Asymmetric Synthesis of α-(Diarylmethyl) Alkyl Amines through Regioselective Lithiation of α-Diarylmethanes and the Diastereoselective Addition to Ellman's Imines

Article abstract of DOI:10.1021/acs.joc.8b00879

A highly regio- and diastereoselective lithiation/addition of α-diarylmethanes to N-tert-butanesulfinylimines is reported. This methodology also affords the preparation of enantiomerically pure α-(diarylmethyl) alkyl amines bearing quaternary centers.

Full text of DOI:10.1021/acs.joc.8b00879

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Article
Asymmetric Synthesis of #-(diarylmethyl) alkyl amines
through Regioselective Lithiation of #-Diarylmethanes
and Diastereoselective Addition to Ellman’s Imines.
Leleti Rajender Reddy, Sharadsrikar Kotturi, Yogesh Waman,
Chirag Patel, Megha Danidharia, and Rajesh Shenoy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00879 • Publication Date (Web): 29 May 2018
Downloaded from http://pubs.acs.org on May 29, 2018
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Asymmetric Synthesis of αꢀ(diarylmethyl) alkyl amines
through Regioselective Lithiation of αꢀDiarylmethanes and
Diastereoselective Addition to Ellman’s Imines.
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Leleti Rajender Reddy,* Sharadsrikar Kotturi, Yogesh Waman, Chirag Patel, Megha Danidharia,
and Rajesh Shenoy.
Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway,
Ahmedabad, Gujarat 382213, India.
rajender.leleti@piramal.com
Abstract:
A highly regioꢀ and diastereoꢀ selective lithiation/addition of αꢀdiarylmethanes to N-tertꢀ
butanesulfinylimines is reported. This methodology also affords the preparation of
enantiomerically pure αꢀ(diarylmethyl) alkyl amines bearing quaternary centers.
Introduction
For an ongoing program within our research group we needed to synthesize asymmetric amines
of the type 1. These type of chiral amines are ubiquitous structural motifs present in many drugs
and drug candidates (Fig. 1).1 Such amines are also effective chiral polydentate ligands in
asymmetric synthesis.2 While the synthesis of these compounds have been an active area of
research, currently available synthetic methods of these privileged structures suffer from long
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synthetic sequences, low yields, or lack of broad substrate scope (Scheme 1).2 We reasoned that
an asymmetric addition of diarylmethyl anion to Ellman’s Imines could afford a direct access to
enantioenriched α−(diarylmethyl) alkyl amines, such a methodology has not been reported to
the best of our knowledge.3 Herein, we report a straightforward and scalable synthesis of
enantioenriched αꢀ(diarylmethyl) alkyl amines in high yield with broad substrate scope (Scheme
1). We envisaged that this synthetic effort could be of value in a variety of research applications,
including the discovery of new bioactive substances.
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Fig. 1. αꢀ(Diarylmethyl) alkyl amines containing biologically important molecules.
Results and discussion
At the outset of our investigation, we chose diphenylmethane (3a) as our model substrate for the
lithiation reactions. We were interested in using nꢀBuLi under mild conditions instead of less
stable, more expensive and highly pyrophoric tꢀBuLi and sꢀBuLi for the deprotonation at low
ο
temperature. The lithiation of 3a5 at 0 C for 1 h in the absence of a ligand and followed by
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addition to N-tertꢀbutanesulfinylphenyl aldimine (RS) 2a4 in THF at −78 C for 2 h afforded αꢀ
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(dipheylmethyl) phenyl amine derivative 4a in 93% yield and with a high diastereomeric ratio
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(dr 98:2). The diastereoselectivity of the reaction was determined to be 98:2 by H NMR
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analysis of the crude product.
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Scheme 1. Approaches to αꢀ(diarylmethyl) alkyl amines.
Once we identified the optimal reaction conditions, the scope of the methodology was
investigated by various aldimines (Table 1) with different diarylmethyl lithium reagents.
Interestingly, a large variety of substituted aromatic N-tertꢀbutanesulfinyl aldimines, such as oꢀ
chloro, oꢀchloroꢀpꢀfluoro, pꢀmethyl, pꢀmethoxy derivatives (2b−e), reacted with 3aꢀLi to lead
the corresponding αꢀ(diphenylmethyl) alkyl amines 4b−e (Table 1, entries 2ꢀ5) in yields of 90 –
95% with high diastereomeric ratios (dr 98:2). Likewise, heterocyclic N-tert-butanesulfinyl
aldimines, such as 2ꢀfuryl (2f) and 2ꢀthiophenyl (2g) reacted with 3aꢀLi to afford the
corresponding αꢀ(diarylmethyl) alkyl amines 4f and 4g (Table 1, entries 6, 7) in 91% and 92%
yields with dr 98:2 respectively. Similarly, several aliphatic N-tertꢀbutanesulfinyl aldimines,
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such as cinnamyl, 3ꢀphenyl ethyl, isopropyl, isobutyryl, nꢀpropyl derivatives (2h−l) were also
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reacted with 3aꢀLi to form αꢀ(diphenylmethyl) alkyl amines 4h−l in yields of 90ꢀ94% with high
diastereomeric ratios (dr 98:2).
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Table 1. Addition of diarylmethyl nucleophile to various N-tertꢀbutanesulfinyl aldimines.a
yield (%)b
drc
entry
Substrate (R)
2a: R= Ph
product
4a
1
93
90
91
90
95
91
92
92
90
93
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>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
2
2b: R= oꢀClC6H5
2c: R= oꢀClꢀpꢀFC6H4
2d: R= pꢀMeC6H5
2e: R= pꢀMeOC6H5
2f: R= 2ꢀFuryl
4b
4c
3
4
4d
4e
5
6
4f
7
2g: R= 2ꢀThiophenyl
2h: R= Cinnamyl
2i: R= PhCH2CH2
2j: R= Isopropyl
2k: R= Isobutyryl
2l: R= nꢀPropyl
4g
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4h
4i
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4j
4k
4l
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a
90
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All the reactions performed with 1.0 equiv of 2 and 2.0 equiv of 3a at −78 C for 2 h. b Isolated
c
1
yield. The diastereoselectivity was determined by H NMR analysis. The “>98:2” dr denotes that
signal for only one diastereomer were observed
To broaden the scope of this method, we investigated the various N-tertꢀbutanesulfinyl ketimines
2 under optimal reaction conditions to generate the quaternary αꢀ(diphenylmethyl) alkyl amines.
Similarly, the reaction of 3aꢀLi with N-tertꢀbutanesulfinyl methyl ketimines 2n and 2o in THF at
−78 οC for 8 h afforded 4n and 4o bearing a quaternary center in 88 and 90% yields with dr 91:9
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and 92:8 diastereomeric ratios respectively. Likewise, reaction of 3aꢀLi with γꢀchlorinated N-
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tertꢀbutanesulfinyl ketimine 2p also proceeded under optimal reaction conditions afford the
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cyclized pyrrolidine derivative 4p with a quaternary center in 92% yield with dr >95:5 (Scheme
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2).
Scheme 2. Addition of diarylmethyl nucleophile to various N-tertꢀbutanesulfinyl ketimines.
