Metal-free, mild, nonepimerizing, chemo- and enantio- or diastereoselective N-alkylation of amines by alcohols via oxidation/imine-iminium formation/reductive amination: A pragmatic synthesis of octahydropyrazinopyridoindoles and higher ring analogues

Article abstract of DOI:10.1021/jo4012249

A mild step and atom-economical nonepimerizing chemo- and enantioselective N-alkylating procedure has been developed via oxidation/imine-iminium formation/reduction cascade using TEMPO-BAIB-HEH-Bronsted acid catalysis in DMPU as solvent and a stoichiometric amount of amine. The optimized conditions were further extended for the nonenzymatic kinetic resolution of the chiral amine thus formed under nonenzymatic in situ hydrogen-transfer conditions using VAPOL-derived phosphoric acid (VAPOL-PA) as the Bronsted acid catalyst. The enantioselective cascade of the presented reaction was successfully utilized in the synthesis of octahydropyrazinopyridoindole and its higher ring analogues.

Full text of DOI:10.1021/jo4012249

Article
pubs.acs.org/joc
Metal-Free, Mild, Nonepimerizing, Chemo- and Enantio-/or
Diastereoselective N‑Alkylation of Amines by Alcohols via Oxidation/
Imine−Iminium Formation/Reductive Amination: A Pragmatic
Synthesis of Octahydropyrazinopyridoindoles and Higher Ring
Analogues
Imran A. Khan and Anil K. Saxena*
Laboratory No. 101, Medicinal and Process Chemistry Division (MPC), CSIR-Central Drug Research Institute (CDRI), Chattar
Manzil Palace, Lucknow, Uttar Pradesh 226-001, India
S
* Supporting Information
ABSTRACT: A mild step and atom-economical nonepimeriz-
ing chemo- and enantioselective N-alkylating procedure has
been developed via oxidation/imine−iminium formation/
reduction cascade using TEMPO−BAIB−HEH−Brønsted
acid catalysis in DMPU as solvent and a stoichiometric
amount of amine. The optimized conditions were further
extended for the nonenzymatic kinetic resolution of the chiral
amine thus formed under nonenzymatic in situ hydrogen-
transfer conditions using VAPOL-derived phosphoric acid (VAPOL-PA) as the Brønsted acid catalyst. The enantioselective
cascade of the presented reaction was successfully utilized in the synthesis of octahydropyrazinopyridoindole and its higher ring
analogues.
good to excellent, but generally the main drawback is the need
for harsh conditions such as high temperature which can be
unfavorable for highly sensitive compounds. The landmark
advancement in the field of understanding iminium activation
through LUMO lowering activation phenomenon by MacMil-
lan1c−k and more importantly Brønsted acid catalyzed imine
activation concepts by Rueping1l−t added key reasons for major
success in the reaction associated with fields like “highly
regulated cascade”.1l
Taylor et al. reported a mild one-pot oxidation/imine
iminium formation/reduction sequence for the conversion of
benzylic, allylic, or propargylic alcohols to amines using MnO2
(as oxidant), a polymer-supported cyanoborohydride (as
reductant), and acetic acid (as additive).14 The homogeneous
catalysts3 such as ruthenium15 or iridium16 catalysts offered
good yields of monoalkylated amines. However, the major
drawbacks were the high temperature and a long reaction time
except under microwave irradiation along with the epimeriza-
tion of optically active alcohols that are involved in the N-
alkylation of amines.14b Recently, N-alkylation of amines by
direct nucleophilic substitution at the sp3 carbon atom of
alcohols was reported using iron and amino acid catalysts but
again at elevated temperature with long reaction times.17 Our
recent research endeavors on developing effective method-
ologies for useful organic transformations18 to construct
INTRODUCTION
■
The reductive amination reaction remains one of the most
powerful and widely utilized transformations available to
practitioners of chemical synthesis in the modern era.1
Conventionally, the N-alkylation of amines is achieved either
by their alkylation with the alkylating agents or by the addition
of the nucleophiles or radicals on imines.2 The most commonly
used method for the preparation of secondary and tertiary
amines is the substitution of alkyl halides by amines in the
presence of a base.3 However, in this process polyalkylation
often occurs, which leads to a mixture of products along with
undesired inorganic waste. Moreover, several alkyl halides are
toxic and unnatural.
The use of accessible, reasonable, and less hazardous reagents
such as alcohols instead of alkyl halides for N-alkylation of
amines is considered as a better alternative approach with high
atom-efficiency leading to the formation of water as a
byproduct. The “borrowing hydrogen strategy (hydrogen
autotransfer)”, has allowed the direct use of alcohols as
alkylating agents. This process has been applied to the
formation of C−N bonds,4 and the use of SiO2 and Al2O3
5
6
as catalysts has been reported; however, under these conditions
both the yields and the selectivities (monoalkylation versus bis-
alkylation) are poor. The best known conditions involve
transition-metal-based catalysts, including heterogeneous and
homogeneous processes. When the reaction is performed with
heterogeneous catalysts3d such as nickel,7 copper,8 platinum,
ruthenium,9 palladium,10 gold,11 silver,12 or iron13 the yields are
Received: June 20, 2013
© XXXX American Chemical Society
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Scheme 1. General Representation of Oxidation/Imine−Iminium Formation Cascade in Both Possibilities of Intramolecular
Coupling
octahydropyrazinopyridoindoles (oHPPs) and like molecules is
of utmost interest. These oHPPs including the drug biriperone
(centbutindole)19 discovered by us have been associated with
several pharmacological activities (Scheme 1).
Table 1. Standardization of Reaction Conditions
CHEMISTRY
■
Herein, we report a one-pot oxidation/imine−iminium
formation/reduction sequence under mild conditions (Scheme
1). This sequence allows the chemo- and enantioselective N-
alkylation of amines with various nonactivated primary and
secondary alcohols and prevents epimerization of optically
active substrates (amines or alcohols) without metal involve-
ment. This is of importance for medicinal chemists for
preparing amines of biological interest because the metal in
traces may lead to undesirable pathological conditions.20 Thus,
the method was further extended to the synthesis of the
octahydropyrazinopyridoindoles and its higher ring analogues.
These tetracyclic cores were synthesized from their respective
aminols via intramolecular oxidation/imine−iminium forma-
tion/reduction cascade in high yield without such noted
epimerization. Among the various conditions reported for the
oxidation of alcohols, we selected the mild 4-hydroxy-2,2,6,6-
tetramethyl-1-piperidinyloxyl (TEMPO)−[bis(acetoxy)iodo]-
benzene (BAIB) system which releases AcOH as an efficient
additive for reductive aminations in the reaction medium.18
3a/
yield of
b
a
entry solvent
“H” (hydride source)
2a
3aa
3a (%)
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
3
DMPU NaBH4
1.0
1.0
1.0
2.0
2.0
2.0
1.0
71/28
64/34
62/28
94/6
54
DMF
DCE
41
61
DCE
84
DCM
MeOH
81/18
65/35
97/3
71
68
DMPU A (1.15 equiv) + I-OH
quant
quant
75
(0.15 equiv)
DMF
95/5
DCE
97/3
DCM
90/10
60/32
68/32
95/5
68
RESULTS AND DISCUSSION
DMPU NaBH3CN
NaBH(OAc)3
1.0
62
■
4
78
First, the reaction sequence was standardized for the N-
alkylation of benzylamine 2a by heptanol 1a for which the latter
1a was oxidized by TEMPO (0.2 equiv) in the presence of
BAIB (1.15 equiv) in DMPU as solvent at rt (25 °C). After 6 h,
different reducing agents along with 2a (3 equiv) were screened
for the optimization of the reaction conditions (Table 1).
Among different reducing agents, the use of NaBH4 led to 3a in
almost quantitative yield with only traces of 3aa (Table 1, entry
1c). The use of 1.0 equiv of benzylamine offered moderate yield
(41−61%) of 3a with a selectivity ratio 3a/3aa = 71/28, 64/34
and 62/28 in the three solvents screened (Table 1, entries 1−
3).
5
B (1.15 equiv) + AcOH
(0.15 equiv)
67
6
7
8
9
B (1.15 equiv) + I-OH
(0.15 equiv)
96/4
97/3
91/8
97/3
74
84
64
95
A (1.1 equiv) + I-OH
(0.1 equiv)
A (1.15 equiv) + AcOH
(0.15 equiv)
A (1.15 equiv) + II-OH
(0.15 equiv)
a
b
1
Determined through HPLC and H NMR. Isolated yield.
The use of excess amine (∼ 2.0 equiv) undoubtedly led to
excellent yields in DCE as solvent. Since the use of excess
amine is not possible in intramolecular cyclization via
oxidation/imine−iminium formation/dehydration, we tried to
avoid the use of excess amine in order to increase the selectivity
for the monoalkylation. The use of commonly employed
reagents viz. NaBH3CN and NaBH(OAc)3 for reductive
amination of aldehydes required longer reaction times and
provided the mono-(3a, major) and di-(3aa, minor)-N-
alkylated amines in low yield (Table 1, entries 3 and 4),
whereas the alkylation of benzylamine (2a) with alcohol (1a) in
stoichiometric amounts in the presence of HEH (A) as the
B
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Figure 1. Mildness and chemoselective aspect of the reaction cascade.
Figure 2. Nonepimerizing cases analyzed under the standardized reaction conditions.
hydride source and a catalytic amount of (PhO)2(PO)OH (I-
OH) as the Brønsted acid gave a quantitative yield of the
desired monoalkylated amine (3a) without any formation of
dialkylated amine (3aa, Table 1, entries 2 and 6−8). The use of
2-phenylbenzothiazoline (B) as hydride source resulted in
lower yields (67% with 3a/3aa ratio of 95/5) but was better
than HEH (A). The former failed to perform better in the
presence of I-OH, which could be explained on the basis of
asymmetric counterion pair catalysis which is observed due to
the formation of a chiral ion pair between imine and
phosphoric acid. The use of BINOL-derived phosphoric acid
C
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Figure 3. Enantioselective conversion of achiral or racemic alcohols to their respective chiral amines.
(II-OH) instead of I-OH was equally effective in affording 3a
selectively under similar reaction conditions (Table 1, entry 8).
The reaction is versatile and allows the monoalkylation of a
wide range of amines including the hindered amines which are
difficult for reductive alkylation. The results obtained with
various amines and alcohols are reported in Figure 1. It is
interesting to note that HEH (Hantszch ester) was a better
substitute than NaBHX3 as reducing agents. Benzylamine 2a
was alkylated with secondary (3b−d, h, m−o) and tertiary (3e)
alcohols including δ-unsaturated primary alcohols (3f) in good
yields (∼70%) (Figure 1). It is also worth noting that N-Boc-3-
hydroxypiperidine was quantitatively transformed to the
corresponding N-alkylated Boc-3-aminopiperidine (3d, h, o)
with the corresponding amines. Allylamine was N-alkylated in
good yields by primary (3e) or secondary alcohols (3d)
without any isomerization of the double bond (Figure 1).
Furthermore, a sterically hindered amine such as tert-butyl-
amine was also monoalkylated to form 3d in good yields.
Secondary amines were also N-alkylated by primary or
secondary alcohols to the corresponding tertiary amines (3f−
h, l, p, Figure 1). This one-pot process is chemoselective as it
showed great selectivity potential of transforming diols (1j−k)
to the respective amino alcohol 3j−k in excellent yield without
isolation of any intermediates (Figure 1).
in good yields with excellent enantiomeric excesses (Figure 2).
Optically active amines may also be employed in this oxidation/
imine−iminium formation/reduction sequence, without any
racemization. Thus, when this sequence was applied to various
achiral alcohols and optically active amine 5a−k (having a
stereogenic center at α position), these compounds were
isolated in quantitative yield and with an excellent enantiomeric
excess (ee > 96%, Figure 2). The compounds 5h and 4h were
isolated in good yields and with diastereoisomeric ratios 89/11
and 78/22, respectively. In the case of N-Boc-3-hydroxypiper-
idine the corresponding product N-Boc-3-aminopiperidine (5i)
was obtained with a diastereoisomeric ratio of 84/16 in favor of
the (3S)-isomer when (S)-4-methoxylphenylethylamine was
used (Figure 2).
After successful standardization of the reaction conditions,
we further extended this methodology for the enantioselective
reduction of the imine formed with 1-phenylethanol and
allylamine. Thus, for this we screened various chiral Brønsted
acids (oxidizing conditions A−D) for catalyzing the HEH-
mediated reduction in one pot. The standardized conditions
were used on various unsymmetrical alcohols (6a−k, Figure 3),
and it was observed that binol derivatives possessing 3-aryl
substituents (III-OH, TRIP-PA) and vaulted derivative (V-OH,
VAPOL-PA) offered excellent enantioselectivity in the reaction.
The employment of VAPOL-derived phosphoric acid as
catalyst for the reductive amination offered excellent conversion
to the chirally enhanced amines from achiral or racemic
alcohols.
