One-pot synthesis of 3-azido- and 3-aminopiperidines by intramolecular cyclization of unsaturated amines

Article abstract of DOI:10.1021/jo4022666

A highly efficient one-pot synthesis of 3- azidopiperidines has been achieved by an intramolecular cyclization of unsaturated amines that allows for the nucleophilic installation of an azide moiety. This method unlocks the versatile employment of the azide functionality in the preparation and biological studies of piperidine-containing structures. This strategy has been expanded for the direct incorporation of a variety of nitrogen nucleophiles, and thus it provides a rapid and modular synthesis of 3-amino and 3- amidopiperidines of important pharmaceutical and biological relevance. Particularly noteworthy is that the regioselectivity of this transformation enables the formation of the anti- Markovnikov-type adduct, complementing Markovnikov-based olefin amino functionalization methods.

Full text of DOI:10.1021/jo4022666

Article
pubs.acs.org/joc
One-Pot Synthesis of 3‑Azido- and 3‑Aminopiperidines by
Intramolecular Cyclization of Unsaturated Amines
Gerardo X. Ortiz, Jr., Bora Kang, and Qiu Wang*
Department of Chemistry, Duke University, Durham, North Carolina 27708, United States
S
* Supporting Information
ABSTRACT: A highly efficient one-pot synthesis of 3-
azidopiperidines has been achieved by an intramolecular
cyclization of unsaturated amines that allows for the
nucleophilic installation of an azide moiety. This method
unlocks the versatile employment of the azide functionality in
the preparation and biological studies of piperidine-containing
structures. This strategy has been expanded for the direct
incorporation of a variety of nitrogen nucleophiles, and thus it
provides a rapid and modular synthesis of 3-amino and 3-
amidopiperidines of important pharmaceutical and biological
relevance. Particularly noteworthy is that the regioselectivity of
this transformation enables the formation of the anti-
Markovnikov-type adduct, complementing Markovnikov-based olefin amino functionalization methods.
approach toward understanding the mode of action of bioactive
piperidine-containing molecules as well as their clinical
potential.6
INTRODUCTION
■
Piperidine-based structures have attracted continuous interest
due to their widespread existence in natural products1 (e.g.,
slaframine and prosophylline), medicine (e.g., pethidine), and
molecules of important biological activities2 (e.g., IdeS
inhibitor;2a σ1 receptor ligand;2e and CP-99,994,2b an NK1
receptor antagonist) (Figure 1). These compounds hold
Our group has been interested in developing new chemical
methods that allow for the installation of such a chemical
reporter onto the piperidine ring. Toward this, we recently
developed a one-pot synthesis of 3-fluoropiperidines (Scheme
1, Nu = F).7 That reaction involves an initial amino cyclization
step of an N-iodoamine intermediate I formed in situ,8 the
subsequent rearrangement of pyrrolidine II to the aziridinium
intermediate9 III, followed by the nucleophilic ring-opening by
a fluoride ion to give the final product. Herein we report our
studies on extending this strategy for the incorporation of an
azide functionality onto the piperidine ring (Scheme 1, Nu =
N3). Such a general approach to access an azidopiperidine ring
will be highly valued as the azide functionality has been proven
to be the most versatile bioorthogonal chemical reporter in
chemical biology and one of the most useful building blocks in
organic synthesis.10−12 For example, the introduced azide will
enable the covalent conjugation of an azidopiperidine molecule
to facilitate the identification of its cellular targets.10,11
Furthermore, the diverse reactivity of the azide moiety will
allow for rapid structural functionalization to an extensive range
of derivatives.12 Although many methods have been developed
to prepare piperidine-containing structures, a direct method for
the incorporation of an azide onto the piperidine ring remains
absent, impeding the biological exploration of these privileged
compounds. In this contribution, we describe our development
of a modular one-pot synthesis of 3-azidopiperidines starting
Figure 1. Examples of piperidine-containing natural products,
medicine, and biologically active compounds.
remarkable promise for the treatment of osteoporosis,
rheumatoid arthritis, depressive and mnemonic disorders,
anxiety, and Alzheimer’s disease, demonstrating the importance
of piperidines in biology and medicine. Therefore, rapid access
of piperidine skeletons from readily available acyclic alkenes is
extremely valuable.3−5 Particularly useful are alkene amino-
functionalizations that enable the incorporation of a chemical
reporter (e.g., fluorine-18 for PET imaging) onto the resulting
piperidine ring; such functionalities will provide a chemical
Received: October 15, 2013
© XXXX American Chemical Society
A
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Scheme 1. Synthesis of 3-Functionalized Piperidines
from unsaturated amines. Auxiliary transformations of the azido
group on the piperidine ring demonstrate the great potential of
this approach in the synthesis and biological studies of
piperidine-based molecules. Additionally, this strategy has
been extended as a general approach to incorporate a variety
of nitrogen nucleophiles for the preparation of 3-amino-
piperidines, which are found widely in natural products and
biologically active compounds (Figure 1). N-Chloroamides,
acting as both the halogenation source and the nucleophilic
nitrogen source, offer an appealing dual role in this formal
olefin diamination reaction. Importantly, this transformation
provides the anti-Markovnikov-type adducts, uniquely com-
plementing traditional Markovnikov-based intramolecular
amination methods.4,5
NaI and NaN3 to this solution led to the formation of 2a in
excellent yield, although a longer reaction time is required
(entries 2−4). Even with only 1.2 equiv of NaN3, 2a was
formed in 92% yield (entry 3). The control experiment suggests
the essential role of NaI in promoting this transformation
(entry 4). It should be noted that, in all conditions, the exo-
ring-opened pyrrolidine 3a was not detected. Thus, its
regioselectivity profile for 6-endo-cyclization products14 comple-
ments traditional Markovnikov-based intramolecular amination
reactions of similar olefin substrates.4,5,15
With effective conditions identified, we examined the
generality and efficiency of this one-pot synthesis of 3-
azidopiperidines on a range of substrates with different
substitutions on the nitrogen atom, olefin moiety, and alkyl
backbone (Table 2). For 1a−1c, pentenyl substrates bearing
different substitutions on the nitrogen, all formed 3-
azidopiperidine products with excellent regioselectivity and
yields (entries 1−3). Disubstituted olefins 1d−1h also
efficiently generated the 3-azidopiperidine products with high
regioselectivity and diastereoselectivity (entries 4−8). In
particular, the Z-alkene gave exclusively the cyclic cis-amine
and the E-alkene provided only the trans product. The low yield
in the case of the trisubstituted alkene 1i suggested that steric
hindrance affects the efficiency of this transformation (entry 9).
Additionally, we examined the effect of the substitution on the
backbone, including both acyclic and cyclic substrates (entries
10−16). Substrate 1j, which lacks substitution on the backbone,
smoothly afforded β-azido heterocycles with little regioselec-
tivity. For substrates 1k−1m, with a methyl substitution at the
α-, β-, and γ-positions relative to the nitrogen atom respectively,
all provided the desired 3-azidopiperidine products (entries
11−13). The observed stereochemical outcome suggests the
regioselectivity of this transformation is influenced by
substitutions on the backbone and that substitution at the β-
position favors the endo nucleophilic ring-opening.16 For cyclic
substrates, 1n with a cyclopropane at the β-position provided
the spiro products with modest endo selectivity (entry 14).
Comparatively, cyclic substrates 1o−1p afforded 3-azidopiper-
idine bicyclic products in good yields (entries 15−16). Finally,
the reaction of hexenyl substrate 1q slightly favored the
formation of endo product 2q, providing β-azidoazapane under
the standard conditions (entry 17).
RESULTS AND DISCUSSION
■
Our studies began with establishing effective conditions for the
formation of 3-azidopiperidine 2a from model substrate 1a
(Table 1). On the basis of our earlier work,7 NaI was found to
Table 1. Condition Optimization for the Synthesis of 3-
a
Azidopiperidine 2a
b
entry alkene NCS (equiv) NaI (mol %) NaN3 (equiv) 2a (%)
1
2
3
4
1a-I
1a
−
1.0
5
5
2.0
2.0
1.2
1.2
69
93
92
1a
1.0
5
c
1a
1.0
−
--
a
Conditions. Entry 1: 1a-I (1.0 equiv, 0.1 mmol, 0.18 M), (0.05
equiv), MeCN, 50 °C, 8 h. Entries 2−4: 1a (1.0 equiv, 0.09 mmol, 0.1
b
M), MeCN, 24 °C, 2 h; then 60 °C, 48 h. NMR yields. No 3a
detected. Determined by 1H NMR spectroscopy using either DMF or
c
CH2Br2 as an internal standard. Neither 2a nor 4a formed; only 1a-I
was observed.
To further explore the applications of this method, we
examined the transformation of 3-azidopiperidine 2h into
differently functionalized piperidine derivatives (Scheme 2).
First, 2h was exposed to reduction conditions to transform the
azido group to an amino functionality.17 The primary amine 5
was formed in 91% yield when 2h was treated with PPh3 in the
presence of water, while the secondary amine 6 was obtained in
54% yield when 2h was treated with PMe3 followed by the
addition of aldehyde and NaBH4. Rather, free diamine 7 was
obtained in 87% yield upon the hydrogenolysis of 2h with Pd/
C, resulting from the simultaneous reduction of the azide group
and removal of the benzyl group in a single step. 1,2,3-Triazole
8 was formed in 99% yield by a facile 1,3-dipolar cycloaddition
be effective as a catalyst to convert the N-chloramine precursor
1a-I to 3-chloropiperidine 4a in the absence of an external
nucleophile. In the presence of NaN3, the nucleophilic ring-
opening with azide outcompeted the reversible reaction with
chloride,8 leading to the formation of the desired 3-
azidopiperidine 2a (entry 1). MeCN was found to be the
most effective solvent in the initial screenings.13 Next, we
focused on developing a simple one-pot protocol that would
directly transform amine precursors to 3-azidopiperidines.
Toward this, N-chloramine 1a-I was formed upon the
treatment of 1a with N-chlorosuccinimide (NCS); addition of
B
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Table 2. One-Pot Synthesis of 3-Azidopiperidines from
Unsaturated Amines
Scheme 2. Derivatization of the Azide Group for
Functionalization and Bioorthogonal Labeling of Piperidines
a
give triazole 9 in 92% yield, while the Staudinger ligation18 of
2h formed the desired product 10 in 90% yield. These
successes suggest the potential applications of this one-pot
synthesis of 3-azidopiperidines for molecular labeling of
bioactive molecules containing the piperidine motif.
Using this aminocyclization/ring-opening strategy, we
subsequently examined the use of amines as nucleophiles for
their direct incorporation onto substrates 1f and 1h (Table 3).