Further we extended this methodology to the asymmetric amino acid derivatives. The reaction
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of 3aꢀLi with N-tertꢀbutanesulfinyl imino acetate 2q in THF at −78 C for 2 h did not yield the
expected product, probably due to N-tertꢀbutanesulfinyl imino acetate 2q being a complex
electrophile with multiple reacting centers. However, the reaction of 3aꢀZnCl2 with 2q in THF at
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−40 C for 8 h proceeded in a facile manner with 82% yield and diastereomeric ratios of 93:7
(Table 2).
Table 2. Addition of various diarylmethyl nucleophile to N-tertꢀbutanesulfinylphenyl aldimine
(RS) 2a.
yield (%)b
drc
entry
reagent (R)
3a: R= H
3b: R= pꢀMe
product
4a
4m
1
2
93
90
>98:2
>98:2
Encouraged by these results, we examined other substituted 3aꢀLi reagents. In a similar manner,
pꢀmethyl substituted 3bꢀLi reacted smoothly with 2a to obtain the corresponding 4m in 90%
yield with high diastereomeric ratio (>98:2). However, surprisingly the reaction of di(pꢀmethoxy
phenyl)methane 3c with nꢀBuLi generated the oꢀlithiated intermediate 6c6 instead of 3cꢀLi
intermediate (Scheme 3).
Scheme 3. Reactive species.
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Treatment of oꢀlithiated intermediate 6c with several N-tertꢀbutanesulfinylphenyl aldimines such
as 2a, 2d, 2f, 2g and 2j lead to the corresponding amines 5a−j (Scheme 4, entries 1−5) in
excellent yields (90−95%) and good diastereomeric ratios (dr 90:10 to 95:5). The structure and
absolute configuration of (RS,S)ꢀ5j was confirmed by single crystal Xꢀray diffraction analysis
(Fig. 2).
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Scheme 4. Addition of oꢀlithiated intermediate 6c to various N-tertꢀbutanesulfinyl Aldimines (2).
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Fig. 2. Xꢀray crystal structure of 5j (CCDC No. 1835984).
Finally, the sulfinyl group was readily cleaved under mild acidic conditions (1N HCl in
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Methanol at 0 C for 30 min.) to provide free amine 1 in quantitative yield. The absolute
configuration of newly generated center in 1j, k were confirmed as “S” by comparison with
literature (Scheme 5).2b
Scheme 5. Cleavage of Sulfinyl Group.
S
NH2
HN
O
a) 1 N HCl in MeOH
b) NaHCO3
1j
4j
[α]D
25 = −4.1 (c = 1, CHCl3),
lit2b −4.2 (c = 10.9, CHCl3)
S
NH2
HN
O
a) 1 N HCl in MeOH
b) NaHCO3
1k
−
32.0 (c = 1, CHCl ),
4k
25
α
[ ]D
=
3
lit2b −31.6 (c = 4.1, CHCl )
3
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Conclusions
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In conclusion, a regioselective lithiation of αꢀDiarylmethanes and followed by highly
diastereoselective addition to various chiral N-tertꢀbutanesulfinylimines has been developed.
This method is also found to be efficient for the preparation of enantiomerically and
diastereomerically pure αꢀ(diarylmethyl) alkyl amines bearing quaternary centers. Extension of
this work is currently in progress.
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Experimental Section
General Information. All the reactions were performed under dry nitrogen gas in glassware that
was flameꢀdried and equipped with a magnetic stirring bar. Thinꢀlayer chromatography (TLC)
was performed using silica gel 60 F254 preꢀcoated plates (0.25 mm). Flash chromatography was
performed using silica gel (40 ꢁm particle size). All compounds were judged pure by TLC
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analysis (single spot/ two solvent systems) using a UV lamp or PMA for detection purposes. H
and 13C NMR spectra were recorded on a FTꢀNMR spectrometer at 400 and 100 MHz,
respectively. Mass spectra (HRMS) were obtained using an electrospray ionization (ESIꢀTOF)
mass spectrometer. The reaction temperatures refer to internal reaction temperatures. All the
Ellman’s Imines (2aꢀq) were synthezied using known procedures.4
General procedure (GP1):
o
A solution of biphenyl methane (5.0 mmol) in THF (2.5 mL) was cooled to 0 C, then nꢀBuLi
(1.6 M in cyclohexane, 3.0 mmol) was added dropwise via syringe and the resulting solution was
o
o
stirred for 1 h at 0 C. After that the reaction was cooled to ꢀ78 C and N-tertꢀbutanesulfinyl
aldimine (RS) 2 (1.0 mmol in 0.5 mL of THF) was added dropwise via syringe over the period of
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30 min. The reaction mixture was stirred for 1 h at ꢀ78 C. After completion of the reaction, it
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was quenched with water (5 mL) and warmed to room temperature over the period of 30 min.
The reaction mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic layer
was removed in vacuo to give crude product. The crude product was purified by column
chromatography using ethyl acetate/hexanes afforded the pure Compound 4.
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(R)ꢀ2ꢀmethylꢀNꢀ((R)ꢀ1,2,2ꢀtriphenylethyl)propaneꢀ2ꢀsulfinamide (4a): Following the general
procedure (GP1), the reaction of N-tertꢀbutanesulfinyl aldimine (RS) 2a (200 mg, 0.95 mmol)
with biphenyl methane (4.77 mmol) and nꢀBuLi (1.6 M in cyclohexane, 2.86 mmol) afforded
amine 4a as white solid (330 mg, 93%). mp =150−152 oC, [α]20 = 46.7 (c. 0.25, CHCl3). IR:
D
1
3273, 3057, 1452, 1045, 700. H NMR (400 MHz, DMSOꢀd6) δ ppm 7.54 (d, J=7.6 Hz, 2H),
7.47 (d, J=7.2 Hz, 2H), 7.30ꢀ7.24 (m, 4H), 7.18ꢀ7.10 (m, 3H), 7.05ꢀ7.02 (m, 3H), 6.94ꢀ6.92 (m,
1H), 5.30 (d, J=10.4 Hz, 1H), 5.12 (t, J=11.2 Hz, 1H), 4.48 (d, J=11.6 Hz, 1H), 0.73 (s, 9H). 13C
NMR (100 MHz, DMSO-d6) δ ppm 149.2, 148.4, 147.6, 133.6, 133.6, 133.3, 133.2, 133.1,
132.8, 131.7, 131.1, 130.9, 69.6, 63.1, 60.5, 27.3. HRMS (ESI) Calcd for C24H28NOS [M+H]+:
378.1886, Found 378.1872
(R)ꢀNꢀ((R)ꢀ1ꢀ(2ꢀchlorophenyl)ꢀ2,2ꢀdiphenylethyl)ꢀ2ꢀmethylpropaneꢀ2ꢀsulfinamide
(4b):
Following the general procedure (GP1), the reaction of N-tertꢀbutanesulfinyl aldimine (RS) 2b
(200 mg, 0.82 mmol) with biphenyl methane (4.10 mmol) and nꢀBuLi (1.6 M in cyclohexane,
2.46 mmol) afforded amine 4b as white solid (300 mg, 90%). mp = 145−147 oC, [α]20D = 16.3 (c.