When the N-alkylation of amines was carried out with
optically active alcohols possessing a stereocenter at the β-
position such as 4a−f, even the use of the recently reported
ruthenium catalyst led to the epimerization of the stereogenic
center,14b while no epimerization of the stereogenic center
occurred when the reaction was carried out using our
aforementioned reaction conditions where 4a−f were isolated
After optimization for the enantioselective amination of the
alcohols, we moved toward the intramolecular conversion of
the aminols to their respective cyclized secondary or tertiary
D
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a
Scheme 2. Example of Dynamic Kinetic Resolution (DKR)
a
Reagents and conditions. Cases I and III: (a) alcohol (1.0 equiv), TEMPO (0.15 equiv), BAIB (1.15 equiv), molecular sieve (20% w/v) DMPU, 15
°C, 2−3 h; (b) HEH (0.8 equiv), VAPOL-PA (0.15 equiv), amine (0.8 equiv), DMPU, 15 °C, 6.5 h. Case II: (a) TEMPO (0.15 equiv), BAIB (1.15
equiv), molecular sieves (20% w/v) DMPU, 15 °C, 2−3 h; (b) amine (0.75 equiv), HEH (0.85 equiv), VAPOL-PA (0.8 equiv), DMPU, 15 °C, 6 h.
amines. Furthermore, we used this strategy for a general
stereoselective synthesis of octahydropyrazinopyridoindole
derivatives (oHPPs).19 It was also observed that TEMPO−
BAIB-catalyzed oxidation followed by (S)-VAPOL-PA−HE-
mediated reductive amination methodology could effectively be
utilized in the kinetic resolution of the amines possessing a
chiral center at the α-center. The chirality at β-carbon center
both in the case of amine amd alcohol were also found to
impart a significant effect at the HEH-mediated and (S)-
VAPOL-PA as chiral-catalyzed reductive amination. Therefore,
kinetic resolution of racemic amines possessing chiral α and/or
β carbon atoms and racemic alcohols bearing β-chiral carbon
atoms was also analyzed for each case (Scheme 2). The
obtained results showed good results in the case of α-
substituted chiral amines (case I), whereas the results in the
case of β-chiral substrates (i.e., amine and aldehyde case II and
III) were moderate, although this dimension of the reaction is
in too early a state in our laboratory to draw conclusions.
Indeed, the initial findings have showed the potential of the
reagent system toward a nonenzymatic kinetic isolation of
racemic mixtures of amine and aldehyde.
In order to standardize the efficacious method of oxidation/
imine−iminium formation/reductive amination protocol for
the synthesis of the substrates bearing both the desired
functionalities by coupling of tetrahydropyridoindoles (tHPs)
with N-protected aminols of required carbon chain length as
the model substrate (Figure 4), the tetracyclic scaffolds 7a−e
were obtained by using N-Boc and N-benzyl derivatives of
aminopropanol,-butanol, -pentanol, and -hexanol in good to
excellent yields with no observed epimerization using I-OH as
catalyst. The precursors for the compounds 7a−e were
obtained in a three-step process comprising BINOL-PA-
catalyzed intermolecular oxidation/imine−iminium forma-
tion/reductive amination followed by LAH-mediated ester
reduction to the corresponding alcohol and then deprotection
of N-Boc by using HCl−dioxane for generation of the desired
aminols in good overall yields. The compounds 7f−h were
obtained with excellent diastereoselectivity (on the basis of
NMR and HPLC) possessing chirality adjacent to the α-carbon
atom (the precursor was derived from l-tryptophan, described
in the Supporting Information) using VAPOL-derived phos-
phoric acid (V-OH) as catalyst at the reductive amination stage.
The tetracyclic products bearing a chiral center at δ-carbon
were also obtained with excellent results both in terms of
stereoselectivities and yields. After the successful stereoselective
construction of larger ring analogues of oHPP we have also
succeeded in the synthesis of oxadiazacino analogues (8e−f) in
good yields with excellent stereoselectivity (Figure 4) using the
vaulted biphenanthrol phosphoric acid (VAPOL-PA) as
catalyst. Furthermore, we also successfully synthesized
compound 9a, which does not carry a β-carboline skeleton,
in good yield and conhydrine (9b) in moderate yield (52%)
due to the equally effective formation of 9c (36%). In both of
these positional isomers we found excellent diastereoselection,
which was further supported through HPLC and NMR studies
using Co(acac)2 as the paramagnetic reagent.
CONCLUSIONS
■
In conclusion, we have shown that amines can be alkylated by
nonactivated alcohols in a metal-free one-pot oxidation/imine−
iminium formation/reduction sequence at rt. This sequence of
reactions is easy to carry out and allows the formation of
secondary and tertiary amines under mild conditions in good
yields and with good functional group tolerance. Optically
active amines and alcohols can be involved in this sequence
without epimerization. We are currently investigating this
E
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Figure 4. Preparation of octahydropyrazinopyridoindoles derivatives (oHPPs) and their higher ring analogues.
14 h) checked by TLC or GC/MS. When the oxidation completion
was not reached after 16 h, additional BAIB (up to 240 mg, 0.75
mmol) was added to the reaction mixture. Then, the specified amine
(2 mmol, 2 equiv), HEH (or similar reagent when specified) (414 mg,
1 mmol, 1 equiv), and chiral Brønsted acid (15 mol %) were added to
the reaction mixture. After a few hours (2−10 h), the mixture was
quenched carefully with aq NaHCO3 (10 mol %, 10 mL) and extracted
with Et2O or EtOAc (3 × 20 mL). The combined organic layers were
dried (MgSO4), filtered, and concentrated under reduced pressure.
Purification was achieved by one of the following methods. Method A
(chlorhydrate precipitation): The crude material was acidified with aq
HCl (10%, 10 mL), and the aqueous layer was extracted with CH2Cl2
(3 × 20 mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated under reduced pressure. The residue was
dissolved in CH2Cl2, and the amine chlorohydrate was precipitated by
addition of diethyl ether (PE) (∼10 mL), recovered by filtration,
basified with aq NaOH (10 mol %, 10 mL), and extracted with Et2O
(3 × 20 mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated under reduced pressure to afford the
product amine. Method B (acido-basic washing): The crude material
was dissolved in Et2O (20 mL), and the organic layer was extracted
with aq HCl (10%, 3 × 15 mL). The acidic extracts were combined,
basified with NaOH at 0 °C, and then extracted with Et2O (3 × 20
mL). The combined organic layers were dried (MgSO4), filtered, and
concentrated under reduced pressure to afford the product amine.
Method C (chromatography): The crude material was purified by flash
chromatography.
sequence of reactions in order to have access to biologically
active amino compounds.
EXPERIMENTAL SECTION
■
General Information. All reagents and solvents were purchased
from commercial sources and used without purification. NMR spectra
were recorded with 300 and 400 MHz spectrometers for 1H NMR and
75 MHz and 100 MHz for 13C NMR. Chemical shifts δ are given in
ppm relative to the residual signals of tetramethylsilane in CDCl3 or
deuterated solvent CDCl3/DMSO-d6 for 1H and 13C NMR.
Multiplicities are reported as follows: singlet (s), doublet (d), doublet
of doublets (dd), doublet of triplets (dt), triplet (t), quratet (q),
multiplet (m). High-resolution mass spectra were taken with a mass
spectrometer. Column chromatography was performed using silica gel
(100−200 mesh) as the stationary phase. All reactions were monitored
by thin-layer chromatography (TLC). The purity and characterization
of these compounds were further established using ESI-MS and
HRMS mass spectra recorded on a microTOF focus spectrometer.
Analytical HPLC were performed on a reversed-phase C-18 column
(250 mm × 4.6 mm). Retention times on HPLC (Chiralpak IA, IC
normal phase and Chiradex and Chirasphere reversed-phase column;
150 × 4.6 mm; 5 μm) with UV detection at 220/254 nm. Melting
points were measured on a capillary melting point apparatus and are
uncorrected.
General Procedure. 2,2,6,6-Tetramethyl-1-piperidinyloxyl
TEMPO (30 mg, 0.18 mmol, 0.18 equiv) and [bis(acetoxy)iodo]-
benzene BAIB (370 mg, 1.15 mmol, 1.15 equiv) were added to a
stirred solution of specified alcohol (1 mmol) in CH2Cl2 (4 mL), and
the mixture was stirred at rt until complete conversion of alcohol (2−
N-Benzylheptan-1-amine (3a): yellow liquid; yield 204 mg
(99.4%); IR (KBr, νmax, cm−1) 3254.2, 2457.2, 1452.2, 1005.4; 1H
NMR (300 MHz, CDCl3, ppm) δ 7.31 (s, 5H), 3.98−3.50 (m, 2H),
F
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2.60 (q, J = 7.0 Hz, 2H), 1.70−1.46 (m, 2H), 1.20 (dq, J = 17.4, 7.1,
6.6 Hz, 8H), 0.87 (dd, J = 9.6, 3.3 Hz, 3H, CH3); 13C NMR (75 MHz,
CDCl3, ppm) δ 142.5, 129.0, 128.7, 127.1, 53.7, 49.7, 32.2, 30.6, 30.2,
27.6, 23.1, 14.4; ES-MS (M + H+, m/z) 205.2; HRMS calcd for
C14H23N 205.1830, found 205.1838.
1.39 (brs, 1H); 13C NMR (75 MHz, CDCl3, ppm) δ 138.3, 127.9,
122.8, 122.6, 120.1, 118.9, 112.6, 111.0, 50.3, 23.3; ES-MS (M + H+,
m/z) 304.2; HRMS calcd for C20H21N3 303.1735, found 303.1732.
( )-2-((2-(1H-Indol-3-yl)ethyl)amino)-1-(1H-indol-3-yl)ethan-
1-ol (3j): dirty yellow solid; yield 274 mg (86%); mp 157 °C; IR
1
N,N-Dibenzylheptan-1-amine (3aa): deep yellow liquid; yield; IR
(KBr, νmax, cm−1) 2136.2, 1425.6, 1235.6; 1H NMR (300 MHz,
CDCl3, ppm); 1H NMR (200 MHz,) δ 7.40 (t, J = 6.3 Hz, 4H), 7.36−
7.07 (m, 6H), 3.59 (s, 4H), 2.34 (t, J = 7.3 Hz, 2H), 1.87−1.63 (m,
2H), 1.56 (dd, J = 14.1, 7.2 Hz, 2H), 1.35−1.03 (m, 6H), 0.88 (t, J =
6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3, ppm) δ 140.2, 129.2, 128.5,
127.5, 59.6, 53.2, 32.0, 30.6, 27.3, 26.9, 22.7, 14.4; ES-MS (M + H+, m/
z) 296.3; HRMS calcd for C21H29N 295.2300, found 295.2305. Anal.
Calcd: C, 85.37; H, 9.89; N, 4.74. Found: C, 85.30; H, 9.82; N, 4.71.
N-Benzylcyclohexanamine (3b): yellow liquid; yield 169.1 mg
(KBr, νmax, cm−1) 3321.5, 3248.7, 2487.2, 1548.2, 1007.4; H NMR
(300 MHz, CDCl3, ppm) δ 9.77−9.02 (m, 1H), 8.82−8.09 (m, 1H),
7.85−7.67 (m, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.44−7.29 (m, 3H), 7.24
(s, 1H), 7.20−6.94 (m, 4H), 5.12−4.71 (m, 1H), 3.56−3.24 (m, 3H),
3.20−2.99 (m, 2H), 2.92−2.73 (m, 1H), 2.73−2.43 (m, 2H); 13C
NMR (75 MHz, CDCl3, ppm) δ 138.3, 137.9, 128.3, 127.6, 124.5,
123.0, 122.8, 122.7, 120.6, 120.2, 120.1, 118.9, 118.5, 112.7, 112.6,
110.1, 61.8, 56.2, 51.1, 23.5; ES-MS (M + H+, m/z) 320.2, 302.5;
HRMS calcd for C20H21N3O 319.1685, found 319.1688.
( )-5-(Cyclohexylamino)pentan-2-ol (3k): yellow liquid; yield
159 mg (86%); IR (KBr, νmax, cm−1) 3254.2, 2457.2, 1452.2, 1005.4;
1H NMR (300 MHz, CDCl3, ppm) δ 3.83−3.51 (m, 1H), 2.93−2.79
(brs, 1H), 2.67 (d, J = 7.2 Hz, 2H), 2.50−2.25 (m, 1H), 1.84−1.32 (m,
12H), 1.32−0.96 (m, 5H); 13C NMR (75 MHz, CDCl3, ppm) δ 68.3,
51.5, 48.5, 35.7, 29.9, 25.7, 24.6, 23.65, 23.59; ES-MS (M + H+, m/z)
186.5.
1
(89%); IR (KBr, νmax, cm−1) 3152.2, 2325.8, 1422.7, 935.4; H NMR
(300 MHz, CDCl3, ppm) δ 7.69−6.93 (m, 5H), 4.05−3.46 (m, 2H),
2.70−2.25 (m, 1H, CH), 2.00−1.32 (m, 9H), 1.34−1.01 (m, 2H); 13C
NMR (75 MHz, CDCl3, ppm) δ 128.9, 128.3, 127.1, 52.1, 52.0, 30.6,
25.7, 24.4; ES-MS (M + H+, m/z) 190.2. Anal. Calcd for C13H19N: C,
82.48; H, 10.12; N, 7.40. Found: C, 82.34; H, 10.01; N, 7.31.
( )-tert-Butyl 4-(tert-butylamino)piperidine-1-carboxylate (3c):
yellow liquid; yield 240 mg (94%); IR (KBr, νmax, cm−1) 3254.2,
2457.2, 1452.2, 1005.4; 1H NMR (300 MHz, CDCl3, ppm) δ 3.75 (dd,
J = 9.8, 6.5 Hz, 1H), 3.60−3.26 (m, 2H), 3.26−2.65 (m, 2H), 1.48 (s,
13H), 1.04 (s, 9H); 13C NMR (75 MHz, CDCl3, ppm) δ 158.8, 77.7,
53.1, 45.6, 38.3, 29.8, 29.5, 28.8; ES-MS (M + H+, m/z) 257.2, 157.2;
HRMS calcd for C14H28N2O2 256.2151, found 256.2147.
