Asymmetric aminoarylation for the synthesis of trans-3-amino-4-aryltetrahydroquinolines: An access to aza-analogue of dihydrexidine

Article abstract of DOI:10.1016/j.tet.2021.132257

A proficient stereoselective aminoarylation reaction of N-cinnamylanilines, based on a two-step protocol of catalytic enantioselective aziridination and subsequent 6-endo-tet Friedel-Crafts cyclization, has been developed and demonstrated. A pair of chiral bis-oxazoline ligand and Cu(OTf)₂ offered an effective combination in the synthesis of trans-3-amino-4-aryltetrahydroquinolines with excellent diastereo- and enantioselectivity (dr: >99: 1 and ee up to 97%). In continuation, a trans-3-amino-4-aryltetrahydroquinoline, availed in one-pot stereoselective aminoarylation reaction, was extended toward a concise synthesis of aza-analogue of dihydrexdine, a potent and selective full dopamine-D1 agonist.

Full text of DOI:10.1016/j.tet.2021.132257

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric aminoarylation for the synthesis of trans-3-amino-4-
aryltetrahydroquinolines: An access to aza-analogue of dihydrexidine
,
b
,
2
,
,
3
,
, *
Sk Md Samim Akhtar a
1, Sukanta Bar b 1, Saumen Hajra a
a Centre of Biomedical Research, Sanjay Gandhi Post Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, 226014, India
b Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur, 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A proficient stereoselective aminoarylation reaction of N-cinnamylanilines, based on a two-step protocol
of catalytic enantioselective aziridination and subsequent 6-endo-tet Friedel-Crafts cyclization, has been
developed and demonstrated. A pair of chiral bis-oxazoline ligand and Cu(OTf)2 offered an effective
combination in the synthesis of trans-3-amino-4-aryltetrahydroquinolines with excellent diastereo- and
Received 1 April 2021
Received in revised form
18 May 2021
Accepted 21 May 2021
Available online xxx
enantioselectivity (dr: >99:
1
and ee up to 97%). In continuation,
a
trans-3-amino-4-
aryltetrahydroquinoline, availed in one-pot stereoselective aminoarylation reaction, was extended to-
ward a concise synthesis of aza-analogue of dihydrexdine, a potent and selective full dopamine-D1
agonist.
Keywords:
Tetrahydroquinoline
Asymmetric reaction
Aminoarylation
Aziridine
© 2021 Elsevier Ltd. All rights reserved.
Friedel-crafts reaction
1. Introduction
aryltetrahydroquinolines based compounds C and D are potent
liver-receptors agonists and with antichagasic activities, respec-
Constructing the core of a wide range of biologically significant
small organic molecules, nitrogen-containing heterocycles received
major attention. This is largely because of their detailed history of
being in the center of several medicinal pharmacophores. Among
them, tetrahydroquinolines represent a class of privileged hetero-
cycles owing to their abundance of natural products and rich bio-
logical background [1e5]. Chiral 1, 2, 3, 4-tetrahydroquinolines,
tively [5]. Further, 3-amino-4-aryltetrahydroquinoline E may
emerge with dopaminergic property in the form of aza-analogue of
dihydrexidine and doxanthrine, the two selective dopamine D1
agonists and potential drug candidates for the treatment of Par-
kinson's disease [6,7]. Thus, extensive research efforts were made
in the synthesis of substituted tetrahydro quinolines [1,8,9], but the
asymmetric synthesis of 3-aminotetrahydroquinolines are still
sparse in the literature [9].
particularly,
3-aminotetrahydroquinolines
[3,4]
and
4-
aryltetrahydroquinolines [5] feature in numerous pharmacolog-
ical agents and natural products such as compounds A-D (Fig. 1).
PNU 95666 E (A) is a selective dopamine D2 agonist and a potential
molecule to treat Parkinson's disease; anachellin H chromophore B
is a microbial agent isolated from the cyanobacterium Anabaena
cylindrica and with moderate antibiotic activity. In addition, 4-
We envisioned that stereoselective intramolecular Friedel-
Crafts cyclization of the in situ generated tethered chiral aziridine
2 derived from N-cinnamylanilines 1 would be routed to 3-amino-
4-aryltetrahydroquinolines
3 (Scheme 1). Herein, we report
asymmetric aminoarylation reactions of olefins 1, having a pendant
aryl unit, toward a catalytic and asymmetric synthesis of trans-3-
amino-4-aryltetrahydroquinolines with high diastereo- (>99:1)
and enantioselectivity (up to 97% ee) and the application in the
asymmetric synthesis of aza-analogue of dihydrexidine derivative.
* Corresponding author.
E-mail
addresses:
saumen.hajra@cbmr.res.in,
saumen.hajra@gmail.com
(S. Hajra).
2. Results and discussion
1
S. M. S. A. and S. B. contributed equally.
Present Address: Department of Chemistry, Bidhan Chandra College, Asansol -
713304, India.
2
Stereoselective aziridination [10] of alkenes has extensively
been studied and well-explored in our laboratory in the recent past
[11]. PhINNs in combination with Cu(OTf)2 offered the best choice
3
Present Address: Department of Structural Biology, St. Jude Children's Research
Hospital, Memphis, TN, 38105, USA.
https://doi.org/10.1016/j.tet.2021.132257
0040-4020/© 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: S.M.S. Akhtar, S. Bar and S. Hajra, Asymmetric aminoarylation for the synthesis of trans-3-amino-4-
aryltetrahydroquinolines: An access to aza-analogue of dihydrexidine, Tetrahedron, https://doi.org/10.1016/j.tet.2021.132257

S.M.S. Akhtar, S. Bar and S. Hajra
Tetrahedron xxx (xxxx) xxx
intractable reaction mixture. Accordingly, N-protected-N-cinna-
mylanilines 1b and 1c were employed under the same reaction
conditions that brought in some encouraging results (Scheme 2).
The reaction of 1b with PhINNs in the presence of Cu(OTf)2 at rt
(25 ꢀC) was slow (no noticeable reaction till 24 h). So, we performed
the reaction at elevated temperature (35 ꢀC) and observed the full
consumption of nitrenoid reagent after 24 h forming the aziridine
( )-2b (confirmed by 1H NMR of the crude reaction mixture). The
reaction mixture was then subjected to supplementary Cu(OTf)2
aiming toward a one-pot Friedel-Crafts cyclization, but even after
24 h, it was unsuccessful. The aziridine ( )-2b was isolated by
column chromatography and detailed spectral analysis confirmed it
as pure trans-aziridine ( )-2b. When the aziridine ( )-2b was
treated with 0.1 equiv. of Cu(OTf)2 in CH2Cl2 at rt in the presence of
molecular sieves (MS 4 Å), it exclusively transformed into the trans-
cyclized product ( )-3b (dr > 99:1) within 1 h (Scheme 2). Next, we
implemented a useful protocol within the course of the reaction
where we skipped the aziridine isolation step. We filtered the re-
action mixture through a short plug of silica gel and then proceed
with the semi-crude reaction mixture for Friedel-Crafts cyclization
with additional Cu(OTf)2. Such an alteration was found to fit well in
this reaction and hence adopted. Mesyl protected substrate 1c did
not appreciably improve the result but experienced a very similar
outcome, providing the cyclized product ( )-3c via the protocol of
aziridination and Friedel-Crafts cyclization (Scheme 2).
Fig. 1. Representative 3-amino- and 4-aryl-tetrahydroquinoline containing bioactive
molecules.
