Syntheses of chiral β- And γ-amino ethers, morpholines, and their homologues via nucleophilic ring-opening of chiral activated aziridines and azetidines

Article abstract of DOI:10.1021/jo300002u

Figure Persented: Lewis acid catalyzed quaternary ammonium salt mediated highly regioselective ring-opening of chiral activated aziridines and azetidines with alcohols to nonracemic β- and γ-amino ethers has been developed. The reaction mainly proceeds vi

Full text of DOI:10.1021/jo300002u

Article
pubs.acs.org/joc
Syntheses of Chiral β- and γ-Amino Ethers, Morpholines, and Their
Homologues via Nucleophilic Ring-Opening of Chiral Activated
Aziridines and Azetidines
Manas K. Ghorai,* Dipti Shukla, and Aditya Bhattacharyya
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
S
* Supporting Information
ABSTRACT: Lewis acid catalyzed quaternary ammonium salt mediated highly regioselective ring-opening of chiral activated
aziridines and azetidines with alcohols to nonracemic β- and γ-amino ethers has been developed. The reaction mainly proceeds
via an SN2 pathway, and the partial racemization of the starting substrate was effectively controlled by using quaternary
ammonium salts. β- and γ-amino ethers are obtained with high enantio- and diastereospecificity (ee up to >99%, de up to 99%).
The methodology was further extended to synthesize morpholines and their homologues with high enantiospecificity (ee up to
90%) when halo alcohols were employed as the nucleophiles.
obtained in the absence of these ammonium salts, e.g.,
nonracemic β- and γ-amino ethers with high ee.5i To
demonstrate the efficiency of our present synthetic method-
ology, we chose the same nucleophile (i.e., alcohols) as the
products amino ethers are an important class of compounds
from biological perspectives. Enantiopure β-amino ethers are
key precursors in the preparation of a wide variety of
pharmaceutical compounds. The β-amino ether mexiletine7 is
a popular antiarrhythmic,8 antimyotonic,9 and analgesic agent.10
It has also been proposed for the treatment of tinnitus.11 β-
Amino ethers are essential fragments in many glucopeptide
antibiotics12 and ether-containing peptide bond surrogate
units.13 There are several reports available for the syntheses
of β-amino ethers in the literature.14 General methods include
alkoxide or Brønsted acid mediated alcoholyses of aziridines,14a
opening of N-nosylaziridines by MeOH,14b KSF clay,14c or
Lewis acid mediated ring-opening of aziridines.14d Ring-
opening of resin-bound aziridines with phenol nucleophiles
has been reported recently.14e Syntheses of β-amino ethers by
substitution of the β-hydroxy ether have also been reported.14f
Their homologues, γ-amino ethers, are widely used for the
treatment of anxiety and depression, e.g., fluoxetine, a novel
antidepressant, is widely used for treatment of various types of
psychiatric disorders, as well as other clinical conditions.15−18
Syntheses of γ-amino ethers are known from chiral alcohol
intermediates,19 N-alkylazetidinols,20 and 2-aryl-N-tosylazeti-
INTRODUCTION
■
In recent years, ring-opening transformations of small ring aza-
heterocycles have been extensively exploited to provide
excellent routes for the construction of important synthetic
targets via nucleophilic ring-opening, cycloaddition, and
rearrangement reactions.1−5 Lewis acid (LA) mediated ring-
opening of 2-phenyl-N-tosylaziridines and -azetidines with
several nucleophiles to afford nonracemic products in high
enantiomeric excess have been reported by us. We demon-
strated the reaction to proceed through a prevalent SN2
pathway, and the partial loss of enantiopurity in all the cases
was due to partial racemization of the starting aziridines or
azetidines.5
Very recently, we have reported SN2-type ring-opening of
aziridines and azetidines using (i) quaternary ammonium salts
with nucleophilic halides as the counterions in the presence of
BF3·Et2O6a and (ii) quaternary ammonium salt with non-
nucleophilic counteranions in the presence of metal halides as
Lewis acids6b to afford haloamines with excellent enantiospe-
cificity. We believe that the dipolar quaternary ammonium salt
stabilizes the dipolar intermediate generated from the
interaction of aziridine with the LA and controls the
racemization of the starting aziridine affording the haloalkyl-
amines with excellent ee (up to 99%).
We anticipated that it could be possible to achieve the Lewis
acid-catalyzed ring-opening of aziridines and azetidines by
nucleophiles in the presence of quaternary ammonium salts
with non-nucleophilic anions which allow the products to be
formed with higher enantiospecificity than those previously
Received: January 7, 2012
Published: March 26, 2012
© 2012 American Chemical Society
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Figure 1. Comparative racemization study of (R)-1a with Cu(OTf)2 at 0 °C in DCM with TBAHS (blue line) and without TBAHS (red line) up to
20 min.
dines.21,22 Various synthetic protocols like chemical or
enzymatic resolution, asymmetric reduction of the prochiral
ketones, dihydroxylation or Sharpless epoxidation of styrene,
and carbonyl−ene reaction of benzaldehyde have been
employed for the syntheses of γ-amino ethers. We report
herein copper(II) triflate-catalyzed and tetrabutylammonium
hydrogen sulfate (TBAHS)-mediated ring-opening of aziridines
and azetidines with alcohols to afford nonracemic amino ethers
in excellent diastereo- and enantiospecificity.
was obtained in good yield and excellent ee (88%) as the only
regioisomer.
To optimize the reaction conditions for better yield and ee,
various other Lewis acids were screened; however, other Lewis
acids took a longer time for completion of the reaction, and the
products were obtained with reduced ee in some cases. The
reaction was found to be more efficient using only 5 mol % of
Cu(OTf)2 and 2.0 equiv of TBAHS to produce the amino ether
3a with 92% ee (entry 7, Table 1). All of the results have been
summarized in Table 1.
RESULTS AND DISCUSSION
■
Table 1. Screening of Lewis Acids for Regioselective
To test the feasibility of our approach, at first we studied the
racemization of enantiopure (R)-2-phenyl-N-tosylaziridine 1a
with Cu(OTf)2 (20 mol %) in dichloromethane without any
nucleophile in the presence of TBAHS. Our earlier studies
showed that the rate of racemization of (R)-2-phenyl-N-
tosylaziridine 1a was very fast with Cu(OTf)2 in dichloro-
methane; the ee of (R)-1a after 5 min was found to be 86%,
and after 20 min it was reduced to 74%.
In the presence of TBAHS, to our great pleasure, we
observed that the racemization of (R)-1a with Cu(OTf)2 (20
mol %) could be controlled to an appreciable extent; the ee of
(R)-1a after 5 min was slightly reduced (ee 98%), and after 20
min it became 94% (Figure 1, details are provided in the
Supporting Information).
Nucleophilic Ring-Opening of (R)-1a with Allyl Alcohol in
a
the Presence of TBAHS
b
c
entry
Lewis acid (20 mol %)
time
yield (%)
ee (%)
1
2
3
4
5
6
Sc(OTf)3
Zn(OTf)2
BF3·OEt2
Yb(OTf)3
AgOTf
4.5 h
4.5 h
1.5 h
2 h
73
74
37
78
77
75
76
88
89
78
77
82
88
92
71
4 h
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
15 min
30 min
25 min
d
7
d,e
8
75
a
b
Allyl alcohol was used as the solvent in all the cases. After column
c
chromatographic purification. The ee was determined by Chiralpak
AS-H column. 5 mol % of Cu(OTf)2 and 2.0 equiv of TBAHS were
used. The reaction was performed at room temperature.
d
Next, we studied the ring-opening of aziridine (R)-1a with
allyl alcohol in the presence of a catalytic amount of LA and
TBAHS (Scheme 1). When (R)-1a was treated with allyl
alcohol in the presence of 20 mol % of Cu(OTf)2 and 1.0 equiv
of TBAHS at 0 °C for 15 min, nonracemic β-amino ether 3a
e
After observing the enhanced enantiospecificity of the
reaction with catalytic amount of Cu(OTf)2 and TBAHS, we
explored the reaction with other quaternary ammonium salts
having different non-nucleophilic counteranions viz. hexafluor-
ophosphate, triflate, perchlorate, and tetrafluoroborate (Scheme
2). However, it took a longer time for the completion of the
reaction in all of the cases affording the product with poor yield
and comparatively low enantiospecificity. TBAHS was found to
be the best salt for the Lewis acid catalyzed ring-opening
reaction with alcohols (entry 1, Table 2). The results are
summarized in Table 2.
Scheme 1. Nucleophilic Ring-Opening of 2-Phenyl-N-
tosylaziridine by Allyl Alcohol in the Presence of Lewis Acid
and Quaternary Ammonium Salt
Under the optimized reaction conditions, the ring-opening of
(R)-1a was generalized with a number of alcohols (propargyl,
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−50 °C (reaction duration 6 h), the enantiospecificity was
enhanced (ee 92%). However, other alcohols did not react at
lower temperature. The absolute configuration of the amino
ether 3b as a representative example has been determined to be
(S) in our previous report.5i
Scheme 2. Nucleophilic Ring-Opening of (R)-2-Phenyl-N-
tosylaziridine by Allyl Alcohol in the Presence of Cu(OTf)2
and Quaternary Ammonium Salt
To study the electronic effect of the N-arylsulfonyl group, a
variety of N-arylsulfonylaziridines 1b−e (ee > 99%)5j were
treated with methanol in the presence of catalytic amount of
Cu(OTf)2 and stoichiometric amount of TBAHS to afford the
corresponding amino ethers 3h−k in good yield and excellent
ee (Scheme 4, Table 4). When (R)-2-phenyl-N-nosylaziridne
1b was employed, the corresponding product 3h was formed in
good yield and excellent enantiospecificity (Table 4, entry 1).
The nosyl group can be easily deprotected under mild reaction
conditions without affecting the enantiomeric excess of the
corresponding product.5b In this context chiral (R)-2-phenyl-N-
acetylaziridine was synthesized utilizing modified reported
procedure,23,25 and its ring-opening reactions with alcohols
(MeOH and allyl alcohol) were studied applying the present
reaction conditions. Unfortunately, with N-acetylaziridine we
were not successful to get any ring-opening product. The
aziridine 1d bearing a weak electron-withdrawing group on
nitrogen took a longer time for the reaction to complete, and
the yield of the reaction was also found to be poor in this case
(Table 4, entry 3). As the preparation of N-tosylaziridnes are
very easy (both racemic and chiral), we have employed the N-
tosylaziridines for most of our studies.
a
Table 2. Optimization of Quaternary Ammonium Salts
b
c
entry
R4N+X−
time (h)
yield (%)
ee (%)
1
2
3
4
5
Bu4N+HSO4
0.5
3.0
2.0
1.75
2.5
76
56
30
56
62
92
88
85
79
89
−
Bu4N+PF6
−
Bu4N+OTf−
Bu4N+ClO4
−
Bu4N+BF4
−
a
b
Allyl alcohol was used as the solvent in all the cases. After column
chromatographic purification. The ee was determined by Chiralpak
c
AS-H column.
benzyl, isopropyl, etc., Scheme 3), and the results are shown in
Table 3. It was observed that under catalytic conditions using
Scheme 3. Cu(OTf)2-Catalyzed TBAHS-Mediated
Regioselective Nucleophilic Ring-Opening of (R)-2-Phenyl-
N-tosylaziridine with Different Alcohols
To broaden the scope of this methodology further, a variety
of 2-alkyl-N-tosylaziridines 1f−i (ee > 99%)5j prepared from
the corresponding amino acids were reacted with methanol
under the same reaction conditions (Scheme 5).
