), 3.58 (A part of an ABX system, J = 10.4, 5.6 Hz, 1H), 3.55
(B part of an ABX system, J = 10.4, 6.4 Hz, 1H), 3.31 (A part of an ABX system, J = 9.9, 8.0 Hz, 1H),
3.13 (B part of an ABX system, J = 9.9, 4.9 Hz, 1H), 2.61ꢀ2.47 (m, 2H), 2.40ꢀ2.26 (m, 1H), 1.01 (s,
9H). 13C{1H} NMR (75 MHz, CDCl3) δ 174.2, 136.7, 135.75 (2C), 135.74 (2C), 133.53, 133.47, 130.0
(2C), 128.9 (2C), 128.3 (2C), 128.0 (4C), 127.7, 65.5, 49.2, 46.8, 34.1, 33.5, 27.0 (3C), 19.5. IR (cm–1):
1684, 1256, 1110. EIꢀMS, m/z (%): 386 (100), 308 (15), 218 (30), 199 (6), 183 (29), 181 (8), 135 (8), 91
(57). HRMS calcd. for C28H34NO2Si [M+H]+: 444.2359, found: 444.2346.
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Methyl 1ꢀbenzylꢀ5ꢀoxopyrrolidineꢀ3ꢀcarboxylate (9). Prepared from 1ꢀbenzylꢀ5ꢀoxopyrrolidineꢀ3ꢀ
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carboxylic acid (46.7 g, 213 mmol) according to a known procedure.69 The lactam 9 (36.4 g, 73%
yield) was obtained as a colorless solid. Physical and spectral data in accordance with the literature.18
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1ꢀBenzylꢀ4ꢀpropionylpyrrolidinꢀ2ꢀone (10). To 1ꢀbenzylꢀ5ꢀoxopyrrolidineꢀ3ꢀcarboxylic acid (3.00 g,
13.7 mmol) in CH2Cl2 (20 mL) was added 1,1’ꢀcarbonyldiimidazole (2.88 g, 17.8 mmol). The stirring
was maintained at rt for 30 min, at which time N,Oꢀdimethylhydroxylamine hydrochloride (1.73 g, 17.7
mmol) was added. After an additional 3 h water was added. The aqueous layer was separated and
extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated
under reduced pressure. Repeated washings with aqueous 1 N HCl and drying in the usual manner
afforded a viscous oil (3.42 g, 95% yield), pure enough to be used directly in the next step.
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The Weinreb amide (1.80 g, 6.86 mmol) was dissolved in THF (30 mL) at rt and cooled down to –78
°C. EtMgBr (5.5 mL, 2.8 M in Et2O) was then added, the temperature being maintained below –60 °C.
The reaction mixture was allowed to warm up slowly to –10 °C (30 min) and aq. 1 N HCl was added
followed by Et2O. The aq. layer was separated and extracted 3 times with CH2Cl2. The combined
organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. FC (silica gel,
pentane/EtOAc 1:2 then EtOAc) afforded 10 as a liquid that crystallized on standing (1.45 g, 91%
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yield). Pale brownish solid. M.p. = 45ꢀ47 °C. H NMR70 (300 MHz, CDCl3) δ 7.37ꢀ7.20 (m, 5H), 4.52
(A part of an AB system, J = 14.9 Hz, 1H), 4.39 (B part of an AB system, J = 14.9 Hz, 1H), 3.48ꢀ3.24
(m, 3H), 2.68 (app d, J = 8.5 Hz, 2H), 2.48 (A part of an ABX3 system, J = 17.9, 7.3 Hz, 1H), 2.43 (B
part of an ABX3 system, 17.9, 7.3 Hz, 1H), 1.06 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ
208.8, 172.1, 135.9, 128.7 (2C), 128.0 (2C), 127.6, 47.4, 46.4, 42.1, 34.6, 33.3, 7.5. IR (cm–1): 1710,
1683. EIꢀMS, m/z (%): 231 (60), 202 (21), 174 (18), 146 (50), 132 (21), 106 (22), 91 (100), 84 (21), 65
(19), 57 (25). HRMS calcd. for C14H18NO2 [M+H]+: 232.1332, found: 232.1328.
Preparation of the substituted thioiminiums 11ꢀ14
1ꢀBenzylꢀ3ꢀ(tertꢀbutyldimethylsilyloxy)pyrrolidineꢀ2ꢀthione. Prepared from the 1ꢀbenzylꢀ3ꢀ(tertꢀ
butyldimethylsilyloxy)pyrrolidinꢀ2ꢀone 7 (0.80 g, 2.62 mmol) according to the procedure for 1ꢀ
benzylpyrrolidineꢀ2ꢀthione with THF instead of CH2Cl2. The thiolactam (0.84 g, quantitative) was
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obtained as a colorless oil. H NMR (300 MHz, CDCl3) δ 7.37ꢀ7.27 (m, 5H), 4.99 (A part of an AB
system, J = 14.4 Hz, 1H), 4.94 (B part of an AB system, J = 14.4 Hz, 1H), 4.62 (t, J = 6.7 Hz, 1H), 3.57
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(ddd, J = 11.2, 8.3, 4.3 Hz, 1H), 3.38 (ddd, J = 11.2, 7.2, 6.3 Hz, 1H), 2.32 (dddd, J = 12.5, 7.2, 6.7, 4.3
Hz, 1H), 1.91 (dddd, J = 12.5, 8.3, 6.7, 6.3 Hz 1H), 0.93 (s, 9H), 0.25 (s, 3H), 0.22 (s, 3H). C{1H}
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NMR (75 MHz, CDCl3) δ 202.4, 134.8, 128.7 (2C), 128.2 (2C), 127.9, 80.7, 51.8, 50.3, 30.6, 25.8 (3C),
18.3, ꢀ4.0, ꢀ5.0. IR (cm–1): 1505, 1251, 1158. EIꢀMS, m/z (%): 306 (7), 264 (100), 188 (8), 174 (11), 91
(80), 75 (9), 73 (12), 65 (8). HRMS calcd. for C17H28NOSSi [M+H]+: 322.1655, found: 322.1649.