Encouragingly, both acyclic and cyclic amines were successfully
introduced onto the piperidine in excellent yields under slightly
modified conditions (entries 1−2). Next we looked into the
scope of other heteroatom nucleophiles such as acetate,
thiocyanate, and cyanide in the reactions of 1f and 1h,
respectively. With NaOAc as the nucleophile, the desired 3-
acetopiperidine products 15 and 16 were readily formed (entry
3), demonstrating the potential extension of this method in
preparing 3-oxygenated piperidines (e.g., natural product
prosophylline, Figure 1). When NaSCN was used, the expected
3-thiocyanatopiperidine was not detected in either reaction of
1f or 1h. Interestingly, thiourea 17 was formed in the reaction
of 1f, and 3-isothiocyanatopiperidine 18 was formed from 1h
(entry 4). Both results suggest that nitrogen nucleophilic ring-
opening outcompetes sulfur ring-opening under current
conditions.19 Particularly interestingly, the 3-isothiocyanatopi-
peridine intermediate from 1f readily formed a cyclic thiourea
17 upon the cleavage of a tert-butyl group. The reaction with
NaCN gave a 1:1 mixture of 3-cyanopiperidine (e.g., 19, 21)
and 3-succinylpiperidine (e.g., 20, 22) (entry 5). This outcome
suggests that succinimide (pKa = 14.7), formed as a byproduct
from NCS in the chlorination step, can serve as an effective
nucleophile for the ring-opening step in the presence of a base
such as NaCN (HCN, pKa = 12.7).
Intrigued by the dual role of NCS as both the chlorinating
reagent and nucleophile source in the formation of 3-
succinylpiperidine (20 and 22), we decided to further explore
this atom-efficient transformation in the reaction of alkene 1h
with NCS using the non-nucleophilic base Na2CO3 (Scheme
3). With succinimide as the sole nucleophile for the ring-
opening step, 3-succinylpiperidine 22 efficiently formed in 77%
yield. To determine if other N-chloroamides could also
promote such a tandem chlorination/cyclization/nucleophilic
ring-opening reaction, we applied chloramine-T (TsNClNa)
and N-chloropyrrolidinone20 to similar reactions with 1h. Both
a
Reactions conditions: 1 (1.0 equiv, 0.3 mmol, 0.1 M), NCS (1.0
equiv), 24 °C, 2 h; NaI (0.05 equiv), NaN3 (1.2 equiv), 60 °C, 48 h.
b
c
Isolated yields. Regioselectivity (2:3) and diastereoselectivity (dr)
were determined by 1H NMR spectroscopy with DMF as a
quantitative internal standard and confirmed by GC/MS analysis of
the reaction mixture. Major diastereomer is shown.
of 2h with dimethyl acetylenedicarboxylate (DMAD). These
representative transformations exhibit the versatility of azide as
a useful synthetic handle. Next, azidopiperidine 2h was
subjected to the two most widely used bioorthogonal reactions;
the azide−alkyne click chemistry10f of 2h with phenyl acetylene
in a mixture of water and tert-butanol proceeded smoothly to
C
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Table 3. Synthesis of 3-Functionalized Piperidines Using N,
O, and C-Nucleophiles
Scheme 3. One-Pot Synthesis of 3-Amidopiperidines from
Unsaturated Amine 1h
a
amidopiperidines, which allows for the rapid access of
piperidine-based natural products and biologically active
compounds containing such functionalities. Particularly useful
is the introduction of the azide as a versatile bioorthogonal
chemical reporter, greatly facilitating the biological studies of
this privileged structure. It is noteworthy that this formal
intramolecular olefin amino-functionalization provides anti-
Markovnikov-type adducts, uniquely complementing traditional
Markovnikov-based olefin functionalizations.
EXPERIMENTAL SECTION
■
General Experiement Information. Unless otherwise
noted, reactions were performed without exclusion of air or
moisture. All commerially available reagents and solvents were
used as received unless otherwise stated. N-chlorosuccinimide
(NCS) was recrystallized from boiling water then dried under a
vacuum and stored in a desiccator. Sodium thiosulfate was
dried under a vacuum at 60 °C before use. Analytical thin-layer
chromatography (TLC) was performed using aluminum plates
precoated with 0.25 mm of 230−400 mesh silica gel
impregnated with a fluorescent indicator (254 nmol). TLC
plates were visualized by exposure to ultraviolet light and/or
exposure to KMnO4 stain. Organic solutions were concentrated
in vacuo using a rotary evaporator. Column chromatography
was performed with silica gel (60 Å, standard grade). Nuclear
magnetic resonance spectra were recorded at ambient temper-
ature (unless otherwise stated) and 400 or 500 MHz. All values
for proton chemical shifts are reported in parts per million (δ)
and are referenced to the residual protium in CDCl3 (δ 7.26).
All values for carbon chemical shifts are reported in parts per
million (δ) and are referenced to the carbon resonances in
CDCl3 (δ 77.0). Infrared spectroscopic data are reported in
wavenumbers (cm−1), and only selected peaks are reported.
High-resolution mass spectra were obtained using a liquid
chromatography−electrospray ionization and time-of-flight
mass spectrometer.
General Procedure for the One-Pot Azido-Cyclization
Reactions. To a solution of unsaturated amine (0.3 mmol, 1
equiv) in anhydrous MeCN (3 mL) was added NCS (0.3
mmol, 1 equiv). The reaction solution was allowed to stir in the
dark for 2 h, after which NaI (0.015 mmol, 0.05 equiv) and
NaN3 (0.36 mmol, 1.2 equiv) were added. The solution was
then immediately heated to 60 °C and allowed to stir for 48 h.
After cooling down to room temperature, the reaction mixture
was diluted with an aqueous solution of NaOH (7 mL, 0.4 M)
and extracted with hexanes (10 mL × 4). The hexane layers
a
Reaction conditions. step 1: 1f or 1h (1.0 equiv, 0.3 mmol, 0.1 M),
b
NCS (1.0 equiv), 24 °C, 2 h; step 2: listed in Table 3. Isolated yields.
c
1
Yields and ratios were determined by H NMR spectroscopy with
CH2Br2 as a quantitative internal standard.
reactions provided the desired products, sulfonamide 23 and 3-
amidopiperidine 24, in 77% and 65% yield, respectively.
Additional base was not even needed in the reaction of
chloramine T. These results not only demonstrate the atom-
efficiency of this tandem transformation but also establish the
applicability of using nonacidic amides (pyrrolidinone pKa =
24) as nucleophiles for an effective and modular synthesis of 3-
amidopiperidines. It is particularly notable that all of these
reactions continued to form the anti-Markovnikov-type product
exclusively, providing opposite regioselectivity when compared
to most olefin intramolecular amination reactions.4,5
CONCLUSION
■
In summary, we have developed a one-pot synthesis of 3-
functionalized piperidines starting from unsaturated amines.
The wide substrate scope and adaptability of the protocol will
greatly expedite the preparation of 3-azido, 3-amino, and 3-
D
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were combined and washed with an aqueous solution of NaOH
(1.25 M, 5 mL) followed by brine (15 mL). The organic layer
was dried over Na2SO4, and filtered. The filtrate was
concentrated in vacuo. The crude residue was purified by either
column chromatography or Kugelrohr distillation.
2.42−2.28 (m, 2H, 2e; m, 2H, 3e), 2.22 (q, J = 8.3 Hz, 1H, 3e),
1.94−1.84 (m, 1H, 2e), 1.84−1.21 (m, 9H, 2e; m, 9H, 3e),
1.01 (t, J = 7.4 Hz, 3H, 3e), 0.94 (t, J = 7.4 Hz, 3H, 2e), 0.91 (t,
J = 7.4 Hz, 3H, 3e), 0.90 (t, J = 7.2 Hz, 3H, 2e); 13C NMR
(125 MHz, CDCl3, 2e): δ 63.4, 58.9, 53.1, 49.8, 27.6, 27.4, 21.5,
20.7, 19.8, 14.0, 11.6; 13C NMR (125 MHz, CDCl3, 3e): δ 68.5,
67.1, 56.5, 54.4, 31.3, 27.7, 27.2, 24.2, 23.2, 20.5, 11.4; FTIR
(thin film), cm−1 2956, 2931, 2091, 1255; HRMS-ESI (m/z)
calcd for C11H23N4 ([M + H]+): 211.1917; found: 211.1918.
cis-3-Azido-1-(tert-butyl)-2-ethylpiperidine (2f). Isola-
tion by column chromatography (1% ethyl acetate−1%
NH4OH−hexanes); Clear liquid (38.0 mg, 60%); Rf = 0.44
(10% ethyl acetate−hexanes); 1H NMR (400 MHz, CDCl3): δ
3.62 (dt, J = 11.7, 4.7 Hz, 1H), 3.18−3.13 (m, 1H), 2.85−2.78
(m, 1H), 2.46 (td, J = 12.9, 2.7 Hz, 1H), 1.86−1.76 (m, 1H),
5-Azido-1-butyl-3,3-dimethylpiperidine (2a). Isolation
by Kugelrohr distillation; Clear liquid (57.8 mg, 92%); Rf =
0.55 (10% ethyl acetate−hexanes); 1H NMR (400 MHz,
CDCl3): δ 3.57 (ddt, J = 11.4, 10.5, 4.5 Hz, 1H), 2.98 (ddt, J =
10.5, 4.5, 1.7 Hz, 1H), 2.38 (dt, J = 11.1, 1.7 Hz, 1H), 2.35−
2.23 (m, 2H), 1.74 (t, J = 10.5 Hz, 1H), 1.71 (ddt, J = 12.5, 4.5,
1.7 Hz, 1H), 1.65 (d, J = 11.1 Hz, 1H), 1.47−1.37 (m, 2H),
1.32 (sextet, J = 7.3 Hz, 2H), 1.09 (t, J = 12.0 Hz, 1H), 1.01 (s,
3H), 0.93 (s, 3H), 0.90 (t, J = 7.3 Hz, 3H); 13C NMR (125
MHz, CDCl3): δ 65.0, 58.5, 57.9, 55.6, 42.8, 31.6, 29.4, 29.1,
25.6, 20.5, 14.0; FTIR (thin film), cm−1 2954, 2929, 2092,
1247; HRMS-ESI (m/z) calcd for C11H23N4 ([M + H]+):
211.1917; found: 211.1919.
1.62−1.38 (m, 5H), 1.11 (s, 9H), 0.97 (t, J = 7.5 Hz, 3H); 13
C
NMR (125 MHz, CDCl3): δ 62.4, 57.3, 54.2, 38.2, 29.5 (3C),
25.9, 25.0, 17.4, 12.8; FTIR (thin film), cm−1 2970, 2094, 1254,
1219; HRMS-ESI (m/z) calcd for C11H23N4 ([M + H]+):
211.1917; found: 211.1916.
5-Azido-1-(tert-butyl)-3,3-dimethylpiperidine (2b).
Isolation by Kugelrohr distillation; Clear liquid (55.3 mg,
1
trans-3-Azido-1-butyl-2,5,5-trimethylpiperidine (2g).
