Addition of the Lithium Anion of Diphenylmethanol Methyl/Methoxymethyl Ether to Nonracemic Sulfinimines: Two-Step Asymmetric Synthesis of Diphenylprolinol Methyl Ether and Chiral (Diphenylmethoxymethyl)amines

Article abstract of DOI:10.1021/acs.joc.8b01381

Addition of the lithium anion generated from diphenylmethanol methyl and methoxymethyl ether to nonracemic sulfinimines afforded the corresponding addition products in excellent diastereoselctivity and yields. Deprotection of the MOM as well as sulfinyl groups rendered the enantiopure (diphenylhydroxymethyl)amines in excellent yields. The procedure was applied for a two-step synthesis of diphenylprolinol, a privileged ligand in asymmetric catalysis.

Full text of DOI:10.1021/acs.joc.8b01381

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Article
Addition of Lithium Anion of Diphenylmethanol Methyl/ MOM Ether
to Non-racemic Sulfinimines: Two Step Asymmetric Synthesis of
Diphenylprolinol Methyl Ether and Chiral Diphenylmethoxymethyl Amines
Arava Amaranadha Reddy, and Kavirayani R Prasad
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 21 Aug 2018
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Page 1 of 31
The Journal of Organic Chemistry
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Addition of Lithium Anion of Diphenylmethanol
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Methyl/ MOM Ether to Nonꢀracemic Sulfinimines: Two
Step Asymmetric Synthesis of Diphenylprolinol Methyl
Ether and Chiral Diphenylmethoxymethyl Amines
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Arava Amaranadha Reddy and Kavirayani R. Prasad*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Eꢀmail: prasad@iisc.ac.in; FAX: +918023600529
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O
S
O
RO Li
Ph
Ph
S
NH
N
OR
R1
R1
R = Me, MOM
Ph Ph
R = Me, MOM
Ph
Ph
Ph
NH2
Ph
OH
OH
N
R
OH
H
N
H
Ph Ph
Ph
Ph
Ph
N
N
Ph
OMe
N
H
Ph
OH
Ph
OH
H
H
Abstract: Addition of lithium anion generated from diphenylmethanol methyl and methoxymethyl
ether to nonꢀracemic sulfinimines afforded the corresponding addition products in excellent
diastereoselctivity and yields. Deprotection of the MOM as well as sulfinyl groups rendered the
enantiopure diphenylhydroxymethylamines in excellent yields. The procedure was applied for a twoꢀ
step synthesis of diphenyl prolinol, a privileged ligand in asymmetric catalysis.
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Introduction
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The geminalꢀdiphenylhydroxy group was often described as a “magic hydroxy group” and a number
of catalysts/ ligands containing the diphenylhydroxy groups were considered as privileged ligands in
asymmetric catalysis (fig. 1).1 Catalysts like TADDOLS and chiral diphenylmethanol containing amino
alcohols such as diphenyl prolinol, diphenyl valinol were proven as excellent catalysts in a number of
catalytic asymmetric transformations. Synthesis of chiral diphenylmethanol containing amino alcohols
in general was accomplished from the naturally occurring Lꢀamino acids, while synthesis of the
corresponding antipodes involves either the use of unnatural amino acids (which is not cost effective) or
multiꢀstep sequence.
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Ph Ph
Ph
Ph
Ph Ph
OMe
Ph Ph
O
OH
OH
R
O
OH
N
O
B
NH
NH2
Ph Ph
Me
3
1
2
4
Fig. 1 Diphenylmethanol containing amino alcohol catalysts/ ligands used in asymmetric synthesis
Sulfinimines derived from chiral sulfinamides were established as excellent sulfur based compounds
for stereoselective addition of a number of nucleophiles. pꢀToulenesulfinamide and tertꢀbutyl
sulfinamide developed by Davis and Ellman respectively has paved the way for the synthesis of a
number of chiral amine containing compounds.2 The reliable selectivities and the ease of deprotection of
the sulfinamide have made these reagents one of the widely used for the synthesis of chiral amines. We
reasoned that the addition of carbanion derived from diphenylmethanol methyl/ methoxymethyl (MOM)
ethers3 to the sulfinimines should provide a straightforward synthesis of the corresponding
diphenylmethanol containing amine compounds, the investigations of which is the subject of this article.
Results and Discussion
We began the study with the addition of carbanion derived from diphenylmethanol methyl ether 5a to
the sulfinimine 6a. Reaction of 5a with nꢀBuLi in presence of TMEDA generated the carbanion which
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on addition to the sulfinimine 6a afforded the addition product 7a in 67% yield with >99:1
diastereomeric ratio.4 The absence of TMEDA in stabilizing the carbanion led to a decreased yield
(43%) of the product with similar diastereomeric ratio. Performing the reaction using LDA as a base did
not furnish the product at all. Replacing the methyl ether 5a with MOM ether 5b furnished the product
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8a to 76% with similar >99:1 diastereomeric ratio (Schemeꢀ1).
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O
RO Li
Ph
Ph
O
S
S
tBu
NH
N
TBDPSO
OR
Ph Ph
R = Me 7a; R = MOM 8a
TBDPSO
R = Me= 5a
R = MOM = 5b
6a
Scheme-1 Addition of lithium anion derived from diphenylmethanol methyl/ MOM ether 5a-b to the
sulfinimine 6a.
Generality of the above reaction was further investigated by the addition of diphenylmethanol
methyl/MOM ether (5a and 5b) to a number of sulfinimines derived from aliphatic as well as aromatic
aldehydes. All the reactions proceeded smoothly to afford the corresponding diphenylmethanol methyl/
MOM ether containing sulfinamides in excellent diastereoselectivity and in good yields. It was found
that the reaction of the diphenylmethanol methyl ether 5a with sulfinimine 6c derived from
acetaldehyde afforded the product 7c as a 93:7 nonꢀseparable mixture of diastereomers in 73% yield.
However, addition of 5a to the sulfinimines 6d-e derived from isobutyraldehyde and pivalaldehyde
furnished the products 7d and 7e in 74% and 75% yield respectively as a 95:5 and 98:2 separable
mixtures of diastereomers. The addition of 5a to sulfinimine 6f derived from cyclohexyl carbaldehyde
yielded the product 7f in 66% yield as a separable 90:10 diastereomeric ratio. Similar selectivity was
observed in addition of the MOM ether 5b to the sulfinimine 6f and the product was obtained in 84%
yield. The addition of 5a and 5b to the sulfinimine 6h derived from benzaldehyde proceeded well to
yield the products 7h and 8h with excellent selectivity. All these results are summarized in chartꢀ1.
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Chart 1: Addition of diphenylmethanol methyl/ MOM ethers to sulfinimines.aꢀd
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O
RO Li
Ph
Ph
O
S
S
tBu
R1
HN
N
RO
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Ph Ph
R = Me= 5a
R = MOM = 5b
R1
6a-h
R = Me 7a-h
R = MOM 8a-h
6a R1= CH2OTBDPS; 6b R1 = CH2OBn
6c R1 = Me, 6d R1= iPr, 6e R1= tBu
6f R1= cyclohexyl, 6g R1= n-hexyl 6h R1= Ph
O
S
O
S
O
S
O
S
NH
tBu
tBu
BnO
tBu
tBu
NH
NH
NH
OR
OR
TBDPSO
OR
OR
Me
Ph Ph
Ph Ph
Ph Ph
Ph Ph
R = Me= 7c 73%
R = Me= 7d 75%
R =MOM=8d 76%
dr 95:5 separablee
R = MOM = 8b 75%
R = Me = 7a 67%
dr 93: 7 (non-separable)
R = MOM= 8a = 76%
O
S
O
S
O
S
O
S
tBu
tBu
tBu
tBu
NH
NH
NH
NH
OR
OR
OR
OR
Ph Ph
R=Me=7g 75%
Ph
4
Ph Ph
Ph Ph
Ph Ph
R =Me= 7h 57%
R =MOM= 8h 84%
R=Me=7e 74%
R=MOM= 8e 76%
dr 98:2 separablee
R=Me= 7f 64%
R=MOM= 8f 76%
dr 90:10 separablee
aAll reactions were carried out in THF as solvent at −78° C. Yields refer to isolated yields after chromatography. The
diastereomeric ratio was determined by H NMR of the crude reaction mixture. Unless stated all the reactions afforded
products with >99% dr. eMinor isomer was not isolated by chromatography.
b
c
1
d
For the synthesis of cyclic amine (aziridne, azitidine, pyrrolidine and pipirdine) containing
diphenylmethanol methyl/ MOM ethers, we investigated the addition of 5a and 5b to the sulfinimines
6i-n derived from chloroacetaldehyde, 3ꢀbromopropanal, 4ꢀbromobutanal, 5ꢀbromopentanal, 6ꢀ
bromohexanal and 8ꢀbromooctanal respectively. We anticipated that the addition of lithium anion to the
sulfinimine will initiate the concomitant displacement of the halogen with the formed lithium amide
leading to the cyclization. Thus, addition of 5b to the sulfinimine derived from chloroacetaldehyde
afforded the product aziridine 8i in 56% yield. Similarly, addition of 5b to the sulfinimines 6j and 6k
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synthesized from bromopropanal and bromobutanal furnsihed the azitidine and pyrrolidine containing
diphenylmethanol ethers 8j and 8k in 66% and 79% yields respectively. However, addition of 5b to the
sulfinimines 6l-n obtained from 5ꢀbromopentanal, 6ꢀbromohexanal and 8ꢀbromooctanal did not yield
the cyclized products instead furnished the corresponding uncyclized products in up to 85% yield.