5-(Cyclohexyl(4-hydroxypentan-2-yl)amino)pentan-2-ol (3l):
yellow liquid; yield 233 mg (86%); IR (KBr, νmax, cm−1) 3254.2,
1
2457.2, 1452.2, 1005.4; H NMR (300 MHz, CDCl3, ppm) δ 4.29−
3.91 (m, 1H), 3.69 (m, 1H), 3.05−2.70 (m, 3H), 2.67−2.25 (m, 3H),
1.88−1.39 (m, 15H), 1.36−0.77 (m, 12H); 13C NMR (75 MHz,
CDCl3, ppm) δ 66.9, 66.0, 57.4, 52.2, 46.6, 42.1, 36.3, 32.4, 25.9, 25.7,
23.7, 23.4, 22.8, 20.; ES-MS (M + H+, m/z) 272.2.
( )-tert-Butyl 3-(allylamino)piperidine-1-carboxylate (3d): light
N-Phenethyladamantan-2-amine (3m): yellow liquid; yield 234
yellow liquid; yield 216 mg (90%); IR (KBr, νmax, cm−1) 3254.2,
1
mg (92%); IR (KBr, νmax, cm−1) 3254.2, 2457.2, 1452.2, 1005.4; H
1
2457.2, 1452.2, 1005.4; H NMR (300 MHz, CDCl3, ppm) δ 5.73
NMR (300 MHz, CDCl3, ppm) δ 7.13 (d, J = 36.3 Hz, 5H), 2.93−
2.58 (m, 5H), 2.56−2.20 (brs, 1H), 1.94−1.30 (m, 10H), 1.25−0.72
(m, 4H); 13C NMR (75 MHz, CDCl3, ppm) δ 139.9, 128.2, 127.9,
126.7, 59.5, 49.6, 36.7, 35.2, 34.5, 33.5, 32.5, 31.5, 30.5, 27.1; ES-MS
(M + H+, m/z) 256.8; HRMS calcd for C18H25N 255.1987, found
255.1983.
(ddd, J = 17.0, 5.8, 2.9 Hz, 1H), 5.10 (dd, J = 19.2, 14.5 Hz, 2H), 3.63
(d, J = 13.1 Hz, 1H), 3.41−2.79 (m, 7H), 1.93−1.62 (m, 2H), 1.63−
1.29 (m, 12H); 13C NMR (75 MHz, CDCl3, ppm) δ 155.5, 133.8,
115.9, 78.8, 52.6, 52.5, 44.4, 42.4, 30.0, 28.8, 17.1; ES-MS (M + H+, m/
z) 241.2, 141.2; HRMS calcd for C13H24N2O2 240.1838, found
240.1841.
N-tert-Butylprop-2-en-1-amine (3e): colorless liquid; yield 104 mg
(92%); bp 112.5 °C; IR (KBr, νmax, cm−1) 3284.2; rest of the data
matched the literature reported data.
4-(2-((Adamantan-2-yl)amino)ethyl)benzene-1,2-diol (3n): yel-
low liquid; yield 204 mg (99.4%); IR (KBr, νmax, cm−1) 3254.2, 2457.2,
1
1452.2, 1005.4; H NMR (300 MHz, CDCl3, ppm) δ 7.37 (brs, 1H),
6.72 (d, J = 7.3 Hz, 1H), 6.58 (s, 1H), 6.48 (d, J = 7.3 Hz, 1H), 5.43
(brs, 1H), 2.91−2.72 (m, 3H), 2.64 (d, J = 6.1 Hz, 2H), 2.55−2.27
(brs, 1H), 1.96−1.38 (m, 12H), 1.27−0.53 (m, 5H); 13C NMR (75
MHz, CDCl3, ppm) δ 143.8, 142.6, 135.7, 120.4, 115.2, 114.3, 59.5,
49.9, 36.7, 36.0, 34.5, 33.5, 32.5, 31.5, 30.5, 27.1; ES-MS (M + H+, m/
z) 288.4; HRMS calcd for C18H25NO2 287.1885, found 287.1881.
tert-Butyl (R)-4-((adamantan-1-yl)amino)-2-oxopiperidine-1-
carboxylate (3o): yellow liquid; yield 299.6 mg (86%); IR (KBr,
νmax, cm−1) 3258.2, 2457.2, 1745.2, 1687.3, 1654.2, 1615.2, 1462.2,
1-Hex-5-en-1-ylpiperidine (3f): faint yellow liquid; yield 160 mg
1
(96%); IR (KBr, νmax, cm−1) 3235.8, 2135.2, 1152.2; H NMR (300
MHz, CDCl3, ppm) δ 6.09−5.40 (m, 1H), 5.14−4.72 (m, 2H), 2.74−
2.46 (m, 4H), 2.35 (t, J = 6.7 Hz, 2H), 1.87 (hept, J = 7.0, 6.1 Hz, 6H),
1.65−1.41 (m, 4H), 1.29 (dd, J = 10.8, 3.8 Hz, 2H); 13C NMR (75
MHz, CDCl3, ppm) δ 139.3, 115.3, 57.1, 56.1, 34.6, 27.8, 26.4, 26.2,
25.67; ES-MS (M + Na+, m/z) 192.5, 168.2. Anal. Calcd for C11H21N:
C, 78.97; H, 12.65; N, 8.37. Found: C, 78.85; H, 12.54; N, 8.29.
1-Heptylpiperidine (3g): deep yellow liquid; yield 172.2 mg
(94%); IR (KBr, νmax, cm−1) 3254.2, 2457.2, 1452.2, 1005.4; 1H NMR
(300 MHz, CDCl3, ppm) δ 2.79−2.46 (m, 4H), 2.33 (s, 2H), 2.06−
1.74 (m, 4H), 1.75−1.39 (m, 6H), 1.41−1.06 (m, 6H), 0.88 (s, 3H);
13C NMR (75 MHz, CDCl3, ppm) δ 59.3, 57.0, 32.0, 30.1, 27.8, 27.1,
26.3, 25.7, 22.7, 14.4; ES-MS (M + Na+, m/z) 208.4, 184.2. Anal.
Calcd for C12H25N C 78.62; H, 13.75; N, 7.64. Found: C 78.55; H,
13.64; N, 7.52.
1
1012.4; H NMR (300 MHz, CDCl3, ppm) δ 4.01−3.64 (m, 2H),
3.57−3.05 (m, 2H), 2.67−2.29 (m, 2H, COCH2), 1.99 (s, 3H), 1.96−
1.74 (m, 7H), 1.75−1.03 (m, 18H); 13C NMR (75 MHz, CDCl3,
ppm) δ 174.4, 154.6, 81.5, 53.7, 44.7, 39.9, 38.9, 37.9, 37.6, 30.4, 28.5,
27.3; ES-MS (M + H+, m/z) 349.6, 249.3; HRMS calcd for
C20H32N2O3 348.2413, found 348.2417.
( )-tert-Butyl 3-((1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-
yl)methyl)-1,3,4,9-tetrahydro-2H-pyrido [3,4-b]indole-2-carboxy-
late (3p): yellow liquid; yield 415 mg (91%); IR (KBr, νmax, cm−1)
( )-tert-Butyl 3-(dibenzylamino)piperidine-1-carboxylate (3h):
yellow gum; yield 204 mg (99.4%); IR (KBr, νmax, cm−1) 3254.2,
3254.2, 2457.2, 1452.2, 1005.4; H NMR (300 MHz, CDCl3, ppm) δ
1
1
2457.2, 1452.2, 1005.4; H NMR (300 MHz, CDCl3, ppm) δ 7.66−
8.19 (brs, 1H) 7.86 (brs, 1H, NH), 7.73−7.55 (m, 1H), 7.55−7.35 (m,
2H), 7.33−7.17 (m, 2H), 7.17−7.06 (m, 2H), 7.06−6.89 (m, 2H),
4.68 (d, J = 16.4 Hz, 1H), 4.36 (d, J = 16.6 Hz, 1H), 4.20−3.96 (m,
1H), 3.49−3.03 (m, 7H), 3.03−2.77 (m, 4H), 2.77−2.42 (m, 2H),
1.39 (s, 9H); 13C NMR (75 MHz, CDCl3, ppm) δ 155.5, 138.3, 134.7,
133.3, 132.3, 128.2, 125.7, 120.8, 120.5, 118.8, 118.5, 118.4, 117.5,
112.0, 111.6, 110.7, 110.6, 79.1, 54.2, 51.1, 44.1, 41.0, 39.2, 29.1, 25.1,
23.4; ES-MS (M + H+, m/z) 457.2; HRMS calcd for C28H32N4O2
456.2525, found 456.2529.
7.37 (m, 5H), 7.20 (s, 5H), 3.88 (d, J = 13.6 Hz, 2H), 3.73 (d, J = 13.7
Hz, 2H), 3.65−3.41 (m, 1H), 3.20−3.02 (m, 2H), 2.98−2.63 (m, 2H),
1.77−1.57 (m, 1H), 1.58−1.36 (m, 9H); 13C NMR (75 MHz, CDCl3,
ppm) δ 155.5, 140.4, 129.3, 128.6, 127.5, 78.8, 58.0, 57.3, 47.1, 42.4,
30.6, 28.8, 18.2; ES-MS (M + H+, m/z) 381.5, 290.1, 281.4, 200.4;
HRMS calcd for C24H32N2O2 380.2464, found 380.2464.
Bis(2-(1H-indol-3-yl)ethyl)amine (3i): yellow solid; yield 257 mg
(85%); mp 198 °C; IR (KBr, νmax, cm−1) 3264.3, 3125.8, 2437.8,
1
1458.2, 1315.5, 1314.2, 935.2; H NMR (300 MHz, CDCl3, ppm) δ
(+)-tert-Butyl 3-((allylamino)methyl)indoline-1-carboxylate
8.66−7.97 (m, 2H), 7.58 (d, J = 7.2 Hz, 2H), 7.37 (d, J = 7.4 Hz, 2H),
7.27−6.94 (m, 6H), 3.37−3.16 (m, 4H), 3.16−2.98 (m, 4H), 2.00−
(4a): yellow semisolid; yield 253.4 mg (88%); [α]22.1 +26.5 (c
D
1.03, CHCl3); HPLC using Chiralpak IC, at flow rate 0.6 mL/min,
G
dx.doi.org/10.1021/jo4012249 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
ACN/Hex (5:95, isocratic) 18.66 min (99%) and 19.8 min (1%); H
NMR (300 MHz, CDCl3, ppm) δ 8.07 (d, J = 7.4 Hz, 1H), 7.32 (s,
2H), 7.09 (dt, J = 4.8, 2.5 Hz, 1H), 6.14−5.76 (m, 1H), 5.15−4.95 (m,
2H), 4.95−4.81 (m, 1H), 3.97−3.83 (m, 1H), 3.41−3.15 (m, 1H),
3.14−2.96 (m, 2H), 2.96−2.81 (m, 1H), 2.81−2.53 (m, 1H), 1.57 (s,
9H); 13C NMR (75 MHz, CDCl3, ppm) δ 153.0, 144.2, 134.9, 131.0,
129.0, 125.7, 123.7, 115.4, 114.4, 77.9, 55.6, 51.2, 49.9, 42.2, 28.5; ES-
MS (M + H+, m/z) 289.3. Anal. Calcd for C17H24N2O2: C, 70.80; H,
8.39; N, 9.71; O, 11.10. Found: C, 70.77; H, 8.25; N, 9.65.
5.45−4.86 (brs, 1H), 4.45 (d, J = 6.3 Hz, 2H), 4.40−4.07 (m, 2H),
3.72 (s, 4H), 3.12−2.83 (m, 2H), 2.75−2.36 (m, 2H), 1.41 (d, J = 20.3
Hz, 15H); 13C NMR (75 MHz, CDCl3, ppm) δ 157.2, 156.2, 144.0,
140.6, 140.1, 128.9, 128.5, 127.9, 127.5, 127.0, 125.0, 119.8, 80.3, 66.1,
60.1, 56.9, 50.6, 47.2, 40.1, 35.4, 29.0, 28.8, 25.7; ES-MS (M + H+, m/
z) 634.4, 657.8; HRMS calcd for C40H47N3O4 633.3567, found
633.3568.
tert-Butyl ((2S)-1-(allylamino)-3-hydroxybutan-2-yl)carbamate
(4g): yellow liquid; yield 22.4 mg (92%); [α]16.9 −62.3 (c 0.2
D
tert-Butyl (S)-2-(((adamantan-1-yl)amino)methyl)indoline-1-
carboxylate (4b): yellow solid; yield 332 mg (87%); mp 136−138
°C; [α]21.6D +52.6 (c 1.05, CHCl3); HPLC using Chiralpak IC at flow
rate 0.6 mL/min, ACN/IPA/Hex (2:95:3) isocratic, 23.1 min (1%)
and 24.73 min (99%); IR (KBr, νmax, cm−1) 3245.6, 2854.3, 1694.1,
CH2Cl2); HPLC using Chiralpak IA, at flow rate 0.6 mL/min, IPA/
Hex/TEA (5:95:0.001, isocratic) tR 8.5 min (1.94%), 8.9 min (0.5%),
1
10.3 (0.94%) and 10.8 min (96.5%); H NMR (300 MHz, CDCl3,
ppm) δ 6.43−5.83 (m, 1H), 5.62−5.31 (m, 1H), 5.16 (d, J = 17.5 Hz,
1H), 3.91−3.48 (m, 2H), 3.23 (s, 4H), 2.95−2.63 (m, 2H), 1.42 (s,
9H), 1.17 (d, J = 5.4 Hz, 3H); 13C NMR (75 MHz, CDCl3, ppm) δ
156.3, 135.0, 115.4, 81.0, 70.8, 54.6, 53.9, 48.8, 28.8, 20.4; ES-MS (M
+ H+, m/z) 245.2; HRMS calcd for C12H24N2O3 244.1787, found
244.1780.