Isolation by column chromatography (1% ethyl acetate−1%
NH4OH−hexanes); Clear liquid (51.4 mg, 76%); Rf = 0.59
(10% ethyl acetate−hexanes); 1H NMR (400 MHz, CDCl3): δ
3.06 (ddd, J = 11.9, 9.4, 4.7 Hz, 1H), 2.66 (ddd, J = 13.2, 9.0,
6.6 Hz, 1H), 2.42 (dd, J = 11.5, 2.3 Hz, 1H), 2.36 (ddd, J =
13.2, 8.5, 5.4 Hz, 1H), 1.96 (dq, J = 9.4, 6.1 Hz, 1H), 1.93 (d, J
= 11.5 Hz, 1H), 1.78 (ddd, J = 12.6, 4.7, 2.3 Hz, 1H), 1.46−
1.21 (m, 4H), 1.23 (t, J = 12.3 Hz, 1H), 1.19 (d, J = 6.1 Hz,
3H), 1.02 (s, 3H), 0.92 (s, 3H), 0.90 (t, J = 7.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3): δ 63.8, 62.5, 60.8, 52.7, 42.7, 31.0,
29.4, 27.2, 25.1, 20.6, 16.3, 14.0; FTIR (thin film), cm−1 2954,
2929, 2097, 1257; HRMS-ESI (m/z) calcd for C12H25N4 ([M +
H]+): 225.2074; found: 225.2076.
trans-3-Azido-1-benzyl-2,5,5-trimethylpiperidine (2h).
Isolation by column chromatography (1% ethyl acetate−1%
NH4OH−hexanes); Clear liquid (69.3 mg, 89%); Rf = 0.37
(10% ethyl acetate−hexanes); 1H NMR (400 MHz, CDCl3): δ
7.35−7.20 (m, 5H), 4.12 (d, J = 13.9 Hz, 1H), 3.21 (ddd, J =
11.7, 9.3, 4.7 Hz, 1H), 3.08 (d, J = 13.9 Hz, 1H), 2.34 (dd, J =
11.5, 2.3 Hz, 1H), 2.06 (dq, J = 9.3, 6.1 Hz, 1H), 1.81 (ddd, J =
12.7, 4.7, 2.3 Hz, 1H), 1.74 (d, J = 11.5 Hz, 1H), 1.31 (d, J =
6.1 Hz, 3H), 1.28 (t, J = 12.2, 1H), 1.00 (s, 3H), 0.84 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 139.9, 128.4 (2C), 128.1
(2C), 126.1, 63.7, 62.4, 61.6, 57.4, 42.7, 31.0, 29.2, 24.9, 16.9;
FTIR (thin film), cm−1 2095, 1255, 737, 697; HRMS-ESI (m/
z) calcd for C15H23N4 ([M + H]+): 259.1917; found: 259.1911.
3-Azido-1-benzyl-2,2,5,5-tetramethylpiperidine (2i).
Isolation by column chromatography (1% ethyl acetate−1%
NH4OH−hexanes); Clear liquid (22.7 mg, 28%); Rf = 0.74
(10% ethyl acetate−hexanes); 1H NMR (400 MHz, CDCl3): δ
7.38−7.19 (m, 5H), 4.08 (d, J = 14.3 Hz, 1H), 3.47 (dd, J =
12.5, 4.7 Hz, 1H), 3.03 (d, J = 14.3 Hz, 1H), 2.10 (d, J = 12.1
Hz, 1H), 2.04 (dd, J = 12.1, 2.0 Hz, 1H), 1.62 (ddd, J = 12.9,
4.7, 2.0 Hz, 1H), 1.46 (t, J = 12.7 Hz, 1H), 1.31 (s, 3H), 1.00
(s, 3H), 0.92 (s, 3H), 0.84 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 141.1, 128.1 (2C), 128.0 (2C), 126.5, 65.1, 58.1,
57.5, 53.1, 38.9, 31.0, 29.3, 26.8, 25.1, 9.6; FTIR (thin film),
cm−1 2953, 2097, 1452, 1254, 733, 697; HRMS-ESI (m/z)
calcd for C16H25N4 ([M + H]+): 273.2074; found: 273.2068.
3-Azido-1-benzylpiperidine (2j). Isolation by column
chromatography (1% ethyl acetate−1% NH4OH−hexanes);
Clear liquid (19.3 mg, 30%); Rf = 0.22 (10% ethyl acetate−
90%); Rf = 0.56 (10% ethyl acetate−hexanes); H NMR (400
MHz, CDCl3): δ 3.48 (ddt, J = 11.1, 10.4, 4.3 Hz, 1H), 3.16
(ddt, J = 10.4, 4.3, 1.9 Hz, 1H), 2.50 (dt, J = 11.1, 1.9 Hz, 1H),
1.84 (t, J = 10.4 Hz, 1H), 1.78 (d, J = 11.1 Hz, 1H), 1.71 (ddt, J
= 12.3, 4.3, 1.9 Hz, 1H), 1.07 (t, J = 11.7 Hz, 1H), 1.03 (s, 9H),
0.99 (s, 3H), 0.93 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
57.9, 56.7, 53.3, 51.5, 43.1, 31.5, 29.4, 26.4 (3C), 25.3; FTIR
(thin film), cm−1 2089, 1362, 1251, 1225; HRMS-ESI (m/z)
calcd for C11H23N4 ([M + H]+): 211.1917; found: 211.1918.
5-Azido-1-benzyl-3,3-dimethylpiperidine (2c). Isola-
tion by Kugelrohr distillation; Clear liquid (69.6 mg, 95%);
1
Rf = 0.52 (10% ethyl acetate−hexanes); H NMR (400 MHz,
CDCl3): δ 7.36−7.22 (m, 5H), 3.61 (ddt, J = 11.5, 10.5, 4.5 Hz,
1H), 3.52 (d, J = 13.5 Hz, 1H), 3.47 (d, J = 13.5 Hz, 1H), 2.99
(ddt, J = 10.5, 4.5, 2.0 Hz, 1H), 2.36 (dt, J = 10.8, 2.0 Hz, 1H),
1.83 (t, J = 10.5 Hz, 1H), 1.74 (ddt, J = 12.5, 4.5, 2.0 Hz, 1H),
1.72 (d, J = 10.8 Hz, 1H), 1.13 (t, J = 12.0 Hz, 1H), 1.05 (s,
3H), 0.91 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 138.5,
128.6 (2C), 128.2 (2C), 127.0, 64.7, 62.5, 58.1, 55.5, 42.8, 31.8,
29.2, 25.5; FTIR (thin film), cm−1 2092, 1254, 737, 697;
HRMS-ESI (m/z) calcd for C14H21N4 ([M + H]+): 245.1761;
found: 245.1761.
3-Azido-1-isobutyl-3,5,5-trimethylpiperidine (2d). Iso-
lation by Kugelrohr distillation; Clear liquid (46.3 mg, 69%); Rf
1
= 0.75 (10% ethyl acetate−hexanes); H NMR (400 MHz,
CDCl3): δ 2.58 (dt, J = 11.9, 1.8 Hz, 1H), 2.32 (dt, J = 10.9, 1.8
Hz, 1H), 2.03 (d, J = 7.4 Hz, 2H), 1.93 (d, J = 11.9 Hz, 1H),
1.76 (septet, J = 6.6 Hz, 1H), 1.73 (d, J = 10.9 Hz, 1H), 1.52
(dt, J = 14.1, 1.8 Hz, 1H), 1.25 (s, 3H), 1.15 (d, J = 14.1 Hz,
1H), 1.14 (s, 3H), 0.97 (d, J = 6.6 Hz, 3H), 0.89 (s, 3H), 0.96
(d, J = 6.6 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 66.4,
66.1, 63.3, 60.4, 47.1, 31.3, 29.9, 26.8, 26.3, 25.9, 20.8, 20.6;
FTIR (thin film), cm−1 2952, 2098, 1258, 1100; HRMS-ESI
(m/z) calcd for C12H25N4 ([M + H]+): 225.2074; found:
225.2074.
cis-3-Azido-1-butyl-2-ethylpiperidine (2e) and 2-(1-
azidopropyl)-1-butylpyrrolidine (3e). Isolation by column
chromatography (10% ethyl acetate−hexanes); Yellow liquid
(39.6 mg, 63%, 6:1 ratio); Rf = 0.14 (20% ethyl acetate−
hexanes); 1H NMR (400 MHz, CDCl3): δ 3.73 (dt, J = 6.3, 3.3
Hz, 1H, 2e), 3.12 (dt, J = 9.7, 4.3 Hz, 1H, 3e) 3.06 (ddd, J =
10.0, 5.2, 3.1 Hz, 1H, 3e), 2.80−2.69 (m, 1H, 2e; m, 1H, 3e),
2.64 (dt, J = 9.0, 5.0 Hz, 1H, 3e), 2.56 (t, J = 7.6 Hz, 2H, 2e),
E
dx.doi.org/10.1021/jo4022666 | J. Org. Chem. XXXX, XXX, XXX−XXX

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hexanes); 1H NMR (400 MHz, CDCl3): δ 7.36−7.23 (m, 5H),
3.53 (s, 2H), 3.49 (tt, J = 9.1, 4.1 Hz, 1H), 2.82 (ddt, J = 10.8,
4.1, 1.5 Hz, 1H), 2.62 (dtt, J = 11.3, 3.3, 1.5 Hz, 1H), 2.20−
2.06 (m, 2H), 1.93 (dqt, J = 12.6, 4.1, 1.5 Hz, 1H), 1.82−1.73
(m, 1H), 1.64−1.52 (m, 1H), 1.45−1.34 (m, 1H); 13C NMR
(125 MHz, CDCl3): δ 137.9, 129.0 (2C), 128.2 (2C), 127.1,
62.9, 57.5, 57.3, 53.0, 29.5, 23.3; FTIR (thin film), cm−1 2089,
1256, 736, 697; HRMS-ESI (m/z) calcd for C12H17N4 ([M +
H]+): 217.1448; found: 217.1446. These data are consistent
with published data.5d
3m), 3.08 (ddd, J = 10.7, 4.2, 1.7 Hz, 1H, 2m), 2.99 (td, J =
10.1, 4.2 Hz, 1H, 2m), 2.94−2.90 (m, 1H, 3m), 2.38−2.25 (m,
2H, 3m), 2.16−2.07 (m, 1H, 3m), 1.99−1.92 (m, 1H, 2m; m,
1H, 3m), 1.93 (t, J = 10.4 Hz, 1H, 2m), 1.71−1.66 (m, 1H,
2m), 1.42−1.32 (m, 2H, 2m; m, 1H, 3m), 1.06 (d, J = 6.0 Hz,
3H, 2m), 1.04 (d, J = 6.9 Hz, 3H, 3m); 13C NMR (125 MHz,
CDCl3, 2m): δ 129.0 (2C), 128.7 (2C), 128.3 (2C), 127.2
(2C), 64.5, 62.7, 57.4, 52.9, 36.2, 32.7, 18.6; FTIR (thin film),
cm−1 2925, 2093, 1454, 1256, 739, 698; HRMS-ESI (m/z)
calcd for C12H19N4 ([M + H]+): 231.1604; found: 231.1602.