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1ꢀBenzylꢀ4ꢀ(tertꢀbutyldimethylsilyloxy)ꢀ5ꢀmethylsulfanylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrolium
iodide
(11).
Prepared from 1ꢀbenzylꢀ3ꢀ(tertꢀbutyldimethylsilyloxy)pyrrolidineꢀ2ꢀthione (0.69 g, 2.15 mmol)
according to the procedure for 1 using CH3NO2 instead of THF. The thioiminium 11 (0.94 g, 95% yield)
was obtained as a colorless solid. M.p. = 135ꢀ136 °C. 1H NMR (300 MHz, CDCl3) δ 7.46ꢀ7.35 (m, 5H),
6.11ꢀ6.07 (m, 1H), 4.99 (A part of an AB system, J = 15.2 Hz, 1H), 4.86 (B part of an AB system, J =
15.2 Hz, 1H), 4.25 (ddd, J = 12.8, 8.5, 5.9 Hz, 1H), 3.89 (ddd, J = 12.8, 8.6, 5.0 Hz, 1H), 3.09 (dddd, J
= 13.2, 8.5, 7.4, 5.0 Hz, 1H), 3.05 (s, 3H), 1.97 (dddd, J = 13.2, 8.6, 5.9, 4.5 Hz, 1H), 0.91 (s, 9H), 0.22
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(s, 3H), 0.17 (s, 3H). C{1H} NMR (75 MHz, CDCl3) δ 193.8, 130.0, 129.8, 129.7 (2C), 129.0 (2C),
80.4, 58.6, 56.2, 30.6, 25.6 (3C), 17.9, 15.9, ꢀ3.6, ꢀ4.6. IR (cm–1): 1599, 1583, 1086. HRMS calcd. for
C18H30NOSSi [MꢀI]+: 336.1812, found: 336.1801.
1ꢀBenzylꢀ4ꢀ[(tertꢀbutyldiphenylsilyloxy)methyl]pyrrolidineꢀ2ꢀthione. Prepared from the 1ꢀbenzylꢀ4ꢀ
[(tertꢀbutyldiphenylsilyloxy)methyl] pyrrolidinꢀ2ꢀone 8 (2.57 g, 5.79 mmol) according to the procedure
for 1ꢀbenzylpyrrolidineꢀ2ꢀthione. The thiolactam (2.64 g, 97%, corrected yield; contains 10 mol%
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residual CH2Cl2) was obtained as a colorless sticky oil. H NMR (300 MHz, CDCl3) δ 7.60ꢀ7.63 (m,
4H), 7.46ꢀ7.26 (m, 11H), 4.95 (s, 2H), 3.61 (A part of an ABX system, J = 11.4, 8.2 Hz, 1H), 3.56 (A
part of an ABX system, J = 10.1, 5.6 Hz, 1H), 3.51 (B part of an ABX system, J = 10.1, 7.1 Hz, 1H),
3.47 (B part of an ABX system, J = 11.4, 4.9 Hz, 1H), 3.18 (A part of an ABX system, J = 18.0, 8.9 Hz,
1H), 2.94 (B part of an ABX system, J = 18.0, 5.8 Hz, 1H), 2.64ꢀ2.50 (m, 1H), 1.00 (s, 9H). C{1H}
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NMR (75 MHz, CDCl3) δ 201.1, 135.65 (2C), 135.63 (2C), 135.2, 133.3, 133.2, 129.99, 129.97, 129.0
(2C), 128.4 (2C), 128.2, 127.92 (2C), 127.91 (2C), 64.8, 56.3, 51.7, 47.5, 35.1, 26.9 (3C), 19.3. IR (cm–
1): 1505, 1248, 1105. EIꢀMS, m/z (%): 402 (94), 324 (25), 234 (7), 199 (8), 190 (8), 183 (42), 135 (6),
105 (9), 91 (100). HRMS calcd. for C28H34NOSSi [M+H]+: 460.2125, found: 460.2118.
1ꢀBenzylꢀ3ꢀ[(tertꢀbutyldiphenylsilyloxy)methyl]ꢀ5ꢀmethylsulfanylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrolium iodide (12).
Prepared from 1ꢀbenzylꢀ4ꢀ[(tertꢀbutyldiphenylsilyloxy)methyl]pyrrolidineꢀ2ꢀthione (2.37 g, 5.16 mmol)
according to the procedure for 1 using CH3NO2 instead of THF. The thioiminium 12 (2.96 g, 95% yield)
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was obtained as a colorless solid. M.p. = 144ꢀ146 °C. H NMR (300 MHz, CDCl3) δ 7.48ꢀ7.30 (m,
15H), 4.86 (A part of an AB system, J = 14.9 Hz, 1H), 4.81 (B part of an AB system, J = 14.9 Hz, 1H),
4.37 (app t, J = 12 Hz, 1H), 4.11 (dd, J = 19, 9 Hz, 1H), 3.77 (dd, J = 12, 4 Hz, 1H), 3.61 (d, J = 4 Hz,
2H), 3.12 (dd, J = 19, 3 Hz, 1H), 3.12ꢀ3.00 (m, 1H), 2.87 (s, 3H), 0.95 (s, 9H). 13C{1H} NMR (75 MHz,
CDCl3) δ 193.0, 135.5 (2C), 135.4 (2C), 132.6, 132.5, 130.2, 130.1, 130.0, 129.7, 129.5 (2C), 129.3
(2C), 128.0 (2C), 127.9 (2C), 64.2, 62.5, 55.6, 43.6, 34.6, 26.9 (3C), 19.2, 17.4. IR (cm–1): 1601, 1585,