Ring-opening of alkyl aziridines 1f−i with methanol was
found to be comparatively slower than arylaziridines (Table 5)
and produced the corresponding amino ethers as a mixture of
regioisomers 3l−o and 4l−o arising from internal attack and
terminal attack, respectively, which could not be separated by
column chromatography. Structures of the regioisomers could
2.0 equiv of TBAHS, there was 7−20% enhancement in ee in
all the cases by comparison with results obtained in the absence
of the quaternary ammonium salts.23
1
not be interpreted from the H NMR of the crude reaction
In the course of performing of the experiments described in
Table 3, it has been observed that the rate of reactions varied in
different alcohols. The dielectric constants of the alcohols are as
follows: MeOH (33.0), allyl alcohol (19.7), propargyl alcohol
(20.8), 2-chloroethanol (25.80), 2-propanol (20.18), tBuOH
(17.26), benzyl alcohol (11.916), and o-cresol (6.76).24
Probably the combination of solvent polarity (depends on
dielectric constant) and hydrogen bonding governs the
reactivity of a particular alcohol. MeOH being the most polar
stabilizes the dipolar intermediate before nucleophilic attack
and probably because of H-bonding nucleophilicity of MeOH is
reduced (reaction becomes slower). Other alcohols are
comparatively less polar and better nucleophiles. As a result,
they stabilize the reactive intermediate to a lesser extent, and
there is a possibility of a double SN2 attack at the reactive site.
This might contribute to the faster reaction but with decreased
stereospecificity.
When more sterically crowded 2-methyl-2-propanol was
used, (R)-1a (Table 3, entry 6) afforded the corresponding
amino ether with excellent enantiospecificity at 25 °C. It is
worth mentioning that 2-methyl-2-propanol failed to give any
ring-opening product with (R)-1a in the absence of TBAHS.
When propargyl alcohol was used as the solvent, (R)-1a
produced the amino ether 3c with 80% ee within 2 min at 0 °C
(Table 3, entry 3). When the same reaction was performed in
dichloromethane as the solvent with 5.0 equiv of the alcohol at
mixture as regioisomeric proton signals were found to be
mostly inseparable, although 13C NMR clearly showed the
presence of amino ethers 3l−o and 4l−o.
The regioisomeric ratio was determined by HPLC analysis.
The structure of the major regioisomer 4 was confirmed
indirectly by comparing with an authentic compound. As a
representative example, 4m was converted to the corresponding
N-methyl derivative (Scheme 6), and its spectral data (1H and
13C NMR) were compared with the authentic compound 5
prepared from (S)-phenylalanine.5i,17
The strategy was further extended to enantiopure trans-2,3-
disubstituted aziridines 1j−m.6 Ring-opening of enantiopure
1j−m (de up to 99%) in the presence of 5 mol % of copper
triflate and 2.0 equiv of TBAHS with methanol afforded the
corresponding anti amino ethers 3p−s as the major
diasteromers (Scheme 7, Table 6, entries 1−4) with high
yield and excellent de. However, the reaction did not proceed
in the absence of TBAHS using catalytic amount of Lewis acid.
After successful demonstration of the strategy for the ring-
opening of aziridines, we envisaged that the ring-opening of
enantiopure (S)-2-phenyl-N-tosylazetidine 2a (ee > 99%) with
alcohols in the presence of catalytic amount of LA and
stoichiometric amount of quaternary ammonium salt would
also afford γ-amino ethers 6 with better specificity. Initially, we
studied the ring-opening of (S)-2a with methanol in the
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Table 3. Cu(OTf)2-Catalyzed TBAHS-Mediated Regioselective Nucleophilic Ring-Opening of (R)-2-Phenyl-N-tosylaziridine
a
with Different Alcohols
a
b
c
Alcohols were used as the solvent in all the cases. After column chromatographic purification. The ee was determined by chiral HPLC analysis.
d
e
f
The reaction was performed at 25 °C. The other regioisomer 4g (from terminal attack) was also obtained in a 2:1 ratio. Combined yield of
regioisomers 3g and 4g after column chromatographic purification.
Scheme 4. Cu(OTf)2-Catalyzed TBAHS-Mediated
Regioselective Nucleophilic Ring-Opening of Various (R)-2-
Phenyl-N-sulfonylaziridines with Methanol
Scheme 5. Nucleophilic Ring-Opening of 2-Alkyl-N-
tosylaziridines with Methanol
presence of 30 mol % of Cu(OTf)2 and a stoichiometric
amount of quaternary ammonium salt at 0 °C to produce
amino ether 6a in high yield (82%) and excellent ee (94%).
The strategy was generalized for the ring-opening of (S)-2a
with a number of alcohols, and the results are summarized in
Table 7. In this case, also we have observed 6−20%
enhancement in ee and appreciable reduction in reaction
time.23
The scope of the methodology was further extended for the
ring-opening of enantiopure cis- and trans-2,4-disubstituted
azetidines 2b−e with methanol to afford the corresponding 1,3-
amino ethers 6g−j. The ring-opening of enantiomerically pure
trans-(2R,4S)-2-allyl-4-phenyl-N-tosylazetidine 2d affords
amino ether 6i as the major diastereomer with syn
configuration, whereas ring-opening of cis-2e affords amino
ether 6j with the anti configuration as the major diastereomer
(Scheme 9, Table 8, entries 3 and 4).
Table 4. Cu(OTf)2-Catalyzed TBAHS-Mediated
Regioselective Nucleophilic Ring-Opening of Various (R)-2-
a
Phenyl-N-sulfonylaziridines with Methanol
b
c
entry
aziridine, Ar
amino ether time (h) yield (%) ee (%)
1
2
3
4
1b, 4-NO2C6H4
1c, 4-MeOC6H4
1d, 4-FC6H4
3h
3i
4
85
77
51
67
>99
98
3.5
3j
12
97
1e, 4-tBuC6H4
3k
4
95
a
b
Methanol was used as solvent in all the cases. After column
c
The 1,3-relative stereochemistry of the diastereomers 6i and
6j was determined by NOESY experiment. When protons Ha
chromatographic purification. The ee was determined by chiral HPLC
analysis.
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a
Table 5. Cu(OTf)2-Catalyzed TBAHS-Mediated Nucleophilic Ring-Opening of 2-Alkyl-N-tosylaziridines with Methanol
a
b
c
Methanol was used as the solvent in all the cases. After column chromatographic purification. The ratio was determined by HPLC analysis.
Scheme 6. Synthesis of Authentic Compound 5
Scheme 7. Cu(OTf)2-Catalyzed TBAHS-Mediated
Regioselective Nucleophilic Ring-Opening of 2,3-
Disubstituted N-Tosylaziridines with Methanol
Scheme 8. Cu(OTf)2-Catalyzed TBAHS-Mediated
Regioselective Nucleophilic Ring-Opening of 2-Phenyl-N-
tosylazetidine with Various Alcohols
and Hb were irradiated, peak enhancement for the cis-
diastereomer was comparatively more than for the trans-
diastereomer (Figure 2).
However, in order to get mechanistic insight and to
demonstrate the effect of TBAHS, we performed the following
set of experiments in dichloromethane using limited excess of
alcohols as the nucleophiles. To our anticipation, the
enantiospecificity of the reactions increased appreciably in all
the cases.
In order to showcase the efficiency of our present
methodology, we have further extended this protocol for the
synthesis of morpholines and homomorpholines by the ring-
opening of various aziridines and azetidines with halo alcohols.
When (R)-2-phenyl-N-sulfonylaziridines (R)-1a,c,d were trea-
ted with 2-chloroethanol in the presence of 5 mol % of
Cu(OTf)2 and a stoichiometric amount of tetrabutylammo-
Table 6. Cu(OTf)2-Catalyzed TBAHS-Mediated
Regioselective Nucleophilic Ring-Opening of 2,3-
Disubstituted N-Tosylaziridines with Methanol
a
b
c
entry
aziridine
amino ether time (h) yield (%) de (%)
1
2
3
R = Et, 1j
3p
3q
3r
3s
1
90
84
68
70
>99
>99
>99
92
R = Me, 1k
R = nPr, 1l
R = allyl, 1m
1
1.5
2
d
4
a
b
Methanol was used as solvent in all the cases. After column
c
1
chromatographic purification. The de was determined by H NMR
and chiral HPLC analysis. The de of starting aziridine was 92%.
d
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Table 7. Cu(OTf)2-Catalyzed TBAHS-Mediated Regioselective Nucleophilic Ring-Opening of 2-Phenyl-N-tosylazetidine with
a
Various Alcohols
a
b
c
d
Alcohols were used as solvent in all cases. After column chromatographic purification. The ee was determined by chiral HPLC analysis. The
e
f
reaction was performed at 25 °C. The other regioisomer 7f (from terminal attack) was also obtained in 2:1 ratio. Combined yield of regioisomers
6f and 7f after column chromatographic purification.
nium hydrogen sulfate at 0 °C, it afforded the corresponding
chloroethoxy amines which upon further treatment with KOH
afforded the N-sulfonylmorpholines 7a−c with improved ee
(Scheme 10, Table 10).
Scheme 9. Cu(OTf)2-Catalyzed TBAHS-Mediated
Regioselective Nucleophilic Ring-Opening of 2,4-
Disubstituted N-tTosylazetidine with Methanol
When the ring-opening reaction of (R)-1a with 2-
chloroethanol in the presence of 5 mol % of Cu(OTf)2 and
stoichiometric amount of TBAHS was performed at −50 °C in
dichloromethane solvent, it afforded the morpholine 7a with
90% ee (Table 10, entry 4).
The reaction was also successful in the case of azetidine.
When the ring-opening reaction of (S)-2a with 3-chloropropa-
nol in the presence of 40 mol % of Cu(OTf)2 and a
stoichiometric amount of TBAHS was performed at 0 °C in
dichloromethane solvent, it afforded the oxazocane 8, the two-
carbon higher homologue of morpholines with 78% ee in 50%
overall yield (Scheme 11).
Table 8. Cu(OTf)2-Catalyzed TBAHS-Mediated
Regioselective Nucleophilic Ring-Opening of 2,4-
Disubstituted N-Tosylazetidine with Methanol
a
MECHANISM
■
The reaction follows an SN2-type mechanism as proposed
previously by us.6 Based on our racemization studies of (R)-1a
and (S)-2a in the presence of quaternary ammonium salt, we
believe that Cu(OTf)2 reacts with aziridine or azetidine to
generate a highly reactive intermediate 9 or 10 that is stabilized
by tetraalkylammonium salt and the rate of racemization of
(R)-1a or (S)-2a is retarded. The alcohol as the nucleophile
then attacks at the benzylic position of 9 or 10 affording the
amino ether with enhanced enantiospecificity (Scheme 12).
a
b
Methanol was used as solvents in all the cases. After column
c
1
chromatographic purification. The dr was determined by H NMR.
CONCLUSION
■
In conclusion, we have developed a simple strategy for the
synthesis of optically enriched or enantiopure β- and γ-amino
ethers via Lewis acid catalyzed quaternary ammonium salt
mediated ring-opening of aziridines and azetidines with
Figure 2. Diagnostic NOE observation for the amino ethers 6i and 6j.
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Table 9. Comparative Experimental Study of Ring-Opening of (R)-2-Phenyl-N-tosylaziridine and (S)-2-Phenyl-N-tosylazetidine
with Various Alcohols as Nucleophiles in Dichloromethane with and without TBAHS
a
b
0.1 equiv of Cu(OTf)2, 1.0 equiv of TBAHS, and 5.0 equiv of alcohol were used. 0.4 equiv of Cu(OTf)2, 1.0 equiv of TBAHS, and 5.0 equiv of
c
d
alcohol were used. After column chromatographic purification. The ee was determined by chiral HPLC analysis.