2-(Azidomethyl)-1-benzyl-3-methylpyrrolidine (3m′).
Isolation by column chromatography (0.1% ethyl acetate−1%
NH4OH−hexanes); Clear liquid (12.6 mg, 18%); Rf = 0.38
(10% ethyl acetate−hexanes); 1H NMR (400 MHz, CDCl3): δ
7.36−7.21 (m, 5H), 3.99 (d, J = 13.1 Hz, 1H), 3.56 (d, J = 13.1
Hz, 1H), 3.25 (dd, J = 12.6, 6.1 Hz, 1H), 3.12 (dd, J = 12.6, 4.7
Hz, 1H), 2.98 (ddd, J = 9.1, 6.9, 2.0 Hz, 1H), 2.82 (ddd, J = 8.3,
6.1, 4.7 Hz, 1H), 2.36−2.24 (m, 2H), 1.86 (dtd, J = 12.1, 6.7,
2.0 Hz, 1H), 1.50 (dtd, J = 12.1, 10.1, 6.9 Hz, 1H), 1.04 (d, J =
7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 139.5, 128.7
(2C), 128.2 (2C), 126.9, 65.0, 59.9, 53.0, 52.0, 35.5, 32.9, 15.0;
FTIR (thin film), cm−1 2925, 2093, 1452, 1309, 1271, 739, 699;
HRMS-ESI (m/z) calcd for C12H19N4 ([M + H]+): 231.1604;
found: 231.1601.
2-(Azidomethyl)-1-benzylpyrrolidine (3j). Isolation by
column chromatography (1% ethyl acetate−1% NH4OH−
hexanes); Clear liquid (25.0 mg, 38%); Rf = 0.29 (10% ethyl
1
acetate−hexanes); H NMR (400 MHz, CDCl3): δ 7.36−7.21
(m, 5H), 4.00 (d, J = 13.0 Hz, 1H), 3.43 (d, J = 13.0 Hz, 1H),
3.27 (dd, J = 12.4, 5.9 Hz, 1H), 3.17 (dd, J = 12.4, 4.0 Hz, 1H),
3.00−2.94 (m, 1H), 2.80−2.72 (m,1H), 2.28−2.20 (m, 1H),
2.01−1.91 (m, 1H), 1.84−1.67 (m, 3H); 13C NMR (125 MHz,
CDCl3): δ 139.4, 128.7 (2C), 128.3 (2C), 127.0, 63.2, 59.4,
54.6, 54.5, 29.0, 23.1; FTIR (thin film), cm−1 2091, 1452, 1270,
736, 697; HRMS-ESI (m/z) calcd for C12H17N4 ([M + H]+):
217.1448; found: 217.1448. These data are consistent with
published data.5d
cis-3-Azido-1-benzyl-5-methylpiperidine (2k). Isolation
by column chromatography (1% ethyl acetate−1% NH4OH−
hexanes); Clear liquid (43.9 mg, 69%); Rf = 0.37 (10% ethyl
7-Azido-5-benzyl-5-azaspiro[2.5]octane (2n). Isolation
by column chromatography (0.5% ethyl acetate−1% NH4OH−
hexanes); Clear liquid (37.7 mg, 52%); Rf = 0.20 (10% ethyl
1
acetate−hexanes); H NMR (400 MHz, CDCl3): δ 7.36−7.23
1
(m, 5H), 3.54 (d, J = 13.3 Hz, 1H), 3.52 (d, J = 13.3 Hz, 1H),
3.46 (ddt, J = 11.5, 10.6, 4.4 Hz, 1H), 3.02 (ddt, J = 10.6, 4.4,
1.7 Hz, 1H), 2.78 (ddt, J = 10.9, 3.7, 1.7 Hz, 1H), 2.05 (dtt, J =
12.6, 4.4, 1.7 Hz, 1H), 1.83−1.69 (m, 1H), 1.78 (d, J = 10.6 Hz,
1H), 1.54 (t, J = 10.9 Hz, 1H), 0.94 (q, J = 12.0 Hz, 1H), 0.90
(d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 137.9,
129.0 (2C), 128.3 (2C), 127.1, 62.7, 60.5, 57.5, 57.4, 38.3, 29.9,
19.0; FTIR (thin film), cm−1 2090, 1263, 738, 697; HRMS-ESI
(m/z) calcd for C13H19N4 ([M + H]+): 231.1604; found:
231.1608.
acetate−hexanes); H NMR (400 MHz, CDCl3): δ 7.35−7.22
(m, 5H), 3.62 (tt, J = 9.1, 4.1 Hz, 1H), 3.57 (d, J = 13.2 Hz,
1H), 3.50 (d, J = 13.2 Hz, 1H), 2.95 (dd, J = 10.7, 4.1 Hz, 1H),
2.26−2.19 (m, 1H), 2.22 (d, J = 11.2 Hz, 1H), 1.99 (d, J = 11.2
Hz, 1H), 1.63 (dd, J = 12.9, 9.1 Hz, 1H), 1.44 (dd, J = 12.9, 4.1
Hz, 1H), 0.43−0.32 (m, 4H); 13C NMR (125 MHz, CDCl3): δ
137.8, 128.9 (2C), 128.3 (2C), 127.1, 62.4, 61.0, 57.6, 56.8,
38.7, 16.4, 12.2, 10.3; FTIR (thin film), cm−1 2926, 2094, 1242,
740, 698; HRMS-ESI (m/z) calcd for C14H19N4 ([M + H]+):
243.1604; found: 243.1604.
trans-5-Azido-1-benzyl-2-methylpiperidine (2l) and
cis-5-azido-1-benzyl-2-methyl-piperidine (2l′). Isolation
by column chromatography (0.5% ethyl acetate−1%
NH4OH−hexanes); Clear liquid (14.5 mg, 21%, 3.3:1 ratio);
6-(Azidomethyl)-5-benzyl-5-azaspiro[2.4]heptane
(3n). Isolation by column chromatography (0.5% ethyl
acetate−1% NH4OH−hexanes); Clear liquid (20.6 mg, 28%);
1
Rf = 0.24 (10% ethyl acetate−hexanes); H NMR (400 MHz,
1
Rf = 0.28 (10% ethyl acetate−hexanes); H NMR (400 MHz,
CDCl3): δ 7.36−7.21 (m, 5H), 4.06 (d, J = 13.0 Hz, 1H), 3.44
(d, J = 13.0 Hz, 1H), 3.38 (dd, J = 12.4, 5.9 Hz, 1H), 3.34 (dd, J
= 12.4, 4.2 Hz, 1H), 3.02 (dddd, J = 8.2, 6.2, 5.9, 4.2 Hz, 1H),
2.59 (d, J = 9.1 Hz, 1H), 2.51 (d, J = 9.1 Hz, 1H), 2.06 (dd, J =
12.5, 8.2 Hz, 1H), 1.65 (dd, J = 12.5, 8.2 Hz, 1H), 0.59−0.40
(m, 4H); 13C NMR (125 MHz, CDCl3): δ 139.2, 128.7 (2C),
128.3 (2C), 127.0, 64.4, 62.7, 59.7, 54.3, 38.4, 19.8, 14.1, 9.4;
FTIR (thin film), cm−1 2092, 1452, 1275, 737, 698; HRMS-ESI
(m/z) calcd for C14H19N4 ([M + H]+): 243.1604; found:
243.1605.
́
CDCl3): δ 7.35−7.21 (m, 5H, 2l; m, 5H, 2l), 4.04 (d, J = 13.4
Hz, 1H, 2l), 3.87 (tt, J = 10.8, 4.0 Hz, 1H, 2l), 3.84 (d, J = 13.4
́
́
Hz, 1H, 2l), 3.55−3.49 (m, 1H, 2l), 3.39 (d, J = 13.4 Hz, 1H,
́
2l), 3.19 (d, J = 13.4 Hz, 1H, 2l), 3.06 (ddd, J = 10.8, 4.0, 2.0
́
Hz, 1H, 2l), 2.68−2.59 (m, 2H, 2l), 2.08 (t, J = 10.8 Hz, 1H,
2l), 2.31−2.26 (m, 1H, 2l), 2.22−2.15 (m, 1H, 2l), 1.79−1.52
́
(m, 2H, 2l; m, 5H, 2l), 1.47−1.39 (m, 1H, 2l), 1.18 (d, J = 6.1
Hz, 3H, 2l), 1.12 (d, J = 6.3 Hz, 3H, 2l); 13C NMR (125 MHz,
́
́
CDCl3, found 2l and 2l): δ 138.7, 128.9 (2C), 128.8 (2C),
128.3 (2C), 128.2 (2C), 126.9, 65.8, 60.1, 58.4, 57.5, 56.1, 55.7,
53.4, 35.5, 34.4, 20.0, 15.3; FTIR (thin film), cm−1 2096, 1453,
1063, 785, 759, 734, 697; HRMS-ESI (m/z) calcd for C13H19N4
([M + H]+): 231.1604; found: 231.1603.
trans-3-Azido-1-benzyl-4-methylpiperidine (2m) and
2-(azidomethyl)-1-benzyl-3-methylpyrrolidine (3m). Iso-
lation by column chromatography (0.1% ethyl acetate−1%
NH4OH−hexanes); Clear liquid (34.4 mg, 50%); Rf = 0.30
(10% ethyl acetate−hexanes); 1H NMR (400 MHz, CDCl3): δ
7.36−7.21 (m, 5H, 2m; m, 5H, 3m), 4.04 (d, J = 13.2 Hz, 1H,
2m), 3.53 (s, 2H, 2m), 3.40 (dd, J = 12.6, 4.9 Hz, 1H, 3m),
3.39 (d, J = 13.2 Hz, 1H, 3m), 3.20 (dd, J = 12.6, 4.1 Hz, 1H,
3-Azido-1-benzyl-trans-decahydroquinoline (2o). Iso-
lation by column chromatography (1% ethyl acetate−1%
NH4OH−hexanes); Yellow liquid (67.2 mg, 83%); Rf = 0.38
(10% ethyl acetate−hexanes); 1H NMR (400 MHz, CDCl3): δ
7.36−7.21 (m, 5H), 4.09 (d, J = 13.6 Hz, 1H), 3.40 (ddt, J =
11.6, 10.9, 4.4 Hz, 1H), 3.22 (d, J = 13.6 Hz, 1H), 2.97 (ddd, J
= 10.9, 4.4, 2.2 Hz, 1H), 2.29−2.21 (m, 1H), 1.98−1.92 (m,
1H), 1.88−1.78 (m, 1H), 1.86 (t, J = 10.9 Hz, 1H), 1.74 (ddd, J
= 10.7, 9.5, 3.6 Hz, 1H), 1.71−1.63 (m, 2H), 1.38−1.23 (m,
3H), 1.17−1.05 (m, 3H); 13C NMR (125 MHz, CDCl3): δ
138.7, 128.9 (2C), 128.2 (2C), 126.9, 65.7, 57.3, 57.0, 56.5,
40.6, 37.7, 32.7, 30.3, 25.8, 25.5; FTIR (thin film), cm−1 2922,
F
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2091, 1253, 738, 697; HRMS-ESI (m/z) calcd for C16H23N4
([M + H]+): 271.1917; found: 271.1917.
trimethylphosphine in toluene (0.3 mL, 1.0 M, 0.3 mmol, 2.0
equiv) under nitrogen atmosphere. The solution was allowed to
stir at room temperature for 1.75 h. Then isobutylaldehyde
(34.0 μL, 0.375 mmol, 2.5 equiv) was added to the solution.
