Metal-free late-stage C(sp2)-H functionalization of: N -aryl amines with various sodium salts

Article abstract of DOI:10.1039/c9ob02217a

Metal-free consecutive C(sp²)-X (X = Cl, Br, S, N) bond formations of N-aryl amines (cyclic, fused, carbamate, and aminium radicals) were achieved under mild conditions using [bis(trifluoroacetoxy)iodo]benzene (PIFA) and simple nonharmful sodium salts. This direct and selective C(sp²)-H functionalization showed excellent functional group compatibility, cost effectiveness, and late-stage applicability for the synthesis of biologically active natural products. Two mechanisms were proposed to explain the ortho- or para-preference, as well as the accelerating effect of CH₃NO₂

Full text of DOI:10.1039/c9ob02217a

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Metal-free late-stage C(sp2)–H functionalization of
N-aryl amines with various sodium salts†
Cite this: DOI: 10.1039/c9ob02217a
Chandrashekar Mudithanapelli and Mi-hyun Kim
*
Metal-free consecutive C(sp2)–X (X = Cl, Br, S, N) bond formations of N-aryl amines (cyclic, fused, carba-
mate, and aminium radicals) were achieved under mild conditions using [bis(trifluoroacetoxy)iodo]
benzene (PIFA) and simple nonharmful sodium salts. This direct and selective C(sp2)–H functionalization
showed excellent functional group compatibility, cost effectiveness, and late-stage applicability for the
synthesis of biologically active natural products. Two mechanisms were proposed to explain the ortho- or
para-preference, as well as the accelerating effect of CH3NO2.
Received 13th October 2019,
Accepted 26th November 2019
DOI: 10.1039/c9ob02217a
rsc.li/obc
ing environmental cost; and (iii) eligibility for late-stage
functionalization.
Introduction
N-Aryl cyclic amines are impressive ring frameworks that have
Hypervalent iodine reagents are widely used as cost-
vast synthetic utility and are found in numerous natural pro- effective metal-free oxidants in C–C and C–heteroatom bond
ducts and biologically active molecules (Fig. 1).1–4 For formation reactions.8 Among iodoarene(III) derivatives, PIFA
example, brucine, an indole-based alkaloid, has several has emerged as a powerful oxidant for C(sp2)–H functionali-
pharmacological properties, such as antitumor, antiapoptotic, zation.9 Before or during our study, direct functionalization
analgesic, and anti-inflammatory properties.2 Brucine has also has been reported, including o-chlorination,9a thiocyanation,9b
been used in traditional Chinese medicine for its therapeutic sulfenylation,9b o-azidation,9c p-bromination,9d p-iodination,9d
effects against arthritic and traumatic pain.3 Furthermore, syn- p-alkoxylation,9e p-acetoxylation,9e and nitration,9f using PIFA
thetic derivatives of brucine are better allosteric modulators of and two types of substrates, namely, phenolic derivatives and
M1 muscarinic receptors compared to brucine.4 Therefore, the N-acyl aniline derivatives (Scheme 1). Despite their efficiency,
development of novel synthetic methods for the late-stage these methodologies have limitations regarding late-stage syn-
functionalization of N-aryl cyclic amines, such as brucine, can thesis. The use of AlCl3 leads to safety issues, such as risk of
provide powerful tools for efficient structure–activity relation- handling, while TMSNCS and TMSN3 are highly volatile
ship (SAR) studies in medicinal chemistry and process liquids that are incompatible with moisture and can cause
chemistry.4,5
explosions when used in large-scale. These disadvantages have
Metal-free C(sp2)–H functionalization is an atom economi- significantly restricted their industrial use in the pharma-
cal strategy that is important for environmental sustainability.6 ceutical sector. The current best conditions for a less toxic and
In particular, direct C–C and C–heteroatom bond formations benign reaction are PIFA-mediated p-bromination and p-iodi-
on bioactive ring frameworks, such as N-aryl cyclic amines, nation using excess NaBr/NaI in ethanol as reported by Li and
can lead to significant advances in the pharmaceutical indus-
try and drug discovery. To our knowledge, selectivity is a major
issue in C(sp2)–X functionalization. Recently, the selective
functionalization of aminoaryl compounds was reported under
both metal catalysis and metal-free conditions.7 However, we
believe that such functionalization requires improvements in
three areas: (i) substituent diversity, resulting from the scope
of reactions/substrates/reagents; (ii) cost-effectiveness, includ-
Gachon Institute of Pharmaceutical Science & Department of Pharmacy, College of
Pharmacy, Gachon University, 191 Hambakmoeiro, Yeonsu-gu, Incheon 21936,
Republic of Korea. E-mail: kmh0515@gachon.ac.kr
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob02217a
Fig. 1 Representative bioactive N-aryl cyclic amines.
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Table 1 Optimization of chlorination conditionsa
Entry
Oxidant
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIDA
IBX
DCM
CHCl3
CH3CN
THF
MeOH
EtOH
DMF
CH3NO2
6
23
10
10
10
6
6
6
6
10
3
3
3
<10
n.d.
n.d.
47
38
55
13
Trace
83
53
41
79
n.d.
33
17
Trace
Scheme 1 PIFA-mediated C(sp2)–H functionalizations.
9
DMSO
10
11
12
13
14
15
16
17
CH3NO2/H2O(9 : 1)
THF/H2O(9 : 1)
CH3CN/H2O(9 : 1)
C2H5NO2/H2O(9 : 1)
PhNO2/H2O(9 : 1)
CH3NO2/H2O(9 : 1)
CH3NO2/H2O(9 : 1)
CH3NO2/H2O(9 : 1)
An.9d During or after our study, NaX/PIFA conditions were also
applied to activated imidazopyridine9g or imidazole/indole.9h
However, current NaX methods provide limited reactivity with
a more activated position (indole, imidazole) or the p-position
of anilide.9d,g,h
3
10
10
10
10
DMP
a Reaction conditions: 1a (1.0 equiv.), oxidant (2.0 equiv.), NaCl (2.0
equiv.) at room temperature (rt). b Isolated yield. n.d. = not detected.
Results and discussion
Optimization of C(sp2)–X functionalization using CH3NO2
desired product. Therefore, we reasoned that the reaction con-
ditions employed were not favorable for the formation of 2a.
Accordingly, the conditions were modified to study the reac-
tion using various organic solvents in combination with water
as a cosolvent. To our delight, the mixed aqueous–organic sol-
vents produced higher yields (entries 10–13). Among these sol-
vents, CH3NO2/H2O (9 : 1, v/v) exhibited the highest efficiency
and provided the desired product 2a in 83% yield (entry 10).
Furthermore, various other nitro solvents were subjected to
the above reaction conditions. Replacing CH3NO2 with
C2H5NO2 also afforded 2a in a slightly lower yield (entry 13),
while PhNO2 failed to provide any products (entry 14). Further
screening of the reaction conditions with other hypervalent
iodine compounds, such as (diacetoxyiodo)benzene (PIDA),
2-iodoxybenzoic acid (IBX), and Dess–Martin periodinane
(DMP), also afforded 2a, but in low yields, even after a reaction
time of 10 h (entries 15–17).
Recently, we reported a novel o-nitration via C(sp3)–N bond
cleavage/C(sp2)–N bond formation using PIFA/NaCN/
CH3NO2.9i In the spite of clarified mechanism, C(sp2)–H
functionalization in this method was limited to o-nitration.
However, we strongly expected that this mechanism could be
applied to diverse functionalizations. Therefore, how to
achieve the following three advances under facile conditions
was considered: (i) broad scope of reactions/substrates/
reagents; (ii) cost effectiveness; and (iii) eligibility for late-stage
functionalization. Herein, we report a metal-free (and Lewis-
acid-free) PIFA + NaX method for cost-effective and diverse
direct C(sp2)–X (Cl, Br, SCN, NO2, N3, SO2R, SR) functionaliza-
tions applicable to late-stage substitution. This research was
initiated using 1-(4-methoxyphenyl)piperidine (1a) as a model
substrate with two possible reactive sites (C(sp2)–H or C(sp3)–H
activation) to investigate chlorination conditions, as described
in Table 1.
Scope of the introduced functionality (X)
Initially, the chlorination of 1a (1.0 equiv.) was performed
using NaCl (2.0 equiv.) in the presence of PIFA (2.0 equiv.) in The optimal chlorination conditions used for 1a were then
DCM at rt, which gave the desired product 2a in 23% yield used to investigate other sodium salts (Scheme 2). The PIFA +
(Table 1, entry 1). However, at the end of the reaction, in- NaX in CH3NO2 were also successfully applied using NaBr and
soluble solid NaCl was observed in the reaction mixture. the corresponding product 3a was obtained in 59% yield.
Similarly, various solvents were tested in sequence Unfortunately, this process was not compatible with NaI and
(entries 2–9). No reaction was observed in CH3CN and THF NaF. However, this method was not limited to halogenation;
(entries 3 and 4), while 2a was isolated in 38%–55% yields gratifyingly, various inorganic functionalizations using NaSCN,
when the reaction was performed in MeOH, EtOH, and DMF NaNO2, and NaN3 were applicable under identical conditions,
(entries 5–7). Unsurprisingly, CH3NO2 did not increase the resulting in excellent isolated yields (4a–6a). Notably, oxidative
yield of the desired product (entry 8). However, screening of azidation of 1a under the optimal conditions resulted in a
various polar and nonpolar solvents indicated that the poor complex mixture (6a obtained in 37% yield). Fortunately, using
NaCl solubility resulted in poor-to-moderate yields of the CH3NO2 without water afforded 6a as the sole product in 78%
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went 6-thiocyanation (sole product 4u in 71% yield) instead of
2-thiocyanation, making us speculate on the para-preference of
the thiocyanation. Next, replacing p-OCH3 (electron-donating)
with p-CO2CH3 (electron-withdrawing) gave the desired pro-
ducts in up to 81% yields (2f and 4f). Furthermore, p-unsubsti-
tuted substrates were examined (1g–1j, 1l, 1n, and 1o).
Surprisingly, thiocyanation showed regioselectivity between
the ortho- and para-positions, producing predominantly p-sub-
stituted product 4g under the optimal conditions. Morpholine
and dibenzoazepine (tricyclic) showed similar regioselectivity
and efficient yields (4h, 4i, and 4o as sole isolable products).
More reactive five-membered ring and tetrahydroisoquinoline
substrates showed less discrimination, producing o,p-di-SCN-
substituted products 4ja and 4la along with 4j and 4l. In the
case of substrate 1n, the Me-substituent on the arene ring
accelerated thiocyanation to afford di-SCN along with mono-
SCN before the complete disappearance of substrate 1n. At the
end of the reaction the di-SCN product 4na could be obtained
with a trace amount of the mono-SCN product. In short, reac-
tivity of thiocyanation and reaction rate critically depend on
the substrate structure: (1) cyclic amine group (e.g.5 ring >6
ring) and (2) a substituent of the aryl group. While H4-isoqui-
noline 1l was reactive enough to produce the mono- (4l) and
di-thiocyanation product (4la), pyrrolidine (5-ring) and benzoa-
zepine (7-fused ring) could produce di-thiocyanation products
(4ja and 4na) under the assistance of electron-donating substi-
tuents. Notably, formation of products 4na and 4o can prove
that the methyl group was critical for mono-/di-competition.