Scheme 10. One-Pot Ring-Opening of Chiral 2-Phenyl-N-
sulfonylaziridines in the Presence of Cu(OTf)2 and TBAHS
by Chloroethanol
Scheme 11. Ring-Opening of (S)-2-Phenyl-N-tosylazetidine
in the Presence of Cu(OTf)2 and TBAHS by 3-
Chloropropanol at 0 °C
alcohols under very mild reaction conditions. The methodology
was further extended for the synthesis of morpholines and their
higher homologues. The present strategy can be treated as a
general methodology which stands superior than other reports
including our earlier results for the preparation of β- and γ-
amino ethers based on the following experimental observations:
(i) using the quaternary ammonium salt the ring-opening
reactions of aziridines and azetidines could be made possible
using catalytic amount of Lewis acid; (ii) the reaction time
becomes considerably shorter when quaternary ammonium salt
is used; (iii) reaction with less reactive nucleophiles (e.g., 2-
methyl-2-propanol) which do not react at all, are made
successful using the quaternary ammonium salt as the additive;
(iv) by adding quaternary ammonium salt in the reaction
Table 10. One-Pot Synthesis of Morpholines and Higher Homologues via Ring-Opening of Aziridines and Azetidines with 2-
a
Chloroethanol in the Presence of TBAHS
a
b
In all cases, the alcohol served as the solvent and a stoichiometric amount of TBAHS was used. After column chromatographic purification.
c
d
Determined by HPLC analysis using Chiralpak AD-H or Chiralcel OD-H. The reaction was performed at −50 °C.
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Scheme 12. Plausible Mechanism for the Ring-Opening of Aziridines and Azetidines with Alcohols
chromatography on silica gel (230−400 mesh) using 15% ethyl
acetate in petroleum ether to provide the pure product.
Method B. A solution of the aziridine (1.0 equiv) and TBAHS (1.0
equiv) in 1.0 mL of methanol was added to anhydrous Cu(OTf)2 (0.2
equiv) at an appropriate temperature under an argon atmosphere. The
mixture was stirred for an appropriate time (Tables 4 and 5), and then
the reaction mixture was quenched with saturated aqueous NaHCO3
solution. The aqueous layer was extracted with CH2Cl2 (3 × 5.0 mL)
and was washed with brine solution. The organic layers were collected
and dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure, and the crude product was purified by flash column
chromatography on silica gel (230−400 mesh) using 15% ethyl acetate
in petroleum ether to provide the pure product.
General Procedure for the Cu(OTf)2-Catalyzed TBAHS-
Mediated Ring-Opening of Azetidines. Method C. A solution
of the azetidine (S)-2a (0.087 mmol, 1.0 equiv) and TBAHS
(0.087 mmol, 1.0 equiv) in alcohol was added to anhydrous
Cu(OTf)2 (0.0261 mmol, 0.3 equiv) at an appropriate
temperature under an argon atmosphere. The mixture was
stirred for an appropriate time (entries 1−6, Table 7), and then
the reaction mixture was quenched with a saturated aqueous
NaHCO3 solution. The aqueous layer was extracted with
CH2Cl2 (3 × 5.0 mL) and was washed with brine solution. The
organic layers were collected and dried over anhydrous Na2SO4.
The solvent was removed under reduced pressure, and the
crude product was purified by flash column chromatography on
silica gel (230−400 mesh) using 15% ethyl acetate in petroleum
ether to provide the pure product.
Method D. A solution of the azetidine 2b−e (1.0 equiv) and
TBAHS (1.0 equiv) in methanol was added to anhydrous Cu(OTf)2
(0.4 equiv) at an appropriate temperature under an argon atmosphere.
The mixture was stirred for an appropriate time (entries 1−4, Table
8), and then the reaction mixture was quenched with saturated
aqueous NaHCO3 solution. The aqueous layer was extracted with
CH2Cl2 (3 × 5.0 mL) and was washed with brine solution. The
organic layers were collected and dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure, and the crude product
was purified by flash column chromatography on silica gel (230−400
mesh) using 15% ethyl acetate in petroleum ether to provide the pure
product.
mixture the competitive racemization of chiral aziridines and
azetidines are controlled; (v) up to 20−24% increase in
enantiospecificity were observed when the quaternary ammo-
nium salt was used in the reaction along with the catalytic
amount of Lewis acid.
EXPERIMENTAL SECTION
■
General Procedures. Analytical thin layer chromatography (TLC)
was carried out using silica gel 60 F254 precoated plates. Visualizations
were accomplished with a UV lamp or I2 stain. Silica gel 100−200 and
230−400 mesh size were used for column chromatography using the
combination of ethyl acetate and petroleum ether as an eluent. Unless
noted, all of the reactions were carried out in oven-dried glassware
under an atmosphere of nitrogen using anhydrous solvents. Where
appropriate, solvents and all reagents were purified prior to use
following the guidelines of Perrin and Armarego.26 Cu(OTf)2 used in
all reactions was prepared using a literature procedure.27 All
commercial reagents were used as received. Proton nuclear magnetic
resonance (1H NMR) spectra were recorded at 400 or 500 MHz.
Chemical shifts were recorded in parts per million (ppm, δ) relative to
1
tetramethyl silane (δ 0.00). H NMR splitting patterns are designated
as singlet (s), broad singlet (br s), doublet (d), triplet (t), quartet (q),
or multiplet (m). Carbon nuclear magnetic resonance (13C NMR)
spectra were recorded at 100 or 125 MHz. Mass spectra (MS) were
obtained using FAB and ESI mass spectrometer. Melting points were
determined using a hot stage apparatus and are reported as
uncorrected. Enantiomeric excess (ee) was determined by HPLC
using a Chiralcel OD-H or Chiralpak AD-H or AS-H analytical column
(detection at 254 nm). Optical rotations are reported as [α]25D (c in g
per 100 mL solvent).
General Procedure for the Cu(OTf)2-Catalyzed TBAHS-
Mediated Ring-Opening of Aziridines. Method A. A solution
of the aziridine (R)-1a (1.0 equiv) and TBAHS (2.0 equiv) in
1.0 mL alcohol was added to anhydrous Cu(OTf)2 (0.05 equiv)
at an appropriate temperature under an argon atmosphere. The
mixture was stirred for an appropriate time (entries 1−7, Table
3 and 6), and then the reaction mixture was quenched with
saturated aqueous NaHCO3 solution. The aqueous layer was
extracted with CH2Cl2 (3 × 5.0 mL) and was washed with brine
solution. The organic layers were collected and dried over
anhydrous Na2SO4. The solvent was removed under reduced
pressure, and the crude product was purified by flash column
General Procedure for the Cu(OTf)2-Catalyzed TBAHS-
Mediated One-Pot Ring-Opening/Cyclization of Aziridines
with Halo Alcohols. Method E. A solution of the aziridines
3747
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Article
1a, 1c, and 1d (1.0 equiv) in halo alcohol (10 equiv) was added
at 0 °C to anhydrous copper triflate (5 mol %) and 1 equiv of
TBAHS under an argon atmosphere. The mixture was stirred
for an appropriate time, and then it was further treated with
KOH in THF to afford the N-sulfonylmorpholines 7a−c with
improved ee. The reaction was quenched with water, and then
the mixture was extracted with dichloromethane (3 × 5.0 mL)
and dried over anhydrous sodium sulfate. The crude product
was purified by flash column chromatography on silica gel
(230−400 mesh) using 10% ethyl acetate in petroleum ether to
provide the pure product.
General Procedure for the Cu(OTf)2-Catalyzed TBAHS-
Mediated One-Pot Ring-Opening/Cyclization of Azetidines
with Halo Alcohols. Method F. A solution of the azetidine 2a
(1.0 equiv) in halo alcohol (10 equiv) was added at 0 °C to
anhydrous copper triflate (40 mol %) and 1 equiv of TBAHS
under an argon atmosphere. The mixture was stirred for an
appropriate time, and then it was further treated with KOH in
THF to afford the N-sulfonyloxazocane 8 with improved ee.
The reaction was quenched with water, and then it was
extracted with dichloromethane (3 × 5.0 mL) and dried over
anhydrous sodium sulfate. The crude product was purified by
flash column chromatography on silica gel (230−400 mesh)
using 10% ethyl acetate in petroleum ether to provide the pure
product.
2.45 (s, 3H); 13C NMR (125 MHz, CDCl3) 143.6, 137.3, 137.0, 129.8,
128.9, 127.2, 126.9, 79.4, 79.1, 75.1, 56.0, 49.1, 21.6; HRMS (ESI)
calcd for C18H19NO3S (M + H)+ 330.1163, found 330.1167.
(S)-N-(2-(Benzyloxy)-2-phenylethyl)-4-methylbenzenesulfona-
mide (3d). The general method A described above was followed when
(R)-1a (25 mg, 0.091 mmol) was reacted with benzyl alcohol to afford
3d as a dense liquid (23.7 mg, 72% yield); [α]25 +17.8 (c 0.216 in
D
CHCl3) for a 92% ee sample. Optical purity was determined by chiral
HPLC analysis (Chiralpak AD-H column), hexane−2-propanol, 90:10;
flow rate = 1.0 mL/min; tR 1: 35.61 min (major), tR 2: 41.11 min
(minor): Rf 0.38 (EtOAc/petroleum ether, 3: 7); IR νmax (film, cm−1)
3253, 2917, 2865, 1597, 1419, 1324, 1163, 1088, 901, 850, 815, 753,
1
549; H NMR (500 MHz, CDCl3) δ 7.66 (d, 2H, J = 8.3 Hz), 7.37−
7.30 (m, 12H), 4.87 (br s, 1H, NH), 4.42−4.39 (m, 2H), 4.18(d, 1H, J
= 11.4 Hz), 3.25−3.20 (m, 1H), 3.06−3.01 (m, 1H), 2.40 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 143.4, 138.4, 137.5, 136.9, 129.7, 128.8,
128.5, 128.0, 127.9, 127.0, 126.8, 79.9, 70.7, 49.3, 21.5; HRMS (ESI)
calcd for C22H23NO3S (M + H)+ 382.1476, found 382.1479.
(S)-N-(2-Isopropoxy-2-phenylethyl)-4-methylbenzenesulfona-
mide (3e). The general method A described above was followed when
(R)-1a (25 mg, 0.091 mmol) reacted with 2-propanol to afford 3e as a
white solid (22.4 mg, 77% yield): mp 98−100 °C; [α]25D +42.0 (c 0.10
in CHCl3) for a 91% ee sample. Optical purity was determined by
chiral HPLC analysis (Chiralpak AS-H column), hexane−2-propanol,
95:5; flow rate = 1.0 mL/min; tR 1: 30.74 min (minor), tR 2: 48.32 min
(major): Rf 0.36 (EtOAc/petroleum ether, 1: 5); IR νmax (KBr, cm−1)
(S)-N-(2-(Allyloxy)-2-phenylethyl)-4-methylbenzenesulfonamide
(3a). The general method A described above was followed when (R)-
1a (25 mg, 0.091 mmol) reacted with allyl alcohol at 0 °C to afford 3a
as a dense liquid (22.0 mg, 76% yield): [α]25D +88.2 (c 0.17 in CHCl3)
for a 92% ee sample. Optical purity was determined by chiral HPLC
analysis (Chiralpak AS-H column), hexane−2-propanol, 90:10; flow
rate = 1.0 mL/min; tR 1: 37.1 min (minor), tR 2: 54.7 min (major): Rf
0.41 (EtOAc/petroleum ether, 3: 7); IR νmax (KBr, cm−1) 3273, 2914,
2862, 1648, 1597, 1405, 1327, 1163, 1098, 924, 813, 760, 702, 664,
1
3447, 3275, 2972, 2922, 1399, 1328, 1168, 1091, 704, 561; H NMR
(500 MHz, CDCl3) δ 7.71 (d, 2H, J = 8.3 Hz), 7.33−7.21 (m, 7H),
4.92−4.90 (br m, 1H, NH), 4.44 (dd, 1H, J = 9.3, 3.8 Hz), 3.48−3.43
(m, 1H), 3.20−3.15 (m, 1H), 2.93−2.88 (m, 1H), 2.41 (s, 3H), 1.10
(d, 3H, J = 6.2 Hz), 1.04 (d, 3H, J = 6.2 Hz); 13C NMR (125 MHz,
CDCl3) δ 143.4, 139.6, 136.9, 129.7, 128.5, 128.2, 127.1, 126.5, 76.7,
69.3, 49.5, 23.3, 21.5, 21.0; HRMS (ESI) calcd for C18H23NO3S (M +
H)+ 334.1476, found 334.1477.
