Asymmetric Transfer Hydrogenation: Dynamic Kinetic Resolution of α-Amino Ketones

Article abstract of DOI:10.1021/acs.joc.0c01438

A series of α-amino ketones were reduced using asymmetric transfer hydrogenation (ATH) through a dynamic kinetic resolution (DKR). The protecting group was matched to the reducing agent, and following optimization, a series of substrates were investigated, giving products in high diastereoselectivity, over 99% ee in several cases and full conversion. The methodology was applied to the enantioselective synthesis of an MDM2-p53 inhibitor precursor.

Full text of DOI:10.1021/acs.joc.0c01438

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Article
Asymmetric Transfer Hydrogenation - Dynamic
Kinetic Resolution of #-Amino Ketones
Shweta Gediya, Guy J. Clarkson, and Martin Wills
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01438 • Publication Date (Web): 07 Aug 2020
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The Journal of Organic Chemistry
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Asymmetric Transfer Hydrogenation - Dynamic Kinetic Resolution of -
Amino Ketones
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Shweta K. Gediya, Guy J. Clarkson and Martin Wills.*
Department of Chemistry, The University of Warwick, Coventry, CV4 7AL, UK.
Corresponding author: m.wills@warwick.ac.uk
Supporting Information Placeholder
OH
O
Ar1, Ar2 = Ph, o.m,p Cl-, MeO-phenyl
PG = Bz, Boc, Ts, Cbz
ATH catalyst
Ar2
Ar2
Ar1
Ar1
HCO2H,
DABCO,
MeCN
NHPG
NHPG
Selectivities in best cases:
dr >99.9:0.1, >99% ee
16-19
12-15
Proposed
reduction mode:
Application:


Cl
OH
precursor of a reported
PG
H
MDM2-p53 Inhibitor:
100% conv, 89% yield,
dr 99.7:0.3, 96% ee
O
R
N
O
S
N
O
H
H
HN
Ru
tBoc
H
Cl
N
Ar1
H
Ph
Ph
ABSTRACT: A series of -amino ketones were reduced using asymmetric transfer hydrogenation (ATH) through a dynamic
kinetic resolution (DKR). The protecting group was matched to the reducing agent and following optimization, a series of
substrates were investigated, giving products in high diastereoselectivity, over 99% ee in several cases and full conversion.
The methodology was applied to the enantioselective synthesis of a MDM2–p53 inhibitor precursor.
1 Introduction
22 synthesis of enantiomeric pure syn-β-hydroxy-α-dibenzylamino
esters8 to make 6.
using2
2 Asymmetric Transfer Hydrogenation (ATH),
[(arene)Ru(TsDPEN)Cl] pre-catalysts 1, including the class of
2
Products
of
ATH-DKR
of
-amino--keto-esters:
OH O
complexes 2 and 3, is a powerful method for the asymmetric
reduction of ketones (Figure 1).1-3 The pre-catalyst forms a
hydride which transfers hydrogen to the substrate in a
7 stereochemically-predictable manner (Figure 1).4
OH
O
OH
O
BnO
OEt
OEt
C15H31
OMe
NBn2
NHCOPh
NHAc
BnO
6
5
4
3
Using catalyst (R,R)- :
98% yield, >20:1 dr, >99% ee
Droxidopa precursor
2
Using catalyst (S,S)-
:
3
Using catalyst (R,R)-
:
83/17 anti/syn and 98% ee
Via reduction of the amine
hydrochloride precursor
69.4% de, 97% ee
prepared on 58 kg scale:
>99% de, >99% ee
2
2
OH
O
X
X
1-3
Catalyst
R = alkyl group
Products of ATH-DKR of other -amino ketones:
R
R
HCO2H/Et3N
Solvent
O
N
F
OH
F
OH
NH
Ph
NHBoc
O


Br
R
iPr
Cl
X
H
F
NHCBz
O
N
via
Ts
N
Ru
N
Ru
N
Ru
N
Ts
Ts
N
Ts
Ru
N
N
7
Cl
F
Cl
F
8
N
H
F
H
Ph
Ph
H
Ph
2
using (R,R)- : dr >200:1, 97% ee
3
using catalyst (R,R)-
:
H
9 (from 8 prepared
using S,S)-catalyst)
Ph
H
H
93% yield, dr 96:4, 99% ee
3
using (R,R)- : dr >200:1, 98% ee
Ph
Ph
Ph
O
R
1
Ph
(R,R)-
3
(R,R)-
2
(R,R)-
N
N
OH
1
Figure 1. Asymmetric Transfer Hydrogenation (ATH) of
OH
2
Using (R,R)-
n=2; 94% yield,
cis/trans 99/1, 99.9% ee
n=1; 91% yield,
:
Ph
N
N
N
11 acetophenones by [(arene)Ru((R,R)-TsDPEN)Cl] catalysts 1-3 and
N
2
Using (R,R)- :
12 orientation of substrate to catalyst in reduction step.
Ph
n
95% yield
99:1 dr, 95.4% ee
11
10
1
cis/trans 99/1, 91.5% ee
27
1
1
1
ATH in combination with dynamic kinetic resolution (DKR),
2
This work:
has been used to good effect.5-12 For -amino ketones,6-12 ATH-
DKR of amino--keto esters have been reported (Figure
OH
O
ATH catalyst
Ar1, Ar2 = o.m,p Cl-, MeO-phenyl
PG = Bz, Boc, Ts, Cbz
Ar2
Ar2
Ar1
Ar1
HCO2H,
DABCO,
MeCN
17 2A).6-9 In an example by Echeverria et al., reduction of a -keto-
NHPG
NHPG
Selectivities in best cases:
dr >99.9:<0.1 dr, >99% ee
16-19
12-15
-amino ester gave 4 in up to 83/17 anti/syn and 98% ee using2
1
1
2
catalyst 2.6 Researchers at Takasago described the large scale
ATH-DKR of -N-acylamino--keto esters using ATH to 5
Figure 2. Products of ATH-DKR of -amino ketones of
1 different classes.
21 using catalyst 3.7 An efficient DKR-ATH was achieved in the
2
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Table 1. Catalyst screening on substrates 12a-15a, and catalysts
1 Amino ketones in which racemisation is slower have been
2 less investigated.10-12 The ATH-DKR of a Boc-protected -
amino ketone to alcohol 7 was employed in the synthesis of the
type 2 diabetes drug omariglyptin (Figure 2B).10 The
ATH/DKR, using a range of catalysts including 2 and 3 gave
amino alcohol 8 in 97-98% ee and a dr of >200:1 (Figure 2B).11
7 Intramolecular cyclisation, with inversion of configuration, led
to the mGluR5 9.11 Other relevant ATH-DKRs of -amino
ketones have led to cis--azolo--cycloalkanols 10 and 11
(Figure 2B).12 We were interested in establishing the scope of
1
2
3
4
5
6
7
8
1 (R,R)-1¸ 2 and 20-22.
PG
O
OH
1
2 20-22
,
1.5 mol% catalyst
,
12a, 16a
13a, 17a
14a, 18a
15a, 19a
COPh
Boc
Ts
5 eq DABCO, 3 eq FA,
Ph
Ph
PG
Ph
Ph
HN
HN
MeCN, rt, [S] = 0.1 M
PG
12a-15a
Cbz
16a-19a
2
MeO
MeO
O2
Ru Cl
Ru Cl
Ru Cl
S
TsN
Ph
N
TsN
Ph
N
N
NH2
C6F5
H
Ph
H
1
Ph
Ph
Ph
9
11 the ATH/DKR of -amino ketones (Figure 2C), as the
12 extension of the methodology would provide access to a range
20
22
21
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
31
32
33
34
35
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38
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Catalyst
Subs-
trate
12a
t/h Conva
/% (dr)b yield
Eec
/%
25
1
1
1
1
of valuable target molecules.
Results and Discussion
(R,R)-2
24
72
72
24
48
24
72
72
24
48
24
72
72
24
48
24
72
48
24
48
100 (>99.9:<0.1d) 60% yield
95 (>99.9:<0.1d)
Compounds 12a-14a (Table 1)were prepared via bromination
of -phenylacetophenone, reaction with potassium
(R,R)-1
12a
12a
12a
12a
13a
13a
13a
13a
13a
14a
14a
14a
14a
14a
15a
15a
15a
15a
15a
76
(R,R)-20
(R,R)-21
(R,R)-22
(R,R)-2
70 (>99.9:<0.1d)
100 (>99.9:<0.1d)
63 (>99.9:<0.1d)
94
17 phthalimide, then deprotection and addition of the N-protecting
61
69 e
1
1
2
group, whereas 15a was prepared through the reaction of an
acylimine with benzaldehyde using a thiazolium catalyst13
(Supporting Information). A series of conditions were tested
100 (>99.9:<0.1) 65% yield
91 (>99.9:<0.1f)
73
(R,R)-1
94
21 using catalyst (R,R)-2. Racemic standards were prepared by
22 reduction with NaBH4, which was less diastereoselective than
(R,R)-20
(R,R)-21
(R,R)-22
(R,R)-2
96 (>99.9:<0.1)
93
100 (>99.9:<0.1)
46 (ca. 95:5g)
76
12 e
2
the ATH-DKR and allowed the minor diastereomers to be
identified by HPLC (other than for 16a). In all cases, the anti-
products 16a-19a (Table S1, Table 1) were predominantly
formed.14 Using FA/TEA azeotrope (5:2) with DCM (A, Table
2
2
2
100 (>99.9:<0.1) 69% yield
89 (>99.9:<0.1h)
99
(R,R)-1
>99
98
27 S1), the medium in the reduction of 12a became heterogeneous
(R,R)-20
(R,R)-21
(R,R)-22
(R,R)-2
97 (>99.9:<0.1)
2
2
after 24h. Both precipitate and filtrate from the reaction
contained product of high dr, however of differing ee. Using a
1:1 ratio of FA:TEA (B, Table S1), conversion was incomplete
1 and the ees were lower. Using a combination of 5:3
2 DABCO/FA (C, Table S1).11 gave a product in improved ee,
which did not change significantly when a 5:6 ratio of reagents
was used (D, Table S1).
100 (>99.9:<0.1)
21 (>99.9:<0.1h)
94
69
100 (>99.9:<0.1) 59% yield
39 (>99.9:<0.1)
44
(R,R)-1
71
(R,R)-20
(R,R)-21
(R,R)-22
98 (>99.9:<0.1)
85
100 (>99.9:<0.1)
54 (>99.9:<0.1)
67
60 d
Reduction of N-Boc-protected substrate 13a using both TEA
and DABCO as base with catalyst (R,R)-2 (A and C, Table S1)
7 also revealed that the latter base gave the best result. Working
up the reductions of 12a and 13a with a DCM extraction gave
a product which reflected the overall ee of the reaction (Table
S1, Table 1). The N-Ts-protected substrate 14a was reduced in
a. HPLC conversions and ee of isolated product using (R,R)-2 and of crude
product for other catalysts; b. >99.9:<0.1 indicates only one diastereoisomer
observed by chiral HPLC. c. ee of major diastereoisomer. d. Minor
diastereoisomer not detected in racemic reduction. e. opposite enantiomer
of product formed. f. tentative as HPLC did not run to minor isomer. g.
Estimated as minor diastereoisomer was not integrated. h. tentatively
assigned as some small HPLC peaks are of similar RT to minor
7
1 an excellent 99% ee under conditions C (Table S1, Table 1)
7
2 with catalyst (R,R)-2 whereas the best ee for the reduction of
71 diastereomer.
the N-Cbz-protected substrate 15a was just 44% (Table S1, 72
Table 1); the reactions for the formation of both 18a and 19a7
We evaluated a series of catalysts; (R,R)-1 and (R,R)-20,9e
(R,R)-21,3f and (R,R)-22,3g under the same conditions for each
substrate (Table 1). Catalyst 1 and the pentafluorinated (R,R)-
20 gave product 16a in good ee however they were slow
remained homogeneous. The X-ray crystallographic structure
7
of the major enantiomer of 18a (Supporting Information)
7
7 confirmed both its absolute configuration and the anti-
7
diastereoselectivity matches the related product 8 containing a 77 compared to the CH2(C6H4)-linked catalyst (R,R)-21. Catalyst
Cbz group.11
7
7
(R,R)-20 generated a product of 94% ee in the reduction of 12a
compared to just 25% ee with catalyst (R,R)-2. The tosyl
substrate 14a gave a product in >90% ee with all the catalysts
1 except (R,R)-22. Catalysts (R,R)-1 and (R,R)-20 gave similar
2 results with N-Boc-protected13a. Although there is no direct
evidence, there is potential for a reduction product such as 18a
to replace the ligand in the catalysts, and this is likely to happen
more rapidly with untethered complexes.2b Catalyst (R,R)-22
was found to be the least active and in several cases gave the
7 opposite enantiomer of product, although still a high dr.
Acetophenone reduction with catalyst (R,R)-22 gave the (R)-
Since slow racemisation can reduce the potential for the
1 formation of high ee products in DKR reactions, they were
2 followed over time. The substrates (with the exception of 18a)
remained essentially racemic throughout (Scheme S1, Table
S2), confirming that racemisation is rapid. The product ees
remained consistent (within ca. 5%) throughout the reductions.
Hence the catalyst controls the reduction of one enantiomer of
7 ketone substrate over the other, however the N-protecting group
also has an influence on the selectivity.
2
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OH
OH
OH
1 alcohol, as expected. As a result of this study, two
2 catalyst/substrate systems were selected for further study;
fluorinated catalyst (R,R)-20 with N-Boc-protected substrate
13a and complex (R,R)-2 with N-Ts-protected compound 14a.
A solvent study was carried out (Supporting information, Table
S3) however none of the alternative solvents, or solvent–free
7 conditions, improved the results.
1
2
3
4
NHTs
NHBoc
25
NHMs
23
24
2
cat. (R,R)- ; 48h,
20
cat. (R,R)- : 6d,
2
cat. (R,R)- ; 24h,
93% conv, 85.2% yield,
dr 68:32, ca. 36/>99% ee
76% conv, 53.1% yield,
100% conv, 79.0% yield,
dr 97.4:2.6, 95% ee
dr 79:21, 34a/82% ee
5
OH
OH
6
7
8
9
The reduction of a range of substrates; 13b-13l and 14b--14l
and the precursors to 23-27, were undertaken (Figure 3). The
N-Boc-protected ketones,13 were prepared initially, then the N-
26
27
NHTs
NHBoc
2
cat. (R,R)- ; 24h,
20
cat. (R,R)- : 24h,
100% conv, 86.8% yield,
dr 98.3:1.7, 95% ee
1
100% conv, 78.4% yield,
dr 75.4:24.6, 97/61% ee
11 Ts-protected ketones were prepared via their deprotection
12 followed by N-tosylation. A representative series of substrates
21
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
22 Figure 3. Reduction products of ketones 13b-13l (using (R,R)-
1
were prepared with electron-donating (OMe) and electron-
2
20) and 14b-14l (using (R,R)-2). Conditions are as in Figure
2/Table 1 except that 2 mol% catalyst was used for the
formation of 17b, 17d, 17g and 17h. Ees are of major
diastereoisomers except where indicated. a. Overlap of peaks in
27 HPLC limits the accuracy of this measurement.
1
1
1
withdrawing (Cl) substituents at the o-, m- and p- positions of
2
each aromatic ring Ar1/Ar2. In addition, one NMs product (23)
2
2
was formed by reduction of the corresponding ketone, as were
17 24-27 in which one phenyl ring was replaced by a methyl.
1
2
2
OH
OMe OH
Substrates containing substituents on the aromatic rings
adjacent to the ketone (Ar1), leading to products 17b-17f and
1 18b-18f, were fully reduced in most cases and in high dr and ee,
2 although the o- and p-chloro substituted products were formed
in slightly lower ee. Although the configurations of products
were generally assigned by analogy to 17a/18a, the X-ray
crystallographic structure of 17d was determined and served to
confirm the assignment (Supporting Information).
MeO
NHPG
PG=Boc; cat. (R,R)-
NHPG
PG=Boc; cat. (R,R)-
17c
20
,
17b
20
,
72h: 100% conv, 87.4% yield,
dr >99.9:0.1, 93% ee
48h: 100% conv, 87.4% yield,
dr >99.9:0.1, 94% ee
18c
2
,
PG=Ts; cat. (R,R)-
18b
2
,
PG=Ts; cat. (R,R)-
24h: 100% c, 85.6% yield,
dr 98.3/1.7, 94% ee
24h: 100% conv, 79.3% yield
dr >99.9:0.1, 95% ee
7
OH
OH
Cl
OH
Cl
NHPG
NHPG
Substrates with substituted aromatic rings proximal to the
amine (Ar2) were generally reduced to 17g-17k and 18g-/18k
1 in high dr although the ee was dependent on both the nature and
2 position of the substituents. The o-chloro N-Ts-protected
substrate 14i gave product 18i in a poor dr however
substrates13k/14k, containing a combination of p- substituents
gave a product in high dr and eeThe furyl-containing products
17l/18l were formed in poor dr and ee. NMs product 23 was
7 formed in an excellent 96% ee and high dr, indicating that the
aromatic ring of the Ts is not required for high selectivity. When
the aromatic ring proximal to the amine (Ar2) was replaced by
20
,
NHPG
PG=Boc; cat. (R,R)-
48h: 95% conv, 71.4% yield,
dr 97.7:2.3, 95% ee
Cl
17f
17e
20
20
PG=Boc; cat. (R,R)- ,
24h: 100% conv, 78.3% yield, 24h: 100% conv, 80.6% yield,
dr >99.9:0.1, 97% ee
dr >99.9:0.1, 99% ee
PG=Boc; cat. (R,R)-
,
17d
20
,
18e
2
18f
2
,
PG=Ts; cat. (R,R)-
,
PG=Ts; cat. (R,R)-
18d
2
,
PG=Ts; cat. (R,R)-
24h: 100% conv, 89.7% yield, 24h: 100% conv, 44.8% yield,
24h: 100% conv, 43.9% yield,
dr >99.9:0.1, 89% ee
dr >99.9:0.1, 94% ee
OH
dr 97.7:2.3, 89% ee
OH
1
OMe
OH
NHPG
OMe
NHPG
NHPGCl
17i
PG=Boc; cat. (R,R)-
17g
20
17h
20
PG=Boc; cat. (R,R)- ,
PG=Boc; cat. (R,R)-
,
96h: 95% conv, 92.2% yield,
dr 99.5:0.5, 90% ee
6d: 90% conv, 64.2% yield,
dr >99.9:0.1, 89% ee
72h: 90% conv, 69.9% yield,
dr 99.1:0.9, 90% ee
a methyl group, products 24 and 25 were formed in poor dr and
1 low ee. On the other hand, replacement of the Ph adjacent to the
2 ketone followed by ATH-DKR gave a high dr and ee for the N-
18i
2
,
PG=Ts; cat. (R,R)-
18g
2
18h
PG=Ts; cat. (R,R)-
2
,
PG=Ts; cat. (R,R)-
,
48h: 100% conv, 69.8% yield,
dr 88:12, 80/18% ee
48h: 100% conv, 85.6% yield, 24h: 100% conv, 95.2% yield,
Boc-protected product 26, but the N-Ts-protected product 27 in
much lower dr. The formation of two products, N-Boc-prtected
17e and N-Ts-protected 18h were carried out on 1.0g scale with
respect to starting material ketone. In both cases the reductions
7 proceeded cleanly to give products in 88.7% and 89.4% yields
20
,
dr 94.8:5.2, 80% ee
OH
dr 98.2:1.8, 90% ee
OH
Cl
OMe
OH
O
NHPG
NHPG
NHPG
Cl
17k
17l
PG=Boc; cat. (R,R)-
20
,
17j
20
PG=Boc; cat. (R,R)-
PG=Boc; cat. (R,R)-
,
respectively, and with 95% and 90% ee respectively (previously
97% and 90% ee) (see the Supporting Information).
72h: 100% conv, 79.2% yield,
dr 96:4, 79/57% ee
72h: 100% conv, 93.5% yield,
dr >99.9:0.1, 97% ee
72h: 100% conv, 92.2% yield,
dr 99.5:0.5, 90% ee
The results indicate that the reductions proceed with
18l
2
,
PG=Ts; cat. (R,R)-
18k
2
,
18j
2
PG=Ts; cat. (R,R)-
PG=Ts; cat. (R,R)-
,
1 preferential formation of the anti-diastereoisomers.11,14 The
48h:100% conv, 92.4% yie2ld, results observed for products 24-27 indicate that the aromatic
ring adjacent to the protected amine (Ar2) is required for control
of dr and ee in the reductions whereas the aromatic ring adjacent
to the ketone (Ar1) is not. Previous studies have indicated that a
H-bond between the substrate and the SO2 of the sulfonamido
7 group can play an important part in the control of the ATH of
imines15a,b and -amino ketones,12c as can an interaction
between an amido on the substrate and the 6-arene of the
48h: 100% conv, 88.2% yield,
dr >99.9:0.1, 98% ee
24h: 100% conv, 84.8% yield,
dr 97.7:2.3, 92/>99% ee
dr 55:45, 72/98% ee
2
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Page 4 of 27
1 catalyst.15c Considering the related studies, and our 1 (Figure 6). Cyclisation of (1S,2R)-29 with inversion of
2 observations, the stereochemical outcome can be explained by 2 configuration, following the reported precedent,18 gave
1
2
3
4
5
6
7
8
a transition state (Figure 4) for hydride transfer which is
stabilised by a hydrogen bond between an N-H in the substrate
and the sulfonamido group, coupled with a CH/ edge/face
interaction as illustrated. This results in the formation of the
7 observed product and agrees with previous reports for this class
of substrate (Figure 1)11 and for a reported -amino
acetophenone reduction.16a However it is not consistent with
other observations on the reduction of non--substituted -
oxazolidinone (4S,5S)-30, a precursor of a recently reported
MDM2–p53 inhibitor molecule which had previously been
prepared in asymmetric form through a chiral resolution.18
Cl-
Cl
Cl
Bn
O
O
N+
Cl
PhO2S
cat.
OH
S
+
HN
HN
1
DCM, TEA,
35 oC, 24 h
Boc
Boc
9
11 amino ketones16b and related products of non-DKR ATH
28
Cl
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
yield
67%
12 reductions using Rh(III) catalysts.17
O
Cl
OH
1
The reduction of analogous compounds lacking the N-H
function generally give products with the opposite
diastereoselectivity to ours, indicating the importance of this
group in the direction of the reduction.9 In order to investigate
1.5 mol%
20
NH
(R,R)-
Ms2O, pyridine
70 oC, 18 h
1
1
1
HN
HCO2H/
DABCO,
rt, 24 h
Cl
Boc
29
Cl (1S,2R)-
30
Cl
17 this factor in our compounds, we investigated the ATH of N-
20
Using (R,R)-
:
74.5% yield
100% conv, 89.2% yield,
dr 99.7:0.3, 96% ee
1
1
2
methylated analogues of 13a and 14a. In the event, the NMe
derivative of 13a was prepared in low yield however its
reduction proceded in low conversion and purity and it was not
20
(Using (S,S)- :100% conv, 95.2% yield
29
>99.9:0.1 dr, 96% ee (ent-
)
7
21 possible to analyse the products by HPLC. Compound 14aMe,
22 which is the NMe derivative of NTs ketone 14a, was prepared
Figure 6. Synthesis of MDM2–p53 inhibitor precursor 30 via
ATH-DKR of -N-Boc-protected ketone 28.
2
and was successfully reduced to give 18aMe in 47% yield, dr:
83:17 with 90% and 35% ee respectively. i.e. lower than for 14a
(Figure 5). The configuration of the major product is not known.