1
1657.2, 1245.6, 1158.9, 985.3; H NMR (300 MHz, CDCl3, ppm) δ
7.79 (d, J = 7.5 Hz, 1H), 7.26 (t, J = 6.6 Hz, 1H), 7.19−7.04 (m, 1H),
6.94 (d, J = 6.6 Hz, 1H), 4.38−3.96 (m, 1H), 3.62−3.36 (brs, 1H),
3.15−2.95 (m, 2H), 2.34−2.06 (m, 1H), 1.91 (s, 3H), 1.72−1.30 (m,
21H); 13C NMR (75 MHz, CDCl3, ppm) δ 150.5, 142.5, 131.6, 128.2,
126.7, 124.3, 119.9, 79.3, 57.7, 53.6, 48.2, 40.3, 36.9, 30.4, 29.8, 28.7;
ES-MS (M + H+, m/z) 383.4, 283.5; HRMS calcd for C24H34N2O2
382.2620, found 382.2624.
tert-Butyl (3′R,4′S)-3′-ethyl-2′-oxo[1,4′-bipiperidine]-1′-carbox-
ylate (4h): orange-yellow liquid; yield 27.2 mg (88%); [α]19.6 −13.9
D
(c 0.1 CHCl3); HPLC using C18 at flow rate 0.7 mL/min, H2O/IPA/
TEA (85:5:0.01) tR 26.5 min (11%) and 26.3 min (89%); IR (neat,
1
νmax, cm−1) 1715.2, 1685.3, 1610.3, 1345.2, 1263.2; H NMR (300
Di-tert-butyl (S)-3-((allylamino)methyl)-3,4-dihydro-1H-pyrido-
MHz, CDCl3, ppm) δ 4.03−3.50 (m, 2H), 2.89−2.67 (m, 1H), 2.63−
2.32 (m, 5H), 2.24−1.89 (m, 3H), 1.81−1.24 (m, 16H), 0.97 (m, 3H);
13C NMR (75 MHz, CDCl3, ppm) δ 176.9, 154.6, 84.3, 63.8, 54.8,
49.9, 41.3, 27.9, 26.3, 26.1, 25.4, 23.1, 12.5; ES-MS (M + H+, m/z)
311.2; HRMS calcd for C17H30N2O3 310.2256, found 310.2257.
Benzyl allyl((2R,3R)-2-(benzylamino)-3-((tert-butyldimethyl-
silyl)oxy)butyl)carbamate (5a): yellow liquid; yield 42.2 mg (88%);
[3,4-b]indole-2,9-dicarboxylate (4c): deep yellow liquid (gum); yield
35.8 mg (81%); [α]23.1 −41.5 (c 0.63, MeOH); HPLC using
D
Chiralpak IA at Flow rate 0.6 mL/min, IPA/Hex:TEA (7:93:0.001), Rt
25.48 min (98%) and 26.7 min (2%); IR (KBr, νmax, cm−1) 3315.6,
1
2854.6, 2158.3, 1723.6, 1687.5, 1645.2, 1456.3, 1235.3, 1015.2; H
NMR (300 MHz, CDCl3, ppm) δ 7.98 (d, J = 7.1 Hz, 1H), 7.64−7.40
(m, 1H), 7.25 (dq, J = 15.3, 7.6 Hz, 2H), 6.16−5.74 (m, 1H), 5.38−
5.07 (m, 2H), 4.86 (d, J = 16.4 Hz, 1H), 4.57−4.15 (m, 2H), 3.46−
3.08 (m, 5H), 3.08−2.79 (m, 2H), 2.75−2.55 (m, 1H), 1.65 (d, J = 5.3
Hz, 9H), 1.40 (s, 9H); 13C NMR (75 MHz, CDCl3, ppm) δ 158.4,
153.9, 138.6, 138.3, 132.3, 128.5, 122.4, 121.1, 120.9, 116.3, 115.8,
111.8, 83.1, 79.2, 54.2, 51.1, 45.0, 39.7, 28.9, 28.5, 26.6; ES-MS (M +
H+, m/z) 442.6, 344.5, 244.4. Anal. Calcd for C25H35N3O4: C, 68.00;
H, 7.99; N, 9.52. Found: C, 67.92; H, 7.92; N, 9.43.
[α]19.5 +52.3 (c 0.1 MeOH); HPLC Chiralpak IA, at flow rate 0.6
D
mL/min IPA/Hex (5:95), tR 11.5 (99.1%) and 15.6 min (0.8%); IR
(KBr, νmax, cm−1) 3324.6, 3053.8, 1731..5, 1684.3, 1634.3, 1215.3,
1
1185.3, 995.3; H NMR (300 MHz, CDCl3, ppm) δ 7.42−7.00 (m,
10H), 6.04−5.34 (m, 1H), 5.10 (d, J = 12.3 Hz, 3H), 5.05−4.95 (m,
1H), 4.13−3.98 (m, 1H), 3.87 (dd, J = 9.1, 2.9 Hz, 2H), 3.85−3.70
(m, 2H), 3.07−2.65 (m, 2H), 2.51−2.17 (m, 1H), 1.98−1.48 (brs,
1H), 0.89 (m, 12H), −0.03 (s, 6H); 13C NMR (75 MHz, CDCl3,
ppm) δ 157.3, 143.2, 138.2, 132.6, 129.1, 128.8, 128.7, 128.1, 127.8,
127.1, 116.6, 71.0, 67.4, 61.6, 52.9, 51.4, 47.7, 26.3, 21.9, 20.9, −4.7;
ES-MS (M + H+, m/z) 483.5; HRMS calcd for C28H42N2O3Si
482.2965, found 482.2968.
tert-Butyl (R)-(2-(allylamino)-1-phenylethyl)carbamate (4d):
yellow liquid; yield 22.2 mg (80%); [α]19.3 +29.3 (c 0.1, MeOH);
D
HPLC using Chiralpak IA at Flow rate 0.7 mL/min; ACN: Hex (8:92,
isocratic), tR 11.19 (98.04%) and 13.13 min (1.95%); IR (KBr, νmax
,
cm−1) 3325.6, 3154.8, 1736..5, 1714.3, 1685.3, 1624.3, 1215.3; 1H
NMR (300 MHz, CDCl3, ppm) δ 7.37 (dt, J = 7.4, 3.7 Hz, 2H), 7.24−
7.02 (m, 1H), 6.90 (d, J = 7.8 Hz, 2H), 6.26−5.85 (m, 1H), 5.83−5.50
(brs, 1H), 5.38 (d, J = 10.3 Hz, 1H), 5.15 (d, J = 17.3 Hz, 1H), 4.74
(d, J = 7.1 Hz, 1H), 3.50−2.75 (m, 6H), 1.38 (s, 9H); 13C NMR (75
MHz, CDCl3, ppm) δ 155.1, 141.8, 135.3, 130.4, 127.7, 126.9, 115.0,
79.3, 54.7, 54.5, 52.7, 28.7; ES-MS (M + H+, m/z) 277.5; HRMS calcd
for C16H24N2O2 276.1838, found 276.1831.
tert-Butyl ((2R,3R)-1-(allylamino)-3-((tert-butyldimethylsilyl)-
oxy)butan-2-yl)carbamate (5b): light yellow glassy solid; yield 34.3
mg (98%); mp 96−98 °C; [α]22.5D +12.5 (c 0.09 EtOH); HPLC using
Chiralpak IA at flow rate 0.6 mL/min, IPA/Hex (5:95, isocratic), 25.2
min (0.9%) and 26.3 min (99.1%); 1H NMR (300 MHz, CDCl3, ppm)
δ 6.24−5.81 (m, 1H), 5.57−5.33 (m, 1H), 5.16 (d, J = 17.5 Hz, 1H),
5.09−4.86 (brs, 1H), 4.28−3.91 (m, 1H), 3.91−3.48 (m, 1H), 3.38−
3.10 (m, 2H), 2.89−2.53 (m, 2H), 1.70−1.55 (brs, 1H), 1.42 (s, 9H),
1.25−1.03 (m, 3H), 0.85 (s, 9H), 0.01 (s, 6H); 13C NMR (75 MHz,
CDCl3, ppm) δ 156.5, 135.0, 115.4, 81.0, 72.1, 54.9, 54.8, 49.0, 28.8,
26.3, 21.6, 18.6, −4.9; ES-MS (M + H+, m/z) 359.4; HRMS calcd for
C18H38N2O3Si 358.2652, found 358.2657.
Methyl (S)-2-((R)-2-((tert-butoxycarbonyl)amino)-3-methylbu-
tyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (4e):
yellow liquid; yield 29.8 mg (72%); [α]19.5 −65.9 (c 0.1 CHCl3);
D
HPLC using Chiradex at flow rate 0.6 mL/min, MeOH/H2O/ACN
(20:70:10, isocratic), tR 15.3 min (2.6%), 16.7 min (88.27%), 21.37
min (8.4%), 23.66 (0.66%); 1H NMR (300 MHz, CDCl3, ppm) δ 8.16
(s, 1H), 7.47 (s, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.12 (dd, J = 10.8, 4.0
Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 5.21−4.62 (brs, 1H), 3.98−3.62 (m,
5H), 3.44 (q, J = 15.1 Hz, 2H), 3.36−3.05 (m, 4H), 1.62 (dd, J = 9.8,
3.5 Hz, 1H), 1.42 (s, 9H), 0.92 (dd, J = 19.9, 6.0 Hz, 6H); 13C NMR
(75 MHz, CDCl3, ppm) δ 174.1, 155.5, 135.2, 133.1, 126.4, 120.9,
119.1, 118.3, 110.7, 103.9, 79.2, 61.4, 53.5, 52.4, 51.7, 49.4, 32.8, 28.6,
20.0, 18.7, 18.3; ES-MS (M + H+, M + Na+, m/z) 416.5, 439.9; HRMS
calcd for C23H33N3O4 415.2471, found 415.2465.
Methyl (S)-1-(2,2-dimethoxyethyl)indoline-2-carboxylate (5c):
yellow solid; yield 228.5 mg (80%); M. P. 96 °C; [α]23.8 +57.3 (c
D
1.0, CHCl3); HPLC using Chiralpak IC at floe rate 0.7 mL/min, IPA/
Hex (5:95, isocratic) tR 11.4 min (99.1%) and 15.6 min (0.9%); IR
(KBr, νmax, cm−1) 1754.2, 1434.7, 1256.3, 1005, 995.3; 1H NMR (300
MHz, CDCl3, ppm) δ 7.26−6.98 (m, 1H), 6.90 (d, J = 7.8 Hz, 1H),
6.83−6.54 (m, 2H), 4.44 (m, 1H), 4.16 (dd, J = 11.9, 4.1 Hz, 1H),
3.89−3.51 (m, 5H), 3.32 (s, 6H), 3.01 (dt, J = 16.7, 8.6 Hz, 1H),
2.87−2.51 (m, 1H); 13C NMR (75 MHz, CDCl3, ppm) δ 171.5, 151.2,
130.6, 126.5, 124.8, 120.2, 118.0, 99.8, 65.1, 54.7, 53.8, 52.0, 29.5; ES-
MS (M + H+, m/z) 266.8. Anal. Calcd for C14H19NO4 (265.1314): C,
63.38; H, 7.22; N, 5.28. Found: C, 63.31; H, 7.18; N, 5.24.
(9H-Fluoren-9-yl)methyl tert-butyl (6-(dibenzylamino)hexane-
1,5-diyl) (S)-dicarbamate (4f): yellow liquid; yield 59.5 mg (94%);
[α]16.8 +22.6 (c 0.14 CHCl3); HPLC using Chiradex at flow rate 0.5
D
mL/min, H2O/TEA/MeCN/IPA (95:0.001:2.2:2.6 → 80:0.001:8:9.5,
gradient over 50 min) tR 40.1 (98%) and 44.0 (2%); H NMR (300
(S)-(1-(2,2-Dimethoxyethyl)indolin-2-yl)methanol (5d): yellow
1
liquid; yield 20.5 mg (86%); [α]19.4 +32.6 (c 0.08, MeOH); HPLC
D
MHz, CDCl3, ppm) δ 7.77 (d, J = 6.9 Hz, 2H), 7.62 (d, J = 7.4 Hz,
2H), 7.54−7.18 (m, 13H), 7.16−6.88 (m, 2H), 5.90−5.46 (brs, 1H),
using Chiralpak IC at flow rate 0.6 mL/min, IPA/Hex (5:95, isocratic),
tR 14.5 (99.1%) and 15.9 min (0.8%); H NMR (300 MHz, CDCl3,
1
H
dx.doi.org/10.1021/jo4012249 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
ppm) δ 6.98 (dt, J = 14.2, 7.2 Hz, 2H), 6.87−6.50 (m, 2H), 4.62 (m,
1H), 4.03−3.69 (m, 2H), 3.69−3.50 (m, 2H), 3.50−3.41 (m, 1H),
3.33 (s, 6H), 3.26−3.05 (m, 1H), 2.74−2.43 (m, 1H); 13C NMR (75
MHz, CDCl3, ppm) δ 152.6, 131.8, 126.0, 124.9, 119.5, 116.4, 100.1,
65.1, 60.8, 55.0, 52.2, 29.8; ES-MS (M + H+, m/z) 238.4. Anal. Calcd
for C13H19NO3 (237.1365): C, 65.80; H, 8.07; N, 5.90. Found: C,
65.72; H, 8.11; N, 6.19.
tert-Butyl (R)-(3-((1-(4-methoxyphenyl)ethyl)amino)propyl)-
(methyl)carbamate (5j): colorless liquid; yield 28.3 mg (88%);
[α]15.9 −21.5 (c 0.15, MeOH); HPLC using Chiralpak IA flow rate
D
0.5 mL/min, IPA/Hex/TEA (6.5:93.5:0.01, isocratic) tR 14.2 (99.4%)
and 19.2 min (0.6%); IR (neat, νmax, cm−1) 3362.3, 1685.3, 1602.3,
1
1582.3, 1286.8; 1026.9, 994.6; H NMR (300 MHz, CDCl3, ppm) δ
7.17 (d, J = 7.9 Hz, 2H), 6.83 (d, J = 7.9 Hz, 2H), 4.03−3.57 (m, 4H),
3.15 (dt, J = 12.4, 7.1 Hz, 5H), 2.87−2.51 (m, 3H), 2.01−1.62 (m,
2H), 1.39 (d, J = 24.6 Hz, 12H); 13C NMR (75 MHz, CDCl3, ppm) δ
160.1, 157.4, 138.8, 128.5, 114.8, 77.4, 57.8, 54.7, 46.3, 45.1, 35.8, 33.5,
28.9, 27.8, 24.1; ES-MS (M + H+, m/z) 323.5; HRMS calcd for
C18H30N2O3 322.2256, found 322.2260.