1094. HRMS calcd. for C29H36NOSSi [MꢀI]+: 474.2281, found: 474.2276.
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Methyl 1ꢀbenzylꢀ5ꢀthioxopyrrolidineꢀ3ꢀcarboxylate. Prepared from the methyl 1ꢀbenzylꢀ5ꢀ
oxopyrrolidineꢀ3ꢀcarboxylate 9 (4.90 g, 21.0 mmol) according to a known procedure.18 The thiolactam
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(4.24 g, 80% yield) was obtained as a colorless liquid. nD = 1.5920 (lit. nD20 1.5880).18 Physical and
spectral data in accordance with the literature.18
1ꢀBenzylꢀ3ꢀmethoxycarbonylꢀ5ꢀmethylsulfanylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrolium iodide (13). Prepared from
methyl 1ꢀbenzylꢀ5ꢀthioxopyrrolidineꢀ3ꢀcarboxylate (0.69 g, 2.15 mmol) according to the procedure for 1
using CH3NO2 instead of THF. The thioiminium 13 (2.20 g, 81% yield) was obtained as a colorless
solid. M.p. = 108ꢀ109 °C. 1H NMR (300 MHz, CDCl3) δ 7.47ꢀ7.42 (m, 3H), 7.40ꢀ7.35 (m, 2H), 4.93 (A
part of an AB system, J = 15.2 Hz, 1H), 4.86 (B part of an AB system, J = 15.2 Hz, 1H), 4.65 (A part of
an ABC system, J = 12.5, 9.3 Hz, 1H), 4.47 (A part of an ABC system, J = 18.8, 10.4 Hz, 1H), 4.13 (B
part of an ABC system, J = 12.5, 4.5 Hz, 1H), 3.95 (app tt, J = 10, 5 Hz, 1H), 3.73 (s, 3H), 3.58 (B part
of an ABC system, J = 18.8, 3.9 Hz, 1H), 2.94 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 192.4, 170.8,
129.6, 129.5, 129.3 (2C), 129.1 (2C), 61.5, 55.2, 53.0, 43.7, 37.2, 17.5. IR (cm–1): 1722, 1608. HRMS
calcd. for C14H18NO2S [MꢀI]+: 264.1053, found: 264.1053.
1ꢀBenzylꢀ4ꢀpropionylpyrrolidineꢀ2ꢀthione. Prepared from the 1ꢀbenzylꢀ4ꢀpropionylpyrrolidinꢀ2ꢀone 10
(1.45 g, 6.27 mmol) according to the procedure for 1ꢀbenzylpyrrolidineꢀ2ꢀthione. The thiolactam (1.35
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g, 87% yield) was obtained as a colorless solid. M.p. = 64ꢀ65 °C. H NMR (300 MHz, CDCl3) δ 7.39ꢀ
7.29 (m, 5H), 5.08 (A part of an AB system, J = 14.4 Hz, 1H), 4.86 (B part of an AB system, J = 14.4
Hz, 1H), 3.94ꢀ3.88 (m, 1H), 3.66ꢀ3.60 (m, 1H), 3.45ꢀ3.16 (m, 3H), 2.50 (A part of an ABX3 system, J =
17.7, 7.3 Hz, 1H), 2.40 (B part of an ABX3 system, J = 17.7, 7.3 Hz, 1H), 1.06 (t, J = 7.3 Hz, 3H).
13C{1H} NMR (75 MHz, CDCl3) δ 208.2, 198.7, 134.8, 129.1 (2C), 128.5 (2C), 128.4, 54.6, 51.8, 47.3,
44.0, 34.9, 7.7. IR (cm–1): 1711, 1506. EIꢀMS, m/z (%): 247 (86), 214 (15), 190 (23), 162 (14), 156 (15),
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148 (17), 123 (17), 106 (62), 103 (20), 99(34), 91 (100), 85 (19), 65 (22). HRMS calcd. for C14H18NOS
[M+H]+: 248.1104, found: 248.1096.
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1ꢀBenzylꢀ3ꢀpropionylꢀ5ꢀmethylsulfanylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrolium iodide (14). Prepared from 1ꢀbenzylꢀ
4ꢀpropionylpyrrolidineꢀ2ꢀthione (1.31 g, 5.30 mmol) according to the procedure for 1. The thioiminium
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14 (1.82 g, 88% yield) was obtained as a pale brownish solid. M.p. = 126ꢀ127 °C. H NMR (300 MHz,
CDCl3) δ 7.47ꢀ741 (m, 3H), 7.38ꢀ7.30 (m, 2H), 4.91 (A part of an AB system, J = 15.0 Hz, 1H), 4.86 (B
part of an AB system, J = 15.0 Hz, 1H), 4.64 (dd, J = 12.2, 10.0 Hz, 1H), 4.47 (dd, J = 18.7, 10.0 Hz,
1H), 4.13 (app tdd, J = 10.0, 5.0, 4.5 Hz, 1H), 4.00 (dd, J = 12.2, 4.5 Hz, 1H), 3.46 (dd, J = 18.7, 5.0
Hz, 1H), 2.96 (s, 3H), 2.58 (A part of an ABX3 system, J = 18.9, 7.2 Hz, 1H), 2.51 (B part of an ABX3
system, J = 18.9, 7.2 Hz, 1H), 1.05 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 207.1, 192.4,
129.7, 129.6, 129.5 (2C), 129.0 (2C), 61.1, 55.3, 43.5, 43.3, 35.3, 17.7, 7.5. IR (cm–1): 1704, 1596,