0.25 in CHCl3). IR: 3172, 3062, 2953, 1494, 1450, 1055, 756, 700. 1H NMR (400 MHz, DMSOꢀ
d6) δ ppm 7.88ꢀ7.86 (m, 1H), 7.50 (d, J=7.6 Hz, 2H), 7.33ꢀ7.14 (m, 7H), 7.10ꢀ7.04 (m, 3H),
6.99ꢀ6.95 (m, 1H), 5.55 (dd, J=21.6, 10.8 Hz, 1H), 5.38 (d, J=9.6 Hz, 1H), 4.59 (d, J=11.2 Hz,
1H), 0.74 (s, 9H). 13C NMR (100 MHz, DMSO-d6) δ ppm 143.6, 142.0, 141.9, 132.8, 129.5,
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129.1, 128.8, 128.7, 128.5, 128.4, 127.6, 126.6, 126.6, 60.0, 57.8, 56.0, 22.5. HRMS (ESI) Calcd
for C24H27ClNOS [M+H]+: 412.1496, Found 412.1490.
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(R)ꢀNꢀ((R)ꢀ1ꢀ(2ꢀchloroꢀ4ꢀfluorophenyl)ꢀ2,2ꢀdiphenylethyl)ꢀ2ꢀmethylpropaneꢀ2ꢀsulfinamide
(4c): Following the general procedure (GP1), the reaction of N-tertꢀbutanesulfinyl aldimine (RS)
2c (200 mg, 0.76 mmol) with biphenyl methane (3.82 mmol) and nꢀBuLi (1.6 M in cyclohexane,
2.29 mmol) afforded amine 4c as white solid (290 mg, 91%). mp =125−127 oC, [α]20D = 24.9 (c.
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1
0.25 in CHCl3). IR: 3174, 2958, 1604, 1494, 1039, 744, 702. H NMR (400 MHz, DMSOꢀd6) δ
ppm 7.96ꢀ7.89 (m, 1H), 7.50 (d, J=7.6 Hz, 2H), 7.32 (t, J=7.6 Hz, 2H), 7.29ꢀ 7.13 (m, 5H), 7.13ꢀ
13
7.08 (m, 2H), 7.02ꢀ6.98 (m, 1H), 5.54 ꢀ5.42 (m, 2H), 4.57 (d, J=11.2 Hz, 1H), 0.76 (s, 9H). C
NMR (100 MHz, DMSO-d6) δ ppm 162.0, 159.6, 143.4, 141.9, 137.6, 133.4, 131.1, 128.8,
128.7, 128.6, 128.4, 126.7, 116.1, 115.9, 115.1, 114.9, 59.6, 57.8, 56.0, 34.0, 22.5, 22.2, 14.3.
HRMS (ESI) Calcd for C24H26ClFNOS [M+H]+: 430.1407, Found 430.1410.
(R)ꢀNꢀ((R)ꢀ2, 2ꢀdiphenylꢀ1ꢀ(pꢀtolyl)ethyl)ꢀ2ꢀmethylpropaneꢀ2ꢀsulfinamide (4d): Following
the general procedure (GP1), the reaction of N-tertꢀbutanesulfinyl aldimine (RS) 2d (250 mg,
1.11 mmol) with biphenyl methane (5.59 mmol) and nꢀBuLi (1.6 M in cyclohexane, 3.35 mmol)
o
afforded amine 4d as white solid (390 mg, 90%). mp =162−164 C, [α]20 = 50.8 (c. 0.25 in
D
1
CHCl3). IR: 3290, 3028, 2947, 1494, 1452, 1066, 704. H NMR (400 MHz, DMSOꢀd6) δ ppm
7.52 (d, J=7.2 Hz, 2H), 7.35 (d, J=7.6 Hz, 2H), 7.34ꢀ7.22 (m, 4H), 7.16ꢀ7.05 (m, 3H), 7.01ꢀ6.94
(m, 3H), 5.18 (d, J=10.0 Hz, 1H), 5.07 (t, J=10.8 Hz, 1H), 4.47 (d, J=11.6 Hz, 1H), 2.17 (s, 3H),
13
0.72 (s, 9H). C NMR (100 MHz, DMSO-d6) δ ppm 144.5, 143.0, 140.7, 135.8, 128.9, 128.8,
128.7, 128.5, 128.4, 128.3, 126.3, 126.2, 64.5, 58.3, 55.7, 22.5, 21.1. HRMS (ESI) Calcd for
C25H30NOS [M+H]+: 392.2043, Found 392.2026.
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(R)ꢀNꢀ((R)ꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ2,2ꢀdiphenylethyl)ꢀ2ꢀmethylpropaneꢀ2ꢀsulfinamide
(4e):
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Following the general procedure (GP1), the reaction of N-tertꢀbutanesulfinyl aldimine (RS) 2e
(200 mg, 0.835 mmol) with biphenyl methane (4.17 mmol) and nꢀBuLi (1.6 M in cyclohexane,
2.50 mmol) afforded amine 4e as white solid (323 mg, 95%). mp = 164−166 oC, [α]20D = 58.6 (c.
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0.25 in CHCl3). IR: 3280, 2947, 1585, 1514, 1454, 1244, 1043, 705. H NMR (400 MHz,
DMSOꢀd6) δ ppm 7.52 (d, J=7.6 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H), 7.35ꢀ7.21 (m, 4H), 7.16ꢀ7.04
(m, 3H), 7.03ꢀ6.92 (m, 1H), 6.71 (d, J=8.4 Hz, 2H), 5.15 (d, J=10.4 Hz, 1H), 5.06 (t, J=11.2 Hz,
1H), 4.46 (d, J=11.2 Hz, 1H), 3.66 (s, 3H), 0.72 (s, 9H). 13C NMR (100 MHz, DMSO-d6) δ ppm
158.1, 144.6, 143.1, 135.8, 129.5, 128.9, 128.9, 128.5, 128.5, 126.3, 126.1, 113.5, 64.2, 58.5,
55.7, 55.2, 22.6. HRMS (ESI) Calcd for C25H30NO2S [M+H]+: 408.1992, Found 408.1981.
(R)ꢀNꢀ((R)ꢀ1ꢀ(furanꢀ2ꢀyl)ꢀ2,2ꢀdiphenylethyl)ꢀ2ꢀmethylpropaneꢀ2ꢀsulfinamide (4f): Following
the general procedure (GP1), the reaction of N-tertꢀbutanesulfinyl aldimine (RS) 2f (250 mg, 1.25
mmol) with biphenyl methane (6.27 mmol) and nꢀBuLi (1.6 M in cyclohexane, 3.76 mmol)
afforded amine 4f as white solid (420 mg, 91%). mp =141−143 C, [α]20 = 79.7 (c. 0.25 in
o
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CHCl3). IR: 3261, 2956, 1496, 1450, 1161, 1060, 705. H NMR (400 MHz, DMSOꢀd6) δ ppm
7.44 (d, J=7.2 Hz, 2H), 7.41ꢀ7.31 (m, 4H), 7.29ꢀ7.21 (m, 2H), 7.19ꢀ7.03 (m, 4H), 6.48 (s, 1H),
5.22ꢀ5.08 (m, 2H), 4.32 (d, J=10.8 Hz, 1H), 0.72 (s, 9H). 13C NMR (100 MHz, DMSO-d6) δ ppm
144.3, 143.3, 142.7, 140.5, 128.8, 128.6, 128.6, 128.6, 127.9, 126.4, 126.3, 110.7, 58.2, 56.3,
55.7, 22.6. HRMS (ESI) Calcd for C22H26NO2S [M+H]+: 368.1679, Found 368.1666.