(S)-2-(Hex-5-en-1-ylamino)-1,1,2-triphenylethan-1-ol (5e): light
yellow syrup; yield 330.2 mg (81%); [α]19.4 −86.6 (c 0.1, CHCl3);
D
HPLC using Chiralpak IA at flow rate 0.9 mL/min, IPA/Hex/n-
pentane (8:62:30, isocratic) tR 12.0 min (0.5%) and 13.2 min (99.5%);
1H NMR (300 MHz, CDCl3, ppm) δ 7.90−7.14 (m, 13H), 7.16−6.83
(m, 2H), 5.98−5.45 (m, 1H), 5.17−4.69 (m, 2H), 4.24 (brs, 1H),
4.12−3.70 (m, 1H), 2.74−2.39 (m, 2H), 2.37−2.08 (brs, 1H), 2.05−
1.67 (m, 2H), 1.62−1.36 (m, 2H), 1.38−1.05 (m, 2H); 13C NMR (75
MHz, CDCl3, ppm) δ 145.2, 144.9, 142.7, 139.5, 128.5, 128.43,
128.39, 127.7, 127.5, 125.9, 115.3, 79.5, 71.4, 47.7, 34.9, 29.3, 29.1; ES-
MS (M + H+, m/z) 372.4. Anal. Calcd for C26H29NO (371.2249): C,
84.06; H, 7.87; N, 3.77. Found: C, 84.00; H, 7.81; N, 3.69.
Methyl (R)-2-(hex-5-en-1-ylamino)-2-(1H-indol-3-yl)acetate
(6a): colorless liquid; yield 24.3 mg (85%); [α]21.5 −8.6 (c 0.2,
D
CH2Cl2); HPLC using Chiralpak IC at flow rate 0.6 mL/min, IPA/
Hex/TEA (6.5:93.5:0.01, isocratic) tR 16.5 min (95.5%) and 19.7 min
(4.5%); IR (neat, νmax, cm−1) 3367.3, 1764.3, 1368.2, 1286.7; 1054.9,
1
964.4; H NMR (300 MHz, CDCl3, ppm) δ 8.54−8.05 (brs, 1H),
8.00−7.74 (m, 1H), 7.71−7.40 (m, 2H), 7.33−6.98 (m, 2H), 6.10−
5.45 (m, 1H), 5.19−4.84 (m, 2H), 4.75 (d, J = 6.2 Hz), 3.70 (s, 3H),
2.89−2.58 (m, 2H), 2.51−2.17 (brs, 1H), 2.01−1.65 (m, 2H), 1.65−
1.44 (m, 2H), 1.41−1.13 (m, 2H); 13C NMR (75 MHz, CDCl3, ppm)
δ 171.9, 136.3, 134.4, 129.6, 124.2, 121.5, 120.7, 119.1, 115.3, 111.2,
111.1, 55.0, 51.6, 47.1, 35.0, 28.9, 28.8; ES-MS (M + H+, m/z) 287.5;
HRMS calcd for C17H22N2O2 286.1681, found 286.1678.
(S)-2-(Allylamino)-2-(4-methoxyphenyl)-1,1-diphenylethan-1-ol
(5f): colorless thick liquid; yield 31.2 mg (87%); [α]15.8D −81.3 (c 1.0
CH2Cl2); HPLC using Chiralpak IA at flow rate 0.7 mL/min, IPA/
Hex (7:93, isocratic) tR 7.43 min (99.1%) and 14.05 min (0.8%); IR
1
(neat, νmax, cm−1) 3356.2, 3135.2, 1532.2, 1325.3, 1054.3, 996.3; H
NMR (300 MHz, CDCl3, ppm) δ 7.99−7.19 (m, 10H), 7.12−6.42 (m,
4H), 6.19−5.67 (m, 1H), 5.15 (d, J = 10.2 Hz, 1H), 5.00 (d, J = 16.6
Hz), 4.24 (brs, 1H), 3.99 (d, J = 7.9 Hz, 1H), 3.77 (s, 3H), 2.20−1.84
(brs, 1H); 13C NMR (75 MHz, CDCl3, ppm) δ 159.8, 144.2, 143.9,
135.1, 134.6, 129.0, 128.5, 127.7, 125.9, 114.7, 114.4, 78.0, 72.1, 54.7,
51.4; ES-MS (M + H+, m/z) 360.5. Anal. Calcd for C24H25NO2
(359.1885): C, 80.19; H, 7.01; N, 3.90. Found: C, 80.10; H, 6.95; N,
3.84.
(S)-N-(1-phenylethyl)prop-2-en-1-amine (6b): colorless liquid;
yield 13.2 mg (86%); [α]21.5 −12.8 (c 0.4, EtOH); HPLC using
D
Chiradex at flow rate 0.6 mL/min, H2O/IPA/TEA (6.5:93.5:0.005,
isocratic) tR 26.5 min (99.2%) and 29.7 min (0.8%); IR (neat, νmax
,
cm−1) 3354.2, 1326.3, 1226.4; 1032.9, 984.6; H NMR (300 MHz,
CDCl3, ppm) δ 7.25 (m, 4H), 7.19−6.91 (m, 1H), 6.14−5.61 (m,
1H), 5.43−4.90 (m, 2H), 4.03−3.65 (m, 1H), 3.53−3.03 (m, 2H),
2.17−1.86 (m, 1H), 1.39 (d, J = 5.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3, ppm) δ 144.8, 133.5, 128.5, 127.4, 126.6, 115.0, 52.1, 50.6,
22.8; ES-MS (M + H+, m/z) 162.5; HRMS calcd for C11H15N
161.1204, found 161.1208.
1
(R)-N-(1-(p-Tolyl)ethyl)heptan-1-amine (5g): colorless liquid;
yield 23.9 mg (98%); [α]23.5 −96.3 (c 0.4, IPA); HPLC using
D
Chiralpak IA at flow rate 0.6 mL/min, IPA/Hex/TEA (97.3:6.5:0.01,
isocratic) tR 5.71 min (99.8%) and 8.6 min (0.8%); IR (neat, νmax
,
(R)-4-(Pyrrolidin-1-yl)piperidin-2-one (6c): colorless liquid; yield
12.6 mg (75%); [α]18.7D −73.9 (c 1.0 MeOH); HPLC using Chiralpak
IA at flow rate 0.6 mL/min, IPA/Hex (6.5:93.5, isocratic) tR 10.3 (96)
and 8.7 min (4%); IR (neat, νmax, cm−1) 3368.3, 1675.2, 1545.3,
cm−1) 3368.3, 1562.3, 1356.2, 1236.8; 1056.9, 994.6; H NMR (300
MHz, CDCl3, ppm) δ 7.17 (d, J = 7.9 Hz, 2H), 6.83 (d, J = 7.9 Hz,
2H), 3.77 (s, 3H), 3.70−3.46 (m, 1H), 2.77−2.39 (m, 2H), 1.72−1.46
(m, 2H), 1.44−1.06 (m, 8H), 1.06−0.68 (m, 4H); 13C NMR (75
MHz, CDCl3, ppm) δ 160.1, 138.7, 128.5, 114.8, 57.8, 54.7, 46.7, 46.3,
33.5, 31.8, 31.6, 30.4, 26.6, 24.1, 23.1, 14.4; ES-MS (M + H+, m/z)
250.7. Anal. Calcd for C16H27NO (249.2093): C, 77.06; H, 10.91; N,
5.62. Found: C, 77.00; H, 10.81; N, 5.60.
1
1
1338.2, 1126.8; H NMR (300 MHz, CDCl3, ppm) δ 6.19−5.62 (m,
1H), 3.70−3.33 (m, 2H), 2.91−2.80 (m, 1H), 2.81−2.53 (m, 4H),
2.44−2.12 (m, 2H), 2.03−1.65 (m, 5H), 1.62−1.17 (m, 1H); 13C
NMR (75 MHz, CDCl3, ppm) δ 174.2, 56.8, 50.8, 40.2, 38.2, 30.3,
23.9; ES-MS (M + H+, m/z) 169.5; HRMS calcd for C9H16N2O
168.1263, found 168.1265.
tert-Butyl 4-(((R)-1-(4-methoxyphenyl)ethyl)amino)-2-oxopi-
peridine-1-carboxylate (5h): colorless liquid (thick); yield 30.6 mg
N-((R)-3,3-Dimethylcyclohexyl)adamantan-1-amine (6d): color-
(88%); [α]22.8 −15.4 (c 0.2, MeOH); HPLC using Chiralpak IC at
less liquid; yield 21.1 mg (81%); [α]19.5 +52.6 (c 0.5, IPA); HPLC
D
D
flow rate 0.6 mL/min, IPA/MeCN/Hex (5:6:89, isocratic), tR 22.98
using Chiralpak IA at flow rate 0.6 mL/min, IPA/Hex (6.5:93.5,
isocratic) tR 16.8 min (96) and 24.7 min (3.5%); IR (neat, νmax, cm−1)
min (87%), 26.11 min (6.4%), 31.86 (5.8%), 0.3%); IR (neat, νmax
,
cm−1) 3285.6, 2154.7, 1685.9, 1635.2, 1045.3, 995.8; H NMR (300
MHz, CDCl3, ppm) δ 7.34 (d, J = 7.7 Hz, 2H), 6.78 (d, J = 8.2 Hz,
2H), 4.15−3.91 (m, 1H), 3.91−3.53 (m, 5H), 2.41−2.15 (m, 2H),
1.57−1.17 (m, 14H); 13C NMR (75 MHz, CDCl3, ppm) δ 175.0,
160.0, 154.1, 138.9, 128.1, 114.3, 83.9, 58.3, 54.7, 48.1, 46.3, 40.4, 39.0,
33.5, 27.9, 27.5, 23.5; ES-MS (M + H+, m/z) 349.5; HRMS calcd for
C19H28N2O4 348.2049, found 348.2040.
1
1
3356.3, 2856.3; H NMR (300 MHz, CDCl3, ppm) δ 2.48 (m, 1H),
2.00 (s, 3H), 1.82−1.41 (m, 19H), 1.41−1.18 (m, 3H), 0.93 (d, J =
23.8 Hz, 6H); 13C NMR (75 MHz, CDCl3, ppm) δ 53.4, 46.8, 43.3,
39.8, 39.2, 38.0, 36.1, 32.4, 32.0, 30.5, 26.8, 22.2; ES-MS (M + H+, m/
z) 262.2. Anal. Calcd for C18H31N (261.2457): C, 82.69; H, 11.95; N,
5.36. Found: C, 82.64; H, 11.90; N, 5.32.
(S)-1-(1-(Cyclohex-1-en-1-yl)pentyl)piperidine (6e): colorless
liquid; yield 18.3 mg (78%); [α]16.5 +19.8 (c 0.2, EtOH); HPLC
tert-Butyl (R)-3-(((R)-1-(4-methoxyphenyl)ethyl)amino)-
piperidine-1-carboxylate (5i): colorless liquid; yield 28.4 mg
D
using Chiralpak IA at flow rate 0.6 mL/min IPA/Hex (1:99 →
(85%); [α]19.6 +32.8 (c 0.23, IPA); HPLC using Chiralpak IA at
6.8:93.2, gradient) tR 15.3 (6%) and 18.7 min (94.1%); IR (neat, νmax
,
D
cm−1) 3248.9, 2856.9, 1562.3, 1258.9; H NMR (300 MHz, CDCl3,
ppm) δ 5.43 (t, J = 6.7 Hz, 1H), 2.89−2.67 (m, 4H), 2.67−2.46 (m,
1H), 2.32−1.81 (m, 4H), 1.81−1.50 (m, 10H), 1.50−1.29 (m, 4H),
1.29−1.03 (m, 2H), 1.03−0.60 (m, 3H); 13C NMR (75 MHz, CDCl3,
ppm) δ 139.8, 119.9, 68.7, 55.4, 32.4, 31.2, 28.2, 26.8, 26.16, 26.10,
25.8, 23.4, 21.6, 13.7; ES-MS (M + H+, m/z) 236.5; HRMS calcd for
C16H29N 235.2300, found 235.2305.
1
flow rate 0.7 mL/min, IPA/Hex/TEA (4.5:93.5:0.01, isocratic) tR 8.8
min (0.093%), 9.5 min (94.26%), 10.3 min (4.7%) and 11.2 min
(0.004%); IR (neat, νmax, cm−1) 3368.3, 1562.3, 1356.2, 1236.8;
1
1056.9, 994.6; H NMR (300 MHz, CDCl3, ppm) δ 7.17 (d, J = 8.0
Hz, 2H), 6.80 (d, J = 7.9 Hz, 2H), 4.08−3.57 (m, 4H), 3.46−3.08 (m,
2H), 3.07−2.58 (m, 3H), 1.79−1.39 (m, 13H), 1.29 (d, J = 6.8 Hz,
3H); 13C NMR (75 MHz, CDCl3, ppm) δ 160.1, 157.2, 138.1, 128.6,
114.9, 78.9, 57.5, 54.7, 51.1, 50.0, 46.3, 42.3, 33.5, 30.3, 28.2, 24.5,
16.8; ES-MS (M + Na+, m/z) 334.8, 335.4; HRMS calcd for
C19H30N2O3 334.2256, found 334.2261.