Owing to the importance of diphenylprolinol methyl ether and the pyrrolidinemethanol methyl ether in
organocatalysis,5 we have investigated the addition of diphenylmethanol methyl ether 5a to the
sulfinimines 6k and 6l. It was observed that the fiveꢀmembered pyrrolidine formed in 73% yield, while
the six membered piperidine formation was not observed and the uncyclized sulfinimine was formed in
69% yield. All these results are summarized in chartꢀ2
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Chart-2: Synthesis of aziridine, azitidine and pyrrolidine containing diphenylmethanols derivatives
Treatment of 7l and 8l with NaH smoothly effected the cyclization to furnish the corresponding
piperidine derivatives 9 and 10 in 69% and 85% yields respectively (Scheme 2). However, reaction of
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the sulfinamides 8m and 8n with NaH did not afford the corresponding cyclic seven and eight
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membered compounds.
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NaH/ THF
Ph
OR
Ph
OR
ꢀ, 4h
Br HN
S
N
S
Ph
Ph
O
O
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9 R = Me 86%
10 R = MOM 85%
Scheme-2: Synthesis of piperidine containing diphenylmethanol
Deprotection of the sulfinyl as well as the MOM groups in the aziridine, azitidine, pyrrolidine and
piperidine containing sulfinamides 8i-k and 10 was accomplished by reaction with saturated methanolic
HCl to furnish the corresponding amino alcohols 11-14 in good yields. Similarly, deprotection of the
sulfinyl and MOM groups in 8d-f and 8h afforded the corresponding diphenylmethanol containing
amino alcohols in excellent yield. Removal of the sulfinyl group in the sulfinamindes 7k and 10
furnished diphenylprolinol methyl ether 15 and diphenylpiperidinol methyl ether 16 in excellent yields
(Schemeꢀ3). This method compliments the existing procedures for the synthesis diphenylprolinol from
natural proline11 but offers a viable alternate route for the synthesis of unnatural diphenylprolinol.
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The Journal of Organic Chemistry
Ph
Ph
Ph
OR
Ph
OH
Ph
1
2
3
4
Ph
OR
Ph
OH
Ph
N
N
S
N
S
N
H
H
12 (67%)
11 (96%)
O
O
5
6
7
8
9
8j R = MOM
8i R = MOM
Ph
OR
Ph
OR
N
N
H
H
Ph
13a R = H (91%)
13b R= Me (99%) 14b R = Me (90%)
i) methanolic HCl
ii) solid NaHCO3
MeOH/ THF
Ph
14a R = H (92%
Ph
OR
Ph
Ph
OR
10
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N
S
N
S
Ph
O
O
Ph Ph
Ph Ph
OH
8k R = MOM
7k R = Me
OH
9 R = Me
NH2
NH2
16 (99%)
10 R = MOM
15 (99%)
Ph Ph
R1
Ph Ph
Ph Ph
OH
Ph
R1= iPr, tBu
cyclohexyl, Ph
8d-f, 14
OMOM
OH
HN
O
NH2
18 (99%)
NH2
S
tBu
17 (96%)
Scheme-3: Synthesis of diphenylmethanol containing cyclic amines
Comparison of the optical rotation of the synthesized diphenylmethoxymethyl amines and the
diphenylhydroxy amines with those known in literature and the Xꢀray crystal structure analysis of the
sulfinamide 8m6 revealed that the addition of nucleophile occurred from a side opposite to the sulfinyl
group. This is contrary to the known addition of simple organolithium reagents to sulfinimines in which
the addition of the nucleophiles proceeds with chelation to the sulfinyl oxygen. The present observation
can be explained by the strong coordination of lithium to the methyl/ MOM ether oxygen in the
carbanion of the diphenylmethanol methyl/ MOM ether and the addition occurring from the least
hindered side of the sulfinimine (from a side opposite to the sulfinyl group) (Fig 2).
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Fig. 2: ORTEP diagram of the crystal structure of 8m and the proposed transition state for the observed selectivity
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Conclusion
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In conclusion, an efficient strategy for the synthesis of diphenylmethanol containing amines was
developed using the addition of lithium carbanions of diphenylmethanol methyl/ MOM ethers to the
sulfinimines. The addition proceeded with very high selectivity and the products were obtained in good
yields. Usefulness of this protocol is showcased in a twoꢀstep synthesis of diphenyl prolinol and the
corresponding methyl ether which are considered as privileged ligands in asymmetric catalysis.
Experimental:
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General Information: Column chromatography was performed on silica gel, Acme grade 100−200
mesh. TLC plates were visualized either with UV in an iodine chamber or with phosphomolybdic acid
spray unless noted otherwise. All reagents were purchased from commercial sources and used without
additional purification. THF was freshly distilled over Naꢀbenzophenone ketyl. Melting points were
recorded using melting point apparatus in capillary tubes and are uncorrected. Unless stated otherwise,
1H (400 MHz) and 13C (100 MHz) spectra were recorded on 400 MHz spectrophotometers in CDCl3 as
solvent with TMS as reference. Highꢀresolution mass spectra (HRMS) were recorded on a QꢀTOF
micromass spectrometer using electron spray ionization mode. All sulfinimines except 6m-n were
prepared according to the procedure described by Ellman7a, Morgas7b and Reddy et al. 8
(S,E)-N-(6-bromohexylidene)-2-methylpropane-2-sulfanamide (6m): Sulfinimine 6m was prepared
from 6ꢀbromohexanal (0.67 g, 3.7 mmol), (S)ꢀ2ꢀmethylpropaneꢀ2ꢀsulfinamide (0.3 g, 2.5 mmol) and
anhydrous CuSO4 (1.66 g, 11.1 mmol) in 85% yield (0.6 g) as a gummy mass using the procedure
described in reference8. [α]D24 +189.5 (c 0.8, CHCl3). IR (Neat): νmax 2954, 1634, 1270, 1135, 1018, 560
cm−1. 1H NMR (400 MHz, CDCl3):
δ
8.07 (t, J = 4.4 Hz, 1H), 3.41 (t, J = 6.8 Hz, 2H), 2.55 (q, J = 6.8
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Hz, 2H), 1.90 (quint, J = 6.8 Hz, 2H), 1.68 (quint, J = 6.4 Hz, 2H), 1.52 (quint, J = 8.4 Hz, 2H), 1.20 (s,
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2
3
13
9H). C NMR (100 MHz, CDCl3):
δ 169.1, 56.5, 35.8, 33.4, 32.4, 27.7, 24.5, 22.3 (3C). HRMS (ESIꢀ
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5
6
TOF) m/z: [M+Na]+ calcd for C10H20BrNOS+Na 304.0347.; found 304.0349.
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(S,E)-N-(8-bromooctylidene)-2-methylpropane-2-sulfanamide (6n): Sulfinimine 6n was prepared
from 8ꢀbromooctanal (0.77 g, 3.7 mmol), (S)ꢀ2ꢀmethylpropaneꢀ2ꢀsulfinamide (0.3 g, 2.5 mmol) and
anhydrous CuSO4 (1.66 g, 11.1 mmol) in 94% yield (0.72 g) as a gummy mass using the procedure
24
described in reference8. [α]D +195.7 (c 1.0, CHCl3). IR (Neat): νmax 2929, 2361, 1627, 1082, 560
1
cm−1. H NMR (400 MHz, CDCl3):
δ
8.06 (t, J = 4.8 Hz, 1H), 3.41 (t, J = 6.8 Hz, 2H), 2.52 (m, 2H),
13
1.86 (quint, J = 6.8 Hz, 2H), 1.64 (quint, J = 7.2 Hz, 2H), 1.51ꢀ1.30 (m, 6H), 1.20 (s, 9H). C NMR
(100 MHz, CDCl3):
δ 169.5, 56.5, 36.0, 33.8, 32.6, 29.0, 28.4, 27.9, 25.3, 22.3 (3C). HRMS (ESIꢀTOF)
m/z: [M+Na]+ calcd for C12H24BrNOS+Na 334.0639.; found 334.0636.
General procedure A for the addition of Methyl or MOM ether of diphenylmethanol to various
sulfinimines: The following preparation of 8a is representative.