In contrast to thiocyanation, the chlorination of compound 1g
was unsuccessful under the optimized conditions shown in
Table 1, leading to substrate decomposition. Notably, a
decreased PIFA loading (from 2.0 equiv. to 1.0 equiv.) with an
excess solvent ratio of CH3NO2/H2O (2 mL) afforded o-chlori-
nated product 2g along with o,p-dichloro product 2ga in low
yields. The solvent quantity was also found to have a major
impact on chlorination. Furthermore, the reaction with other
sodium salts resulted in the detection of either decomposition
or oxidative biaryl coupling products.14 ortho-Preference of the
chlorination with poor conversion made us suggest different
mechanisms between thiocyanation and halogenation.
Notably, the difference in the reaction rate between 4b and 2b
(or 3b) could be another evidence of this suggestion. Finally,
we extended the scope of C(sp2)-functionalization from cyclic
amines to amides (carbamates). When substrates 1p and 1q
were subjected to the thiocyanation reaction, p-selective thio-
cyanation product 4p and o-thiocyanation product 4q were
obtained in 43% and 91% yields. However, the chlorination of
Scheme 2 Scope of various functionalization reactions. Reaction con-
ditions: 1a (1.0 equiv.), PIFA (2.0 equiv.), NaX (2.0 equiv.) in CH3NO2/H2O
(9 : 1, v/v) at rt. a NaX is TMSCl. b NaX is NBS. c 1a (1.0 equiv.), PIFA (2.0
equiv.), NaN3 (2.0 equiv.) in CH3NO2 at rt.
isolated yield. Interestingly, although NaN3 has been used as
an additive for iodine(III) reactions in the literature,10a,b azida-
tion product 6a was obtained instead of cross-coupling with
CH3NO2.11 We suspected that our method could contribute to
the above conversion. In fact, nitromethane, a polar solvent,
has previously been used for PIFA-promoted reactions.12
However, during our studies on PIFA-mediated reactions,
CH3NO2 played a new role as a nitrating agent.9i These con-
ditions were also suitable for C(sp2)–X functionalization. To
further explore the reaction scope, TMSCl and NBS (reported
activators of PIFA oxidative reactions)10c,d were subjected to the
above optimized reaction conditions. Substrate 1a was success-
fully converted into expected C–X products 2a and 3a with the
recovered 1a. TMSCl (–Cl) or NBS (–Br) resulted in lower
product yields compared with NaCl or NaBr. Furthermore, we
investigated innovative organo-C(sp2)–H functionalization
using readily available organosulfur sodium salts, such as
sodium benzenesulfinate (NaSO2Ph), sodium methanesulfi-
nate (NaSO2CH3), and sodium benzenethiolate (NaSPh) using
a similar reaction pathway, which afforded the desired organo-
sulfur products 7a, 8a, and 9a in 69%–76% yields.9d,e,13
Substrate scope of p-substitution and o,p-disubstitution
The substrate scope for C(sp2)–H functionalization was exam- 1p and 1v (derivative of 8-aminoquinoline)15 gave similar
ined under the optimal conditions as shown in Scheme 2, with results to that of 2g, producing 2p and 2v along with 2pa and
the results summarized in Scheme 3. First, diverse electron- 2va. Notably, chlorination was accelerated by the addition
rich cyclic amines were tested with sodium salts (NaX). These of CH3COONa (1.0 equiv.), giving an increased yield of the
substrates were successfully converted into the expected o,p-di-Cl product 2pa (84%).
C(sp2)-functionalized products 2b–2e, 3b, 4b–4e, 4k, 4m, 5b–
5c, 5m and 6b–6d with excellent yields, while p-Me groups
Late-stage C(sp2)–X functionalization with NaX
gave slightly decreased yields (Scheme 3, 2e and 4e). We next turned our attention to late-stage functionalization.
Interestingly, 1,2,3,4-tetrahydroquinoline substrate 1u under- Therefore, commercially available brucine (1r) was used for
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Scheme 3 Substrate scope of various functionalizations. Reaction conditions: 1b–q, 1u–v (1.0 equiv.) in CH3NO2/H2O (1 mL; 9 : 1, v/v). a 1g (1.0 equiv.),
PIFA (1.0 equiv.), and NaCl (1.2 equiv.) in CH3NO2 : H2O (2 mL; 9 : 1, v/v). b 1a–1d (1.0 equiv.) in CH3NO2 (1 mL). c Addition of CH3COONa (1.0 equiv.).
selective C(sp2)–H azidation with PIFA (2.0 equiv.) and NaN3 underwent smooth coupling with julolidine 1s to form product
(2.0 equiv.) in nitromethane at rt. Gratifyingly, without the 4s in 71% yield, as shown in Scheme 4(b). 6r and 4s are novel
interference of other functional groups of brucine (3° amines, examples that highlight the scope of this method. In addition,
alkenes, homoallylic ethers, and amides),16 C(sp2)–H the efficiency of thiocyanation was maintained on an increased
functionalization afforded 6r (79% yield) as shown in scale, giving 81% yield, as shown in Scheme 4(c). Notably, a
Scheme 4(a). After success with brucine, the reactivity of juloli- trace amount of di-SCN product 4ha (7% yield) was observed
dine was investigated. As julolidine derivatives are mainly along with 4h. Finally, we obtained an example application of
useful for preparing dyes (or probes) and photoconductive thiocyanation products 4h and 4ha through the modification
materials, and due to their pharmacological activities, such as into mono- and di-tetrazoles 10h and 10ha, as shown in
anti-hepatitis B activity,17 our p-SCN functionalization would Scheme 4(d) and (e).18 As tetrazoles are biologically privileged
be valuable for extending the julolidine scaffold. The SCN− ion motifs,19 they can be highly useful in applications. In detail,
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Reaction mechanism based on radical trapping
To gain an understanding of the C(sp2)–H functionalization
mechanism, we conducted chlorination and thiocyanation in
the presence of 2,2,6,6-tetramethylpiperidin-1-yl-oxidanyl
(TEMPO) and 1,1-diphenylethylene as radical scavengers under
the optimal conditions (Scheme 5). The chlorination reaction
with excess TEMPO (3.0 equiv.) did not give product 2a at all
indicating
a homolytic mechanism. 1,1-Diphenylethylene
(3.0 equiv.), another radical scavenger, dramatically decreased
the isolation yield of product 2a from 83% to 14%. In contrast,
neither TEMPO nor 1,1-diphenylethylene affected the isolation
yield of thiocyanation and its reaction time. The identical
results using the radical scavengers supported that C(sp2)-thio-
cyanation did not follow a single electron transfer (SET)
mechanism. Considering that the reaction with TMSNCS was
reported to follow a SET mechanism,9b the ionic mechanism
of NaSCN is surprising. Based on the experimental results and
previous literature,23 mechanistic models were proposed for
oxidative C(sp2)–H functionalization, as shown in Scheme 6.
First, PIFA coordinates with the N-aryl cyclic amine via
halogen–π interactions between the benzene ring and iodine
to give intermediate I. CF3CO2Na elimination can be attributed
to ligand exchange with SCN− or Cl−. CH3NO2 seems to act as
an additive9i,23e,f affording the complex through coordination
with intermediate I. Nucleophilic attack on the o- or p-position
via transition state IIS then generates intermediate IIIA or IIIB
Scheme 4 Synthetic applications.
because tetrazole is a well-known bioisostere of –CO2H, drug
candidates having terazole are present in COX2 inhibitors
such as celecoxib analogues or antiulcer agents. In particular,
S-tetrazole is observed in antibiotics,19 protease inhibitors,20
or activators of autophagic flux and phospholipase D.21 To
further illustrate the efficiency of these methods, the chlori-
nation of stable radical 1t, which shares the substructure of
our substrates, was conducted. Interestingly, this reaction gave
the optimal outcome, with trichlorinated product 2taa
obtained from NaCl and SbCl6−, as shown in Scheme 4(f).
Triarylamine of 2taa is commonly used to synthesize conduc-
tive polymers and high-spin polyradicals exhibiting ferro-
magnetic coupling, representing another useful application.22
Scheme 5 Control experiment.
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Scheme 6 Plausible mechanistic pathway for C(sp2)–H functionalization.
with the loss of PhI and CH3NO2. While coordination between
Furthermore, although a SET mechanism needs to be con-
intermediate I and CH3NO2 can be replicated using other sol- sidered based on Kita’s charge-transfer (CT) complex of elec-
vents, CH3NO2 can give additional intermediate II via C(sp3)–N tron-rich arenes,23c our method does not use either a fluoro-
cleavage9i to accelerate the reaction. Finally, the aromaticity alcohol solvent or a Lewis acid. Therefore, a CT-complex via
can be recovered by the loss of a proton from IIIA or IIIB, SET and biradicals via radical cleavage need to be considered
which gives the final products. When integrating the mecha- together for the homolytic mechanism. When integrating the
nism with the experimental results (Scheme 3), we propose mechanism with experimental results (Scheme 3), radical VI
that the electron density of the aromatic group in substrates seems to prefer o-substitution over p-substitution based on
(4j and 4k, 4na and 4o, and 4p and 4q) affects the initiation of products 2g and 2p, owing to the different steric environment
thiocyanation to give intermediate I, while the steric environ- at the o-position. The ratio of o-chlorinated product 2p to o,p-
ment near the o-iodo complex provides p-regioselectivity. After dichlorinated product 2pa could be adjusted by altering the
p-substitution, p-substituted 4k, 4o, and 4p were not acidity of the reaction mixture.
sufficiently reactive for the next substitution. When comparing
nitration9i and thiocyanation using our method (NaCN vs.
NaSCN), despite the similar nucleophilicity of the anions, CN−
Conclusions
was consumed as a base and SCN− could attack iminium inter-
mediate II due to its basicity (pKa of conjugated acids in water: The metal-free and readily available ArI(O2CF3)2 and NaX
HCH2NO2 (10) > HCN (9.4) ≫ HN3 (4.72) > HSCN (4.0) > HNO2 method has been used to achieve C(sp2)–X bond formations
(3.29) ≫ HCl). However, halogenation or azidation, following a (halogenation, azidation, nitration, thiocyanation, and sulfony-
homolytic mechanism, can be explained by the generation of lation). This straightforward C–H functionalization was func-
iodanyl radical V. As reported previously,23 initial homolytic tional-group-compatible, cost-effective, and applicable to the
cleavage of the I–X bond can produce iodanyl radical V and late-stage synthesis of pharmacological molecules, such as
iminium radical VI. When TEMPO trapping was conducted, brucine and julolidine. In particular, the method required
chlorination was stopped, with no consumption of substrate neither metal catalysts nor strong acids, proving to be environ-
1a observed, but no trapped products from substrate deriva- mentally friendly and cost effective at room temperature. The
tives, including radical VI, were isolated. Therefore, we predict mechanism of ortho- or para-preference could be achieved with
that the formation of intermediate IIIA or IIIB is very fast and the coordination of nitromethane. Consecutive C–X formation,
the capture of radical V stops the reaction.
via p- and o-functionalization, encouraged us to design a
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regiospecific reaction according to the reactivity of nucleo- (m, 4H) ppm; 13C NMR (150 MHz, CDCl3) δ 153.92, 145.60,
philes and substrates. Notably, the known additives acted as 117.76, 114.46, 67.00, 55.51, 50.77 ppm; the analytical data are
reactants in our method to indicate the future direction of consistent with the literature.25c
study. Furthermore, the nonionic mechanism presents the
1-(p-Tolyl)piperidine (1e). Light yellow oil, 88% yield
possibility for o-selective functionalization in the near future. (0.77 g); 1H NMR (600 MHz, CDCl3) δ 7.09–6.98 (m, 2H),
We believe that this method will be highly attractive for the 6.89–6.78 (m, 2H), 3.13–2.98 (m, 4H), 2.24 (s, 3H), 1.68 (dt, J =
functionalization of natural products.