1
551; H NMR (400 MHz, CDCl3) δ 7.64 (d, 2H, J = 8.0 Hz), 7.27−
(S)-N-(2-tert-Butoxy-2-phenylethyl)-4-methylbenzenesulfona-
mide (3f). The general method A described above was followed when
(R)-1a (25 mg, 0.091 mmol) reacted with 2-methyl-2-propanol to
7.13 (m, 7H), 5.80−5.70 (m, 1H), 5.11 (dd, 1H, J = 15.6, 1.4 Hz),
5.06 (br s, 1H, NH), 4.94 (dd, 1H, J = 9.0, 2.7 Hz), 4.30 (dd, 1H, J =
9.3, 3.7 Hz), 3.80 (dd, 1H, J = 12.4, 5.4 Hz), 3.62 (dd, 1H, J = 12.4, 6.1
Hz), 3.18−3.11 (m, 1H), 2.96−2.89 (m, 1H), 2.35 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 143.4, 138.4, 136.9, 134.0, 129.7, 128.6, 128.4,
127.0, 126.6, 117.5, 79.6, 69.6, 49.3, 21.5; HRMS (ESI) calcd for
C18H21NO3S (M + H)+ 332.1320, found 332.1326.
afford 3f as a white solid (21.0 mg, 70% yield): mp 92−94 °C; [α]25
D
+85.7 (c 0.084 in CHCl3) for a 88% ee sample. Optical purity was
determined by chiral HPLC analysis (Chiralpak AS-H column),
hexane−2-propanol, 95:5; flow rate =1.0 mL/min; tR 1: 23.53 min
(minor), tR 2: 33.24 min (major): Rf 0.36 (EtOAc/petroleum ether,
1:5); IR νmax (KBr, cm−1) 3447, 3274, 2974, 2924, 1457, 1398, 1367,
(S)-N-(2-Methoxy-2-phenylethyl)-4-methylbenzenesulfonamide
(3b). The general method A described above was followed when (R)-
1a (25 mg, 0.091 mmol) reacted with methanol to afford 3b as white
1
1191, 1164, 1090, 704, 557; H NMR (500 MHz, CDCl3) δ 7.68 (d,
2H, J = 8.3 Hz), 7.30−7.22(m, 7H), 4.75 (br m, 1H, NH), 4.60 (dd,
1H, J = 8.9, 3.8 Hz), 3.13−3.07 (m, 1H), 2.85−2.80 (m, 1H), 2.41 (s,
3H), 1.09 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 143.3, 142.4,
136.9, 129.7, 128.4, 127.6, 127.1, 126.2, 75.2, 73.3, 50.1, 28.7, 21.5;
HRMS (ESI) calcd for C19H25NO3S (M + H)+ 348.1633, found
348.1635.
( S ) - 4 - M e t h y l - N - ( 2 - p h e n y l - 2 - ( o - t o l y l o x y ) e t h y l ) -
benzenesulfonamide (3g). The general method A described above
was followed when (R)-1a (25 mg, 0.091 mmol) reacted with o-cresol
to afford 3g and 4g as a regioisomeric mixture in 2.5:1 ratio. 3g: 21.1
mg (65% yield), white solid; mp 100−102 °C; [α]25D +15.9 (c 0.119 in
CHCl3); IR νmax (KBr, cm−1) 3287, 2923, 1596, 1493, 1331, 1237,
1161, 1094, 751, 548; 1H NMR (500 MHz, CDCl3) δ 7.71 (d, 2H, J =
8.3 Hz), 7.70−7.24 (m, 7H), 7.10−7.09 (m, 1H), 6.93−6.89 (m, 1H),
6.80−6.77 (m, 1H), 6.43−6.41 (m, 1H), 5.13 (dd, 1H, J = 8.9, 4.5
Hz), 4.88−4.87 (br m, 1H, NH), 3.45−3.40 (m, 1H), 3.33−3.29 (m,
1H), 2.40 (s, 3H), 2.25 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
155.2, 143.7, 138.1, 137.2, 130.9, 129.9, 128.9, 128.5, 127.1, 126.8,
126.7, 126.1, 121.1, 112.8, 78.2, 49.6, 21.6, 16.6; HRMS (ESI) calcd
for C22H23NO3S (M + H)+ 382.1477, found 382.1479.
solid (21.6 mg, 80% yield): mp 105 °C; [α]25 +47.5 (c = 0.16 in
D
CHCl3) for a >99% ee sample. Optical purity was determined by chiral
HPLC analysis (Chiralpak AD-H column), hexane−2-propanol, 90:10;
flow rate = 1.0 mL/min: tR 1: 34.2 min (major): Rf 0.34 (EtOAc/
petroleum ether, 3:7); IR νmax (KBr, cm−1) 3284, 2910, 2820, 1600,
1448, 1321, 1160, 1074, 900, 812, 761, 700, 548; 1H NMR (400 MHz,
CDCl3) δ 7.70 (d, 2H, J = 8.3 Hz), 7.34−7.17 (m, 7H), 4.94 (br m,
1H, NH), 4.17 (dd, 1H, J = 9.3, 3.7 Hz), 3.21−3.16 (m, 1H), 3.15 (s,
3H), 2.95−2.89 (m, 1H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 143.4, 138.2, 136.8, 129.8, 129.6, 128.6, 127.0, 126.5, 82.4, 56.8, 49.3,
21.5; HRMS (ESI) calcd for C16H19NO3S (M + H)+ 306.1163, found
306.1168.
(S)-4-Methyl-N-(2-phenyl-2-(prop-2-ynyloxy)ethyl)-
benzenesulfonamide (3c). The general method A described above
was followed when (R)-1a (25 mg, 0.091 mmol) reacted with
propargyl alcohol to afford 3c as a dense liquid (21.6 mg, 75% yield):
[α]25 +15.8 (c 0.19 in CHCl3) for an 80% ee sample. Optical purity
D
was determined by chiral HPLC analysis (Chiralpak AD-H column),
hexane−2-propanol, 90:10; flow rate = 1.0 mL/min; tR 1: 27.71 min
(minor), tR 2: 33.56 min (major): Rf 0.38 (EtOAc/petroleum ether, 3:
7); IR νmax (film, cm−1) 3284, 2920, 2859, 2118, 1597, 1411, 1328,
( R ) - 4 - M e t h y l - N - ( 1 - p h e n y l - 2 - ( o - t o l y l o x y ) e t h y l ) -
benzenesulfonamide (4g): dense liquid (8.1 mg, 30% yield); [α]25
D
1
1159, 1086, 868, 813, 701, 665, 546; H NMR (500 MHz, CDCl3) δ
−2.6 (c 0.074 in CHCl3); Rf 0.42 (EtOAc/petroleum ether, 3:7); IR
7.72 (d, 2H, J = 8.3 Hz), 7.35−7.20 (m, 7H), 4.99−4.97 (m, 1H, NH),
4.55 (dd, 1H, J = 7.8, 3.6 Hz), 4.06 (dd, 1H, J = 15.8, 2.4 Hz), 3.81
(dd, 1H, J = 15.8, 2.5 Hz), 3.26−3.20 (m, 1H), 3.06−3.01 (m, 1H),
νmax (KBr, cm−1) 3472, 3261, 2926, 1596, 1464, 1309, 1151, 1091,
1
706, 551; H NMR (400 MHz, CDCl3) δ 7.61 (d, 2H, J = 8.3 Hz),
7.23−7.13 (m, 7H), 7.08−7.06 (m, 1H), 6.94−6.92 (m, 1H), 6.75−
3748
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6.67 (m, 2H), 4.37 (t, 2H, J = 7.56), 3.53−3.45 (m, 2H), 2.37 (s, 3H),
2.13 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 151.9, 143.6, 140.4,
136.8, 129.8, 129.7, 128.9, 128.2, 127.3, 126.8, 125.9, 123.9, 120.8,
46.5, 44.4, 21.6, 15.9; HRMS (ESI) calcd for C22H23NO3S (M + H)+
382.1477, found 382.1475.
−24.0 (c 0.075 in CHCl3). Regioisomeric ratio was determined by
chiral HPLC analysis (Chiralpak AS-H column), hexane−2-propanol,
90:10; flow rate = 1.0 mL/min; tR 1: 28.73 min (major), tR 2: 33.33
min (minor): Rf 0.21 (EtOAc/petroleum ether, 1:5); IR νmax (KBr,
cm−1) 3280, 2977, 2929, 2829, 1599, 1494, 1452, 1380, 1328, 1257,
1
(S)-N-(2-Methoxy-2-phenylethyl)-4-nitrobenzenesulfonamide
(3h). The general method A described above was followed when (R)-
1b (25 mg, 0.0822 mmol) reacted with methanol to afford 3h as a
white solid (22.7 mg, 85% yield): mp 86−88 °C; [α]25D +46.1 (c 0.24
in CHCl3) for a >99% ee sample. Optical purity was determined by
chiral HPLC analysis (Chiralpak AD-H column), hexane−2-propanol,
90:10; flow rate = 1.0 mL/min; tR 1: 25.88 min (major). Rf 0.42
(EtOAc/petroleum ether, 2:3); IR νmax (KBr, cm−1) 3445, 3276, 2923,
2854, 1532, 1348, 1164, 1072, 704, 546; 1H NMR (400 MHz, CDCl3)
δ 8.28−8.25 (m, 2H), 7.95−7.92 (m, 2H), 7.29−7.24 (m, 3H), 7.15−
7.12 (m, 2H), 5.13 (dd, 1H, NH, J = 8.6, 2.7 Hz), 4.19 (dd, 1H, J =
9.0, 3.6 Hz), 3.28−3.21 (m, 1H), 3.12 (s, 3H), 2.97−2.91 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 149.9, 145.8, 137.7, 128.8, 128.6,
1161, 1092, 1055, 1019, 907, 846, 815, 706, 666, 553, 456; H NMR
(400 MHz, CDCl3) δ 7.70−7.66 (m, 2H), 7.25−7.20 (m, 2H), 4.81
(br s, 1H), 3.32−3.30 (m, 1H), 3.17 (s, 3H), 3.03−3.00 (m, 1H),
2.70−2.65 (m, 1H), 2.36 (s, 3H), 1.03−1.00 (m, 3H); 13C NMR (100
MHz, CDCl3) δ 143.5, 136.9, 129.8, 129.7, 127.1, 75.1, 56.3, 48.1,
21.6, 16.5 (for major regioisomer); HRMS (ESI) calcd for
C11H17NO3S (M + H)+ 244.1007, found 244.1009.