O
S
HN
MOMO
Ph
Ph OTBDPS
8a
(R)-N-(tert-butyl(λ1-oxidanyl)- λ3-sulfanyl)amino)-10,10-dimethyl-5,5,9,9-tetraphenyl-2,4,8-trioxa-
9-silaundecan-6-amine
(8a):
To
a
preꢀcooled
(−40
°C)
stirred
solution
of
((methoxymethoxy)methylene)dibenzene (0.11 g, 0.48 mmol) in dry THF (10 mL) under argon
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atmosphere at −40 °C was added TMEDA (0.08 mL, 0.53 mmol) followed by nBuLi (2.0 M solution in
hexane 0.27 mL, 0.54 mmol). The resultant bright red colored reaction mixture was stirred for 0.5 h at
the same temperature and then it was cooled to −78 °C. Sulfinimine 6a (0.1 g, 0.25 mmol) dissolved in
4 mL dry THF was added to the reaction mixture at −78 °C. The reaction mixture was stirred at the
same temperature for additional 1h and was quenched by addition of saturated NH4Cl solution (20 mL)
and was extracted with EtOAc (2 × 20 mL). The organic layer was washed with brine (20 mL) and dried
over anhydrous Na2SO4. Evaporation of solvent followed by silica gel column chromatography of the
resulting crude residue with petroleum ether/EtOAc as eluent afforded the sulfinamide 8a in 76 % yield
(0.12 g) as a gummy mass. [α]D24 +31.2 (c 0.95, CHCl3). IR (Neat): νmax 3194, 2954, 2929, 2361, 1627,
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1082 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.63 (d, J = 7.6 Hz, 2H), 7.57 (d, J = 7.6 Hz, 2H), 7.46ꢀ7.26
(m, 10H), 7.25ꢀ7.12 (m, 6H), 4.61ꢀ4.47 (m, 2H), 4.44 (d, J = 6.8 Hz, 1H), 4.37 (d, J = 9.2 Hz, 1H), 3.95
13
(dd, J = 10.8, 4.4 Hz, 1H), 3.80 (dd, J = 10.8, 4.0 Hz, 1H), 3.17 (s, 3H), 1.10 (s, 9H), 0.93 (s, 9H). C
NMR (100 MHz, CDCl3):
δ 142.4, 141.4, 135.9 (4C), 133.1, 132.8, 129.4, 129.37, 128.2 (2C), 127.9
(2C), 127.8 (2C), 127.7 (2C), 127.5 (2C), 127.4 (2C), 127.2, 127.1, 92.6, 85.4, 63.5, 62.4, 56.6, 56.0,
26.8 (3C), 22.9 (3C), 18.9. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C37H47NO4SSi+Na 652.2893.;
found 652.2892.
(R)-1-tert-butyl-N-(3-((tert-butyldiphenylsilyl)oxy)-1-methoxy-1,1-diphenylpropan-2-yl)-1-(λ1-
oxidanyl)- λ3-sulfanamine (7a): Compound 7a was prepared from (methoxymethylene)dibenzene (0.09
g, 0.48 mmol) and sulfinimine 7a (0.1 g, 0.25 mmol) using the general procedure A described above in
67% yield (0.1 g) as a gummy mass. [α]D24 +13.6 (c 2.35, CHCl3). IR (Neat): νmax 3400, 2931, 2856,
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1653, 1110, 1079 cm−1 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.69 (dd, J = 7.2, 1.6 Hz, 2H), 7.60 (dd, J
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= 7.6, 1.2 Hz, 2H), 7.47ꢀ7.31 (m, 6H), 7.30ꢀ7.17 (m, 10H), 4.52ꢀ4.37 (m, 1H), 4.01 (dd, J = 10.4, 4.4
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6
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Hz, 1H), 3.79ꢀ3.63 (m, 2H), 2.82 (s, 3H), 1.10 (s, 9H), 0.96 (s, 9H). C NMR (100 MHz, CDCl3):
δ
7
8
9
140.6, 139.8, 136.1 (2C), 135.8 (2C), 133.1, 132.8, 129.6, 129.5, 129.3 (2C), 128.7 (2), 127.5 (5C),
127.4 (3C), 127.2, 84.7, 63.3, 61.2, 56.4, 51.6, 26.9 (3C), 22.7 (3C), 18.9. HRMS (ESIꢀTOF) m/z:
[M+Na]+ calcd for C36H45NO3SSi+Na 622.2787.; found 622.2784.
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(R)-N-(3-(benzyloxy)-1-(methoxymethoxy)-1,1-diphenylpropan-2-yl)-1-(tert-butyl)-1-(λ1-
oxidaneyl)-(λ3-sulfanamine (8b): Compound 8b was prepared from (methoxymethylene)dibenzene
(0.18 g, 0.79 mmol) and sulfinimine 6b (0.1 g, 0.39 mmol) using the general procedure A described
above in 75% yield (0.142 g) as a gummy mass. [α]D24 +72.7 (c 2.15, CHCl3). IR (Neat): νmax 3194,
1
2923, 2853, 2360, 1627, 1023 cm−1. H NMR (400 MHz, CDCl3):
δ 7.44ꢀ7.34 (m, 4H), 7.33ꢀ7.09 (m,
11H), 4.66 (d, J = 7.2 Hz, 1H), 4.59ꢀ4.41 (m, 3H), 3.85 (dd, J = 16.0, 12.0 Hz, 2H), 3.80 (dd, J = 10.0,
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3.6 Hz, 1H), 3.55 (dd, J = 10.0, 4.4 Hz, 1H), 3.33 (s, 3H), 1.08 (s, 9H). C NMR (100 MHz, CDCl3):
δ
142.7, 141.8, 138.3, 128.1 (2C), 128.0 (2C), 127.83 (2C), 127.79 (2C), 127.5 (2C), 127.4 (2C), 127.2,
127.14, 127.10, 92.8, 85.5, 72.8, 71.1, 61.5, 56.7, 56.2, 22.8 (3C). HRMS (ESIꢀTOF) m/z: [M+Na]+
calcd for C28H35NO4S+Na 504.2185.; found 504.2189.
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(R)-1-tert-butyl-N-(1-(methoxymethoxy)-1,1-diphenylpropan-2-yl)-1-(λ1-oxidaneyl)-(λ3-
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sulfanamine (7c): Compound 7c was prepared from (methoxymethylene)dibenzene (0.3 g, 1.5 mmol)
and sulfinimine 6c (0.11 g, 0.75 mmol) using the general procedure A described above as an inseparable
93:7 diastereomeric mixture in 73% yield (0.19 g). mp: 115ꢀ118 °C. [α]D24 +52.1 (c 0.7, CHCl3). IR
(KBr): νmax 3309, 2952, 2825, 2361, 2336, 1651, 1070 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.44ꢀ7.22
(m, 10H), 4.58ꢀ4.40 (m, 1H), 2.98 (s, 0.2H minor), 2.93 (s, 3H major), 2.57 (d, J = 10.8 Hz, 1H), 1.24
13
(d, J = 6.8 Hz, 2H), 1.07 (s, 9.9 H). C NMR (100 MHz, CDCl3):
δ 140.5, 139.7, 129.8 (2C), 129.2
(2C), 127.6, 127.5 (3C), 127.4 (2C), 85.4, 56.5, 55.6, 51.0, 22.7 (3C), 19.3. HRMS (ESIꢀTOF) m/z:
[M+Na]+ calcd for C20H27NO2S+Na 368.1660.; found 368.1664.
(R)-1-tert-butyl-N-(1-(methoxy-3-methyl-1,1-diphenylbutan-2-yl)-1-(λ1-oxidaneyl)-(λ3-sulfanamine
(7d): Compound 7d was prepared from (methoxymethylene)dibenzene (0.23 g, 1.14 mmol) and
sulfinimine 6d (0.1 g, 0.57 mmol) using the general procedure A described above as a separable 95:5
diastereomeric mixture. Major isomer was separated using silica gel column chromatography in 75%
yield (0.16 g) as a gummy mass. [α]D24 +83.7 (c 1.45, CHCl3). IR (Neat): νmax 3347, 2957, 2872, 2361,
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2336, 1650, 1074 cm−1. H NMR (400 MHz, CDCl3):
δ 7.46ꢀ7.22 (m, 10H), 4.12 (d, J = 10.4 Hz, 1H),
3.15 (d, J = 10.8 Hz, 1H), 2.89 (s, 3H), 2.31 (quin, J = 6.8 Hz, 1H), 1.21 (d, J = 7.2 Hz, 3H), 1.01 (s,
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9H), 0.05 (d, J = 6.8 HZ, 3H). C NMR (100 MHz, CDCl3):
δ 140.5, 139.3, 129.8 (2C), 128.8 (2C),
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127.7 (2C), 127.63 (2C), 127.58, 127.5, 85.9, 65.7, 56.5, 51.5, 26.4, 22.9, 22.7 (3C), 16.6. HRMS (ESIꢀ
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TOF) m/z: [M+Na]+ calcd for C22H31NO2S+Na 396.1973.; found 396.1970.