11.4, 5.7 Hz, 4H), 1.61–1.45 (m, 2H) ppm; 13C NMR (150 MHz,
CDCl3) δ 150.26, 129.48, 128.64, 116.93, 51.29, 25.95, 24.29,
20.40 ppm; the analytical data are consistent with the
literature.25a
Methyl 4-(piperidin-1-yl)benzoate (1f). Light yellow solid,
mp 89–91 °C, 71% yield (0.78 g); 1H NMR (600 MHz, CDCl3)
Experimental
General procedure for the synthesis of compounds 1a–1o and 1u
The following reaction procedure is a slightly modified δ 7.89 (d, J = 9.1 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H), 3.86 (s, 3H),
reported procedure.24 mixture of Pd2(dba)3 (0.137 g, 3.35–3.30 (m, 4H), 1.74–1.60 (m, 6H) ppm; 13C NMR (150 MHz,
A
0.15 mmol, 3 mol%), ligand (2-dicyclohexylphosphino-2′,6′- CDCl3) δ 167.25, 154.50, 131.22, 118.65, 113.56, 51.57, 48.79,
dimethoxybiphenyl) (0.164 g, 0.40 mmol, 8 mol%) and 5.0 mL 25.40, 24.36 ppm; the analytical data are consistent with the
of dry toluene was added into an oven dried seal tube. The literature.25d
resulting solution was degassed with N2 for 1 hour. Then, bro-
1-Phenylpiperidine (1g). Light yellow oil, 93% yield (0.75 g);
moarene (5.0 mmol, 1.0 equiv.), cyclic amine (6.0 mmol, 1.2 1H NMR (600 MHz, CDCl3) δ 7.23 (dddd, J = 9.0, 7.2, 3.5,
equiv.), and tBuONa (0.672 g, 7.0 mmol, 1.4 equiv.) were 1.5 Hz, 2H), 6.96–6.90 (m, 2H), 6.84–6.78 (m, 1H), 3.18–3.09
sequentially added with a syringe to the reaction mixture. (m, 4H), 1.74–1.66 (m, 4H), 1.56 (ddd, J = 6.3, 5.7, 1.8 Hz, 2H)
Then the reaction mixture was heated to 100 °C for 20 h. After ppm; 13C NMR (150 MHz, CDCl3) δ 152.24, 128.96, 119.13,
completion of the reaction, the resulting reaction mixture was 116.49, 50.65, 25.86, 24.31 ppm; the analytical data are consist-
slowly brought to rt, and then quenched by adding water and ent with the literature.25c
extracted with ethyl acetate. The organic layer was dried over
4-Phenylmorpholine (1h). Light yellow solid, mp 54–56 °C,
1
sodium sulphate and concentrated under reduced pressure. 89% yield (0.73 g); H NMR (600 MHz, CDCl3) δ 7.31–7.26 (m,
The crude product was purified by column chromatography on 2H), 6.92 (d, J = 7.9 Hz, 2H), 6.88 (t, J = 7.3 Hz, 1H), 3.90–3.82
silica gel using hexane/EtOAc (20 : 1) as the eluent to afford the (m, 4H), 3.21–3.12 (m, 4H) ppm; 13C NMR (150 MHz, CDCl3)
desired products.
δ 151.27, 129.18, 120.04, 115.70, 66.94, 49.36 ppm; the analyti-
1-(4-Methoxyphenyl)piperidine (1a). Light yellow oil, 94% cal data are consistent with the literature.25c
1
yield (0.90 g); H NMR (600 MHz, CDCl3) δ 6.93–6.88 (m, 2H),
1-(m-Tolyl)piperidine (1i). Light yellow oil, 76% yield
1
6.84–6.80 (m, 2H), 3.75 (s, 3H), 3.05–2.98 (m, 4H), 1.71 (dt, J = (0.67 g); H NMR (600 MHz, CDCl3) δ 7.11 (t, J = 7.8 Hz, 1H),
11.4, 5.7 Hz, 4H), 1.57–1.50 (m, 2H) ppm; 13C NMR (150 MHz, 6.79–6.68 (m, 2H), 6.63 (d, J = 7.4 Hz, 1H), 3.19–3.04 (m, 4H),
CDCl3) δ 153.51, 146.91, 118.71, 114.27, 55.51, 52.27, 26.13, 2.29 (s, 3H), 1.68 (dt, J = 14.9, 5.7 Hz, 4H), 1.60–1.48 (m, 2H)
24.18 ppm. The analytical data are consistent with the ppm; 13C NMR (150 MHz, CDCl3) δ 152.33, 138.52, 128.80,
literature.25a
120.11, 117.41, 113.67, 50.78, 25.91, 24.35, 21.77 ppm; the
8-(4-Methoxyphenyl)-1,4-dioxa-8-azaspiro[4.5]decane
Light yellow solid, mp 63–65 °C, 87% yield (1.08 g); H NMR
(1b). analytical data are consistent with the literature.25e
1
1-(m-Tolyl)pyrrolidine (1j). Light yellow oil, 73% yield
1
(600 MHz, CDCl3) δ 6.96–6.87 (m, 2H), 6.85–6.78 (m, 2H), 3.97 (0.59 g); H NMR (600 MHz, CDCl3) δ 7.14–7.07 (m, 1H), 6.48
(s, 4H), 3.75 (s, 3H), 3.26–3.10 (m, 4H), 1.91–1.76 (m, 4H) ppm; (d, J = 7.5 Hz, 1H), 6.37 (d, J = 6.1 Hz, 2H), 3.32–3.17 (m, 4H),
13C NMR (150 MHz, CDCl3) δ 153.69, 145.61, 118.91, 114.32, 2.30 (s, 3H), 2.01–1.89 (m, 4H) ppm; 13C NMR (150 MHz,
107.03, 64.27, 55.50, 49.34, 34.83 ppm; the analytical data are CDCl3) δ 148.04, 138.72, 128.96, 116.33, 112.34, 108.88, 47.56,
consistent with the literature.25b
4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-(4-methoxyphenyl) literature.25f
25.43, 21.84 ppm; the analytical data are consistent with the
piperidine (1c). White solid, mp 117–119 °C, 78% yield
1-(4-Methoxyphenyl)pyrrolidine (1k). Light orange solid, mp
(1.48 g); 1H NMR (600 MHz, CDCl3) δ 7.34 (dd, J = 11.4, 4.3 Hz, 43–45 °C, 77% yield (0.68 g); 1H NMR (600 MHz, CDCl3)
4H), 7.27–7.20 (m, 4H), 6.92 (s, 2H), 6.88–6.84 (m, 2H), δ 6.92–6.78 (m, 2H), 6.56 (d, J = 8.4 Hz, 2H), 3.75 (s, 3H), 3.23
6.83–6.78 (m, 2H), 3.75 (s, 3H), 3.25–3.17 (m, 2H), 2.84–2.77 (d, J = 5.7 Hz, 4H), 2.03–1.95 (m, 4H) ppm; 13C NMR (150 MHz,
(m, 2H), 2.47 (ddd, J = 13.3, 9.0, 4.1 Hz, 2H), 2.28 (ddd, J = CDCl3) δ 130.87, 127.65, 115.00, 55.99, 48.47, 25.35 ppm; the
13.7, 5.8, 3.6 Hz, 2H) ppm; 13C NMR (150 MHz, CDCl3) analytical data are consistent with the literature.25f
δ 153.59, 145.80, 139.06, 135.32, 134.81, 133.67, 131.01,
128.47, 128.23, 127.79, 126.30, 118.67, 114.35, 55.55, 52.90, mp 45–47 °C, 79% yield (0.83 g); 1H NMR (600 MHz, CDCl3)
30.12 ppm; LRMS (ESI, m/z): 380 ([M + H]+).
δ 7.28 (dd, J = 8.4, 7.4 Hz, 2H), 7.22–7.11 (m, 4H), 6.98 (d, J =
2-Phenyl-1,2,3,4-tetrahydroisoquinoline (1l). Orange solid,
4-(4-Methoxyphenyl)morpholine (1d). Yellow solid, mp 8.2 Hz, 2H), 6.82 (t, J = 7.2 Hz, 1H), 4.40 (s, 2H), 3.56 (t, J =
70–71 °C, 85% yield (0.82 g); 1H NMR (600 MHz, CDCl3) 5.9 Hz, 2H), 2.98 (t, J = 5.8 Hz, 2H) ppm; 13C NMR (150 MHz,
δ 6.93–6.80 (m, 4H), 3.89–3.80 (m, 4H), 3.75 (s, 3H), 3.09–2.99 CDCl3) δ 150.54, 134.86, 134.45, 129.19, 128.51, 126.53, 126.31,
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126.01, 118.64, 115.12, 50.71, 46.50, 29.11 ppm; the analytical (t, J = 8.0 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1H), 6.70 (s, 1H), 5.19 (s,
data are consistent with the literature.25g 2H) ppm; 13C NMR (150 MHz, CDCl3) δ 153.29, 137.73, 136.02,
5-(4-Methoxyphenyl)-10,11-dihydro-5H-dibenzo[b,f]azepine 129.35, 129.06, 128.91, 128.82, 128.73, 128.61, 128.56, 128.36,
(1m). High viscous brown oil; 67% yield (1.0 g); 1H NMR 128.31, 126.98, 123.51, 118.64, 67.01 ppm; the analytical data
(600 MHz, CDCl3) δ 7.45–7.41 (m, 2H), 7.29–7.25 (m, 4H), 7.22 are consistent with the literature.25j
(td, J = 7.4, 1.4 Hz, 2H), 6.73 (d, J = 9.1 Hz, 2H), 6.59 (d, J =
Benzyl benzo[d][1,3]dioxol-5-ylcarbamate (1q). White solid,
9.1 Hz, 2H), 3.76 (s, 3H), 3.02 (s, 4H) ppm; 13C NMR (150 MHz, mp 95–97 °C, 83% yield (0.73 g); 1H NMR (600 MHz, CDCl3)
CDCl3) δ 151.95, 143.96, 143.65, 138.42, 130.83, 130.66, 130.20, δ 7.45–7.29 (m, 5H), 7.09 (s, 1H), 6.69 (dd, J = 30.0, 8.0 Hz, 2H),
128.63, 126.96, 126.80, 126.71, 119.43, 117.90, 114.33, 114.02, 6.55 (s, 1H), 5.93 (d, J = 2.3 Hz, 2H), 5.18 (s, 2H) ppm;
55.73, 31.03 ppm; the analytical data are consistent with the 13C NMR (150 MHz, CDCl3) δ 147.96, 136.05, 128.61, 128.35,
literature.25h
128.32, 108.10, 101.24, 67.02 ppm; the analytical data are con-
5-(o-Tolyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (1n). White sistent with the literature.25k
1
solid, mp 107–109 °C, 81% yield (1.16 g); H NMR (600 MHz,
Benzyl quinolin-8-ylcarbamate (1v). White solid, mp
CDCl3) δ 7.32 (ddt, J = 12.9, 7.2, 6.6 Hz, 4H), 7.07 (dd, J = 7.4, 75–77 °C, 87% yield ( 0.79 g); 1H NMR (600 MHz, CDCl3) δ 9.28
1.6 Hz, 2H), 6.95–6.84 (m, 2H), 6.76 (td, J = 7.3, 0.9 Hz, 2H), (s, 1H), 8.77 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 (d, J = 6.2 Hz, 1H),
6.48 (dd, J = 8.5, 0.8 Hz, 2H), 3.20 (s, 4H), 2.06 (s, 3H) ppm; 8.14 (dd, J = 8.2, 1.6 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.50–7.37
13C NMR (150 MHz, CDCl3) δ 145.31, 144.92, 137.51, 132.30, (m, 6H), 7.35 (ddd, J = 7.3, 3.8, 1.2 Hz, 1H), 5.29 (s, 2H) ppm;
132.22, 131.67, 130.31, 127.66, 127.25, 126.25, 121.04, 119.84, 13C NMR (150 MHz, CDCl3) δ 153.41, 148.12, 138.22, 136.23,
37.16, 18.00 ppm; the analytical data are consistent with the 134.67, 128.61, 128.31, 128.29, 128.02, 127.31, 121.63, 120.66,
literature.25h
114.64, 66.96 ppm; the analytical data are consistent with the
5-Phenyl-10,11-dihydro-5H-dibenzo[b,f]azepine (1o). White literature.25l
solid, mp 99–101 °C, 87% yield (1.18 g); 1H NMR (600 MHz,
General procedure for C(sp2)–H functionalization
CDCl3) δ 7.41 (d, J = 7.7 Hz, 2H), 7.29–7.17 (m, 6H), 7.09 (t, J =
8.0 Hz, 2H), 6.70 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 8.1 Hz, 2H), Cyclic amine (0.15 mmol, 1.0 equiv.) and NaX (0.3 mmol, 2.0
2.98 (s, 4H) ppm; 13C NMR (150 MHz, CDCl3) δ 149.06, 143.43, equiv.) (NaX = NaCl or NaBr or NaSCN or NaNO2 or NaSO2Ph
138.34, 130.91, 130.14, 128.82, 127.06, 127.04, 117.44, 112.54, or NaSO2CH3 or NaSPh) were dissolved in a 1 mL mixture of
77.22, 77.00, 76.79, 30.84 ppm; the analytical data are consist- nitromethane and water (9 : 1) and PIFA (0.3 mmol, 2.0 equiv.)