This again evidences the importance of the NH group in the
2
2
2
1 Conclusions
2 In conclusion, we report the optimization and scope expansion
of the ATH-DKR of -aminoketones with varying N-protecting
groups and substitution patterns. We have identified the most
suitable catalysts from a series for the N-Boc-protected and N–
Ts-protected substrates and have explored the scope of the
7 applications. This study allowed us to identify a suitable
catalyst for a very concise synthesis of an MDM2–p53
inihibitor precursor in high ee, representing a valuable approach
to this class of target molecule.
27 reduction selectivity. The different protecting groups will also
2
2
have a moderating influence on the selectivity, presumably due
to their differing bulk and electronic properties.
1 Hence the detailed and complex controlling factors in the ATH
2 reaction of -amino ketones described herein remain to be fully
understood and are the subject of ongong studies In addition,
7
the reversal of configuration using catalyst (R,R)-22 in several
cases is not fully understood (Table 1) but reflects the potential 71
for subtle additional interactions between the substrates 72 EXPERIMENTAL SECTION
7 described herein and the groups on the 6-arene ring.
7
General procedures for the syntheses.
7
7
7
Solvents and reagents for the synthesis of complexes and
catalytic reactions were degassed prior to use and all reactions
were carried out under either a nitrogen or argon atmosphere.

PG

H
OH
(S) Ph
HO
Ar1
NHPG
Ph
O
R
N
O
Ru
S
Ar1 (R)
77 Reactions were monitored by TLC using aluminum backed
=
N
O
H
H
H
NHPG
7
7
silica gel 60 (F254) plates, visualized using UV 254 nm and
phosphomolybdic acid (PMA), potassium permanganate or
vanillin dips as appropriate. Flash column chromatography was
1 carried out routinely using 60 micrometer silica gel. Reagents
2 were used as received from commercial sources unless
N
(Ar1 = Ph, PG = Ts)
(Ar1 = o-ClC6H4, PG = Boc)
18a
Ar1
H
Ph
17d
Ph
Figure 4. Proposed mode of reduction of 14a and 13d to 18a
1 and 17d respectively, stabilised by hydrogen bonding and the
2 known CH/ edge/face interaction.
1
otherwise stated. H NMR spectra were recorded on a Bruker
DPX (300, 400 or 500 MHz) spectrometer. Chemical shifts are
reported in δ units, parts per million relative to the singlet at
7.26 ppm for chloroform and 0.00 ppm for TMS. Coupling
7 constants (J) are measured in Hertz. Structural assignments
were made with additional information from gCOSY, gHSQC,
and gHMBC experiments. IR spectra were recorded on a
Perkin-Elmer Spectrum One FT-IR Golden Gate. Mass spectra
1 were recorded on a Bruker Esquire2000 or a Bruker MicroTOF
2 mass spectrometer. Melting points were recorded on a Stuart
Scientific SMP 1 instrument and are uncorrected. Dry solvents
were purchased and used as received. HPLC analyses were
carried out on a Hewlett-Packard 1050 instrument. Optical
OH
O
47% yield,
dr: 83:17
90/35% ee
Ph
Ts
Ph
Ts
Ph
Ph
MeN
MeN
14aMe
18aMe
Figure 5. N-methylated derivative substrate 14aMe and
reducation product 18aMe.
7
As an example of the value of the ATH-DKR, we reduced
ketone 28 to each enantiomer of amino alcohol 29 using catalyst
(R,R)-20. In both cases a product of high dr and ee was formed
4
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The Journal of Organic Chemistry
1 rotations were measured on an AA-1000 polarimeter. The X- 2 1358, 1115, 713, 703, 688, 625, 528 cm-1; 1H NMR (CDCl3,400
1
2
3
4
5
6
7
8
2 ray crystallographic structures were recorded on a Rigaku
Oxford Diffraction SuperNova diffractometer with a duel
source (Cu at zero) equipped with an AtlasS2 CCD area
detector. Enantiomeric excesses were measured to one decimal
place, however the results in Table 1 in the paper have been
7 rounded to whole numbers or to >99% ee where the measured
ee was 99.5% or above, and drs are given as >99.9:<0.1 where
only one diastereoisomer was observed.
MHz):  7.86 (d, 2H, J = 7.4 Hz), 7.83-7.82 (m, 2H), 7.77-7.76
(m, 1H), 7.71-7.70 (m, 2H), 7.51 - 7.47 (m, 3H), 7.39-7.32 (m,
4H), 6.78 (s, 1H); 13C{1H} NMR (CDCl3, 101 MHz):  193.2,
167.6, 135.1, 134.6, 134.5, 134.3, 133.4, 131.9, 130.5, 128.9,
7 128.8, 128.8, 123. 8, 123.7, 60.4; m/z (ESI) 364.2 [(M+Na)+,
100%]. The data matches the reported data.
7
2-Oxo-1,2-diphenylethan-1-aminium chloride.
71 This compound is known and has been previously
72 characterised.20 2-(2-Oxo-1,2-diphenylethyl)isoindoline-1,3-
dione (6.00 g, 17.5 mmol) in acetic acid (45 mL) and 6N HCl
1
9
11 General procedure A for the synthesis of racemic alcohols. 7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12 To a solution of ketone (1.0 eq.) in MeOH ([S] = 0.1 M) was
7
(45 mL) was stirred at 100 ºC for 3 days. The reaction mixture
was cooled to rt and washed with DCM (30 mL). The aqueous
layer was concentrated under reduced pressure to afford the
1
1
1
1
added NaBH4 (2.0 eq.) portion-wise. The solution was stirred at
rt until the ketone had been consumed. The solvent was then7
removed under reduced pressure and the residue partitioned7
between water and EtOAc. The organic extract was collected 77 product as a white solid. (3.01 g, 12.1 mmol, 69.1%) which was
7
used in the next step without further purification. 1H NMR (D2O
,400 MHz):  7.97 (d, 2H, J = 7.6 Hz), 7.79-7.77 (m, 1H), 7.66-
7.61 (m, 2H), 7.48-7.47 (m, 5H), 6.27 (s, 1H); 13C{1H} NMR
1 (D2O, 101 MHz):  194.5, 135.1, 132.4, 131.7 131.3, 130.4,
2 129.9, 129.2, 129.0, 128.4, 128.7, 59.7; m/z (ESI) 212.2
[(M+H)+, 100%]. The data matches the reported data.
17 and the aqueous layer extracted a further 2 times with EtOAc.
The organic layers were combined, dried over MgSO , filtered7
1
1
2
4
and the solvent removed under reduced pressure to afford
racemic alcohols.
21
22 Section on initial substrates 12a-15a and their reductions.
2
2-Bromo-1, 2-diphenylethan-1-one.
2
2
2
This compound is known and has been previously
characterised.19 N-Bromosuccinimide (4.50 g, 38.3 mmol, 1.5
N-(2-Oxo-1,2-diphenylethyl)benzamide 12a.
eq) and p-toluenesulphonic acid (0.88 g, 5.1 mmol, 0.20 eq) 7 This compound is known and has been previously
27 were dissolved in anhydrous DCM (50 mL) and the reaction
characterised.21 2-Oxo-1, 2-diphenylethan-1-aminium chloride
(1.0 g, 4.0 mmol, 1.0 eq) was suspended in DCM (15 mL) and
cooled to 0 ºC in an ice bath. Triethylamine (1.6 g, 2.2 mL, 16
º
2
2
mixture was cooled to 0 C. To the cold reaction mixture, a
solution of 1, 2-diphenylethan-1-one (5.00 g, 25.5 mmol, 1.0
eq) in dry DCM (25 mL) was added dropwise over a period of 1 mmol, 4.0 eq) was added dropwise to the reaction mixture and
1 1h. After the addition, the reaction mixture was stirred under N2 2 stirred at same temperature for 30 minutes. During the addition
º
2 for 8 hours at 40 C. The completion of the reaction was
confirmed by 1H NMR. After the completion of the reaction, the
reaction mixture was cooled to rt and H2O (100 mL) and DCM
(25 mL) were added and organic layer was separated. The
of triethylamine, the initially cloudy reaction mixture became
clear. To the reaction mixture, benzoyl chloride (0.84 g, 0.76
mL, 6.0 mmol, 1.5 eq) was added dropwise and the resulting
reaction mixture was stirred at 0 ºC for 30 minutes followed by
aqueous layer was extracted with DCM (2 x 30 mL). The 7 overnight stirring at rt. Once the reaction was complete
7 combined organic layers were washed with brine (50 mL) and
dried over MgSO4. The organic layer was concentrated under
reduced pressure to afford the product as an off-white solid (61.9
(assessed by TLC), water (50 mL) and DCM (25 mL) were
added and organic layer was separated. The aqueous layer was
extracted with DCM (2 x 30 mL). The combined organic layers
g, 25 mmol, 98%) which was used in the next step withou1t 1 were washed with brine (50 mL), dried over MgSO4 and
1 further purification. TLC: Rf ca 0.5 (9:1, Hexane: EtOAc1), 2 concentrated under reduced pressure to give the crude product.
1
The crude material was purified by column chromatography
(30% EtOAc in petroleum ether (40-60)) to afford the product
12a as a white solid (0.60 g, 1.9 mmol, 47%).TLC: Rf ca 0.4
(7:3, Hexane: EtOAc), strong UV active; max 3388, 3056,
2 strong UV active; max 1678, 1593, 1446, 1171, 991, 754, 677,
-1
1
1
611 cm ; H NMR (CDCl3, 400 MHz):  7.99 (d, 2H, J = 7.2
1
Hz), 7.57-7.53 (m, 3H) , 7.47-7.45 (m, 2H), 7.38-7.36 (m, 3H),
1
6.38 (s, 1H) ; 13C{1H} NMR (CDCl3, 101 MHz,):  191.2,
1 7 3031, 1716, 1685, 1647, 1509, 1481, 1447, 1297, 1252, 706,
136.0 134.31, 133.8, 129.3, 129.2, 128.9, 51.2. The data
1
1
690, 531 cm-1; H NMR (CDCl3, 400 MHz):  7.97 (d, 2H, J =
7.1 Hz), 7.79 (d, 2H, J = 6.9 Hz), 7.68 (d, 1H, J = 4.4 Hz) 7.47-
7.36 (m, 8H), 7.28-7.24 (m, 2H), 7.19 (s, 1H), 6.70 (d, 1H, J =
7 matches the reported data.
1
11
2-(2-Oxo-1,2-diphenylethyl)isoindoline-1,3-dione.
111 6.7 Hz); 13C{1H} NMR (CDCl3, 101 MHz):  196.0, 166.4,
This compound is known and has been previously
1 characterised.20 2-Bromo-1, 2-diphenylethan-1-one (5.0 g, 18112 137.4, 134.4, 134.0, 131.9, 130.3, 129.4, 129.3, 128.9, 128.7,
2 mmol, 1.0 eq) and potassium phthalimide (5.07 g, 27.3 mmo1l,1
1.5 eq) were dissolved in anhydrous DMF (50 mL) and th1e1
resulting reaction mixture was stirred under N2 for 24 hours 1at1
rt. After the completion of the reaction, indicated by TLC, th1e1
128.6, 128.5, 127.3, 59.0; m/z (ESI) 338.2 [(M+Na)+, 100%].
The data matches the reported data.
t-Butyl (2-oxo-1,2-diphenylethyl)carbamate) 13a.
reaction mixture was quenched with ice-cold water H2O (1 L)1. 17 This compound is known and has been previously
7 The obtained solid was filtered through Buchner filtration an1d1
washed with ice cold water (1 L) and dried to afford the produ1ct1
as a white solid (6.02 g, 17.6 mmol, 97.7%) which was used i1n2
characterised.22 2-Oxo-1,2-diphenylethan-1-aminium chloride
(0.70 g, 2.8 mmol, 1.0 eq) was suspended in THF (10 mL) and
cooled to 0 ºC in an ice salt bath. Triethylamine (1.8 g, 2.5 mL,
next step without further purification. TLC: Rf ca 0.3 (9:11, 21 18 mmol, 6.5 eq) was added dropwise to the reaction mixture
122 and stirred at same temperature for 30 minutes. During the
1 Hexane: EtOAc), strong UV active; max 1711, 1684,1382,
5
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The Journal of Organic Chemistry
Page 6 of 27
1 addition of triethylamine, the initially cloudy reaction mixture 2 with nitrogen for 15 min. To this mixture was added CH2Cl2 (30
1
2
3
4
5
6
7
8
2 became clear. To the reaction mixture, Boc anhydride (1.23 g,
mL) followed by benzaldehyde (0.30 g, 2.8 mmol, 1.5 eq) and
the resulting mixture was stirred and heated to 35 ºC.
Triethylamine (3.8 mL, 2.8 g, 27 mmol, 15 eq) was added in
one portion via syringe and the reaction mixture was stirred at
5.66 mmol, 2.0 eq) in THF (5 mL) was added dropwise and the
o
resulting reaction mixture was stirred at 0 C for 30 minutes
followed by overnight stirring at rt. Once the reaction was
complete (assessed by TLC), water (150 mL) and DCM (50 7 35 °C for 24 h. After the reaction was complete (assessed by
7 mL) were added and the organic layer was separated. The
aqueous layer was extracted with DCM (3 x 50 mL). The
combined organic layers were washed with brine (50 mL) and7
TLC), it was cooled to 25 °C and water (50 mL) and DCM (25
mL) were added and organic layer was separated. The aqueous
layer was extracted with DCM (2 x 30 mL). The combined
1
dried over MgSO4 and concentrated under reduced pressure to 71 organic layers were washed with brine (50 mL) and dried over
9
11 give the crude product. The crude material was purified by 72 MgSO4 and concentrated under reduced pressure to give the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12 column chromatography (20% EtOAc in petroleum ether (40-7
crude product. The crude material was purified by column
chromatography (30% EtOAc in petroleum ether (40-60)) to
afford the product 15a as a pale yellow solid (0.28 g, 0.81
mmol, 45%). TLC: Rf ca 0.3 (8:2, Hexane: EtOAc), strong UV
1
60)) to afford the product 13a as a white solid (0.410 g, 1.317
mmol, 46.6%).TLC: Rf ca 0.3 (8:2, Hexane: EtOAc), strong UV7
1
1
1
7
active; max 3384, 3364, 2980, 2934, 1703, 1694, 1675, 1493,
77 active; M.P. 92-93 ºC; HRMS (ESI): found [M+Na]+ 368.1261,
-1
1
1158, 752, 693, cm ; H NMR (CDCl3, 400 MHz): δ 7.96 (d,
7
C22H19NNaO3 requires [M+Na]+ 368.1257, (error 1.1
ppm); max 3386, 1719, 1676, 1502, 1231, 1028, 694 cm-1; 1H
NMR (CDCl3, 400 MHz): 7.95 (d, 2H, J = 7.6 Hz), 7.50 (m,
17 2H, J = 6.4 Hz), 7.49 (d, 2H, J = 6.4 Hz), 7.39-7.37 (m, 4H)
1
1
2
7.30-7.24 (m, 2H), 6.28 (d, 1H, J = 6.2 Hz), 6.04 (1H, s), 1.377
(s, 9H); 13C{1H} NMR (CDCl3, 101 MHz): δ 196.2, 155.1,
137.6, 134.6, 133.7, 129.3, 129.1, 128.7, 128.5, 128.2, 80.0, 1 1H), 7.41-7.37 (m, 4H), 7.35 – 7.24 (m, 8H), -) 6.33-6.23 (m,
21 59.9, 28.5; m/z (ESI) 334.2 [(M+Na)+, 100%]. The data 2 2H), 5.14 (d, 1H, J = 12.2 Hz), 5.04 (d, 1H, J = 12.6 Hz) ;
22 matches the reported data.
13C{1H} NMR (CDCl3, 101 MHz): 195.6, 155.6, 137.4, 137.3
136.4, 124.4, 134.4 133.8, 129.3, 129.2, 128.8, 128.6, 128.6,
128.3, 128.3, 67.1, 60.3; m/z (ESI) 368.2 [(M+Na)+, 100%].
2
2
2
2
4-Methyl-N-(2-oxo-1,2-diphenylethyl)benzenesulfonamide
14a.
This compound is known and has been previously 7 N-((1S,2R)-2-hydroxy-1,2-diphenylethyl)benzamide 16a.
27 characterised.23 2-Oxo-1, 2-diphenylethan-1-aminium chloride
This compound is known and has been previously characterised
in racemic form.14a t-Butyl (2-oxo-1, 2-diphenylethyl)
carbamate) 12a (0.100 g, 0.317 mmol, 1.0 eq) and DABCO
2
2
(1.0 g, 4.0 mmol, 1 eq) was suspended in DCM (20 mL) and
cooled to 0 ºC in an ice bath. Triethylamine (1.6 g, 2.2 mL, 16
mmol, 4 eq) was added dropwise to the reaction mixture and 1 (0.181 g, 1.61 mmol, 5.0 eq) were dissolved in acetonitrile (2
1 stirred at the same temperature for 30 minutes. During the 2 mL). Once the reaction became clear, catalyst (R,R)-2 (3.0 mg,
2 addition of triethylamine, the initially cloudy reaction mixture
became clear. To the reaction mixture, tosyl chloride (1.5 g, 8.1
mmol, 2 eq) i n DCM (5 mL) was added dropwise and the
4.8 µmol, 0.015 eq) in MeCN (1 mL) followed by formic acid
(36 μL, 0.96 mmol, 3.0 eq) were added and the resulting
reaction mixture was stirred at room temperature for 24 h. After
overnight stirring, the reaction mixture was concentrated. The
º
resulting reaction mixture was stirred at 0 C for 30 minutes
followed by overnight stirring at rt. Once the reaction was 7 residue was dissolved in DCM (50 mL) and organic layer was
7 complete (assessed by TLC), water (50 mL) and DCM (25 mL)
were added and the organic layer was separated. The aqueous
layer was extracted with DCM (2 x 30 mL). The combin1ed
washed with water (30 mL). The aqueous layer was extracted
with DCM (2 x 50 mL). The combined organic layers were
washed with brine (50 mL), dried over MgSO4 and concentrated
organic layers were washed with brine (50 mL) and dried ove1r 1 under reduced pressure to give the crude product. The crude
1 MgSO4 and concentrated under reduced pressure to give th1e 2 material was purified by trituration in diethyl ether to afford the
2 crude product. The crude material was purified by colum1n
chromatography (40% EtOAc in petroleum ether (40-60))1to
afford the product 14a as a white solid (0.57 g, 16 mmol, 39%1).
TLC: Rf ca 0.3 (7:3, Petroleum ether (40-60): EtOAc), stro1ng
product 16a as a white solid (0.060 g, 0.189 mmol, 59.7%).
TLC: Rf ca 0.4 (6:4, Hexane: EtOAc), less UV active, strong
KMnO4 & PMA reactive; [α]D25 = -33.5 (c = 0.05, CHCl3) 25%
ee; Enantiomeric excess and conversion determined by HPLC
3286, 1715, 1290, 1258, 1216, 1115, 665, 6218, 7 analysis (Chiralpak IC, 250 mm x 4.6 mm column, iPrOH:
UV active; max
-1
1
1
hexane 8:92, 1 mL/min, 210 nm, T = 25 ºC), major diastereomer
25.4 min and 27.5 min; minor diastereomer 17.0 min and 20.3
min, >99.9:<0.1 dr; HRMS (ESI): found [M+Na]+ 340.1308,
111 C H NNaO requires [M+Na]+ 340.1308 (error 0.0 ppm);
7 646, 494 cm ; H NMR (CDCl3, 400 MHz):) δ 7.80 (d, 2H, J
= 7.0 Hz), 7.53 (d, 2H, J = 7.8 Hz), 7.48 (d, 1H, J = 6.9 H1z),
11
7.37-7.35 (m, 2H), 7.18 (m, 5H), 7.05 (d, 2H, J = 7.5 Hz), 6.26
(d, 1H, J = 6.0 Hz), 6.00 (d, 1H, J = 8.0 Hz), 2.29 (s, 3H);
13C{1H} NMR (CDCl3,101 MHz): δ 194.7, 143.3 143.2, 137.51, 12
21 19
2
1

max 3342, 3036, 3032, 1633, 1523, 1303, 754, 699, 602 cm-1;
2 135.7, 134.1, 133.9, 129.4, 129.2, 129.1, 128.8, 128.6, 128.12,1
1H NMR (DMSO-d6,400 MHz): δ 8.62 (d, 1H, J = 8.9 Hz), 7.63
(d, 2H, J = 7.0 Hz), 7.50 – 7.36 (m, 7H), 7.28-7.24 (m, 4H),
7.21-7.19 (m, 2H), 5.45 (s, 1H), 5.13 (t, 1H, J = 8.6 Hz), 4.92
(d, 1H, J = 4.5 Hz); 13C{1H} NMR (DMSO-d6, 101 MHz): δ
127.1, 61.9, 21.1; m/z (ESI) 388.2 [(M+Na)+, 100%]. The da1ta1
matches the reported data.
11
11
Benzyl (2-oxo-1,2-diphenylethyl)carbamate 15a.
117 165.2, 143.7, 141.4, 134.6, 131.0, 128.4 128.1, 127.6, 127.6,
7 This compound is known however it has not been full1y1
127.1, 127.0 126.9 126.7, 74.6, 59.1; m/z (ESI) 340.2
characterized
previously.24
Benzy1l1
[(M+Na)+, 100%]. The data matches the reported data. A
racemic standard was prepared by reduction with NaBH4 via
(phenyl(benzenesulfonyl)methyl)carbamate (0.70 g, 1.8 mmo1l,2
1.0 eq) and 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium121 procedure A.
1 chloride (0.15 g, 0.55 mmol, 0.3 eq) were degassed and purged122
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The Journal of Organic Chemistry
1 t-Butyl ((1S,2R)-2-hydroxy-1,2-diphenylethyl)carbamate 2 hexane 20:80, 1 mL/min, 210 nm, T = 25 ºC), (1S,2R) 14.9 min,
1
2
3
4
5
6
7
8
2 17a.
This compound is known and has been previously
characterised.14b,14c t-Butyl
(2-oxo-1, 2-diphenylethyl)
(1R,2S) 18.0 min, other diastereomer 12.0 min and 13.6 min,
>99.9:<0.1 dr; HRMS (ESI): found [M+Na]+ 390.1136,
C21H21NNaO3S requires [M+Na]+ 390.1134 (error 0.5
ppm); max 3459, 3322, 3063, 1402, 1303, 1254, 1150, 699,
7 560, 539 cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.48 (d, 2H, J =
8.2 Hz), 7.22-7.05 (m, 8H), 6.95 – 6.93 (m, 2H), 6.82 (d, 2H, J
= 7.2 Hz), 5.30-5.28 (m, 1H), 5.00 (d, 1H, J = 4.3 Hz), 4.55 (dd,
1H, J = 7.8, 4.4 Hz), 2.33 (s, 4H); 1H NMR (DMSO-d6, 400
71 MHz): δ 8.12 (d, 1H, J = 8.0 Hz), 7.29 (d, 2H, J = 8.0 Hz), 7.18
72 (s, 3H), 7.13 (s, 2H), 7.09-6.98 (m, 7H), 5.38 (s, 1H), 4.61 (s,
carbamate) 13a (0.100 g, 0.321 mmol, 1.0 eq) and DABCO
(0.181 g, 1.61 mmol, 5.0 eq) were dissolved in 2 mL
7 acetonitrile. Once the reaction became clear solution, catalyst
(R,R)-2 (3.0 mg, 4.8 µmol, 0.015 eq) in MeCN (1 mL) followed
by formic acid (36 μL, 0.96 mmol, 0.030 eq) were added and
7
1
the resulting reaction mixture was stirred at room temperature
9
11 for 24 h. After overnight stirring, the reaction mixture was
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H), 4.28 (t, 1H, J = 7.6 Hz), 2.26 (s, 3H); 13C{1H} NMR
(DMSO-d6, 101 MHz): δ 142.7, 141.7, 138.9, 138.6, 128.9,
128.3, 127.6, 127.1 127.0, 126.7, 126.4, 126.2, 75.4, 63.4, 20.9;
m/z (ESI) 390.2 [(M+H)+, 100%]. The data matches the
77 reported data. A racemic standard was prepared by reduction
12 concentrated. The residue was dissolved in DCM (20 mL) and
7
1
1
1
1
the organic layer was washed with water (30 mL). The aqueous
7
layer was extracted with DCM (2 x 15 mL). The combined
organic layers were washed with brine (50 mL) and dried over
7
7
MgSO and concentrated under reduced pressure to give the
4
17 crude product. The crude material was purified by trituration in
7
7
with NaBH4 via procedure A.