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(R)-1-tert-butyl-N-(1-(methoxymethoxy)-3-methyl-1,1-diphenylbutan-2-yl)-1-(λ1-oxidaneyl)-(λ3-
sulfanamine (8d): Compound 8d was prepared from (methoxymethylene)dibenzene (0.52 g, 2.29
mmol) and sulfinimine 6d (0.18 g, 1.0 mmol) using the general procedure A described above a
separable 95:5 diastereomeric mixture. Major isomer was separated using silica gel column
chromatography in 70% yield (0.29 g) as a white solid. mp: 121ꢀ124 °C. [α]D24 +65.0 (c 0.45, CHCl3).
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IR (Neat): νmax 3385, 2925, 2853, 2363, 2338, 1590, 1021 cm−1. H NMR (400 MHz, CDCl3):
δ 7.49ꢀ
7.16 (m, 10H), 4.66 (d, J = 6.4 Hz, 1H), 4.43 (d, J = 6.4 Hz, 1H), 4.17 (d, J = 10.8 Hz, 1H), 3.73 (d, J =
10.8 Hz, 1H), 3.36 (s, 3H), 2.21 (quin, J = 6.8 Hz, 1H), 1.10 (d, J = 6.8 Hz, 3H), 1.06 (s, 9H), 0.26 (d, J
= 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 142.1, 141.0, 128.7 (2C), 128.4 (2C), 127.79 (2C),
127.72 (2C), 127.39, 127.36, 92.8, 86.4, 66.0, 56.8, 56.4, 26.7, 22.9 (3C), 22.8, 17.1. HRMS (ESIꢀTOF)
m/z: [M+Na]+ calcd for C23H33NO3S+Na 426.2079.; found 426.2079.
(R)-1-tert-butyl-N-(1-methoxy-3,3-dimethyl-1,1diphenylbutan-2-yl)-1-(λ1-oxidaneyl)-(λ3-
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sulfanamine (7e): Compound 7e was prepared from (methoxymethylene)dibenzene (0.21 g, 1.0 mmol)
and sulfinimine 7e (0.1 g, 0.53 mmol) using the general procedure A described above as a separable
98:2 diastereomeric mixture. Major isomer was separated using silica gel column chromatography in
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74% yield (0.204 g) as a white solid. mp: 117ꢀ120 °C. [α]D24 +123.9 (c 1.2, CHCl3). IR (KBr): νmax
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1
3357, 3058, 2942, 2868, 2202, 1446, 1067 cm−1. H NMR (400 MHz, CDCl3):
δ 7.54 (d, J = 7.6 Hz,
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2H), 7.50ꢀ7.32 (m, 5H), 7.31ꢀ7.17 (m, 3H), 4.05 (d, J = 8.0 Hz, 1H), 3.29 (d, J = 8.0 Hz, 1H), 2.79 (s,
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3H), 0.85 (s, 9H), 0.76 (s, 9H). C NMR (100 MHz, CDCl3):
δ 141.0, 137.8, 129.9 (2C), 129.3 (2C),
127.73 (2C), 127.7 (2C), 127.5, 127.3, 88.5, 70.4, 55.9, 52.8, 35.9, 28.7 (3C), 22.3 (3C). HRMS (ESIꢀ
TOF b) m/z: [M+Na]+ calcd for C23H33NO2S+Na 410.2130.; found 410.2108.
(R)-1-tert-butyl-N-(1-methoxymethoxy)-3,3-dimethyl-1,1diphenylbutan-2-yl)-1-(λ1-oxidaneyl)-(λ3-
sulfanamine (8e): Compound 8e was prepared from (methoxymethylene)dibenzene (0.24 g, 1.06 mmol)
and sulfinimine 7e (0.1 g, 0.53 mmol) using the general procedure A described above as a separable
98:2 diastereomeric mixture. Major isomer was separated using silica gel column chromatography in in
73% yield (0.16 g) as a white solid. mp: 89ꢀ94 °C. [α]D24 +118.0 (c 0.5, CHCl3). IR (KBr): νmax 3354,
1
2949, 2856, 2291, 2247, 1597, 1069 cm−1. H NMR (400 MHz, CDCl3):
δ 7.60 (d, J = 7.2 Hz, 2H),
7.51ꢀ7.30 (m, 5H), 7.29ꢀ7.14 (m, 3H), 4.45 (d, J = 5.6 Hz, 1H), 4.13 (d, J = 8.0 Hz, 1H), 4.03 (d, J = 5.6
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Hz, 1H), 3.43ꢀ3.31 (m, 4H), 0.83 (s, 9H), 0.78 (s, 9H). C NMR (100 MHz, CDCl3):
δ 141.5, 138.4,
129.4 (2C), 128.9 (2C), 127.9 (2C), 127.7, 127.6 (2C), 127.5, 93.3, 88.1, 70.2, 56.4, 56.0, 36.0, 28.9
(3C), 22.3 (3C). HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C24H35NO3S+Na 440.2235.; found
440.2237.
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(R)-1-tert-butyl-N-(1-(cyclohexyl-2-methoxy-2,2-diphenylethyl)-1-(λ1-oxidaneyl)-(λ3-sulfanamine
(7f): Compound 7f was prepared from (methoxymethylene)dibenzene (0.18 g, 0.92 mmol) and
sulfinimine 6f (0.1 g, 0.46 mmol) using the general procedure A described above a separable 90:10
diastereomeric mixture. Major isomer was separated using silica gel column chromatography in 84%
yield (0.16 g) as a white solid. mp: 121ꢀ124 °C. [α]D24 +75.6 (c 5.5, CHCl3). IR (KBr): νmax 3282, 2924,
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2853, 1447, 1184, 1069 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.48ꢀ7.22 (m, 10H), 4.03 (d, J = 10.8 Hz,
1H), 3.20 (d, J = 10.8 Hz, 1H), 2.88 (s, 3H), 1.98ꢀ1.61 (m, 4H), 1.50 (d, J = 13.2 Hz, 1H), 1.40ꢀ1.26 9m,
2H), 1.09 (tq, J = 12.8, 3.6 Hz, 1H), 1.03 (s, 9H), 0.89 (tq, J = 12.8, 3.6 Hz, 1H), 0.37 (dq, J = 14.4, 2.8
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Hz, 1H),
̶
0.30 (d, J = 11.6 Hz, 1H). C NMR (100 MHz, CDCl3):
δ
140.6, 139.6, 129.7 (2C), 128.7
(2C), 127.7 (2C), 127.6 (2C), 127.56, 127.51, 85.9, 66.1, 56.5, 51.4, 37.2, 33.2, 28.8, 27.2, 26.2, 26.0,
22.7 (3C). HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C25H35NO2S+Na 436.2286.; found 436.2287.
(R)-1-tert-butyl-N-(1-(cyclohexyl-2-(methoxymethoxy)-2,2-diphenylethyl)-1-(λ1-oxidaneyl)-(λ3-
sulfanamine (8f): Compound 8f was prepared from (methoxymethylene)dibenzene (0.42 g, 1.8 mmol)
and sulfinimine 6f (0.2 g, 0.93mmol) using the general procedure A described above as a separable
90:10 diastereomeric mixture. Major isomer was separated using silica gel column chromatography in
66% yield (0.27 g) as a white solid. mp: 91ꢀ96 °C. [α]D24 +86.5 (c 5.5, CHCl3). IR (KBr): νmax 3279,
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2924, 2853, 1591, 1020 cm−1. H NMR (400 MHz, CDCl3):
δ 7.49ꢀ7.17 (m, 10H), 4.55 (d, J = 6.4 Hz,
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3
4
5
1H), 4.43 (d, J = 6.4 Hz, 1H), 4.07 (d, J = 10.8 Hz, 1H), 3.72 (d, J = 10.8 Hz, 1H), 3.34 (s, 3H), 1.97ꢀ
1.62 (m, 3H), 1.56ꢀ1.38 (m, 3H), 1.25ꢀ1.06 (m, 2H), 1.05 (s, 9H), 1.03ꢀ0.35 (m, 2H), 0.25 (d, J = 10.0
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Hz, 1H). 13C NMR (100 MHz, CDCl3):
δ 141.8, 141.1, 128.9 (2C), 128.3 (2C), 127.7 (2C), 127.6 (2C),
9
127.4 (2C), 92.5, 86.2, 66.2, 56.7, 56.3, 37.3, 33.1, 28.5, 27.1, 26.4, 25.9, 22.9 (3C). HRMS (ESIꢀTOF)
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m/z: [M+Na]+ calcd for C26H37NO3S+Na 466.2392.; found 466.2392.