ent with the literature.25h
was cautiously added portionwise to the reaction mixture, and
1-(4-Methoxyphenyl)-1,2,3,4-tetrahydroquinoline (1u). White then the solution was stirred at room temperature for 5 min to
solid, mp 69–71 °C, 81% yield ( 0.97 g); 1H NMR (600 MHz, 8 h, monitored by TLC. Then, the reaction mixture was diluted
CDCl3) δ 7.18–7.13 (m, 2H), 7.03–6.98 (m, 1H), 6.94–6.85 (m, with water and extracted with ethyl acetate. The organic layer
3H), 6.62 (td, J = 7.3, 1.0 Hz, 1H), 6.47 (dd, J = 8.2, 0.6 Hz, 1H), was washed with a saturated solution of NaHCO3 and brine,
3.81 (s, 3H), 3.57–3.50 (m, 2H), 2.86 (t, J = 6.4 Hz, 2H), dried over Na2SO4 and concentrated in vacuo. The residue was
2.08–1.99 (m, 2H)pp; 13C NMR (150 MHz, CDCl3) δ 156.76, purified by column chromatography (hexane/EtOAc) to afford
145.53, 141.35, 129.29, 127.66, 126.46, 122.93, 117.16, 114.82, the corresponding products.
114.29, 55.46, 51.64, 27.86, 22.50 ppm; the analytical data are
consistent with the literature.25i
1-(2-Chloro-4-methoxyphenyl)piperidine (2a). White solid,
mp 44–46 °C, 83% yield ( 28.0 mg); 1H NMR (600 MHz, CDCl3)
δ 6.98 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 2.9 Hz, 1H), 6.76 (dd, J =
8.8, 2.9 Hz, 1H), 3.76 (s, 3H), 2.88 (s, 4H), 1.73 (dt, J = 11.1, 5.6
Synthetic procedure of compounds 1p–1q and 1v
To a mixture of aniline (3.25 mmol, 1.0 equiv.) and Na2CO3 Hz, 4H), 1.59–1.52 (m, 2H) ppm; 13C NMR (150 MHz, CDCl3) δ
(6.5 mmol, 2.0 equiv.) 3.0 mL THF/H2O (v/v = 1 : 1) was added, 155.34, 144.19, 129.79, 120.98, 115.96, 112.85, 55.64, 53.40,
and then the reaction mixture was cooled to 0 °C. A solution 26.37, 24.24 ppm; FT-IR ν 2936, 1496, 1209, 1044, 872,
of benzyl chloroformate (CbzCl) (3.38 mmol, 1.04 equiv.) in 862 cm−1; HRMS (EI, m/z): M+ calculated for C12H16ClNO
THF was slowly added dropwise to the reaction mixture. 225.0920, found 225.0924.
After the addition, the reaction mixture was continuously
8-(2-Chloro-4-methoxyphenyl)-1,4-dioxa-8-azaspiro[4.5]decane
stirred for 3 h at rt. After completion of the reaction, checked (2b). Light yellow solid, mp 56–58 °C, 79% yield (34.0 mg);
by TLC, the organic solvent was removed under reduced 1H NMR (600 MHz, CDCl3) δ 7.01 (d, J = 8.8 Hz, 1H), 6.95 (d,
pressure and extracted with EtOAc. The organic layer was J = 2.9 Hz, 1H), 6.76 (dd, J = 8.8, 2.9 Hz, 1H), 4.00 (s, 4H), 3.76
washed with brine and dried over Na2SO4. The solvent was (s, 3H), 3.12–2.94 (m, 4H), 1.97–1.82 (m, 4H) ppm; 13C NMR
concentrated in vacuo and the crude product was purified by (150 MHz, CDCl3) δ 155.63, 143.06, 129.81, 121.22, 115.96,
column chromatography over silica gel (gradient elution of 112.87, 107.06, 64.29, 55.64, 50.17, 35.41 ppm; FT-IR ν 2957,
EtOAc/hexane 1 : 15).
1496, 1208, 1107, 1039, 903, 863 cm−1; HRMS (EI, m/z): M+ cal-
culated for C14H18ClNO3 283.0975, found 283.0977.
Benzyl phenylcarbamate (1p)
1-(2-Chloro-4-methoxyphenyl)-4-(5H-dibenzo[a,d][7]annulen-
White solid, mp 71–73 °C, 91% yield (0.67 g); 1H NMR 5-ylidene)piperidine (2c). Yellow solid, mp 146–148 °C, 73%
(600 MHz, CDCl3) δ 7.42–7.35 (m, 6H), 7.35–7.31 (m, 1H), 7.30 yield (45.0 mg); 1H NMR (600 MHz, CDCl3) δ 7.37–7.30 (m,
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4H), 7.24 (d, J = 7.5 Hz, 4H), 6.97–6.92 (m, 3H), 6.90 (d, J = 6.99 (td, J = 7.7, 1.4 Hz, 1H), 5.22 (s, 2H) ppm; 13C NMR
8.9 Hz, 1H), 6.72 (dd, J = 8.8, 2.9 Hz, 1H), 3.74 (s, 3H), (150 MHz, CDCl3) δ 152.99, 135.77, 134.64, 133.46, 129.06,
3.07–3.01 (m, 2H), 2.61 (dd, J = 14.1, 5.8 Hz, 2H), 2.52 (ddd, J = 128.74, 128.70, 128.67, 128.59, 128.49, 128.44, 127.92, 127.76,
13.4, 9.3, 4.0 Hz, 2H), 2.34–2.28 (m, 2H) ppm; 13C NMR 123.78, 122.06, 119.89, 67.33 ppm; FT-IR ν 1695, 1528, 1441,
(150 MHz, CDCl3) δ 155.50, 143.16, 139.14, 134.80, 131.00, 1235, 1034, 740 cm−1; HRMS (EI, m/z): M+ calculated for
128.55, 128.19, 127.77, 126.26, 121.10, 115.98, 112.82, 95.67, C14H12ClNO2 261.0557, found 261.0554.
55.63, 53.73, 30.62 ppm; FT-IR ν 2923, 1496, 1212, 1044, 801,
Benzyl(2,4-dichlorophenyl)carbamate (2pa). White solid, mp
742 cm−1; HRMS (EI, m/z): M+ calculated for C27H24ClNO 75–77 °C, 84% yield (addition of 1.0 equiv. CH3COONa)
413.1546, found 413.1546.
(37.0 mg); 1H NMR (600 MHz, CDCl3) δ 8.15 (d, J = 8.4 Hz, 1H),
4-(2-Chloro-4-methoxyphenyl)morpholine
(2d).
Brown 7.55–7.32 (m, 6H), 7.26–7.21 (m, 1H), 7.15 (s, 1H), 5.22 (s, 2H)
liquid, 59% yield (20.0 mg); H NMR (600 MHz, CDCl3) δ 6.98 ppm; 13C NMR (150 MHz, CDCl3) δ 152.84, 135.56, 133.46,
(dd, J = 19.1, 5.9 Hz, 2H), 6.79 (dd, J = 8.8, 2.9 Hz, 1H), 129.06, 128.74, 128.70, 128.66, 128.59, 128.49, 128.44, 128.23,
3.94–3.84 (m, 4H), 3.78 (s, 3H), 3.05–2.93 (m, 4H) ppm; 127.91, 127.76, 123.77, 122.51, 120.61, 67.53 ppm; FT-IR
13C NMR (150 MHz, CDCl3) δ 155.92, 142.52, 129.79, 120.96, ν 2919, 2850, 1687, 1522, 1474, 1238, 745, 694 cm−1; HRMS
116.19, 113.05, 67.28, 55.68, 52.16 ppm; FT-IR ν 2922, 1490, (EI, m/z): M+ calculated for C14H11Cl2NO2 295.0167, found
1218, 1117, 1046, 939, 874 cm−1; HRMS (EI, m/z): M+ calcu- 295.0167.
1
lated for C11H14ClNO2 227.0713, found 227.0712.
Benzyl(5-chloroquinolin-8-yl)carbamate (2v). White solid,
1-(2-Chloro-4-methylphenyl)piperidine (2e). Light yellow mp 99–101 °C, 69% yield ( 32.0 mg); 1H NMR (600 MHz,
1
liquid, 47% yield (15.0 mg); H NMR (600 MHz, CDCl3) δ 7.17 CDCl3) δ 9.24 (s, 1H), 8.81 (dd, J = 4.2, 1.5 Hz, 1H), 8.54 (dd, J =
(d, J = 1.8 Hz, 1H), 7.00 (ddd, J = 8.1, 1.4, 0.6 Hz, 1H), 6.93 (d, J 8.5, 1.6 Hz, 1H), 8.39 (d, J = 7.4 Hz, 1H), 7.59 (d, J = 8.4 Hz,
= 8.1 Hz, 1H), 2.93 (s, 4H), 2.26 (s, 3H), 1.73 (dt, J = 11.1, 5.6 1H), 7.55 (dd, J = 8.5, 4.2 Hz, 1H), 7.47 (d, J = 7.3 Hz, 2H),
Hz, 4H), 1.60–1.54 (m, 2H) ppm; 13C NMR (150 MHz, CDCl3) δ 7.43–7.38 (m, 2H), 7.35 (dd, J = 8.4, 6.2 Hz, 1H), 5.28 (s, 2H)
148.13, 133.01, 130.94, 128.65, 127.99, 120.18, 53.08, 26.30, ppm; 13C NMR (150 MHz, CDCl3) δ 153.27, 148.59, 138.71,
24.27, 20.38 ppm; FT-IR ν 2927, 1497, 1235, 1068, 870, 136.05, 133.98, 133.29, 128.64, 128.38, 128.36, 127.15, 125.97,
813 cm−1; HRMS (EI, m/z): M+ calculated for C12H16ClN 123.47, 122.37, 114.57, 67.13 ppm; HRMS (ESI, m/z): [M + H]+
209.0971, found 209.0974.
calculated for C17H14ClN2O2 313.0738, found 313.0768.