(R)ꢀNꢀ((R)ꢀ2,2ꢀdiphenylꢀ1ꢀ(thiophenꢀ2ꢀyl)ethyl)ꢀ2ꢀmethylpropaneꢀ2ꢀsulfinamide
(4g):
Following the general procedure (GP1), the reaction of N-tertꢀbutanesulfinyl aldimine (RS) 2g
(200 mg, 0.93 mmol) with biphenyl methane (4.64 mmol) and nꢀBuLi (1.6 M in cyclohexane,
2.78 mmol) afforded amine 4g as white solid (327 mg, 92%). mp =140−142 oC, [α]20D = 82.7 (c.
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0.25 in CHCl3). IR: 3333, 3028, 2985, 1452, 1060, 704. H NMR (400 MHz, DMSOꢀd6) δ ppm
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7.49 (d, J=7.6 Hz, 2H), 7.36 (d, J=7.2 Hz, 2H), 7.32ꢀ7.18 (m, 3H), 7.17ꢀ7.06 (m, 4H), 7.05ꢀ6.95
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(m, 1H), 6.82ꢀ6.76 (m, 1H), 5.47ꢀ5.35 (m, 2H), 4.46 (d, J=11.2 Hz, 1H), 0.72 (s, 9H). C NMR
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(100 MHz, DMSO-d6) δ ppm 147.1, 144.2, 143.0, 128.7, 128.6, 128.5, 126.4, 126.4, 126.3,
125.1, 59.8, 59.3, 55.9, 22.6. HRMS (ESI) Calcd for C22H26NOS2 [M+H]+ : 384.1450 Found
384.1438.
(R)ꢀ2ꢀmethylꢀNꢀ((S,E)ꢀ1,1,4ꢀtriphenylbutꢀ3ꢀenꢀ2ꢀyl)propaneꢀ2ꢀsulfinamide (4h): Following
the general procedure (GP1), the reaction of N-tertꢀbutanesulfinyl aldimine (RS) 2h (300 mg,
1.27 mmol) with biphenyl methane (6.37 mmol) and nꢀBuLi (1.6 M in cyclohexane, 3.82 mmol)
o
afforded amine 4h as white solid (473 mg, 92%). mp =128−130 C, [α]20 = 20.0 (c. 0.25 in
D
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CHCl3). IR: 3446, 2922, 1450, 1354, 1047, 748, 700. H NMR (400 MHz, DMSOꢀd6) δ ppm
7.46ꢀ7.39 (m, 5H), 7.31ꢀ7.15 (m, 8H), 7.15ꢀ7.05(m, 2H), 6.55 (d, J=15.9 Hz, 1H), 6.18ꢀ6.08 (m,
1H), 5.32 (d, J=10.0 Hz, 1H), 4.79ꢀ4.68 (m, 1H), 4.15 (d, J=11.2 Hz, 1H), 0.75 (s, 9H). 13C
NMR (100 MHz, DMSO-d6) δ ppm 144.0, 143.0, 137.2, 132.4, 131.0, 129.0, 128.9, 128.8,
128.7, 128.5, 127.7, 126.6, 126.4, 126.3, 63.2, 57.9, 55.7, 22.6. HRMS (ESI) Calcd for
C26H30NOS [M+H] +: 404.2043, Found 404.2036.
(R)ꢀ2ꢀmethylꢀNꢀ((S)ꢀ1,1,4ꢀtriphenylbutanꢀ2ꢀyl)propaneꢀ2ꢀsulfinamide (4i): Following the
general procedure (GP1), the reaction of N-tertꢀbutanesulfinyl aldimine (RS) 2i (300 mg, 1.26
mmol) with biphenyl methane (6.31 mmol) and nꢀBuLi (1.6 M in cyclohexane, 3.79 mmol)
afforded amine 4i as white solid (461 mg, 90%). mp = 112−114 oC, [α]20 = −34.8 (c. 0.25 in
D
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CHCl3). IR: 3481, 3120, 1452, 1016, 700. H NMR (400 MHz, DMSOꢀd6) δ ppm 7.34 (d, J=7.6
Hz, 2H), 7.31ꢀ7.18 (m, 8H), 7.17ꢀ7.12 (m, 2H), 7.11ꢀ7.04 (m, 3H), 4.98 (d, J=8.8 Hz, 1H), 4.1ꢀ
4.02 (m, 1H), 3.97 (d, J=11.2 Hz, 1H), 2.92ꢀ 2.80 (m, 1H), 2.76ꢀ2.64 (m, 1H), 1.74ꢀ1.66 (m, 2H),
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0.75 (s, 9H). C NMR (100 MHz, DMSO-d6) δ ppm 144.4, 144.0, 142.7, 129.0, 128.9, 128.7,
128.6, 128.6, 128.2, 126.6, 126.3, 126.0, 60.3, 58.7, 55.7, 36.9, 31.2, 22.8. HRMS (ESI) Calcd
for C26H32NOS [M+H]+: 406.2199, Found 406.2180.
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(R)ꢀ2ꢀmethylꢀNꢀ((S)ꢀ3ꢀmethylꢀ1,1ꢀdiphenylbutanꢀ2ꢀyl)propaneꢀ2ꢀsulfinamide
(4j):
Following the general procedure (GP1), the reaction of N-tertꢀbutanesulfinyl aldimine (RS) 2j
(300 mg, 1.71 mmol) with Biphenyl methane (8.55 mmol) and nꢀButyllithium (1.6 M in
o
cyclohexane, 5.13 mmol) afforded amine 4j as white solid (546 mg, 93%). mp =169−171 C,
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[α]20D = 31.7 (c. 0.25 in CHCl3). IR: 3300, 2949, 1450, 1047, 704. H NMR (400 MHz, DMSOꢀ
d6) δ ppm 7.48ꢀ7.38 (m, 4H), 7.32ꢀ7.18 (m, 4H), 7.16ꢀ7.06 (m, 2H), 4.44ꢀ4.37 (m, 1H), 4.06ꢀ4.01
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(m, 2H), 1.70ꢀ1.62 (m, 1H), 1.03 (d, J=6.8 Hz, 3H), 0.78 (d, J=6.8 Hz, 3H), 0.68 (s, 9H). C
NMR (100 MHz, DMSO-d6) δ ppm 144.8, 144.3, 129.0, 129.0, 128.6, 128.3, 126.5, 126.3, 65.7,
56.8, 55.9, 29.3, 22.6, 21.3, 15.3. HRMS (ESI) Calcd for C21H30NOS [M+H]+: 344.2043, Found
344.2027.