(R)-1-tert-butyl-N-(1-(methoxy-1,1-diphenyloctan-2-yl)-1-(λ1-oxidaneyl)-(λ3-sulfanamine
(7g):
Compound 7g was prepared from (methoxymethylene)dibenzene (0.18 g, 0.92 mmol) and sulfinimine
6g (0.1 g, 0.46 mmol) using the general procedure A described above in 75% yield (0.15 g) as a gummy
mass. [α]D24 +50.4 (c 0.5, CHCl3). IR (Neat): νmax 3435, 2927, 2857, 2361, 2336, 1644, 1074 cm−1. 1H
NMR (400 MHz, CDCl3):
δ 7.47ꢀ7.22 (m, 10H), 4.17 (t, J = 9.6 Hz, 1H), 2.87 (s, 3H), 2.51 (d, J = 9.2
Hz, 1H), 1.99ꢀ1.85 (m, 1H), 1.83ꢀ1.69 (m, 1H), 1.52ꢀ1.36 (m, 1H), 1.33ꢀ1.21 (m, 6H), 1.04 (s, 9H), 0.85
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(t, J = 6.8 Hz, 3H), 0.71ꢀ0.52 (m, 1H). C NMR (100 MHz, CDCl3):
δ 139.7, 139.1, 129.8 (2C), 129.2
(2C), 127.61 (2C), 127.60 (2C), 127.5 (2C), 86.4, 62.2, 56.6, 51.5, 31.7, 29.4, 26.2, 22.7 (5C), 14.1
HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C25H37NO2S+Na 438.2443.; found 438.2437.
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(R)-1-tert-butyl-N-(2-methoxy-1,2,2-triphenylethyl)-1-(λ1-oxidaneyl)-(λ3-sulfanamine
(7h):
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Compound 7h was prepared from (methoxymethylene)dibenzene (0.19 g, 0.95 mmol) and sulfinimine
6h (0.1 g, 0.5 mmol) using the general procedure A described above in 57% yield (0.112 g) as a gummy
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mass. [α]D +62.5 (c 0.8, CHCl3). IR (Neat): νmax 3323, 2953, 2931, 2859, 2365, 2338, 1651, 1077
cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.45 (dd, J = 8.4, 1.6 Hz, 2H), 7.39ꢀ7.24 (m, 6H), 7.23ꢀ7.04 (m,
5H), 6.70 (d, J = 7.2 Hz, 2H), 5.36 (d, J = 10.4 Hz, 1H), 3.66 (d, J = 10.4 Hz, 1H), 2.89 (s, 3H), 1.02 (s,
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9H). C NMR (100 MHz, CDCl3):
δ 139.5, 138.9, 138.2, 130.1 (2C), 129.5 (2C), 128.8 (2C), 127.8,
127.7 (2C), 127.6, 127.3, 127.2 (2C), 127.0 (2C), 86.6, 65.6, 56.5, 52.0, 22.5 (3C). HRMS (ESIꢀTOF)
m/z: [M+Na]+ calcd for C25H29NO2S+Na 430.1817.; found 430.1819.
(R)-1-tert-butyl-N-(2-methoxymethoxy)-1,2,2-triphenylethyl)-1-(λ1-oxidaneyl)-(λ3-sulfanamine
(8h): Compound 8h was prepared from (methoxymethylene)dibenzene (0.44 g, 1.9 mmol) and
sulfinimine 6h (0.2 g, 0.93 mmol) using the general procedure A described above in 84% yield (0.35 g)
as a white solid. mp: 76ꢀ80 °C. [α]D24 +165.0 (c 1.5, CHCl3). IR (KBr): νmax 3269, 2924, 2856, 2387,
1
2289, 1590, 1020 cm−1. H NMR (400 MHz, CDCl3):
δ 7.39 (dd, J = 8.4, 1.6 Hz, 2H), 7.37ꢀ7.24 (m,
4H), 7.17ꢀ7.00 (m, 7H), 6.91 (dd, J = 7.2, 1.6 Hz, 2H), 5.29 (d, J = 11.2, Hz, 1H), 5.08 (d, J = 11.2 Hz,
1H), 4.81 (d, J = 7.2 Hz, 1H), 4.61 (d, J = 6.8 Hz, 1H), 3.56 (s, 3H), 1.13 (s, 9H). 13C NMR (100 MHz,
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CDCl3):
δ 143.7, 141.3, 139.2, 129.2 (2C), 128.7 (2C), 127.8 (2C), 127.6, 127.5 (2C), 127.4 (2C), 127.2
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(2C), 126.9, 126.8, 93.9, 87.4, 66.2, 57.0, 56.8, 22.8 (3C). HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for
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C26H31NO3S+Na 460.1922.; found 460.1920.
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(R)-1-(tert-butyl(λ1-oxidaneyl)-(λ3-sulfaneyl)-2-((methoxymethoxy)diphenylmethyl)aziridine (8i):
Compound 8i was prepared from (methoxymethylene)dibenzene (0.18 g, 0.77 mmol) and sulfinimine 6i
(0.07 g, 0.4 mmol) using the general procedure A described above in 56% yield (0.09 g) as a gummy
mass. [α]D24 +157.1 (c 1.35, CHCl3). IR (Neat): νmax 3420, 2923, 2861, 235, 2337, 1641, 1026 cm−1. 1H
NMR (400 MHz, CDCl3):
δ 7.48ꢀ7.20 (m, 10H), 4.72 (d, J = 6.8 Hz, 1H), 4.62 (d, J = 6.8 Hz, 1H), 3.42
(s, 3H), 3.06 (dd, J = 6.4, 4.0 Hz, 1H), 2.58 (d, J = 6.8 Hz, 1H), 1.59ꢀ (d, J = 4.0 Hz, 1H), 1.16 (s, 9H).
13C NMR (100 MHz, CDCl3):
δ
142.8, 141.5, 128.6 (2C), 127.9 (2C), 127.8, 127.7 (2C), 127.6 (2C),
127.5, 92.7, 83.0, 57.3, 55.9, 37.6, 22.6 (3C), 21.1. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for
C21H27NO3S+Na 396.1609.; found 396.1609.
(R)-1-(tert-butyl(λ1-oxidaneyl)-(λ3-sulfaneyl)-2-((methoxymethoxy)diphenylmethyl)azetidine (8j):
Compound 8j was prepared from (methoxymethylene)dibenzene (0.19 g, 0.83 mmol) and sulfinimine 6j
(0.1 g, 0.42 mmol) using the general procedure A described above in 66% yield (0.13 g) as a gummy
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mass. [α]D +155.7 (c 1.35, CHCl3). IR (Neat): νmax 3195, 2920, 2856, 2362, 1629, 1021 cm−1. H
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NMR (400 MHz, CDCl3):
δ
7.46 (d, J = 7.6 Hz, 2H), 7.40ꢀ7.21 (m, 8H), 5.14 (dd, J = 8.8, 6.8 Hz, 1H),
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4.74 (d, J = 6.4 Hz, 1H), 4.59 (d, J = 6.0 Hz, 1H), 4.18 (q, J = 7.6 Hz, 1H), 3.41 (s, 3H), 2.79 (q, J = 8.8
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6
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hz, 1H), 2.36 (sept, J = 6.4 Hz, 1H), 1.04 (s, 9H). C NMR (100 MHz, CDCl3):
δ 141.5, 140.9, 128.8
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(4C), 127.6 (2C), 127.59, 127.55, 127.5 (2C), 92.6, 85.3, 67.7, 57.3, 56.1, 39.6, 23.6 (3C).21.7. HRMS
9
(ESIꢀTOF) m/z: [M+Na]+ calcd for C22H29NO3S+Na 410.1766.; found 410.1765.
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(R)-1-(tert-butyl(λ1-oxidaneyl)-(λ3-sulfaneyl)-2-(methoxy)diphenylmethyl)pyrrolidine
(7k):
Compound 7k was prepared from (methoxymethylene)dibenzene (0.16 g, 0.8 mmol) and sulfinimine 6k
(0.11 g, 0.44 mmol) using the general procedure A described above in 79% yield (0.13 g) as a gummy
mass. [α]D24 +103.3 (c 2.1, CHCl3). IR (Neat): νmax 3195, 2920, 2856, 2362, 1629, 1021 cm−1. 1H NMR
(400 MHz, CDCl3):
δ 7.55ꢀ7.23 (m, 10H), 4.89 (dd, J = 9.2, 3,2 Hz, 1H), 3.48 (ddd, J = 10.2, 8.8, 6.8
Hz, 1H), 2.9 (s, 3H), 2.10ꢀ1.88 (m, 2H), 1.94ꢀ1.76 (m, 1H), 1.54ꢀ1.34 (m, 1H), 1.08 (s, 9H), 0.58ꢀ0.37
(m, 1H). 13C NMR (100 MHz, CDCl3):
δ
140.1, 139.1, 130.3 (2C), 129.7 (2C), 127.6 (2C), 127.54,
127.48, 127.3 (2C), 86.1, 72.8, 58.1, 51.6, 42.5, 27.7, 25.6, 24.0 (3C). HRMS (ESIꢀTOF) m/z: [M+Na]+
calcd for C22H29NO2S+Na 394.1817.; found 394.1819.