The reaction was allowed to stir at room temperature for 4.25 h
and was then concentrated in vacuo. The concentrated residue
was dissolved in MeOH (2 mL) and placed in a 0 °C ice bath.
To the resulting solution was added solid NaBH4 (17.0 mg,
0.45 mmol, 3.0 equiv), and the reaction mixture was stirred for
10 min at 0 °C. The reaction was warmed to room temperature,
and after 1 h, the reaction mixture was quenched with a
saturated solution of NaHCO3. The reaction mixture was
diluted with water (15 mL) and extracted with Et2O (15 mL ×
4). The ether layers were combined, dried over K2CO3, and
concentrated in vacuo. The crude residue was purified by
column chromatography (10% methanol−dichloromethane) to
give 6 as a yellow oil (23.1 mg, 54%). Rf = 0.66 (20%
3-Azido-1-benzyl-cis-decahydroquinoline (2p). Isola-
tion by column chromatography (0.5% ethyl acetate−1%
NH4OH−hexanes); Clear liquid (30.1 mg, 37%); Rf = 0.50
(10% ethyl acetate−hexanes); Rf = 0.50 (10% ethyl acetate−
hexanes); 1H NMR (400 MHz, CDCl3): δ 7.33−7.21 (m, 5H),
3.74 (d, J = 13.6 Hz, 1H), 3.58 (d, J = 13.6 Hz, 1H), 3.48 (tt, J
= 11.0, 5.0 Hz, 1H), 2.72 (dt, J = 11.1, 4.6 Hz, 1H), 2.66 (ddd, J
= 11.0, 5.0, 1.2 Hz, 1H), 2.35 (t, J = 11.0 Hz, 1H), 2.06 (tq, J =
8.0, 4.6 Hz, 1H), 1.82−1.52 (m, 7H), 1.45−1.39 (m, 1H),
1.36−1.27 (m, 1H), 1.19−1.06 (m, 1H); 13C NMR (125 MHz,
CDCl3): δ 139.4, 128.4 (2C), 128.2 (2C), 126.9, 58.5, 58.2
(2C), 49.5, 34.5, 31.1, 29.9, 25.3, 21.0, 17.7; FTIR (thin film),
cm−1 2925, 2091, 1253, 736, 697; HRMS-ESI (m/z) calcd for
C16H23N4 ([M + H]+): 271.1917; found: 271.1917.
3-Azido-1-benzylazepane (2q). Isolation by column
chromatography (1% ethyl acetate−1% NH4OH−hexanes);
Clear liquid (21.2 mg, 31%); Rf = 0.35 (10% ethyl acetate−
hexanes); 1H NMR (400 MHz, CDCl3): δ 7.39−7.21 (m, 5H),
3.73 (d, J = 13.5 Hz, 1H), 3.66 (d, J = 13.5 Hz, 1H), 3.49 (tt, J
= 7.8, 4.4 Hz, 1H), 2.87 (dd, J = 13.8, 4.4 Hz, 1H), 2.69 (dd, J =
13.8, 7.8 Hz, 1H), 2.63 (t, J = 6.0 Hz, 2H), 2.09−1.99 (m, 1H),
1.80−1.51 (m, 5H); 13C NMR (125 MHz, CDCl3): δ 139.5,
128.6 (2C), 128.2 (2C), 127.0, 63.1, 61.4, 59.1, 55.9, 32.9, 29.0,
22.2; FTIR (thin film), cm−1 2922, 2089, 1452, 1251, 966, 735,
697; HRMS-ESI (m/z) calcd for C13H19N4 ([M + H]+):
231.1904; found: 231.1906.
1
methanol−dichloromethane); H NMR (400 MHz, CDCl3): δ
7.35−7.16 (m, 5H), 4.08 (d, J = 13.9 Hz, 1H), 3.10 (d, J = 13.9
Hz, 1H), 2.53−2.48 (m, 1H), 2.39−2.24 (m, 3H), 1.97 (dq, J =
8.4, 6.0 Hz, 1H), 1.73 (ddd, J = 10.5, 4.5, 2.2 Hz, 1H), 1.72 (d, J
= 11.2 Hz, 1H), 1.66 (septet, J = 6.6 Hz, 1H), 1.28 (d, J = 6.0
Hz, 3H), 0.96 (s, 3H), 0.94 (s, br, 1H), 0.93−0.88 (m, 1H),
0.90 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H), 0.83 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 140.6, 128.4 (2C), 128.0
(2C), 126.4, 63.9, 62.7, 58.1 (2C), 55.9, 44.5, 30.6, 29.6, 28.9,
25.6, 20.8, 20.7, 16.2; FTIR (thin film), cm−1 2950, 1453, 1364,
1123, 735, 697; HRMS-ESI (m/z) calcd for C19H33N2 ([M +
H]+): 289.2638; found: 289.2635.
2-(Azidomethyl)-1-benzylpiperidine (3q). Isolation by
column chromatography (1% ethyl acetate−1% NH4OH−
hexanes); Clear liquid (16.5 mg, 24%); Rf = 0.25 (10% ethyl
trans-2,5,5-Trimethylpiperidin-3-amine (7).21 To a
solution of 2h (38.8 mg, 0.15 mmol, 1.0 equiv) in MeOH (3
mL) under nitrogen, was added palladium on carbon (23.2 mg,
10 wt %, 0.0225 mmol, 0.15 equiv). The reaction mixture was
purged and refilled with hydrogen. After 2 h, the reaction
mixture was diluted with MeOH and filtered through Celite.
The filtrate was concentrated in vacuo to give 7 as a light-yellow
1
acetate−hexanes); H NMR (400 MHz, CDCl3): δ 7.38−7.20
(m, 5H), 4.00 (d, J = 13.5 Hz, 1H), 3.33 (d, J = 13.5 Hz, 1H),
3.50 (dd, J = 12.7, 5.8 Hz, 1H), 3.47 (dd, J = 12.7, 4.0 Hz, 1H),
2.77 (dt, J = 12.1, 4.3 Hz, 1H), 2.51 (ddt J = 8.6, 5.8, 4.0 Hz,
1H), 2.09 (ddd J = 12.1, 9.2, 3.4 Hz, 1H), 1.79−1.64 (m, 2H),
1.62−1.29 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 139.1,
128.7 (2C), 128.2 (2C), 126.9, 60.2, 58.5, 53.0, 51.5, 29.4, 25.0,
23.1; FTIR (thin film), cm−1 2933, 2092, 1270, 734, 698;
HRMS-ESI (m/z) calcd for C13H19N4 ([M + H]+): 231.1904;
found: 231.1906.
1
liquid (18.6 mg, 87%). H NMR (400 MHz, CDCl3): δ 2.53
(dd, J = 12.2, 2.5 Hz, 1H), 2.41 (d, J = 12.2 Hz, 1H), 2.38 (ddd,
J = 11.5, 9.1, 4.1 Hz, 1H), 2.11 (dq, J = 9.1, 6.3 Hz, 1H), 1.58
(ddd, J = 12.9, 4.1, 2.5 Hz, 1H), 1.41 (s, br, 3H), 1.14 (d, J =
6.3 Hz, 3H), 0.98 (t, J = 12.2 Hz, 1H), 0.98 (s, 3H), 0.85 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 60.0, 58.2, 52.1, 47.9,
32.1, 29.5, 24.5, 19.2; FTIR (thin film), cm−1 2949, 2903, 1459,
789, 714, 606; HRMS-ESI (m/z) calcd for C8H19N2 ([M +
H]+): 143.1543; found: 143.1541.
Dimethyl 1-(trans-1′-Benzyl-2′,5′,5′-trimethylpiperi-
din-3′-yl)-1H-1,2,3-triazole-4,5-dicarboxylate (8).22 A sol-
ution of 2h (38.8 mg, 0.15 mmol, 1.0 equiv) and dimethyl
acetylenedicarboxylate (55.3 μL, 0.45 mmol, 3.0 equiv) in
toluene (1.5 mL) was refluxed under nitrogen for 24 h. After
cooling down to room temperature, the reaction mixture was
concentrated in vacuo. The crude residue was purified by
column chromatography (25% diethyl ether−hexanes) to give
8 as a clear oil (59.6 mg, 99%). Rf = 0.25 (25% ethyl acetate−
hexanes); 1H NMR (400 MHz, CDCl3): δ 7.33−7.19 (m, 5H),
4.74 (ddd, J = 12.6, 9.8, 4.4 Hz, 1H), 4.18 (d, J = 13.7 Hz, 1H),
4.03 (s, 3H), 3.97 (s, 3H), 3.16 (d, J = 13.7 Hz, 1H), 3.02 (dq, J
= 9.8, 6.0 Hz, 1H), 2.46 (dd, J = 11.6, 2.2 Hz, 1H), 2.00 (d, J =
11.6 Hz, 1H), 1.99 (t, J = 12.6 Hz, 1H), 1.81 (ddd, J = 12.6, 4.4,
2.2 Hz, 1H), 1.09 (s, 3H), 0.92 (s, 3H), 0.86 (s, 3H); 13C NMR
(125 MHz, CDCl3): δ 160.6, 159.3, 139.6, 138.8, 131.2, 128.3
(2C), 128.2 (2C), 126.8, 64.0, 62.6, 61.1, 57.3, 53.5, 52.6, 45.0,
31.2, 29.0, 24.2, 16.3; FTIR (thin film), cm−1 1731, 1213, 734,
trans-1-Benzyl-2,5,5-trimethylpiperidin-3-amine
(5).17a,b A solution of 2h (38.8 mg, 0.15 mmol, 1.0 equiv) and
triphenylphosphine (59.0 mg, 0.225 mmol, 1.5 equiv) in water
(18.9 μL, 1.05 mmol, 7 equiv) and THF (3 mL) was refluxed
for 5 h. After cooling down to room temperature, the reaction
was concentrated in vacuo. The residue was purified by column
chromatography (10% methanol−dichloromethane) to pro-
duce 5 as a clear liquid (34.9 mg, 93%). Rf = 0.14 (10%
1
methanol−dichloromethane); H NMR (400 MHz, CDCl3): δ
7.37−7.18 (m, 5H), 4.12 (d, J = 13.9 Hz, 1H), 3.08 (d, J = 13.9
Hz, 1H), 2.63 (ddd, J = 11.4, 8.6, 4.6 Hz, 1H), 2.34 (dd, J =
11.3, 2.4 Hz, 1H), 1.81 (dq, J = 8.6, 6.0 Hz, 1H), 1.72 (d, J =
11.3 Hz, 1H), 1.60 (ddd, J = 12.6, 4.6, 2.4 Hz, 1H), 1.27 (d, J =
6.0 Hz, 2H), 1.24 (s, br, 2H), 0.99 (s, 3H), 0.98 (dd, J = 11.4,
11.3 Hz, 1H), 0.78 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
140.5, 128.4 (2C), 128.0 (2C), 126.4, 65.3, 64.4, 57.8, 51.7,
41.7, 30.7, 29.6, 25.3, 16.5; FTIR (thin film), cm−1 2949, 1452,
1368, 1122, 736, 697; HRMS-ESI (m/z) calcd for C15H25N2
([M + H]+): 233.2012; found: 233.2011.