1582. HRMS calcd. for C15H20NOS [MꢀI]+: 262.1260, found: 262.1253.
Preparation of the substituted amines 15ꢀ19
1ꢀBenzylꢀ2ꢀbutylꢀ3ꢀ(tertꢀbutyldimethylsilyloxy)pyrrolidine (15). Prepared from the 1ꢀbenzylꢀ4ꢀ(tertꢀ
butyldimethylsilyloxy)ꢀ5ꢀmethylsulfanylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrolium iodide 11 (400 mg, 0.86 mmol)
according to the procedure for 2a (dr 91:9 by GC). CC (neutral aluminum oxide, pentane/Et2O 95:5 then
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Et2O) afforded 15 (253 mg, 84% yield, dr 89:11) as a paleꢀyellow liquid. H NMR (300 MHz, CDCl3)
Cis derivative, major isomer, δ 7.33ꢀ7.19 (m, 5H), 4.27 (dd, J = 11.7, 6.0 Hz, 1H), 3.98 (A part of an
AB system, J = 13.2 Hz, 1H), 3.26 (B part of an AB system, J = 13.2 Hz, 1H), 2.91 (app t, J = 7.5 Hz,
1H), 2.34ꢀ2.20 (m, 1H), 2.10ꢀ1.92 (m, 2H), 1.77ꢀ1.59 (m, 2H), 1.52ꢀ1.26 (m, 5H), 0.97ꢀ0.85 (m, 12H),
0.06 (br s, 6H). Trans derivative, minor isomer (characteristic signals), δ 2.81 (app t, J = 8.3 Hz, 1H),
2.44ꢀ2.34 (m, 2H). 13C{1H} NMR (75MHz, CDCl3) Major, δ 139.5, 129.1 (2C), 128.2 (2C), 126.8, 73.0,
68.6, 59.0, 51.4, 34.4, 29.2, 27.8, 26.0 (3C), 23.5, 18.2, 14.3, ꢀ4.1, ꢀ4.9; Minor, δ 140.0, 129.0 (2C),
128.3 (2C), 126.9, 76.7, 72.6, 59.5, 51.9, 33.5, 32.0, 27.8, 26.0 (3C), 23.3, 18.1, 14.3, ꢀ4.2, ꢀ4.6. IR (cm–
1): 3026, 1115, 1073, 1057, 732, 697. EIꢀMS, m/z (%): Major, 290 (97), 188 (13), 160 (40), 147 (27), 98
(20), 91 (100), 73 (18); Minor, 290 (96), 188 (6), 160 (16), 147 (11), 98 (10), 91 (100), 73 (10). HRMS
calcd. for C21H38NOSi [M+H]+: 348.2717, found: 348.2706. The relative cis configuration of the major
diastereomer was tentatively attributed based on mechanistic considerations and by analogy to the work
of Huang and coꢀworker.6ꢀ7, 22
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1ꢀBenzylꢀ2ꢀbutylꢀ4ꢀ[(tertꢀbutyldiphenylsilyloxy)methyl]pyrrolidine (16). Prepared from the 1ꢀBenzylꢀ3ꢀ
[(tertꢀbutyldiphenylsilyloxy)methyl]ꢀ5ꢀmethylsulfanylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrolium iodide 12 (602 mg,
1.00 mmol) according to the procedure for 2a. The amine 16 (465 mg, 96%, dr 89:11 by GC) was
obtained as a colorless liquid. 1H NMR (300 MHz, CDCl3) Cis derivative, major isomer, δ 7.70ꢀ7.60 (m,
4H), 7.46ꢀ7.20 (m, 11H), 4.05 (A part of an AB system, J = 13.3 Hz, 1H), 3.61 (A part of an ABX
system, J = 9.3, 7.7 Hz, 1H), 3.52 (B part of an ABX system, J = 9.3, 6.6 Hz, 1H), 3.14 (B part of an
AB system, J = 13.3 Hz, 1H), 2.88 (dd, J = 8.7, 1.8 Hz, 1H), 2.42ꢀ2.17 (m, 3H), 2.06 (ddd, J = 12.6, 8.4,
7.1 Hz, 1H), 1.80ꢀ1.64 (m, 1H), 1.41ꢀ1.09 (m, 6H), 1.03 (s, 9H), 0.93 (t, J = 6.9 Hz, 3H). 13C{1H} NMR
(75 MHz, CDCl3) Major, δ 140.2, 135.7 (4C), 134.4, 134.2, 129.6 (2C), 128.8 (2C), 128.2 (2C), 127.7
(4C), 126.7, 67.9, 64.6, 58.1, 56.6, 38.1, 34.3, 33.6, 28.5, 27.0 (3C), 23.3, 19.4, 14.3; Minor, δ 139.7,
135.7 (4C), 134.2, 134.1, 129.7 (2C), 129.2 (2C), 128.3 (2C), 127.7 (4C), 126.9, 66.9, 64.1, 58.8, 57.9,
38.2, 34.1, 33.9, 28.7, 27.0 (3C), 23.3, 19.4, 14.3. IR (cm–1): 3026, 1111, 1087, 738, 697. EIꢀMS, m/z
(%): Major, 428 (100), 280 (4), 199 (7), 183 (9), 172 (15), 135 (6), 91 (63); Minor 428 (100), 280(3),
199 (6), 183 (7), 172 (13), 135 (5), 91 (55). HRMS calcd. for C32H44NOSi [M+H]+: 486.3187, found:
486.3176. The relative cis configuration of the major diastereomer was assigned based on analysis of
n.O.e. difference spectra and by analogy to the work of Huang and coꢀworker.6ꢀ7, 22
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Methyl 1ꢀbenzylꢀ5ꢀbutylpyrrolidineꢀ3ꢀcarboxylate (17). Prepared from the 1ꢀbenzylꢀ3ꢀmethoxycarbonylꢀ
5ꢀmethylsulfanylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrolium iodide 13 (390 mg, 1.00 mmol) according to the procedure