(R)-1-(tert-butyl(λ1-oxidaneyl)-(λ3-sulfaneyl)-2-(methoxymethoxy)diphenylmethyl)pyrrolidine
(8k): Compound 8k was prepared from (methoxymethylene)dibenzene (0.18 g, 0.8 mmol) and
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sulfinimine 6k (0.1 g, 0.39 mmol) using the general procedure A described above in 73% yield (0.14 g)
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as a gummy mass. [α]D24 +55.5 (c 1.4, CHCl3). IR (Neat): νmax 3195, 2921, 2854, 2552, 1629, 1021
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5
6
1
cm−1. H NMR (400 MHz, CDCl3):
δ 7.58ꢀ7.46 (m, 4H), 7.41ꢀ7.25 (m, 6H), 4.97 (dd, J = 8.8 Hz, 2.8
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Hz, 1H), 4.53 (d, J = 5.6 Hz, 1H), 4.33 (d, J = 5.6 Hz, 1H), 3.49 (q, J = 8.8 Hz, 1H), 3.26 (s, 3H), 2.08ꢀ
1.85 (m, 3H), 1.55ꢀ1.38 (m, 1H), 1.05 (s, 9H), 0.62ꢀ0.41 (m, 1H). 13C NMR (100 MHz, CDCl3):
δ
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140.1, 139.7, 130.3 (2C), 129.5 (2C), 129.8, 127.6, 127.5 (2C), 127.3 (2C), 92.2, 85.8, 73.6, 58.2, 55.9,
42.7, 27.7, 25.6, 24.1 (3C). HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C23H31NO3S+Na 424.1922.;
found 424.1927.
(R)-N-(6-bromo-1-methoxy-1,1-diphenylhexan-2-yl)-1-(tert-butyl)-1-(λ1-oxidaneyl)-(λ3-
sulfanamine) (7l): Compound 7l was prepared from (methoxymethylene)dibenzene (0.17 g, 0.88 mmol)
and sulfinimine 6l (0.1 g, 0.44 mmol) using the general procedure A described above in 68% yield (0.12
g) as a gummy mass. [α]D24 +38.0 (c 0.5, CHCl3). IR (Neat): νmax 3418, 2922, 2856, 2360, 1630, 1023
cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.46ꢀ7.22 (m, 10H), 4.16 (t, J = 9.6 Hz, 1H), 3.38 (t, J = 6.4 Hz,
2H), 2.87 (s, 3H), 2.56 (d, J = 9.2 Hz, 1H), 2.07ꢀ1.71 (m, 4H), 1.68ꢀ1.51 (m, 1H), 1.02 (s, 9H), 0.73ꢀ
0.54 (m, 1H). 13C NMR (100 MHz, CDCl3):
δ
139.5, 138.7, 129.8 (2C), 129.1 (2C), 127.73, 127.70
(2C), 127.63 (2C), 127.60, 86.4, 62.1, 56.6, 51.6, 33.4, 32.9, 32.4, 24.9, 22.6 (3C). HRMS (ESIꢀTOF)
m/z: [M+Na]+ calcd for C23H32BrNO2S+Na 488.1235; found 488.1234.
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(R)-N-(6-bromo-1-(methoxymethoxy)-1,1-diphenylhexan-2-yl)-1-(tert-butyl)-1-(λ1-oxidaneyl)-(λ3-
sulfamine) (8l): Compound 8i was prepared from (methoxymethylene)dibenzene (0.2 g, 0.88 mmol)
and sulfinimine 6l (0.1 g, 0.44 mmol) using the general procedure A described above in 69% yield (0.13
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g) as a gummy mass. [α]D24 +92.4 (c 2.6, CHCl3). IR (Neat): νmax 3418, 2922, 2856, 2360, 1630, 1023
1
cm−1. H NMR (400 MHz, CDCl3):
δ 7.47ꢀ7.33 (m, 4H), 7.38ꢀ7.12 (m, 6H), 4.76 (d, J = 7.2 Hz, 1H),
4.61 (d, J = 7.2 Hz, 1H), 4.20 (t, J = 8.8 Hz, 2H), 3.48 (s, 3H), 3.25 (t, J = 6.8 Hz, 2H), 1.84ꢀ1.60 (m,
13
4H), 1.43ꢀ1.27 (m, 1H), 1.26ꢀ1.16 (m, 1H), 1.04 (s, 9H). C NMR (100 MHz, CDCl3):
δ 141.5, 128.3
(2C), 127.98 (3C), 127.95 (3C), 127.2, 127.0, 126.8, 93.0, 87.1, 62.4, 56.9, 56.3, 33.4, 32.7, 32.0, 25.2,
22.9 (3C). HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C24H34BrNO3S+Na 518.1340.; found 518.1346.
(R)-N-(9-bromo-1-(methoxymethoxy)-1,1-diphenylnonan-2-yl)-1-(tert-butyl)-1-(λ1-oxidaneyl)-(λ3-
sulfamine) (8m): Compound 8m was prepared from (methoxymethylene)dibenzene (0.15 g, 0.66
mmol) and sulfinimine 6m (0.6 g, 0.33 mmol) using the general procedure A described above in 84%
yield (0.15 g) as a solid. mp: 100ꢀ105 °C. [α]D24 +100.5 (c 1.7, CHCl3). IR (Neat): νmax 3297, 2951,
1
2863, 2198, 1445, 1018 cm−1. H NMR (400 MHz, CDCl3):
δ 7.47ꢀ7.34 (m, 4H), 7.38ꢀ7.12 (m, 6H),
4.76 (d, J = 7.2 Hz, 1H), 4.61 (d, J = 7.2 Hz, 1H), 4.24ꢀ4.12 (m, 1H), 3.47 (s, 3H), 3.31 (t, J = 6.8 Hz,
13
2H), 1.85ꢀ1.61 (m, 4H), 1.37ꢀ1.13 (m, 5H), 1.04 (s, 9H). C NMR (100 MHz, CDCl3):
δ
141.6, 128.3
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(3C), 127.9 (5C), 127.2, 127.0 (2C), 92.9, 87.1, 62.6, 56.9, 56.2, 34.1, 32.7, 32.4, 27.9, 25.6, 23.0 (3C).
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HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C25H36BrNO3S+Na 532.1497.; found 532.1496.
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(R)-N-(9-bromo-1-(methoxymethoxy)-1,1-diphenylnonan-2-yl)-1-(tert-butyl)-1-(λ1-oxidaneyl)-(λ3-
sulfamine) (8n): Compound 8n was prepared from (methoxymethylene)dibenzene (0.145 g, 0.64 mmol)
and sulfinimine 6n (0.1 g, 0.32 mmol) using the general procedure A described above in 81% yield
(0.14 g) as a gummy mass. [α]D24 +85.5 (c 2.35, CHCl3). IR (Neat): νmax 3283, 2928, 2845, 2358, 1636,
1084 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.42 (t, J = 6.8 Hz, 4H), 7.37ꢀ7.11 (m, 6H), 4.76 (d, J = 7.2
Hz, 1H), 4.61 (d, J = 7.2 Hz, 1H), 4.19 (t, J = 7.2 Hz, 1H), 3.46 (s, 3H), 3.35 (t, J = 6.8 Hz, 2H), 1.86ꢀ
1.70 (m, 3H), 1.69ꢀ1.59 (m, 1H), 1.37ꢀ1.21 (m, 3H), 1.20ꢀ1.06 (m, 6H), 1.03 (s, 9H). 13C NMR (100
MHz, CDCl3):
δ 141.7, 128.3 (2C), 127.9 (2C), 127.8 (2C), 127.1, 127.02, 127.0, 126.96, 126.9, 93.0,
87.1, 62.7, 56.8, 56.2, 34.0, 32.9, 32.7, 29.1, 28.3, 28.0, 26.4, 22.9 (3C). HRMS (ESIꢀTOF) m/z:
[M+Na]+ calcd for C27H40BrNO3S+Na 560.1810.; found 560.1805.
(R)-1-(tert-butyl(λ1-oxidaneyl)-(λ3-sulfaneyl)-2-(methoxy)diphenylmethyl)piperidine (9): To
a
stirred solution of 7l (0.065 g, 0.14 mmol) in dry THF (35 mL) at 0 °C was added NaH (60% in mineral
oil, 0.01 g, 0.14 mmol). The reaction mixture was refluxed for 4 h at 70 °C. After completion of reaction
(TLC) it was quenched with ice cold water and extracted with EtOAc (2 × 40 mL). The organic layer
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was washed with brine (30 mL) and dried over Na2SO4. Evaporation of solvent afforded the product in
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86% yield (0.045 g) as a gummy mass. [α]D24 +51.5 (c 1.05, CHCl3). IR (Neat): νmax 3134, 2929, 2860,
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1
2392, 1590, 1219, 1020 cm−1. H NMR (400 MHz, CDCl3):
δ 7.59ꢀ7.42 (m, 4H), 7.44ꢀ7.27 (m, 6H),
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4.61 (t, J = 7.2 Hz, 1H), 3.16 (dd, J = 14.0, 6.8 Hz, 1H), 2.77 (s, 3H), 2.01ꢀ1.85 (m, 1H), 1.84ꢀ1.71 (m,
9
1H), 1.65ꢀ1.50 (m, 2H), 1.48ꢀ1.34 (m, 1H), 1.26 (m, 1H), 1.17 (s, 9H), 1.02ꢀ0.85 (m, 1H). 13C NMR
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(100 MHz, CDCl3):
δ 138.7, 138.6, 130.6 (2C), 130.0 (2C), 127.7 (2C), 127.6, 127.5, 127.3 (2C), 86.9,
67.5, 59.6, 51.3, 40.5, 24.8 (3C), 24.5, 23.8, 18.8. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for
C23H31NO2S+Na 408.1973; found 408.1978.