(R)-1-(2-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-4-methyl-9H-
carbazol-3-yl)-N,N-dimethylethan-1-amine (6f): colorless solid;
yield 34.8 mg (85%); mp 154 °C; [α]22.8 +21.5 (c 0.2, MeOH);
D
I
dx.doi.org/10.1021/jo4012249 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 3. Representative Scheme Used for the Synthesis of Compounds 7a−h and 8a−f
HPLC using Chiralpak IC flow rate 0.6 mL/min, IPA/Hex:TEA
(6.5:93.5:0.005, isocratic) tR 10.5 min (97) and 8.7 min (3%); IR
(neat, νmax, cm−1) 3154.8, 2857.9, 1502.6, 1254.7, 1128.9, 1084.6,
995.7; 1H NMR (300 MHz, CDCl3, ppm) δ 8.17 (t, J = 11.8 Hz, 2H),
7.42−7.19 (m, 3H), 7.14 (s, 1H), 4.16 (d, J = 6.6 Hz, 1H), 4.01−3.67
(m, 2H), 2.89−2.74 (m, 2H), 2.66 (s, 3H), 2.20 (s, 6H), 1.45 (d, J =
6.5 Hz, 3H), 0.98 (s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz, CDCl3,
ppm) δ 140.7, 135.1, 131.8, 128.2, 127.4, 126.2, 122.2, 121.0, 120.8,
116.8, 111.8, 103.4, 63.2, 59.9, 41.5, 33.6, 26.5, 21.6, 18.9, 15.7, −5.7;
ES-MS (E + H+, m/z) 411.5; HRMS calcd for C25H38N2OSi 410.2753,
found 410.2751.
using Chiralpak IA at flow rate 0.8 mL/min, IPA/Hex/DIPEA
(6.0:93.5:0.003, isocratic) tR 18.3 min (94.5%) and 16.7 min (5.5%);
1
IR (neat, νmax, cm−1) 2586.3, 1514.3; H NMR (300 MHz, CDCl3,
ppm) δ 7.61−7.34 (m, 3H), 7.34−6.99 (m, 2H), 3.45 (q, J = 13.9 Hz,
2H), 3.19−3.04 (m, 1H), 2.27 (s, 3H), 2.13−1.89 (m, 1H), 1.89−1.53
(m, 4H), 1.53−1.28 (m, 3H), 1.19−0.74 (m, 4H); 13C NMR (75
MHz, CDCl3, ppm) δ 136.2, 132.0, 129.7, 121.3, 120.1, 118.0, 110.8,
107.7, 51.9, 49.2, 28.7, 23.2, 22.5, 22.2; ES-MS (M + H+, m/z) 204.2;
HRMS calcd for C14H21N 203.1674, found 203.1672.
(R)-N-Allyl-1,2,3,4-tetrahydronaphthalen-1-amine (6k): colorless
liquid; yield 13.5 mg (72%); [α]17.5 +8.5 (c 0.095, EtOH); HPLC
D
(R)-N-(1-(9H-Carbazol-3-yl)ethyl)-N-isopropylpropan-2-amine
(6g): yellow solid; yield 34.8 mg (85%); mp 169−170 °C; [α]D
using Chiralpak IA at flow rate 0.5 mL/min, IPA/Hex (5:96.5) tR 11.3
18.8
min (97.5%) and 16.3 min (2.5%); IR (neat, νmax, cm−1) 3312.5,
1
+52.5 (c 0.55, EtOH); HPLC using Chiralpak IC flow rate 0.6 mL/
min, IPA/Hex (7:93, isocratic) tR 25.27 min (97.5) and 26.5 min
(2.5%); 1H NMR (300 MHz, CDCl3, ppm) δ 8.51 (brs, 1H), 7.96 (d, J
= 7.8 Hz, 1H), 7.61−7.22 (m, 5H), 7.11 (td, J = 7.0, 3.2 Hz, 1H), 4.20
(d, J = 6.4 Hz, 1H), 2.99 (dd, J = 12.9, 6.6 Hz, 2H), 1.43 (d, J = 6.2
Hz, 3H), 1.09 (d, J = 5.6 Hz, 12H); 13C NMR (75 MHz, CDCl3, ppm)
δ 141.7, 140.6, 138.4, 125.5, 125.2, 122.3, 121.9, 120.6, 117.7, 117.2,
112.4, 107.3, 56.3, 52.3, 46.3, 33.4, 24.8, 22.9, 22.5; ES-MS (M + H+,
m/z) 295.3. Anal. Calcd for C20H26N2 (294.2096): C, 81.58; H, 8.90;
N, 9.51. Found: C, 81.52; H, 8.85; N, 9.42.
3456.2, 2857.4, 1562.3, 1254.6, 1156.3, 1005.3; H NMR (300 MHz,
CDCl3, ppm) δ 7.39−6.61 (m, 4H, ArH), 6.06−5.68 (m, 1H), 5.21 (d,
J = 9.5 Hz, 1H), 5.03 (d, J = 16.8 Hz, 1H), 3.94 (d, J = 8.8 Hz, 1H),
3.14−3.01 (m, 2H), 2.92−2.61 (m, 2H), 2.43−2.09 (m, 3H), 2.07−
1.88 (brs, 1H), 1.68−1.28 (m, 1H); 13C NMR (75 MHz, CDCl3,
ppm) δ 137.3, 136.2, 134.2, 129.6, 127.8, 126.7, 125.9, 115.2, 51.2,
51.1, 31.3, 29.5, 21.8; ES-MS (M + H+) 188.4. Anal. Calcd for
C13H17N: C, 83.37; H, 9.15; N, 7.48. Found: C, 83.30; H, 9.05; N,
7.46.
General Procedure for the Synthesis of Compounds 7a−h
and 8a−f Using the Intramolecular Oxidation/Imine−Iminium
Formation/Reductive Amination Cascade. Step I. 2,2,6,6-
Tetramethyl-1-piperidinyloxyl TEMPO (30 mg, 0.2 mmol, 0.2
equiv) and [bis(acetoxy)iodo]benzene BAIB (370 mg, 1.15 mmol,
1.15 equiv) were added to a stirred solution of specified alkanols
(alkanol a−j, 1 mmol) in CH2Cl2 (4 mL), and the mixture was stirred
at rt until complete conversion of alcohol (2−10 h) checked by TLC
or GC/MS. Then, the specified amine (βC1−3; 1 mmol, 1 equiv),
HEH (or similar reagent when specified) (414 mg, 1 mmol, 1 equiv),
and chiral Brønsted acid (15 mol %) were added to the reaction
mixture. After a few hours (2−10 h), the mixture was quenched
carefully with aq NaHCO3 (10 mol %, 10 mL) and extracted with
Et2O or EtOAc (3 × 20 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated under reduced pressure.
Purification was achieved by using one of the methods (method A−
C) mentioned above in the intramolecular oxidation/imine−iminium
formation/reductive amination procedure to obtain SMa−j.
Step II. The compounds (SMa−j) thus obtained were dissolved in 3
mL of THF (dry) under nitrogen atmosphere, and the thus obtained
solution was then added dropwise to a suspension of LAH (0.6 equiv)
under nitrogen atmosphere at 0 °C after the completion of the
reduction the reduced crude product obtained by the aqueous work.
The isolated crude product was purified through column chromatog-
raphy. The purified product was then dissolved in HCl−dioxane to
obtain the starting material for the intramolecular cyclization mediated
through oxidation/imine−iminium formation/reductive amination
following the general procedure mentioned above (Scheme 3).
(S)-N,N-Diisopropyl-2,3,4,9-tetrahydro-1H-carbazol-3-amine
(6h): colorless liquid; yield 23.0 mg (85%); [α]18.2 −28.7 (c 0.12,
D
CHCl3); HPLC using Chiralpak IA at flow rate 0.7 mL/min, IPA/Hex
(6.5:93.5, isocratic) tR 19.4 min (96%) and 21.8 min (4%); IR (neat,
1
νmax, cm−1) 3162.5, 2658.4, 1468.3, 1279.6, 1284.5, 1156.2; H NMR
(300 MHz, CDCl3, ppm) δ 7.80 (brs, 1H), 7.47 (s, 1H), 7.34−6.83
(m, 3H), 3.44−3.06 (m, 3H), 2.92−2.68 (m, 3H), 2.61−2.32 (m, 1H),
2.01−1.58 (m, 1H), 1.58−1.14 (m, 1H), 0.79 (d, J = 5.8 Hz, 14H);
13C NMR (75 MHz, CDCl3, ppm) δ 136.2, 132.0, 129.7, 121.3, 120.1,
118.0, 110.8, 107.7, 51.9, 49.2, 28.7, 23.2, 22.5, 22.2; ES-MS (M + H+,
m/z) 271.5. Anal. Calcd for C18H26N2 (270.2096): C, 79.85; H, 9.69;
N, 10.36. Found: C, 79.81; H 9.65; N, 10.30.
(S)-N-Allyl-2,3-dihydro-1H-inden-1-amine (6i): colorless liquid;
yield 16.6 mg (98%); [α]13.7 −22.5 (c 0.08, MeOH); HPLC using
D
Chiralpak IA at flow rate 0.6 mL/min, IPA/Hex (1:99 → 6.5:93.5,
gradient over 30 min) tR 8.7 min (4.7%) and 14.5 min (95.3%); IR
1
(neat, νmax, cm−1) 3456.2, 2587.6, 1524.3, 1256.3, 1152.3, 991.3; H
NMR (300 MHz, CDCl3, ppm) δ 7.41−7.27 (m, 1H), 7.24−6.86 (m,
3H), 5.86 (dt, J = 10.0, 5.1 Hz, 1H), 5.21 (d, J = 10.2 Hz, 1H), 5.03 (d,
J = 16.6 Hz, 1H), 4.22 (d, J = 7.7 Hz, 1H), 3.47−3.06 (m, 4H), 3.04−
2.86 (m, 1H), 2.84−2.61 (m, 1H), 2.31−2.01 (m, 1H), 2.02−1.63 (m,
2H); 13C NMR (75 MHz, CDCl3, ppm) δ 142.2, 139.7, 134.0, 128.3,
128.2, 127.0, 125.2, 115.2, 61.2, 51.4, 31.8, 24.4; ES-MS (M + H+, m/
z) 174.2. Anal. Calcd for C12H15N (173.1204): C, 83.19; H, 8.73; N,
8.08. Found: C, 83.12; H, 8.70; N, 8.67.
(1R)-N-Benzyl-N,3-dimethylcyclohexan-1-amine (6j): colorless
liquid; yield 15.4 mg (76%); [α]18.8 −38.5 (c 0.21, CHCl3); HPLC
D
J
dx.doi.org/10.1021/jo4012249 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(S)-2-Benzyl-1,2,3,4,6,7,12,12a-octahydropyrazino[1′,2′:1,6]-
pyrido[3,4-b]indole (7a): colorless solid; yield 27.5 mg (87%); mp
3H), 7.11 (t, J = 7.5 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 3.68 (s, 2H),
3.26 (q, J = 15.0 Hz, 2H), 3.11−2.98 (m, 1H), 2.96−2.76 (m, 1H),
2.66 (dd, J = 12.2, 4.8 Hz, 4H), 2.54 (dd, J = 16.0, 5.4 Hz, 1H), 2.45 (t,
J = 4.8 Hz, 2H), 1.67−1.48 (m, 2H), 1.47−1.34 (m, 2H), 1.28 (td, J =
4.9, 0.9 Hz, 6H); 13C NMR (100 MHz, CDCl3, ppm) δ 140.9, 136.3,
135.3, 128.8, 128.2, 127.5, 120.9, 118.8, 118.1, 111.7, 110.9, 63.49,
59.41, 55.36, 53.7, 53.2, 51.4, 30.0, 29.5, 26.8, 25.95 25.0, 24.5; ES-MS
(M + H+, m/z) 388.8; HRMS calcd for C26H33N3 387.2674, found
387.2668.
124−128 °C; [α]21.6 −58.6 (c 0.3, CHCl3); HPLC using Chiralpak
D
IA tR at flow rate 0.6 mL/min, IPA/Hex/DIPEA (6.5:93.5:0.01,
gradient) 21.3 min (99%) and 26.7 min (1%); IR (neat, νmax, cm−1)
1
3154.6, 2568.6, 1502.3, 1463.2, 1256.3, 1102.3, 996.3; H NMR (400
MHz, CDCl3, ppm) δ 8.01 (brs, 1H), 7.53 (d, J = 7.4 Hz, 1H), 7.38 (d,
J = 7.1 Hz, 2H), 7.24−7.05 (m, 5H), 6.96 (q, J = 7.4 Hz, 1H), 3.55
(dd, J = 29.3, 15.2 Hz, 2H), 3.48 (s, 2H), 3.29 (dd, J = 11.6, 4.3 Hz,
1H), 2.94 (dd, J = 15.9, 7.2 Hz, 1H), 2.76 (dd, J = 11.3, 8.2 Hz, 1H),
2.71−2.39 (m, 5H), 2.03 (dd, J = 11.2, 8.3 Hz, 1H); 13C NMR (100
MHz, CDCl3, ppm) δ 139.7, 136.5, 131.9, 129.3, 128.2, 127.1, 125.8,
120.9, 118.8, 118.3, 110.6, 108.4, 63.3, 62.0, 58.0, 51.3, 51.0, 26.0; ES-
MS (M + H+, m/z) 318.3. Anal. Calcd for C21H23N3 (317.1892): C,
79.46; H, 7.30; N, 13.24. Found: C, 79.40; H, 7.26; N, 13.18.