All acyl (RCO-) protecting groups [acetyl (Ac), benzoyl (Bz),
pivaloyl (Piv), 4-nitrobenzoyl (NBz)] containing N-cinnamylanilines
were found unsuitable for aziridination reaction under the devel-
oped conditions. We continued to investigate the scope of this
catalytic method for the synthesis of N-protected tetrahy-
droaminoquinoline derivatives ( )-3 under the optimized reaction
condition with a panel of N-tosyl and N-mesyl-protected N-cinna-
mylanilines 1d-1m, containing both electron-donating and -with-
drawing groups attached to either of the arene rings (Scheme 3). In
our earlier studies, the aryl group on the aziridine was found to be
mandatory for the cyclization, where an alkyl substituent on azir-
idine could not accomplish to a similar intramolecular cyclization
under such reaction conditions [11c,11g]. Thus herein we focused
only on aryl-substituted alkene substrates 1. Mesyl protected sub-
strate 1d, having a para-methoxy substituent provided an insepa-
rable mixture of products after 16 h at 35 ꢀC. Another mesyl-
protected substrate 1e, having para-chloro and para-fluoro groups
at either end, did not respond in aziridination reaction and the
Scheme 1. Proposed reaction for the synthesis of aminotetrahydroquinolines.
as a precursor of nitrene to transfer it to the double bond and dually
functioning Cu(OTf)2 served as an effective catalyst for the Friedel-
Crafts reaction too. Hence, the pair was used in the reaction of N-
cinnamylaniline 1 under the well-established condition i.e. the re-
action with PhINNs in the presence of Cu(OTf)2 catalyst and mo-
lecular sieves (MS 4 Å) in CH2Cl2. Since substrates with
exchangeable proton are not suitable for such reaction, the N-
protection was expected to be obligatory for this purpose. We also
found that the reaction of 1a, having a bare eNH, led to an
nitenoid reagent decomposed to NsNH2.
A similar reaction
outcome was noticed for the substrate 1f. However, para-methoxy
and para-fluoro-containing substrate 1g stood well in
aziridination-cyclization, and the corresponding cyclized product
( )-3g was isolated in 74% of yield. Similarly, substrates 1h and 1i,
in reaction with PhINNs and Cu(OTf)2 followed by Friedel-Crafts
cyclization, provided the products ( )-3h and ( )-3i in 78% and
70% of yields, respectively. All tosyl (Ts) protected substrates 1j, 1k,
1l, and 1m rendered better results under the standard protocol of
aminoarylation reaction, and among them, 4-methoxy containing
substrate 1l earned ( )-3l with a maximum yield of 82%. More
electron-donating N-cinnamyl-3,4-dimethoxyaniline 1m under-
went a direct cyclization of the in situ generated aziridine in one-
pot without any additional Cu(OTf)2 to provide the trans-cyclized
product ( )-3m in 71% yield.
The
fruitful
synthesis
of
( )-trans-3-amino-4-
aryltetrahydroquinolines ( )-3 via two-step aminoarylation reac-
tion prompted us to investigate the scope of its catalytic enantio-
selective version. Purposefully, the reaction was introduced to
chiral Box ligand chelated copper catalyst for chiral induction. The
in-depth study was set with the reaction of N-tosyl-N-cinnamyla-
niline 1b with PhINNs in the presence of Cu(OTf)2 and bis-oxazoline
Scheme 2. Screening of N-protecting group for the aminoarylation.
2

S.M.S. Akhtar, S. Bar and S. Hajra
Tetrahedron xxx (xxxx) xxx
Table 1
Optimization of catalytic asymmetric aminoarylation using Cu(OTf)2-BOX catalyst.
Entry
Ligand
Time (h)
Yield 3ba (%)
ee 3bb (%)
1
2
3
4
L1
L2
L3
L4
L5
L5
16
16
16
16
24
24
34
29
28
44
72
31
26c
29c
17c
57c
75
5
6d
54
a
Isolated yield of 3b after column chromatography.
Enantiomeric excess (ee) was determined by chiral HPLC using AD-H column.
The other enantiomer ent-3b was formed.
b
c
d
Dichloroethane (DCE) was used instead of CH2Cl2.
improvement of enantioselectivity was accomplished when the
Box ligand L5 derived from (1R, 2S)-indanol amine was used. In an
extended reaction time of 24 h, an enhanced yield (72%) and
enantioselectivity of trans-cyclized product 3b (75%) was achieved
(Table 1; entry 5).
Between the indenyl amine derived Box L5 and phenyl Box L4,
the former being more rigid (the oxazoline units held the phenyl
rings with an extra methylene bridge, which brings more rigidity
into the structure) offers more chiral-induction, which ultimately
manifested in higher ee. The reaction was initiated in a catalytic
enantioselective aziridination and the same selectivity was
retained through the next step, the stereospecific SN2 ring-opening
of aziridine. Our group has already reported such a relay of enan-
tioselectivity [11]. The absolute stereochemistry of trans-cyclized
product 3b was assigned by analogy with the literature and our
earlier works [10,11]. The two-step asymmetric aminoarylation
protocol was also studied in different solvents using indenyl Box
ligand L5. The reaction of 1b with PhINNs in CHCl3 provided traces
of the aziridine 2b, whereas there was a poor reaction or no reac-
tion in solvents like CH3CN, DME, and C6H6, rather complete
decomposition of PhINNs to NsNH2 was observed (not shown in
Table 1). Reaction in DCE provided the desired cyclized product 3b
in 31% of yield without any notable increase in ee (Table 1; entry 6).
We implemented this two-step catalytic asymmetric protocol
with some tosyl and mesyl protected N-cinnamylaniline derivatives
under the optimal reaction conditions (Scheme 4). Among all the
mesyl-protected N-cinnamylanilines, only 1h finished the reaction
and the cyclized product 3h was isolated in high yield (81%) with an
ee of 87%. The tosyl protected N-cinnamyl-4-chloroaniline 1j
reacted efficiently to afford the tetrahydroquinoline compound 3j,
which exhibited quite a high ee (89%), isolated in 83% yield. N-
Tosyl-N-cinnamyl-4-methylaniline 1k offered a satisfactory yield in
aziridination-cyclization (74%), yet ee of the corresponding ami-
notetrahydroquinoline 3k dropped to 73%. Substrate 1l, having an
electron-donating methoxy group went through a smooth aziridi-
nation and the end cyclized product 3l was obtained in a decent
yield (79%) with 90% of ee. More electron-rich substrate 1m con-
taining two methoxy groups underwent relatively faster reaction
Scheme 3. Cu(OTf)2-catalyzed synthesis of N-protected trans-3-amino-4-
aryltetrahydroquinolins ( )-3.
(Box) ligands L1-L5, mainly derived from
L
-amino alcohols
(Table 1). Aziridination with bis-oxazoline ligand L1, under the
optimum method, ended in 16 h that on further treatment with
Cu(OTf)2 afforded the trans-cyclized product 3b within 1 h in 34%
yield. HPLC analysis of 3b exhibited 26% ee. Maintaining the iden-
tical reaction conditions, we examined other Box ligands as well.
Box ligand L2 furnished almost a similar result to that of the ligand
L1 with a lower yield of 29% (Table 1; entries 1, 2). Enantiose-
lectivity of the cyclized product 3b was also found similar to that for
the ligand L1 (entry 2). The structural difference between L3 and L4
is the presence of benzylic methylenes (CH2) in L3, which distanced
the phenyl rings from the chiral centers. As a result, the enantio-
selectivity of product 3b reduced (entry 3). When L-phenylglycinol
derived Box ligand L4 was deployed, it earned an improved yield of
tetrahydroquinoline 3b (44%), and the enantioselectivity also
appreciably enhanced to 57% (Table 1; entry 4). Further
3

S.M.S. Akhtar, S. Bar and S. Hajra
Tetrahedron xxx (xxxx) xxx
Scheme 5. A proposed mechanism of asymmetric aminoarylation.
immediate precursor for the asymmetric synthesis of N-bioisostere
of dihydrexidine via Pictet-Spengler cyclization. Toward that, so-
dium salt of 3- amino-4-phenyltetrahydroquinoline 3m was treated
with MOMCl in CH2Cl2 at 0 ꢀC. The reaction was completed within
4 h and provided the N-MOM compound 4 in an excellent yield of
98% (Scheme 6). Having compound 4, we attempted the Pictet-
Spengler cyclization using TMSOTf and also with BF3eOEt2 in
CH2Cl2 at different temperatures and conditions [11d]. Unfortu-
nately, none of the conditions was successful to provide the desired
product but ended up with MOM-deprotected compound 3m as
the only product.