1
1
2
diethyl ether to afford the product 17a as a white solid. (0.065
g, 0.207 mmol, 64.5%). TLC: Rf ca 0.4 (6:4, Hexane: EtOAc),
Benzyl ((1S,2R)-2-hydroxy-1,2-diphenylethyl)carbamate
less UV active, strong KMnO4 & PMA reactive; [α]D25 = -21.6
1 19a.
25
21 (c = 0.1, CHCl3) 73% ee [lit14c [α]D = -57.6 (c = 1, CHCl3)
2 This compound is known and has been previously
characterised.14c.14e
Benzyl (2-oxo-1, 2-diphenylethyl)
22 100% ee]; Enantiomeric excess and conversion determined by
2
HPLC analysis (Chiralpak IC, 250 mm x 4.6 mm column,
iPrOH: hexane 10:90, 1 mL/min, 210 nm, T = 25 ºC), (1S,2R)
6.4 min, (1R,2S) 8.2 min, other diastereomer 18.8 min and 21.9
min, >99.9:<0.1 dr; HRMS (ESI): found [M+Na]+ 336.1570,
carbamate) 15a (0.100 g, 0.289 mmol, 1.0 eq) and DABCO
(0.162 g, 1.45 mmol, 5.0 eq) were dissolved in 2 mL
acetonitrile. Once the reaction became clear, catalyst (R,R)-2
7 (2.6 mg, 4.3 µmol, 0.015 eq) in MeCN (1 mL) followed by
formic acid (33 μL, 0.87 mmol, 3.0 eq) were added and the
resulting reaction mixture was stirred at room temperature for
24 h. After overnight stirring, the reaction mixture was
2
2
2
27 C19H23NNaO3 requires [M+Na]+ 336.1570 (error 0.0 ppm); max
2
2
3378, 2978, 1680, 1645, 1519, 1250, 1170, 997, 698, 603 cm-1;
1H NMR (CDCl3, 400 MHz): δ 7.26- 7.23 (m, 6H), 7.06-7.02
(m, 4H), 5.30 (br.s., 1H), 5.04 (s, 1H) 4.96 (br.s., 1H), 2.70 1 concentrated. The residue weas dissolved in DCM (20 mL) and
1 (br.s., 1H), 1.40 (s, 9H); 1H NMR (DMSO-d6, 400 MHz): δ 2 organic layer was washed with water (30 mL). The aqueous
2 7.31-7.20 (m, 11H), 5.29 (s, 1H), 4.66 (s, 1H), 4.58 (t, 1H, J =
8.3 Hz), 1.21 (s, 9H); 13C{1H} NMR (DMSO-d6, 101 MHz): δ
154.5, 143.4, 141.5, 128.1 127.4, 127.0, 126.8, 126.5, 77.6,
75.2, 60.1, 40.1, 28.1; m/z (ESI) 336.2 [(M+Na)+, 100%]. The
layer was extracted with DCM (2 x 15 mL). The combined
organic layers were washed with brine (50 mL) and dried over
MgSO4 and concentrated under reduced pressure to give the
crude product. The crude material was purified by trituration in
data matches the reported data. A racemic standard was 7 diethyl ether to afford the product 19a as a white solid (0.050 g,
7 prepared by reduction with NaBH4 via procedure A.
0.144 mmol, 49.8 %). TLC: Rf ca 0.4 (6:4, Hexane: EtOAc),
less UV active, strong KMnO4 & PMA reactive; [α]D25 = -28.4
(c = 0.05, CHCl3) 44% ee [lit14c [α]D25 = -67.4 (c = 0.1, CHCl3)
N-((1S,2R)-2-Hydroxy-1,2-diphenylethyl)-4-
methylbenzenesulfonamide 18a.
1
1 1 100% ee]; Enantiomeric excess and conversion determined by
1 This compound is known and has been previousl1y 2 HPLC analysis (Chiralpak IG, 250 mm x 4.6 mm column,
2 characterised.14c,14d,
4-Methyl-N-(2-oxo-1,2-diphenyleth1yl)
iPrOH: hexane 10:90, 1 mL/min, 210 nm, T = 25 ºC), (1S,2R)
11.1 min, (1R,2S) 15.5 min, other diastereomer 7.1 min and 10.1
min, >99.9:<0.1 dr; HRMS (ESI): found [M+Na]+ 370.1117,
C22H21NNaO3 requires [M+Na]+ 370.1414 (error 0.8 ppm); max
benzene sulfonamide 14a (0.100 g, 0.274 mmol, 1.0 eq) a1nd
DABCO (0.153 g, 1.37 mmol, 5.0 eq) were dissolved 1in
acetonitrile (2 mL). Once the reaction became clear, catalyst
1
-1
1
(R,R)-2 (2.5 mg, 4.1 µmol, 0.015 eq) in MeCN (0.7 mL),
1 7 3346, 3061, 3034, 1687, 1535, 1254, 1009, 697 cm ; H NMR
(CDCl3,400 MHz): δ 7.33 (s, 5H), 7.26-7.23 (m, 6H), 7.04-7.03
(m, 4H), 5.56 (br.s., 1H), 5.12-5.09 (m, 4H), 2.46 (br.s., 1H);
7 followed by formic acid (30 μL, 0.82 mmol, 3.0 eq) were added
1
1
11
and the resulting reaction mixture was stirred at room
temperature for 24 h. After this time, the reaction mixture was
concentrated. The residue was dissolved in DCM (20 mL) and
1H NMR (DMSO-d6, 400 MHz): δ 7.73 (d, 1H, J = 8.7 Hz),
111 7.42 – 7.17 (m, 13H), 7.12-7.13 (m, 2H), 5.35 (s, 1H), 4.91 (d,
112 1H, J = 12.6 Hz), 4.82 (d, 1H, J = 12.6 Hz), 4.69 (s, 1H), 4.65-
1 the organic layer was washed with water (20 mL). The aqueous
11
4.61 (m, 1H, ); 13C{1H} NMR (DMSO-d6, 101 MHz): δ 155.1
143.4, 141.4, 137.1, 128.3, 128.1, 127.3, 127.6, 127.3, 127.0,
126.7, 75.0, 65.0 60.8; m/z (ESI) 370.3 [(M+H)+, 100%]. The
data matches the reported data. A racemic standard was
117 prepared by reduction with NaBH4 via procedure A.
2 layer was extracted with DCM (2 x 15 mL). The combined
organic layers were washed with brine (50 mL) and dried over
11
MgSO and concentrated under reduced pressure to give the
11
4
crude product. The crude material was purified by trituration in
diethyl ether to afford product 18a as a white solid (0.69 g, 0.19
11
7 mmol, 69 %). TLC: R ca 0.4 (5:5, Hexane: EtOAc), less UV
11
f
25
active, strong KMnO4 & PMA reactive; [α]D = -45 (c = 0.1,
11
Section on the later derivatives (Figure 3).
General procedure B for formation of -NBoc amino
121 ketones.
THF) 99% ee [lit14d [α]D = -97.0 (c = 0.1, THF) 100% ee];
25
12
Enantiomeric excess and conversion determined by HPLC
1 analysis (Chiralpak IC, 250 mm x 4.6 mm column, iPrOH:
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 27
1 Substituted tert-butyl (phenyl (benzenesulfonyl) methyl) 2 Hz), 7.39 (s, 1H), 7.30 – 7.28 (m, 2H), 7.24-7.16 (m, 4H), 6.97
1
2
3
4
5
6
7
8
2 carbamate
and
3-benzyl-5-(2-hydroxyethyl)-4-
(dd, 1H, J = 8.2, 2.3 Hz), 6.18 (d, 1H, J = 7.5 Hz), 5.93 (d, 1H,
J = 7.0 Hz), 3.72 (s, 3H), 1.36 (s, 9H) 13C{1H} NMR
(CDCl3,126 MHz): δ 196.1, 159.9, 155.1, 137.7, 135.9 129.8,
129.3, 128.4, 128.2, 121.8, 120.4, 113.2, 80.1, 60.0, 55.5, 28.5;
methylthiazolium chloride were degassed and purged with
nitrogen for 15 min. To this mixture was added DCM followed
by the corresponding aldehyde and the resulting mixture was
stirred and heated to 35 °C. Triethylamine was added in one 7 m/z (ESI) 364.3 [(M+Na)+, 100%]. The data matches the
7 portion via syringe and the reaction mixture was stirred at 35 °C
for 24 h. After the reaction was complete (assessed by TLC), it
was cooled to 25 °C and water and DCM were added and
reported data.
7
t-Butyl-(2-(2-chlorophenyl)-2-oxo-1-
1
organic layer was separated. The aqueous layer was extracted
71 phenylethyl)carbamate 13d.
9
11 with DCM. The organic layer was washed with 2% aqueous
72 This compound is novel and was prepared following the general
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12 HCl solution to remove triethylamine. The combined organic
7
procedure
B
using
2-tert-butyl
1
1
1
1
layers were washed with brine and dried over MgSO and
4
7
(phenyl(benzenesulfonyl)methyl)carbamate (3.00 g, 8.64
mmol, 1.0 eq) in DCM (60 mL), 2-chlorobenzaldehyde (1.33 g,
9.51 mmol, 1.1 eq), 3-benzyl-5-(2-hydroxyethyl)-4-
77 methylthiazolium chloride (0.700 g, 2.59 mmol, 0.3 eq) and
triethylamine (13.1g, 18 mL, 129 mmol, 15 eq) for 24 h, water
concentrated under reduced pressure to give the crude product,
7
which was purified by column chromatography to afford the -7
N-Boc-protected amino ketone.
17
7
7
1
1
2
t-Butyl-(2-(2-methoxyphenyl)-2-oxo-1-phenylethyl)
carbamate 13b.
(100 mL) to quench and was washed twice with 5% aqueous
HCl (250 mL) to generate the crude product which was purified
This compound is novel and was prepared following the 1 by column chromatography (30% EtOAc in petroleum ether
21 standard
procedure using 2-tert- 2 (40-60)) to give 13d as a yellow solid (1.88 g, 5.44 mmol,
B
22 butyl(phenyl(benzenesulfonyl)methyl)carbamate (3.00 g, 8.64
63.1%). TLC: Rf ca 0.5 (8:2, Hexane: EtOAc), strong UV
active; MP: 94-96 ºC; HRMS (ESI): found [M+Na]+ 368.1021,
C19H20ClNNaO3 requires [M+Na]+ 368.1024 (error 0.9
ppm); max 3329, 2970, 1692, 1587, 1156, 699 cm-1; 1H NMR
7 (CDCl3, 500 MHz): δ 7.37-7.29 (m, 3H), 7.26-7.20 (m, 6H),
6.12 (d, 1H, J = 7.0 Hz), 6.01 (d, 1H, J = 6.0 Hz), 1.44 (s, 9H);
13C{1H} NMR (CDCl3, 126 MHz): δ 198.3, 155.1, 136.8, 135.7,
132.2, 130.7, 129.5, 129.1, 128.6, 128.2, 126.7, 80.2, 63.4, 28.5;
1 m/z (ESI) 368.2 [(M+Na)+, 100%] 370.2 [(M+2+Na)+, 40%].
2
2
mmol, 1.0 eq) in DCM (60 mL), 2-methoxybenzaldehyde (1.29
g, 9.51 mmol, 1.1 eq), 3-benzyl-5-(2-hydroxyethyl)-4-
methylthiazolium chloride (0.700 g, 2.59 mmol, 0.3 eq) and
triethylamine (13.1 g, 18 mL, 129 mmol, 15 eq) for 48 h, water
2
2
2
27 (100 mL) to quench and was washed twice with 5% aqueous
2
2
HCl (250 mL) to generate the crude product which was purified
by column chromatography (30% EtOAc in petroleum ether
(40-60)) to give 13b as a yellow liquid (1.89 g, 5.54 mmol,
1 64.1%). TLC: Rf ca 0.3 (8:2, Hexane: EtOAc), strong UV
2 active; HRMS (ESI): found [M+Na]+ 364.1516, C20H23NNaO4
requires [M+Na]+ 364.1519 (error 0.9 ppm); max 3369, 2980,
1700, 1660, 1505, 1486, 1240, 698 cm-1; 1H NMR (CDCl3, 500
MHz): δ 7.67 (d, 1H, J = 7.5 Hz), 7.39 (t, 1H, J = 7.8 Hz), 7.26-
t-Butyl-(2-(3-chlorophenyl)-2-oxo-1-
phenylethyl)carbamate 13e.
This compound is novel and was prepared following the general
procedure
B
using
2-tert-butyl
7.17 (m, 5H) 6.91 (t, 1H, J = 7.5 Hz), 6.84 (d, 1H, J = 8.3 Hz), 7 (phenyl(benzenesulfonyl)methyl)carbamate (3.00 g, 8.64
7 6.41 (d, 1H, J = 7.6 Hz), 6.04 (d, 1H, J = 6.8 Hz), 3.83 (s, 3H),
mmol, 1.0 eq) in DCM (60 mL), 3-chlorobenzaldehyde (1.33 g,
9.51 mmol, 1.1 eq), 3-benzyl-5-(2-hydroxyethyl)-4-
methylthiazolium chloride (0.700 g, 2.59 mmol, 0.3 eq) and
1.43 (s, 9H); 13C{1H} NMR (CDCl3, 126 MHz): δ 197.7, 158.4
155.1, 134.4, 131.4, 128.9, 128.7, 128.2, 127.9, 127.6, 1201.8,
+
111.6, 79.7, 63.5, 55.5, 28.5; m/z (ESI) 364.3 [(M+Na)1, 1 triethylamine (13.1 g, 18 mL, 129 mmol, 15 eq) for 24 h, water
1 100%].
1 2 (100 mL) to quench and was washed twice with 5% aqueous
1
HCl (250 mL) to generate the crude product which was purified
by column chromatography (10% EtOAc in petroleum ether
(40-60)) to give 13e as a yellow solid (2.45 g, 7.10 mmol,
82.2%).TLC: Rf ca 0.3 (8:2, Hexane: EtOAc), strong UV active;
1 7 MP: 121-123 ºC; HRMS (ESI): found [M+Na]+ 368.1021,
2
1
1
1
t-Butyl-(2-(3-methoxyphenyl)-2-oxo-1-phenylethyl)
carbamate 13c.
This compound is known and has been previously
characterised.13a This compound was prepared following the
2-tert-bu1tyl
C19H20ClNNaO3 requires [M+Na]+ 368.1024 (error 0.8
7 standard
procedure
B
using
1
(phenyl(benzenesulfonyl)methyl)carbamate (1.00 g, 2.188
ppm); max 3391,1680, 1492, 1243, 1090, 695 cm-1; H NMR
mmol, 1.0 eq) in DCM (20 mL), 3-methoxybenzaldehyd1e1
(CDCl3, 500 MHz): δ 7.94 (s, 1H), 7.80 (d, 1H, J = 7.8 Hz), 7.47
(0.431 g, 3.17 mmol, 1.1 eq), 3-benzyl-5-(2-hydroxyethyl)-41- 11 (d, 1H, J = 8.0 Hz), 7.35-7.30 (m, 5H), 7.28 -7.25 (m, 1H), 6.21
1 methylthiazolium chloride (0.233 g, 0.864 mmol, 0.3 eq) and112 (d, 1H, J = 7.5 Hz), 5.92 (d, 1H, J = 7.1 Hz), 1.43 (s, 9H);
2 triethylamine (4.37 g, 6 mL, 43.2 mmol, 15 eq) for 24 h, wate1r1
(50 mL) to quench and was washed twice with 5% aqueous HC1l1
(80 mL) to generate the crude product which was purified b1y1
column chromatography (10% EtOAc in petroleum ether (401-1
60)) to give 13c as a yellow solid (0.645 g, 1.89 mmol, 65.6%)1. 17
7 TLC: Rf ca 0.3 (8:2, Hexane: EtOAc), strong UV active; MP1:1
102-104 ºC; HRMS (ESI): found [M+Na]+ 364.15212,1
C20H23NNaO4 requires [M+Na]+ 364.1519 (error -01.82
13C{1H} NMR (CDCl3, 126 MHz): δ 195.2, 155.1, 136.9, 136.3,
135.2, 133.6, 130.1 129.5, 129.1, 128.7, 128.2, 127.2, 80.2,
60.1, 28.5; m/z (ESI) 368.2 [(M+Na)+, 100%], 370.2
[(M+2+Na)+, 30%].
t-Butyl-(2-(4-chlorophenyl)-2-oxo-1-
phenylethyl)carbamate 13f.
This compound is novel and was prepared following the general
121 procedure
ppm); max 3395, 2973, 1703, 1674, 1581, 1493, 1287, 1160,
B
using
2-tert-butyl
-1
1
122 (phenyl(benzenesulfonyl)methyl)carbamate (3.00 g, 8.64
1 702 cm ; H NMR (CDCl3, 500 MHz): δ 7.47 (d, 1H, J = 7.6
8
ACS Paragon Plus Environment

Page 9 of 27
The Journal of Organic Chemistry
1 mmol, 1.0 eq) in DCM (60 mL), 4-chlorobenzaldehyde (1.33 g, 2 364.1518, C20H23NNaO4 requires [M+Na]+ 364.1519 (error 0.3
ppm); max 3375, 1702, 1675, 1510, 1248, 1159, 688, 585 cm-1;
1H NMR (CDCl3, 500 MHz): δ 7.95-7.91 (m, 2H), 7.49-7.32
(m, 4H), 7.29-7.26 (m, 1H), 6.82 (d, 2H, J = 8.7 Hz), 6.22 (d,
1H, J = 7.5 Hz), 5.98-5.95 (m, 1H), 3.74 (s, 3H), 1.43 (s, 9H);
13C{1H} NMR (CDCl3, 126 MHz): δ 196.3, 159.6, 155.1, 134.7,
134.0, 133.6, 129.7, 129.5, 129.2, 129.2, 129.1, 128.8, 128.7,
127.9, 114.6, 79.9, 59.3, 55.3, 28.5; m/z (ESI) 364.2 [(M+Na)+,
100%].
1
2
3
4
5
6
7
8
2 9.51 mmol, 1.1 eq), 3-benzyl-5-(2-hydroxyethyl)-4-
methylthiazolium chloride (0.700 g, 2.59 mmol, 0.3 eq) and
triethylamine (13.1 g, 18 mL, 129 mmol, 15 eq) for 24 h, water
(100 mL) to quench and was washed twice with 5% aqueous
HCl (250 mL) to generate the crude product which was purified
7 by column chromatography (20% EtOAc in petroleum ether
(40-60)) to give 13f as a yellow solid (2.20 g, 6.38 mmol,
73.8%). TLC: R ca 0.3 (9:1, petroleum ether (40-60): EtOAc),
7
7
f
1
strong UV active; MP: 115-117 ºC; HRMS (ESI): found
71
9
11 [M+Na]+ 368.1021, C19H20ClNNaO3 requires [M+Na]+
12 368.1024 (error 0.8 ppm); max 3393, 2977, 1702, 1675, 1493,7
72 t-Butyl-(1-(2-chlorophenyl)-2-oxo-2-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
phenylethyl)carbamate 13i.
This compound is novel and was prepared following the general
1
1242, 1092, 699, 534 cm-1; 1H NMR (CDCl3, 500 MHz): δ 7.897
(d, 2H, J = 8.5 Hz), 7.37- 7.24 (m, 7H), 6.21 (d, 1H, J = 7.5 Hz),7
5.94 (d, 1H, J = 7.1 Hz), 1.43 (s, 9H); 13C{1H} NMR (CDCl3,7
1
1
1
procedure
B
using
tert-butyl
((2-
chlorophenyl)(benzenesulfonyl)methyl)carbamate (3.00 g, 7.87
126 MHz): δ 195.1, 155.1, 140.2, 137.3, 133.0, 130.5, 129.4, 77 mmol, 1.0 eq) in DCM (60 mL), benzaldehyde (1.25 g, 11.8
17 129.2, 128.6, 128.2, 80.2, 60.0, 28.5; m/z (ESI) 368.27
mmol,
1.5
eq),
3-benzyl-5-(2-hydroxyethyl)-4-
1
1
2
[(M+Na)+, 100%], 370.2 [(M+2+Na)+, 40%].
7
methylthiazolium chloride (0.637 g, 2.36 mmol, 0.3 eq) and
triethylamine (11.9 g, 16 mL, 118 mmol, 15 eq), water (100
1 mL) to quench and was washed twice with 5% aqueous HCl
2 (250 mL) to generate the crude product which was purified by
column chromatography (20% EtOAc in petroleum ether (40-
60)) to give 13i as a white solid (0.897 g, 2.60 mmol, 31.4%).
TLC: Rf ca 0.3 (8:2, Hexane: EtOAc), strong UV active; MP:
114-117 ºC; HRMS (ESI): found [M+Na]+ 368.1020,
t-Butyl-(1-(2-methoxyphenyl)-2-oxo-2-
21 phenylethyl)carbamate 13g.
22 This compound is novel and was prepared following the general
2
2
2
2
procedure
B
using
tert-butyl
((2-
methoxyphenyl)(benzenesulfonyl)methyl)carbamate (3.00 g,
7.95 mmol, 1.0 eq) in DCM (60 mL), benzaldehyde (1.26 g,
11.9 mmol, 1.5 eq), 3-benzyl-5-(2-hydroxyethyl)-4- 7 C19H20ClNNaO3 requires [M+Na]+ 368.1024 (error 1.0
27 methylthiazolium chloride (0.644 g, 2.38 mmol, 0.3 eq) and
ppm); max 3370, 2971, 1712, 1680, 1520, 1244, 1158, 750, 590
cm-1; 1H NMR (CDCl3, 500 MHz): δ 7.98 (d, 2H, J = 7.6 Hz),
7.51 (t, 1H , J = 7.3 Hz), 7.41-7.37 (m, 3H), 7.27-7.17 (m, 3H),
1 6.64 (d, 1H, J = 7.6 Hz), 5.82 (d, 1H, J = 6.7 Hz), 1.44 (s, 9H);
2
2
triethylamine (12.0 g, 17 mL, 119 mmol, 15 eq) for 24 h, water
(100 mL) to quench and was washed twice with 5% aqueous
HCl (250 mL) to generate the crude product which was purified
1 by column chromatography (20% EtOAc in petroleum ether
2 (40-60)) to give 13g as a yellow solid (2.10 g, 6.15 mmol,
77.5%). TLC: Rf ca 0.3 (8:2, Hexane: EtOAc), strong UV
active; MP: 126-129 ºC; HRMS (ESI): found [M+Na]+
364.1520, C20H23NNaO4 requires [M+Na]+ 364.1519 (error -0.2
2
13C{1H} NMR (CDCl3, 126 MHz): δ 196.2, 155.0, 135.3,
134.7, 133.9, 133.8, 130.6, 129.8, 129.5, 128.9, 128.8, 127.6,
80.2, 57.2, 28.5; m/z (ESI) 368.2 [(M+Na)+,100%], 370.2
[(M+2+Na)+, 40%].
ppm); max 3375, 2983, 1685, 1493, 1240, 1161, 690, 532 cm-1; 7 t-Butyl-(1-(4-chlorophenyl)-2-oxo-2-
7
1H NMR (CDCl3, 500 MHz): δ 7.96 (d, 2H, J = 7.7 Hz), 7.46
(t, 1H, J = 7.3 Hz), 7.34 (t, 2H, J = 7.6 Hz), 7.29 (d, 1H, J =
7.4 Hz), 7.21 (t, 1H, J = 7.8 Hz), 6.89 (t, 1H, J = 7.5 Hz), 6.181
phenylethyl)carbamate 13j.