Methyl 3-chloro-4-(piperidin-1-yl)benzoate (2f). Brown
Benzyl(5,7-dichloroquinolin-8-yl)carbamate (2va). Yellow
liquid, 66% yield (25.0 mg); H NMR (600 MHz, CDCl3) δ 8.01 solid, mp 141–143 °C, 13% yield ( 7.0 mg); 1H NMR (600 MHz,
(d, J = 2.0 Hz, 1H), 7.86 (dd, J = 8.4, 2.0 Hz, 1H), 7.00 (d, J = 8.4 CDCl3) δ 8.91 (dd, J = 4.2, 1.6 Hz, 1H), 8.51 (dd, J = 8.5, 1.6 Hz,
Hz, 1H), 3.88 (s, 3H), 3.09–3.02 (m, 4H), 1.79–1.72 (m, 4H), 1H), 7.76 (s, 1H), 7.70 (s, 1H), 7.54 (dd, J = 8.5, 4.2 Hz, 1H),
1.61 (dt, J = 11.8, 6.0 Hz, 2H) ppm; 13C NMR (150 MHz, CDCl3) 7.46–7.40 (m, 2H), 7.42–7.30 (m, 3H), 5.26 (s, 2H) ppm;
δ 166.13, 154.47, 132.06, 129.10, 127.81, 124.14, 119.54, 52.33, 13C NMR (150 MHz, CDCl3) δ 153.59, 150.86, 143.64, 135.96,
52.05, 26.02, 24.16 ppm; FT-IR ν 2934, 1721, 1597, 1435, 1244, 133.29, 131.19, 129.76, 128.67, 128.54, 128.36, 128.26, 125.22,
1
1120, 768 cm−1
;
HRMS (EI, m/z): M+ calculated for 122.33, 67.73 ppm; HRMS (ESI, m/z): [M + H]+ calculated for
C13H16ClNO2 253.0870, found 253.0869.
C17H13Cl2N2O2 347.0349, found 347.0364.
1-(2-Chlorophenyl)piperidine (2g). Yellow liquid, 17% yield
1-(2-Bromo-4-methoxyphenyl)piperidine (3a). Red viscous
(addition of 1.0 equiv. PIFA) (5.0 mg); 1H NMR (600 MHz, liquid, 59% yield (24.0 mg); H NMR (600 MHz, CDCl3) δ 7.14
CDCl3) δ 7.38–7.32 (m, 1H), 7.23–7.14 (m, 1H), 7.03 (dd, J = (d, J = 2.9 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.81 (dd, J = 8.8, 2.9
8.0, 1.4 Hz, 1H), 6.93 (ddd, J = 9.1, 5.7, 1.9 Hz, 1H), 3.03–2.88 Hz, 1H), 3.76 (s, 3H), 2.87 (s, 4H), 1.73 (dt, J = 11.0, 5.6 Hz,
(m, 4H), 1.79–1.70 (m, 4H), 1.58 (t, J = 7.3 Hz, 2H) pp; 13C 4H), 1.55 (d, J = 4.9 Hz, 2H) ppm; 13C NMR (150 MHz, CDCl3) δ
NMR (150 MHz, CDCl3) δ 149.38, 130.49, 127.40, 123.11, 155.61, 145.50, 121.31, 120.91, 118.89, 113.61, 55.68, 53.81,
121.17, 120.44, 52.89, 26.26, 24.27 ppm; FT-IR ν 2933, 2851, 26.36, 24.21 ppm; FT-IR ν 2937, 1492, 1208, 1103, 1036,
1442, 1238, 1042, 746 cm−1; HRMS (EI, m/z): M+ calculated for 737 cm−1; HRMS (EI, m/z): M+ calculated for C12H16BrNO
1
C11H14ClN 195.0815, found 195.0817.
269.0415, found 269.0420.
1-(2,4-Dichlorophenyl)piperidine (2ga). Yellow liquid, 35%
8-(2-Bromo-4-methoxyphenyl)-1,4-dioxa-8-azaspiro[4.5]decane
yield (addition of 1.0 equiv. PIFA) (12.0 mg); 1H NMR (3b). White solid, mp 89–91 °C, 82% yield (40.0 mg); H NMR
(600 MHz, CDCl3) δ 7.34 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 8.6, (600 MHz, CDCl3) δ 7.14 (d, J = 2.9 Hz, 1H), 7.02 (d, J = 8.8 Hz,
2.5 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 3.03–2.84 (m, 4H), 1.73 1H), 6.81 (dd, J = 8.8, 2.9 Hz, 1H), 4.00 (s, 4H), 3.76 (s, 3H),
(dt, J = 11.2, 5.6 Hz, 4H), 1.58 (d, J = 11.4 Hz, 2H) ppm; 13C 3.10–2.94 (m, 4H), 1.96–1.83 (m, 4H) ppm; 13C NMR (150 MHz,
NMR (150 MHz, CDCl3) δ 149.40, 130.16, 129.58, 127.55, CDCl3) δ 155.89, 144.36, 121.52, 120.88, 118.88, 113.60, 107.08,
127.44, 121.19, 52.87, 26.16, 24.15 ppm; FT-IR ν 2921, 2851, 64.28, 55.67, 50.55, 35.42 ppm; FT-IR ν 2957, 1491, 1208, 1106,
1
1532, 1478, 1233, 751, 690 cm−1; HRMS (EI, m/z): M+ calcu- 1038, 736 cm−1
;
HRMS (EI, m/z): M+ calculated for
lated for C11H13Cl2N 229.0425, found 229.0426.
C14H18BrNO3 327.0470, found 327.0473.
Benzyl(2-chlorophenyl)carbamate (2p). White solid, mp
1-(4-Methoxy-2-thiocyanatophenyl)piperidine (4a). Brown
1
44–46 °C, 37% yield (15.0 mg); 1H NMR (600 MHz, CDCl3) liquid, 76% yield (28.0 mg); H NMR (600 MHz, CDCl3) δ 7.15
δ 8.19 (d, J = 7.6 Hz, 1H), 7.59–7.31 (m, 6H), 7.32–7.11 (m, 2H), (d, J = 2.7 Hz, 1H), 7.11 (d, J = 8.7 Hz, 1H), 6.81 (dd, J = 8.7, 2.7
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Hz, 1H), 3.83 (s, 3H), 2.80–2.71 (m, 4H), 1.71–1.65 (m, 4H), 1.71–1.65 (m, 4H), 1.64–1.59 (m, 2H) ppm; 13C NMR (150 MHz,
1.57–1.53 (m, 2H) ppm; 13C NMR (150 MHz, CDCl3) δ 158.02, CDCl3) δ 153.00, 134.01, 116.43, 112.27, 109.03, 49.20, 25.34,
143.29, 127.38, 122.84, 114.49, 112.51, 110.64, 55.74, 54.21, 24.20 ppm; FT-IR ν 2931, 2153, 1590, 1500, 1240, 1129,
26.37, 23.82 ppm; FT-IR ν 2936, 2155, 1493, 1221, 1044, 815 cm−1; HRMS (EI, m/z): M+ calculated for C12H14N2S
859 cm−1; HRMS (EI, m/z): M+ calculated for C13H16N2OS 218.0878, found 218.0877.
248.0983, found 248.0983.
1-(3-Methyl-4-thiocyanatophenyl)piperidine
(4i).
Brown
1
8-(4-Methoxy-2-thiocyanatophenyl)-1,4-dioxa-8-azaspiro[4.5] liquid, 73% yield (25.0 mg); H NMR (600 MHz, CDCl3) δ 7.42
decane (4b). White solid, mp 86–87 °C, 85% yield (39.0 mg); (d, J = 8.7 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 6.72 (dd, J = 8.7, 2.8
1H NMR (600 MHz, CDCl3) δ 7.16 (t, J = 5.4 Hz, 2H), 6.81 (dd, Hz, 1H), 3.31–3.18 (m, 4H), 2.48 (s, 3H), 1.75–1.64 (m, 4H),
J = 8.7, 2.8 Hz, 1H), 4.00 (s, 4H), 3.83 (s, 3H), 3.00–2.84 (m, 1.63–1.57 (m, 2H) ppm; 13C NMR (150 MHz, CDCl3) δ 153.52,
4H), 1.93–1.77 (m, 4H) ppm; 13C NMR (150 MHz, CDCl3) 142.32, 135.72, 117.57, 114.10, 111.90, 108.67, 49.16, 25.38,
δ 158.25, 142.22, 127.09, 123.01, 114.54, 112.15, 110.84, 24.24, 21.36 ppm; FT-IR ν 2935, 2152, 1590, 1490, 1243, 1129,
106.51, 64.36, 55.75, 51.24, 35.45 ppm; FT-IR ν 2926, 2156, 736 cm−1; HRMS (EI, m/z): M+ calculated for C13H16N2S
1492, 1294, 1109, 1038, 735 cm−1; HRMS (EI, m/z): M+ calcu- 232.1034, found 232.1031.
lated for C15H18N2O3S 306.1038, found 306.1041.
1-(3-Methyl-4-thiocyanatophenyl)pyrrolidine (4j). White
4-(5H-Dibenzo[a,d][7]annulen-5-ylidene)-1-(4-methoxy-2-thiocya- solid, mp 109–111 °C, 32% yield (10.0 mg); 1H NMR (600 MHz,
natophenyl)piperidine (4c). Light yellow solid, mp 153–154 °C, CDCl3) δ 7.41 (d, J = 8.6 Hz, 1H), 6.45 (d, J = 2.6 Hz, 1H), 6.38
1
78% yield (51.0 mg); H NMR (600 MHz, CDCl3) δ 7.34 (ddd, (dd, J = 8.6, 2.8 Hz, 1H), 3.29 (ddd, J = 6.6, 4.3, 2.6 Hz, 4H),
J = 6.6, 3.7, 1.7 Hz, 4H), 7.26–7.20 (m, 4H), 7.13 (d, J = 2.7 Hz, 2.51 (s, 3H), 2.09–1.96 (m, 4H) ppm; 13C NMR (150 MHz,
1H), 7.04 (d, J = 8.6 Hz, 1H), 6.94 (s, 2H), 6.77 (dd, J = 8.7, CDCl3) δ 149.78, 142.87, 136.43, 114.04, 112.46, 110.68, 105.11,
2.7 Hz, 1H), 3.81 (s, 3H), 2.86–2.79 (m, 2H), 2.60 (dd, J = 19.9, 47.51, 25.47, 21.40 ppm; FT-IR ν 2923, 2146, 1592, 1497, 1386,
13.9 Hz, 2H), 2.45 (ddd, J = 13.3, 9.2, 4.0 Hz, 2H), 2.32–2.25 1114, 831 cm−1; HRMS (EI, m/z): M+ calculated for C12H14N2S
(m, 2H) ppm; 13C NMR (150 MHz, CDCl3) δ 158.15, 142.28, 218.0878, found 218.0875.