(S)-N-(1-Methoxy-3-phenylpropan-2-yl)-4-methylbenzenesulfo-
namide (4m). The general method B described above was followed
when (S)-1g (25 mg, 0.087 mmol) was reacted with methanol to
afford 3m and 4m as a dense liquid as an inseparable mixture (23.8
mg, 88% yield): [α]25 +13.3 (c 0.03 in CHCl3). The regioisomeric
D
ratio was determined by chiral HPLC analysis (Chiralcel OD-H
column), hexane−2-propanol, 90:10; flow rate = 1.0 mL/min; tR 1:
9.10 min (major), tR 2: 13.81 min (minor); Rf 0.29 (EtOAc/petroleum
ether, 1:5); IR νmax (KBr, cm−1) 3283, 2925, 1599, 1453, 1329, 1159,
128.2, 126.5, 124.4, 81.9, 56.8, 49.3; HRMS (ESI) calcd for
C15H17N2O5S (M + H)+ 337.0858, found 337.0854.
(S)-4-Methoxy-N-(2-methoxy-2-phenylethyl)benzenesulfonamide
(3i). The general method B described above was followed when (R)-1c
(25 mg, 0.0864 mmol) reacted with methanol to afford 3i as white
1
1091, 702, 551; H NMR (500 MHz, CDCl3) δ 7.64 (d, 2H, J = 8.0
Hz), 7.25−7.17 (m, 5H), 7.03−7.02 (m, 2H), 4.78 (d, 1H, J = 7.7 Hz),
3.52−3.49 (m, 1H), 3.25−3.20 (m, 1H), 3.21 (s, 3H), 3.19−3.12 (m,
1H), 2.78−2.77 (m, 2H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 143.3, 137.7, 137.3, 129.8, 129.7, 129.4, 128.6, 127.2, 127.1, 126.7,
72.5, 58.9, 54.6, 38.3, 21.6; HRMS (ESI) calcd for C17H22NO3S (M +
H)+ 320.1320, found 320.1321.
solid (20.5 mg, 77% yield): mp >350 °C; [α]25 +18.3 (c 0.163 in
D
CHCl3) for a 98% ee sample. Optical purity was determined by chiral
HPLC analysis (Chiralpak AD-H column), hexane−2-propanol, 90:10;
flow rate = 1.0 mL/min; tR 1: 23.3 min (minor), tR 2: 26.6 min
(major); Rf 0.46 (EtOAc/petroleum ether, 2:3); IR νmax (KBr, cm−1)
1
3284, 2926, 1597, 1498, 1330, 1260, 1156, 1092, 1026, 762, 563; H
(R)-N-(1-Methoxy-3-methylbutan-2-yl)-4-methylbenzenesulfona-
mide (4n). The general method B described above was followed when
(R)-1h (25 mg, 0.1045 mmol) reacted with methanol to afford 3n and
4n as a dense liquid as an inseparable mixture (13.4 mg, 53% yield):
NMR (400 MHz, CDCl3) δ 7.72−7.69 (m, 2H), 7.29−7.21 (m, 3H),
7.14−7.12 (m, 2H), 6.91−6.87 (m, 2H), 4.89 (dd, 1H, J = 12.0, 8.0
Hz), 4.13 (dd, 1H, J = 12.0, 4.0 Hz), 3.79 (s, 3H), 3.15−3.10 (m, 1H),
3.09 (s, 3H), 2.90−2.84 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
162.8, 138.2, 131.4, 129.2, 128.7, 128.4, 126.6, 114.2, 81.9, 56.8, 55.6,
49.3; HRMS (ESI) calcd for C16H19NO4S (M + H)+ 322.1113, found
322.1117.
[α]25 +46.6 (c 0.03 in CHCl3). Regioisomeric ratio was determined
D
by chiral HPLC analysis (Chiralpak AS-H column), hexane−2-
propanol, 90:10; flow rate = 1.0 mL/min; tR 1: 19.82 min (minor),
tR 2: 25.28 min (major); Rf 0.32 (EtOAc/petroleum ether, 1:5); IR
νmax (KBr, cm−1) 3290, 2959, 2924, 1440, 1329, 1162, 1086, 680, 550;
1H NMR (400 MHz, CDCl3) δ 7.70−7.67 (m, 2H), 7.26−7.20 (m,
2H), 4.73 (br s, 1H), 3.26−3.22 (m, 1H), 3.09 (s, 3H), 2.99−2.96 (m,
1H), 2.36 (s, 3H), 1.81−1.76 (m, 1H), 0.82−0.72 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 143.1, 138.2, 129.7, 129.5, 127.1, 84.3, 71.7,
58.9, 58.7, 29.7, 21.5, 18.9, 18.5; HRMS (ESI) calcd for C13H22NO3S
(M + H)+ 272.1320, found 272.1324.
(S)-4-Fluoro-N-(2-methoxy-2-phenylethyl)benzenesulfonamide
(3j). The general method B described above was followed when (R)-
1d (25 mg, 0.0902 mmol) reacted with methanol to afford 3j as a
white solid (12.5 mg, 51% yield): mp 102−104 °C; [α]25 +107.8 (c
D
0.213 in CHCl3) for a 97% ee sample. Optical purity was determined
by chiral HPLC analysis (Chiralpak AD-H column), hexane−2-
propanol, 90:10; flow rate = 1.0 mL/min; tR 1: 13.2 min (major), tR 2:
18.8 min (minor); Rf 0.57 (EtOAc/petroleum ether, 2:3); IR νmax
(KBr, cm−1) 3441, 3273, 2918, 1596, 1498, 1332, 1161, 1072, 867,
(R)-N-(1-Methoxy-4-methylpentan-2-yl)-4-methylbenzenesulfo-
namide (4o). The general method A described above was followed
when (R)-1i (25 mg, 0.0987 mmol) reacted with methanol to afford
3o and 4o as a dense liquid as an inseparable mixture (16.7 mg, 64%
1
705, 551; H NMR (400 MHz, CDCl3) δ 8.79−7.75 (m, 2H), 7.29−
7.22 (m, 3H), 7.15−7.08 (m, 4H), 4.96−4.95 (m, 1H), 4.15 (dd, 1H, J
= 9.3, 3.7 Hz), 3.19−3.14 (m, 1H), 3.12 (s, 3H), 2.92−2.86 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 138.0, 129.8, 129.7, 128.7, 128.5,
yield): [α]25 −11.0 (c 0.11 in CHCl3). The regioisomeric ratio was
D
determined by chiral HPLC analysis (Chiralpak AS-H column),
hexane−2-propanol, 90:10; flow rate = 1.0 mL/min; tR 1: 19.06 min
(major), tR 2: 25.90 min (minor); Rf 0.36 (EtOAc/petroleum ether,
1:5); IR νmax (KBr, cm−1) 3281, 2955, 2929, 1461, 1329, 1160, 1093,
126.6, 116.4, 116.2, 81.9, 56.8, 49.3; HRMS (ESI) calcd for
C15H16FNO3S (M − H)+ 308.0756, found 308.0754.
( S ) - 4 - t e r t - B u t y l - N - ( 2 - m e t h o x y - 2 - p h e n y l e t h y l ) -
benzenesulfonamide (3k). The general method B described above
was followed when (R)-1e (25 mg, 0.0793 mmol) reacted with
1
814, 706, 552; H NMR (400 MHz, CDCl3) δ 7.70−7.67 (m, 2H),
7.26−7.20 (m, 2H), 4.82 (br s, 1H), 3.20−3.00 (m, 5H), 2.71−2.68
(m, 1H), 2.35(s, 3H), 1.53−1.46 (m, 1H), 1.38−1.31 (m, 1H), 1.29−
1.20 (m, 1H), 1.09−1.02 (m, 1H), 0.81−0.75 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 143.4, 139.1, 138.2, 129.7, 129.5, 127.0, 74.0,
58.9, 56.6, 51.7, 45.7, 41.6, 40.4, 24.5, 24.3, 22.9, 22.8, 22.5, 21.9, 21.5;
HRMS (ESI) calcd for C14H24NO3S (M + H)+ 286.1477, found
286.1475.
methanol to afford 3k as a white solid (17.3 mg, 67% yield): [α]25
D
+72.4 (c 0.25 in CHCl3) for a 95% ee sample. Optical purity was
determined by chiral HPLC analysis (Chiralpak AD-H column),
hexane−2-propanol, 90:10; flow rate =1.0 mL/min; tR 1: 10.7 min
(major), tR 2: 18.0 min (minor); Rf 0.32 (EtOAc/petroleum ether,
1
1:5); H NMR (400 MHz, CDCl3) δ 7.70−7.67 (m, 2H), 7.45−7.42
(m, 2 H), 7.29−7.12 (m, 5H), 4.93 (dd, 1H, J = 8.0, 4.0 Hz), 4.14 (dd,
1H, J = 8.0, 4.0 Hz), 3.18−3.10 (m, 3H), 2.94−2.87 (m, 1H), 1.25 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 156.4, 138.3, 136.9, 136.8,
128.7, 128.4, 126.9, 126.6, 126.1, 82.1, 56.8, 56.7, 49,3, 35.1, 31.2;
HRMS (ESI) calcd for C19H25NO3S (M + H)+ 348.1633, found
348.1661.
(S)-N-(1-Methoxy-3-phenylpropan-2-yl)-N,4-dimethylbenzenesul-
fonamide (5). A hexane solution of nBuLi (0.18 mL, 0.2893 mmol, 1.6
M) was added carefully to anhydrous DMSO (0.18 mL) in a two-
necked round-bottomed flask. (S)-N-(1-Methoxy-3-phenylpropan-2-
yl)-4-methylbenzenesulfonamide 4m (42 mg, 0.1315 mmol) in 2.5 mL
of DMSO was added, and the resulting solution was stirred under
nitrogen for 2 h. MeI (40 μL, 0.639 mmol) was then added, and the
reaction mixture was stirred for 1 h. The reaction mixture was poured
into H2O and extracted with Et2O. The combined organic layers were
washed with brine and dried over anhydrous Na2SO4, and the solvent
(R)-N-(1-Methoxypropan-2-yl)-4-methylbenzenesulfonamide
(4l). The general method B described above was followed when (R)-1f
(25 mg, 0.1183 mmol) reacted with methanol to afford 3l and 4l as a
dense liquid as an inseparable mixture (17.8 mg, 66% yield): [α]25
D
3749
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The Journal of Organic Chemistry
Article
was removed under reduced pressure. The crude product was purified
by flash column chromatography on silica gel (230−400 mesh) using
10% ethyl acetate in petroleum ether to provide 5 (31.5 mg, 75%):
2a (25 mg, 0.087 mmol) reacted with MeOH in the presence of 30
mol % of Cu(OTf)2 and 1.0 equiv of TBAHS at 0 °C for 7 h to afford
6a as a white solid (22.0 mg, 82% yield): mp 108 −110 °C; [α]25
D
[α]25 −11.0 (c 0.11 in CHCl3); IR νmax (film, cm−1) 2923, 2371,
+44.5 (c 0.20 in CHCl3) for a 94% ee sample. Optical purity was
determined by chiral HPLC analysis (Chiralpak AD-H column),
hexane−2-propanol, 90:10; flow rate = 1.0 mL/min; tR 1: 35.5 min
(major), tR 2: 43.7 min (minor): Rf 0.28 (EtOAc/petroleum ether, 3:
7); IR νmax (KBr, cm−1) 3300, 3267, 2923, 1416, 1321, 1162, 1086,
814, 763, 701, 666, 547; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, 2H, J
= 8.3 Hz), 7.25−7.17 (m, 5H), 7.08−7.06 (m, 2H), 5.15 (br s, 1H,
NH), 4.12 (dd, 1H, J = 7.6, 5.1 Hz), 3.08 (s, 3H), 3.06−3.02 (m, 1H),
2.97−2.92 (m, 1H), 2.37 (s, 3H), 1.77−1.72 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 143.3, 140.8, 136.9, 129.7, 128.5, 127.8, 127.1, 126.3,
83.1, 56.7, 41.0, 36.9, 21.5; HRMS (ESI) calcd for C17H21NO3S (M +
H)+ 320.1320, found 320.1328.