The above unsuccessful result led us to envision the synthesis of
3-amino-4-aryl-tetrahydroquinoline intermediate 3n, where late-
stage incorporation of an aldehyde group at the ortho-position
would be an alternate strategy. Accordingly, alkene 1n was sub-
jected to the optimized aminoarylation reaction conditions. To our
delight, the substrate 1n experienced a smooth reaction to produce
the trans-3-amino-4-aryl-tetrahydroquinoline 3n directly in 71%
yield with an excellent ee of 97% (Scheme 7). Such high enantio-
selectivity might be attributed due to the extra added bulk of ortho-
bromo-substituent to the substrate 1n. Our initial attempts of
Scheme 4. Asymmetric synthesis of trans-3-amino-4-aryltethrahydro-quinolines 3 via
two-step reactions.
and within 6 h at 35 ꢀC it provided the one-pot cyclized product 3m
without any additional Lewis acid in 67% of yield and satisfactory ee
of 82%.
Since aziridination is the first stereo-induction step, thus the
stereochemistry of the intermediate aziridine 2 is expected to
dictate the absolute configuration of the aminotetrahydroquino-
lines 3. The former is assigned based on the literature reports
[10,11] and accordingly,
a plausible mechanism is proposed
(Scheme 5). The chirality of Cu(OTf)2-L5 complex and the coordi-
nation of the nitrogen of the N-cinnamyl aniline 1b to the copper of
the catalyst orient the double bond towards the metal-nitrene for
preferential attack from the top as shown in the transition state
model TS1. This leads to the formation of 2b with a configuration of
(2R, 3R). In the second step, the nitrogen of the aziridine co-
ordinates to the Cu(OTf)2 catalyst activating the benzylic position of
the aziridine towards 6-endo-tet Friedel-Crafts cyclization via SN2
mechanism [11] and affords the 3-amino-4-phenyl tetrahy-
droquinoline 3b with trans-stereochemistry having (3S,4R)-
configuration.
After the successful development of the catalytic asymmetric
protocol
for
the
synthesis
of
trans-3-amino-4-
aryltetrahydroquinolines 3, we set our strategy to the synthesis of
N-bioisostere of dihydrexidine. 3-Amino-4-phenyl-tetrahy-
droquinoline 3m was synthesized considering it could be an
Scheme 6. Attempt toward Pictet-Spengler cyclization of 3m.
4

S.M.S. Akhtar, S. Bar and S. Hajra
Tetrahedron xxx (xxxx) xxx
Scheme 7. Catalytic asymmetric aminoarylation of 1n and formylation attempt.
bromine-lithium exchange followed by formylation with DMF us-
ing n-BuLi or t-BuLi or a combination of MeLi/t-BuLi on N-nosyl
compound 3n were not successful [12]. However, N-Boc substrate
8, which was obtained by two-step protocol from 3n, gave the
desired formylated product 9, but with poor yield (<10%), when the
combination of MeLi/t-BuLi and DMF was used (Scheme 7).
Screening of the several reaction conditions was failed to improve
the yield of the desired aldehyde 9.
Scheme 8. Asymmetric synthesis of N,O-protected aza-dihydrexidine.
in CH3CN at 45 ꢀC. The overnight reaction led to achieve the final
cyclization to furnish compound 11 in 91% yield over the last three
steps. Compound 11 is an advanced intermediate for the synthesis
of nitrogen bioisostere of dihydrexidine. Tosyl deprotection and
demethylation would complete the synthesis. However, our at-
tempts for the deprotection of the N-tosyl group were unsuccessful.
The above formylation results led us to opt for the Stille vinyl-
ation reaction followed by oxidative cleavage. For this. purpose,
compound 8 was treated with 1.5 equiv. of tributylvinyl tin in the
presence of 10 mol% of Pd(PPh3)4 catalyst and LiCl additive in DMF,
4 h heating at 80 ꢀC furnished the expected ortho-vinyl compound
10 (Scheme 8). The next was the oxidative cleavage of the vinyl unit
into the desired aldehyde compound 9. We followed the classical
OsO4eNaIO4 mediated oxidative cleavage reaction [13]. The reac-
tion in the presence of 2, 6-lutidine as an additive in 1:1 dioxane-
water at rt successfully converted the vinyl group in compound
10 into the requisite aldehyde functionality in 69% yield in two
steps. After the installation of the aldehyde group, the Boc-group
was deprotected on treatment with TFA at 0 ꢀC producing the in-
termediate imine and amino aldehyde mixture, as expected.
Further reduction of the crude mixture with NaBH3CN or NaB-
H(OAc)3 at 0 ꢀC was presumed to favor the selective imine reduc-
tion and hence to facilitate the imine-amino aldehyde equilibrium
towards imine reduced cyclized product 11. However, we ended up
with a mixture of 11 and amino alcohol 12. Changing the borohy-
dride proportion or temperature did not improve the result. In an
alternative route, the Boc-deprotection was postponed until the
requisite final cyclization and the compound 9 was subjected to
NaBH4 reduction at 0 ꢀC that readily transformed it into compound
13, which without further purification upon treatment with PBr3 in
the ethereal solution provided an intermediate compound having a
benzylic bromo-functionality. Detailed mass spectroscopy analysis
of the intermediate compound revealed that it did not have the Boc
component on it. We assumed that acidic medium created in
presence of PBr3 led to Boc-deprotection in this step. The crude
compound, after isolation used for the K2CO3-promoted cyclization
3. Conclusion
We have developed a two-step protocol for the efficient syn-
thesis of trans-3-amino-4-aryl tetrahydroquinolines with excellent
diastereo- and enantioselectivity (dr: >99: 1 and ee up to 97%). The
method is based on catalytic enantioselective aziridination and
subsequent 6-endo-tet Friedel-Crafts cyclization called amino-
arylation. It originates the enantioselectivity at the aziridination
step and carries forwarded to the cyclization. In application, a
synthesis of aza-analogue of dihydrexdine derivative is efficiently
accomplished from easily accessible 3-amino-4-aryl tetrahy-
droquiniline. Combination of several anilines and cinnamyl units
can enlist a wide variety of substrates and a subsequent asymmetric
aminoarylation can attain a pool of tetrahydroquinolines enriched
in diversity, which will be beneficial in medicinal and drug dis-
covery chemistry.
4. Experimental section
4.1. General methods
We conducted all reactions using oven-dried glassware under
Argon atmosphere. We used commercial grade reagents without
further purification. Solvents were dried and distilled following
standard protocols. Flash chromatography was carried out using
5

S.M.S. Akhtar, S. Bar and S. Hajra
Tetrahedron xxx (xxxx) xxx
silica gel (230e400 mesh). TLC was performed on aluminium-
backed plates coated with silica gel 60 with F254 indicator. The 1H
NMR and 13C NMR spectra were recorded with 400 MHz and
100 MHz using CDCl3. 1H NMR chemical shifts are expressed in
N-(4-chlorophenyl)-N-cinnamyl-4-methylbenzene-sulfonamide,
1j. Yield ¼ 88%; 1H NMR (CDCl3, 200 MHz):
7.52 (d, J ¼ 8.2 Hz, 2H),
d
7.29e7.22 (m, 9H), 7.02 (d, J ¼ 8.6 Hz, 2H), 6.40 (d, J ¼ 16.0 Hz, 1H),
6.13e6.02 (m, 1H), 4.30 (d, J ¼ 6.6 Hz, 2H), 2.43 (s, 3H).
parts per million (
d
) relative to CHCl3 (d ¼ 7.26); 13C NMR chemical
N-cinnamyl-4-methyl-N-(p-tolyl)benzenesulfonamide,
1k.
shifts are expressed in parts per million (
d) relative to the CDCl3
Yield ¼ 90%; 1H NMR (CDCl3, 200 MHz):
d
7.53 (d, J ¼ 8.0 Hz, 2H),
resonance (
d
¼ 77.0). High resolution mass spectra (HRMS) and
7.27e7.24 (m, 7H), 7.07 (d, J ¼ 8.2 Hz, 2H), 6.94 (d, J ¼ 8.2 Hz, 2H),
6.36 (d, J ¼ 15.8 Hz, 1H), 6.15e6.05 (m, 1H), 4.30 (d, J ¼ 6.4 Hz, 2H),
2.43 (s, 3H), 2.30 (s, 3H).
electron spray ionization (ESI) mass spectrometry (MS) experiment
were performed on Agilent Technologies 6530 Accurate-Mass Q-
TOF LC/MS. Elemental analyses were carried out on a PerkinElmer
2400-II (IIT Kharagpur). HPLC analyses were done with a chiral
stationary phase using Chiralpak AD-H column (4.6 mm ꢁ 150 mm)
N-cinnamyl-N-(4-methoxyphenyl)-4-methylbenzene-sulfon-
amide, 1l. Yield ¼ 91%; 1H NMR (CDCl3, 200 MHz):
d 7.53 (d,
J ¼ 8.0 Hz, 2H), 7.27e7.24 (m, 7H), 6.96 (d, J ¼ 9.0 Hz, 2H), 6.77 (d,
J ¼ 9.0 Hz, 2H), 6.35 (d, J ¼ 16.0 Hz, 1H), 6.15e6.01 (m, 1H), 4.29 (d,
J ¼ 6.4 Hz, 2H), 3.77 (s, 3H), 2.43 (s, 3H).
and AD-3 column (4.6 mm ꢁ 250 mm and particle size 5
mm and
3
mm). Specific optical rotation values were measured on a Jasco-
P1200 polarimeter.