(S)-2-Benzyl-2,3,4,5,7,8,13,13a-octahydro-1H-[1,4]diazepino-
[1′,2′:1,6]pyrido[3,4-b]indole (7b): colorless sticky semisolid; yield
(1R,12aS)-2-Benzyl-1-methyl-1,2,3,4,6,7,12,12a-octahydro-
pyrazino[1′,2′:1,6]pyrido[3,4-b]indole (7f): deep yellow solid; yield
27.4 mg (81%); mp 148 °C; [α]16.8 +14.9 (c 0.39, MeOH); HPLC
D
using Chiralpak IA at flow rate 0.6 mL/min IPA/Hex:DIPEA
(5:95:0.002, isocratic) tR 10.5 (2.46%), 11.3 min (96.03%), 13.8 min
(1.46%%), 14.6 min (0.03%); IR (neat, νmax, cm−1) 3325.3, 2856.6,
1
1547.7, 1254.8, 1105.6, 968.3; H NMR (400 MHz, CDCl3, ppm) δ
8.01 (brs, 1H, NH), 7.57−7.42 (m, 3H), 7.36−7.23 (m, 3H), 7.18 (d, J
= 7.8 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 3.90
(d, J = 13.2 Hz, 1H, BenzylCHH), 3.67−3.32 (m, 3H, benzylCHH, 2-
indoleCH2), 3.13−2.94 (m, 2H, 3-indoleCHH, α-CH), 2.94−2.77 (m,
1H, CH), 2.76−2.62 (m, 3H, 3-indoleCHH, NCHHCHHN), 2.61−
2.46 (m, 2H), 1.26 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3,
ppm) δ 139.1, 137.0, 131.7, 129.1, 128.4, 127.3, 125.6, 120.9, 118.8,
118.3, 110.6, 109.3, 63.9, 62.9, 59.4, 51.4, 51.1, 50.9, 24.9, 11.7; ES-
MS(M + H+, m/z) 332.6; HRMS calcd for C22H25N3 331.2048, found
331.2051.
26.8 mg (81%); [α]21.6 −42.8 (c 0.25, CHCl3); HPLC using
D
Chiralpak IA at flow rate 0.6 mL/min, IPA/Hex (6.5:93.5, isocratic), tR
14.3 min (97%) and 12.3 min (3%); IR (neat, νmax, cm−1) 3185.6,
1
3105.2, 2154.6, 1358.6, 1204.2, 1152.3, 985.3; H NMR (400 MHz,
CDCl3, ppm) δ 8.01 (brs, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.27 (dt, J =
13.1, 5.7 Hz, 2H), 7.23−7.15 (m, 4H), 7.11 (t, J = 7.5 Hz, 1H), 6.96
(t, J = 7.6 Hz, 1H), 3.65 (s, 2H), 3.39 (q, J = 15.0 Hz, 2H), 3.17 (tt, J =
11.1, 5.6 Hz, 1H), 3.03 (dt, J = 12.7, 6.0 Hz, 1H), 2.93−2.60 (m, 6H),
2.59−2.42 (m, 2H), 1.65 (p, J = 5.9 Hz, 2H); 13C NMR (100 MHz,
CDCl3, ppm) δ 140.8, 136.5, 133.8, 129.2, 128.2, 127.6, 127.5, 120.9,
118.8, 117.8, 111.0, 110.6, 63.3, 58.0, 56.5, 52.0, 50.2, 48.0, 27.9, 25.4;
ES-MS (M + Na+, M + H+, m/z) 354.2, 332.5. Anal. Calcd for
C22H25N3 (331.2048): C, 79.72; H, 7.60; N, 12.68. Found: C, 79.65;
H, 7.54; N, 12.60.
(1R,13aS)-2-Benzyl-1-phenyl-2,3,4,5,7,8,13,13a-octahydro-1H-
[1,4]diazepino[1′,2′:1,6]pyrido[3,4-b]indole (7g): colorless semi-
solid; yield 32.1 mg (81%); [α]22.4 +19.4 (c 0.15, MeOH; HPLC
D
using Chiralpak IA at flow rate 0.6 mL/min IPA/Hex/DIPEA
(5:95:0.05, isocratic) tR 8.2 min (0.2%); 8.7 min (0.09%); 9.7 min
(2.7%) and 9.9 min (96%); IR (neat, νmax, cm−1) 3354.6, 2865.3,
(S)-2-Benzyl-1,2,3,4,5,6,8,9,14,14a-decahydro[1,4]diazocino-
[1′,2′:1,6]pyrido[3,4-b]indole (7c): colorless solid; yield 24.8 mg
(72%); mp 167−169 °C; [α]D18.5 −28.4 (c 0.18, MeOH); HPLC using
Chiralpak IA at flow rate 0.6 mL/min, IPA/Hex (6.5:93.5), tR 16.3
(97%) and 18.7 min (2.5%); IR (KBr, νmax, cm−1) 3125.6, 2845.7,
1
1563.2, 1228.6, 1004.3; H NMR (400 MHz, CDCl3, ppm) δ 8.01
(brs, 1H, NH), 7.54 (d, J = 7.8 Hz, 1H), 7.23 (dtdd, J = 32.6, 25.2,
11.0, 7.1 Hz, 13H), 6.96 (t, J = 7.6 Hz, 1H), 4.21 (d, J = 4.9 Hz, 1H,
PhCH), 3.98−3.69 (m, 2H, benzylCHH), 3.47 (q, J = 15.0 Hz, 2H, 2-
indoleCH2), 3.28 (ddd, J = 12.4, 10.2, 9.5 Hz, 2H), 3.17−2.94 (m,
3H), 2.88 (d, J = 8.1 Hz, 2H), 2.86−2.69 (m, 3H), 2.64 (dd, J = 15.6,
5.7 Hz, 1H), 1.84−1.50 (m, 2H); 13C NMR (100 MHz, CDCl3, ppm)
δ 140.8, 139.5, 136.3, 133.7, 129.2, 128.2, 128.1, 127.6, 127.4, 127.0,
126.2, 120.9, 118.8, 117.6, 110.6, 108.7, 62.7, 59.4, 51.0, 50.8, 50.0,
46.3, 33.4, 27.7, 24.6, 22.5; ES-MS (M + H+, m/z) 408.5. Anal. Calcd
for C28H29N3 (407.2361): C, 82.52; H, 7.17; N, 10.31. Found: C,
82.40; H, 7.10; N, 10.28.
1
1563.2, 1236.3, 1185.6, 1054.6, 986.3; H NMR (400 MHz, CDCl3,
ppm) δ 8.01 (brs, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.38−7.28 (m, 2H),
7.23 (d, J = 7.8 Hz, 1H), 7.20−7.15 (m, 3H), 7.11 (t, J = 7.5 Hz, 1H),
6.96 (t, J = 7.6 Hz, 1H), 3.64 (s, 2H), 3.38 (q, J = 15.0 Hz, 2H), 3.12
(dd, J = 8.5, 5.3 Hz, 1H), 2.86−2.76 (m, 1H), 2.71 (t, J = 4.7 Hz, 2H),
2.58 (d, J = 4.7 Hz, 2H), 2.47 (dt, J = 9.6, 5.2 Hz, 3H), 1.57−1.47 (m,
2H, CH2), 1.46−1.36 (m, 2H, CH2); 13C NMR (100 MHz,CDCl3,
ppm) δ 140.8, 136.5, 133.8, 129.2, 128.2, 127.6, 127.5, 120.92, 118.8,
117.8, 111.0, 110.6, 63.3, 58.0, 56.5, 52.0, 50.2, 48.0, 27.9, 25.4; ES-MS
(M + H+, m/z) 346.5. Anal. Calcd for C23H27N3 (345.2205): C, 79.96;
H, 7.88; N, 12.16. Found: C, 79.90; H, 7.84; N, 12.10.
(1R,14aS)-2-Benzyl-1-phenyl-1,2,3,4,5,6,8,9,14,14a-decahydro-
[1,4]diazocino[1′,2′:1,6]pyrido[3,4-b]indole (7h): yellow glassy
liquid, yield 33.6 mg (75%); [α]22.4 +19.4 (c 0.15, MeOH); HPLC
D
(S)-2-Benzyl-2,3,4,5,6,7,9,10,15,15a-decahydro-1H-[1,4]-
diazonino[1′,2′:1,6]pyrido[3,4-b] indole (7d): colorless solid; yield
using Chiralpak IA at flow rate 0.6 mL/min IPA/Hex:DIPEA
(6.5:93.5:0.005, isocratic) tR 8.3 (97.5%) and 7.7 min (2.5); IR
24.4 mg (68%); mp 142 °C; [α]19.5 −38.9 (c 0.36, MeOH); HPLC
1
(neat, νmax, cm−1) 3321.4, 2562.3, 1425.3, 1263.5, 1002.3; H NMR
D
using Chiralpak IA at flow rate 0.6 mL/min IPA/Hex (6.5:93.5,
(400 MHz, CDCl3, ppm) δ 8.01 (brs, 1H), 7.59 (d, J = 7.5 Hz, 1H),
7.40−7.34 (m, 2H), 7.33−7.21 (m, 6H), 7.20−7.14 (m, 3H), 7.12 (dd,
J = 13.3, 5.9 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 4.21 (d, J = 4.9 Hz, 1H,
PhCH), 3.80 (d, J = 13.4 Hz, 1H, benzylCHH), 3.46 (q, J = 15.0 Hz,
2H, benzylCHH, α−CH), 3.31 (d, J = 13.5 Hz, 1H), 3.25−3.13 (m,
1H), 2.97 (dd, J = 15.4, 8.6 Hz, 1H), 2.83 (ddd, J = 14.4, 7.9, 4.7 Hz,
4H), 2.61 (dd, J = 15.6, 5.7 Hz, 1H), 1.57 (ddd, J = 6.3, 4.3, 2.5 Hz,
2H), 1.44 (dd, J = 7.9, 4.0 Hz, 2H); 13C NMR (100 MHz, CDCl3,
ppm) δ 128.7, 128.2, 127.6, 126.7, 126.2, 120.9, 118.8, 117.9, 110.9,
77.4, 77.0, 76.6, 73.3, 62.2, 59.0, 54.4, 53.5, 49.9, 46.2, 33.4, 31.4, 27.3,
24.2; ES-MS (M + H+, m/z) 422.4. Anal. Calcd for C29H31N3
(421.2518): C, 82.62; H, 7.14; N, 9.97. Found: C, 82.58; H, 7.11;
N, 9.92.
isocratic), tR 17.3 min (93%) and 18.7 min (6.8%); IR (KBr, νmax
,
1
cm−1) 3256.6, 2157.6, 1569.3, 1426.3, 1205.3, 995.3; H NMR (400
MHz, CDCl3, ppm) δ 8.01 (brs, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.30
(dt, J = 10.3, 4.7 Hz, 2H), 7.23 (t, J = 5.5 Hz, 1H, ArH), 7.17 (dd, J =
3.0, 0.7 Hz, 3H), 7.14−7.05 (m, 1H), 6.96 (t, J = 7.6 Hz, 1H), 3.70 (s,
2H), 3.26 (q, J = 15.0 Hz, 2H), 3.17−3.04 (m, 1H), 2.95−2.83 (m,
1H), 2.70 (t, J = 4.8 Hz, 2H), 2.55 (dd, J = 14.2, 5.3 Hz, 3H,), 2.49 (t,
J = 4.7 Hz, 2H), 1.57−1.45 (m, 2H), 1.45−1.31 (m, 2H), 0.98 (dq, J =
13.4, 6.7 Hz, 2H); 13C NMR (100 MHz, CDCl3, ppm) δ 141.3, 136.3,
136.0, 128.8, 128.2, 127.5, 127.4, 120.9, 118.8, 118.1, 112.4, 110.9,
63.1, 56.7, 54.8, 54.1, 52.3, 51.7, 29.4, 28.6, 26.2, 22.3; ES-MS (M +
H+, m/z) 360.2; HRMS calcd for C24H29N3 359.2361, found 359.2354.
(S)-2-Benzyl-2,3,4,5,6,7,8,9,11,12,17,17a-dodecahydro-1H-[1,4]-
diazacycloundecino[1′,2′:1,6]pyrido-[3,4-b]indole (7e): yellow
(3S,12aS)-2-Benzyl-3-methyl-1,2,3,4,6,7,12,12a-octahydro-
pyrazino[1′,2′:1,6]pyrido[3,4-b]indole (8a): yellow solid; yield 28.7
solid; yield 23.6 mg (61%); mp 157−159 °C; [α]19.5 −31.8 (c
mg (87%); mp 163−165 °C; [α]20.2 +29.9 (c 0.09, MeOH); HPLC
D
D
0.24, MeOH); HPLC using Chiralpak IA at flow rate 0.6 mL/min,
IPA/Hex (6.5:93.5, isocratic) tR 14.3 min (96%) and 17.3 min (4%);
1H NMR (400 MHz, CDCl3, ppm) δ 8.01 (brs, 1H), 7.61 (d, J = 7.6
Hz, 1H), 7.39−7.28 (m, 2H), 7.23 (t, J = 5.5 Hz, 1H), 7.20−7.15 (m,
using Chiralpak IA at flow rate 0.7 mL/min, IPA/Hex (6.5:93.5,
isocratic) tR 10.2 (99%) and 9.5 min (1%);1H NMR (400 MHz,
CDCl3, ppm) δ 8.01 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.34−7.15 (m,
6H), 7.11 (t, J = 7.5 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 4.00−3.84 (m,
K
dx.doi.org/10.1021/jo4012249 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1H), 3.53−3.30 (m, 3H), 3.30−3.07 (m, 1H), 3.04−2.85 (m, 2H),
2.79 (ddd, J = 18.1, 7.7, 4.1 Hz, 2H), 2.64 (dd, J = 16.8, 7.8 Hz, 1H),
2.18−1.93 (m, 2H), 1.18 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3, ppm) δ 140.8, 136.4, 134.0, 128.9, 128.2, 127.4, 125.6, 120.9,
118.7, 118.6, 110.9, 109.7, 59.2, 58.4, 56.0, 55.8, 53.1, 50.5, 26.4, 16.0;
ES-MS (M + H+, m/z) 332.5; HRMS calcd for C22H25N3 331.2048,
found 331.2035.