D
1594, 1452, 1328, 1153, 939, 812, 699, 655, 548; 1H NMR (500 MHz,
CDCl3) δ 7.51 (d, 2H, J = 8.6 Hz), 7.26−7.17 (m, 5H), 7.13−7.12 (m,
2H), 4.33−4.30 (m, 1H), 3.33−3.32 (m, 2H), 3.20 (s, 3H), 2.89−2.85
(dd, 1H, J = 13.5, 8.3 Hz), 2.81 (s, 3H), 2.59 (dd, 1H, J = 13.4, 6.7
Hz), 2.38 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 142.9, 138.1, 136.9,
129.5, 129.2, 128.6, 127.4, 126.6, 72.7, 58.8, 58.0, 35.4, 29.7, 21.6;
HRMS (ESI) calcd for C18H23NO3S (M + H)+ 334.1476, found
334.1474.
N-((1R,2S)-1-Methoxy-1-phenylbutan-2-yl)-4-methylbenzenesul-
fonamide (3p). The general method A described above was followed
when 1j (25 mg, 0.083 mmol) reacted with methanol to afford 3p as a
colorless liquid (24.3 mg, 90% yield); de of the sample was found to be
(R)-N-(3-(Allyloxy)-3-phenylpropyl)-4-methylbenzenesulfona-
mide (6b). The general method C described above was followed when
(S)-2a (25 mg, 0.087 mmol) reacted with allyl alcohol to afford 6b as a
dense liquid (21.5 mg, 75% yield): [α]25D +45.6 (c 0.16 in CHCl3) for
an 84% ee sample. Optical purity was determined by chiral HPLC
analysis (Chiralpak AS-H column), hexane−2-propanol, 90:10; flow
rate = 1.0 mL/min; tR 1: 30.94 min (major), tR 2: 35.80 min (minor):
Rf 0.38 (EtOAc/petroleum ether, 3: 7); IR νmax (film, cm−1) 3286,
1
>99% from H NMR: Rf 0.32 (EtOAc/petroleum ether, 1:5); IR νmax
(film, cm−1) 3290, 2923, 2852, 1452, 1329, 1159, 1093, 1027, 815,
1
705, 663, 571, 550; H NMR (500 MHz, CDCl3) δ 7.79 (d, 2H, J =
8.6 Hz), 7.31−7.23 (m, 5H), 7.09 (d, 2H, J = 7.3 Hz), 4.80 (d, 1H, J =
10.0 Hz), 4.06 (d, 1H, J = 3.1 Hz), 3.29−3.24 (m, 1H), 3.14 (s, 3H),
2.42 (s, 3H), 1.33−1.23 (m, 2H), 0.67 (t, 3H, J = 7.3 Hz); 13C NMR
(125 MHz, CDCl3) δ 143.2, 138.5, 137.9, 129.6, 128.4, 127.6, 127.1,
126.5, 84.8, 60.5, 57.7, 29.7, 21.5, 20.8, 10.4; HRMS (ESI) calcd for
C18H24NO3S (M + H)+ 334.1476, found 334.1475.
1
2924, 2859, 1598, 1418, 1326, 1158, 1092, 813, 702, 664; H NMR
(400 MHz, CDCl3) δ 7.67 (d, 2H, J = 8.3 Hz), 7.25−7.18 (m, 5H),
7.08 (d, 2H, J = 7.8 Hz), 5.78−5.70 (m, 1H), 5.18 (t, 1H, J = 4.9 Hz),
5.14−5.08 (m, 2H), 4.30 (q, 1H, J = 8.0, 4.4 Hz), 3.79 (dd, 1H, J =
12.4, 4.9 Hz), 3.59 (dd, 1H, J = 12.7, 6.1 Hz), 3.08−3.02 (m, 1H),
2.98−2.92 (m, 1H), 2.37 (s, 3H), 1.82−1.71 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 143.2, 141.0, 136.9, 134.3, 129.6, 128.5, 127.8, 127.1,
126.3, 117.3, 80.4, 69.5, 41.0, 36.9, 21.5; HRMS (ESI) calcd for
C19H23NO3S (M + H)+ 346.1476, found 346.1475.
N-((1R,2S)-1-Methoxy-1-phenylpropan-2-yl)-4-methylbenzene-
sulfonamide (3q). The general method A described above was
followed when 1k (25 mg, 0.087 mmol) reacted with methanol to
afford 3q as a colorless liquid (22.6 mg, 84% yield); de of the sample
1
was found to be >99% from H NMR: Rf 0.36 (EtOAc/petroleum
ether, 1:5); IR νmax (film, cm−1) 3281, 2983, 1329, 1160, 1089, 704,
1
667, 552; H NMR (400 MHz, CDCl3) δ 7.70 (d, 2H, J = 8.3 Hz),
7.27−7.17 (m, 5H), 7.06 (d, 2H, J = 7.1 Hz), 4.82 (d, 1H, J = 9.0 Hz),
4.06 (d, 1H, J = 3.2 Hz), 3.46−3.41 (m, 1H), 3.13 (s, 3H), 2.35 (s,
3H), 0.79 (d, 3H, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 143.2,
138.5, 138.0, 129.6, 128.4, 128.2, 127.8, 127.0, 126.6, 85.4, 57.5, 54.5,
29.7, 21.5, 14.6; HRMS (ESI) calcd for C17H21NO3S (M + H)+
320.1320, found 320.1323.
(R)-4-Methyl-N-(3-phenyl-3-(prop-2-ynyloxy)propyl)-
benzenesulfonamide (6c). The general method C described above
was followed when (S)-2a (25 mg, 0.087 mmol) reacted with
propargyl alcohol to afford 6c as a dense liquid (22.9 mg, 80% yield);
[α]25 +77.8 (c 0.14 in CHCl3) for a 86% ee sample. Optical purity
D
was determined by chiral HPLC analysis (Chiralcel OD-H column)
90:10 hexane−2-propanol, flow rate = 1.0 mL/min; tR 1: 20.28 min
(major), tR 2: 27.96 min (minor): Rf 0.28 (EtOAc/petroleum ether, 3:
7); IR νmax (film, cm−1) 3286, 2923, 2856, 2117, 1598, 1325, 1159,
N-((1R,2S)-1-Methoxy-1-phenylpentan-2-yl)-4-methylbenzene-
sulfonamide (3r). The general method B described above was
followed when 1l (25 mg, 0.079 mmol) reacted with methanol to
afford 3r as a colorless liquid (17.5 mg, 68% yield); de of the sample
1
1091, 813,702, 634; H NMR (400 MHz, CDCl3) δ 7.69 (d, 2H, J =
1
was found to be >99% from H NMR: Rf 0.38 (EtOAc/petroleum
8.0 Hz), 7.26−7.19 (m, 5H), 7.10 (dd, 1H, J = 7.3, 1.2 Hz), 5.03 (t,
1H, J = 5.9 Hz), 4.48 (q, 1H, J = 4.4 Hz), 4.02 (dd, 1H, J = 15.9, 2.4
Hz), 3.70 (dd, 1H, J = 15.9, 2.2 Hz), 3.11−3.06 (m, 1H), 3.05−2.96
(m, 1H), 2.37 (s, 3H), 2.36−2.35 (m, 1H), 1.83−1.74 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 143.2, 139.9, 136.9, 129.6, 128.6, 128.2,
127.1, 126.5, 79.6, 79.1, 74.7, 55.5, 40.7, 36.8. 21.5; HRMS (ESI) calcd
for C19H21NO3S (M + H)+ 344.1320, found 344.1320.
ether, 1:5); IR νmax (film, cm−1) 3295, 2928, 2872, 1451, 1419, 1323,
1160, 1096, 1034, 815, 706, 663, 584, 550; 1H NMR (400 MHz,
CDCl3) δ 7.80 (d, 2H, J = 8.4 Hz), 7.32−7.29 (m, 4H), 7.26−7.23 (m,
1H), 7.09 (d, 2H, J = 7.3 Hz), 4.84 (d, 1H, J = 9.6 Hz), 4.05 (d, 1H, J
= 3.1 Hz), 3.38−3.34 (m, 1H), 3.12 (s, 3H), 2.42 (s, 3H), 1.39−1.23
(m, 2H), 1.16−1.13 (m, 1H), 0.95−0.87 (m, 1H), 0.65 (t, 3H, J = 7.3
Hz); 13C NMR (100 MHz, CDCl3) δ 143.2, 138.6, 137.9, 129.6, 129.5,
128.4, 127.6, 127.1, 126.5, 84.9, 58.8, 57.7, 29.8, 21.5, 18.9, 13.5;
HRMS (ESI) calcd for C19H25NO3S (M + H)+ 348.1633, found
348.1637.
(R)-N-(3-(Benzyloxy)-3-phenylpropyl)-4-methylbenzenesulfona-
mide (6d). The general method C described above was followed when
(S)-2a (25 mg, 0.087 mmol) reacted with benzyl alcohol to afford 6d
as a dense liquid (21.9 mg, 68% yield): [α]25 +60.9 (c 0.141 in
D
N-((1R,2S)-1-Methoxy-1-phenylpent-4-en-2-yl)-4-methylbenzene-
sulfonamide (3s). The general method B described above was
followed when 1m (25 mg, 0.079 mmol) reacted with methanol to
afford 3s as colorless liquid (17.3 mg, 70% yield); de of the sample was
CHCl3) for a 82% ee sample. Optical purity was determined by chiral
HPLC analysis (Chiralpak AD-H column), hexane−2-propanol, 90:10;
flow rate = 1.0 mL/min; tR 1: 16.36 min (minor), tR 2: 18.92 min
(major): Rf 0.34 (EtOAc/petroleum ether, 3: 7); IR νmax (film, cm−1)
3284, 2924, 2863, 1597, 1450, 1416, 1326, 1158, 1092, 814, 742, 700,
1
found to be 92% from H NMR: Rf 0.36 (EtOAc/petroleum ether,
1:5); IR νmax (film, cm−1) 3286, 2921, 2851, 1598, 1494, 1452, 1419,
1329, 1185, 1160, 1114, 1093, 1049, 990, 814, 759, 705, 663, 550, 419;
1H NMR (500 MHz, CDCl3) δ 7.73 (d, 2H, J = 8.3 Hz), 7.32−7.24
1
664; H NMR (500 MHz, CDCl3) δ 7.66 (d, 2H, J = 8.3 Hz), 7.36−
7.18 (m, 12H), 5.05 (br s, 1H, NH), 4.42 (d, 1H, J = 11.6 Hz), 4.37
(dd, 1H, J = 8.6, 4.0 Hz), 4.15 (d, 1H, J = 11.6 Hz), 3.15−3.09 (m,
1H), 3.02−2.98 (m, 1H), 2.44 (s, 3H), 1.88−1.79 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 143.2, 141.0, 137.8, 137.0, 129.6, 128.6, 128.5,
128.0, 127.9, 127.1, 126.4, 79.8, 70.4, 40.8, 37.1, 21.5; HRMS (ESI)
calcd for C23H25NO3S (M + H)+ 396.1633, found 396.1631.