N-cinnamyl-N-(3,4-dimethoxyphenyl)-4-methyl-benzenesulfona-
Nitrenoid reagent [14] (PhINNs) and bis(oxazoline) ligands [15]
L were prepared according to standard procedures.
General procedure for the synthesis of N-protected-N-
cinnamylanilines.
Synthesis of N-protected-N-cinnamylanilines 1b, 1c.
Coupling of N-cinnamylaniline [16a] 1a (2.40 mmol) and
different acyl or sulfonyl chloride (2.88 mmol) using Et3N
(3.60 mmol) in CH2Cl2 afforded the N-protected-N-cinnamylani-
lines 1b and 1c.
Synthesis of N-protected-N-cinnamylanilines 1d-1n.
Rest of the N-protected-N-cinnamylanilines [16b] 1d-1n were
prepared by conventional alkylation method via the reaction of
protected aniline derivatives (5.08 mmol) with corresponding cin-
namyl bromide derivatives (7.61 mmol) in the presence of NaH
(10.15 mmol) in THF.
mide, 1m. Yield ¼ 88%; 1H NMR (CDCl3, 200 MHz):
d 7.55 (d,
J ¼ 8.2 Hz, 2H), 7.35e7.15 (m, 7H), 6.72 (d, J ¼ 8.2 Hz, 1H), 6.58e6.52
(m, 2H), 6.37 (d, J ¼ 15.8 Hz, 1H), 6.18e6.07 (m, 1H), 4.29 (d,
J ¼ 6.4 Hz, 2H), 3.83 (s, 3H), 3.72 (s, 3H), 2.43 (s, 3H).
(E)-N-(3-(2-bromophenyl)allyl)-N-(3,4-dimethoxyphenyl)-4-
methylbenzenesulfonamide, 1n. Yield ¼ 89%; 1H NMR (CDCl3,
400 MHz):
d
7.58e7.53 (m, 2H), 7.48 (dd, J ¼ 8.0, 1.3 Hz, 1H), 7.34
(dd, J ¼ 7.8, 1.7 Hz, 1H), 7.30e7.25 (m, 2H), 7.23e7.19 (m, 1H),
7.09e7.04 (m, 1H), 6.74e6.69 (m, 2H), 6.61e6.57 (m, 2H), 6.09e6.02
(m, 1H), 4.33 (dd, J ¼ 6.6, 1.5 Hz, 2H), 3.85 (s, 3H), 3.74 (s, 3H), 2.43
(s, 3H).
4.2. General procedure for synthesis of racemic 3-amino-4-
aryltetrahydroquinolines ( )-3
Analytical Data of N-protected-N-cinnamylanilines 1a-1n:
To a well-stirred suspended solution of PhINNs (1.0 equiv) and
N-cinnamylaniline 1 (5.0 equiv) and 4 Å MS in 2.4 mL CH2Cl2,
Cu(OTf)2 (0.1 equiv) was added and the reaction was allowed to stir
at 35 ꢀC under an argon atmosphere. The reaction was judged to be
complete as soon as the entire nitrenoid reagent was dissolved in
the reaction medium. On completion, the reaction mixture was
diluted with CH2Cl2 (10 mL) and filtered through a short plug of
silica gel. The silica gel was washed with an additional 10 mL of
CH2Cl2. The filtrate was concentrated by rotary evaporation under
reduced pressure. The semi-crude reaction mass was taken in a
10 mL two-neck round-bottom flask and dry CH2Cl2 (4 mL) was
added. Cu(OTf)2 (0.1 equiv) and 0.2 g of powdered molecular sieves
(4 Å) were added and the reaction mixture was allowed to stir at rt
under an argon atmosphere. Within 0.75e2 h, the reaction was
completed and the crude mass was purified by column chroma-
tography using EtOAc/hexane as an eluent, which provided the 3-
amino-4-aryltetrahydroquinoline ( )-3.
N-cinnamylaniline, 1a. Yield ¼ 95%; 1H NMR (CDCl3, 200 MHz):
d
7.43e7.10 (m, 7H), 6.82e6.59 (m, 4H), 6.36 (dt, J ¼ 12.0, 6.0 Hz,
1H), 3.95 (d, J ¼ 6.0 Hz, 2H), 3.74 (bs, 1H).
N-cinnamyl-4-methyl-N-phenylbenzenesulfonamide,
1b.
Yield ¼ 84%; 1H NMR (CDCl3, 200 MHz):
d
7.52 (d, J ¼ 8.0 Hz, 2H),
7.26e7.23 (m, 10H), 7.08 (d, J ¼ 8.0 Hz, 2H), 6.37 (d, J ¼ 15.8 Hz, 1H),
6.16e6.02 (m, 1H), 4.33 (d, J ¼ 6.6 Hz, 2H), 2.43 (3H, s).
N-cinnamyl-N-phenylmethanesulfonamide, 1c. Yield ¼ 80%; 1H
NMR (CDCl3, 200 MHz):
d
7.44e7.25 (m, 10H), 6.48 (d, J ¼ 15.8 Hz,
1H), 6.27e6.16 (m, 1H), 4.44 (d, J ¼ 6.6 Hz, 2H), 2.94 (s, 3H).
N-cinnamyl-N-(4-methoxyphenyl)methanesulfonamide,
1d.
Yield ¼ 86%; 1H NMR (CDCl3, 200 MHz):
d 7.29e7.23 (m, 7H), 6.88
(d, J ¼ 8.8 Hz, 2H), 6.45 (d, J ¼ 15.8 Hz, 1H), 6.27e6.12 (m, 1H), 4.38
(d, J ¼ 6.4 Hz, 2H), 3.79 (s, 3H), 2.93 (s, 3H).
(E)-N-(4-chlorophenyl)-N-(3-(4-fluorophenyl)allyl)-meth-
anesulfonamide, 1e. Yield ¼ 70%; 1H NMR (CDCl3, 200 MHz):
d
7.38e7.23 (m, 6H), 6.97 (t, J ¼ 8.4 Hz, 2H), 6.42 (d, J ¼ 15.8 Hz, 1H),
6.15e6.04 (m, 1H), 4.40 (d, J ¼ 6.4 Hz, 2H), 2.93 (s, 3H).
4.3. General procedure for asymmetric synthesis of 3-amino-4-
aryltetrahydroquinolines 3
N-(4-chlorophenyl)-N-cinnamylmethanesulfonamide,
1f.
Yield ¼ 80%; 1H NMR (CDCl3, 200 MHz):
d 7.29e7.22 (m, 7H), 7.02
(d, J ¼ 8.6 Hz, 2H), 6.41 (d, J ¼ 15.8 Hz, 1H), 6.17e6.04 (m, 1H), 4.41
(d, J ¼ 6.4 Hz, 2H), 2.93 (s, 3H).
A 10 mL two-neck round-bottom flask was charged with Box
ligand (1R, 2S)-L5 (0.011 g, 0.03 mmol, 0.12 equiv) and Cu(OTf)2
(0.009 g, 0.025 mmol, 0.1 equiv). Anhydrous CH2Cl2 (1.2 mL) was
added by syringe and the resulting mixture was stirred for 30 min.