(R)-1-(tert-butyl(λ1-oxidaneyl)-(λ3-sulfaneyl)-2-(methoxymethoxy)diphenylmethyl)piperidine (10):
To a stirred solution of 8l (0.15 g, 0.3 mmol) in dry THF (15 mL) at 0 °C was added NaH (60% in
mineral oil, 0.036 g, 0.9 mmol). The reaction mixture was refluxed for 4 h at 70 °C. After completion of
reaction (TLC) it was quenched with ice cold water and extracted with EtOAc (2 × 40 mL). The organic
layer was washed with brine (30 mL) and dried over Na2SO4. Evaporation of solvent afforded the
product in 85% yield (0.11 g) as a gummy mass. [α]D24 +51.5 (c 1.05, CHCl3). IR (Neat): νmax 3395,
3057, 2929, 2852, 1601, 1446, 1075 cm−1. H NMR (400 MHz, CDCl3):
δ 7.62ꢀ7.47 (4H), 7.44ꢀ7.29
1
(m, 6H), 4.69 (t, J = 7.6 Hz, 1H), 4.34 (q, J = 5.6 Hz, 2H), 3.20 (s, 3H), 3.11 (ddd, J = 15.2, 7.0, 1.6 Hz,
1H), 2.04ꢀ1.80 (m, 2H), 1.70 ꢀ1.53 (m, 2H), 1.50ꢀ1.38 (m, 1H), 1.37ꢀ1.21 (m, 1H), 1.15 (s, 9H), 1.06ꢀ
0.91 (m, 1H). 13C NMR (100 MHz, CDCl3):
δ 139.2, 139.1, 130.4 (2C), 129.8 (2C), 127.9, 127.8, 127.7
(2C), 127.4 (2C), 92.1, 86.7, 67.7, 59.5, 55.9, 40.7, 24.9 (3C), 24.4, 23.6, 18.8. HRMS (ESIꢀTOF) m/z:
[M+Na]+ calcd for C24H33NO3S+Na 438.2079; found 438.2077.
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General procedure B for the deprotection of MOM as well as sulfinyl group: The following
preparation of 11 is representative.
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(R)-aziridin-2-yldiphenylmethanol (11): To a precooled stirred solution of 8i (0.05 g, 0.13 mmol) in
MeOH (3 mL) at 0 °C was added a saturated solution of HCl in MeOH (0.7 mL). The reaction mixture
was stirred for 4 h at the room temperature. After completion of the reaction (TLC), the solvent was
evaporated off, and the resultant white salt was dissolved in THFꢀMeOH (4 mL). Solid NaHCO3 (0.25
g, 3 mmol) was added to the reaction mixture and was stirred for 6h at rt. The reaction mixture was
filtered on a short celite pad. Evaporation of solvent followed by crystallization in CH2Cl2 afforded the
product 11 in 96% yield (0.029g) as a colorless crystal. mp: 152ꢀ155 °C, [lit.9 155ꢀ157 °C]. [α]D24 +28°
(c 2.35, CHCl3), [for enantiomer lit.9 −22.6° (c 1.0, CHCl3)]. IR (KBr): νmax 3283, 2928, 2845, 2358,
1636, 1084 cm−1. 1H NMR (400 MHz, CDCl3):
1H), 1.77 (d, 3.6 Hz, 1H). 13C NMR (100 MHz, CDCl3):
δ 7.53ꢀ7.20 (m, 10H), 2.9 (m, 1H), 1.49 (d, J = 5.6 Hz,
δ
147.2, 145.1, 128.2 (2C), 128.1 (2C), 127.15,
127.11, 126.6 (2C), 126.3 (2C), 74.4, 37.0, 22.0. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for
C15H15NO+H 226.1232.; found 226.1236.
(R)-azetidin-2-yldiphenylmethanol (12): Compound 12 was prepared from 8j (0.12 g, 0.31 mmol)
using the general procedure B described above in 67% yield (0.05 g) as a white solid. mp: 111ꢀ115 °C,
[lit.10 116 °C]. [α]D24 +73° (c 0.8, MeOH), [lit.10 +75° (c 1.0, MeOH)]. IR (KBr): νmax 3283, 2928, 2845,
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2358, 1636, 1084 cm−1. H NMR (400 MHz, CDCl3):
δ
7.47ꢀ7.10 (m, 10H), 4.88 (t, J = 8.0 Hz, 1H),
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3
13
3.61 (q, J = 8.8 Hz, 1H), 3.17 (ddd, J = 8.4, 7.2, 3.2 Hz, 1H), 2.46ꢀ2.26 (m, 1H), 2.02ꢀ1.84 (m, 1H). C
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NMR (100 MHz, CDCl3):
δ 146.5, 143.5, 128.1 (2C), 128.0 (2C), 126.7, 126.6, 126.2 (2C), 126.0 (2C),
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8
76.6, 64.8, 42.4, 22.0. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C16H17NO+H 240.1388.; found
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240.1390.
(R)-diphenyl(pyrrolidin-2-yl)methanol (13a): Compound 13a was prepared from 8k (1.1 g, 2.74
mmol) using the general procedure B described above in 91% yield (0.63 g) as a yellowish gummy
mass, which up on recrystallization in EtOAc gave the pale yellow crystals. mp: 75ꢀ78 °C, [lit.11 74 °C].
[α]D24 +71° (c 3.0, MeOH), [lit.11 −68° (c 3.0, MeOH for the enantiomer)]. IR (KBr): νmax 3368, 2930,
2865, 2373, 1597, 1026 cm−1. 1H NMR (400 MHz, CDCl3):
δ
7.62ꢀ7.07 (m, 10H), 4.25 (t, J = 7.6 Hz,
148.1, 145.4, 128.2 (2C),
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1H), 3.08ꢀ2.84 (m, 2H), 1.79ꢀ1.48 (m, 5H). C NMR (100 MHz, CDCl3):
δ
127.9 (2C), 126.4, 126.3, 125.8, 125.5, 77.1, 64.4, 46.7, 26.2, 25.5. HRMS (ESIꢀTOF) m/z: [M+H]+
calcd for C17H19NO+H 254.1545.; found 254.1545.
(R)-2-(methoxydiphenylmethyl)pyrrolidine (13b): Compound 13b was prepared from 7k (0.045 g,
0.1 mmol) using the general procedure B described above in 99% yield (0.027 g) as a gummy mass.
[α]D24 +108.3° (c 1.0, CHCl3). [lit.12 −110° (c 1.23, CHCl3 for the enantiomer)] IR (Neat): νmax 3283,
2928, 2845, 2358, 1636, 1084 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.49ꢀ7.19 (m, 10H), 4.13 (t, J = 7.6
Hz, 1H), 3.08 (s, 3H), 2.80ꢀ2.64 (m, 1H), 2.63ꢀ2.48 (m, 1H), 1.95ꢀ1.80 (m, 1H), 1.79 (brs, 1H), 1.73ꢀ
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1.42 (m, 2H), 1.18ꢀ0.98 (m, 1H). 13C NMR (100 MHz, CDCl3):
δ 142.8, 141.8, 129.2 (2C), 129.0 (2C),
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4
5
127.5 (2C), 127.4 (2C), 127.10, 127.08, 85.3, 62.2, 51.3, 46.9, 27.4, 25.4. HRMS (ESIꢀTOF) m/z:
[M+H]+ calcd for C18H21NO+H 268.1701.; found 268.1702.
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(R)-diphenyl(piperidin-2-yl)methanol (14a): Compound 14a was prepared from 9 (0.1 g, 0.24 mmol)
using the general procedure B described above in 92% yield (0.071 g) as a white solid. mp: 94ꢀ97 °C,
[lit.13 99 °C]. [α]D24 +76° (c 0.8, CHCl3), [lit.13 +60° (MeOH)]. IR (KBr): νmax 3054, 2938, 2826, 1442,
1366, 1173, 746, 698 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.62 (dd, J = 8.8, 1.6 Hz, 2H), 7.47 (dd, H =
8.8, 1.6 Hz, 2H), 7.39ꢀ7.07 (m, 6H), 3.52 (dd, J = 10.4, 2.4 Hz, 1H), 3.01 (dquint, J = 10.8, 2.0 Hz, 1H),
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2.72 (dt, J = 11.6, 2.4 Hz, 1H), 1.81ꢀ1.49 (m, 3H), 1.47ꢀ1.18 (m, 4H). C NMR (100 MHz, CDCl3):
δ
146.3, 144.2, 128.5 (2C), 127.9 (2C), 126.8, 126.3, 125.9 (2C), 125.5 (2C), 78.4, 61.7, 46.7, 25.6, 25.5,
24.6. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C18H21NO+H 268.1701.; found 268.1702.