(R)ꢀ2ꢀmethylꢀNꢀ((S)ꢀ4ꢀmethylꢀ1,1ꢀdiphenylpentanꢀ2ꢀyl)propaneꢀ2ꢀsulfinamide
(4k):
Following the general procedure (GP1), the reaction of N-tertꢀbutanesulfinyl aldimine (RS) 2k
(300 mg, 1.58 mmol) with biphenyl methane (7.92 mmol) and nꢀBuLi (1.6 M in cyclohexane,
4.75 mmol) afforded amine 4k as white solid (532 mg, 94%). mp =113−115 oC, [α]20 = −32.0
D
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(c. 0.25 in CHCl3). IR: 3493, 3103, 1450, 1028, 704. H NMR (400 MHz, DMSOꢀd6) δ ppm
7.42ꢀ7.33 (m, 4H), 7.31ꢀ7.18 (m, 4H), 7.15ꢀ7.05 (m, 2H), 4.76 (d, J=8.8 Hz, 1H), 4.09ꢀ3.99 (m,
1H), 3.85 (d, J=10.6 Hz, 1H), 2.09ꢀ2.05 (m, 1H), 1.48ꢀ1.39 (m, 1H), 1.09 ꢀ1.01 (m, 1H), 0.83 (d,
J=6.4 Hz, 3H), 0.75 (d, J=6.8 Hz, 3H), 0.68 (s, 9H). 13C NMR (100 MHz, DMSO-d6) δ ppm
144.6, 144.5, 129.1, 129.0, 128.6, 128.2, 126.6, 126.2, 60.1, 58.9, 55.6, 44.5, 24.4, 23.2, 22.8,
21.7. HRMS (ESI) Calcd for C22H32NOS [M+H]+: 358.2199, Found 358.2188.
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(R)ꢀNꢀ((S)ꢀ1,1ꢀdiphenylpentanꢀ2ꢀyl)ꢀ2ꢀmethylpropaneꢀ2ꢀsulfinamide (4l): Following the
general procedure (GP1), the reaction of N-tertꢀbutanesulfinyl aldimine (RS) 2l (200 mg, 1.14
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afforded amine 4l as white solid (358 mg, 90%). mp = 100−102 C, [α]20 = −5.8 (c. 0.25 in
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CHCl3). IR: 3425, 3107, 1454, 1030, 704. H NMR (400 MHz, DMSOꢀd6) δ ppm 7.41ꢀ7.36 (m,
4H), 7.28ꢀ7.18 (m, 4H), 7.17ꢀ7.06 (m, 2H), 4.77 (d, J=9.2 Hz, 1H), 4.04ꢀ4.01 (m, 1H), 3.90 (d,
J=11.2 Hz, 1H),1.59ꢀ1.52 (m, 1H), 1.42ꢀ1.35 (m, 3H), 0.76 (t, J=6.8 Hz, 3H), 0.70 (s, 9H). 13C
NMR (100 MHz, DMSO-d6) δ ppm 144.6, 144.3, 129.0, 128.9, 128.5, 128.2, 126.5, 126.2, 60.5,
59.1, 55.6, 37.0, 24.4, 22.7, 18.3, 14.4. HRMS (ESI) Calcd for C21H30NOS [M+H]+: 344.2043,
Found 344.2027.
(R)ꢀ2ꢀmethylꢀNꢀ((R)ꢀ1ꢀphenylꢀ2,2ꢀdiꢀpꢀtolylethyl)propaneꢀ2ꢀsulfinamide (4m): Following the
general procedure (GP1), the reaction of N-tertꢀbutanesulfinyl aldimine (RS) 2m (200 mg, 0.95
mmol) with diꢀpꢀtolylmethane (4.77 mmol) and nꢀBuLi (1.6 M in cyclohexane, 2.86 mmol)
afforded amine 4m as white solid (438 mg, 90%). mp =143−145 oC, [α]20 = 45.9 (c. 0.25 in
D
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CHCl3). IR: 3334, 2978, 2954, 1597, 1494, 1350, 1066, 709. H NMR (400 MHz, DMSOꢀd6) δ
ppm 7.45 (d, J=7.6 Hz, 2H), 7.37 (d, J=7.6 Hz, 2H), 7.20ꢀ7.01 (m, 7H), 6.84 (d, J=8 Hz, 2H),
5.23 (d, J=10.4 Hz, 1H), 5.03 (t, J=11.2Hz, 1H), 4.40 (d, J=11.2 Hz, 1H), 2.22 (s, 3H), 2.08 (s,
3H), 0.74 (s, 9H). 13C NMR (100 MHz, DMSO-d6) δ ppm 143.4, 141.2, 141.1, 135.6, 130.9,
130.4, 128.2, 128.1, 128.0, 127.8, 126.8, 126.6, 63.3, 63.2, 56.1, 24.6, 22.7, 20.9. HRMS (ESI)
Calcd for C26H32NOS [M+H]+: 406.2199, Found 406.2180.
(R)ꢀ2ꢀmethylꢀNꢀ((R)ꢀ1,1,2ꢀtriphenylpropanꢀ2ꢀyl)propaneꢀ2ꢀsulfinamide (4n): Following the
general procedure (GP1), the reaction of N-tertꢀbutanesulfinyl ketimines (RS) 2n (200 mg, 0.89
mmol) with Biphenyl methane (4.47 mmol) and nꢀBuLi (1.6 M in cyclohexane, 2.68 mmol)
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afforded amine 4n as white solid (438 mg, 88%). mp = 107−109 oC, [α]20 = 108.2 (c. 0.25 in
D
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CHCl3). 1H NMR (400 MHz, DMSOꢀd6) δ 7.41ꢀ7.36 (m, 2H), 7.32ꢀ7.18 (m, 10H), 7.03ꢀ6.98 (m,
2H), 4.39 (s, 1H), 4.12 (s, 1H), 1.84 (s, 3H), 1.26 (s, 9H). 13C NMR (100 MHz, CDCl3) δ ppm
144.7, 140.1, 139.1, 130.4, 128.1, 128.0, 127.9, 127.4, 127.1, 126.9, 65.3, 63.7, 56.5, 27.2, 22.8.
HRMS (ESI) Calcd for C25H30NOS [M+H]+: 392.2043, Found 392.2027.
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(R)ꢀNꢀ((R)ꢀ2ꢀ(4ꢀfluorophenyl)ꢀ1,1ꢀdiphenylpropanꢀ2ꢀyl)ꢀ2ꢀmethylpropaneꢀ2ꢀsulfinamide
(4o): Following the general procedure (GP1), the reaction of N-tertꢀbutanesulfinyl ketimines (RS)
2o (200 mg, 0.83 mmol) with biphenyl methane (4.14 mmol) and nꢀBuLi (1.6 M in cyclohexane,
2.48 mmol) afforded amine 4o as white solid (438 mg, 88%). mp = 101−103 oC, [α]20D = 78.3 (c.