To this solution, substrate 1b (0.449 g, 1.23 mmol, 5.0 equiv) taken
in 1.2 mL CH2Cl2, PhINNs (0.1 g, 0.24 mmol, 1.0 equiv), and 0.2 g of
powdered molecular sieves (4 Å) were added and the reaction
mixture was allowed to stir at 35 ꢀC under argon atmosphere. As
soon as the entire nitrenoid reagent was dissolved in the reaction
medium, the reaction mixture was diluted with CH2Cl2 (10 mL) and
filtered through a short plug of silica gel. The silica gel was washed
with an additional 10 mL of CH2Cl2. The filtrate was concentrated by
rotary evaporation under reduced pressure. The semi-crude reac-
tion mass was taken in a 10 mL two-neck round-bottom flask and
(E)-N-(3-(4-fluorophenyl)allyl)-N-(4-methoxyphenyl)-meth-
anesulfonamide, 1g. Yield ¼ 81%; 1H NMR (CDCl3, 200 MHz):
d
7.30e7.23 (m, 4H), 7.01e6.86 (m, 4H), 6.41 (d, J ¼ 15.8 Hz, 1H),
6.17e6.03 (m, 1H), 4.36 (d, J ¼ 6.4 Hz, 2H), 3.78 (s, 3H), 2.92 (s, 3H).
(E)-N-(3-(4-chlorophenyl)allyl)-N-(p-tolyl)methane-sulfonamide,
1h. Yield ¼ 78%; 1H NMR (CDCl3, 200 MHz):
d 7.30e7.13 (m, 6H),
6.97 (t, J ¼ 8.4 Hz, 2H), 6.43 (d, J ¼ 15.8 Hz, 1H), 6.18e6.03 (m, 1H),
4.40 (d, J ¼ 6.4 Hz, 2H), 2.93 (s, 3H), 2.34 (s, 3H).
(E)-N-(3-(4-fluorophenyl)allyl)-N-(p-tolyl)methane-sulfonamide,
1i. Yield ¼ 68%; 1H NMR (CDCl3, 200 MHz):
d 7.29e7.15 (m, 8H),
6.42 (d, J ¼ 15.8 Hz, 1H), 6.23e6.12 (m, 1H), 4.39 (d, J ¼ 6.4 Hz, 2H),
2.92 (s, 3H), 2.34 (s, 3H).
6

S.M.S. Akhtar, S. Bar and S. Hajra
Tetrahedron xxx (xxxx) xxx
4 mL dry CH2Cl2 was added. Cu(OTf)2 (0.009 g, 0.025 mmol, 0.1
equiv) and 0.2 g of powdered molecular sieves (4 Å) were added
and the reaction mixture was allowed to stir at rt under an argon
atmosphere. Within 1 h, the reaction was completed and the crude
mass was purified by column chromatography using EtOAc/hexane
0.107 g, 81% yield; white solid, mp 64e65 ꢀC; 1H NMR (200 MHz,
CDCl3):
d
8.22 (d, J ¼ 8.8 Hz, 2H), 7.83 (d, J ¼ 8.8 Hz, 2H), 7.46 (d,
J ¼ 9.0 Hz, 1H), 7.15e7.04 (m, 3H), 6.85 (2H, d, J ¼ 8.2 Hz), 6.55 (1H,
s), 5.06 (1H, d, J ¼ 7.0 Hz), 3.96e3.90 (m, 2H), 3.80e3.65 (m, 1H),
3.59e3.48 (m, 1H), 3.15 (s, 3H), 2.16 (s, 3H); 13C NMR (100 MHz,
as
an
eluent,
which
provided
the
3-amino-4-
CDCl3): d 149.8, 145.0, 139.8, 134.9, 133.6, 133.5, 131.4, 129.9 (2C),
aryltetrahydroquinoline 3b (0.1 g, 72% yield).
128.9 (2C), 128.6, 128.0 (2C), 124.2 (3C), 121.5, 54.4, 49.4, 48.4, 40.1,
20.5; Anal. (CHN %) Calcd for C23H22ClN3O6S2: C, 51.54; H, 4.14; N,
7.84. Found: C, 51.62; H, 4.29; N, 7.80; HPLC: Daicel Chiralpak AD-H,
4.3.1. Analytical data of aziridine ( )-2b and 3-amino-4-
aryltetrahydroquinolines 3
4.3.1.1. 4-Methyl-N-(((2R,3R)-1-((4-nitrophenyl)sulfonyl)-3-
hexane/i-propanol ¼ 80/20, 1.0 ml/min, 220 nm, major 12.9 min
28
and minor 18.8 min; [
a
]
¼ ꢂ32 (c 0.30, CH2Cl2) for 87% ee.
D
phenylaziridin-2-yl)methyl)-N-phenylbenzenesulfonamide
( )-2b.
8.29 (d, J ¼ 8.4 Hz, 2H), 8.05 (d,
1H NMR (200 MHz, CDCl3):
d
4.3.1.6. N-[4-(4-Fluoro-phenyl)-1-methanesulfonyl-6-methyl-1,2,3,4-
tetrahydro-quinolin-3-yl]-4-nitro-benzenesulfonamide ( )-3i.
0.090 g, 70% yield; white solid, mp 95e96 ꢀC; 1H NMR (200 MHz,
CDCl3):
J ¼ 8.6 Hz, 2H), 7.51 (d, J ¼ 7.6 Hz, 2H), 7.34e7.20 (m, 8H), 7.03 (d,
J ¼ 5.4 Hz, 2H), 6.86 (d, J ¼ 5.8 Hz, 2H) 4.62 (dd, J ¼ 14.4, 3.2 Hz, 1H),
3.95 (dd, J ¼ 14.4, 9.8 Hz, 1H), 3.68 (d, J ¼ 4.0 Hz, 1H),3.26e3.20 (m,
d
8.23 (d, J ¼ 8.6 Hz, 2H), 7.87 (d, J ¼ 9.0 Hz, 2H), 7.48 (d,
1H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
129.7, 129.5, 129.1,
J ¼ 8.4 Hz, 1H), 7.06 (d, J ¼ 8.6 Hz, 1H), 6.88 (d, J ¼ 7.0 Hz, 4H), 6.58
(s, 1H), 5.06 (d, J ¼ 4.2 Hz, 1H), 4.00e3.76 (m, 3H), 3.89e3.65 (m,
2H), 3.61e3.51 (m, 1H), 3.14 (s, 3H), 2.17 (s, 3H); 13C NMR (100 MHz,
128.7, 128.6, 128.6, 128.4, 127.7, 126.3, 124.3, 50.8, 50.3, 50.0, 21.6;
Anal. (CHN %) Calcd for C28H25N3O6S2: C, 59.67; H, 4.47; N, 7.46.
Found: C, 59.74; H, 4.54; N, 7.35.
CDCl3):
d
161.9 (1C, d, J ¼ 246.0 Hz), 149.8, 145.1, 137.2, 134.7, 133.5,
131.5, 130.2, 130.1, 128.8, 128.1 (2C), 127.3, 124.4 (2C), 121.2, 115.8,
115.7, 54.3, 49.2, 48.1, 40.0, 20.5; Anal. (CHN %) Calcd for
4.3.1.2. 4-Nitro-N-[4-phenyl-1-(toluene-4-sulfonyl)-1,2,3,4-
tetrahydro-quinolin-3-yl]-benzenesulfonamide 3b. 0.100 g, 72%
yield; white solid, mp 200e201 ꢀC; 1H NMR (400 MHz, CDCl3):
C
23H22FN3O6S2: C, 53.17; H, 4.27; N, 8.09. Found: C, 53.28; H, 4.30;
N, 7.98.