This compound is novel and was prepared following the general
procedure
B
using
tert-butyl
((4-
(d, 1H, J = 8.2 Hz), 6.50 (d, 1H, J = 8.1 Hz), 5.86 (d, 1H, J1= 1 chlorophenyl)(benzenesulfonyl)methyl)carbamate (3.00 g, 7.87
1 7.5 Hz), 3.83 (s, 3H), 1.44 (s, 9H); 13C{1H} NMR (CDCl3, 1216 2 mmol, 1.0 eq) in DCM (60 mL), benzaldehyde (1.25 g, 11.8
2 MHz): δ 196.9 156.7, 155.3, 135.1, 133.3, 129.8, 129.5, 1281.8,
128.5, 126.2, 121.2, 111.6, 79.8, 55.7, 55.3, 28.5; m/z (ES1I)
mmol,
1.5
eq),
3-benzyl-5-(2-hydroxyethyl)-4-
methylthiazolium chloride (0.637 g, 2.36 mmol, 0.3 eq) and
triethylamine (11.9 g, 16 mL, 118 mmol, 15 eq) for 24 h, water
(100 mL) to quench and was washed twice with 5% aqueous
364.2 [(M+Na)+, 100%].
1
1
t-Butyl-(1-(4-methoxyphenyl)-2-oxo-2-
1 7 HCl (250 mL) to generate the crude product which was purified
7 phenylethyl)carbamate 13h.
1
by column chromatography (10% EtOAc in petroleum ether
(40-60)) to give 13j as a white solid (1.50 g, 4.34 mmol, 55.2%).
TLC: Rf ca 0.4 (8:2, Hexane: EtOAc), strong UV active; MP:
This compound is known however it has not been fu1lly
characterized previously.25 This compound was prepare1d1
following the general procedure B using tert-butyl ((41- 11 148-151 ºC; HRMS (ESI): found [M+Na]+ 368.1028,
1 methoxyphenyl)(benzenesulfonyl)methyl)carbamate (2.55 g1, 12 C19H20ClNNaO3 requires [M+Na]+ 368.1024 (error -1.1
2 6.63 mmol, 1.0 eq) in DCM (60 mL), benzaldehyde (1.05 g,
11
ppm); max 3373, 2981, 1703, 1673, 1520, 1491, 1239, 1158,
719, 580 cm-1; 1H NMR (CDCl3, 600 MHz): δ 7.93 (d, 2H, J =
7.7 Hz), 7.52 (t, 1H, J = 7.4 Hz), 7.42-7.39 (m, 2H), 7.31-7.26
(m, 4H), 6.24 (d, 1H, J = 7.2 Hz), 6.09 (d, 1H, J = 6.8 Hz), 1.43
117 (s, 9H); 13C{1H} NMR (CDCl3, 151 MHz): δ 195.8, 155.0,
9.49 mmol, 1.5 eq), 3-benzyl-5-(2-hydroxyethyl)-4-
11
methylthiazolium chloride (0.537 g, 1.98 mmol, 0.3 eq) and
11
triethylamine (10.0 g, 14 mL, 99.5 mmol, 15 eq) for 24 h, water
11
(100 mL) to quench and was washed twice with 5% aqueous
7 HCl (250 mL) to generate the crude product which was purified
11
136.3, 134.4, 134.0, 129.6, 129.4, 129.1, 128.9, 80.2, 59.1, 28.5;
m/z (ESI) 368.2 [(M+Na)+, 80%], 370.2 [(M+2+Na)+, 30%].
by column chromatography (20% EtOAc in petroleum ether
11
(40-60)) to give 13h as a yellow solid (1.60 g, 4.68 mmol,
12
70.7%). TLC: R ca 0.2 (8:2, Hexane: EtOAc), strong UV
121 tert-Butyl-(2-(4-chlorophenyl)-1-(4-methoxyphenyl)-2-
122 oxoethyl)carbamate 13k.
f
1 active; MP: 126-129 ºC; HRMS (ESI): found [M+Na]+
9
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1 This compound is novel and was prepared following the general 2 under reduced pressure to afford the product as a dark brown
1
2
3
4
5
6
7
8
2 procedure
B
using
tert-butyl
((4-
viscous liquid (4.50 g, 21.2 mmol, 96.0%) which was used in
the next step without further purification. TLC: Rf ca 0.4 (9:1,
Hexane: EtOAc), strong UV active; max 1682, 1447, 1235, 948,
704, 683 cm-1; 1H NMR (CDCl3, 400 MHz): δ 8.03 (d, 2H, J =
7 8.6 Hz), 7.60 (t, 1H, J = 7.4 Hz), 7.51-7.47 (m, 2H), 5.30 (q, 1H,
J = 6.6 Hz), 1.91 (d, 3H, J = 6.6 Hz); 13C{1H} NMR (CDCl3,
101 MHz): δ 193.5, 134.2, 133.8, 129.1 128.9, 41.6, 20.3. The
data matches the reported data.
methoxyphenyl)(benzenesulfonyl)methyl)carbamate (3.00 g,
7.95 mmol, 1.0 eq) in DCM (60 mL), 4-chlorobenzaldehyde
(1.67 g, 11.9 mmol, 1.5 eq), 3-benzyl-5-(2-hydroxyethyl)-4-
methylthiazolium chloride (0.644 g, 2.38 mmol, 0.3 eq) and
7 triethylamine (12.0 g, 17 mL, 119 mmol, 15 eq) for 48 h, water
(100 mL) to quench and was washed twice with 5% aqueous
HCl (250 mL) to generate the crude product which was purified
7
1
by column chromatography (15% EtOAc in petroleum ether
71
9
11 (40-60)) to give 13k as a yellow solid (1.77 g, 4.98 mmol,
72 2-(1-Oxo-1-phenylpropan-2-yl) isoindoline-1,3-dione (route
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12 62.7%). TLC: R ca 0.4 (8:2, Hexane: EtOAc), strong UV
7
to 24 and 25).
f
This compound has been reported and fully characterised.27
This compound was prepared following the same procedure as
used for 2-(2-oxo-1,2-diphenylethyl)isoindoline-1,3-dione
1
1
1
1
active; MP: 134-137 ºC; HRMS (ESI): found [M+Na]+
7
398.1132, C H ClNNaO requires [M+Na]+ 398.1130 (error -
7
20 22
4
0.6 ppm); max 3380, 2977, 1702, 1676, 1509, 1239, 1159, 824,7
532 cm-1; H NMR (CDCl3, 600 MHz): δ 7.88 (d, 2H, J = 8.4 77 using 2-bromo-1-phenylpropan-1-one (4.50 g, 21.2 mmol, 1.0
1
17 Hz), 7.36 (d, 2H, J = 8.4 Hz), 7.25 (d, 2H, J = 11.0 Hz), 6.83 (d,7
eq) in DMF (60 mL) and potassium phthalimide (5.60 g, 31.8
mmol, 1.5 eq) and ice cold water (1 L) to quench and was
washed twice with ice cold water (300 mL) to give the product
1
1
2
2H, J = 8.6 Hz), 6.15 (d, 1H, J = 7.4 Hz), 5.90 (d, 1H, J = 7.27
Hz), 3.75 (s, 3H), 1.43 (s, 9H); 13C{1H} NMR (CDCl3, 151
MHz): δ 195.2, 159.8, 155.1, 140.1, 133.1, 130.5, 129.5, 129.3, 1 as a white solid (5.10 g, 18.3 mmol, 86.2%). TLC: Rf ca 0.3
21 129.1, 114.8, 80.1, 59.4, 55.4, 28.5; m/z (ESI) 398.3 [(M+Na)+,
2 (7:3, Hexane: EtOAc), strong UV active; HRMS (ESI): found
[M+Na]+ 302.0788, C17H13NNaO3 requires [M+Na]+ 302.0788
(error -0.1 ppm); max 1706, 1693, 1384, 1231, 1139, 971, 712,
22 100%], 400.2 [(M+2+Na)+, 40%].
2
1
692 cm-1; H NMR (CDCl3, 400 MHz): δ 7.83-7.79 (m, 4H),
2
2
2
t-Butyl-(2-(furan-2-yl)-2-oxo-1-phenylethyl)carbamate 13l.
This compound is known and has been previously
characterised.13a This compound was prepared following the
7.72-7.68 (m, 2H), 7.51-7.47 (m, 1H), 7.41-7.38 (m, 2H), 5.66
7 (q, 1H, J = 7.1 Hz), 1.73 (d, 3H, J = 7.1 Hz); 13C{1H} NMR
(CDCl3, 101 MHz): δ 196.2, 167.6, 135.4, 134.3, 133.2, 131.9,
128.8 128.1, 123.6, 51.1, 15.0; m/z (ESI) 302.2 [(M+Na)+,
100%]. The data matches the reported data.
27 general
procedure
B
using
2-tert-butyl
2
2
(phenyl(benzenesulfonyl)methyl)carbamate (3.00 g, 8.64
mmol, 1.0 eq) in DCM (60 mL), furan-2-carbaldehyde (0.931
g, 9.51 mmol, 1.1 eq), 3-benzyl-5-(2-hydroxyethyl)-4-
1 methylthiazolium chloride (0.700 g, 2.59 mmol, 0.3 eq) and
2 triethylamine (13.1 g, 18 mL, 129 mmol, 15 eq) for 48 h, water
(100 mL) to quench and was washed twice with 5% aqueous
HCl (250 mL) to generate the crude product which was purified
by column chromatography (40% EtOAc in petroleum ether
(40-60)) to give 13l as a yellow solid (2.20 g, 7.31 mmol,
7 84.6%). TLC: Rf ca 0.4 (7:3, Hexane: EtOAc), strong UV
active; HRMS (ESI): found [M+Na]+ 324.1209, C17H19NNaO4
1
2 1-Oxo-1-phenylpropan-2-aminium hydrochloride (route to
24 and 25).
This compound has been reported and fully characterised.28
This compound was prepared following the same procedure as
used for 2-oxo-1,2-diphenylethan-1-aminium chloride using 2-
7 (1-oxo-1-phenylpropan-2-yl) isoindoline-1,3-dione (5.10 g,
18.3 mmol, 1.0 eq) in 6N HCl (60 mL) and glacial acetic acid
(60 mL) to generate the crude product which was stirred in
acetone (3 x 30 mL) to give the product as a white solid (2.10
requires [M+Na]+ 324.1206 (error -0.9 ppm); max 3400, 2976,
1
1
1706, 1663, 1490, 1465, 1392, 1161, 762, 528 cm-1; H NMR
+
1 1 g, 11.3 mmol, 61.7%). HRMS (ESI): found [M+Na] 172.0732,
+
1 (CDCl , 500 MHz): δ 7.55 (s, 1H), 7.41 (d, 2H, J = 7.5 Hz),
1 2 C9H11NNaO requires [M+Na] 172.0733 (error 0.3 ppm) This
3
2 7.33-7.30 (m, 2H), 7.28 – 7.23 (m, 2H), 6.48 (s, 1H), 6.06 1(d,
corresponds to the RNH2Na ion; max 1688, 1597, 1499, 1451,
1242, 1217, 1104, 973, 698 cm-1; 1H NMR (D2O, 400 MHz): δ
8.03 (d, 2H, J = 7.3 Hz), 7.79 (t, 1H, J = 7.5 Hz), 7.65-7.61 (m,
2H), 5.21 (q, 1H, J = 7.3 Hz), 1.61 (d, 3H, J = 7.3 Hz); 13C{1H}
1 7 NMR (D2O, 101 MHz): δ 198.1, 135.2, 132.3, 129.2, 128.8,
1H, J = 7.5 Hz), 5.92 (d, 1H, J = 6.4 Hz), 1.42 (s, 9H); 13C{1H}
1
NMR (CDCl3, 126 MHz): δ 184.9, 155.0, 150.8, 147.2 137.2
1
1
129.1, 128.5, 128.1, 119.4, 113.2, 112.7, 80.1, 60.0, 28.4; m/z
(ESI) 324.2 [(M+Na)+, 100%]. The data matches the reported
51.9, 16.6; m/z (ESI) 150.1 [(M+1)+, 100%], 172.2 [(M+Na)+,
35%]. The data matches the reported data.
7 data.
1
1
2-Bromo-1-phenylpropan-1-one (route to 24 and 25).
11
This compound has been reported and fully characterised.26
111 t-Butyl-(1-oxo-1-phenylpropan-2-yl)carbamate (precursor
112 of 24).
1 To a stirred ice cold solution of propiophenone (3.00 g, 22.3
2 mmol, 1.0 eq) in DCM (50 mL) was added bromine (1.1 mL,
11
This compound has been reported and fully characterised.29
This compound was prepared following the same procedure as
used for t-butyl-(2-oxo-1,2-diphenylethyl)carbamate) 13a
using 1-oxo-1-phenylpropan-2-aminium hydrochloride (0.700
117 g, 3.78 mmol, 1.0 eq) in DCM (20 mL), triethylamine (1.53 g,
22 mmol, 1.0 eq) dropwise under N atmosphere and stirred 1at1
2
0o C for 1h and then at room temperature for 30 minutes (colour
11
changed from dark red to orange. The completion of the
11
reaction was confirmed by 1H NMR. After the completion, the
7 reaction was quenched with saturated NaHCO3 solution (200
11
2.1mL, 15.1 mmol, 4 eq) and boc anhydride (1.65g, 7.56 mmol,
1.5 eq), water (100 mL) to quench and DCM (2 x 30 mL) for
extraction to generate the crude product which was purified by
121 column chromatography (30% EtOAc in petroleum ether (40-
122 60)) to give the prodcut as a white solid (0.55 g, 2.20 mmol,
mL) and DCM (50 mL) were added and organic layer was
11
separated. The aqueous layer was extracted with DCM (2 x 30
12
mL). The combined organic layers were washed with brine (80
1 mL) and dried over MgSO4. The organic layer was concentrated
10
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The Journal of Organic Chemistry
1 58.4%). TLC: Rf ca 0.3 (8:2, Hexane: EtOAc), less UV active, 1 (ESI): found [M+ H]+ 242.1174, C15H16NO2 requires [M+H]+
2 strong KMnO4; MP: 72-74 ºC; HRMS (ESI): found [M+Na]+
272.1257, C14H19NNaO3 requires [M+Na]+ 272.1257 (error 0.0
ppm); max 3333, 2973, 1708, 1679, 1523, 1234, 1158, 682 cm-
1; 1H NMR (CDCl3, 500 MHz): δ 7.98 (d, 2H, J = 7.7 Hz), 7.60
(t, 1H, J = 7.4 Hz), 7.49 (t, 2H, J = 7.7 Hz), 5.58 (d, 1H, J = 6.5
1
2
3
4
5
6
7
8
2 242.1176 (error 0.7 ppm); max 1656, 1596, 1532, 1186, 762,
1
700 cm-1; H NMR (D2O, 500 MHz): δ 7.82 (dd, 1H, J = 7.9,
1.5 Hz), 7.53-7.49 (m, 1H), 7.40 (s, 5H), 7.01 (t, 1H, J = 7.6
Hz), 6.96 (d, 1H, J = 8.5 Hz), 6.26 (s, 1H), 3.81 (s, 3H); 13C{1H}
NMR (D2O, 126 MHz): δ 195.2, 158.7, 136.5, 131.2, 131.0,
7 Hz), 5.33 – 5.27 (m, 1H), 1.46 (s, 9H), 1.40 (d, 3H, J = 7.1 Hz); 7 130.1, 129.4, 128.9, 122.5, 120.9, 112.4, 62.6, 55.3; m/z (ESI)
13C{1H} NMR (CDCl3, 126 MHz): δ 199.6, 155.3, 134.3,
242.2 [(M+H)+, 10%], 483.4 [(2M+H]+, 100%].
133.8. 128.9, 128.8, 79.8, 51.2, 28.5, 20.0; m/z (ESI) 272.2
1
[(M+Na)+, 100%]. The data matches the reported data.
7
2-(3-Methoxyphenyl)-2-oxo-1-phenylethan-1-aminium
71 trifluoroacetate.
9
11
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
72 This compound is novel and was prepared following the
7
7
12 t-Butyl-(2-oxo-1-phenylpropyl)carbamate (precursor to
general procedure C using tert-butyl (2-(3-methoxyphenyl)-2-
oxo-1-phenylethyl)carbamate (0.341 g, 1.00 mmol, 1.0 eq.) and
trifluoroacetic acid (1.14 g, 10 mmol, 10 eq) in DCM (5 mL)
and the crude product was purified by trituration using n-
1
26).
1
1
1
This compound is known and has been
previously7
characterised.13abThis compound was prepared following the
7
general
procedure
B
using
2-tert-butyl 77 pentane : EtOAc (8:2 v/v, 30 mL) to give the product as a brown
17 (phenyl(benzenesulfonyl)methyl)carbamate (2.00 g,
5.767
solid (0.44 g, 1.23 mmol, quantitative yield, excess TFA
present). TLC: Rf 0.0 (7:3, Hexane: EtOAc), strong UV active,
TLC checked to confirm the consumption of starting material;
1 MP: 90-101 ºC; HRMS (ESI): found [M+H]+ 242.1172,
2 C15H16NO2 requires [M+H]+ 242.1176 (error 1.5 ppm); max
mmol, 1.0 eq) in DCM (40 mL), acetaldehyde (0.633 g, 14.47
1
1
2
mmol,
2.5
eq),
3-benzyl-5-(2-hydroxyethyl)-4-
methylthiazolium chloride (0.46 g, 1.78 mmol, 0.3 eq) and
21 triethylamine (5.71 g, 12 mL, 86.4 mmol, 15 eq) for 48 h, water
22 (150 mL) to quench and was washed twice with 5% aqueous
1
1665, 1566, 1496, 1165, 1144, 781, 701 cm-1; H NMR (D2O,
2
HCl (200 mL) to generate the crude product which was purified
by column chromatography (20% EtOAc in petroleum ether
(40-60)) to give the product as a yellow solid (0.800 g, 3.21
mmol, 55.7%).TLC: Rf ca 0.3 (8:2, Hexane: EtOAc), less UV
500 MHz)): δ 7.55 (d, 1H, J = 7.8 Hz), 7.48-7.45 (m, 6H), 7.36
(t, 1H, J = 8.0 Hz), 7.19-7.17 (m, 1H), 6.24 (s, 1H), 3.78 (s, 3H);
13C{1H} NMR (D2O, 126 MHz): δ 194.1, 159.2, 133.8, 131.3,
7 130.4, 130.3, 130.0 128.6 122.1, 121.0, 113.6, 59.8 55.5; m/z
(ESI) 242.2 [(M+H)+, 10%], 483.4 [(2M+H)+, 100%].
2
2
2
27 active, strong KMnO4 active; HRMS (ESI): found [M+Na]+
2
2
272.1257, C14H19NNaO3 requires [M+Na]+ 272.1257 (error 0.0
ppm); max 3399, 29601693, 1493, 1309, 1154, 702 cm-1; H
1
2-(2-Chlorophenyl)-2-oxo-1-phenylethan-1-aminium
1 trifluoroacetate.
NMR (CDCl3, 500 MHz): δ 7.38 – 7.28 (m, 5H), 5.90 (s, 1H),
1 5.29 (d, 1H, J = 5.8 Hz), 2.08 (s, 3H), 1.40 (s, 9H); 13C{1H}
2 NMR (126 MHz, CDCl3): δ 203.7, 155.0 137.0, 129.3, 128.6,
127.9, 79.9, 64.8, 28.4, 27.1; m/z (ESI) 272.2 [(M+Na)+,
100%]. The data matches the reported data.
2 This compound is novel and was prepared following the general
procedure C using tert-butyl (2-(2-chlorophenyl)-2-oxo-1-
phenylethyl)carbamate (1.00 g, 2.89 mmol, 1.0 eq) and
trifluoroacetic acid (3.29 g, 28.9 mmol, 10 eq) in DCM (20 mL)
and the crude product was purified by trituration using n-
7 pentane : EtOAc (8:2 v/v, 60 mL) to give the product as a brown
solid (1.20g, 3.35 mmol, quantitative yield , excess TFA
present). TLC: Rf 0.0 (7:3, Hexane: EtOAc), strong UV active,
TLC checked to confirm the consumption of starting material;
Synthesis of amine salts for N-Ts protection.
7 General procedure C for N-Boc deprotection.
N-Boc intermediate was dissolved in dichloromethane and
º
cooled to 0 C using an ice bath. To this stirred solution was
1
added trifluoroacetic acid dropwise under
a
nitrogen
1 atmosphere and the resulting reaction mixture was stirred at10 1 MP: 161-163 ºC; HRMS (ESI): found [M+H]+ 246.0678,
1 2 C14H13ClNO requires [M+H]+ 246.0680 (error 0.9 ppm); max
2
ºC for 30 minutes followed by stirring at rt for 6h. Once the
1
1
1709, 1649, 1512, 1187, 1141, 765, 696 cm-1; 1H NMR
(CD3OD, 500 MHz): δ 7.67-7.65 (m, 1H), 7.47-7.39 (m, 7H),
7.37-7.33 (m, 1H), 6.12 (s, 1H); 13C{1H} NMR (CD3OD, 126
MHz): δ 195.4, 135.7, 134.3, 133.0, 132.2, 132.0, 131.4, 131.1,
reaction was complete (assessed by TLC), the reaction mixture
was concentrated under reduced pressure to give the crude
1
amine trifluoroacaetic acid salt. The crude material was purified
1
by trituration using n-pentane: ethyl acetate (8:2) to afford the
7 corresponding amines as a trifluoroacetate salt. HRMS (ES1I) 7 130.8, 130.0, 128.3, 63.0; m/z (ESI) 246.1 [(M+H)+, 10%],
1
1
491.3 [(2M+H)+, 100%].
correspond to the RNH3 component.
11
2-(3-Chlorophenyl)-2-oxo-1-phenylethan-1-aminium
2-(2-Methoxyphenyl)-2-oxo-1-phenylethan-1-aminium
111 trifluoroacetate.
1 trifluoroacetate.