trans-1-Benzyl-N-isobutyl-2,5,5-trimethylpiperidin-3-
amine (6).17c,d To a solution of 2h (38.8 mg, 0.15 mmol, 1.0
equiv) in anhydrous CH2Cl2 (1.5 mL), was added a solution of
G
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698; HRMS-ESI (m/z) calcd for C21H29N4O4 ([M + H]+):
401.2183; found: 401.2178.
mL). The organic layer was dried over Na2SO4 and filtered, and
the filtrate was concentrated in vacuo. The crude residue was
then purified by either column chromatography or Kugelrohr
distillation.
trans-1-Benzyl-2,5,5-trimethyl-3-(4′-phenyl-1H-
1′,2′,3′-triazol-1-yl)piperidine (9).10f To a suspension of 2h
(38.8 mg, 0.15 mmol, 1.0 equiv) in water (0.3 mL) and tert-
butanol (0.3 mL) were added phenylacetylene (16.5 μL, 0.15
mmol, 1.0 equiv), sodium ascorbate (30.0 mg, 0.015 mmol, 0.1
equiv), and CuSO4·5H2O (0.8 mg, 0.003 mmol, 0.02 equiv).
The suspension was stirred vigorously and heated to 60 °C.
After 15 h, a light-pink solid had precipitated out of solution.
The solid was filtered and washed with copious amounts of
water to give 9 as a light-pink solid (49.6 mg, 92%). Rf = 0.54
(20% ethyl acetate−hexanes); 1H NMR (400 MHz, CDCl3): δ
7.87−7.81 (m, 2H), 7.76 (s, 1H), 7.46−7.40 (m, 2H), 7.37−
7.30 (m, 6H), 4.58 (ddd, J = 12.5, 9.8, 4.7 Hz, 1H), 4.19 (d, J =
13.8 Hz, 1H), 3.19 (d, J = 13.8 Hz, 1H), 2.68 (dq, J = 9.8, 6.0
Hz, 1H), 2.50 (dd, J = 11.7, 2.2 Hz, 1H), 1.98 (d, J = 11.7 Hz,
1H), 1.91 (ddd, J = 12.7, 4.7, 2.2 Hz, 1H), 1.82 (t, J = 12.6 Hz,
1H), 1.12 (s, 3H), 1.02 (d, J = 6.0 Hz, 3H), 0.88 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ 147.6, 139.5, 130.7, 128.8 (2C),
128.4 (2C), 128.2 (2C), 128.1, 126.8, 125.6 (2C), 118.2, 64.1,
62.5, 62.1, 57.5, 45.2, 31.1, 29.1, 24.6, 16.3; FTIR (neat), cm−1
1370, 1049, 908, 766, 731, 693; HRMS-ESI (m/z) calcd for
C23H29N4 ([M + H]+): 361.2387; found: 361.2387.
cis-1-(tert-Butyl)-N,N,2-triethylpiperidin-3-amine (11).
Isolation by column chromatography (7.5% methanol−1%
NH4OH−dichloromethane); White solid (38.4 mg, 53%); Rf =
0.19 (25% ethyl acetate−hexanes); 1H NMR (400 MHz,
CDCl3): δ 3.15 (dt, J = 8.0, 4.1 Hz, 1H), 2.86−2.80 (m, br,
1H), 2.65 (dq, J = 13.8, 7.1 Hz, 2H), 2.60 (dq, J = 13.8, 7.1 Hz,
2H), 2.60−2.49 (m, 2H), 1.78−1.71 (m, br, 1H), 1.54−1.36
(m, 5H), 1.12 (s, 9H), 0.96 (t, J = 7.1 Hz, 6H), 0.90 (t, J = 7.4
Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 60.6, 56.1, 54.0, 42.1
(2C), 38.7, 29.9 (3C), 26.5, 24.1, 17.2, 12.9, 11.4 (2C); FTIR
(thin film), cm−1 2967, 2931, 1215; HRMS-ESI (m/z) calcd for
C15H33N2 ([M + H]+): 241.2638; found: 241.2634.
trans-1-Benzyl-N,N-diethyl-2,5,5-trimethylpiperidin-3-
amine (12). Isolation by Kugelrohr distillation; Clear liquid
1
(77.4 mg, 89%); Rf = 0.16 (10% ethyl acetate−hexanes); H
NMR (400 MHz, CDCl3): δ 7.35−7.18 (m, 5H), 4.17 (d, J =
13.9 Hz, 1H), 3.01 (d, J = 13.9 Hz, 1H), 2.55 (dq, J = 12.8, 7.1
Hz, 2H), 2.52 (ddd, J = 12.5, 11.2, 4.0 Hz, 1H), 2.30 (dq, J =
12.8, 7.1 Hz, 2H), 2.29 (dd, J = 11.2, 2.7 Hz, 1H), 2.06 (dq, J =
9.6, 6.0 Hz, 1H), 1.61 (d, J = 11.2 Hz, 1H), 1.43 (ddd, J = 12.5,
4.0, 2.7 Hz, 1H), 1.33 (d, J = 6.0 Hz, 3H), 1.05 (t, J = 12.5 Hz,
1H), 1.00 (t, J = 7.1 Hz, 6H), 0.96 (s, 3H), 0.77 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ 140.8, 128.4 (2C), 128.0 (2C),
126.3, 64.7, 60.5, 59.0, 58.5, 43.9 (2C), 35.5, 30.4, 30.1, 24.7,
17.1, 14.9 (2C); FTIR (thin film), cm−1 2966, 2926, 737, 697;
HRMS-ESI (m/z) calcd for C19H33N2 ([M + H]+): 289.2638;
found: 289.2644 .
N-(trans-1′-Benzyl-2′,5′,5′-trimethylpiperidin-3′-yl)-2-
(diphenylphosphoryl)benzamide (10).18 A solution of 2h
(38.8 mg, 0.15 mmol, 1.0 equiv) and methyl 2-
(diphenylphosphino)benzoate (48.0 mg, 0.15 mmol, 1.0
equiv) in MeCN (1.32 mL) and water (0.11 mL) was heated
at 37 °C for 48 h. The reaction mixture was concentrated in
vacuo. The crude residue was immediately purified by column
chromatography (6% methanol−dichloromethane) to give 10
as a light-yellow solid (72.4 mg, 90%). Rf = 0.32 (4%
tert-Butyl-4-(cis-1′-(tert-butyl)-2′-ethylpiperidin-3′-yl)-
piperazine-1-carboxylate (13). Isolation by column chro-
matography (5% methanol−1% NH4OH−dichloromethane);
Yellow oil (63.5 mg, 53%); Rf = 0.39 (20% ethyl acetate−
1
methanol−dichloromethane); H NMR (400 MHz, CDCl3): δ
8.99 (d, br, J = 8.9 Hz, 1H), 8.19−8.15 (m, 1H), 7.66 (tt, J =
7.6, 1.6 Hz, 1H), 7.64−7.54 (m, 5H), 7.53−7.44 (m, 5H), 7.37
(tt, J = 7.6, 1.6 Hz, 1H), 7.31−7.16 (m, 5H), 7.05−6.98 (m,
1H), 4.05 (d, J = 13.9 Hz, 1H), 3.86−3.77 (m, 1H), 3.01 (d, J =
13.9 Hz, 1H), 2.24 (dd, J = 11.2, 2.1 Hz, 1H), 2.03 (dq, J = 9.5,
6.0 Hz, 1H), 1.70 (d, J = 11.2 Hz, 1H), 1.02−0.92 (m, 2H),
0.94 (d, J = 6.0 Hz, 3H), 0.89 (s, 3H), 0.65 (s, 3H); 13C NMR
1
hexanes); H NMR (400 MHz, CDCl3): δ 3.38 (t, J = 5.0 Hz,
4H), 3.24−3.19 (m, 1H), 2.80 (dt, J = 13.1, 3.6 Hz, 1H), 2.51
(ddd, J = 13.6, 11.8, 2.9 Hz, 1H), 2.43 (t, J = 5.0 Hz, 4H), 2.20
(dt, J = 11.8, 4.2 Hz, 1H), 1.80−1.74 (m, 1H), 1.61−1.25 (m,
5H), 1.45 (s, 9H), 1.10 (s, 9H), 0.92 (t, J = 7.4 Hz, 3H); 13C
NMR (125 MHz, CDCl3, 60 °C): δ 154.8, 79.3, 64.9, 55.4,
54.2, 50.2 (2C), 44.2 (2C), 38.7, 29.7 (3C), 28.5 (3C), 26.1,
23.6, 17.8, 12.9; FTIR (thin film), cm−1 2967, 1699, 1365,
1250, 1171; HRMS-ESI (m/z) calcd for C20H40N3O2 ([M +
H]+): 354.3115; found: 354.3118.