for 2a. The amine 17 (279 mg, 96% yield, dr 88:12 by GC) was obtained as a colorless liquid. 1H NMR
(300 MHz, CDCl3) Cis derivative, major isomer, δ 7.33ꢀ7.20 (m, 5H), 4.04 (A part of an AB system, J =
13.4 Hz, 1H), 3.65 (s, 3H), 3.21 (A part of an ABC system, J = 9.8, 3.6 Hz, 1H), 3.18 (B part of an AB
system, J = 13.4 Hz, 1H), 2.86 (app tdd, J = 9.2, 7.2, 3.6 Hz, 1H), 2.47ꢀ2.31 (m, 1H), 2.36 (B part of an
ABC system, J = 9.8, 9.2 Hz, 1H), 2.21 (ddd, J = 12.7, 9.3, 6.7 Hz, 1H), 1.86 (ddd, J = 12.7, 9.1, 7.2 Hz,
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1H), 1.80ꢀ1.70 (m, 1H), 1.43ꢀ1.23 (m, 5H), 0.91 (t, J = 6.8 Hz, 3H). C{1H} NMR (75 MHz, CDCl3)
Major, δ 175.6, 139.3, 128.7 (2C), 128.2 (2C), 126.8, 64.3, 57.6, 56.1, 51.8, 40.3, 34.3, 33.0, 28.4, 23.2,
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14.2; Minor, δ 175.6, 139.3, 128.9 (2C), 128.3 (2C), 127.0, 64.0, 58.3, 57.1, 51.8, 40.5, 34.2, 33.6, 28.3,
23.1, 14.2. IR (cm–1): 3026, 1737, 1195, 1172, 738, 698. EIꢀMS, m/z (%): Major, 244 (18), 218 (95),
158 (8), 91 (100), 65 (14); Minor, 244 (6), 218 (91), 158 (3), 91 (100), 65 (7). HRMS calcd. for
C17H26NO2 [M+H]+: 276.1958, found: 276.1958. The relative cis configuration of the major
diastereomer was tentatively attributed by analogy with compound 16 and by analogy to the work of
Huang and coꢀworker.6ꢀ7, 22
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1ꢀBenzylꢀ2ꢀbutylꢀ4ꢀpropionylpyrrolidine (18). Prepared from the 1ꢀBenzylꢀ3ꢀpropionylꢀ5ꢀ
methylsulfanylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrolium iodide 14 (392 mg, 1.01 mmol) according to the procedure
for 2a (dr 88:12 by GC). CC (neutral aluminum oxide, pentane/EtOAc 95:5 then 85:15) afforded 18 as a
colorless liquid and as an unseparable mixture of diastereoisomers with inversion of the
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diastereoisomeric ratio (232 mg, 84% yield, dr 33:67). H NMR (300 MHz, CDCl3) Trans derivative,
major isomer after column, δ 7.33ꢀ7.20 (m, 5H), 4.05 (A part of an AB system, J = 13.4 Hz, 1H), 3.15ꢀ
3.05 (m, 2H), 2.88 (app tdd, J = 9.2, 7.1, 3.3 Hz, 1H), 2.46ꢀ2.10 (m, 5H), 1.81ꢀ1.63 (m, 2H), 1.41ꢀ1.23
(m, 5H), 1.02 (t, J = 7.3 Hz, 3H), 0.91 (t, J = 6.3 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) Trans
isomer, δ 212.0, 139.6, 129.0 (2C), 128.4 (2C), 127.0, 64.2, 58.4, 56.6, 47.8, 35.4, 33.7, 33.2, 28.4, 23.2,
14.3, 7.9; Cis isomer, δ 212.1, 139.5, 128.7 (2C), 128.3 (2C), 126.9, 64.5, 57.7, 55.3, 47.8, 33.7, 33.4,
33.1, 28.4, 23.2, 14.2, 8.1. IR (cm–1): 3031, 1712, 1144, 1119, 738, 697. EIꢀMS, m/z (%): Trans isomer,
244 (2), 216 (96), 182 (19), 158 (14), 91 (100), 68 (4), 65 (10); Cis isomer, 273 (2), 216 (88), 182 (2),
158 (11), 91 (100), 68 (3), 65 (8). HRMS calcd. for C18H28NO [M+H]+: 274.2165, found: 274.2160. The
relative cis configuration of the major diastereomer was tentatively attributed by analogy with
compound 16 and by analogy to the work of Huang and coꢀworker.6ꢀ7, 22
1ꢀBenzylꢀ2ꢀbutylꢀ4ꢀpropionylꢀ1Hꢀpyrrole (19). Isolated as a side product in the synthesis of 1ꢀbenzylꢀ2ꢀ
butylꢀ4ꢀpropionylpyrrolidine 18. The pyrrole 19 (25 mg, 9% yield) was obtained as a paleꢀyellow oil. 1H
NMR (300 MHz, CDCl3) δ 7.340ꢀ7.22 (m, 4H), 7.05ꢀ6.98 (m, 2H), 6.42ꢀ6.37 (m, 1H), 5.04 (s, 2H),
2.73 (q, J = 7.4 Hz, 2H), 2.41 (t, J = 7.4 Hz, 2H), 1.55 (quint, J = 7.4 Hz, 2H), 1.34 (sext, J = 7.4 Hz,
2H), 1.17 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 196.8, 137.1,
135.6, 129.0 (2C), 127.9, 126.6 (2C), 125.9, 124.5, 106.6, 50.9, 32.5, 30.6, 25.8, 22.5, 13.9, 9.1. IR (cm–
1): 3120, 3031, 1653, 1516, 1453, 730, 700. EIꢀMS, m/z (%): 269 (14), 240 (74), 226 (12), 170 (5), 106
(4), 91 (100), 65 (5). HRMS calcd. for C18H24NO [M+H]+: 270.1852, found: 270.1857.