112 This compound is novel and was prepared following the general
procedure C using tert-butyl (2-(3-chlorophenyl)-2-oxo-1-
phenylethyl)carbamate (1.00 g, 2.89 mmol, 1.0 eq) and
trifluoroacetic acid (3.29 g, 28.9 mmol, 10 eq) in DCM (20 mL)
and the crude product was purified by trituration using n-
2 This compound is novel and was prepared following gener1al1
procedure C using tert-butyl (2-(2-methoxyphenyl)-2-oxo-1-
11
phenylethyl)carbamate (1.30 g, 3.81 mmol, 1.0 eq) and
trifluoroacetic acid (4.35 g, 38.1 mmol, 10 eq) in DCM (30 mL)
11
11
and generated crude product was purified by trituration using n1- 17 pentane : EtOAc (8:2 v/v, 60 mL) to give the product as a brown
7 pentane : EtOAc (8:2 v/v, 60 mL) to give the product as a brown
11
solid (1.20 g, 3.35 mmol in quantitative yield, excess TFA
present). TLC: Rf 0.0 (7:3, Hexane: EtOAc), strong UV active,
TLC checked to confirm the consumption of starting material;
121 MP: 102-105 ºC; HRMS (ESI): found [M+H]+ 246.0681,
solid (1.05 g, 2.95 mmol, 77.8%). TLC: Rf 0.0 (8:2, Hexan1e:1
EtOAc), strong UV active, TLC checked to confirm the
consumption of starting material; MP: 158-160 ºC; HRM1S2
11
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Page 12 of 27
1 C14H13ClNO requires [M+H]+ 246.0680 (error -0.2 ppm); max
2 1682, 1531, 1431, 1180, 1135, 799, 699 cm-1; 1H NMR
(CD3OD, 500 MHz): δ 7.98 (s, 1H), 7.90 (d, 1H, J = 7.9 Hz),
7.61 (d, 1H, J = 8.1 Hz), 7.52 – 7.43 (m, 6H), 6.22 (s, 1H);
13C{1H} NMR (CD3OD, 126 MHz): δ 193.2, 136.2, 136.2,
2 strong UV active, TLC checked to confirm the consumption of
starting material; MP: 139-142 ºC; HRMS (ESI): found [M+H]+
242.1172, C15H16NO2 requires [M+H]+ 242.1176 (error 1.4
1
2
3
4
5
6
7
8
1
ppm); max 1650, 1595, 1515, 1183, 1137, 723, 687 cm-1; H
NMR (CD3OD, 600 MHz): δ 7.98 (d, 2H, J = 7.6 Hz), 7.58 (t,
135.4, 133.1 131.7, 131.5, 131.1, 130.0, 129.9, 128.7, 60.8; m/z 7 1H, J = 7.4 Hz), 7.46 – 7.41 (m, 4H), 6.97 (d, 2H, J = 8.7 Hz),
7 (ESI) 246.2 [(M+H)+, 10%], 491.3 [(2M+H)+, 100%].
6.14 (s, 1H), 3.76 (s, 3H); 13C{1H} NMR (CD3OD, 151 MHz):
δ 194.3, 162.5, 135.5, 134.6, 131.4, 130.2, 130.0 125.2, 116.2,
60.2, 55.9; m/z (ESI) 242.2 [(M+H)+, 10%], 483.4 [(2M+H)+,
2-(4-Chlorophenyl)-2-oxo-1-phenylethan-1-aminium
trifluoroacetate.
7
1
71 100%].
9
11 This compound is known however it has not been fully
72
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12 characterized previously.30 This compound was prepared
7
1-(2-Chlorophenyl)-2-oxo-2-phenylethan-1-
aminiumtrifluoroacetate.
1
1
1
1
following the general procedure C using tert-butyl (2-(4-
7
chlorophenyl)-2-oxo-1-phenylethyl)carbamate (1.00 g, 2.89
7
This compound is novel and was prepared following the general
procedure C using tert-butyl (1-(2-chlorophenyl)-2-oxo-2-
mmol, 1.0 eq) and trifluoroacetic acid (3.29 g, 28.9 mmol, 10
7
eq) in DCM (20 mL) and generated crude product was purified
77 phenylethyl)carbamate (0.500 g, 1.45 mmol, 1.0 eq) and
17 by trituration using n-pentane : EtOAc (8:2 v/v, 60 mL) to give
7
trifluoroacetic acid (1.65 g, 14.5 mmol, 10 eq) in DCM (10 mL)
and generated crude product was purified by trituration using n-
pentane : EtOAc (8:2 v/v, 80 mL) to give the product as a brown
1
1
2
the product as a brown solid (1.22 g, 3.40 mmol, quantitative
7
yield, excess TFA present). TLC: Rf 0.0 (7:3, Hexane: EtOAc),
strong UV active, TLC checked to confirm the consumption of 1 solid (0.418 g, 1.16 mmol, 80%). TLC: Rf 0.0 (7:3, Hexane:
21 starting material; MP: 77-80 ºC; HRMS (ESI): found [M+H]+ 2 EtOAc), strong UV active, TLC checked to confirm the
22 246.0680, C14H13ClNO requires [M+H]+ 246.0680 (error 0.1
consumption of starting material; MP: 130-133 ºC; HRMS
(ESI): found [M+H]+ 246.0677, C14H13ClNO requires [M+H]+
246.0680 (error 1.5 ppm); max 1664, 1533, 1176, 1138, 797,
719, cm-1; 1H NMR (CD3OD, 500 MHz): δ 7.92 (d, 2H, J = 7.9
1
2
ppm); max 1676, 1651, 1537, 1175, 1139, 797, 723 cm-1; H
NMR (D2O, 500 MHz): δ 7.77-7.75 (m, 2H), 7.41 – 7.38 (m,
5H), 7.21-7.20 (m, 2H), 6.15 (s, 1H); 13C{1H} NMR (D2O, 126
2
2
2
MHz, ): δ 193.2, 140.7, 131.0, 130.6, 130.5, 130.5, 130.0, 7 Hz), 7.64-7.60 (m, 2H), 7.49-7.44 (m, 3H), 7.37-7.32 (m, 2H),
27 129.1, 128.6, 59.6; m/z (ESI) 246.1 [(M+H)+, 100%], 491.3
6.49 (s, 1H); 13C{1H} NMR (CD3OD, 126 MHz): δ 193.7,
135.4, 135.5 134.3, 133.3, 132.1, 131.3 131.0, 130.2, 129.9,
129.6, 57.5; m/z (ESI) 246.1 [(M+H)+, 100%], 491.3 [(2M+H)+,
2
2
[(2M+H)+, 70%].
1-(2-Methoxyphenyl)-2-oxo-2-phenylethan-1-aminium
1 trifluoroacetate.
1 70%].
2
2 The compound is novel and was prepared following the general
procedure C using tert- Butyl (1-(2-methoxyphenyl)-2-oxo-2-
phenylethyl)carbamate (1.00 g, 2.93 mmol, 1.0 eq) and
trifluoroacetic acid (3.34 g, 29.3 mmol, 10 eq) in DCM (20 mL)
and generated crude product was purified by trituration using n-
7 pentane : EtOAc (8:2 v/v, 60 mL) to give the product as a brown
solid (1.30 g, 3.66 mmol in quantitative yield, excess TFA
1-(4-Chlorophenyl)-2-oxo-2-phenylethan-1-
aminiumtrifluoroacetate.
This compound is known however it has not been fully
characterized previously.32 This compound was prepared
7 following the general procedure C using tert-butyl (1-(4-
chlorophenyl)-2-oxo-2-phenylethyl)carbamate (1.00 g, 2.89
mmol, 1.0 eq) and trifluoroacetic acid (3.30 g, 28.9 mmol, 10
eq) in DCM (20 mL) and generated crude product was purified
1 1 by trituration using n-pentane : EtOAc (8:2 v/v, 80 mL) to give
1 2 the product as a brown solid (0.980 g, 2.74 mmol, 94.9%). TLC:
Rf 0.0 (7:3, Hexane: EtOAc), strong UV active, TLC checked
to confirm the consumption of starting material; MP: 126-130
ºC; HRMS (ESI): found [M+H]+ 246.0680, C14H13ClNO
requires [M+H]+ 246.0680 (error -0.1 ppm); max 1642, 1540,
present). TLC: Rf 0.0 (8:2, Hexane: EtOAc), strong UV active,
1
TLC checked to confirm the consumption of starting material;
1 MP: 87-91 ºC; HRMS (ESI): found [M+H]+ 242.1173,
2 C15H16NO2 requires [M+H]+ 242.1176 (error 0.9 ppm); 1
max
1685, 1599, 1495, 1164, 1104, 754, 697 cm-1; 1H NM1R
(CD3OD, 500 MHz): δ 7.90 (d, 2H, J = 7.5 Hz), , 7.57 (t, 1H1, J
= 7.5 Hz), , 7.44-7.42 (m, 3H), 7.33-7.31 (m, 1H), 7.10 (d, 1H,
1
-1
1
J = 8.4 Hz), 6.99 (t, 1H, J = 7.5 Hz), 6.26 (s, 1H), 3.92 (s, 3H);
1 7 1208, 1184, 1137, 801, 714, cm ; H NMR (CD3OD, 500
MHz): δ 7.98 (d, 2H, J = 7.7 Hz), 7.62 (t, 1H, J = 7.5 Hz), 7.51-
7.46 (m, 6H), 6.24 (s, 1H); 13C{1H} NMR (CD3OD, 126 MHz):
7
13C{1H} NMR (CD OD, 126 MHz): δ 194.6, 158.3, 135.3.
1
3
134.7, 133.3, 131.0, 129.9, 129.78 122.6, 121.9, 113.1, 56.3,
1
11
56.1; m/z (ESI) 242.3 [(M+H)+, 20%], 483.4 [(2M+H)+, 100%].
δ 193.9, 137.5, 135.8, 134.3, 132.2, 131.7 131.1, 130.3, 130.1,
111 59.9; m/z (ESI) 246.0 [(M+H)+, 100%].
1 1-(4-Methoxyphenyl)-2-oxo-2-phenylethan-1-aminium
2 trifluoroacetate.
112
11
2-(4-Chlorophenyl)-1-(4-methoxyphenyl)-2-oxoethan-1-
aminium trifluoroacetate.
This compound is known however it has not been fully
11
characterized previously.31 This compound was prepared
following the general procedure C using tert-butyl (1-(4-
methoxyphenyl)-2-oxo-2-phenylethyl)carbamate (1.00 g, 2.93
11
11
This compound is known however it has not been fully
characterized previously.33 This compound was prepared
117 following the general procedure C using tert-butyl (1-(4-
chlorophenyl)-2-(4-methoxyphenyl)-2-oxoethyl)carbamate
(1.00 g, 2.81 mmol, 1.0 eq) and trifluoroacetic acid (3.20 g, 28.1
mmol, 10 eq) in DCM (20 mL) and the crude product was
121 purified by trituration using n-pentane : EtOAc (9:1 v/v,
122 100 mL) to give the product as a yellow solid (0.750 g, 1.92
7 mmol, 1.0 eq) and trifluoroacetic acid (3.34 g, 29.3 mmol, 10
11
eq) in DCM (20 mL) and generated crude product was purified
11
by trituration using n-pentane : EtOAc (8:2 v/v, 60 mL) to give
12
the product as a brown solid (1.23 g, 3.46 mmol in quantitative
1 yield, excess TFA present). TLC: Rf 0.0 (8:2, Hexane: EtOAc),
12
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The Journal of Organic Chemistry
1 mmol, 68.6%). TLC: Rf 0.0 (7:3, Hexane: EtOAc), strong UV 1 extracted with DCM. The combined organic layers were
2 active, checked to confirm the consumption of starting material; 2 washed with brine and dried over MgSO4 and concentrated
1
2
3
4
5
6
7
8
MP: 79-80 ºC; HRMS (ESI): found [M+H]+, 276.0790,
C15H15ClNO2 requires [M+H]+ 276.0786 (error -1.6 ppm); max
1665, 1588, 1512, 1492, 1176, 1130, 1092, 797, 720, 565 cm-1;
1H NMR (CD3OD, 600 MHz): δ 7.95 (d, 2H, J = 8.6 Hz), 7.47
7 (d, 2H, J = 8.6 Hz), 7.41 (d, 2H, J = 8.7 Hz), 6.98 (d, 2H, J =
8.7 Hz), 6.12 (s, 1H), 3.77 (s, 3H); 13C{1H} NMR (CD3OD, 151
MHz): δ 193.3, 162.6 141.8, 133.1 131.9, 131.4, 130.3, 124.8,
under reduced pressure to give the crude product. The crude
material was purified by column chromatography to afford the
desired product.
7 Method E
Substituted amine trifluoroacetate derivative was suspended in
acetone and cooled to 00 C in an ice bath. Saturated aqueous
NaHCO3 and solution of tosyl chloride was added dropwise
71 simultaneously to the reaction mixture and stirred at same
72 temperature for 30 minutes followed by stirring at rt for 7h.
+
116.3, 60.2, 55.989); m/z (ESI) 276.2 [(M+H) , 100%], 278.27
1
9
11 [(M+2+H)+, 100%].
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12
7
During the addition, the initially clear reaction mixture started
to become a suspension. Once the reaction was complete
(assessed by TLC), the reaction mixture was filtered through a
Buchner filter and the residue was washed with acetone. The
1
2-(Furan-2-yl)-2-oxo-1-phenylethan-1-aminium
trifluoroacetate.
This compound is novel and was prepared following the general
7
7
7
1
1
1
(2-(furan-2-yl)-2-oxo-1- 77 combined filtrate was concentrated. To the obtained residue,
procedure
C
using tert-butyl
17 phenylethyl)carbamate (1.00 g, 3.32 mmol, 1.0 eq) and7
water and DCM were added and organic layer was separated.
The aqueous layer was extracted with DCM . The combined
organic layers were washed with brine and dried over MgSO4
1 and concentrated under reduced pressure to give the crude
2 product. The crude material was purified by column
chromatography to afford the desire product.
1
1
2
trifluoroacetic acid (3.78 g, 33.2 mmol, 10 eq) in DCM (20 mL)
and generated crude product was purified by trituration using n-
pentane : EtOAc (9:1 v/v, 60 mL) to give the product as a white
7
21 solid (0.980 g, 3.11 mmol, 93.6%). TLC: Rf 0.0 (7:3, Hexane:
22 EtOAc), strong UV active, TLC checked to confirm the
2
consumption of starting material; MP: 152-155 ºC; HRMS
(ESI): found [M+H]+, 202.0868, C12H12NO2 requires [M+H]+
202.0863 (error -2.5 ppm); max 1677, 1463, 1406, 1179, 1132,
2
2
2
N-(2-(2-Methoxyphenyl)-2-oxo-1-phenylethyl)-4-
methylbenzenesulfonamide 14b.
798, 780, 576 cm-1; H NMR (CD3OD, 500 MHz): δ 7.79 (s,
1
7 This compound is novel and was prepared following the general
procedure D using 2-(2-methoxyphenyl)-2-oxo-1-phenylethan-
1-aminium trifluoroacetate (1.00 g, 2.81mmol, 1.0 eq) in DCM
(20 mL), triethylamine (1.42 g, 1.95 mL, 22.6 mmol, 5 eq) and
1 tosyl chloride (1.17 g, 6.19 mmol, 2.2 eq) in DCM (30 mL),
2 water (50 mL) to quench and DCM (2 x 30 mL) for extraction
to generate the crude product which was purified by column
chromatography (30% EtOAc in petroleum ether (40-60)) to
give 14b as a yellow solid (0.69 g, 1.74 mmol, 62.1%). TLC: Rf
ca 0.3 (6:4, Hexane: EtOAc), strong UV active; MP: 138-140
7 ºC; HRMS (ESI): found [M+Na]+ 418.1085, C22H21NNaO4S
requires [M+Na]+ 418.1083 (error -0.3 ppm); max 3264, 1662,
27 1H), 7.54 (d, 2H, J = 7.1 Hz), 7.48 – 7.46 (m, 3H), 7.43 (d, 1H,
2
2
J = 3.7 Hz), 6.63 (d, 1H, J = 3.7 Hz), 5.89 (s, 1H); 13C{1H} NMR
(CD3OD, 126 MHz): δ 182.3, 151.0 , 150.1, 133.4, 131.3,
130.8, 129.8, 122.1, 114.1, 60.4); m/z (ESI) 202.0 [(M+H)+,
1 30%], 403.2 [(2M+H)+, 100%].
2
2-Oxo-1-phenylpropan-1-aminium trifluoroacetate.
This compound has been reported as hydrochloride salt.34
This compound was prepared following the general procedure
C using tert-butyl (2-oxo-1-phenylpropyl) carbamate (0.600 g,
7 2.55 mmol, and 1.0 eq) and trifluoroacetic acid (2.90 g, 25.5
mmol, 10 eq) in DCM (10 mL) and the crude product was
1
1595, 1209, 1175, 756, 673, 535 cm-1; H NMR (CDCl3, 500
purified by trituration using n-pentane: EtOAc (8:2 v/v, 80 m1L)
MHz): δ 7.60 (d, 2H, J = 8.2 Hz), 7.48-7.46 (m, 1H), 7.40 – 7.36
to give the product as a yellow solid (0.530 g, 2.12 mmol,
1 1 (m, 1H), 7.14 -7.09 (m, 7H), 6.87 – 6.81 (m, 2H), 6.27 (d, 1H,
1 83.1%). HRMS (ESI): found [M+H]+
9
12
150.0911, C H N1O 2 J = 7.5 Hz), 6.20 (d, 1H, J = 7.5 Hz), 3.80 (s, 3H), 2.31 (s, 3H);
2 requires [M+H]+ 150.0913 (error 0.3 ppm); max 1762, 1655,
1
13C{1H} NMR(CDCl3,126 MHz): δ 196.4, 158.2, 143.1, 137.6,
136.1, 134.8 131.4, 129.4, 128.7, 128.2, 128.2, 127.2, 124.7,
120.9, 111.6, 65.1, 55.5, 21.5; m/z (ESI) 418.3 [(M+Na)+,
100%].
1614, 1528, 1190, 1132, 839, 722, 697cm-1; 1H NMR (CD OD,
1
3
500 MHz): δ 7.54-7.52 (m, 3H), 7.47-7.45 (m, 2H), 5.27 (s, 1H),
1
1
2.11 (s, 3H); 13C{1H} NMR (CD OD, 126 MHz): δ 202.2,
3
132.9, 131.5, 131.0, 129.8, 64.2, 26.5; m/z (ESI) 150.1 [(M+1)+,
1 7
7 25%]. The data matches the reported data.
1
1
N-(2-(3-Methoxyphenyl)-2-oxo-1-phenylethyl)-4-
methylbenzenesulfonamide 14c.
11
This compound is novel and was prepared following the
111 standard procedure D using 2-(3-methoxyphenyl)-2-oxo-1-
112 phenylethan-1-aminium trifluoroacetate (0.400 g, 1.12 mmol,
General procedure for formation of -NTs-amino ketones.
Method D
1 Substituted amine trifluoroacetate derivative was suspended in
2 DCM and cooled to 0 C in an ice bath. Triethylamine was
0
11
1.0 eq) in DCM (10 mL), triethylamine (0.453 g, 0.62 mL, 4.48
mmol, 4 eq) and tosyl chloride (0.322 g, 1.68 mmol, 1.5 eq) in
DCM (10 mL), water (50 mL) to quench and DCM (2 x 30 mL)
for extraction to generate the crude product which was purified
added dropwise to the reaction mixture and stirred at th1is1
11
11
temperature for 30 minutes. During the addition of
triethylamine, the initially cloudy reaction mixture became
clear. To the reaction mixture, tosyl chloride in DCM was added
117 by column chromatography (30% EtOAc in petroleum ether
º
11
(40-60)) to give 14c as a white solid (0.205 g, 0.519 mmol,
46.3%). TLC: Rf ca 0.3 (7:3, Hexane: EtOAc), strong UV
active; MP: 158-160 ºC; HRMS (ESI): found [M+Na]+
7 dropwise and the resulting reaction mixture was stirred at 0 C
11
for 30 minutes followed by overnight stirring at rt. Once the
12
reaction was complete (assessed by TLC), water and DCM were
added and organic layer was separated. The aqueous layer wa1s 21 418.1086, C22H21NNaO4S requires [M+Na]+ 418.1083 (error -
13
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Page 14 of 27
1 0.5 ppm); max 3276, 1677, 1588, 1254, 1159, 662, 530 cm-1; 1H
2 NMR (CDCl3, 500 MHz): δ 7.52 (d, 2H, J = 8.2 Hz), 7.37 (d,
1H, J = 7.7 Hz), 7.30 – 7.24 (m, 2H), 7.18 (s, 5H), 7.07– 7.02
(m, 3H), 6.20 (d, 1H, J = 7.4 Hz), 5.96 (d, 1H, J = 7.4 Hz),, 3.77
(s, 3H), 2.30 (s, 3H); 13C{1H} NMR (CDCl3, 126 MHz): δ
195.0 159.9 143.3, 137.6, 1359, 135.2, 129.8, 129.5129.2,
7 128.6, 128.2, 127.1, 121.7, 120.6, 113.3, 62.0, 55.5, 21.5; m/z
(ESI) 418.1 [(M+Na)+, 100%].
2 water (60 mL) to quench and DCM (2 x 30 mL) for extraction
1
2
3
4
5
6
7
8
to generate the crude product which was purified by column
chromatography (30% EtOAc in petroleum ether (40-60)) to
give 14f as a brown solid (0.385 g, 0.964 mmol, 31.4%). TLC:
Rf ca 0.3 (8:2, Hexane: EtOAc), strong UV active; MP: 161-163
7 ºC; HRMS (ESI): found [M+Na]+ 422.0591, C21H18ClNNaO3S
requires [M+Na]+ 422.0588 (error -0.7 ppm); max 3250, 1697,
1329, 1154, 664, 532 cm-1; 1H NMR (CDCl3, 500 MHz): δ7.74
(d, 2H, J = 8.6 Hz), 7.51 (d, 2H, J = 8.2 Hz), 7.33 (d, 2H, J =
7
71 8.6 Hz), 7.19 – 7.14 (m, 5H),7.07 (d, 2H, J = 8.1 Hz), 6.18 (d,
1
N-(2-(2-Chlorophenyl)-2-oxo-1-phenylethyl)-4-
9
72 1H, J = 7.3 Hz), 5.94 (d, 1H, J = 7.4 Hz), 2.31 (s, 3H); 13C{1H}
11 methylbenzenesulfonamide 14d.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
NMR (CDCl3, 126 MHz): δ 193.5, 143.3, 140.7, 137.5, 135.5,
132.2, 130.4, 129.5, 129.3, 129.2, 128.8, 128.2, 127.1, 61.9,
21.5; m/z (ESI) 422.1 [(M+Na)+, 100%] 424.3 [(M+2+Na)+,
40%].
12 This compound is novel and was prepared following the general
7
procedure E using 2-(2-chlorophenyl)-2-oxo-1-phenylethan-1-
aminium trifluoroacetate (1.00 g, 2.79 mmol, 1.0 eq.) in acetone
(20 mL), saturated aqueous NaHCO3 (20 mL) and tosyl chloride
1
1
1
1
7
7
(0.590 g, 3.07 mmol, 1.1 eq) in acetone (20 mL), water (80 mL) 77
17 to quench and DCM (2 x 30 mL) for extraction to generate the7
N-(1-(2-Methoxyphenyl)-2-oxo-2-phenylethyl)-4-
methylbenzenesulfonamide 14g.
1
1
2
crude product which was purified by column chromatography7
(10% EtOAc in petroleum ether (40-60)) to give 14d as a yellow
This compound is novel and was prepared following the general
solid (0.45 g, 1.12 mmol, 44.9%). TLC: Rf ca 0.2 (8:2, Hexane: 1 procedure E using 1-(2-methoxyphenyl)-2-oxo-2-phenylethan-
21 EtOAc), strong UV active; MP: 87-89 ºC; HRMS (ESI): found 2 1-aminium (1.20 g, 3.37 mmol, 1.0 eq) in acetone (25 mL),
22 [M+Na]+ 422.0592, C21H18ClNNaO3S requires [M+Na]+
saturated aqueous NaHCO3 (25 mL) and tosyl chloride (0.708
g, 3.71 mmol, 1.1 eq) in acetone (25 mL), water (80 mL) to
quench and DCM (2 x 30 mL) for extraction to generate the
crude product which was purified by column chromatography
7 (20% EtOAc in petroleum ether (40-60)) to give 14g as a white
solid (0.750 g, 1.89 mmol, 56.1%). TLC: Rf ca 0.35 (6:4,
Hexane: EtOAc), strong UV active; MP: 162-165 ºC; HRMS
(ESI): found [M+Na]+ 418.1082, C22H21NNaO4S requires
1 [M+Na]+ 418.1083 (error 0.4 ppm); max 3260, 2983, 1697,
2
422.0588 (error -0.9 ppm); max 3258, 1691, 1587, 1335, 1161,
1
2
2
2
758, 532 cm-1; H NMR (CDCl3, 500 MHz): 7.60 (d, 2H, J =
8.3 Hz), 7.29-7.26 (m, 2H), 7.16 -7.17 (m, 6H), 7.07-7.05 (m,
3H), 6.26 (d, 1H, J = 6.3 Hz), 5.91 (d, 1H, J = 6.4 Hz), 2.34 (s,
27 3H); 13C{1H} NMR (CDCl3, 126 MHz): δ 196.8, 143.5, 137.4,
2
2
135.8, 134.3, 132.5, 131.3, 129.6, 129.5, 129.0, 128.7, 128.2,
127.2, 126.8, 64.9, 21.6; m/z (ESI) 422.1 [(M+Na)+, 100%]
424.3 [(M+2+Na)+, 35%]
1
1
2 1597, 1229, 1160, 754, 688, 536 cm-1; H NMR (CDCl3, 500
2 N-(2-(3-Chlorophenyl)-2-oxo-1-phenylethyl)-4-
MHz): δ 7.83 (d, 2H, J = 7.9 Hz), 7.57 (d, 2H, J = 7.6 Hz), 7.45
(t, 1H, J = 7.4 Hz), 7.33-7.30 (m, 2H), 7.12 (t, 1H, J = 7.8 Hz),
7.07 (m, 3H), 6.76 (t, 1H, J = 7.5 Hz), 6.67 (d, 1H, J = 8.1 Hz),
6.25-6.22 (m, 2H), 3.74 (s, 3H), 2.30 (s, 3H); 13C{1H} NMR
methylbenzenesulfonamide 14e.