1
0.25 in CHCl3). IR: 3304, 2960, 1598, 1510, 1450, 1348, 1072, 835, 705. H NMR (400 MHz,
DMSOꢀd6) δ 7.46ꢀ7.37 (m, 4H), 7.32ꢀ7.22 (m, 4H), 7.22ꢀ7.06 (m, 4H), 7.03ꢀ6.94 (m, 2H), 5.08
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(s, 1H), 4.61 (s, 1H), 1.77 (s, 3H), 0.98 (s, 9H), C NMR (100 MHz, DMSO-d6) δ ppm 147.5,
145.7, 145.7, 135.7, 135.1, 134.7, 134.6, 133.0, 132.8, 131.6, 131.4, 118.9, 118.6, 68.0, 67.9,
60.9, 28.9, 27.4. HRMS (ESI) Calcd for C25H29FNOS [M+H]+:410.1948, Found 410.1929.
(R)ꢀ2ꢀbenzhydrylꢀ1ꢀ((R)ꢀtertꢀbutylsulfinyl)ꢀ2ꢀphenylpyrrolidine (4p): Following the general
procedure (GP1), the reaction of N-tertꢀbutanesulfinyl ketimines 2p (200 mg, 0.7 mmol) with
biphenyl methane (3.50 mmol) and nꢀBuLi (1.6 M in cyclohexane, 2.10 mmol) afforded amine
4p as white solid (438 mg, 92%). mp =128−130 oC, [α]20 = 73.2 (c. 0.25 in CHCl3). IR: 3088,
D
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2929, 1494, 1450, 1359, 1064, 714. H NMR (400 MHz, DMSOꢀd6) δ 7.31ꢀ7.20 (m, 8H), 7.16ꢀ
7.08 (m, 5H), 7.05ꢀ6.98 (m, 2H), 5.14 (s, 1H), 3.67ꢀ3.58 (m, 1H), 2.73ꢀ2.64 (m, 1H), 2.33ꢀ2.25
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(m, 1H), 2.21ꢀ2.09 (m, 1H), 1.47ꢀ1.39 (m, 1H), 1.12ꢀ1.08 (m, 1H), 0.79 (s, 9H). C NMR (100
MHz, DMSO-d6) δ ppm 146.5, 146.2, 146.0, 136.3, 136.0, 133.8, 132.7, 132.7, 132.3, 132.3,
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131.9, 131.2, 82.5, 63.6, 63.1, 28.6, 28.1. HRMS (ESI) Calcd for C27H32NOS [M+H]+ :
418.2199, Found 418.2179.
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Ethyl (R)ꢀ2ꢀ(((R)ꢀtertꢀbutylsulfinyl)amino)ꢀ3,3ꢀdiphenylpropanoate (4q): A solution of
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biphenyl methane (4.87 mmol) in THF (2.5 mL) was cooled to 0 C then nꢀBuLi (1.6 M in
cyclohexane, 2.92 mmol) was added dropwise via syringe and the resulting reaction mixture was
o
stirred for 1 h at 0 C. To the reaction mixture ZnCl2 (0.5 M solution in THF, 4.87 mmol) was
added at 0 oC and stirred for 1 h. After that the reaction mixture was cooled to ꢀ78 oC and N-tertꢀ
butanesulfinyl aldimine (RS) 2q (200 mg, 0.97 mmol in 0.5 mL of THF) was added dropwise via
o
syringe over the period of 30 min. The reaction mixture was allowed to come at ꢀ40 C and
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stirred for 8 h at ꢀ40 C. After completion of reaction, it was quenched with water (5 mL) and
warmed to room temperature over the period of 30 min. The reaction mixture was extracted with
ethyl acetate (3 X 5 mL) and combined organic layers was washed with water (1 X 5 mL) and
oncentrated under vacum to dryness to obtained crude compound. The crude compound was
purified by column chromatography using ethyl acetate/hexanes to afford amine 4q as white
solid (438 mg, 83%). mp =89−91 oC, [α]20 = 44.1 (c. 0.25 in CHCl3). IR: 3028, 2927, 1735,
D
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1598, 1494, 1452, 1346, 1037, 702. H NMR (400 MHz, DMSOꢀd6) δ ppm 7.46ꢀ7.34 (m, 4H),
7.31ꢀ7.22 (m, 4H), 7.21ꢀ7.13 (m, 2H), 5.73 (dd, J=10.4, 7.2 Hz, 1H), 4.70ꢀ4.51 (m, 1H), 4.40ꢀ
4.33 (m, 1H), 3.89ꢀ3.81 (m, 2H), 0.87ꢀ0.78 (m, 12H). 13C NMR (100 MHz, DMSO-d6) δ ppm
172.7, 142.1, 141.1, 129.0, 128.8, 128.6, 128.5, 127.2, 126.7, 63.1, 60.5, 56.1, 54.5, 22.6, 13.9.
HRMS (ESI) Calcd for C21H28NO3S [M+H]+: 374.1784, Found 374.1778.
(R)ꢀNꢀ((S)ꢀ(2ꢀmethoxyꢀ5ꢀ(4ꢀmethoxybenzyl)phenyl)(phenyl)methyl)ꢀ2ꢀmethylpropaneꢀ2ꢀ
sulfinamide (5a): Following the general procedure (GP1), the reaction of N-tertꢀbutanesulfinyl
aldimine (RS) 2a (200 mg, 0.95 mmol) with bis(4ꢀmethoxyphenyl)methane (4.77 mmol) and nꢀ
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BuLi (1.6 M in cyclohexane, 2.86 mmol) afforded amine 5a as white solid (384 mg, 92%). mp =
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98−100 oC, [α]20 = −6.7 (c. 0.25 in CHCl3). H NMR (400 MHz, CDCl3) δ ppm 7.42ꢀ7.36 (m,
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2H), 7.36ꢀ7.21 (m, 3H), 7.13ꢀ7.05 (m, 3H), 6.84ꢀ6.77 (m, 3H), 6.02 (s, 1H), 3.91(s, 2H), 3.82 (s,
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3H), 3.77(s, 3H), 1.18 (s, 9H). C NMR (100 MHz, CDCl3) δ ppm 157.9, 155.3, 142.5, 133.6,
133.4, 129.8, 129.6, 128.7, 128.5, 127.5, 127.4, 113.8, 110.9, 56.3, 55.8, 55.6, 55.3, 40.3, 22.6.
HRMS (ESI) Calcd for C26H32NO3S [M+H]+: 438.2097, Found 438.2078.