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(3ꢀ(2ꢀ Propylꢀ1,3ꢀdioxolanꢀ2ꢀyl)propyl)magnesium bromide. Prepared from the 2ꢀ(3ꢀ bromopropyl)ꢀ2ꢀ
propylꢀ1,3ꢀdioxolane 2048 (1.26 g, 4.99 mmol) and magnesium turnings (0.25g, 10.3 mmol) in 5.0 mL
THF according to a known procedure.41 The Grignard reagent (0.51 M, 50% yield) was obtained as a
clear solution and was used directly in the following step.
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1ꢀBenzylꢀ2ꢀ[3ꢀ(2ꢀpropylꢀ1,3ꢀdioxolanꢀ2ꢀyl)propyl]pyrrolidine (21). Prepared from the 1ꢀbenzylꢀ5ꢀ
methylsulfanylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrolium iodide 1 (202 mg, 0.61 mmol) and (3ꢀ(2ꢀ propylꢀ1,3ꢀ
dioxolanꢀ2ꢀyl)propyl)magnesium bromide according to the procedure for 2a. CC (neutral aluminum
oxide, CH2Cl2/MeOH 99:1 then cyclohexane/EtOAc 80:20) afforded 21 (154 mg, 80% yield) as a paleꢀ
yellow liquid. 1H NMR (300 MHz, CDCl3) δ 7.34ꢀ7.18 (m, 5H), 4.03 (A part of an AB system, J = 12.9
Hz, 1H), 3.92 (s, 4H), 3.13 (B part of an AB system, J = 12.9 Hz, 1H), 2.94ꢀ2.85 (m, 1H), 2.38ꢀ2.26 (m,
1H), 2.08 (app q, J = 9 Hz, 1H), 2.01ꢀ1.86 (m, 1H), 1.78ꢀ1.26 (m, 13H), 0.93 (t, J = 7.3 Hz, 3H).
13C{1H} NMR (75 MHz, CDCl3) δ 139.9, 129.0 (2C), 128.1 (2C), 126.7, 111.7, 64.9 (2C), 64.4, 58.8,
54.3, 39.5, 37.6, 34.6, 30.5, 22.0, 20.7, 17.2, 14.5. IR (cm–1): 3025, 1073, 1051, 1028, 737, 698. EIꢀMS,
m/z (%): 274 (11), 186 (4), 160 (100), 115 (21), 91 (97), 86 (3), 71 (3), 65 (3). HRMS calcd. for
C20H32NO2 [M+H]+: 318.2428, found: 318.2422.
(±)ꢀIndolizidine 167B, hydrochloric salt (22·HCl). To the 1ꢀbenzylꢀ2ꢀ[3ꢀ(2ꢀpropylꢀ1,3ꢀdioxolanꢀ2ꢀ
yl)propyl] pyrrolidine 21 (265 mg, 0.83 mmol) in EtOH (15 mL) were added HCl (2.0 mL, 1 N in H2O)
and 10% Pd/C (107 mg, 0.10 mmol). H2 was bubbled through the vigorously stirred reaction mixture for
10 min and atmospheric pressure was then maintained for 48 h. The black suspension was filtered over a
pad of Celite and concentrated under reduced pressure. The residue was diluted with H2O and Et2O. The
aqueous phase was separated, basified with solid Na2CO3 and extracted twice with Et2O. The combined
organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. An etheral
solution of HCl (3 mL, 1 M in Et2O) was added to the residue and the solvent was removed under
reduced pressure. Trituration of the residue with Et2O afforded 22·HCl (131 mg, 77% yield) as a pale
brownish solid. M.p. = 166–169 °C (lit.71 167–169 °C). Given the limited solubility of 22·HCl in
CDCl3, the NMR spectra were also recorded with the corresponding free amine 22. Physical and
spectral data in accordance with the literature.27, 36, 41, 71
Formation and reactivity of the enamines
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1ꢀBenzylꢀ5ꢀbutylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrolium iodide (23). To 5ꢀbutylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrole72 (215 mg,
1.72 mmol) in CH3NO2 (2.5 mL) was added benzyl iodide (0.23 mL, 1.84 mmol). The flask was
wrapped in aluminum foil and the reaction mixture was stirred at rt for 8ꢀ12 h. The volatiles were
removed under reduced pressure. After precipitation/crystallization with Et2O, the supernatant was
removed and the remaining solid was repeatedly washed with Et2O. Drying under reduced pressure
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afforded the iminium salt 23 (513 mg, 87% yield) as a yellow solid. M.p. = 64ꢀ68 °C. H NMR (300
MHz, CDCl3) δ 7.48ꢀ7.38 (m, 5H), 5.08 (s, 2H), 4.18 (app t, J = 7.9 Hz, 2H), 3.49 (app t, J = 8.0 Hz,
2H), 3.04 (app t, J = 8.1 Hz, 2H), 2.29 (app quint, J = 8 Hz, 2H), 1.78 (app quint, J = 8 Hz, 2H), 1.48
(sext, J = 7.3 Hz, 2H), 0.98 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 195.2, 130.1, 129.6,
129.5 (2C), 129.0, 60.7, 55.2, 40.1, 32.2, 27.9, 22.9, 18.1, 13.6. IR (cm–1): 2957, 2930, 2871, 1659,
1455, 1373, 727, 696. HRMS calcd. for C15H22N [MꢀI]+: 216.1747, found: 216.1749.