MS (M + H+, m/z) 404.2; HRMS calcd for C26H33N3O 403.2624,
found 403.2629.
(3S,8S)-2-Benzyl-3-ethyl-8-methyl-2,3,4,5,7,8,10,11,16,16a-deca-
hydro-1H-[1,4,7]oxadiazecino[4′,5′:1,6]pyrido[3,4-b]indole (8f):
colorless liquid; yield 31.2 mg (75%); [α]21.4 +19.2 (c 0.23,
D
MeOH); HPLC using Chiralpak IC at flow rate 0.6 mL/min IPA/
Hex (6.5:93.5, gradient) tR 11.3 min (98%) and 12.7 min (1.99%); IR
1
(neat, νmax, cm−1) 3251.2, 2685.4, 1524.3, 1263.7, 1002.6, 996.8; H
(3S,4S,12aS)-2-Benzyl-3,4-dimethyl-1,2,3,4,6,7,12,12a-octa-
hydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole (8b): colorless gum;
NMR (400 MHz, CDCl3, ppm) δ 8.00 (s, 1H), 7.56 (d, J = 7.5 Hz,
1H), 7.48 (d, J = 7.2 Hz, 2H), 7.36−7.28 (m, 1H), 7.24 (t, J = 7.2 Hz,
2H), 7.18 (d, J = 7.8 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.96 (t, J = 7.6
Hz, 1H), 3.96−3.76 (m, 1H), 3.60 (q, J = 15.0 Hz, 2H), 3.44 (dd, J =
13.4, 9.0 Hz, 3H), 3.26−3.05 (m, 1H), 2.95 (ddd, J = 10.1, 6.7, 3.6 Hz,
1H), 2.87−2.68 (m, 4H), 2.50 (dd, J = 15.9, 6.9 Hz, 1H), 2.44 (d, J =
5.7 Hz, 2H), 2.38 (ddd, J = 13.1, 11.7, 6.6 Hz, 1H), 1.76 (ddd, J =
12.4, 6.7, 5.2 Hz, 1H), 1.62 (dd, J = 11.4, 5.2 Hz, 2H), 1.38−1.16 (m,
1H), 0.96 (d, J = 6.6 Hz, 3H), 0.87 (t, J = 7.4 Hz, 3H); 13C NMR (100
MHz, CDCl3, ppm) δ 139.8, 137.2, 135.2, 128.7, 128.2, 128.0, 127.6,
120.9, 118.8, 117.9, 112.1, 110.7, 67.9, 64.1, 62.5, 59.7, 58.9, 58.1, 53.6,
49.8, 33.5, 28.1, 24.9, 17.5, 9.6; ES-MS (M + H+, m/z) 418.6; HRMS
calcd for C27H35N3O 417.2780, found 417.2776.
yield 27.9 mg (81%); [α]22.9 +19.6 (c 0.21, MeOH); HPLC
D
Chiralpak using Chiralpak IA flow rate 0.6 mL/min, IPA/Hex/DIPEA
(4:95.5:0.001, isocratic) tR 15.8 min (1%) anf 19.3 min (99%); IR
(neat, νmax, cm−1) 3354.2, 1524.3, 1236.5, 995.6; 1H NMR (400 MHz,
CDCl3, ppm) δ 8.00 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.36−7.19 (m,
6H), 7.11 (t, J = 7.5 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 3.81 (dt, J =
27.6, 14.3 Hz, 3H), 3.44 (d, J = 13.8 Hz, 1H), 3.36−3.16 (m, 1H),
2.86−2.62 (m, 4H), 2.54 (dd, J = 16.8, 7.8 Hz, 1H), 2.02 (dd, J = 11.6,
8.2 Hz, 1H), 1.06 (d, J = 5.9 Hz, 3H), 1.01 (d, J = 5.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3, ppm) δ 140.4, 136.8, 133.6, 129.0, 128.4,
127.6, 126.0, 120.9, 118.8, 118.6, 110.9, 109.6, 60.9, 60.8, 59.7, 56.2,
52.1, 50.6, 26.2, 13.5, 12.4; ES-MS (M + H+, m/z) 346.5; HRMS calcd
for C23H27N3 345.2205, found 345.2201.
(3S,8S)-4-Benzyl-3-ethyl-8-methyl-7-(naphthalen-1-yl)-1,4,7-oxa-
diazecane (9a): colorless liquid; yield 12.6 mg (75%); [α]19.4 +22.5
D
(1R,3S,4S,12aS)-2-Benzyl-3,4-dimethyl-1-phenyl-
1,2,3,4,6,7,12,12a-octahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole
(c 0.32, MeOH); HPLC using Chirasphere flow rate 0.6 mL/min
H2O/IPA/L-proline (4%) (40:30:10, isocratic) tR 18.1 min (2.0%) and
22.3 (97.9%); IR (neat, νmax, cm−1) 1524.3, 1363.2, 1285.6, 1163.7,
1085, 997.5; 1H NMR (400 MHz, CDCl3, ppm) δ 8.08 (d, J = 8.1 Hz,
1H), 7.69 (d, J = 7.9 Hz, 1H), 7.52−7.40 (m, 3H), 7.35 (t, J = 7.3 Hz,
2H), 7.32−7.18 (m, 5H), 3.98 (t, J = 5.6 Hz, 2H), 3.92−3.78 (m, 1H),
3.65 (t, J = 5.0 Hz, 2H), 3.39 (d, J = 13.5 Hz, 1H), 3.29 (dd, J = 12.3,
6.8 Hz, 3H), 3.25−3.12 (m, 1H), 3.05 (d, J = 2.9 Hz, 2H), 2.01 (dd, J
= 11.5, 5.3 Hz, 2H), 1.57 (ddd, J = 12.7, 6.7, 5.9 Hz, 1H), 1.44−1.26
(m, 1H), 1.16 (d, J = 6.2 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3, ppm) δ 149.0, 138.7, 130.9, 129.4, 129.3, 128.8,
128.5, 127.3, 125.3, 125.0, 124.0, 117.6, 115.2, 72.5, 67.3, 66.2, 56.1,
55.5, 49.2, 44.2, 34.1, 21.6, 19.6, 10.0; ES-MS (M + H+. m/z) 403.5;
HRMS calcd for C27H34N2O 402.2671, found 402.2666.
(8c): light pink solid; yield 35.7 mg (81%); mp 144−146 °C; [α]18.4
D
−6.3 (c 0.2 MeOH); HPLC using a Chiradex flow rate 0.6 mL/min
H2O/IPA (86.5:14.4, gradient over 25 min), tR 10.3 min (99.01%) and
12.36 min (0.98%); IR (neat, νmax, cm−1) 3524.2, 2785.4, 1524.3,
1324.8, 1185.6, 996.1; 1H NMR (400 MHz, CDCl3, ppm) δ 8.00 (brs,
1H), 7.56 (d, J = 7.5 Hz, 1H), 7.37−7.29 (m, 4H), 7.29−7.21 (m,
4H), 7.21−7.14 (m, 3H), 7.11 (t, J = 7.5 Hz, 1H), 6.96 (t, J = 7.6 Hz,
1H), 3.93 (d, J = 13.5 Hz, 1H), 3.82 (dt, J = 27.3, 9.5 Hz, 2H), 3.61 (d,
J = 13.5 Hz, 1H), 3.38 (s, 1H), 3.14−3.04 (m, 1H), 2.96 (dd, J = 16.8,
5.7 Hz, 1H), 2.92−2.73 (m, 3H), 2.67 (dd, J = 16.8, 11.7 Hz, 1H),
1.12 (d, J = 6.1 Hz, 3H), 0.97 (d, J = 6.0 Hz, 3H); 13C NMR (100
MHz, CDCl3, ppm) δ 140.1, 139.5, 136.7, 133.4, 131.9, 129.0, 128.3,
127.6, 127.0, 126.6, 125.8, 120.9, 118.7, 118.4, 110.9, 107.5, 63.6, 62.0,
60.7, 56.2, 50.6, 25.4, 13.3, 11.4; ES-MS (M + H+, m/z) 422.3; HRMS
calcd for C29H31N3 421.2518, found 421.2514.
(R)-1-((S)-Piperidin-2-yl)propan-1-ol (9b): colorless solid; yield
1
74.6 mg (52%); H NMR (300 MHz, CDCl3, ppm) δ 3.71−3.39 (m,
1H), 3.38−3.04 (m, 3H), 2.89−2.51 (m, 2H), 2.41−2.14 (m, 1H),
2.11−1.93 (m, 2H), 1.86−1.63 (m, 2H), 1.61−1.34 (m, 2H), 1.33−
1.08 (m, 2H), 0.99 (d, J = 6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3,
ppm) δ 75.4, 56.8, 48.2, 31.9, 28.0, 25.6, 23.5, 10.9; ES-MS (M + H+,
m/z) 144.3. Anal. Calcd for C8H17NO (143.1310): C, 67.09; H, 11.96;
N, 9.78. Found: C, 67.01; H, 11.90; H, 9.71. The rest of the data were
obtained in a manner similar to that for the literature reported data.
(3S,6S,14aS)-2-Benzyl-3,6-dimethyl-1,2,3,4,5,6,8,9,14,14a-
decahydro[1,4]diazocino[1′,2′:1,6]pyrido[3,4-b]indole (8d): color-
less gum; yield 29.4 mg (79%); [α]21.8D −11.9 (c 0.32, MeOH); HPLC
using Chiralpak IA flow rate 0.6 mL/min IPA/Hex/n-butanol (5:94:1,
isocratic) tR 17.3 (96.0%) and 24.7 min (3.99%); IR (neat, νmax, cm−1)
1
3125, 1563.4, 1436.2, 1165.3, 1036.2, 991.2; H NMR (400 MHz,
CDCl3, ppm) δ 8.00 (brs, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.35−7.18
(m, 6H), 7.11 (t, J = 7.5 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 3.94 (d, J =
13.5 Hz, 1H), 3.64−3.28 (m, 3H), 3.23−3.01 (m, 1H), 2.98−2.66 (m,
4H), 2.57 (d, J = 5.6 Hz, 2H), 2.44 (dd, J = 16.8, 6.9 Hz, 1H), 1.95−
1.72 (m, 2H), 1.63 (dd, J = 12.4, 5.8 Hz, 2H), 1.09 (d, J = 6.3 Hz, 3H),
1.00 (d, J = 6.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 139.8,
136.8, 135.3, 129.1, 128.4, 127.9, 127.6, 120.9, 118.7, 118.1, 112.5,
110.9, 65.9, 61.3, 59.4, 55.2, 54.6, 51.5, 34.4, 33.6, 27.9, 18.0, 17.5; ES-
MS (M + H+, m/z) 374.5; HRMS calcd for C25H31N3 373.2518, found
373.2510.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of compounds 3a−p, 4a−h, 5a−j,
6a−k, 7a−h, 8a−f, and 9a,b and HPLC details of compounds
4a−h, 5a−j, 6a−k, 7a−h, 8a−f, and 9a. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
(3S,8S,16aS)-2-Benzyl-3,8-dimethyl-1,2,3,4,7,8,10,11,16,16a-dec-
ahydro-6H-[1,4,7]oxadiazecino[7′,6′:1,6]pyrido[3,4-b]indole (8e):
■
Corresponding Author
*Fax: 0091-522-2623405; Tel: 0091-522-2612411-18 (2268).
E-mail: anilsak@gmail.com, ak_saxena@cdri.res.in.
yellow liquid; yield 30.6 mg (76%); [α]21.9 −33.4 (c 0.42, MeOH);
D
HPLC using Chiralpak IA at flow rate 0.6 mL/min IPA/Hex (8:93.5,
isocratic) tR 15.7 min (96.99%) and 18.0 min (3.04%); 1H NMR (400
MHz, CDCl3, ppm) δ 8.00 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.36−
7.21 (m, 4H), 7.20−7.15 (m, 2H), 7.11 (t, J = 7.5 Hz, 1H), 6.96 (t, J =
7.6 Hz, 1H), 3.87 (t, J = 10.3 Hz, 1H), 3.59 (q, J = 15.0 Hz, 2H), 3.42
(d, J = 13.8 Hz, 1H), 3.32 (t, J = 5.0 Hz, 2H), 3.19−3.08 (m, 1H),
3.04−2.93 (m, 3H), 2.85−2.64 (m, 4H), 2.48 (dd, J = 16.8, 6.9 Hz,
1H), 1.40 (dd, J = 11.5, 5.3 Hz, 2H), 1.10 (d, J = 6.3 Hz, 3H), 0.87 (d,
J = 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3, ppm) δ 140.9, 136.8,
135.1, 128.4, 128.2, 127.8, 127.4, 120.9, 118.7, 118.2, 112.8, 110.9,
69.5, 62.9, 62.8, 58.8, 58.3, 55.8, 52.5, 49.8, 33.6, 27.5, 18.4, 15.7; ES-
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thankfully acknowledge the technical and analytical support
by Mr. R. K. Purshottam, Mr. D. N. Viswakarma, Mr. A. S.
Kushwaha, Mr. Zahid Ali, and SAIF-CDRI. One of us (I.A.K.)
is thankful to CSIR-UGC, New Delhi, for the award of SRF and
L
dx.doi.org/10.1021/jo4012249 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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dx.doi.org/10.1021/jo4012249 | J. Org. Chem. XXXX, XXX, XXX−XXX