(m, 5H), 7.15 (d, 2H, J = 7.5 Hz), 5.46−5.41 (m, 1H), 4.90 (s, 1H),
4.87 (d, 1H, J = 7.5 Hz), 4.79 (d, 1H, J = 8.9 Hz), 4.20 (d, 1H, J = 3.7
Hz), 3.44−3.40 (m, 1H), 3.18 (s, 3H), 2.41 (s, 3H), 2.18−2.11 (m,
1H), 2.01−1.97 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 143.4,
138.1, 138.0, 134.4, 129.7, 129.6, 128.6, 128.5, 127.9, 127.3, 127.2,
126.7, 126.6, 118.2, 84.7, 58.4, 57.8, 32.7, 21.6; HRMS (ESI) calcd for
C19H23NO3S (M + H)+ 346.1474, found 346.1476.
(R)-N-(3-Isopropoxy-3-phenylpropyl)-4-methylbenzenesulfona-
mide (6e). The general method C described above was followed when
(S)-2a (25 mg, 0.087 mmol) reacted with isopropyl alcohol to afford
6e as a dense liquid (22.3 mg, 77% yield): [α]25 +46.5 (c 0.18 in
(R)-N-(3-Methoxy-3-phenylpropyl)-4-methylbenzenesulfonamide
(6a). The general method C described above was followed when (S)-
D
CHCl3) for a 88% ee sample. Optical purity was determined by chiral
3750
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HPLC analysis (Chiralcel OD-H column), hexane−2-propanol, 90:10;
flow rate = 1.0 mL/min; tR 1: 17.9 min (major), tR 2: 28.3 min
(minor): Rf 0.28 (EtOAc/petroleum ether, 3: 7); IR νmax (film, cm−1)
N-((1R,3R)-1-Methoxy-1-phenylhex-5-en-3-yl)-4-methylbenzene-
sulfonamide (6i). The general method D described above was
followed when 2d (25 mg, 0.0695 mmol) reacted with methanol to
afford 6i as a dense colorless liquid (25.6 mg, 95% yield): Rf 0.36
(EtOAc/petroleum ether, 1: 4); IR νmax (film, cm−1) 3277, 3064, 2924,
1641, 1599, 1494, 1453, 1325, 1160, 1093, 1039, 996, 916, 815, 760,
1
3284, 2970, 1598, 1327, 1161, 1093, 814, 703, 551; H NMR (500
MHz, CDCl3) δ 7.76−7.74 (m, 2H), 7.32−7.11 (m, 7H), 5.38−5.36
(m, 1H), 4.43 (t, 1H, J = 12.35, 6.2 Hz), 3.43−3.38 (m, 1H), 3.11−
3.06 (m, 1H), 3.02−2.95 (m, 1H), 2.44 (s, 3H), 1.79−1.59 (m, 2H),
1.07−0.87 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 143.2, 142.0,
137.0, 129.6, 128.4, 127.6, 127.2, 126.2, 78.4, 69.1, 41.2, 36.9, 23.4,
21.5, 21.0. HRMS (ESI) calcd for C19H25NO3S (M + H)+ 348.1633,
found 348.1632.
1
703, 665, 551; H NMR (500 MHz, CDCl3) δ 7.77 (d, 1H, J = 8.0
Hz), 7.32−7.12 (m, 7H), 5.62−5.54 (m, 1H), 5.37 (d, 1H, NH), 4.99
(d, 1H, J = 10.1 Hz), 4.93 (d, 1H, J = 17.2 Hz), 4.00 (dd, 1H, J = 8.9,
3.8 Hz), 3.39−3.35 (m, 1H), 3.05 (s, 3H), 2.44 (s, 3H), 2.29−2.16 (m,
2H), 1.86−1.80 (m, 1H), 1.68−1.64 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 143.4, 141.2, 137.9, 133.3, 129.7, 128.7, 128.1, 127.4, 126.6,
118.9, 82.5, 56.4, 52.7, 41.9, 39.7, 21.6; HRMS (ESI) calcd for
C20H25NO3S 360.1633, found (M + H)+ 360.1636.
( R ) - 4 - M e t h y l - N - ( 3 - p h e ny l - 3 - ( o - t o l y l o x y ) p r o p y l ) -
benzenesulfonamide (6f). The general method C described above
was followed when (S)-2a (25 mg, 0.087 mmol) reacted with o-cresol
to afford a mixture of regioisomers 6f and 7f (2:1 ratio) as a dense
liquid (22.6 mg, 70% combined yield); regioisomer 6f: [α]25D +48.5 (c
0.20 in CHCl3) for a 46% ee sample. Optical purity was determined by
chiral HPLC analysis (Chiralcel OD-H column), hexane−2-propanol,
85:15; flow rate = 1.0 mL/min; tR 1: 13.4 min (major), tR 2: 18.0 min
(minor): Rf 0.34 (EtOAc/petroleum ether, 3: 7); IR νmax (Neat, cm−1)
3493, 3288, 2924, 2871, 1653, 1490, 1322, 1155, 1092, 814, 739, 700,
N-((1R,3S)-1-Methoxy-1-phenylhex-5-en-3-yl)-4-methylbenzene-
sulfonamide (6j). The general method D described above was
followed when 2e (25 mg, 0.0695 mmol) reacted with methanol to
afford 6j as a dense colorless liquid (24.0 mg, 90% yield); Rf 0.43
(EtOAc/petroleum ether, 1:4); IR νmax (film, cm−1) 3280, 3064, 2923,
2852, 1736, 1641, 1599, 1494, 1453, 1418, 1327, 1261, 1159, 1093,
1
1037, 918, 842, 814, 760, 702, 664, 629, 586, 551; H NMR (500
MHz, CDCl3) δ 7.78 (d, 1H, J = 6.9 Hz), 7.32−7.23 (m, 5H), 7.13 (d,
1H, J = 17.3 Hz), 4.29 (dd, 1H, J = 10.3, 3.7 Hz), 3.59−3.56 (m, 1H),
3.12 (s, 3H), 2.42 (s, 3H), 2.28−2.23 (m, 1H), 2.15−2.06 (m, 1H),
1.70−1.65 (m, 1H), 1.52−1.49 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 143.1, 141.5, 138.3, 133.4, 129.7, 129.6, 128.5, 127.7, 127.2,
126.3, 118.7, 80.2, 56.4, 50.9, 42.3, 39.3, 21.5; HRMS (ESI) calcd for
C20H25NO3S (M + H)+ 360.1633, found 360.1634.
1
662; H NMR (400 MHz, CDCl3) δ 7.61 (d, 2H, J = 8.3 Hz), 7.19−
7.08 (m, 8H), 6.90−6.83 (m, 2H), 6.70 (t, 1H, J = 7.6 Hz), 4.65 (br s,
1H, NH), 4.26 (t, 1H, J = 7.8 Hz), 2.96−2.91 (m, 1H), 2.79−2.76 (m,
1H), 2.33 (s, 3H), 2.13 (s, 3H), 2.12−2.07 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 151.5, 143.4, 143.1, 136.8, 129.7, 129.0. 128.6, 128.0,
127.1, 126.5, 125.9, 123.6, 120.7, 41.5, 40.5, 34.5, 21.5, 16.0; HRMS
(ESI) calcd for C23H25NO3S (M + H)+ 396.1633, found 396.1634.
3-(o-Tolyloxy)-1-phenyl-N-tosylpropan-1-amine (regiosomer 7f).
(S)-2-Phenyl-4-tosylmorpholine (7a). The general method E
described above was followed when 1a reacted with KOH at room
temperature for 30 min in dry THF to afford 7a as a white solid (62%
[α]25 −35.6 (c 0.10 in CHCl3) for a 51% ee sample. Optical purity
D
was determined by chiral HPLC analysis (Chiralcel OD-H column),
hexane−2-propanol, 85:15; flow rate =1.0 mL/min; tR 1: 34.1 min
(major), tR 2: 49.2 min (minor): Rf 0.22 (EtOAc/petroleum ether, 3:
7); IR νmax (Film, cm−1) 3445, 3291, 2925, 1599, 1506, 1320, 1155,
1092, 814, 735, 701, 663; 1H NMR (400 MHz, CDCl3) δ 7.59 (d, 2H,
J = 8.3 Hz), 7.20−7.03 (m, 8H), 6.80−6.75 (m, 2H), 6.58 (d, 1H, J =
8.1 Hz), 4.28 (br s, 1H), 3.75 (t, 1H, J = 8.0 Hz), 2.83 (t, 2H, J = 6.1
Hz), 2.35 (s, 3H), 2.13−2.06 (m, 2H), 2.10 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 152.3, 144.1, 143.4, 136.7, 135.7, 130.3, 129.7, 128.6,
127.5, 127.1, 126.3, 126.1, 123.8, 114.9, 47.4, 41.7, 35.5, 21.5, 15.9;
HRMS (ESI) calcd for C23H25NO3S (M + H)+ 396.1633, found
396.1634.
yield), mp 102−104 °C. Optical rotation: [α]25 +160.8 (c 0.049,
D
CHCl3) for a 82% ee sample. Enantiomeric purity was determined by
chiral HPLC analysis (Chiralcel OD-H column), hexane−2-propanol,
95:5; flow rate = 1.0 mL/min; tR 1: 18.15 min (major), tR 2: 36.14 min
(minor): Rf 0.37 (ethyl acetate/hexane, 1:4); IR νmax (film, cm−1)
2963, 2924, 2855, 1448, 1342, 1306, 1167, 1109, 964, 814, 745, 588;
1H NMR (400 MHz, CDCl3) δ 7.54 (d, 2H, J = 8.3 Hz), 7.29−7.21
(m, 7H), 4.53 (dd, 1H, J = 10.5, 2.7 Hz), 4.00 (dd, 1H, J = 11.7, 2.2
Hz), 3.78 (ddd, 1H, J = 14.2, 11.4, 2.4 Hz), 3.71−3.67 (m, 1H), 3.58−
3.55 (m, 1H), 2.43 (ddd, 1H, J = 14.9, 11.5, 3.4), 2.36 (s, 3H), 2.20−
2.14 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 143.9, 138.7, 132.3,
129.8, 128.5, 128.3, 127.9, 127.8, 126.0, 77.4, 66.2, 51.9, 45.4, 21.5;
HRMS (ESI) calcd for C17H19NO3S (M + H)+ 318.1165, found
318.1165.
N-((1R,3R)-1-Methoxy-1-phenylpentan-3-yl)-4-methylbenzene-
sulfonamide (6g). The general method D described above was
followed when 2b (25 mg, 0.079 mmol) reacted with methanol to
afford 6g as a dense colorless liquid (22.9 mg, 86% yield): Rf 0.39
(EtOAc/petroleum ether, 1:4); IR νmax (film, cm−1) 3282, 3029, 2926,
1734, 1599, 1494, 1453, 1418, 1160, 1094, 1044, 963, 843, 815, 759,
(S)-4-(4-Methoxyphenylsulfonyl)-2-phenylmorpholine (7b). The
general method E described above was followed when 1c reacted with
KOH in THF at rt for 1 h to afford 7b as a white solid (58% yield);
mp 95−97 °C; optical rotation [α]25D +41.7 (c 0.15, CHCl3) for a 84%
ee sample; enantiomeric purity was determined by chiral HPLC
analysis (Chiralpak AS-H column), hexane−2-propanol, 95:5, flow rate
= 1.0 mL/min; tR 1: 36.46 min (minor), tR 2: 42.77 min (major): Rf
0.41 (ethyl acetate/hexane, 3: 7); IR νmax (KBr, cm−1) 2921, 1594,
1
702, 665. 551; H NMR (400 MHz, CDCl3) δ 7.70 (d, 1H, J = 8.0
Hz), 7.32−7.25 (m, 5H), 7.11 (d, 2H, J = 6.8 Hz), 5.37 (br d, 1H,
NH), 4.27 (dd, 1H, J = 10.2, 2.7 Hz), 3.38−3.34 (m, 1H), 3.11 (s,
3H), 2.43 (s, 3H), 1.67−1.43 (m, 4H), 0.85 (t, 3H, J = 7.3 Hz); 13C
NMR (125 MHz, CDCl3) δ 143.0, 141.5, 138.6, 129.5, 128.5, 127.7,
127.2, 126.3, 80.6, 56.4, 53.3 41.7, 27.7, 21.5, 10.1; HRMS (ESI) calcd
for C19H25NO3S (M + H)+ 348.1633, found 348.1638.