This compound is novel and was prepared following the
general procedure D 2-(3-chlorophenyl)-2-oxo-1-phenylethan-
1-aminium trifluoroacetate (1.00 g, 2.79 mmol, 1.0 eq) in DCM 7 (CDCl3, 126 MHz): δ 194.8, 156.3, 143.0, 137.6, 134.1, 133.7,
7 (25 mL), triethylamine (1.40 g, 2.00 mL, 13.9 mmol, 5 eq) and
130.0, 129.4, 129.3, 128.8, 128.6, 127.2, 124.7, 121.3, 111.4,
56.8, 55.6, 21.5; m/z (ESI) 418.3 [(M+Na)+, 100%].
tosyl chloride (1.17 g, 6.14 mmol, 2.2 eq) in DCM (25 mL),
water (80 mL) to quench and DCM (2 x 30 mL) for extraction
1
to generate the crude product which was purified by column
1 1 N-(1-(4-Methoxyphenyl)-2-oxo-2-phenylethyl)-4-
1 2 methylbenzenesulfonamide 14h.
1 chromatography (50% EtOAc in petroleum ether (40-60)) to
1
This compound has been reported.23 This compound was
prepared following the general procedure E using 1-(4-
methoxyphenyl)-2-oxo-2-phenylethan-1-aminium (1.20 g, 3.37
2 give 14e as a yellow solid (0.290 g, 0.726 mmol, 26.0%). TLC:
R ca 0.2 (8:2, Hexane: EtOAc), strong UV active; MP: 210-211
1
f
ºC; HRMS (ESI): found [M+Na]+ 422.0593, C H ClNNaO S
1
3
21 18
requires [M+Na]+ 422.0588 (error -1.1 ppm); max 3250, 16917,
mmol, 1.0 eq) in acetone (25 mL), saturated aqueous NaHCO3
1329, 1154, 664, 532 cm-1; 1H NMR (CDCl3, 500 MHz): δ 7.715 7 (25 mL) and tosyl chloride (0.708 g, 3.71 mmol, 1.1 eq) in
7 (s, 1H), 7.65 (d, 1H, J = 7.9 Hz) 7.52 (d, 2H, J = 8.2 Hz), 7.417-
7.46 (m, 1H), 7.30 (t, 1H, J = 7.9 Hz), 7.20-7.15 (m, 5H), 7.107
(d, 2H, J = 8.1 Hz), 6.14 (d, 1H, J = 7.5 Hz), 5.93 (d, 1H, J1=1
acetone (25 mL), water (80 mL) to quench and DCM (2 x 30
mL) for extraction to generate the crude product which was
purified by column chromatography (30% EtOAc in petroleum
7.5 Hz), 2.32 (s, 3H); 13C{1H} NMR (CDCl3, 126 MHz3): δ111 ether (40-60)) to give 14h as a white solid (1.00 g, 2.53 mmol,
1 193.7, 143.4, 137.4, 135.5, 135.3, 135.2, 134.0, 130.1, 129.51, 12 75.1%). TLC: Rf ca 0.4 (6:4, Hexane: EtOAc), strong UV
2 129.4, 128.9, 128.2, 127.1, 127.1, 62.0 21.6; m/z (ESI) 4221.11
active; MP: 61-62 ºC; HRMS (ESI): found [M+Na]+ 418.1083,
C22H21NNaO4S requires [M+Na]+ 418.1083 (error 0.0
ppm); max 3270, 1680, 1580, 1248, 1154, 752, 676, 529 cm-1;
1H NMR (CDCl3, 500 MHz): δ 7.79 (d, 2H, J = 7.8 Hz), 7.53 –
[(M+Na)+, 90%] 424.3 [(M+2+Na)+, 50%].
11
11
11
N-(2-(4-Chlorophenyl)-2-oxo-1-phenylethyl)-4-
methylbenzenesulfonamide 14f.
117 7.47 (m, 3H), 7.37-7.33 (m, 2H)), 7.09-7.06 (m, 4H), 6.68 (d,
2H, J = 8.4 Hz), 6.18 (d, 1H, J = 7.3 Hz), 5.95 (d, 1H, J = 7.3
Hz), 3.70 (s, 3H), 2.30 (s, 3H); 13C{1H} NMR (CDCl3, 126
MHz): δ 194.7 159.8, 143.1, 137.7, 134.0, 133.9, 129.6, 129.4,
7 This compound is novel and was prepared following the gener1al1
procedure D using 2-(4-chlorophenyl)-2-oxo-1-phenylethan-11-1
aminium trifluoroacetate (1.10 g, 3.07 mmol, 1.0 eq) in DCM12
(20 mL), triethylamine (1.24 g, 1.71 mL, 12.3 mmol, 4 eq) and121 129.0, 128.8, 127.8, 127.1, 114.6, 61.3, 55.3, 21.5; m/z (ESI)
1 tosyl chloride (0.878 g, 4.60 mmol, 1.5 eq) in DCM (20 mL)1, 22 418.2 [(M+Na)+, 100%].
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1
1
2 663, 532 cm-1; H NMR (CDCl3, 500 MHz): δ 7.74-7.72 (m,
2H), 7.53-7.51 (m, 2H), 7.34-7.31 (m, 2H), 7.08-7.04 (m, 4H),
6.70-6.67 (m, 2H), 6.15 (d, 1H, J = 7.3 Hz), 5.90 (d, 1H, J = 7.3
Hz), 3.71 (s, 3H), 2.31 (s, 3H); 13C{1H} NMR (CDCl3, 126
MHz):) δ 193.6, 159.9, 143.2, 140.5, 137.7, 132.3, 130.4, 129.5,
1
2
3
2 N-(1-(2-Chlorophenyl)-2-oxo-2-phenylethyl)-4-
methylbenzenesulfonamide 14i.
This compound is novel and was prepared following the general
procedure E using 1-(2-chlorophenyl)-2-oxo-2-phenylethan-1-
4
5
6
7
8
9
aminium (0.400 g, 1.11 mmol, 1.0 eq) in acetone (10 mL), 7 129.5, 129.2, 127.4, 127.1, 114.7, 61.4, 55.4, 21.5; m/z (ESI)
7 saturated aqueous NaHCO3 (10 mL) and tosyl chloride (0.233
g, 1.22 mmol, 1.1 eq) in acetone (10 mL), water (50 mL) to
quench and DCM (2 x 20 mL) for extraction to generate the7
452.2 [(M+Na)+, 100%], 454.2 [(M+2+Na)+, 35%].
N-(2-(Furan-2-yl)-2-oxo-1-phenylethyl)-4-
crude product which was purified by column chromatography 71 methylbenzenesulfonamide 14l.
11 (30% EtOAc in petroleum ether (40-60)) to give 14i as a white 72 This compound is novel and was prepared following the general
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12 solid (0.310 g, 0.776 mmol, 70.6%). TLC: Rf ca 0.3 (8:2,7
procedure using 2-(furan-2-yl)-2-oxo-1-phenylethan-1-
E
1
Hexane: EtOAc), strong UV active; MP: 134-135 ºC, HRMS7
aminium trifluoroacetate (0.800 g, 2.53 mmol, 1.0 eq) in
acetone (18 mL), saturated aqueous NaHCO3 (18 mL) and tosyl
chloride (0.532 g, 2.79 mmol, 1.1 eq) in acetone (18 mL), water
+
1
1
1
(ESI): found [M+Na] 422.0591, C21H18ClNNaO3S requires7
[M+Na]+ 422.0588 (error -0.6 ppm); max 3261, 1690, 1596,
7
-1
1
77 (80 mL) to quench and DCM (2 x 30 mL) for extraction to
1328, 1152, 717, 546 cm ; H NMR (CDCl3, 500 MHz): δ 7.85
7
generate the crude product which was purified by column
chromatography (50% EtOAc in petroleum ether (40-60))to
give 14l as a white solid (0.706 g, 1.98 mmol, 78.6%). TLC: Rf
1 ca 0.2 (8:2, Hexane: EtOAc), strong UV active; MP: 147-149
2 ºC; HRMS (ESI): found [M+Na]+ 378.0769, C19H17NNaO4S
requires [M+Na]+ 378.0770 (error 0.5 ppm); max 3268, 1658,
1464, 1345, 1159, 1090, 989, 773, 525 cm-1; 1H NMR (CDCl3,
500 MHz): δ 7.54-7.52 (m, 3H), 7.23-7.18 (m, 5H), 7.14 (d, 1H,
J = 3.6 Hz), 7.07 (d, 2H, J = 8.1 Hz), 6.46 (d, 1H, J = 5.2 Hz),
7 6.13 (d, 1H, J = 7.6 Hz), 5.81 (d, 1H, J = 7.6 Hz), 2.31 (s, 3H);
13C{1H} NMR (CDCl3, 126 MHz): δ 183.32 150.2, 147.5,
143.3, 137.5, 135.5, 129.4, 129.0, 128.6, 128.2, 127.1, 119.8,
112.9, 61.7, 21.5; m/z (ESI) 378.1 [(M+Na)+, 100%].
1
17 (d, 2H, J = 7.9 Hz), 7.62 (d, 2H, J = 7.9 Hz), 7.50 (t, 1H, J = 7.4
7
1
1
2
Hz), 7.36 (m, 2H), 7.26-7.23 (m, 1H), , 7.11-7.04 (m, 5H), 6.34
(d, 1H, J = 7.0 Hz), 6.26 (d, 1H , J = 7.0 Hz), 2.32 (s, 3H);
13C{1H} NMR (CDCl3, 126 MHz): δ 194.3, 143.4, 137.2, 134.2,
21 133.8, 133.8, 133.7, 130.4, 130.0, 129.7, 129.5, 128.9, 128.8,
22 127.7, 127.3, 58.7, 21.6; m/z (ESI) 422.2 [(M+Na)+, 100%]
2
424.1 [(M+2+Na)+, 35%].
2
2
2
N-(1-(4-Chlorophenyl)-2-oxo-2-phenylethyl)-4-
methylbenzenesulfonamide 14j.
27 This compound is novel and was prepared following the general
2
2
procedure E using 1-(4-chlorophenyl)-2-oxo-2-phenylethan-1-
aminium trifluoroacetate (0.900 g, 2.51 mmol, 1.0 eq) in
acetone (18 mL), saturated aqueous NaHCO3 (18 mL) and tosyl
1 chloride (0.528 g, 2.76 mmol, 1.1 eq) in acetone (18 mL), water
2 (80 mL) to quench and DCM (2 x 30 mL) for extraction to
generate the crude product which was purified by column
chromatography (30% EtOAc in petroleum ether (40-60)) to
give 14j as a white solid (0.586 g, 1.57 mmol, 58.5%). TLC: Rf
ca 0.3 (8:2, Hexane: EtOAc), strong UV active; MP: 166-169
7 ºC; HRMS (ESI): found [M+Na]+ 422.0588, C21H18ClNNaO3S
requires [M+Na]+ 422.0588 (error 0.1 ppm); max 3219, 1696,
1399, 1155, 652, 543 cm-1; 1H NMR (CDCl3, 500 MHz): δ 7.178
2 N-(2-Oxo-1,2-diphenylethyl)methanesulfonamide
(precursor of 23).
This compound has been reported.35 This compound was
prepared following the general procedure D using 2-oxo-1,2-
diphenylethan-1-aminium hydrochloride (0.500 g, 2.02 mmol,
7 1.0 eq) in DCM (10 mL), triethylamine (0.816 g, 1.12mL, 8.08
mmol, 4.0 eq) and mesyl chloride (0.348 g, 3.03 mmol, 1.5 eq)
in DCM (10 mL), water (50 mL) to quench and DCM (2 x 25
mL) for extraction to generate the crude product which was
(d, 2H , J = 7.9 Hz), 7.54-7.49 (m, 3H), 7.38 (t, 2H, J = 7.6 Hz1), 1 purified by column chromatography (30% EtOAc in petroleum
1 7.26 (s, 1H) , 7.13-7.07 (m, 5H), 6.22 (d, 1H, J = 6.9 Hz), 5.916 2 ether (40-60)) to give the product as a white solid (0.310 g, 1.07
2 (d, 1H, J = 7.0 Hz), 2.32 (s, 3H); 13C{1H} NMR (CDCl3, 1126
MHz): δ 194.2, 143.5, 137.5, 134.8, 134.3, 134.3, 133.7, 1291.6,
129.5, 129.4, 129.1, 128.9, 127.1, 61.1, 21.5; m/z (ESI) 4221.2
mmol, 52.9%). TLC: Rf ca 0.3 (7:3, Hexane: EtOAc), strong
UV active; HRMS (ESI): found [M+Na]+ 312.0696,
C15H15NNaO3S requires [M+Na]+ 312.0665 (error 0.7
ppm); max 3242, 1687, 1313, 1293, 1247, 994, 731, 508 cm-1;
[(M+Na)+, 100%] 424.1 [(M+2+Na)+, 35%].
1
1 7 1H NMR (CDCl3, 400 MHz): δ 7.93 (d, 2H, J = 7.3 Hz), 7.53 (t,
1H, J = 7.4 Hz), 7.42 – 7.24 (m, 7H), 6.13 (d, 1H, J = 6.4 Hz),
6.07 (d, 1H, J = 6.2 Hz), 2.58 (s, 3H); 13C{1H} NMR (CDCl3,
7 N-(2-(4-Chlorophenyl)-1-(4-methoxyphenyl)-2-oxoethyl)-4-
1
1
11
methylbenzenesulfonamide 14k.
This compound is novel and was prepared following the general
101 MHz): δ 194.3, 136.3, 134.2, 133.7 129.7, 129.3 129.2,
+
procedure E using 1-(4-chlorophenyl)-2-(4-methoxyphenyl)-2-
1 oxoethan-1-aminium trifluoroacetate (0.750 g, 1.92 mmol, 1.0
111 128.9, 128.4, 62.2, 42.4; m/z (ESI) 312.2 [(M+Na) , 100%].
112 The data matches the reported data.
2 eq) in acetone (14 mL), saturated aqueous NaHCO (20 mL)
11
3
and tosyl chloride (0.405 g, 2.12 mmol, 1.1 eq) in acetone (14
11
4-Methyl-N-(1-oxo-1-phenylpropan-2-
yl)benzenesulfonamide (precursor to 25).
mL), water (50 mL) to quench and DCM (2 x 30 mL) for
extraction to generate the crude product which was purified by
column chromatography (30% EtOAc in petroleum ether (40-
11
11
This compound has been reported and fully characterised.36
117 This compound was prepared following the same procedure as
7 60)) to give 14k as a yellow solid (0.600 g, 1.39 mmol, 72.8%).
11
used
for
4-methyl-N-(2-oxo-1,2-
TLC: R ca 0.3 (7:3, Hexane: EtOAc), strong UV active; MP:
11
diphenylethyl)benzenesulfonamide 14a using 1-oxo-1-
phenylpropan-2-aminium hydrochloride (1.50 g, 8.10 mmol,
121 1.0 eq) in DCM (40 mL), triethylamine (3.28 g, 4.50 mL, 32.4
f
72-76 ºC; HRMS (ESI): found [M+Na]+ 452.0694,
12
C22H20ClNNaO4S requires [M+Na]+ 452.0694 (error -0.0
1 ppm); max 3269, 1682, 1588, 1510, 1249, 1156, 1089, 8101, 22 mmol, 4 eq) and tosyl chloride (3.10g, 16.2 mmol, 1.2 eq) in
15
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The Journal of Organic Chemistry
Page 16 of 27
1 DCM (20 mL), water (100 mL) to quench and DCM (2 x 40 1 This compound is novel and was prepared following the
2 mL) for extraction to generate the crude product which was 2 general procedure F using tert-butyl (2-(2-methoxyphenyl)-2-
1
2
3
4
5
6
7
8
purified by column chromatography (15% EtOAc in petroleum
ether (40-60)) to give the product as a white solid (0.55 g, 1.81
mmol, 22.3%). TLC: Rf ca 0.2 (8:2, Hexane: EtOAc), strong
UV active; HRMS (ESI): found [M+Na]+ 326.0819,
oxo-1-phenylethyl)carbamate 13b (0.171 g, 0.5 mmol, 1.0 eq)
in MeCN (5 mL), catalyst (R,R)-20 (7.1 mg, 0.01 mmol, 0.02
eq), DABCO (0.280 g, 2.50 mmol, 5.0 eq) and formic acid (56
µL, 1.50 mmol, 3.0 eq) for 48h when 100% conversion of
7 C16H17NNaO3S requires [M+Na]+ 326.0821 (error 0.8 7 ketone achieved (determined by H NMR), water (30 mL) to
1
quench and DCM (2 x 10 mL) for extraction to generate the
crude product which was purified by column chromatography
(40% EtOAc in petroleum ether (40-60)) to give 17b as a white
ppm); max 3267, 1679, 1596, 1337, 1164, 965, 702, 680, 551
-1
1
cm ; H NMR (CDCl , 400 MHz): δ 7.78 – 7.75 (m, 2H), 7.697
3
1
(d, 2H, J = 8.3 Hz), 7.59 (t, 1H, J = 7.4 Hz), 7.47-7.43 (t, 2H, J
9
71 solid (0.150 g, 0.437 mmol, 87.4%). TLC: R ca 0.3 (6:4,
11 = 7.7 Hz), 7.17 (d, 2H, J = 8.0 Hz), 5.79 (d, 1H, J = 8.0 Hz),
f
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12 4.97-4.90 (m, 1H), 2.32 (s, 3H), 1.40 (d, 3H, J = 7.2 Hz); 72 Hexane: EtOAc), less UV active, strong KMnO4 & PMA
7
C{ H} NMR (CDCl3, 101 MHz): δ 198.2, 143.6, 137.2, 134.2,
reactive; MP: 115-118 ºC; HRMS (ESI): found [M+Na]+
366.1677, C20H25NNaO4 requires [M+Na]+ 366.1676 (error -0.2
ppm); max 3531, 3381, 1679, 1520, 1218, 1166, 988, 699 cm-1;
Enantiomeric excess determined by HPLC analysis (Chiralpak
77 IC, 250 mm x 4.6 mm column, iPrOH: hexane 12:88, 0.5
13
1
1
1
1
1
7
133.5, 129.8, 128.9, 128.6, 127.2, 53.5, 21.6, 21.2; m/z (ESI)
326.2 [(M+Na)+, 100%]. The data matches the reported data. 7
7
17 4-Methyl-N-(2-oxo-1-phenylpropyl)benzenesulfonamide
7
7
mL/min, T = 25 ºC), (1S,2R) 16.4 min, (1R,2S) 19.1 min, other
1
1
2
(precursor to 27).
22
diastereomer 52.2 min and 62.4 min; [α]D = -122 (c = 0.1,
This compound has been reported and fully characterised.37
CHCl3); dr: >99.9:<0.1, major diastereomer 94% ee; 1H NMR
1 (DMSO-d6, 500 MHz): δ 7.17-7.12 (m, 4H), 7.03-6.90 (m, 5H),
2 6.73-6.70 (m, 1H), 5.21 (d, 1H, J = 4.8 Hz), 5.09 (t, 1H, J = 5.0
Hz), 4.75 (dd, 1H, J = 8.7, 5.5 Hz), 3.84 (s, 3H), 1.29 (s, 9H);
13C{1H} NMR (DMSO-d6, 126 MHz): δ 155.8, 154.5, 140.4,
130.2, 128.1, 127.9 127.3, 127.0, 126.4, 119.7, 110.2, 77.8,
69.5, 58.1, 55.4, 28.2; m/z (ESI) 366.3 [(M+Na)+, 100%].
7
This compound was prepared following the general procedure
21 E using 2-oxo-1-phenylpropan-1-aminium trifluoroacetate
22 (0.780 g, 2.96 mmol, 1.0 eq) in acetone (20 mL), saturated
2
aqueous NaHCO3 (20 mL) and tosyl chloride (0.621 g, 3.26
mmol, 1.1 eq) in acetone (20 mL), water (60 mL) to quench and
DCM (2 x 20 mL) for extraction to generate the crude product
which was purified by column chromatography (60% EtOAc in
2
2
2
27 petroleum ether (40-60)) to give the product as a white solid
t-Butyl ((1S,2R)-2-hydroxy-2-(3-methoxyphenyl)-1-
phenylethyl)carbamate 17c.
2
2
(0.400 g, 1.32 mmol, 45.8%). TLC: Rf ca 0.3 (8:2, Hexane:
EtOAc), strong UV active; HRMS (ESI): found [M+Na]+
326.0822, C16H17NNaO3S requires [M+Na]+ 326.0821 (error -
1 0.3 ppm); max 3373, 3266, 1705, 1672, 1339, 1244, 1158, 774,
2 667, 565 cm-1; 1H NMR (CDCl3, 500 MHz): δ 7.47 (d, 2H, J =
7.6 Hz), 7.26 – 7.21 (m, 3H), 7.11-7.08 (m, 4H), 6.06 (d, 1H, J
= 4.4 Hz), 5.02 (d, 1H, J = 4.9 Hz), 2.34 (s, 3H), 1.99 (s, 3H);
13C{1H} NMR (CDCl3, 126 MHz): δ 201.9, 143.3, 137.4, 135.2,
129.4, 129.2, 128.8, 128.2, 127.1, 66.5, 26.7, 21.6); m/z (ESI)
7 326.1 [(M+Na)+, 100%]. The data matches the reported data.
This compound is novel and was prepared following the general
1 procedure F using tert-butyl (2-(3-methoxyphenyl)-2-oxo-1-
2 phenylethyl)carbamate 13c (0.171 g, 0.5 mmol, 1.0 eq) in
MeCN (5 mL), catalyst (R,R)-20 (5.3 mg, 7.5 µmol, 0.015 eq),
DABCO (0.280 g, 2.50 mmol, 5.0 eq) and formic acid (56 µL,
1.50 mmol, 3.0 eq) for 72h when 100% conversion of ketone
1
achieved (determined by H NMR), water (30 mL) to quench
7 and DCM (2 x 10 mL) for extraction to generate the crude
product which was purified by column chromatography (50%
EtOAc in petroleum ether (40-60)) to give 17c as a white solid
for asymmetric transfer
(0.150 g, 0.437 mmol, 87.4%). TLC: Rf ca 0.2 (8:2, Hexane:
General procedure
hydrogenation (ATH).