3
(125 MHz, CDCl3): δ 166.3 (d, JP−C = 3.0 Hz), 141.6 (d,
2JP−C = 7.7 Hz), 140.4, 133.6 (d, 3JP−C = 12.2 Hz), 132.7, 132.4
(2C), 132.3 (d, 2JP−C = 10.2 Hz, 2C), 132.2 (d, 2JP−C = 10.2 Hz,
2
1
2C), 132.0 (d, JP−C = 10.2 Hz), 131.6 (d, JP−C = 107.5 Hz),
1
3
tert-Butyl-4-(trans-1′-benzyl-2′,5′,5′-trimethylpiperi-
din-3′-yl)piperazine-1-carboxylate (14). Isolation by col-
umn chromatography (5% ethyl acetate−1% NH4OH−
hexanes); Clear oil (110.0 mg, 91%); Rf = 0.63 (25% ethyl
131.2 (d, JP−C = 107.5 Hz), 129.8 (d, JP−C = 12.0 Hz), 128.8
(d, 3JP−C = 12.2 Hz, 2C), 128.7 (d, 3JP−C = 12.2 Hz, 2C), 128.4
(2C), 128.0 (2C), 127.9 (d, 1JP−C = 90.3 Hz), 126.4, 63.7, 61.7,
57.6, 51.3, 43.2, 30.6, 29.2, 24.7, 16.4; FTIR (neat), cm−1 1650,
1118, 723, 693; HRMS-ESI (m/z) calcd for C34H38N2O2P ([M
+ H]+): 537.2665; found: 537.2663.
1
acetate−hexanes); H NMR (400 MHz, CDCl3): δ 7.33−7.19
(m, 5H), 4.15 (d, J = 13.8 Hz, 1H), 3.45−3.31 (m, 4H), 3.01
(d, J = 13.8 Hz, 1H), 2.60−2.52 (m, 2H), 2.41 (ddd, J = 12.5,
9.7, 3.8, 1H), 2.37−2.32 (m, 2H), 2.30 (dd, J = 11.3, 2.3 Hz,
1H), 2.10 (dq, J = 9.7, 6.0 Hz, 1H), 1.61 (d, J = 11.3 Hz, 1H),
1.48−1.43 (m, 1H), 1.46 (s, 9H), 1.34 (d, J = 6.0 Hz, 3H), 1.05
(t, J = 12.5 Hz, 1H), 0.95 (s, 3H), 0.77 (s, 3H); 13C NMR (125
MHz, CDCl3, 60 °C): δ 154.9, 140.7, 128.5 (2C), 128.0 (2C),
126.4, 79.3, 64.7, 64.2, 59.9, 58.4, 48.8 (2C), 44.5 (2C), 35.8,
30.4, 30.0, 28.5 (3C), 24.7, 16.8; FTIR (thin film), cm−1 1695,
1365, 1246, 1173, 1119; HRMS-ESI (m/z) calcd for
C24H40N3O2 ([M + H]+): 402.3114; found: 402.3114.
General Procedure for the One-Pot Nucleophile-
Cyclization Reactions in Table 3. General Procedure for
Entries 1−2 in Table 3. To a solution of unsaturated amine 1f
or 1h (0.3 mmol, 1 equiv) in anhydrous MeCN (3 mL) was
added NCS (0.3 mmol, 1 equiv). The reaction solution was
allowed to stir in the dark for 1 h, after which NaI (0.015 mmol,
0.05 equiv) was added, and the solution was immediately
heated to 60 °C. After 2.5 h, the amine nucleophile (0.75
mmol, 2.5 equiv) was added. The reaction was monitored by
TLC until determined complete and was then diluted with
EtOAc (40 mL). The organic layer was washed with aqueous
solutions of NaOH (1.0 M, 10 mL × 2) followed by brine (10
General Procedure for Entries 3−4 in Table 3. To a
solution of unsaturated amine 1f or 1h (0.3 mmol, 1 equiv) in
H
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anhydrous MeCN (3 mL) was added NCS (0.3 mmol, 1
equiv). The reaction solution was stirred in the dark for 1 h.
Then nucleophile (NaOAc or NaSCN, 0.36 mmol, 1.2 equiv)
and NaI (0.015 mmol, 0.05 equiv) were added. The solution
was then heated at 60 °C for 48 h. After cooling down to room
temperature, the reaction mixture was diluted with water (10
mL) and extracted with hexanes (10 mL × 4). The hexane
layers were combined and washed with aqueous solutions of
NaOH (1.0 M, 10 mL × 2) followed by brine (10 mL). The
organic layer was dried over Na2SO4 and filtered. The filtrate
was concentrated in vacuo, and the crude residue was then
purified by either column chromatography or Kugelrohr
distillation.
cis-1-(tert-Butyl)-2-ethylpiperidin-3-yl acetate (15).
Isolation by column chromatography (1% ethyl acetate−1%
NH4OH−hexanes); White solid (37.6 mg, 55%); Rf = 0.56
(20% ethyl acetate−hexanes); 1H NMR (400 MHz, CDCl3): δ
4.88 (dt, J = 11.6, 5.0 Hz, 1H), 3.27−3.21 (m, 1H), 2.83−2.77
(m, 1H), 2.48 (ddd, J = 13.3, 11.9, 3.2 Hz, 1H), 2.02 (s, 3H),
1.77−1.71 (m, 1H), 1.64−1.43 (m, 5H), 1.11 (s, 9H), 0.90 (t, J
= 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 170.5, 73.9,
55.8, 54.0, 38.3, 29.6 (3C), 25.8, 25.4, 21.4, 17.5, 12.6; FTIR
(thin film), cm−1 2959, 1733, 1366, 1240, 1217, 1030; HRMS-
ESI (m/z) calcd for C13H26NO2 ([M + H]+): 228.1958; found:
228.1958.
(broad), 1452, 1365, 1125, 722, 697; HRMS-ESI (m/z) calcd
for C16H23N2S ([M + H]+): 275.1576; found: 275.1579.
General Procedure for Entry 5 in Table 3. To a solution of
unsaturated amine 1f or 1h (0.3 mmol, 1 equiv) in anhydrous
MeCN (3 mL) was added NCS (0.3 mmol, 1 equiv). The
reaction solution was allowed to stir in the dark for 1 h, after
which NaI (0.015 mmol, 0.05 equiv) was added, and the
solution was immediately heated to 60 °C. After 2.5 h, NaCN
(0.36 mmol, 1.2 equiv) was added. The reaction was monitored
by TLC until determined complete. Then the reaction mixture
was diluted with water (10 mL) and extracted with hexanes (10
mL × 4). The hexane layers were combined and washed with
aqueous solutions of NaOH (1.0 M, 10 mL × 2) followed by
brine (10 mL). The organic layer was dried over Na2SO4 and
filtered, and the filtrate was concentrated in vacuo. The crude
residue was then purified by column chromatography.
cis-1-(tert-Butyl)-2-ethylpiperidin-3-carbonitrile (19).
Isolation by column chromatography (2% ethyl acetate−
hexanes); Clear oil (9.0 mg, 15%, mass loss due to the
1
volatility); Rf = 0.46 (25% ethyl acetate−hexanes); H NMR
(400 MHz, CDCl3): δ 3.33 (dt, J = 7.4, 4.7 Hz, 1H), 2.95−2.88
(m, br, 1H), 2.78 (dt, J = 12.9, 4.2 Hz, 1H), 2.59 (ddd, J = 13.9,
12.9, 3.0 Hz, 1H), 1.99−1.91 (m, br, 1H), 1.83 (qd, J = 13.0,
4.5 Hz, 1H), 1.80−1.59 (m, 2H), 1.52−1.45 (m, br, 1H), 1.41−
1.29 (m, 1H), 1.11 (s, 9H), 1.00 (t, J = 7.4 Hz, 3H); 13C NMR
(125 MHz, CDCl3): δ 122.3, 54.7, 54.3, 38.1, 31.7, 29.6 (3C),
24.7, 24.0, 19.6, 12.5; FTIR (thin film), cm−1 2962, 1361, 1219,
1204; HRMS-ESI (m/z) calcd for C12H23N2 ([M + H]+):
195.1856; found: 195.1856.
trans-1-Benzyl-2,5,5-trimethylpiperidin-3-yl acetate
(16). Isolation by Kugelrohr distillation; White solid (69.2
1
mg, 84%); Rf = 0.34 (10% ethyl acetate−hexanes); H NMR
(400 MHz, CDCl3): δ 7.36−7.19 (m, 5H), 4.74 (ddd, J = 10.5,
8.8, 4.8 Hz, 1H), 4.09 (d, J = 13.8 Hz, 1H), 3.12 (d, J = 13.8
Hz, 1H), 2.34 (dd, J = 11.3, 2.0 Hz, 1H), 2.26 (dq, J = 8.8, 6.1
Hz, 1H), 2.06 (s, 3H), 1.77 (ddd, J = 12.2, 4.8, 2.0 Hz, 1H),
1.77 (d, J = 11.3 Hz, 1H), 1.16 (d, J = 6.1 Hz, 3H), 1.15 (dd, J
= 12.5, 10.5 Hz, 1H), 1.01 (s, 3H), 0.82 (s, 3H); 13C NMR
(125 MHz, CDCl3): δ 170.4, 140.0, 128.4 (2C), 128.1 (2C),
126.6, 63.5, 60.7, 57.4, 42.6, 31.1, 29.1, 25.5, 21.3, 15.4; FTIR
(thin film), cm−1 1734, 1368, 1238, 1029; HRMS-ESI (m/z)
calcd for C17H26NO2 ([M + H]+): 276.1958; found: 276.1964.
cis-8-Ethyl-1,6-diazabicyclo[3.2.1]octane-7-thione
(17). Isolation by column chromatography (20% ethyl acetate−
hexanes to 40% ethyl acetate−hexanes); Orange oil (15.6 mg,
1-(cis-1′-(tert-Butyl)-2′-ethylpiperidin-3′-yl)-
succinimide (20). Isolation by column chromatography (25%
ethyl acetate−1% NH4OH−hexanes); Yellow oil (20.0 mg,
1
25%); Rf = 0.51 (50% ethyl acetate−hexanes); H NMR (400
MHz, CDCl3): δ 4.22 (dt, J = 13.5, 4.1 Hz, 1H), 3.16−3.10 (m,
1H), 2.97−2.80 (m, 2H), 2.68−2.58 (m, 1H), 2.63 (s, br, 4H),
1.80−1.68 (m, 1H), 1.66−1.53 (m, 2H), 1.44 (qt, J = 12.9, 4.2
Hz, 1H), 1.30−1.18 (m, 1H), 1.15 (s, 9H), 0.79 (t, J = 7.4 Hz,
3H); 13C NMR (125 MHz, CDCl3): δ 178.0 (2C), 56.3, 55.4,
54.2, 38.5, 30.0 (3C), 28.1 (2C), 26.8, 22.6, 18.3, 12.3; FTIR
(thin film), cm−1 1691, 1368, 1159, 700; HRMS-ESI (m/z)
calcd for C15H27N2O2 ([M + H]+): 267.2067; found: 267.2072.
trans-1-Benzyl-2,5,5-trimethylpiperidine-3-carboni-
trile (21). Isolation by column chromatography (2% ethyl
acetate−1% NH4OH−hexanes); Clear oil (30.7 mg, 42%); Rf =
0.62 (25% ethyl acetate−hexanes); 1H NMR (400 MHz,
CDCl3): δ 7.26−7.21 (m, 5H), 4.11 (d, J = 13.7 Hz, 1H), 3.11
(d, J = 13.7 Hz, 1H), 2.64 (ddd, J = 12.6, 9.7, 4.1 Hz, 1H), 2.41
(dq, J = 9.7, 6.1 Hz, 1H), 2.36 (dd, J = 11.5, 2.3 Hz, 1H), 1.79
(ddd, J = 13.2, 4.1, 2.3 Hz, 1H), 1.78 (d, J = 11.5 Hz, 1H), 1.50
(t, J = 12.9 Hz, 1H), 1.42 (d, J = 6.1 Hz, 3H), 0.96 (s, 3H), 0.84
(s, 3H); 13C NMR (125 MHz, CDCl3): δ 139.2, 128.3 (2C),
128.2 (2C), 126.8, 121.9, 63.5, 58.9, 57.5, 41.1, 33.8, 30.4, 28.7,
24.2, 18.6; FTIR (thin film), cm−1 2953, 1453, 1127, 740, 698;
HRMS-ESI (m/z) calcd for C16H23N2 ([M + H]+): 243.1856;
found: 243.1857.