d
8.01 (d, J ¼ 8.8 Hz, 2H), 7.87 (d, J ¼ 8.4 Hz, 2H), 7.70 (d, J ¼ 8.4 Hz,
2H), 7.54 (d, J ¼ 8.8 Hz, 2H), 7.29 (2H, d, J ¼ 8.0 Hz), 7.22 (1H, t,
J ¼ 8.4 Hz), 7.08 (1H, t, J ¼ 7.2 Hz), 6.98 (t, J ¼ 7.6 Hz, 1H), 6.92 (t,
J ¼ 7.2 Hz, 2H), 6.58 (d, J ¼ 7.6 Hz, 1H), 6.36 (d, J ¼ 7.6 Hz, 2H), 4.77
(d, J ¼ 5.2 Hz, 1H), 4.58e4.50 (m, 1H), 3.63 (d, J ¼ 8.0 Hz, 1H),
4.3.1.7. N-[6-Chloro-4-phenyl-1-(toluene-4-sulfonyl)-1,2,3,4-
tetrahydro-quinolin-3-yl]-4-nitro-benzenesulfonamide
0.123 g, 83% yield; white solid, mp 195e196 ꢀC; 1H NMR (200 MHz,
CDCl3):
3j.
d
8.07 (d, J ¼ 8.8 Hz, 2H), 7.90 (d, J ¼ 9.0 Hz, 1H), 7.76 (d,
3.46e3.40 (m, 2H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
149.6,
J ¼ 8.2 Hz, 2H), 7.58 (d, J ¼ 9.0 Hz, 2H), 7.36 (d, J ¼ 8.0 Hz, 2H),
7.22e7.13 (m, 2H), 6.99 (t, J ¼ 7.4 Hz, 2H), 6.60 (s, 1H), 6.40 (t,
J ¼ 7.2 Hz, 2H), 4.67 (d, J ¼ 5.2 Hz, 1H), 4.60e4.54 (m, 1H), 3.63 (d,
J ¼ 7.8 Hz, 1H), 3.48e3.42 (m, 2H), 2.53 (s, 3H); 13C NMR (100 MHz,
145.0, 144.1, 140.9, 136.4, 135.7, 130.6, 130.1, 129.9 (2C), 128.65 (2C),
128.63 (2C), 127.82 (2C), 127.81 (3C), 127.6, 127.3, 124.4, 123.9 (2C),
52.9, 50.6, 50.3, 21.6; Anal. (CHN %) Calcd for C28H25N3O6S2: C,
59.67; H, 4.47; N, 7.46. Found: C, 59.75; H, 4.56; N, 7.36; HPLC:
CDCl3):
d 148.5, 145.7, 143.8, 140.5, 135.8, 133.8, 133.7, 130.7, 129.8,
Daicel Chiralpak AD-H, hexane/i-propanol ¼ 80/20, 1.0 ml/min,
129.6 (2C), 128.3 (2C), 127.8 (2C), 127.4 (2C), 126.8 (3C), 126.5, 126.0,
123.1 (2C), 51.4, 51.1, 48.6, 21.1; Anal. (CHN %) Calcd for
28
220 nm, major 11.7 min and minor 22.9 min; [
CH2Cl2) for 75% ee.
a]
¼ ꢂ97 (c 0.30,
D
C
28H24ClN3O6S2: C, 56.23; H, 4.04; N, 7.03. Found: C, 56.33; H, 4.13;
N, 6.96. HPLC: Daicel Chiralpak AD-H, hexane/i-propanol ¼ 80/20,
4.3.1.3. N-(1-Methanesulfonyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-
1.0 ml/min, 220 nm, major 9.7 min and minor 46.3 min;
28
3-yl)-4-nitro-benzenesulfonamide ( )-3c. 0.080 g, 66% yield; white
[
a
]
¼ ꢂ101 (c 0.30, CH2Cl2) for 89% ee.
D
solid, mp 165e166 ꢀC; 1H NMR (400 MHz, CDCl3):
d 8.13 (d,
J ¼ 8.4 Hz, 2H), 7.76 (d, J ¼ 8.4 Hz, 2H), 7.59 (d, J ¼ 8.4 Hz, 1H),
7.26e7.11 (m, 4H), 6.98 (t, J ¼ 7.6 Hz,1H), 6.87 (t, J ¼ 7.2 Hz, 2H), 6.76
(d, J ¼ 8.0 Hz, 1H), 5.28 (d, J ¼ 6.4 Hz, 1H), 4.11 (dd, J ¼ 2.4, 7.6 Hz,
1H), 3.96 (d, J ¼ 7.2 Hz, 1H), 3.76 (d, J ¼ 5.2 Hz, 1H), 3.55 (dd, J ¼ 8.0,
4.3.1.8. N-[6-Methyl-4-phenyl-1-(toluene-4-sulfonyl)-1,2,3,4-
tetrahydro-quinolin-3-yl]-4-nitro-benzenesulfonamide 3k.
0.106 g, 74% yield; white solid, mp 270e271 ꢀC; 1H NMR (400 MHz,
CDCl3):
d
8.06 (d, J ¼ 7.6 Hz, 2H), 7.81e7.72 (m, 3H), 7.57 (d,
13.2 Hz, 1H), 3.17 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
149.8, 144.8,
J ¼ 8.8 Hz, 2H), 7.35e7.29 (m, 1H), 7.11e6.91 (4H, m), 6.42 (3H, d,
J ¼ 6.2 Hz), 4.88 (1H, d, J ¼ 5.4 Hz), 4.57e4.52 (m, 1H), 3.62 (d,
J ¼ 8.0 Hz,1H), 3.45e3.40 (m, 2H), 2.50 (s, 3H), 2.15 (s, 3H); 13C NMR
141.1, 136.1, 131.3, 128.9 (2C), 128.5 (2C), 128.0 (2C), 127.9, 127.7,
127.5, 124.8, 124.2 (2C), 121.3, 54.1, 50.1, 48.3, 40.1; Anal. (CHN %)
Calcd for C22H21N3O6S2: C, 54.20; H, 4.34; N, 8.62. Found: C, 54.32;
H, 4.29; N, 8.72.
(100 MHz, CDCl3):
d 148.9, 146.1, 143.7, 141.7, 136.6, 135.4, 133.0,
131.5,130.8,129.7 (2C),128.8 (2C),128.0,127.9 (2C),127.8 (2C),127.2
(2C), 126.6, 124.8, 123.5 (2C), 52.5, 51.4, 49.4, 21.4, 20.6; Anal. (CHN
%) Calcd for C29H27N3O6S2: C, 60.30; H, 4.71; N, 7.27. Found: C,
60.43; H, 4.78; N, 7.19; HPLC: Daicel Chiralpak AD-H, hexane/i-
4.3.1.4. N-[4-(4-Fluoro-phenyl)-1-methanesulfonyl-6-methoxy-
1,2,3,4-tetrahydro-quinolin-3-yl]-4-nitro-benzenesulfonamide
( )-3g. 0.098 g, 74% yield; white solid, mp 155e156 ꢀC; 1H NMR
propanol ¼ 80/20, 1.0 ml/min, 220 nm, major 9.1 min and minor
28
(400 MHz, CDCl3):
d
8.21 (d, J ¼ 8.8 Hz, 2H), 7.83 (d, J ¼ 8.8 Hz, 2H),
33.0 min; [
a
]
¼ ꢂ87 (c 0.30, CH2Cl2) for 73% ee.
D
7.48 (d, J ¼ 8.8 Hz, 1H), 6.92e6.79 (m, 5H), 6.24 (d, J ¼ 2.8 Hz, 1H),
5.15 (bs, 1H), 3.97e3.92 (m, 2H), 3.78e3.74 (m, 1H), 3.63 (m, 3H),
4.3.1.9. N-[6-Methoxy-4-phenyl-1-(toluene-4-sulfonyl)-1,2,3,4-
tetrahydro-quinolin-3-yl]-4-nitro-benzenesulfonamide 3l.