138.89, 134.73, 134.49, 134.16, 130.99, 128.38, 128.24, 127.84,
1-(5-Methyl-2,4-dithiocyanatophenyl)pyrrolidine (4ja). White
1
127.10, 126.39, 122.92, 114.51, 112.22, 110.82, 55.74, 54.65, solid, mp 67–69 °C, 57% yield (24.0 mg); H NMR (600 MHz,
30.60 ppm; FT-IR ν 2924, 2155, 1493, 1215, 1042, 756, CDCl3) δ 7.80 (s, 1H), 6.75 (s, 1H), 3.54 (t, J = 6.6 Hz, 4H), 2.52
741 cm−1; HRMS (EI, m/z): M+ calculated for C28H24N2OS (s, 3H), 2.07–1.98 (m, 4H) ppm; 13C NMR (150 MHz, CDCl3)
436.1609, found 436.1610.
δ 152.04, 145.25, 143.81, 118.84, 111.63, 110.91, 110.29,
4-(4-Methoxy-2-thiocyanatophenyl)morpholine (4d). Light 105.65, 51.61, 25.78, 21.23 ppm; FT-IR ν 2919, 2154, 1581,
yellow solid, mp 92–94 °C, 83% yield (31.0 mg); 1H NMR 1478, 1134, 735, 703 cm−1; HRMS (EI, m/z): M+ calculated for
(600 MHz, CDCl3) δ 7.16 (dd, J = 5.7, 4.5 Hz, 2H), 6.85 (dd, J = C13H13N3S2 275.0551, found 275.0547.
8.7, 2.8 Hz, 1H), 3.84 (s, 3H), 3.83–3.78 (m, 4H), 2.88–2.81 (m,
1-(4-Methoxy-2-thiocyanatophenyl)pyrrolidine (4k). Light
1
4H) ppm; 13C NMR (150 MHz, CDCl3) δ 158.49, 141.58, 127.10, yellow liquid, 69% yield (24.0 mg); H NMR (600 MHz, CDCl3)
123.17, 114.78, 111.81, 111.09, 67.23, 55.78, 52.89 ppm; FT-IR δ 7.14 (d, J = 2.8 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 6.83 (dd, J =
ν 2960, 2156, 1493, 1217, 1114, 933, 735 cm−1; HRMS (EI, m/z): 8.7, 2.8 Hz, 1H), 3.82 (s, 3H), 3.08–2.96 (m, 4H), 1.99–1.90 (m,
M+ calculated for C12H14N2O2S 250.0776, found 250.0780.
1-(4-Methyl-2-thiocyanatophenyl)piperidine (4e).
4H) ppm; 13C NMR (150 MHz, CDCl3) δ 157.47, 140.94, 125.71,
Light 122.48, 115.25, 112.36, 111.71, 55.79, 53.32, 24.65 ppm; FT-IR
1
yellow liquid, 63% yield (22.0 mg); H NMR (600 MHz, CDCl3) ν 2923, 2155, 1492, 1284, 1228, 1044 cm−1; HRMS (EI, m/z): M+
δ 7.41 (s, 1H), 7.11–7.01 (m, 2H), 2.83–2.73 (m, 4H), 2.36 calculated for C12H14N2OS 234.0827, found 234.0826.
(s, 3H), 1.72–1.66 (m, 4H), 1.53–1.53 (m, 2H) ppm; 13C NMR
2-(4-Thiocyanatophenyl)-1,2,3,4-tetrahydroisoquinoline (4l).
(150 MHz, CDCl3) δ 147.95, 136.65, 129.33, 126.41, 125.49, Orange solid, mp 114–116 °C, 64% yield (26.0 mg); 1H NMR
121.73, 112.55, 54.02, 26.32, 23.87, 21.09 ppm; FT-IR ν 2935, (600 MHz, CDCl3) δ 7.53–7.40 (m, 2H), 7.24–7.10 (m, 4H),
2155, 1491, 1233, 1108, 925, 818 cm−1; HRMS (EI, m/z): M+ 6.94–6.85 (m, 2H), 4.45 (s, 2H), 3.59 (t, J = 5.9 Hz, 2H), 2.98 (t,
calculated for C13H16N2S 232.1034, found 232.1035.
J = 5.9 Hz, 2H) ppm; 13C NMR (150 MHz, CDCl3) δ 151.38,
Methyl 4-(piperidin-1-yl)-3-thiocyanatobenzoate (4f). Light 134.80, 134.29, 133.61, 128.28, 126.75, 126.47, 126.37, 114.76,
1
yellow liquid, 81% yield (34.0 mg); H NMR (600 MHz, CDCl3) 112.33, 108.38, 49.29, 45.13, 28.91 ppm; FT-IR ν 2927, 2154,
δ 8.27 (d, J = 1.8 Hz, 1H), 7.99 (dd, J = 8.3, 1.8 Hz, 1H), 7.19 (d, 1592, 1500, 1265, 734 cm−1; HRMS (EI, m/z): M+ calculated for
J = 8.3 Hz, 1H), 3.92 (s, 3H), 2.96–2.84 (m, 4H), 1.78–1.69 (m, C16H14N2S 266.0878, found 266.0880.
4H), 1.60 (dt, J = 11.3, 5.8 Hz, 2H) ppm; 13C NMR (150 MHz,
2-(2,4-Dithiocyanatophenyl)-1,2,3,4-tetrahydroisoquinoline (4la).
CDCl3) δ 165.70, 154.75, 130.72, 128.48, 127.60, 124.98, 121.24, Orange solid, mp 61–63 °C, 23% yield (11.0 mg); 1H NMR
111.12, 53.60, 52.38, 26.04, 23.79 ppm; FT-IR ν 2935, 2154, (600 MHz, CDCl3) δ 7.80 (d, J = 2.1 Hz, 1H), 7.58 (dd, J = 8.3,
1724, 1493, 1245, 858 cm−1; HRMS (EI, m/z): M+ calculated for 2.1 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.21 (ddd, J = 17.0, 11.5,
C14H16N2O2S 276.0932, found 276.0931.
6.9 Hz, 3H), 7.07 (d, J = 7.0 Hz, 1H), 4.15 (s, 2H), 3.26 (t, J =
1-(4-Thiocyanatophenyl)piperidine (4g). Light yellow solid, 5.8 Hz, 2H), 3.03 (t, J = 5.7 Hz, 2H) ppm; 13C NMR (150 MHz,
1
mp 44–46 °C, 85% yield (28.0 mg); H NMR (600 MHz, CDCl3) CDCl3) δ 150.82, 133.44, 133.33, 131.67, 129.06, 128.77, 128.17,
δ 7.47–7.35 (m, 2H), 6.88 (d, J = 9.0 Hz, 2H), 3.29–3.20 (m, 4H), 126.89, 126.31, 126.21, 123.85, 122.20, 110.72, 110.40, 109.89,
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54.22, 50.65, 28.97 ppm; FT-IR ν 2925, 2155, 1582, 1483, 1135, 128.50, 113.50, 109.92, 102.49, 77.25, 77.04, 76.83, 67.74 ppm;
737 cm−1; HRMS (EI, m/z): M+ calculated for C17H13N3S2 FT-IR ν 2919, 2851, 2157, 1697, 1529, 1233, 1066, 877 cm−1
323.0551, found 323.0550.
HRMS (EI, m/z): M+ calculated for C16H12N2O4S 328.0518,
5-(4-Methoxy-2-thiocyanatophenyl)-10,11-dihydro-5H-dibenzo found 328.0518.
[b,f]azepine (4m). White solid, mp 153–155 °C, 78% yield 1-(4-Methoxy-2-nitrophenyl)piperidine (5a). Red liquid, 85%
;
(42.0 mg); 1H NMR (600 MHz, CDCl3) δ 7.50 (d, J = 8.7 Hz, 1H), yield (30.0 mg); 1H NMR (600 MHz, CDCl3) δ 7.26 (d, J = 1.1
7.35–7.21 (m, 3H), 7.17–7.04 (m, 3H), 7.03–6.86 (m, 2H), 6.62 Hz, 1H), 7.13 (d, J = 9.0 Hz, 1H), 7.04 (dd, J = 9.0, 3.0 Hz, 1H),
(dd, J = 8.3, 0.8 Hz, 1H), 6.55 (d, J = 8.9 Hz, 1H), 3.93 (s, 3H), 3.81 (s, 3H), 2.94–2.89 (m, 4H), 1.73–1.65 (m, 4H), 1.57–1.53
3.32–3.15 (m, 4H) ppm; 13C NMR (150 MHz, CDCl3) δ 159.99, (m, 2H) ppm; 13C NMR (150 MHz, CDCl3) δ 154.38, 144.60,
146.13, 143.39, 134.84, 134.47, 134.37, 134.29, 133.28, 130.21, 141.18, 123.09, 120.09, 109.36, 55.87, 54.02, 26.22, 24.05 ppm;
129.85, 128.43, 126.78, 122.99, 122.08, 121.35, 116.12, 113.66, FT-IR ν 2936, 1529, 1301, 1225, 1043, 802 cm−1; HRMS (EI,
111.31, 109.65, 55.95, 36.87, 35.12 ppm; FT-IR ν 2923, 2154, m/z): M+ calculated for C12H16N2O3 236.1161, found 236.1163.
1497, 1234, 1047, 755, 731 cm−1; HRMS (EI, m/z): M+ calcu-
8-(4-Methoxy-2-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane
lated for C22H18N2OS 358.1140, found 358.1139.
(5b). Yellow solid, mp 107–109 °C, 93% yield (41.0 mg);
5-(2-Methyl-4,6-dithiocyanatophenyl)-10,11-dihydro-5H-dibenzo 1H NMR (600 MHz, CDCl3) δ 7.29–7.26 (m, 1H), 7.19 (d, J =
[b,f]azepine (4na). White solid, mp 141–143 °C, 71% yield 9.0 Hz, 1H), 7.05 (dd, J = 9.0, 3.0 Hz, 1H), 3.99 (s, 4H), 3.81 (s,
(43.0 mg); 1H NMR (600 MHz, CDCl3) δ 7.54–7.33 (m, 3H), 7.29 3H), 3.12–2.98 (m, 4H), 1.92–1.79 (m, 4H) ppm; 13C NMR
(s, 2H), 7.21 (d, J = 6.5 Hz, 1H), 7.07 (d, J = 8.2 Hz, 2H), 6.44 (d, (150 MHz, CDCl3) δ 154.99, 145.17, 140.17, 123.50, 119.97,
J = 8.8 Hz, 2H), 3.20 (s, 4H), 2.01 (s, 3H) ppm; 13C NMR 109.40, 106.79, 64.31, 55.88, 51.18, 35.35 ppm; FT-IR ν 2962,
(150 MHz, CDCl3) δ 145.93, 144.15, 137.04, 133.71, 133.58, 1528, 1266, 1107, 1040, 734, 703 cm−1; HRMS (EI, m/z): M+ cal-
132.84, 130.93, 130.05, 128.66, 128.54, 122.60, 113.07, 111.38, culated for C14H18N2O5 294.1216, found 294.1219.