F
1
1 1 EtOAc), less UV active, strong KMnO4 & PMA reactive; MP:
1 2 163-165 ºC; HRMS (ESI): found [M+Na]+ 366.1674,
C20H25NNaO4 requires [M+Na]+ 366.1676 (error 0.6 ppm); max
3420, 1660, 1520, 1291, 1160, 1166, 980, 698 cm-1;
Enantiomeric excess determined by HPLC analysis (Chiralpak
IC, 250 mm x 4.6 mm column, iPrOH: hexane 12:88, 0.5
1 Substituted ketone derivatives and DABCO were dissolved in
2 small amount of MeCN. Once the reaction became cle1ar,
catalyst ((R,R)-20 for N-Boc-protected substrates and (R,R)-2
1
for N-Ts-protected substrates) and remaining solvent added 1(to
give [S] = 0.1M) after which formic acid was added and the
1
resulting reaction mixture was stirred at room temperatur1e. 7 mL/min, 210 nm, T = 25 ºC), (1S,2R) 16.5 min, (1R,2S) isomer
7 After stirring for the time indicated, the reaction mixture was
22
1
1
21.6 min, other diastereomer 47.3 min and 143.1 min; [α]D
=
concentrated. The residue was dissolved in DCM and the
-109 (c=0.1, CHCl3), dr: >99.9:<0.1, 93% ee; 1H NMR
(CDCl3, 500 MHz): δ 7.26-7.23 (m, 3H), 7.15 (t, 1H, J = 7.9
111 Hz), 7.04 (s, 2H), 6.78-6.76 (m, 1H), 6.66 (d, 1H, J = 7.2 Hz),
112 6.53 (s, 1H), 5.33 (d, 1H, J = 6.3 Hz), 5.02-4.97 (m, 2H), 3.65
organic layer was washed with water. The aqueous layer was
11
extracted with DCM. The combined organic layers were
1 washed with brine and dried over MgSO4 and concentrated
2 under reduced pressure to give the crude product. The crude
11
(s, 3H), 2.75 (s, 1H), 1.41 (s, 9H); 13C{1H} NMR (CDCl3, 126
MHz): δ 159.4, 155.8, 141.6, 137.8, 129.1, 128.2, 127.9, 127.7,
119.1, 114.0, 111.7, 80.1, 77.2, 60.6, 55.2 28.4; m/z (ESI) 366.3
[(M+Na)+, 100%].
material was purified by column chromatography to afford the
11
substituted amino alcohol. In cases where only a sing1le1
diastereoisomer of ATH product was observed, the dr is given
as >99.9:<0.1. Racemic standards were prepared using gener1al1
117
7 procedure A.
11
11
12
t-Butyl-((1S,2R)-2-hydroxy-2-(2-chlorophenyl)-1-
phenylethyl)carbamate 17d.
This compound is novel and was prepared following the general
t-Butyl-((1S,2R)-2-hydroxy-2-(2-methoxyphenyl)-1-
phenylethyl)carbamate 17b.
121 procedure F using tert-butyl (2-(2-chlorophenyl)-2-oxo-1-
16
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The Journal of Organic Chemistry
1 phenylethyl)carbamate 13d (0.173 g, 0.5 mmol, 1.0 eq) in 2 1.50 mmol, 3.0 eq) for 24 h when 100% conversion of ketone
1
1
2
3
4
5
6
7
8
2 MeCN (5 mL), catalyst (R,R)-20 (7.1 mg, 0.01 mmol, 0.02 eq),
DABCO (0.280 g, 2.50 mmol, 5.0 eq) and formic acid (56 µL,
1.50 mmol, 3.0 eq) for 48h when 95% conversion of ketone
achieved (determined by H NMR), water (30 mL) to quench
and DCM (2 x 10 mL) for extraction to generate the crude
product which was purified by column chromatography (30%
EtOAc in petroleum ether (40-60)) to give 17f as a white solid
1
achieved (determined by H NMR), water (30 mL) to quench
and DCM (2 x 10 mL) for extraction to generate the crude 7 (0.140 g, 0.403 mmol, 80.6%). TLC: Rf ca 0.3 (6:4, Hexane:
7 product which was purified by column chromatography (20%
EtOAc in petroleum ether (40-60)) to give 17d as a white solid
(0.124 g, 0.357 mmol, 71.4%). TLC: Rf ca 0.3 (6:4, Hexane:7
EtOAc), less UV active, strong KMnO4 & PMA reactive; MP:
200-201 ºC; HRMS (ESI): found [M+Na]+ 370.1182,
C19H22ClNNaO3 requires [M+Na]+ 370.1180 (error -0.5 ppm);
71 IR max 3375, 2981, 1677, 1524, 1166, 1000, 702 cm-1;
72 Enantiomeric excess determined by HPLC analysis (Chiralpak
1
EtOAc), less UV active, strong KMnO & PMA reactive; MP:
4
9
11 128-130 ºC; HRMS (ESI): found [M+Na]+ 370.1179,
12 C19H22ClNNaO3 requires [M+Na]+ 370.1180 (error 0.5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
IC, 250 mm x 4.6 mm column, iPrOH: hexane 12:88, 0.5
mL/min, 210 nm, T = 25 ºC), (1S,2R) 9.4 min, (1R,2S) 10.9
min, other diastereomer at 17.0 min and 26.4 min; [α]D22 = -82
1
ppm); max 3399, 2982, 1684, 1492, 1154, 698 cm-1;7
Enantiomeric excess determined by HPLC analysis (Chiralpak7
IG, 250 mm x 4.6 mm column, iPrOH: hexane 7:93, 0.57
1
1
1
1
(c = 0.1 in CHCl3), dr: >99.9:<0.1, 99.4% ee; H NMR
mL/min, 210 nm, T = 25 ºC), (1R,2S) 21.9 min, (1S,2R) 23.5 77 (DMSO-d6, 500 MHz): δ 7.33-7.19 (m, 10H), 5.42 (d, 1H, J =
17 min, other diastereomer 42.8 min and 47.2 min; [α]D22 = -1507
5.1 Hz), 4.65 (dd, 1H, J = 8.1, 5.2 Hz), 4.53 (t, 1H, J = 8.9 Hz),
1.20 (s, 9H); 13C{1H} NMR (DMSO-d6, 126 MHz): δ 154.5,
142.5, 141.3, 131.4, 128.9, 128.2, 127.4, 126.7, 77.7, 74.6, 60.0,
1
1
2
(c = 0.1, CHCl3), dr: 97.7:2.3, major diastereomer 95% ee; 1H7
NMR (CDCl3, 500 MHz3): δ 7.32 (d, 1H, J = 7.9 Hz), 7.23-7.22
(m, 3H), 7.16 (t, 1H, J = 8.4 Hz), 7.10-7.06 (m, 4H), 5.51-5.46 1 28.1; m/z (ESI) 370.2 [(M+Na)+, 100%], 372.2 [(M+2+Na)+,
21 (m, 2H), 5.01 (s, 1H), 2.53 (s, 1H), 1.37 (s, 9H); 13C{1H} NMR 2 35%].
22 (CDCl3, 126 MHz): δ 155.3, 138.0, 138.1, 132.4, 129.2, 128.9,
2
128.5, 128.2, 1278.0., 127.7, 126.7, 79.9, 73.1, 58.9, 28.4; m/z
(ESI) 370.3 [(M+Na)+, 100%], 372.2 [(M+2+Na)+, 40%].
t- Butyl-((1S,2R)-2-hydroxy-1-(2-methoxyphenyl)-2-
phenylethyl)carbamate 17g.
2
2
2
This compound is novel and was prepared following the general
7 procedure F using tert-butyl (1-(2-methoxyphenyl)-2-oxo-2-
phenylethyl)carbamate 13g (0.171 g, 0.50 mmol, 1.0 eq) in
MeCN (5 mL), catalyst (R,R)-20 (7.1 mg, 0.01 mmol, 0.02 eq),
DABCO (0.280 g, 2.50 mmol, 5.0 eq) and formic acid (56 µL,
t-Butyl-((1S,2R)-2-(3-chlorophenyl)-2-hydroxy-1-
27 phenylethyl)carbamate 17e
2
2
This compound is novel and was prepared following the general
procedure F using tert-butyl (2-(3-chlorophenyl)-2-oxo-1-
phenylethyl)carbamate 13e (0.173 g, 0.5 mmol, 1.0 eq) in 1 1.50 mmol, 3.0 eq) for 6 days when 90% conversion of ketone
1
1 MeCN (5 mL), catalyst (R,R)-20 (5.3 mg, 7.5 µmol, 0.015 eq), 2 achieved (determined by H NMR), water (30 mL) to quench
2 DABCO (0.280 g, 2.50 mmol, 5.0 eq) and formic acid (56 µL,
and DCM (2 X 10 mL) for extraction to generate the crude
product which was purified by column chromatography (25%
EtOAc in petroleum ether (40-60)) to give 17g as a white solid
(0.110 g, 0.320 mmol, 64.2%). TLC: Rf ca 0.2 (6:4, Hexane:
1.50 mmol, 1.5 eq) for 24 h when 100% conversion of ketone
1
achieved (determined by H NMR), water (30 mL) to quench
and DCM (2 x 10 mL) for extraction to generate the crude
product which was purified by column chromatography (20- 7 EtOAc), less UV active, strong KMnO4 & PMA reactive; MP:
7 60% EtOAc in petroleum ether (40-60)) to give 17e as a white
120-124 ºC; HRMS (ESI): found [M+Na]+ 366.1672,
C20H25NNaO4 requires [M+Na]+ 366.1676 (error 1 ppm); max
3400, 2975, 1696, 1517, 1494, 1245, 1169, 996, 750 cm-1;
1 1 Enantiomeric excess determined by HPLC analysis (Chiralpak
1 2 IC, 250 mm x 4.6 mm column, iPrOH: hexane 12:88, 0.5
solid (0.136 g, 0.391 mmol, 78.3%). TLC: Rf ca 0.2 (8:2,
Hexane: EtOAc), less UV active, strong KMnO & PMA
1
4
reactive; MP: 202-205 ºC; HRMS (ESI): found [M+Na]+
1 370.1185, C H ClNNaO requires [M+Na]+ 370.1180 (error -
19 22
3
-1
2 1.3 ppm); max 3374, 2977, 1681, 1529, 1165, 1003, 696 cm1 ;
Enantiomeric excess determined by HPLC analysis (Chiralp1ak
IG, 250 mm x 4.6 mm column, iPrOH: hexane 7:93, 01.5
mL/min, 210 nm, T = 25 ºC), (1S,2R) 16.6 min, (1R,2S) isomer
22
20.6 min, other diastereomer 52.3 min and 108.2 min; [α]D
=
1
-5 (c = 0.1 in CHCl3), dr: >99.9:<0.1, 89% ee; H NMR
(CDCl3, 500 MHz,): δ 7.26-7.23 (m, 4H), 7.14 (s, 2H), 6.97 (d,
mL/min, 210 nm, T = 25 ºC), (1S,2R) 16.1 min, (1R,2S) 211.2
22
min, other diastereomer 28.9 min and 36.8 min; [α]D = -1016 7 1H, J = 6.4 Hz), 6.88-6.83 (m, 2H), 5.60 (d, 1H, J = 7.8 Hz),
7 (c = 0.1 in CHCl3), dr: >99.9:<0.1, 967% ee; 1H NM1R
(DMSO-d6, 500 MHz): δ 7.37 – 7.20 (m, 10H), 5.45 (d, 1H, J1=
5.2 Hz), 4.64-4.62 (m, 1H), 4.53 (t, 1H, J = 9.1 Hz), 1.20 (1s,1
5.26 (s, 1H), 5.02 (s, 1H), 3.71 (s, 3H), 2.90 (s, 1H), 1.36 (s,
9H); 13C{1H} NMR (CDCl3, 126 MHz): δ 157.0, 155.8, 140.6,
129.9, 129.0, 127.8, 127.6, 127.0, 126.1, 120.7 110.9, 79.7,
9H); 13C{1H} NMR (DMSO-d6, 126 MHz): δ 154.4, 146.41, 11 57.9, 55.4, 28.5; m/z (ESI) 366.2 [(M+Na)+, 100%].
1 146.1 141.3, 132.2, 129.4, 128.1, 127.6, 126.9, 126.7, 126.71, 12
+
2 125.7, 77.7, 74.7, 74.4, 59.7, 28.1; m/z (ESI) 370.2 [(M+Na)1,1
t-Butyl-((1S,2R)-2-hydroxy-1-(4-methoxyphenyl)-2-
phenylethyl)carbamate 17h.
100%), 372.2 [(M+2+Na)+, 40%].
11
11
This compound is novel and was prepared following the general
procedure F using tert-butyl (1-(4-methoxyphenyl)-2-oxo-2-
117 phenylethyl)carbamate 13h (0.171 g, 0.50 mmol, 1.0 eq) in
MeCN (5 mL), catalyst (R,R)-20 (7.1 mg, 0.01 mmol, 0.02 eq),
DABCO (0.280 g, 2.50 mmol, 5.0 eq) and formic acid (56 µL,
t-Butyl-((1S,2R)-2-(4-chlorophenyl)-2-hydroxy-1-
11
phenylethyl)carbamate 17f.
7 This compound is novel and was prepared following the gener1al1
procedure F using tert-butyl (2-(4-chlorophenyl)-2-oxo-11-1
phenylethyl)carbamate 13f (0.173 g, 0.5 mmol, 1.0 eq) i1n2
MeCN (5 mL), catalyst (R,R)-20 (5.3 mg, 7.5 µmol, 0.015 eq)1, 21 achieved (determined by H NMR), water (30 mL) to quench
1 DABCO (0.280 g, 2.50 mmol, 5.0 eq) and formic acid (56 µL1, 22 and DCM (2 x 10 mL) for extraction to generate the crude
1.5 mmol, 3.0 eq) for 72h when 90% conversion of ketone
1
17
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The Journal of Organic Chemistry
Page 18 of 27
1 product which was purified by column chromatography (25% 2 KMnO4 & PMA reactive; MP: 191-193 ºC; HRMS (ESI):
found [M+Na]+ 370.1182, C19H22ClNNaO3 requires [M+Na]+
370.1180 (error -0.6 ppm); max 3373, 2979, 1681, 1282,
1167, 999, 703 cm-1; Enantiomeric excess determined by
HPLC analysis (Chiralcel OD-H, 250 x 4,6 mm column,
7 iPrOH: hexane 5:95, 1 mL/min, 210 nm, T = 25 ºC), (1R,2S)
1
2
3
4
5
6
7
8
2 EtOAc in petroleum ether (40-60)) to give 17h as a yellowish
white solid (0.120 g, 0.349 mmol, 69.9%). TLC: Rf ca 0.2 (8:2,
Hexane: EtOAc), less UV active, strong KMnO4 & PMA
reactive; MP: 172-175 ºC; HRMS (ESI): found [M+Na]+
366.1675, C20H25NNaO4 requires [M+Na]+ 366.1676 (error 0.2
7 ppm); max 3374, 2979, 1679, 1511, 1242, 1164, 996, 757 cm-
10.8 min, (1S,2R) 12.5 min, other diastereomer 6.5, 16.6 min;
[α]D22 = -164.3 (c = 0.1 in CHCl3), dr: 99.5:0.5, 90% ee; 1H
NMR (CDCl3, 500 MHz): δ 7.26-7.24 (m, 3H), 7.18 (d, 2H, J
1
;
Enantiomeric excess determined by HPLC analysis
(Chiralpak IG, 250 mm x 4.6 mm column, iPrOH: hexane7
1
10:90, 1 mL/min, 210 nm, T = 25 ºC), (1S,2R) 17.7 min, (1R,2S) 71 = 8.3 Hz), 7.04-7.03 (m, 2H), 6.94 (d, 2H, J = 7.9 Hz), 5.38
9
22
11 27.6 min, other diastereomer 32.1 min and 35.2 min; [α]D - 72 (s, 1H), 5.06 (s, 1H), 4.90 (s, 1H), 2.48 (s, 1H), 1.40 (s, 9H);
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12 82.3 (c 0.1 in CHCl3), dr: 99.1:0.9, major diastereomer 90%7
13C{1H} NMR (CDCl3, 126 MHz): δ 155.4, 139.8, 133.3,
129.2, 128.2, 128.1, 127.9, 126.4, 80.1, 76.7, 59.8, 28.3 m/z
(ESI) 370.2 [(M+Na)+, 100%), 372.2 [(M+2+Na)+, 35%].
1
ee; 1H NMR (CDCl3, 500 MHz): δ 7.24-7.22 (m, 3H), 7.07-7
7.06 (m, 2H), 6.94 (d, 2H, J = 8.5 Hz), 6.78-6.75 (m, 2H), 5.257
(d, 1H, J = 6.3 Hz), 5.00 (s, 1H), 4.90 (s, 1H), 3.77 (s, 3H),7
1
1
1
2.71 (s, 1H), 1.39 (s, 9H); 13C{1H} NMR (CDCl3, 126 MHz): δ 77 t-Butyl-((1S,2R)-2-(4-chlorophenyl)-2-hydroxy-1-(4-
17 159.1, 155.8 140.2, 140.1, 129.0, 128.2, 128.1, 127.8, 127.1,7
methoxyphenyl)ethyl)carbamate 17k.
This compound is novel and was prepared following the general
1
1
2
126.8, 113.7, 80.0, 79.3, 77.3, 55.3, 28.5; m/z (ESI) 366.27
[(M+Na)+, 100%].
procedure
F
using tert-butyl (2-(4-chlorophenyl)-1-(4-
1 methoxyphenyl)-2-oxoethyl)carbamate 13k (0.089 g, 0.25
2 mmol, 1.0 eq) in MeCN (2.5 mL), catalyst (R,R)-20 (2.7 mg,
3.8 µmol, 0.015 eq), DABCO (0.140 g, 1.25 mmol, 5.0 eq) and
formic acid (28 µL, 0.750 mmol, 3.0 eq) for 72h when 100%
conversion of ketone achieved (determined by 1H NMR), water
(20 mL) to quench and obtained solid material was filtered and
7 dried to give 17k as a brown solid (0.083 g, 0.233 mmol,
93.5%). TLC: Rf ca 0.3 (6:4, Hexane: EtOAc), less UV active,
strong KMnO4 & PMA reactive; MP: 208-211 ºC; HRMS
(ESI): found [M+Na]+, 400.1284, C20H24ClNNaO4 requires
21 t-Butyl-((1S,2R)-1-(2-chlorophenyl)-2-hydroxy-2-
22 phenylethyl)carbamate 17i.
2
This compound is novel and was prepared following the general
procedure F using tert-butyl (1-(2-chlorophenyl)-2-oxo-2-
phenylethyl)carbamate 13i (0.173 g, 0.5 mmol, 1.0 eq) in
MeCN (5 mL), catalyst (R,R)-20 (5.3 mg, 7.5 µmol, 0.015 eq),
2
2
2
27 DABCO (0.280 g, 2.50 mmol, 5.0 eq) and formic acid (56 µL,
2
2
1.50 mmol, 3.0 eq) for 96h when 95% conversion of ketone
1
achieved (determined by H NMR), water (30 mL) to quench
and DCM (2 x 10 mL) for extraction to generate the crude 1 [M+Na]+ 400.1286 (error 0.5 ppm); max 3372, 2977, 1674,
1 product which was purified by column chromatography (20% 2 1495, 1296, 1240, 1168, 1000, 814, 541 cm-1; Enantiomeric
2 EtOAc in petroleum ether (40-60)) to give 17i as a white solid
(0.150 g, 0.461 mmol, 92.2%). TLC: Rf ca 0.4 (6:4, Hexane:
EtOAc), less UV active, strong KMnO4 & PMA reactive; MP:
123-126 ºC; HRMS (ESI): found [M+Na]+ 370.1181,
C19H22ClNNaO3 requires [M+Na]+ 370.1180 (error -0.1
7 ppm); max 3371, 2977, 1687, 1523, 1165, 773, 702 cm-1;
Enantiomeric excess determined by HPLC analysis (Chiralpak
IC, 250 mm x 4.6 mm column, iPrOH: hexane 12:88, 01.5
excess determined by HPLC analysis (Chiralpak IG, 250 mm x
4.6 mm column, iPrOH: hexane 20:80, 1 mL/min, 210 nm, T =
25 ºC), (1S,2R) 7.9 min, (1R,2S) isomer 9.2 min, other
22
diastereomer 12.8 min and 17.9 min; [α]D = -118 (c 0.1 in
7 CHCl3), dr >99.9:<0.1%, major diastereomer 97% ee  1H
NMR (DMSO-d6, 500 MHz):δ 7.31 (s, 4H), 7.19 (d, 2H, J =
11.6 Hz), 7.13 (d, 1H, J = 9.6 Hz), 6.81 (d, 2H, J = 8.5 Hz), 5.39
(d, 1H, J = 5.1 Hz), 4.63-4.61 (m, 1H), 4.48 (t, 1H, J = 8.7 Hz),
mL/min, 210 nm, T = 25 ºC), (1S,2R) 11.8 min, (1R,2S) 131.4 1 3.71 (s, 3H), 1.20 (s, 9H); 13C{1H} NMR (DMSO-d6, 126
1 min, other diastereomer 35.1 and 50.4 min; [α]D22 = -76.6 (c1= 2 MHz): δ 158.2, 154.6, 142.6, 133.2, 131.4, 129.3, 128.9, 127.5,
1
2 0.1 in CHCl3), dr: 95.5:0.5, major diastereomer 90% ee; 1H
NMR (DMSO-d6, 500 MHz): δ 7.65 (d, 1H, J = 7.4 Hz), 7.310-
7.26 (m, 6H), 7.25-7.21 (m, 3H), 5.35 (d, 1H, J = 4.1 Hz), 5.121
(t, 1H, J = 8.6 Hz), 4.72-4.70 (m, 1H), 1.21 (s, 9H); 13C{1H1}
113.1, 77.8, 74.8, 59.5, 55.1, 28.2; m/z (ESI) 400.3 [(M+Na)+,
100%].
t-Butyl-((1S,2S)-2-(furan-2-yl)-2-hydroxy-1-
NMR (DMSO-d6, 126 MHz): δ 154.9, 143.5, 139.9, 134.11, 7 phenylethyl)carbamate 17l.
7 129.8, 128.9, 128.6, 127.9, 127.5, 127.2, 78.3, 75.6, 56.3, 281.6;
This compound is novel and was prepared following the general
procedure using tert-butyl (2-(furan-2-yl)-2-oxo-1-
phenylethyl)carbamate 13l (0.151 g, 0.50 mmol, 1.0 eq) in
m/z (ESI) 370.2 [(M+Na)+, 100%], 372.2 [(M+2+Na)+, 35%1].
F
11
111 MeCN (5 mL), catalyst (R,R)-20 (5.3 mg, 7.5 µmol, 0.015 eq),
112 DABCO (0.280 g, 2.50 mmol, 5.0 eq) and formic acid (56 µL,
t- Butyl-((1S,2R)-1-(4-chlorophenyl)-2-hydroxy-2-
1 phenylethyl)carbamate 17j.