0.116 g, 79% yield; white solid, mp 172e173 ꢀC; 1H NMR (400 MHz,
CDCl3):
3.56e3.51 (m, 1H), 3.14 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 161.8
(d, J ¼ 245.1 Hz, 1C), 156.7, 149.3, 146.0, 137.1, 131.4, 130.48, 130.40,
129.0, 127.7 (2C), 124.1, 123.8 (2C), 115.5, 115.4, 115.2, 113.2, 55.2,
54.6, 50.0, 48.9, 39.7; Anal. (CHN %) Calcd for C23H22FN3O7S2: C,
51.58; H, 4.14; N, 7.85. Found: C, 51.70; H, 4.19; N, 7.77.
d
7.97 (d, J ¼ 8.4 Hz, 2H), 7.80 (d, J ¼ 8.8 Hz, 1H), 7.67 (d,
J ¼ 8.0 Hz, 2H), 7.49 (d, J ¼ 8.8 Hz, 2H), 7.29 (d, J ¼ 8.0 Hz, 2H), 7.05 (t,
J ¼ 7.6 Hz, 1H), 6.87 (t, J ¼ 7.6 Hz, 2H), 6.78 (dd, J ¼ 2.8, 9.2 Hz, 1H),
6.28 (d, J ¼ 7.2 Hz, 2H), 6.02 (d, J ¼ 2.8 Hz, 1H), 4.91 (d, J ¼ 6.4 Hz,
1H), 4.60e4.53 (m, 1H), 3.59 (s, 3H), 3.54 (d, J ¼ 9.2 Hz, 1H),
4.3.1.5. N-[4-(4-Chloro-phenyl)-1-methanesulfonyl-6-methyl-
1,2,3,4-tetrahydro-quinolin-3-yl]-4-nitro-benzenesulfonamide
3h.
3.40e3.30 (m, 2H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 157.2,
7

S.M.S. Akhtar, S. Bar and S. Hajra
Tetrahedron xxx (xxxx) xxx
149.4, 144.9, 144.0, 140.5, 136.2, 132.0, 129.8 (3C), 128.5 (4C), 127.9
(2C), 127.6 (2C), 127.3, 126.2, 123.8 (2C), 115.2, 113.1, 55.2, 52.6, 50.7
(2C), 21.5; Anal. (CHN %) Calcd for C29H27N3O7S2: C, 58.67; H, 4.58;
N, 7.08. Found: C, 58.72; H, 4.61; N, 6.91; HPLC: Daicel Chiralpak
4.3.2.2. tert-butyl ((3S,4S)-4-(2-bromophenyl)-6,7-dimethoxy-1-
tosyl-1,2,3,4-tetrahydroquinolin-3-yl)carbamate 8. To a well stirred
solution of 3n (0.137 g, 0.195 mmol) taken in 4 mL CH3CN:DMSO
(49:1) at 40 ꢀC, 1.2 equiv 4-methoxythiophenol (0.03 mL,
0.234 mmol) and 1.2 equiv of activated K2CO3 (0.032 g, 0.234 mmol)
were added and the heterogeneous reaction mixture was allowed
to stir vigorously at 40 ꢀC for 4 h. Upon completion of the reaction
the solvent was evaporated under reduced pressure and the residue
was taken in ethyl acetate (10 mL). The organic portion was washed
with water, brine, dried over Na2SO4, and concentrated. The
denosylated compound formed exclusively as confirmed from
LCMS data taken from the crude reaction mass and hence not
subjected to further purification instead used in the next step. ESI-
MS m/z: [MþH]þ Calcd for C24H25BrN2O4S 517.0797; found
517.0809.
The crude reaction mass containing nosyl deprotected com-
pound was taken in 2 mL dry THF. 3 equiv of Boc2O (0.135 mL,
0.586 mmol) was added and the reaction mixture was allowed to
stir for overnight. The solvent was evaporated under reduced
pressure and 10 mL of ethyl acetate was added. The organic layer
was washed with water, brine and dried over Na2SO4. After solvent
evaporation, the crude reaction mixture was subjected to column
purification using 15% ethyl acetate and pet-ether as an eluent to
afford titled compound 8 as white solid (0.110 g, yield 92% in overall
two steps). White solid, mp 151e153 ꢀC; 1H NMR (400 MHz, CDCl3):
AD-H, hexane/i-propanol ¼ 80/20, 1.0 ml/min, 220 nm, major
28
13.6 min and minor 48.4 min; [
ee.
a
]
¼ ꢂ137 (c 0.30, CH2Cl2) for 90%
D
4.3.1.10. N-[6,7-Dimethoxy-4-phenyl-1-(toluene-4-sulfonyl)-1,2,3,4-
tetrahydro-quinolin-3-yl]-4-nitro-benzenesulfonamide 3m.
0.103 g, 67% yield; white solid, mp 235e236 ꢀC; 1H NMR (400 MHz,
CDCl3):
d
7.99 (d, J ¼ 8.8 Hz, 2H), 7.71 (d, J ¼ 8.0 Hz, 2H), 7.50 (d,
J ¼ 9.2 Hz, 3H), 7.31 (d, J ¼ 8.0 Hz, 2H), 7.06 (t, J ¼ 7.6 Hz, 1H), 6.89 (t,
J ¼ 7.6 Hz, 2H), 6.28 (d, J ¼ 7.6 Hz, 2H), 5.94 (s,1H), 4.87 (d, J ¼ 7.6 Hz,
1H), 4.64e4.60 (dd, J ¼ 3.2, 13.6 Hz, 1H), 3.90 (s, 3H), 3.54 (d,
J ¼ 7.2 Hz, 1H), 3.53 (s, 3H), 3.41e3.27 (m, 2H), 3.49 (s, 3H); 13C NMR
(100 MHz, CDCl3):
d 149.1, 147.8, 147.1, 145.6, 143.9, 141.3, 136.2,
129.7 (2C), 128.5 (2C), 128.1 (2C), 127.9 (2C), 127.4 (2C), 126.9, 123.6
(3C), 123.3, 111.8, 108.1, 56.0, 55.6, 52.6, 51.4, 49.7, 21.5; DEPT-135
NMR (100 MHz, CDCl3):
d 130.7, 129.9, 128.7, 128.6, 127.8, 127.8,
127.6, 127.4, 125.8, 124.4, 123.9, 52.9, 50.7, 50.4, 21.6; Anal. (CHN %)
Calcd for C30H29N3O8S2: C, 57.77; H, 4.69; N, 6.74. Found: C, 57.83;
H, 4.56; N, 6.76; HPLC: Daicel Chiralpak AD-H, hexane/i-prop-
anol ¼ 80/20, 1.0 ml/min, 220 nm, major 16.0 min and minor
28
37.7 min; [
a
]
¼ ꢂ133 (c 0.30, CH2Cl2) for 82% ee.
D
d
7.71 (d, J ¼ 7.8 Hz, 2H), 7.56 (s,1H), 7.50 (dd, J ¼ 8.1,1.2 Hz,1H), 7.28
4.3.1.11. N-((3S,4S)-4-(2-bromophenyl)-6,7-dimethoxy-1-tosyl-
1,2,3,4-tetrahydroquinolin-3-yl)-4-nitrobenzene-sulfonamide 3n.
0.123 g, 71% yield; white solid, mp 211e213 ꢀC; 1H NMR (400 MHz,
CDCl3):
(d, J ¼ 8.0 Hz, 2H), 7.03e6.99 (m, 1H), 6.86e6.82 (m, 1H), 6.01 (s,
1H), 5.70 (d, J ¼ 7.8 Hz, 1H), 4.51 (s, 1H), 4.32 (dd, J ¼ 23.7, 11.2 Hz,
2H), 3.93 (s, 3H), 3.86e3.71 (m, 1H), 3.59 (s, 3H), 3.56e3.42 (m, 1H),
d
7.95 (d, J ¼ 8.8 Hz, 2H), 7.74 (d, J ¼ 8.2 Hz, 2H), 7.56 (d,
2.44 (s, 3H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3):
d 154.5, 148.0,
J ¼ 8.8 Hz, 2H), 7.46 (s, 1H), 7.34 (d, J ¼ 8.0 Hz, 2H), 7.13 (dd, J ¼ 8.2,
1.3 Hz, 1H), 6.82e6.78 (m, 1H), 6.62 (t, J ¼ 7.6 Hz, 1H), 5.78 (s, 1H),
5.15 (d, J ¼ 6.9 Hz, 1H), 4.62 (d, J ¼ 10.1 Hz, 1H), 4.26 (d, J ¼ 9.1 Hz,
1H), 3.90 (s, 3H), 3.50 (s, 3H), 2.49 (s, 3H); 13C NMR (100 MHz,
146.9, 143.9, 141.8, 136.3, 132.5, 130.1, 129.9, 129.4, 128.5, 128.0,
127.6, 125.3, 122.1, 112.0, 107.3, 79.7, 56.1, 55.9, 49.6, 48.2, 28.3, 21.6;
ESI-MS m/z: [MþNa]þ Calcd for C29H33BrN2O6S 639.1140; found
639.1131.