1
1498, 1351, 1258, 1165, 1094, 957, 804, 699, 564; H NMR (400
MHz, CDCl3) δ 7.60 (d, 2H, J = 8.8 Hz), 7.29−7.21 (m, 5H), 6.93 (d,
1H, J = 9.0 Hz), 4.53 (dd, 1H, J = 10.3, 2.4 Hz), 4.03−3.99 (m, 1H),
3.80 (s, 3H), 3.78 (ddd, 1H, J = 11.7, 8.3, 2.7 Hz), 3.70−3.66 (m, 1H),
3.57−3.54 (m, 1H), 2.43 (ddd, 1H, J = 11.5, 11.5, 3.4 Hz), 2.16, (dd,
1H, J = 10.4, 10.3 Hz); 13C NMR (100 MHz, CDCl3) δ 163.3, 138.8,
129.9, 128.5, 128.2, 126.0, 114.4, 77.4, 66.2, 55.6, 51.9, 45.4; HRMS
(ESI) calcd for C17H19NO4S (M + H)+ 334.1113, found 334.1113.
(S)-4-(4-Fluorophenylsulfonyl)-2-phenylmorpholine (7c). The
general method E described above was followed when 1d reacted
with KOH in THF at rt for 20 min to afford 7c as a white solid (56%
N-((1R,3S)-1-Methoxy-1-phenylpentan-3-yl)-4-methylbenzene-
sulfonamide (6h). The general method D described above was
followed when 2c (25 mg, 0.079 mmol) reacted with methanol to
afford 6h as a dense colorless liquid (21.2 mg, 80% yield): Rf 0.32
(EtOAc/petroleum ether, 1:4); IR νmax (film, cm−1) 3279, 3030, 2929,
2823, 1599, 1494, 1454, 1326, 1161, 1093, 1042, 1006, 912, 815, 759,
1
703, 665, 551; H NMR (500 MHz, CDCl3) δ 7.78 (d, 2H, J = 8.3
Hz), 7.31−7.23 (m, 5H), 7.10 (d, 2H, J = 6.9 Hz), 5.37 (d, 1H, NH, J
= 8.9 Hz), 4.27 (dd, 1H, J = 10.6, 2.9 Hz), 3.37−3.35 (m, 1H), 3.11 (s,
3H), 2.42 (s, 3H), 1.65−1.60 (m, 2H). 1.53−1.44 (m, 2H), 0.75 (t,
3H, J = 7.3 Hz); 13C NMR (125 MHz, CDCl3) δ 143.1, 141.3, 138.1,
129.6, 129.5, 128.5, 127.9, 127.2, 126.5, 82.6, 82.5, 56.3, 56.2, 41.7,
28.0, 21.5, 8.9; HRMS (ESI) calcd for C19H25NO3S (M + H)+
348.1633, found 348.1631.
yield): mp 98−101 °C; optical rotation: [α]25 +144.6 (c 0.057,
D
CHCl3) for a 86% ee sample. Enantiomeric purity was determined by
chiral HPLC analysis (Chiralcel OD-H column), hexane−2-propanol,
95:5; flow rate =1.0 mL/min; tR 1: 18.31 min (major), tR 2: 34.54 min
1
(minor): Rf 0.45 (ethyl acetate/hexane, 3:7); H NMR (400 MHz,
CDCl3) δ 7.70−7.67 (m, 2H), 7.30−7.12 (m, 7H), 4.53 (d, 1H, J = 10
3751
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The Journal of Organic Chemistry
Article
Hz), 4.02 (dd, 1H, J = 11.7, 3.2 Hz), 3.80 (ddd, 1H, J = 11.5, 11.5, 2.4
Hz), 3.71−3.68 (m, 1H), 3.59−3.56 (m, 1H), 2.44 (ddd, 1H, J = 11.5,
11.5, 3.4 Hz), 2.20−2.15 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
138.5, 130.5, 130.4, 128.6, 128.4, 126.0, 116.6, 116.4, 66.2, 51.9, 45.4;
HRMS (ESI) calcd for C16H16FNO3S (M + H)+ 322.0913, found
322.0916.
C.-H.; Dai, L.-X.; Hou, X.-L. Tetrahedron 2005, 61, 9586. (d) Pineschi,
M.; Bertolini, F.; Haak, R. M.; Crotti, P.; Macchia, F. Chem. Commun.
2005, 1426. (e) Minakata, S.; Hotta, T.; Oderaotoshi, Y.; Komatsu, M.
J. Org. Chem. 2006, 71, 7471. (f) Fukuta, Y.; Mita, T.; Fukuda, N.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 6312.
(g) Crestey, F.; Witt, M.; Jaroszewski, J. W.; Franzyk, H. J. Org.
Chem. 2009, 74, 5652. (h) Wang, Z.; Cui, Y.-T.; Xu, Z.-B.; Qu, J. J.
Org. Chem. 2008, 73, 2270. (i) Moss, T. A.; Fenwick, D. R.; Dixon, D.
J. J. Am. Chem. Soc. 2008, 130, 10076. (j) Sureshkumar, D.; Ganesh,
V.; Sasitha Vidyarini, R. S.; Chandrasekaran, S. J. Org. Chem. 2009, 74,
7958. (k) D’hooghe, M.; Vervisch, K.; De Kimpe, N. J. Org. Chem.
2007, 72, 7329. (l) Banks, H. D. J. Org. Chem. 2010, 75, 2510.
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of azetidines, see: (n) Almena, J.; Foubelo, F.; Yus, M. Tetrahedron
1994, 50, 5775. (o) Vargas-Sanchez, M.; Couty, F.; Evano, G.; Prim,
D.; Marrot, J. Org. Lett. 2005, 7, 5861. (p) Domostoj, M.; Ungureanu,
I.; Schoenfelder, A.; Klotz, P.; Mann, A. Tetrahedron Lett. 2006, 47,
2205. (q) Van Brabandt, W.; Van Landeghem, R.; De Kimpe, N. Org.
Lett. 2006, 8, 1105. (r) Couty, F.; David, O.; Durrat, F. Tetrahedron
Lett. 2007, 48, 1027. (s) Akiyama, T.; Daidouji, K.; Fuchibe, K. Org.
Lett. 2003, 5, 3691. (t) D’Hooghe, M.; Dekeukeleire, S.; Mollet, K.;
Lategan, C.; Smith, P. J.; Chibale, K.; De Kimpe, N. J. Med. Chem.
2009, 52, 4058.
(R)-2-Phenyl-5-tosyl-1,5-oxazocane (8). General procedure F for
one-pot synthesis of morpholine homologues was followed when (S)-
2a was reacted with bromopropanol at 0 °C for 30 min followed by
cyclization with excess KOH in dry THF at rt for 28 h to afford 8 as a
dense liquid (50% yield); optical rotation [α]25 +82.8 (c 0.16,
D
CHCl3) for a 78% ee sample. Enantiomeric purity was determined by
chiral HPLC analysis (Chiralcel OD-H column), hexane−2-propanol,
95:5, flow rate = 1.0 mL/min; tR 1: 13.17 min (major), tR 2: 15.06 min
(minor): Rf 0.30 (ethyl acetate/hexane, 1: 4); IR νmax (neat, cm−1)
1
2922, 2854, 1335, 1156, 1104, 713, 697, 549; H NMR (400 MHz,
CDCl3) δ 7.66 (d, 2H, J = 8.0 Hz), 7.27−7.18 (m, 7H), 4.66 (dd, 1H, J
= 10.0, 4.2 Hz), 3.82−3.78 (m, 1H), 3.72−3.62 (m, 2H), 3.52−3.48
(m, 1H), 3.17−3.11 (m, 1H), 2.99−2.93 (m, 1H), 2.36 (s, 3H), 2.23−
2.14 (m, 2H), 1.84−1.76 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
143.1, 129.7, 128.3, 126.9, 125.7, 66.5, 49.0. 47.6, 37.4, 30.4, 21.5;
HRMS (ESI) calcd for C19H23NO3S (M + Na)+ 368.1296, found
368.1292.
(3) For cycloaddition of aziridines, see: (a) Concellon
́
, J. M.; Riego,
ASSOCIATED CONTENT
E.; Suarez, J. R.; García-Granda, S.; Díaz, M. R. Org. Lett. 2004, 6,
́
■
4499. (b) Zhu, W.; Cai, G.; Ma, D. Org. Lett. 2005, 7, 5545. (c) Guo,
H.; Xu, Q.; Kwon, O. J. Am. Chem. Soc. 2009, 131, 6318.
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Aragoncillo, C.; Salgado, N. R. J. Org. Chem. 1999, 64, 9596 and
references cited therein.. (b) Vanecko, J. A.; West, F. G. Org. Lett.
2005, 7, 2949. (c) Rosser, C. M.; Coote, S. C.; Kirby, J. P.; O’Brien, P.;
Caine, D. Org. Lett. 2004, 6, 4817. (d) Zhao, X.; Zhang, E.; Tu, Y.-Q.;
Zhang, Y.-Q.; Yuan, D.-Y.; Cao, K.; Fan, C.-A.; Zhang, F.-M. Org. Lett.
2009, 11, 4002. (e) Sugihara, Y.; Iimura, S.; Nakayama, J. Chem.
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Chem. 2007, 5926.
S
* Supporting Information
Details of the racemization studies, copies of 1H and 13C NMR
spectra of the compounds, and HPLC chromatograms for ee
determination. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Fax: (+91)-512-2597436. Tel: (+91)-512-2597518. E-mail:
mkghorai@iitk.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
M.K.G. is grateful to IIT-Kanpur and DST, India. D.S. and A.B.
thank IIT-Kanpur and CSIR, India, respectively, for research
fellowships.
(5) (a) Ghorai, M. K.; Das, K.; Kumar, A.; Ghosh, K. Tetrahedron
Lett. 2005, 46, 4103. (b) Ghorai, M. K.; Tiwari, D. P. J. Org. Chem.
2010, 75, 6173. (c) Ghorai, M. K.; Das, K.; Kumar, A.; Das, A.
Tetrahedron Lett. 2006, 47, 5393. (d) Ghorai, M. K.; Ghosh, K.; Das,
K. Tetrahedron Lett. 2006, 47, 5399. (e) Ghorai, M. K.; Ghosh, K.
Tetrahedron Lett. 2007, 48, 3191. (f) Ghorai, M. K.; Das, K.; Kumar, A.
Tetrahedron Lett. 2007, 48, 4373. (g) Ghorai, M. K.; Das, K.; Kumar,
A. Tetrahedron Lett. 2009, 50, 1105. (h) Ghorai, M. K.; Kumar, A.;
Das, K. Org. Lett. 2007, 9, 5441. (i) Ghorai, M. K.; Das, K.; Shukla, D.
J. Org. Chem. 2007, 72, 5859. (j) Ghorai, M. K.; Shukla, D.; Das, K. J.
Org. Chem. 2009, 74, 7013 and references cited therein.. (k) Ghorai,
M. K.; Nanaji, Y.; Yadav, A. K. Org. Lett. 2011, 13, 4256. (l) Ghorai, M.
K.; Sahoo, A. K.; Kumar, S. Org. Lett. 2011, 13, 5972.
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