(R)ꢀNꢀ((S)ꢀ(2ꢀmethoxyꢀ5ꢀ(4ꢀmethoxybenzyl)phenyl)(pꢀtolyl)methyl)ꢀ2ꢀmethylpropaneꢀ2ꢀ
sulfinamide (5d): Following the general procedure (GP1), the reaction of N-tertꢀbutanesulfinyl
aldimine (RS) 2d (247 mg, 1.11 mmol) with bis(4ꢀmethoxyphenyl)methane (5.59 mmol) and nꢀ
BuLi (1.6 M in cyclohexane, 3.35 mmol) afforded amine 5d as white solid (460 mg, 92%). mp
=107−108 oC, [α]20D = −61.8 (c. 0.25 in CHCl3). 1H NMR (400 MHz, DMSOꢀd6) δ ppm 7.32 (s,
1H), 7.21ꢀ7.15 (m, 2H), 7.12ꢀ7.02 (m, 5H), 6.90ꢀ6.80 (m, 3H), 5.75 (d, J=5.6 Hz, 1H), 5.58 (d,
J=5.6 Hz, 1H), 3.79 (s, 2H), 3.71(s, 6H), 2.25 (s, 3H), 1.06 (s, 9H). 13C NMR (100 MHz, CDCl3)
δ ppm 157.9, 155.3, 139.5, 137.1, 133.7, 133.4, 129.8, 129.7, 129.2, 128.6, 128.6, 127.4, 113.8,
110.8, 56.0, 55.8, 55.6, 55.3, 40.3, 22.6, 21.1. HRMS (ESI) Calcd for C27H34NO3S [M+H]+:
452.2260, Found 452.2284.
(R)ꢀNꢀ((R)ꢀfuranꢀ2ꢀyl(2ꢀmethoxyꢀ5ꢀ(4ꢀmethoxybenzyl)phenyl)methyl)ꢀ2ꢀmethylpropaneꢀ2ꢀ
sulfinamide (5f): Following the general procedure (GP1), the reaction of N-tertꢀbutanesulfinyl
aldimine (RS) 2f (248 mg, 1.25 mmol) with bis(4ꢀmethoxyphenyl)methane (6.27 mmol) and nꢀ
BuLi (1.6 M in cyclohexane, 3.76 mmol) afforded amine 5f as white solid (490 mg, 92%). mp
o
1
=113−115 C, [α]20 = −24.2 (c. 0.25 in CHCl3). H NMR (400 MHz, CDCl3) δ ppm 7.38ꢀ7.17
D
(m, 3H), 7.14ꢀ7.06 (m, 3H), 6.88ꢀ6.80 (m, 3H), 6.40 (s, 1H), 5.87 (s, 1H), 3.90 (s, 2H), 3.82 (s,
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3H), 3.81 (s, 3H), 1.18 (s, 9H). C NMR (100 MHz, CDCl3) δ ppm 157.9, 155.1, 143.2, 140.2,
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133.6,133.5, 129.7, 129.4, 128.8, 128.5, 127.8, 113.8, 110.9, 110.0, 55.8, 55.6, 55.3, 50.1, 40.2,
22.5. HRMS(ESI) Calcd for C24H30NO4S [M+H]+ : 428.1890, Found 428.1874.
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(R)ꢀNꢀ((R)ꢀ(2ꢀmethoxyꢀ5ꢀ(4ꢀmethoxybenzyl)phenyl)(thiophenꢀ2ꢀyl)methyl)ꢀ2ꢀ
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methylpropaneꢀ2ꢀsulfinamide (5g): Following the general procedure (GP1), the reaction of N-
tertꢀbutanesulfinyl aldimine (RS) 2g (200 mg, 0.93 mmol) with bis(4ꢀmethoxyphenyl)methane
(4.64 mmol) and nꢀ BuLi (1.6 M in cyclohexane, 2.78 mmol) afforded amine 5g as white solid
o
1
(387 mg, 94%). mp =117−119 C, [α]20 = −24.5 (c. 0.25 in CHCl3). H NMR (400 MHz,
D
CDCl3) δ 7.28ꢀ7.22 (m, 2H), 7.17ꢀ7.05 (m, 4H), 6.94ꢀ6.91 (m, 1H), 6.90ꢀ6.80 (m, 3H), 6.26ꢀ6.21
(m, 1H), 3.97ꢀ3.93 (m, 1H), 3.91 (s, 2H), 3.82 (s, 6H), 1.18 (s, 9H). 13C NMR (100 MHz, CDCl3)
δ ppm 157.8, 155.2, 146.7, 133.6, 133.5, 129.8, 129.5, 129.1, 128.5, 126.7, 125.4, 125.0, 113.8,
111.0, 55.9, 55.6, 55.2, 52.6, 40.2, 22.5. HRMS (ESI) Calcd for C24H30NO3S2 [M+H]+:
444.1662, Found 444.1647.
(R)ꢀNꢀ((S)ꢀ1ꢀ(2ꢀmethoxyꢀ5ꢀ(4ꢀmethoxybenzyl)phenyl)ꢀ2ꢀmethylpropyl)ꢀ2ꢀmethylpropaneꢀ2ꢀ
sulfinamide (5j): Following the general procedure (GP1), the reaction of N-tertꢀbutanesulfinyl
aldimine (RS) 2j (170 mg, 0.95 mmol) with bis(4ꢀmethoxyphenyl)methane (4.77 mmol) and nꢀ
BuLi (1.6 M in cyclohexane, 2.86 mmol ) afforded amine 5j as white solid (365 mg, 95%). mp
1
=122−124 oC, [α]20 = −52.8(c. 0.25 in CHCl3). H NMR (400 MHz, CDCl3) δ ppm 7.10ꢀ7.02
D
(m, 3H), 6.99 (s, 1H), 6.85ꢀ6.81 (m, 3H), 4.50ꢀ4.46 (m, 1H), 3.88 (s, 2H), 3.86 (s, 3H), 3.85 (s,
3H), 3.74ꢀ3.70 (m, 1H), 2.10ꢀ2.04 (m, 1H), 1.10 (s, 9H), 1.01(d, J=6.4 Hz, 3H), 0.86 (d, J=6.8
13
Hz,3H), . C NMR (100 MHz, CDCl3) δ ppm 157.8, 155.5, 133.7, 133.1, 129.7, 129.5, 128.2,
113.8, 110.7, 55.5, 55.5, 55.3, 40.2, 33.8, 22.4, 19.6, 19.0. HRMS (ESI) Calcd for C23H34NO3S
[M+H]+: 404.2254, Found 404.2244.
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General procedure (GP2): A solution of αꢀ(diarylmethyl) alkyl amines (1.0 mmol) in 1,4ꢀ
Dioxane (1 mL) was added HCl (4.0 M solultion in 1,4ꢀDioxane, 10.0 mmol) at room
temperature. It was stirred at room temperature for 2 h and then reaction mixture was
concentrated under vacuo. The crude was diluted with water (2 ml) and ethyl acetate (5 mL) and
pH was adjust to 12ꢀ13 using 6 M NaOH aqueous solution. It was extracted with ethyl acetate (3
x 5 mL) and combined organic layer was concentrated under vacuum to obtain product.