1
31%); Rf = 0.14 (25% ethyl acetate−hexanes); H NMR (400
MHz, CDCl3): δ 6.11 (s, br, 1H), 3.90 (dt, J = 11.6, 8.0 Hz,
1H), 3.68 (dt, J = 9.9, 5.4 Hz, 1H), 3.61 (tdd, J = 6.3, 5.4, 1.0
Hz, 1H), 3.31 (ddd, J = 11.6, 9.2, 3.7 Hz, 1H), 2.15−1.87 (m,
3H), 1.72−1.44 (m, 4H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR
(125 MHz, CDCl3): δ 185.4, 68.9, 62.2, 46.7, 30.8, 28.4, 25.5,
9.7; FTIR (thin film), cm−1 3201, 2961, 1459, 1421, 1318,
1256; HRMS-ESI (m/z) calcd for C8H15N2S ([M + H]+):
171.0950; found: 171.0949.
trans-1-Benzyl-3-isothiocyanato-2,5,5-trimethylpiper-
idine (18). Isolation by column chromatography (1% ethyl
acetate−1% NH4OH−hexanes); Clear oil (68.3 mg, 83%); Rf =
0.59 (10% ethyl acetate−hexanes); 1H NMR (500 MHz,
CDCl3): δ 7.39−7.21 (m, 5H), 4.10 (d, J = 13.8 Hz, 1H), 3.57
(ddd, J = 11.6, 9.0, 4.4 Hz, 1H), 3.12 (d, J = 13.8 Hz, 1H), 2.34
(dd, J = 11.4, 2.0 Hz, 1H), 2.29 (dq, J = 9.0, 6.1 Hz, 1H), 1.90
(ddd, J = 12.9, 4.4, 2.0 Hz, 1H), 1.79 (d J = 11.4 Hz, 1H), 1.45
(dd, J = 12.9, 11.6 Hz, 1H), 1.35 (d, J = 6.1 Hz, 3H), 0.96 (s,
3H), 0.84 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 139.7,
131.0, 128.6 (2C), 128.5 (2C), 127.1, 63.7, 62.5, 59.4, 57.6,
45.3, 31.2, 29.1, 25.1, 17.3; FTIR (thin film), cm−1 2055
N-(trans-1-Benzyl-2,5,5-trimethylpiperidin-3-yl)-
succinimide (22). To a solution of unsaturated amine 1h (0.3
mmol, 1 equiv) in anhydrous MeCN (3 mL) was added NCS
(0.3 mmol, 1 equiv). The reaction solution was allowed to stir
in the dark for 1 h, after which NaI (0.015 mmol, 0.05 equiv)
was added, and the solution was immediately heated to 60 °C.
After 2.5 h, Na2CO3 (0.36 mmol, 1.2 equiv) was added. The
reaction was monitored by TLC until determined complete.
I
dx.doi.org/10.1021/jo4022666 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Then the reaction mixture was diluted with water (10 mL) and
extracted with hexanes (10 mL × 4). The hexane layers were
combined and washed with aqueous solutions of NaOH (1.0
M, 10 mL × 2) followed by brine (10 mL). The organic layer
was dried over Na2SO4 and filtered, and the filtrate was
concentrated in vacuo. The crude residue was then purified by
column chromatography (20% ethyl acetate−hexanes) to give
22 as a white solid (72.6 mg, 77%). Rf = 0.40 (40% ethyl
J = 13.9 Hz, 1H), 2.43−2.34 (m, 3H), 2.28−2.21 (m, 1H),
2.02−1.96 (m, 2H), 1.71 (d, J = 11.4 Hz, 1H), 1.40 (ddd, J =
12.4, 4.6, 2.2 Hz, 1H), 1.35 (dd, J = 12.4, 12.3 Hz, 1H), 1.14 (d,
J = 6.0 Hz, 3H), 1.08 (s, 3H), 0.81 (s, 3H); 13C NMR (125
MHz, CDCl3): δ 174.8, 140.2, 128.4 (2C), 128.1 (2C), 126.6,
64.8, 59.5, 58.1, 52.2, 43.2, 41.1, 31.5, 30.9, 29.5, 24.8, 18.6,
16.4; FTIR (thin film), cm−1 2949, 1684, 1420, 1283, 1268;
HRMS-ESI (m/z) calcd for C19H29N2O ([M + H]+): 301.2274;
found: 301.2273.
1
acetate−hexanes); H NMR (400 MHz, CDCl3): δ 7.36−7.19
(m, 5H), 4.17 (ddd, J = 13.0, 10.1, 4.4 Hz, 1H), 4.14 (d, J =
13.8 Hz, 1H), 3.06 (d, J = 13.8 Hz, 1H), 3.01 (dq, J = 10.1, 6.1
Hz, 1H), 2.68 (s, br, 4H), 2.34 (dd, J = 11.5, 2.3 Hz, 1H), 2.07
(t, J = 12.6 Hz, 1H), 1.90 (d J = 11.5 Hz, 1H), 1.28 (ddd, J =
12.3, 4.4, 2.3 Hz, 1H), 1.06 (s, 3H), 1.02 (d, J = 6.1 Hz, 3H),
0.80 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 177.3 (2C),
140.4, 128.3 (2C), 128.1 (2C), 126.5, 64.2, 57.6, 57.0, 53.6,
39.7, 31.1, 29.2, 28.0 (2C), 24.5, 16.6; FTIR (thin film), cm−1
1699, 1390, 1369, 1193, 1148, 735; HRMS-ESI (m/z) calcd for
C19H27N2O2 ([M + H]+): 315.2067; found: 315.2072.
ASSOCIATED CONTENT
■
S
* Supporting Information
Additional screening data and copies of H and 13C NMR
spectra for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
AUTHOR INFORMATION
Corresponding Author
* E-mail: qiu.wang@duke.edu
■
N-(trans-1-Benzyl-2,5,5-trimethylpiperidin-3-yl)-
tosylsulfonamide (23). To a solution of 1h (21.7 mg, 0.1
mmol, 1 equiv) in anhydrous MeCN (1 mL) was added
TsNClNa·3H2O (28.2 mg, 0.1 mmol, 1 equiv). The reaction
solution was allowed to stir in the dark for 1 h, and then NaI
(0.7 mg, 0.005 mmol, 0.05 equiv) was added. The reaction was
then immediately heated to 60 °C and allowed to stir for 2 h.
Then the reaction was cooled down to room temperature,
diluted with CH2Cl2 (10 mL), and filtered through Celite. The
filtrate was concentrated in vacuo, and the crude residue was
then purified by column chromatography (10% ethyl acetate−
hexanes) to give 23 as a colorless oil (29.6 mg, 77%). Rf = 0.32
(25% ethyl acetate−hexanes); 1H NMR (400 MHz, CDCl3): δ
7.70 (d, J = 8.4 Hz, 2H), 7.33−7.20 (m, 7H), 4.34 (d, J = 9.5
Hz, 1H), 3.39 (d, J = 13.6 Hz, 1H), 3.15 (tdd, J = 9.5, 7.6, 4.4
Hz, 1H), 3.13 (d, J = 13.6 Hz, 1H), 2.42 (s, 3H), 2.27 (dd, J =
11.5, 1.5 Hz, 1H), 2.02 (dq, J = 7.6, 6.2 Hz, 1H), 1.74 (d, J =
11.5 Hz, 1H), 1.39 (ddd, J = 13.1, 4.4, 1.5 Hz, 1H), 1.12 (d, J =
6.2 Hz, 3H), 1.00 (dd, J = 13.1, 9.5 Hz, 1H), 0.83 (s, 3H), 0.76
(s, 3H); 13C NMR (125 MHz, CDCl3, 60 °C): δ 143.1, 139.8,
138.6, 129.6 (2C), 128.5 (2C), 128.2 (2C), 127.1 (2C), 126.8,
62.1, 61.2, 58.2, 54.8, 44.0, 30.7, 28.9, 26.2, 21.4, 14.2; FTIR
(thin film), cm−1 1153, 732, 663, 564; HRMS-ESI (m/z) calcd
for C22H31N2O2S ([M + H]+): 387.2101; found: 387.2103.
1-(trans-1′-Benzyl-2′,5′,5′-trimethylpiperidin-3′-yl)-
pyrrolidin-2-one (24). To a solution of 1h (65.2 mg, 0.3
mmol, 1 equiv) in anhydrous MeCN (3 mL) was added N-
chloro-2-pyrrolidinone20 (35.9 mg, 0.3 mmol, 1 equiv). The
reaction solution was allowed to stir in the dark for 1 h. NaI
(2.2 mg, 0.015 mmol, 0.05 equiv) was then added, and the
solution was immediately heated to 60 °C and allowed to stir
for 2 h. Na2CO3 (38.2 mg, 0.36 mmol, 1.2 equiv) was then
added, and the reaction was allowed to stir for an additional 72
h. The reaction was cooled down to room temperature, diluted
with EtOAc (40 mL), and placed into a separatory funnel. The
organic layer was washed with aqueous solutions of NaOH (1.0
M, 10 mL × 2) followed by brine (10 mL). The organic layer
was dried over Na2SO4 and filtered. The filtrate was
concentrated in vacuo. The crude residue was then purified
by column chromatography (25% ethyl acetate−hexanes) to
give 24 as a slightly yellow solid (58.2 mg, 65%). Rf = 0.14
(40% ethyl acetate−hexanes); 1H NMR (500 MHz, CDCl3, 60
°C): δ 7.33−7.19 (m, 5H), 4.15 (d, J = 13.9 Hz, 1H), 4.14−
4.06 (m, 1H), 3.39−3.24 (m, 1H), 3.29−2.24 (m, 1H), 3.04 (d,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Duke University for financial support for the project
and the Dean’s Fellowship support to G.X.O.
■
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