1ꢀBenzylꢀ2ꢀbutylidenepyrrolidine (24). Me2S (0.40 mL, 5.45 mmol) was added to a suspension of CuI
(333 mg, 1.75 mmol) in THF (5 mL), at rt. The colorless solution obtained was cooled with a dryꢀ
ice/acetone bath and nꢀBuLi (0.85 mL, 2.5 M in hexanes, 1.7 mmol) was added dropwise. The
temperature was maintained below –65 °C during the addition. The resulting suspension was allowed to
warm up to –20/–15 °C and was immediately cooled back to –78 °C. 1ꢀBenzylꢀ5ꢀbutylꢀ3,4ꢀdihydroꢀ2Hꢀ
pyrrolium iodide 23. (309 mg, 0.90 mmol) was then added as a CH2Cl2 solution (4 mL). The stirring
was maintained at –35/–30 °C for 0.5 h. An iceꢀbrine bath was put in place and the stirring maintained
for an additional 0.5 h. After decantation, an aliquot of the solution was evaporated and submitted to 1H
NMR showing exoꢀ24 as sole product. 1H NMR (300 MHz, C6D6) δ 7.23ꢀ7.07 (m, 5H), 4.17 (t, J = 7.2
Hz, 1H), 3.98 (s, 2H), 2.76 (t, J = 6.5 Hz, 2H), 2.33 (t, J = 7.6 Hz, 2H), 2.08 (q, J = 7.2 Hz, 2H), 1.50ꢀ
1.45 (m, 4H), 0.97 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (75 MHz, CD2Cl2) δ 147.5, 140.0, 128.8 (2C),
128.3 (2C), 127.1, 90.1, 53.0, 52.3, 31.3, 29.0, 25.1, 22.5, 14.1. IR (cm–1): 3032, 1617, 1453, 1329, 732,
699. HRMS calcd. for C15H22N [M+H]+: 216.1741, found: 216.1747. The exocyclic nature and the
geometry of the enamine was assigned from n.O.e. difference spectra.
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1ꢀBenzylꢀ6ꢀbutylꢀ1,2,3,4ꢀtetrahydropyridine (25). Me2S (0.40 mL, 5.45 mmol) was added to a
suspension of CuI (333 mg, 1.75 mmol) in THF (5 mL), at rt. The colorless solution obtained was
cooled with a dryꢀice/acetone bath and nꢀBuLi (0.85 mL, 2.5 M in hexanes, 1.7 mmol) was added
dropwise. The temperature was maintained below –65 °C during the addition. The resulting suspension
was allowed to warm up to –20/–15 °C and was immediately cooled back to –78 °C. 1ꢀbenzylꢀ6ꢀ
methylsulfanylꢀ2,3,4,5ꢀtetrahydro pyridinium iodide 3 (208 mg, 0.60 mmol) was then added as a
CH2Cl2 solution (4 mL). The stirring was maintained at –35/–30 °C for 0.5 h. An iceꢀbrine bath was put
in place and the stirring maintained for an additional 0.5 h. After decantation, an aliquot of the solution
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was evaporated and submitted to H NMR showing endoꢀ25 as sole product. H NMR (300 MHz,
CD2Cl2) δ 7.37ꢀ7.23 (m, 5H), 4.45 (app s, 1H), 4.11 (s, 2H), 2.93ꢀ2.90 (m, 2H), 2.17 (t, J = 7.4 Hz, 2H),
2.04 (t, J = 5.9 Hz, 2H), 1.72ꢀ1.65 (m, 2H), 1.56ꢀ1.46 (m, 2H), 1.42ꢀ1.32 (m, 2H), 0.94 (t, J = 7.2 Hz,
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3H). C{1H} NMR (75 MHz, CD2Cl2) δ 145.5, 141.2, 128.9 (2C), 128.1 (2C), 127.2, 97.8, 54.5, 48.9,
34.2, 31.6, 23.7, 23.0, 22.3, 14.4. IR (cm–1): 3059, 1640, 1451, 728, 696. HRMS calcd. for C16H24N
[M+H]+: 230.1903, found: 230.1903.
1ꢀBenzylꢀ2ꢀpropylpiperidinꢀ3ꢀone (27). To CuI (571 mg, 3.00 mmol) in THF (6 mL) was added Me2S
(0.66 mL, 9.00 mmol) at rt. The colorless solution obtained was cooled with a dryꢀice/acetone bath and
nꢀBuLi (1.2 mL, 2.5 M in hexanes) was added dropwise with the temperature being maintained below –
65 °C. The resulting suspension was allowed to warm up to –15 °C and was cooled back to –78 °C. 1ꢀ
Benzylꢀ5ꢀmethylsulfanylꢀ3,4ꢀdihydroꢀ2Hꢀpyrrolium iodide (334 mg, 1.00 mmol) in CH2Cl2 (4.5 mL)
was added. The stirring was maintained at –35/–30 °C for 0.5 h. An iceꢀbrine bath was put in place and
the stirring was maintained for an additional 0.5 h. H2O (5 mL) was added and the stirring was
maintained at rt overnight. EtOAc and solid Na2CO3 were added. The mixture was allowed to decant
and filtered over a pad of Celite. The aqueous phase was separated and extracted twice with EtOAc. The
combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure.