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(S)ꢀ3ꢀmethylꢀ1,1ꢀdiphenylbutanꢀ2ꢀamine (1j): Following the general procedure (GP2), the
reaction of αꢀ(diarylmethyl) alkyl amines 4j (100 mg, 0.29 mmol) with HCl (4.0 M in dioxane,
2.9 mmol, 0.72 mL) afforded amine 1j as white solid (69 mg, 99%). mp = 70−71 oC, [α]20
=
D
−4.1 (c. 1.0 in CHCl3), reported −4.2 (c, 10.9 in CHCl3). IR: 3361, 30 64, 3024, 2958, 2926,
1
1597, 1490, 1450, 1361, 748, 702. H NMR (400 MHz, DMSOꢀd6) δ ppm 7.48ꢀ7.42 (m, 2H),
7.40ꢀ7.34 (m, 2H), 7.27ꢀ7.21 (m, 4H), 7.18ꢀ7.08 (m, 2H), 3.74 (d, J=10.8 Hz, 1H), 3.50 (dd,
J=10.8, 2.0 Hz, 1H), 1.54ꢀ1.47 (m, 1H), 0.98 (bs, 2H), 0.90 (d, J=6.8 Hz, 3H), 0.76 (d, J=6.8
Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ ppm 144.7, 144.5, 128.9, 128.7, 128.3, 126.4, 126.3,
57.9, 57.7, 28.9, 21.5, 14.1. HRMS (ESI) Calcd for C17H22N [M+H]+: 240.1747, Found
240.1750.
(S)ꢀ4ꢀmethylꢀ1,1ꢀdiphenylpentanꢀ2ꢀamine (1k): Following the general procedure (GP2), the
reaction of αꢀ(diarylmethyl) alkyl amines 4k (100 mg, 0.28 mmol) with HCl in dioxane (4.0 M
in dioxane, 2.8 mmol, 0.7 mL) afforded amine 1k as white solid (70 mg, 99%). mp = 48−50 oC,
[α]20 = −32.0 (c. 1.0 in CHCl3) reported −31.6 (c, 4.1 in CHCl3). IR: 3379, 3026, 2953, 2900,
D
1
1597, 1494, 1450, 1355, 1080, 744, 704. H NMR (400 MHz, DMSOꢀd6) δ ppm 7.44ꢀ7.39 (m,
2H), 7.36ꢀ7.24 (m, 6H), 7.19ꢀ7.10 (m, 2H), 3.62ꢀ3.53 (m, 2H), 1.83ꢀ1.78 (m, 1H), 1.25ꢀ1.17 (m,
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2H), 1.10ꢀ 0.96 (m, 2H), 0.83ꢀ0.75 (m, 6H). 13C NMR (100 MHz, DMSO-d6) δ ppm 144.6,
144.3, 128.9, 128.8, 128.8, 128.3, 126.5, 126.4, 61.1, 51.8, 45.3, 24.6, 24.6, 21.7. HRMS (ESI)
Calcd for C18H24N [M+H]+: 254.1903, Found 254.1898
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Supporting Information Available: Copies of NMR spectra of all the compounds and Xꢀray
crystallography data of compound 5j. This material is available free of charge via the Internet a
http://pubs.acs.org.
t
Acknowledgment
We thank Mr.Vivek Sharma and Suresh Raghava (Piramal Enterprises Limited) for valuable
support.
References
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(diphenylmethyl)alkyl amines from amino acids. Tetrahedron: Asymmetry 1999, 10,
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(4) N-tertꢀbutanesulfinyl aldimines and Ketimines are prepared as per our previously
reported procedures (a) Rajender, L.R.; Bin, H.; Prashad, M.; Prasad, K. Asymmetric
Synthesis of Homoallylic Amines Bearing Adjacent Stereogenic Centers by Addition of
Substituted Allylic Zinc Reagents to N-tertꢀButanesulfinylimines. Org. Lett., 2008, 10,
3109. (b) Reddy, L.R.; Sonia, G. D.; Liu, Y.; Prashad, M. A Facile Asymmetric Synthesis
of Either Enantiomer of 2ꢀSubstituted Pyrrolidines. J. Org. Chem. 2010, 75, 2236. (c)
Reddy, L.R.; Aditya, P.G.; Eric, V.; Liu, Y. RhodiumꢀCatalyzed Asymmetric Arylation of
Nꢀ(tertꢀButanesulfinyl)imines with Sodium Tetraarylborates. J. Org. Chem. 2012, 77,
1095. (d) Reddy, L.R.; Aditya, P.G.; Liu, Y.Asymmetric Synthesis of αꢀAmino Acids by
Reduction of NꢀtertꢀButanesulfinyl Ketimine Esters. J. Org. Chem. 2011, 76, 3409. (e)
Reddy, L.R.; Prashad, M.; Prasad, K. A Protocol for an Asymmetric Synthesis of γꢀ
Amino Acids. J. Org. Chem. 2012, 77, 6296 (f) Reddy, L.R.; Prashad, M. Asymmetric
synthesis of 2ꢀsubstituted pyrrolidines by addition of Grignard reagents to γꢀchlorinated
N-tertꢀbutanesulfinyl imine. Chem. Commun. 2010, 46, 222.
(5) Preparation 3ꢀLi: To stirred solution of 3 (2.0 mmol) in THF at 0 οC nꢀBuLi (1.9 mmol)
was added dropwise and stirred for 1 h at the same temperature afford 3ꢀLi reagent.
(6) (a) Snieckus, V. Directed ortho metalation. Tertiary amide and Oꢀcarbamate directors in
synthetic strategies for polysubstituted aromatics. Chem. Rev. 1990, 90, 879. (b) Whisler,
M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Beyond Thermodynamic Acidity: A
Perspective on the Complex-Induced Proximity Effect (CIPE) in Deprotonation
Reactions. Angew. Chem. Int. Ed. 2004, 43, 2206. (c) Steffen, P.; Unkelbach, C.;
Christmann, M.; Hiller, W.; Strohmann, C. Catalytic and Stereoselective ortho-Lithiation
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of a Ferrocene Derivative. Angew. Chem. Int. Ed. 2013, 52, 9836. (d) Jastrzebski, J. T.;
Arink, A. M.; Kleijn, H.; Braam, T. W.; Lutz, M.; Spek, A. L.; van Koten, G. Directed
orthoꢀLithiation: Observation of an Unexpected 1ꢀLithio to 3ꢀLithio Conversion of 1ꢀ
Lithioꢀnaphthyllithium Compounds with an ortho-Directing 2ꢀ(Dimethylamino)methyl
Group.J. Am. Chem. Soc. 2013, 135, 13371. (e) Mallardo, V.; Rizzi, R.; Sassone, F. C.;
Mansueto, R.; Perna, F. M.; Salomone, A.; Capriati, V. Regioselective desymmetrization
of diaryltetrahydrofurans via directed orthoꢀlithiation: an unexpected help from green
chemistry. Chem. Commun. 2014, 50, 8655. (f) Rouquet, G.; Blakemore, D. C.; Ley, S.
V. Highly regioselective lithiation of pyridines bearing an oxetane unit by nꢀbutyllithium.
Chem. Commun. 2014, 50, 8908. (g) Slocum, D. W.; Reinscheld, T. K.; White, C. B.;
Timmons, M. D.; Shelton, P. A.; Slocum, M. G.; Sandlin, R. D.; Holland, E. G.; Kusmic,
D.; Jennings, J. A.; Tekin, K. C.; Nguyen, Q.; Bush, S. J.; Keller, J. M.; Whitley, P. E.
orthoꢀLithiations Reassessed: the Advantages of Deficiency Catalysis in Hydrocarbon
Media. Organometallics 2013, 32, 1674.
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