37.11, 17.52 ppm; FT-IR ν 2923, 2856, 2152, 2104, 1578, 1474,
1297, 812 cm−1; HRMS (ESI, m/z): [M + Na]+ calculated for phenyl)piperidine (5c). Orange solid, mp 167–168 °C, 81%
C23H17N3NaS2 422.0762, found 422.0776.
yield (52.0 mg); 1H NMR (600 MHz, CDCl3) δ 7.37–7.30 (m,
4-(5H-Dibenzo[a,d][7]annulen-5-ylidene)-1-(4-methoxy-2-nitro-
5-(4-Thiocyanatophenyl)-10,11-dihydro-5H-dibenzo[b,f]azepine 4H), 7.26–7.24 (m, 3H), 7.24–7.20 (m, 2H), 7.06 (d, J = 9.0 Hz,
(4o). White solid, mp 175–176 °C, 83% yield (41.0 mg); 1H), 7.01 (dd, J = 9.0, 2.9 Hz, 1H), 6.93 (s, 2H), 3.79 (s, 3H),
1H NMR (600 MHz, CDCl3) δ 7.35 (dd, J = 7.3, 1.4 Hz, 2H), 3.05–2.99 (m, 2H), 2.71–2.64 (m, 2H), 2.49 (ddd, J = 13.6, 9.5,
7.31–7.19 (m, 8H), 6.65–6.52 (m, 2H), 2.98 (s, 4H) ppm; 4.1 Hz, 2H), 2.32–2.26 (m, 2H) ppm; 13C NMR (150 MHz,
13C NMR (150 MHz, CDCl3) δ 150.83, 142.45, 137.89, 134.15, CDCl3) δ 138.98, 134.75, 130.99, 128.49, 128.21, 127.82, 126.33,
131.18, 129.36, 127.75, 127.38, 113.97, 112.34, 108.55, 123.29, 120.02, 109.40, 55.87, 54.46, 30.51 ppm; FT-IR ν 2926,
30.60 ppm; FT-IR ν 2927, 2155, 1592, 1501, 1247, 803 cm−1
HRMS (EI, m/z): M+ calculated for C21H16N2S 328.1034, found lated for C27H24N2O3 424.1787, found 424.1786.
328.1038. 5-(4-Methoxy-2-nitrophenyl)-10,11-dihydro-5H-dibenzo[b,f]
;
1528, 1362, 1221, 1092, 802 cm−1; HRMS (EI, m/z): M+ calcu-
1-(4-Methoxyphenyl)-6-thiocyanato-1,2,3,4-tetrahydroquinoline azepine (5m). Brown solid, mp 136–137 °C, 84% yield
1
(4u). White solid, mp 89–91 °C, 71% yield (32.0 mg); H NMR (44.0 mg); 1H NMR (600 MHz, CDCl3) δ 7.33 (d, J = 9.2 Hz, 1H),
(600 MHz, CDCl3) δ 7.20 (d, J = 1.3 Hz, 1H), 7.16–7.10 (m, 2H), 7.18 (dd, J = 8.5, 2.5 Hz, 3H), 7.12–6.99 (m, 7H), 3.82 (s, 3H),
7.04 (dd, J = 8.7, 2.2 Hz, 1H), 6.97–6.91 (m, 2H), 6.36 (d, J = 3.19 (s, 4H) ppm; 13C NMR (150 MHz, CDCl3) δ 153.61, 144.28,
8.7 Hz, 1H), 3.83 (s, 3H), 3.65–3.53 (m, 2H), 2.85 (t, J = 6.3 Hz, 141.57, 136.56, 133.94, 130.69, 126.58, 125.34, 124.85, 124.75,
2H), 2.06 (dt, J = 12.5, 6.2 Hz, 2H) ppm; 13C NMR (150 MHz, 120.23, 109.79, 55.99, 32.47 ppm; FT-IR ν 2924, 1527, 1487,
CDCl3) δ 157.68, 147.71, 139.57, 134.05, 131.86, 128.15, 124.09, 1264, 1037, 758 cm−1
;
HRMS (EI, m/z): M+ Calcd for
115.20, 114.79, 112.67, 106.85, 55.48, 51.68, 27.75, 21.84 ppm; C21H18N2O3 346.1317, found 346.1317.
HRMS (ESI, m/z): [M + Na]+ calculated for C17H16N2NaOS
319.0876, found 319.0863.
1-(4-Methoxy-2-(phenylsulfonyl)phenyl)piperidine(7a). White
solid; mp 111–112 °C; 76% yield (38.0 mg); 1H NMR (600 MHz,
Benzyl(4-thiocyanatophenyl)carbamate (4p). White solid, CDCl3) δ 7.87 (d, J = 7.7 Hz, 2H), 7.81 (d, J = 3.0 Hz, 1H), 7.52
1
mp 83–85 °C, 43% yield (18.0 mg); H NMR (600 MHz, CDCl3) (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.21 (d, J = 8.7 Hz,
δ 7.53–7.46 (m, 4H), 7.43–7.34 (m, 5H), 6.81 (s, 1H), 5.22 (s, 1H), 7.11 (dd, J = 8.7, 3.0 Hz, 1H), 3.88 (s, 3H), 2.69–2.43 (m,
2H) ppm; 13C NMR (150 MHz, CDCl3) δ 152.88, 139.77, 135.58, 4H), 1.55–1.33 (m, 6H) ppm; 13C NMR (150 MHz, CDCl3)
132.46, 128.72, 128.61, 128.44, 119.82, 117.19, 111.05, δ 156.57, 146.90, 142.71, 137.73, 132.27, 128.21, 127.43,
67.48 ppm; FT-IR ν 2920, 2851, 2152, 1713, 1590, 1220, 1043, 125.63, 121.31, 113.81, 55.90, 54.84, 25.60, 23.87 ppm; FT-IR
811, 689 cm−1; HRMS (EI, m/z): M+ calculated for C15H12N2O2S ν 2928, 2145, 1515, 1311, 1114, 876 cm−1; HRMS (ESI, m/z):
284.0619, found 284.0616.
Benzyl(6-thiocyanatobenzo[d][1,3]dioxol-5-yl)carbamate (4q).
[M + H]+ calculated for C18H22NO3S 332.1320, found 332.1316.
1-(4-Methoxy-2-(methylsulfonyl)phenyl)piperidine (8a).
White solid, mp above 250 °C, 91% yield (45.0 mg); H NMR Light orange solid, mp 99–101 °C, 73% yield (29.0 mg); 1H
(600 MHz, CDCl3) δ 7.62 (s, 1H), 7.52–7.32 (m, 5H), 7.15 (s, NMR (600 MHz, CDCl3) δ 7.56 (d, J = 3.0 Hz, 1H), 7.31 (d, J =
1H), 7.06 (s, 1H), 6.03 (s, 2H), 5.23 (s, 2H) ppm; 13C NMR 8.8 Hz, 1H), 7.11 (dd, J = 8.7, 3.0 Hz, 1H), 3.83 (s, 3H), 3.37 (s,
(150 MHz, CDCl3) δ 153.23, 151.50, 135.48, 128.71, 128.61, 3H), 3.24–2.89 (bs, 2H), 2.88–2.47 (bs, 2H), 1.96–1.52 (m, 6H)
1
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ppm; 13C NMR (150 MHz, CDCl3) δ 156.64, 146.46, 137.76, 737 cm−1; HRMS (EI, m/z): M+ calculated for C27H24N4O
125.24, 121.02, 112.99, 55.85, 55.29, 42.73, 26.44, 23.99 ppm; 420.1950, found 420.1953.
FT-IR ν 2936, 2800, 1492, 1294, 1137, 1018, 758 cm−1; HRMS
4-(2-Azido-4-methoxyphenyl)morpholine (6d). Brown liquid,
1
(EI, m/z): M+ calculated for C13H19NO3S 269.1086, found 72% yield (25.0 mg); H NMR (600 MHz, CDCl3) δ 6.97 (d, J =
269.1090. 8.7 Hz, 1H), 6.66 (dd, J = 8.7, 2.8 Hz, 1H), 6.62 (d, J = 2.8 Hz,
1-(4-Methoxy-2-(phenylthio)phenyl)piperidine (9a). Brown 1H), 3.89–3.84 (m, 4H), 3.78 (s, 3H), 2.95 (dd, J = 5.4, 3.8 Hz,
viscous liquid, 69% yield (31.0 mg); 1H NMR (600 MHz, CDCl3) 4H) ppm; 13C NMR (150 MHz, CDCl3) δ 156.45, 137.94, 134.37,
δ 7.55–7.46 (m, 2H), 7.40–7.31 (m, 3H), 7.00 (d, J = 8.6 Hz, 1H), 120.91, 110.41, 106.30, 66.90, 55.57, 52.43 ppm; FT-IR ν 2959,
6.63 (dd, J = 8.6, 2.9 Hz, 1H), 6.31 (d, J = 2.9 Hz, 1H), 3.60 (s, 2110, 1504, 1219, 1115, 1035, 735 cm−1; HRMS (EI, m/z): M+
3H), 2.96–2.81 (bs, 4H), 1.71 (dt, J = 11.1, 5.6 Hz, 4H), 1.54 (d, calculated for C11H14N4O2 234.1117, found 234.1120.
J = 5.1 Hz, 2H) ppm; 13C NMR (150 MHz, CDCl3) δ 156.18,
Late-stage azidation of brucine
144.51, 136.70, 134.53, 133.28, 129.37, 128.21, 120.72, 113.30,
110.50, 55.29, 53.90, 26.52, 24.28 ppm; FT-IR ν 2930, 2851, Brucine 1r (0.1 g, 0.254 mmol) and NaN3 (0.033 g,
1611, 1482, 1209, 1044, 749 cm−1; HRMS (EI, m/z): M+ calcu- 0.508 mmol) were dissolved in 3 mL of nitromethane and PIFA
lated for C18H21NOS 299.1344, found 299.1344.
(0.218 g, 0.508 mmol) was cautiously added portionwise to the
reaction mixture, and then the solution was stirred at rt for 10
to 30 min, monitored by TLC. Then, the reaction mixture was
diluted with water (3 mL) and extracted with chloroform (3 ×
General procedure for azidation
Cyclic amine (0.15 mmol, 1.0 equiv.) and NaN3 (0.3 mmol, 2.0 15 mL). The organic layer was washed with 10 mL saturated
equiv.) were dissolved in 1 mL of nitromethane and PIFA solution of NaHCO3 and 5 mL brine solution, dried over
(0.3 mmol, 2.0 equiv.) was cautiously added portionwise to the Na2SO4 and concentrated in vacuo. The residue was purified by
reaction mixture, and then the solution was stirred at room column chromatography (MeOH/CH2Cl2, 1 : 20) to afford the
temperature for 30 min to 8 h, monitored by TLC. Then, the desired product 6r as a light brown solid; mp above 250 °C;
1
reaction mixture was diluted with water and extracted with 79% yield (87.4 mg); H NMR (600 MHz, CDCl3) δ 7.69 (s, 1H),
ethyl acetate. The organic layer was washed with 10 mL satu- 5.91 (s, 1H), 4.76 (s, 1H), 4.28 (d, J = 8.4 Hz, 1H), 4.14 (dd, J =
rated solution of NaHCO3 and 5 mL brine, dried over Na2SO4 13.8, 7.0 Hz, 1H), 4.06 (dd, J = 13.7, 6.0 Hz, 1H), 3.88 (s, 3H),
and concentrated in vacuo. The residue was purified by 3.86 (s, 3H), 3.73 (dd, J = 23.7, 12.6 Hz, 2H), 3.20 (dd, J = 9.4,
column chromatography (hexane/EtOAc, 20 : 1) to afford the 8.1 Hz, 1H), 3.16–3.06 (m, 2H), 2.88–2.70 (m, 2H), 2.62 (dd, J =
corresponding products.