CDCl3):
d 149.5, 148.2, 147.4, 145.2, 144.2, 136.4, 132.5, 129.9, 128.9,
128.7, 128.2,127.8,127.6, 127.5, 125.1, 124.4, 123.8,122.4,111.4,108.3,
77.4, 77.1, 76.8, 56.1, 55.8, 53.6, 51.4, 48.1, 21.7; ESI-MS m/z: [MþH]þ
Calcd for C30H28BrN3O8S2 702.0579; found 702.0582; HPLC: Daicel
4.3.2.3. tert-butyl ((3S,4R)-6,7-dimethoxy-1-tosyl-4-(2-vinylphenyl)-
1,2,3,4-tetrahydroquinolin-3-yl)carbamate 10. To
a solution of
compound 8 (0.1 g, 0.162 mmol) in dry DMF (1.6 mL), 2 equiv LiCl
(0.014 g, 0.324 mmol) and 10 mol% Pd(PPh3)4 catalyst (0.019 g,
0.016 mmol) were added under argon atmosphere. Five times
evacuation of the reaction vessel and consequent argon purge-in
process was conducted before the addition of 1.5 equivalent of
tributyl vinyl tin reagent (0.07 mL, 0.243 mmol). The reaction
mixture was heated to 80 ꢀC and stirred for 4 h. After completion of
the reaction, the reaction mixture was quenched with water and
extracted with ethyl acetate (3X10 mL). The combined extracts
were dried over sodium sulfate and evaporated. LCMS data from
the crude mixture detects the formation of compound 10 along
with excess tributyl vinyl tin reagent. Finally, the crude mass was
triturated using distilled n-pentane (5 times) to remove excess
tributyl vinyl tin reagent which provided a sufficiently pure com-
pound 10 for the next step. ESI-MS m/z: [MþNa]þ Calcd for
Chiralpak AD-3, hexane/i-propanol ¼ 70/30, 1.0 ml/min, 254 nm,
28
major 13.4 min and minor 31.4 min; [
for 98% ee.
a
]
¼ ꢂ152 (c 0.50, CH2Cl2)
D
4.3.2. Experimental procedure and analytical data of compounds 4,
8, 10, 9, 13, 11
4.3.2.1. N-[6,7-Dimethoxy-4-phenyl-1-(toluene-4-sulfonyl)-1,2,3,4-
tetrahydro-quinolin-3-yl]-N-methoxymethyl-4-nitro-benzenesulfo-
namide 4. NaH (0.13 g, 0.321 mmol) was added to a solution of 3m
(0.1 g, 0.160 mmol) in CH2Cl2 (3 mL) at 0 ꢀC and allowed to stir for
30 min under argon atmosphere. MOMCl (2 equiv, 0.025 mL,
0.321 mmol) was added to the reaction mixture slowly and stirred.
After 4 h, the reaction was quenched with a saturated NH4Cl solu-
tion and extracted with CH2Cl2 and dried with NaSO4. The reaction
mixture was subjected to column purification using 20% ethyl ac-
etate in hexane as an eluent to obtain compound 4 (0.102 g, 95%).
C
31H36N2O6S 587.2192; found 587.2192.
White solid, mp 190 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.90 (d,
4.3.2.4. tert-butyl ((3S,4R)-4-(2-formylphenyl)-6,7-dimethoxy-1-
tosyl-1,2,3,4-tetrahydroquinolin-3-yl)carbamate 9. The crude viny-
lated compound 10 (0.089 g, 0.158 mmol) was dissolved in 1:1
dioxane-water (3 mL). 4 equiv of both 2, 6-lutidine (0.075 mL,
0.63 mmol) and NaIO4 (0.135 g, 0.63 mmol) were added and the
reaction flask was covered with aluminium foil. 0.05(M) solution of
OsO4 in H2O (0.16 mL, 0.008 mmol, 5 mol%) was cautiously added to
the reaction mixture and allowed it to stir at room temperature
with constant monitoring by TLC. After 4 h, the reaction mixture
was quenched by saturated aq. NaHSO3 and extracted with ethyl
acetate (3x10 mL). Combined organic layers were washed with
J ¼ 8.4 Hz, 2H), 7.77 (d, J ¼ 8.0 Hz, 2H), 7.45 (t, J ¼ 9.2 Hz, 3H), 7.35 (d,
J ¼ 8.0 Hz, 2H), 6.96 (t, J ¼ 7.2 Hz, 1H), 6.74 (t, J ¼ 7.6 Hz, 2H), 6.09 (d,
J ¼ 7.2 Hz, 2H), 5.90 (s, 1H), 5.02 (d, J ¼ 11.2 Hz, 1H), 4.69e4.64 (m,
2H), 4.04 (d, J ¼ 10.8 Hz, 1H), 3.90 (s, 3H), 3.91e3.87 (m, 1H), 3.58 (t,
J ¼ 13.2 Hz, 1H), 3.50 (s, 3H), 3.40 (s, 3H), 2.53 (s, 3H); 13C NMR
(100 MHz, CDCl3):
d 149.2, 147.7, 147.2, 145.2, 143.9, 141.8, 136.5,
129.8 (2C), 128.5 (2C), 128.2, 128.1 (4C), 127.8 (2C), 126.8, 124.4,
123.5 (2C), 111.8, 108.1, 75.9, 56.9, 56.0, 55.63, 55.60, 50.4, 46.0, 21.6;
Anal. (CHN %) Calcd for C32H33N3O92S82: C, 57.56; H, 4.98; N, 6.29.
Found: C, 57.65; H, 5.09; N, 6.21; [
a]
¼ ꢂ113 (c 0.30, CH2Cl2).
D
8

S.M.S. Akhtar, S. Bar and S. Hajra
Tetrahedron xxx (xxxx) xxx
brine and dried over Na2SO4. The solvent was evaporated in vacuo
and the crude product was purified by flash chromatography using
10% ethyl acetate and hexane to get the titled aldehyde compound 9
(0.063 g, yield 69% in overall two steps). Gummy liquid; 1H NMR
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgements
(400 MHz, CDCl3):
d 10.12 (s, 1H), 7.82e7.66 (m, 3H), 7.58 (s, 1H),
7.37 (t, J ¼ 7.5 Hz, 1H), 7.27 (d, J ¼ 7.3 Hz, 2H), 7.11e7.07 (m, 1H),
5.88e5.83 (m, 2H), 5.07 (d, J ¼ 9.4 Hz, 1H), 5.01 (d, J ¼ 6.8 Hz, 1H),
4.52 (d, J ¼ 12.6 Hz, 1H), 3.94 (s, 3H), 3.67e3.53 (m, 1H), 3.42 (s, 3H),
3.38 (t, J ¼ 12.7 Hz,1H), 2.44 (s, 3H), 1.35 (s, 9H); 13C NMR (100 MHz,
We thank SERB, India (Grant No. SR/S1/OC-97/2012 and CRG/
2020/000650) for providing financial support.
Appendix A. Supplementary data
CDCl3):
d 194.5(CHO), 154.7, 147.9, 146.9, 145.3, 143.8, 139.3, 136.4,
134.6, 134.0, 133.7, 130.4, 129.8, 128.1, 127.4, 123.3, 112.4, 107.7, 79.4,
56.1, 55.8, 51.1, 49.9, 42.5, 28.3, 21.6; ESI-MS m/z: [MþNa]þand
[M þ MeOH þ Na]þ Calcd for C30H34N2O7S 589.1984 and 621.2247;
found 589.1982 and 621.2245.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132257.
References
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d
7.47 (d, J ¼ 8.3 Hz, 2H),
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d 147.6, 147.1, 143.7, 137.0, 135.4, 132.1, 129.7, 129.5, 127.7,
127.0,126.9,126.6,126.2,112.0,107.5, 59.9, 56.2, 56.0, 51.1, 48.9, 41.7,
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d
126.2, 112.0, 107.5, 59.9, 56.2, 56.0, 51.1, 48.9, 41.7, 21.5; ESI-MS m/z:
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