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Filtration (neutral aluminum oxide, CH2Cl2) afforded 27 (133 mg, 57% yield) as a yellow oil along with
1ꢀbenzylꢀ2ꢀpyrrolidinone 26 (69 mg, 39% yield) upon elution with EtOAc. 1H NMR (300 MHz, CDCl3)
δ 7.34ꢀ7.24 (m, 5H), 3.77 (A part of an AB system, J = 13.5 Hz, 1H), 3.61 (B part of an AB system, J =
13.5 Hz, 1H), 3.07 (br t, J = 7 Hz, 1H), 3.02 (ddd, J = 13, 9, 5 Hz, 1H), 2.59 (app dt, J = 13, 6 Hz, 1H),
2.53 (ddd, J = 15, 9, 6 Hz, 1H), 2.35 (ddd, J = 15, 6, 5 Hz, 1H), 2.11ꢀ1.91 (m, 2H), 1.86ꢀ1.60 (m, 2H),
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1.34 (app sext, J = 7 Hz, 2H), 0.89 (t, J = 7 Hz, 3H). C{1H} NMR (75 MHz, CDCl3) δ 212.0, 139.0,
128.8 (2C), 128.4 (2C), 127.2, 70.7, 57.4, 46.0, 37.9, 29.4, 24.2, 19.2, 14.2. IR (cm–1): 2955, 1712,
1495, 1452, 730, 697. EIꢀMS, m/z (%): 203 (15), 188 (10), 174 (12), 160 (72), 91 (100), 84 (9), 65 (11).
HRMS calcd. for C15H22NO [M+H]+: 232.1696, found: 232.1696.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: philippe.renaud@dcb.unibe.ch
ORCID
Philippe Renaud: 0000ꢀ0002ꢀ9069ꢀ7109
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The Swiss National Science Foundation (Projects 200020_152782 and 200020_172621) is gratefully
acknowledged for financial support. M. Meyer Mojzes was generously supported by the State
Secretariat for Education, Research and Innovation (SERI) via a Swiss Government Excellence
Scholarships for Foreign Scholars and Artists.
ASSOCIATED CONTENT
Supporting Information
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REFERENCES
1. Seebach, D., Angew. Chem. Int. Ed. 2010, 50, 96ꢀ101.
2. Huo, H.ꢀH.; Zhang, H.ꢀK.; Xia, X.ꢀE.; Huang, P.ꢀQ., Org. Lett. 2012, 14, 4834ꢀ4837.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
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59
60
3. Deng, H.ꢀQ.; Qian, X.ꢀY.; Li, Y.ꢀX.; Zheng, J.ꢀF.; Xie, L.; Huang, P.ꢀQ., Org. Chem. Front. 2014, 1,
258ꢀ266.
4. Falmagne, J. B.; Escudero, J.; Taleb Sahraoui, S.; Ghosez, L., Angew. Chem. Int. Ed. 1981, 20, 879ꢀ
880.
5. Barbaro, G.; Battaglia, A.; Bruno, C.; Giorgianni, P.; Guerrini, A., J. Org. Chem. 1996, 61, 8480ꢀ
8488.
6. Xiao, K.; Luo, J.; Ye, K.; Wang, Y.; Huang, P., Angew. Chem. Int. Ed. 2010, 49, 3037ꢀ3040.
7. Xiao, K.ꢀJ.; Wang, Y.; Ye, K.ꢀY.; Huang, P.ꢀQ., Chem. Eur. J. 2010, 16, 12792ꢀ12796.
8. Agosti, A.; Britto, S.; Renaud, P., Org. Lett. 2008, 10, 1417ꢀ1420.
9. Takahata, H.; Takahashi, K.; Wang, E.ꢀC.; Yamazaki, T., J. Chem. Soc., Perkin Trans. 1 1989,
1211ꢀ1214.
10. Murai, T.; Mutoh, Y.; Ohta, Y.; Murakami, M., J. Am. Chem. Soc. 2004, 126, 5968ꢀ5969.
11. Murai, T.; Toshio, R.; Mutoh, Y., Tetrahedron 2006, 62, 6312ꢀ6320.
12. Klaver, W. J.; Hiemstra, H.; Speckamp, W. N., J. Am. Chem. Soc. 1989, 111, 2588ꢀ2595.
13. Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J., J. Org. Chem. 2003, 68, 1919ꢀ1928.
14. House, H. O.; Chu, C.ꢀY.; Wilkins, J. M.; Umen, M. J., J. Org. Chem. 1975, 40, 1460ꢀ1469.
15. Lipshutz, B. H., In Organometallics in Synthesis A Manual, 2. ed.; Schlosser, M., Ed. John Wiley:
Chichester, 2002; pp 665ꢀ815.
16. Staubitz, A.; Robertson, A.; Sloan, M.; Manners, I., Chem. Rev. 2010, 110, 4023ꢀ4078.
17. CCDC 1560696 contains the supplementary crystallographic data for compound 48. These data can
be obtained free of charge from The Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk/data_request/cif.
18. Stanetty, P.; Turner, M.; Mihovilovic, M., Molecules 2005, 10, 367ꢀ375.
19. Singh, R.; Sinha, N.; Jain, S.; Salman, M.; Naqvi, F.; Anand, N., Tetrahedron 2005, 61, 8868ꢀ8874.
20. Kurasaki, H.; Okamoto, I.; Morita, N.; Tamura, O., Chem. Eur. J. 2009, 15, 12754ꢀ12763.
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