17.4, 3.3 Hz, 1H), 2.43–2.26 (m, 2H), 1.66 (dd, J = 12.5, 5.9 Hz,
1-(2-Azido-4-methoxyphenyl)piperidine (6a). Brown liquid, 1H), 1.48 (d, J = 14.5 Hz, 1H), 1.31–1.28 (m, 1H) ppm; 13C NMR
1
78% yield (27.0 mg); H NMR (600 MHz, CDCl3) δ 6.98 (d, J = (150 MHz, CDCl3) δ 169.14, 153.33, 139.90, 138.90, 129.42,
8.8 Hz, 1H), 6.63 (dd, J = 8.8, 2.8 Hz, 1H), 6.59 (d, J = 2.8 Hz, 127.86, 114.00, 97.76, 77.55, 64.61, 61.77, 60.48, 56.34, 56.18,
1H), 3.77 (s, 3H), 2.89–2.83 (m, 4H), 1.74 (dt, J = 11.2, 5.7 Hz, 52.67,
52.32,
49.24,
48.41,
42.40,
38.58,
31.21,
4H), 1.57–1.51 (m, 2H) ppm; 13C NMR (150 MHz, CDCl3) 26.86 ppm; FT-IR ν 2907, 2104, 1660, 1397, 1045, 837 cm−1
;
δ 156.03, 139.79, 134.47, 121.17, 110.31, 106.15, 55.55, 53.76, HRMS (ESI, m/z): [M + H]+ calculated for C23H26N5O4 436.1985,
25.93, 24.17 ppm; FT-IR ν 2936, 2109, 1503, 1442, 1225, found 436.1978.
1045 cm−1; HRMS (EI, m/z): M+ calculated for C12H16N4O
232.1324, found 232.1328.
Thiocyanation of julolidine
8-(2-Azido-4-methoxyphenyl)-1,4-dioxa-8-azaspiro[4.5]decane Julolidine 1s (20.8 mg, 0.12 mmol) and NaSCN (19.4 mg,
(6b). Brown liquid, 76% yield (33.0 mg); 1H NMR (600 MHz, 0.24 mmol) were dissolved in a 1.0 mL mixture of nitro-
CDCl3) δ 7.02 (d, J = 8.7 Hz, 1H), 6.63 (dd, J = 8.7, 2.8 Hz, 1H), methane and water (9 : 1) and PIFA (103.2 mg, 0.24 mmol) was
6.60 (d, J = 2.8 Hz, 1H), 4.00 (s, 4H), 3.77 (s, 3H), 3.09–2.94 (m, cautiously added portionwise to the reaction mixture, and
4H), 1.97–1.82 (m, 4H) ppm; 13C NMR (150 MHz, CDCl3) then the solution was stirred at rt for 10 to 30 min, monitored
δ 156.30, 138.51, 134.45, 121.43, 110.31, 106.89, 106.16, 64.30, by TLC. Then, the reaction mixture was diluted with water
55.55, 50.60, 34.96 ppm; FT-IR ν 2957, 2109, 1504, 1214, 1109, (3 mL) and extracted with ethyl acetate (3 × 10 mL). The
1041, 735 cm−1; HRMS (EI, m/z): M+ calculated for C14H18N4O3 organic layer was washed with 10 mL saturated solution of
290.1379, found 290.1384.
NaHCO3 and 5 mL brine solution, dried over Na2SO4 and con-
1-(2-Azido-4-methoxyphenyl)-4-(5H-dibenzo[a,d][7]annulen-5- centrated in vacuo. The residue was purified by column chrom-
ylidene)piperidine (6c). Brown viscous liquid, 68% yield atography (hexane/EtOAc, 20 : 1) to afford the desired product
(43.0 mg); 1H NMR (600 MHz, CDCl3) δ 7.40–7.33 (m, 4H), 4s as a white solid; mp 99–100 °C; 71% yield (20.0 mg); 1H
7.28–7.23 (m, 4H), 6.96 (s, 2H), 6.92 (d, J = 8.7 Hz, 1H), NMR (600 MHz, acetone-d6) δ 6.99 (s, 2H), 3.28–3.18 (m, 4H),
6.65–6.57 (m, 2H), 3.78 (s, 3H), 3.07–3.00 (m, 2H), 2.68–2.60 2.71 (t, J = 6.4 Hz, 4H), 1.96–1.86 (m, 4H) ppm; 13C NMR
(m, 2H), 2.55 (ddd, J = 13.4, 9.4, 4.0 Hz, 2H), 2.37–2.31 (m, 2H) (150 MHz, acetone) δ 145.55, 132.65, 123.76, 113.02, 104.87,
ppm; 13C NMR (150 MHz, CDCl3) δ 156.20, 139.08, 134.80, 50.23, 28.17, 22.00 ppm; FT-IR ν 2849, 2145, 1516, 1313, 1202,
131.00, 128.53, 128.20, 127.78, 126.29, 121.35, 110.30, 106.20, 875 cm−1; HRMS (ESI, m/z): [M + H]+ calculated for C13H15N2S
55.54, 54.21, 30.16 ppm; FT-IR ν 2937, 2108, 1504, 1221, 1044, 231.0956, found 231.0950.
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1
mmol scale synthesis of 4h. To a dried round-bottom (150 MHz, CD3OD) δ 157.80, 153.18, 135.08, 120.68, 117.29,
flask were added 4-phenylmorpholine 1h (163.2 mg, 67.82, 49.84 ppm; FT-IR ν 2838, 1500, 1235, 1116, 923,
1.0 mmol) and NaSCN (162.1 mg, 2.0 mmol) and they were dis- 817 cm−1 HRMS (ESI, m/z): [M + H]+ calculated for C11H14N5OS
solved in a 6.0 mL mixture of nitromethane and water (9 : 1). 264.0919, found 264.0913.
[Bis(trifluoroacetoxy)iodo]benzene (PIFA) (860.0 mg, 2.0 mmol)
4-(2,4-Bis((1H-tetrazol-5-yl)thio)phenyl)morpholine (10ha).
1
was cautiously added portionwise to the reaction mixture at White solid, mp above 250 °C, 63% yield (23.0 mg); H NMR
0 °C and then the solution was stirred at rt for 10 to 30 min, (600 MHz, CD3OD) δ 7.13–7.02 (m, 2H), 6.70 (s, 1H), 3.86–3.72
monitored by TLC. Then, the reaction mixture was diluted (m, 4H), 3.04–2.92 (m, 4H) ppm; 13C NMR (150 MHz, CD3OD)
with water (3 mL) and extracted with ethyl acetate (3 × 15 mL). δ 156.68, 154.99, 150.09, 134.86, 131.09, 130.52, 130.21,
The organic layer was washed with 10 mL saturated solution of 122.35, 68.27, 53.20 ppm; FT-IR ν 2971, 1501, 1236, 1112, 930,
NaHCO3 and 5 mL brine solution, dried over Na2SO4 and con- 818 cm−1
centrated in vacuo. The residue was purified by column chrom- C12H14N9OS2 364.0763, found 364.0760.
atography (hexane/EtOAc, 20 : 1) to afford the desired product Tris(4-bromo-2-chlorophenyl)amine (2taa). 1t (0.03 mmol,
; HRMS (ESI, m/z): [M +
H]+ calculated for
4-(4-thiocyanatophenyl)morpholine 4h as a white solid, mp 1.0 equiv.) and NaCl (0.06 mmol, 2.0 equiv.) were dissolved in
1
90–92 °C, 81% yield (178.4 mg); H NMR (600 MHz, CDCl3) δ a 1 mL mixture of nitromethane and water (9 : 1) and PIFA
7.50–7.40 (m, 2H), 6.89 (dd, J = 9.6, 2.5 Hz, 2H), 3.93–3.79 (m, (0.06 mmol, 2.0 equiv.) was cautiously added portionwise to
4H), 3.24–3.15 (m, 4H) ppm; 13C NMR (150 MHz, CDCl3) δ the reaction mixture, and then the solution was stirred at rt for
152.51, 133.72, 116.15, 111.90, 111.15, 66.54, 48.04 ppm; FT-IR 1 h, monitored by TLC. Then, the reaction mixture was diluted
ν 2960, 2155, 1494, 1204, 1115, 737 cm−1; HRMS (EI, m/z): M+ with chloroform, dried over Na2SO4 and concentrated in vacuo.
calculated for C11H12N2OS 220.0670, found 220.0674, and di- The residue was purified by column chromatography with
SCN product 4-(2,4-dithiocyanatophenyl)morpholine 4ha as a hexane only to afford the corresponding product 2taa as a
1
light yellow solid; mp 82–83 °C; 7% yield (19.4 mg); H NMR white solid; mp 56–58 °C; 51% yield (9.0 mg); 1H NMR
(600 MHz, CDCl3) δ 7.76 (d, J = 2.1 Hz, 1H), 7.58 (dd, J = 8.3, (600 MHz, CDCl3) δ 7.55 (d, J = 2.2 Hz, 3H), 7.31–7.28 (m, 3H),
2.1 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 3.94–3.75 (m, 4H), 6.74 (d, J = 8.6 Hz, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ
3.01–2.87 (m, 4H) ppm; 13C NMR (150 MHz, CDCl3) δ 150.38, 142.55, 133.94, 131.40, 130.74, 127.51, 118.18 ppm; FT-IR ν
131.68, 128.71, 127.94, 123.69, 122.67, 110.10, 109.76, 66.88, 2919, 2850, 1469, 1299, 1084, 813, 705 cm−1; HRMS (ESI, m/z):
52.33 ppm; FT-IR ν 2851, 2163, 2145, 1586, 1314, 1113, [M
876 cm−1 H]+ calculated for 583.7405.
HRMS (ESI, m/z): [M
+
H]+ calculated for C18H10Br3Cl3N 583.7403, found
;
+
C12H12N3OS2 278.0422, found 278.0418.
Tetrazole formation18
Conflicts of interest
A dried round-bottom flask was charged with a solution of 4h
(1.0 equiv.) in isopropyl alcohol (3 mL). Then, NaN3 (1.2 equiv.)
and ZnCl2 (1.0 equiv.) were added to the reaction mixture.
There are no conflicts to declare.
Di-tetrazole formation
Acknowledgements
A dried round-bottom flask was charged with a solution of 4ha
(1.0 equiv.) in isopropyl alcohol (3 mL). Then, NaN3 (2.4 equiv.)
and ZnCl2 (2.0 equiv.) were added to the reaction mixture.
The reaction mixture was then continuously stirred at 50 °C
for 1.5 to 3 h until 4h or 4ha was completely consumed (TLC).
After completion of the reaction, the solvent was evaporated
from the reaction mixture under reduced pressure. Afterward,
a solution of 5% NaOH (10 mL) was added to the mixture and
it was stirred for 20 min at rt. The suspension of Zn(OH)2 was
filtered and washed with 5% NaOH (10 ml). Next, the pH of
the combined filtrate was adjusted to 1.0 with con. HCl, but
precipitation did not occur. Afterward, the filtrate was
extracted with ethyl acetate (3 × 15 mL), dried over Na2SO4 and
concentrated in vacuo. The residue was purified by column
chromatography (MeOH/CH2Cl2, 1 : 4) to afford the desired
products.
This study was supported by the Basic Science Research
Program of the National Research Foundation of Korea (NRF)
funded by the Ministry of Education, Science, and Technology
(No. 2017R1E1A1A01076642). It was also supported by the
Gachon University Research fund of 2019 (GCU-2019-
0328). C. M. would like to thank the CSIR, India.
Notes and references
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