(R)-2-(methoxydiphenylmethyl)piperidine (14b): Compound 14b was prepared from 10 (0.16 g, 0.44
24
mmol) using the general procedure described above in 90% yield (0.111 g) as a gummy mass. [α]D
+70.4° (c 0.5, CHCl3). IR (Neat): νmax 3058, 3028, 2932, 2852, 2823, 1492, 1445, 1074 cm−1. 1H NMR
(400 MHz, CDCl3):
δ 7.48ꢀ7.21 (m, 10H), 3.50 (dd, J = 10.8, 1.2 Hz, 1H), 3.10 (dd, J = 12.4, 4.4 Hz,
1H), 2.95 (s, 3H), 2.70 (dt, J = 12.0, 2.4 Hz, 1H), 1.91ꢀ1.69 (m, 2H), 1.56ꢀ1.36 (m, 2H), 1.34ꢀ1.20 (m,
1H), 1.19ꢀ1.06 (m, 1H), 0.94ꢀ0.74 (m, 1H). 13C
δ
NMR (100 MHz, CDCl3): 141.3, 141.0, 129.5 (2C),
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129.2 (2C), 127.5 (2C), 127.3 (2C), 127.2 (2C), 127.1, 55.4, 61.3, 51.1, 47.6, 27.8, 25.2. HRMS (ESIꢀ
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TOF) m/z: [M+H]+ calcd for C19H23NO+H 268.1701.; found 268.1702.
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(R)-2-amino-3-methyl-1,1-diphenylbutan-1-ol (15): Compound 15 was prepared from 8d (0.09 g,
0.22 mmol) using the general procedure B described above in 99% yield (0.057 g) as a white solid. mp:
89ꢀ94 °C, [lit.14 93ꢀ94 °C]. [α]D24 +122° (c 0.5, CHCl3), [lit.14 −126° (c 0.7, CHCl3 for the enantiomer)].
IR (KBr): νmax 33337, 2923, 2872, 2382, 1588, 1444, 771 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.62 (d,
J = 7.6 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.39ꢀ7.25 (m, 4H), 7.24ꢀ7.10 (m, 2H), 3.85 (d, J = 2.0 Hz,
1H), 1.85ꢀ1.68 (m, 1H), 0.94 (d, J = 7.2 Hz, 3H), 0.90 (d, J = 6.3 Hz, 3H). 13C NMR (100 MHz,
CDCl3):
δ 148.0, 144.8, 128.4 (2C), 128.0 (2C), 126.6, 126.2, 125.9 (2C), 125.4 (2C), 79.6, 60.1, 27.8,
22.9, 16.0. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C17H21NO+H 256.1701.; found 256.1703.
(R)-2-amino-3,3-dimethyl-1,1-diphenylbutan-1-ol (16): Compound 16 was prepared from 8e (0.09 g,
0.22 mmol) using the general procedure B described above in 99% yield (0.058 g) as a white solid. mp:
135ꢀ140 °C. [lit.15 138 °C]. [α]D24 +135.0 (c 1.0, EtOH). [lit.15 +147.4° (c 0.4, EtOH)]. IR (KBr): νmax
3344, 3282, 2953, 2862, 1582, 1444, 697 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.66 (d, J = 8.0 Hz, 2H),
7.56 (d, J = 7.6 Hz, 2H), 7.39ꢀ7.28 (m, 4H), 7.26ꢀ7.05 (m, 2H), 3.84 (d, J = 2.0 Hz, 1H), 0.80 (s,
9H).13C NMR (100 MHz, CDCl3):
δ
149.8, 145.2, 128.5 (2C), 127.6 (2C), 126.4, 126.1, 126.0 (2C),
125.5 (2C), 79.8, 63.6, 35.5, 29.0 (3C). HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C18H23NO+H
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270.1858.; found 270.1861.
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(R)-2-amino-2-cyclohexyl-1,1-diphenylethan-1-ol (17): Compound 17 was prepared from 8f (0.14 g,
0.32 mmol) using the general procedure B described above in 96% yield (0.09 g) as a white solid. mp:
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171ꢀ175 °C. [α]D +122.0 (c 0.5, CHCl3). IR (KBr): νmax 3280, 3024, 2923, 2850, 1585, 1446, 696
1
cm−1. H NMR (400 MHz, CDCl3):
δ
7.59 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.36ꢀ7.20 (m,
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4H), 7.19ꢀ7.08 (m, 2H), 3.74 (d, J = 1.6 Hz, 1H), 1.95 (d, J = 12.8 Hz, 1H), 1.72ꢀ0.83 (m, 10H). C
NMR (100 MHz, CDCl3):
δ 147.9, 144.8, 128.3 (2C), 127.9 (2C), 126.5, 126.2, 125.9 (2C), 125.5 (2C),
79.8, 60.7, 38.2, 33.1, 26.8 (2C), 26.3, 26.2. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C20H25NO+H
296.2014.; found 296.2014.
(R)-2-amino-1,1,2-triphenylethan-1-ol (18): Compound 18 was prepared from 8h (0.1 g, 0.23 mmol)
using the general procedure described above in 99% yield (0.66 g) as a white solid. mp: 121ꢀ124 °C,
[lit.16 132 °C]. [α]D24 +243.0 (c 1.0, CHCl3), [lit.16 +240° (c 1.0, CHCl3)]. IR (KBr): νmax 3380, 3314,
2953, 2862, 1594, 1445, 890, 694 cm−1. 1H NMR (400 MHz, CDCl3):
7.36 (m, 2H), 7.35ꢀ7.21 (m, 2H), 7.20ꢀ7.09 (m, 6H), 7.08ꢀ6.95 (m, 3H), 5.02 (s, 1H). 13C NMR (100
δ 7.73 (d, J = 7.6 Hz, 2H), 7.49ꢀ
MHz, CDCl3):
δ 146.4, 143.8, 140.0, 128.6 (2C), 128.5 (2C), 127.4 (2C), 127.3 (2C), 127.2, 127.0,
126.5 (2C), 126.2, 126.0 (2C), 79.5, 61.7. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C20H19NO+H
290.1545.; found 290.1545.
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Supporting information: Supporting information containing H and C NMR spectra of all the new
compounds, ORTEP image of compound 8m and Xꢀray data for 8m are provided. “This material is
available free of charge via the Internet at http://pubs.acs.org.”
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Acknowledgements: A. A. R. thanks the Council of Scientific and Industrial Research (CSIR) for a
senior research fellowship. We thank Dr. Arava Veera Reddy of Suven Pharma, Hyderabad, India for a
kind gift of the tꢀbutylsulfinamide used in this investigation.
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References:
1) (a) Braun. M. The “Magic” diarylhydroxymethyl group. Angew. Chem. Int. Edn. 1996, 35, 519ꢀ
522. (b) Braun. M. The diaryl(oxy)methyl group: More than an innocent bystander in chiral
auxiliaries, catalysts, and dopants. Angew. Chem. Int. Edn. 2012, 51, 2550ꢀ2562.
2) For review on sulfinimine chemistry see: (a) Davis, F. A. Adventures in sulfurꢀnitrogen
chemistry. J. Org. Chem. 2006, 71, 8993ꢀ9003. (b) Zhou, P.; Chen, B.; Davis, F. A. Recent
advances in asymmetric reactions using sulfinimines (Nꢀsulfinyl imines). Tetrahedron, 2004, 60,
8003ꢀ8030. (c) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Robak, M. T.; Herbage, M. A.;
Ellman, J. A. Synthesis and applications of tertꢀbutanesulfinamide.; Chem. Rev. 2010, 110,
3600ꢀ3740. (d) For a comprehensive treatise on methods for the synthesis of chiral amines see:
Chiral amine synthesis, methods, development and applications. Nugent, T. C. (Ed), WileyꢀVCH
Verlag GmbH, Weinheim 2010.
3) For lithiated diphenylmethanol MOM ether see: (a) U.; Pisano, L.; Mocci, S. Direct metalation
of methoxymethyl arylmethyl ethers: A tinꢀfree approach to the generation of aꢀalkoxyalkoxyꢀ
substituted aryllithiums J. Organomet. Chem. 2009, 694, 3619ꢀ3625. During the preparation and
submission of this manuscript we came across a report on the addition of lithiated
diarylmethanes to Ellman sulfinimines: (b) Reddy, L. R.; Kotturi, S.; Waman, Y.; Patel, C.;
Danidharia, M.; Shenoy, R. Asymmetric Synthesis of (diarylmethyl) alkyl amines through
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