11
1.50 mmol, 3.0 eq) for 72h when 100% conversion of ketone
achieved (determined by 1H NMR), water (30 mL) to quench
and DCM (2 x 10 mL) for extraction to generate the crude
product which was purified by column chromatography (30%
117 EtOAc in petroleum ether (40-60)) to give 17l as a brown solid
2 This compound is novel and was prepared following the
11
general procedure F using tert-butyl (1-(4-chlorophenyl)-2-
11
oxo-2-phenylethyl)carbamate 13j (0.087 g, 0.25 mmol, 1.0 eq)
in MeCN (2.5 mL), catalyst (R,R)-20 (2.7 mg, 3.8 µmol, 0.01151
eq), DABCO (0.140 g, 1.25 mmol, 5.0 eq) and formic acid
11
(0.120 g, 0.396 mmol, 79.2%). TLC: Rf ca 0.3 (6:4, Hexane:
EtOAc), less UV active, strong KMnO4 & PMA reactive; MP:
163-164 ºC, HRMS (ESI): found [M+Na]+ 326.1362,
7 (28 µL, 0.75 mmol, 3.0 eq) for 72h when 100% conversion of
1
ketone achieved (determined by H NMR), water (30 mL) to 11
12
quench and obtained solid material was filtered and dried to
give 17j as a white solid (0.080 g, 0.230 mmol, 92.2%). TLC:121 C17H21NNaO4 requires [M+Na]+ 326.1363 (error 0.1 ppm); max
1 Rf ca 0.3 (6:4, Hexane: EtOAc), less UV active, strong
122 3373, 2976, 1681, 1527, 1292, 1169, 1001, 734, 698 cm-1;
18
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The Journal of Organic Chemistry
1 Enantiomeric excess determined by HPLC analysis (Chiralpak 2 EtOAc), less UV active, strong KMnO4 & PMA reactive; MP:
113-116 ºC; HRMS (ESI): found [M+Na]+ 274.1410,
1
2
3
4
5
6
7
8
2 IC, 250 mm x 4.6 mm column, iPrOH: hexane 10:90, 1 mL/min,
210nm, T = 25 ºC), (1S, 2S) 10.4 min, (1R,2R) isomer 19.2 min,
other diastereomer 14.1 min and 34.0; [α]D22 = -42.3 (c 0.1 in
CHCl3), dr, 96:4, major diastereomer 79% ee, minor
C14H21NNaO3 requires [M+Na]+ 274.1414 (error 1.3 ppm); max
3371, 2976, 1679, 1520, 1368, 1291, 1165, 1009, 877, 698 cm-
1
;
Enantiomeric excess determined by HPLC analysis
1
diastereomer 56.7%; H NMR (CDCl3, 500 MHz): δ 7.36 (s,
7 (Chiralpak IG, 250 mm x 4.6 mm column, iPrOH: hexane
7 1H), 7.28-7.22 (m, 3H), 7.09 (d, 2H, J = 7.8 Hz), 6.27 (d, 1H, J
12:88, 0.5 mL/min, 210 nm, T = 25 ºC), (1S,2R) 15.8 min,
22
= 5.0 Hz), 6.06 (d, 1H, J = 3.2 Hz), 5.45 (s, 1H), 5.12 (s, 1H),
(1R,2S) 19.5 min, other diastereomer 20.9 min and 24.7; [α]D
4.98 (s, 1H), 2.81 (s, 1H), 1.42 (s, 9H); 13C{1H} NMR (CDCl ,
3 7
= + 22.6 (c = 0.1 in CHCl3), dr, 98.3: 1.7, 95% ee; litabove [α]20
71 D = +24.0 (c = 0.1, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 7.36
72 – 7.26 (m, 5H), 5.42 (d, 1H, J = 6.8 Hz), 4.62 (s, 1H), 4.07 (s,
1
126 MHz): δ 155.8 153.2, 142.2, 138.2, 128.5, 127.9, 127.2,
11 126.9, 110.4, 108.0, 80.2, 71.5, 59.2, 28.5; m/z (ESI) 326.2
12 [(M+Na)+, 100%].
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
1H), 1.89 (s, 1H), 1.42 (s, 9H), 1.08 (s, 3H, J = 6.4 Hz); 13C{1H}
NMR (CDCl3, 126 MHz): δ 155.8 138.4, 128.6, 127.8, 126.7
79.9, 70.5, 60.2, 28.5, 19.8; m/z (ESI) 274.2 [(M+Na)+, 100%].
The data matches the reported data.
1
7
7
7
1
1
1
t-Butyl-((1R,2S)-1-hydroxy-1-phenylpropan-2-
yl)carbamate 24.
This compound is known and has been previously
77
17 characterised:..29b,38 This compound was prepared following the7
N-((1S,2R)-2-Hydroxy-2-(2-methoxyphenyl)-1-
phenylethyl)-4-methylbenzene sulfonamide 18b.
This compound is novel and was prepared following the
1
1
2
general procedure F using tert-butyl (1-oxo-1-phenylpropan-2-7
yl)carbamate (0.125 g, 0.5 mmol, 1.0 eq) in MeCN (5 mL),
catalyst (R,R)-20 (5.3 mg, 7.5 µmol, 0.015 eq), DABCO (0.280 1 general procedure F using N-(2-(2-methoxyphenyl)-2-oxo-1-
21 g, 2.50 mmol, 5.0 eq) and formic acid (56 µL, 1.50 mmol, 3.0 2 phenylethyl)-4-methylbenzenesulfonamide 14b (0.197 g, 0.5
22 eq) for 6 days when 76% conversion of ketone achieved
mmol, 1.0 eq) in MeCN (5 mL), catalyst (R,R)-2 (4.7 mg, 7.5
µmol, 0.015 eq), DABCO (0.280 g, 2.50 mmol, 5.0 eq) and
formic acid (56 µL, 1.50 mmol, 3.0 eq) for 24 h when 100%
conversion of ketone achieved (determined by 1H NMR), water
2
(determined by 1H NMR), water (30 mL) to quench and DCM
(2 x 10 mL) for extraction to generate the crude product which
was purified by column chromatography (30% EtOAc in
2
2
2
petroleum ether (40-60)) to give 24 as a colourless oil (0.066 g, 7 (30 mL) to quench and DCM (2 x 10 mL) for extraction to
27 0.265 mmol, 53.1%). TLC: Rf ca 0.3 (6:4, Hexane: EtOAc) less
generate the crude product which was purified by column
chromatography (20-60% EtOAc in petroleum ether (40-60)) to
give 18b as a white solid (0.158 g, 0.396 mmol, 79.3%). TLC:
1 Rf ca 0.2 (8:2, Hexane: EtOAc), less UV active, strong KMnO4
2 & PMA reactive; MP: 120-121 ºC; HRMS (ESI): found
[M+Na]+ 420.1242, C22H23NNaO4S requires [M+Na]+
420.1240 (error -0.4 ppm); max 3519, 3324, 1323, 1236, 1158,
1053, 536 cm-1; Enantiomeric excess determined by HPLC
analysis (Chiralpak IC, 250 mm x 4.6 mm column, iPrOH:
2
2
UV active, strong KMnO4 & PMA reactive; HRMS (ESI):
found [M+Na]+ 274.1417, C14H21NNaO3 requires [M+Na]+
274.1414 (error 1.3 ppm); max 3413, 2977, 1681, 1496, 1365,
1 1124, 1050, 734 cm-1; Enantiomeric excess determined by
2 HPLC analysis (Chiralpak IG, 250 mm x 4.6 mm column,
iPrOH: hexane 12:88, 0.5 mL/min, 210 nm, T = 25 ºC), (1R,2S)
10.9 min, (1S,2R) isomer 11.7 min, other diastereomer 12.9 min
and 23.8; dr: 79:21, major diastereomer 34% ee (accuracy
limited by overlap of peaks), minor diastereomer 82% ee; ) 7 hexane 20:80, 1 mL/min, 210 nm, T = 25 ºC), (1S,2R) 21.2 min,
7 Major diastereomer 1H NMR (CDCl3, 500 MHz): δ 7.41-7.09
(m, 5H), 4.82-4.79 (m, 2H), 3.97 (s, 1H), 3.55 (s, 1H), 1.45 (s,
9H), 0.96 (d, 3H, J = 6.9 Hz); 13C{1H} NMR (CDCl3, 1126
(1R,2S) isomer 28.1min, other diastereomer 45.0 min and 66.2
22
min; [α]D = -42.3 (c = 0.1 in CHCl3), dr: >99.9:<0.1, 95%
ee; 1H NMR (CDCl3, 500 MHz): δ 7.48 (d, 2H, J = 8.2 Hz),
MHz): 156.3, 140.9, 128.1, 127.4, 126.3, 79.7, 76.6, 52.01.919, 1 7.18 (m, 1H), 7.14-7.06 (m, 5H), 6.91-6.88 (m, 3H), 6.79-6.74
1 28.4, 14.7; m/z (ESI) 274.2 (M+Na, 100%); Mino1r 2 (m, 2H), 5.70 (d, 1H, J = 7.5 Hz), 5.13 (t, 1H, J = 5.8 Hz), 4.57-
1
2 diastereomer H NMR (CDCl3, 500 MHz): δ 7.41-7.09 (1m,
5H), 4.82-4.79 (m, 1H), 4.53 (s, 1H), 3.85-3.84 (d, 1H J = 51.8
Hz), 1.99 (s, 1H), 1.39 (s, 9H), 1.06 (s, 3H, J = 6.9 Hz); 13C{1H1}
NMR (CDCl3, 126 MHz): δ 156.3, 141.7, 128.3, 127.7, 1261.6,
79.7, 77.8 52.4, 28.3, 17.5; m/z (ESI) 274.2 [(M+Na)+, 100%1]. 7
4.55 (m, 1H), 3.64 (s, 3H), 2.71 (d, 1H, J = 6.6 Hz), 2.34 (s,
3H); 13C{1H} NMR (CDCl3, 126 MHz: δ 156.2, 142.9, 137.5,
137.1, 129.4, 129.0, 128.0, 127.9, 127.6, 127.1, 120.9, 110.5,
62.4, 55.4, 21.6; m/z (ESI) 420.3 [(M+Na)+, 100%].
7 The data matches the reported data.
1
1
N-((1S,2R)-2-Hydroxy-2-(3-methoxyphenyl)-1-
phenylethyl)-4-methylbenzene sulfonamide 18c.
This compound is novel and was prepared following the general
t-Butyl-((1S,2R)-2-hydroxy-1-phenylpropyl)carbamate 261. 1
111 procedure
F
using
N-(2-(3-methoxyphenyl)-2-oxo-1-
This compound is known and has been previously
1 characterised.29 This compound was prepared following the
112 phenylethyl)-4-methylbenzenesulfonamide 14c (0.100 g, 0.25
11
(2-oxo-1-
mmol, 1.0 eq) in MeCN (2.5 mL), catalyst (R,R)-2 (2.3 mg, 3.8
µmol, 0.015 eq), DABCO (0.140 g, 1.25 mmol, 5.0 eq) and
formic acid (28 µL, 0.750 mmol, 3.0 eq) for 24 h when 100%
conversion of ketone achieved (determined by 1H NMR), water
117 (20 mL) to quench and DCM (2 x 5 mL) for extraction to
2 general
procedure
F
using
tert-butyl
phenylpropyl)carbamate (0.125 g, 0.5 mmol, 1.0 eq) in MeC1N1
(5 mL), catalyst (R,R)-20 (5.3 mg, 7.5 µmol, 0.015 eq), DABC1O1
(0.280 g, 2.50 mmol, 5.0 eq) and formic acid (56 µL, 1.50
11
mmol, 3.0 eq) for 24 h when 100% conversion of ketone
1
11
generate the crude product which was purified by column
chromatography (30% EtOAc in petroleum ether (40-60)) to
give 18c as a white solid (0.085 g, 0.214 mmol, 85.6%). TLC:
121 R ca 0.2 (8:2, Hexane: EtOAc), less UV active, strong KMnO
7 achieved (determined by H NMR), water (30 mL) to quench
11
and DCM (2 x 10 mL) for extraction to generate the crude
12
product which was purified by column chromatography (30%
EtOAc in petroleum ether (40-60)) to give 26 as a brown solid
1 (0.109 g, 0.434 mmol, 86.8%). TLC: Rf ca 0.3 (6:4, Hexane:
f
4
122 & PMA reactive; MP: 153-155 ºC; HRMS (ESI): found
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
1 [M+Na]+ 420.1239, C22H23NNaO4S requires [M+Na]+
Page 20 of 27
2 [M+Na]+ 424.0745 (error 0.2 ppm); max 3466, 3325, 1404,
1289, 1152, 1032, 530 cm-1; Enantiomeric excess determined
by HPLC analysis (Chiralpak IC, 250 mm x 4.6 mm column,
iPrOH: hexane 20:80, 1 mL/min, 210 nm, T = 25 ºC), (1S,2R)
10.9 min, (1R,2S) 12.5 min, other diastereomer 26.2 min and
1
2
3
4
5
6
7
8
2 420.1240 (error 0.3 ppm); max 3482, 3317, 1312, 1247, 1151,
1086, 560 cm-1; Enantiomeric excess determined by HPLC
analysis (Chiralpak IC, 250 mm x 4.6 mm column, iPrOH:
hexane 20:80, 1 mL/min, 210 nm, T = 25 ºC), (1S,2R) 24.1 min,
(1R,2S) 26.2 min, other diastereomer 51.9 min and 81.2 min; 7 30.1 min; [α]D22 = -40 (c = 0.1 in CHCl3), dr: >99.9:<0.1, 94%
22
7 [α]D = -17.4 (c = 0.1 in CHCl3), dr: 98.3: 1.7, major
ee; 1H NMR (DMSO-d6,500 MHz): δ 8.14 (d, 1H, J = 10.0 Hz),
7.26 (d, 2H, J = 8.2 Hz), 7.22-7.21 (m, 2H), 7.15-7.13 (m, 2H),
7.10 (s, 5H), 7.05 (d, 2H, J = 8.0 Hz), 5.52 (d, 1H, J = 10.0 Hz),
1
diastereomer 94% ee; H NMR (CDCl3, 500 MHz): δ 7.48 (d,
2H, J = 8.2 Hz), 7.16-7.07 (m, 6H), 6.87 (d, 2H, J = 7.4 Hz),7
1
6.75 (d, 1H, J = 10.3 Hz), 6.58 (d, 1H, J = 7.6 Hz), 6.40 (s, 1H), 71 4.58-4.56 (m, 1H), 4.24 (m, 1H), 2.27 (s, 3H); 13C{1H} NMR
9
11 5.32 (d, 1H, J = 7.8 Hz), 4.95 (t, 1H, J = 4.5 Hz), 4.52-4.50 (m, 72 (DMSO-d6, 126 MHz): δ 145.9, 142.2, 139.8, 138.9, 132.9,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12 1H), 3.61 (s, 3H), 2.37 (d, 1H, J = 4.6 Hz), 2.33 (s, 3H); 13C{1H}7
129.9, 129.4, 128.6, 127.7, 127.4, 127.2, 127.1, 126.5, 126.1,
75.2, 63.6, 21.4; m/z (ESI) 424.2 [(M+Na)+, 100%], 426.2
[(M+2+Na)+, 35%].
1
NMR (CDCl3, 126 MHz): δ 159.6, 143.3, 140.8, 137.1, 136.1,7
129.5, 129.4, 128.1, 128.1, 127.8, 127.2, 118.9, 114.4, 111.6,7
1
1
1
76.9, 63.2, 55.2 21.6; m/z (ESI) 420.2 [(M+Na)+, 100%].
7
77 N-((1S,2R)-2-Hydroxy-2-(4-chlorophenyl)-1-phenylethyl)-
17 N-((1S,2R)-2-Hydroxy-2-(2-chlorophenyl)-1-phenylethyl)-
7
7
4-methylbenzene sulfonamide 18f.
1
4-methylbenzene sulfonamide 18d.
This compound is novel and was prepared following the general
procedure using N-(2-(2-chlorophenyl)-2-oxo-1-
This compound is known however it has not been fully
characterized previously.40 This compound was prepared
1
2
F
1 following the general procedure
2 chlorophenyl)-2-oxo-1-phenylethyl)-4-
F
using N-(2-(4-
21 phenylethyl)-4-methylbenzenesulfonamide 14d (0.100 g, 0.25
22 mmol, 1.0 eq) in MeCN (2.5 mL), catalyst (R,R)-2 (2.3 mg, 3.8
methylbenzenesulfonamide 14f (0.199 g, 0.50 mmol, 1.0 eq) in
MeCN (5 mL), catalyst (R,R)-2 (4.7 mg, 7.5 µmol, 0.015 eq),
DABCO (0.280 g, 2.50 mmol, 5.0 eq) and formic acid (56 µL,
1.50 mmol, 3.0 eq) for 24 h when 100% conversion of ketone
2
µmol, 0.015 eq), DABCO (0.140 g, 1.25 mmol, 5.0 eq) and
formic acid (28 µL, 0.750 mmol, 3.0 eq) for 24 h when 100%
conversion of ketone achieved (determined by 1H NMR), water
(20 mL) to quench and DCM (2 x 5 mL) for extraction to
2
2
2
1
7 achieved (determined by H NMR), water (30 mL) to quench
27 generate the crude product which was purified by column
and DCM (2 x 10 mL) for extraction to generate the crude
product which was purified by column chromatography (80%
EtOAc in petroleum ether (40-60)) to give 18f as a white solid
1 (0.090 g, 0.224 mmol, 44.8%). TLC: Rf ca 0.3 (7:3, Hexane:
2 EtOAc), less UV active, strong KMnO4 & PMA reactive; MP:
243-245 ºC; HRMS (ESI): found [M+Na]+ 424.0746,
C21H20ClNNaO3S requires [M+Na]+ 424.0745 (error 0.4
ppm); max 3460, 3321, 1457, 1309, 1150, 1087, 722 cm-1;
Enantiomeric excess determined by HPLC analysis (Chiralpak
7 IC, 250 mm x 4.6 mm column, iPrOH: hexane 20:80, 1 mL/min,
210 nm, T = 25 ºC), (1S,2R) 11.0 min, (1R,2S) isomer 12.9 min,
2
2
chromatography (30% EtOAc in petroleum ether (40-60)) to
give 18d as a white solid (0.044 g, 0.109 mmol, 43.9%). TLC:
Rf ca 0.2 (8:2, Hexane: EtOAc), less UV active, strong KMnO4
1 & PMA reactive; MP: 150-153 ºC; HRMS (ESI): found
2 [M+Na]+ 424.0746, C21H20ClNNaO3S requires [M+Na]+
424.0745 (error -0.3 ppm); max 3483, 3319, 1409, 1302, 1155,
1030, 659 cm-1; Enantiomeric excess determined by HPLC
analysis (Chiralpak IG, 250 mm x 4.6 mm column, iPrOH:
hexane 20:80, 1 mL/min, 210 nm, T = 25 ºC), (1R,2S) 17.3 min,
7 (1S,2R) isomer 20.6 min, other diastereomer 24.0 min and 37.1
min; [α]D22 = -271.6 (c = 0.1 in CHCl3), dr: >99.9:<0.1, 89%
22
other diastereomer 21.7 min and 44.4 min; [α]D = -25.6 (c =
1
1
ee; H NMR (CDCl , 500 MHz): δ 7.59 (d, 2H, J = 8.2 Hz),
1
0.1 in THF), dr: 97.7:2.3, major diastereomer 89% ee; H
3
7.26-7.23 (d, 1H, J = 3.8 Hz), 7.11-7.07 (m, 4H), 7.00 (t, 2H, J
1 1 NMR (DMSO-d6, 500 MHz): δ 8.15 (d, 1H, J = 9.6 Hz), 7.25
1 2 (d, 2H, J = 8.2 Hz), 7.19 (d, 2H, J = 8.5 Hz), 7.14 (d, 2H, J =
8.4 Hz), 7.11 (s, 5H), 7.06 (d, 2H, J = 8.0 Hz), 5.45 (d, 1H, J =
5.0 Hz), 4.58-4.56 (m, 1H), 4.23 – 4.20 (m, 1H), 2.29 (s, 3H);
13C{1H} NMR (DMSO-d6, 126 MHz): δ 142.3, 142.1, 134.0,
139.0, 132.0, 129.4, 129.1, 128.6, 127.9, 127.7, 127.1, 126.5,
1 7 75.1, 63.7, 21.2; m/z (ESI) 424.2 [(M+Na)+, 100%], 426.2
1 = 7.6 Hz), 6.92 (t, 1H, J = 7.5 Hz), 6.81-6.80 (m, 3H), 5.87 (d,
2 1H, J = 8.1 Hz), 5.45 (s, 1H), 4.69-4.67 (m, 1H), 2.74 (s, 1H),
1
2.31 (s, 3H); 13C{1H} NMR (CDCl , 126 MHz): δ 143.3, 137.4,
1
3
137.2, 135.8, 131.7, 129.5, 129.0, 128.9, 128.3, 128.2, 127.8,
1
127.7, 127.3, 126.6 72.9, 60.6, 21.6; m/z (ESI) 424.2 [(M+Na)+,
1
100%], 426.1 [(M+2+Na)+, 35%].
1
[(M+2+Na)+, 35%].
7
N-((1S,2R)-2-Hydroxy-2-(3-chlorophenyl)-1-phenylethyl)-
1
4-methylbenzene sulfonamide 18e.
This compound is novel and was prepared following the general
1 procedure using N-(2-(3-chlorophenyl)-2-oxo-1-
2 phenylethyl)-4-methylbenzenesulfonamide 14e (0.100 g, 0.25
11
N-((1S,2R)-2-Hydroxy-1-(2-methoxyphenyl)-2-
111 phenylethyl)-4-methylbenzenesulfonamide 18g.
112 This compound is novel and was prepared following the general
F
11
procedure
F
using
N-(1-(2-methoxyphenyl)-2-oxo-2-
mmol, 1.0 eq) in MeCN (2.5 mL), catalyst (R,R)-2 (2.3 mg, 3.8
µmol, 0.015 eq), DABCO (0.140 g, 1.25 mmol, 5 eq) and
11
phenylethyl)-4-methylbenzenesulfonamide 14g (0.198 g, 0.50
mmol, 1.0 eq) in MeCN (5 mL), catalyst (R,R)-2 (4.7 mg, 7.5
µmol, 0.015 eq), DABCO (0.280 g, 2.50 mmol, 5.0 eq) and
117 formic acid (56 µL, 1.50 mmol, 3.0 eq) for 48h when 100%
11
formic acid (28 µL, 0.750 mmol, 3 eq) for 24 h when 100%
11
conversion of ketone achieved (determined by 1H NMR), water
7 (20 mL) to quench and obtained solid material was filtered and
11
11
12
conversion of ketone achieved (determined by 1H NMR), water
(30 mL) to quench and DCM (2 x 10 mL) for extraction to
generate the crude product which was purified by column
121 chromatography (30% EtOAc in petroleum ether (40-60)) to
122 give 18g as a colourless semi solid (0.170 g, 0.428 mmol,
dried to give 18e as a brown solid (0.090 g, 0.229 mmol,
89.7%). TLC: R ca 0.2 (8:2, Hexane: EtOAc), less UV active,
f
strong KMnO & PMA reactive; MP: 210-213 ºC; HRMS
4
1 (ESI): found [M+Na]+ 424.0744, C H ClNNaO S requires
21 20
3
20
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Page 21 of 27
The Journal of Organic Chemistry
1 85.6%). TLC: Rf ca 0.2 (8:2, Hexane: EtOAc) less UV active, 2 Rf ca 0.2 (7:3, Hexane: EtOAc), less UV active, strong KMnO4
2 strong KMnO4 & PMA reactive; HRMS (ESI): found [M+Na]+
420.1242, C22H23NNaO4S requires [M+Na]+ 420.1240 (error -
0.4 ppm); max 3392, 2926, 1493, 1244, 1155, 1001, 750 cm-1;
Enantiomeric excess determined by HPLC analysis (Chiralpak
& PMA reactive; MP: 143- 146 ºC; HRMS (ESI): found
[M+Na]+ 424.0744, C21H20ClNNaO3S requires [M+Na]+
424.0745 (error 0.2 ppm); max 3502, 3356, 2954, 1297, 1152,
1065, 535 cm-1; Enantiomeric excess determined by HPLC
1
2
3
4
5
6
7
8
IC, 250 mm x 4.6 mm column, iPrOH: hexane 20:80, 1 mL/min, 7 analysis (Chiralpak IC, 250 mm x 4.6 mm column, iPrOH:
7 210 nm, T = 25 ºC), (1S,2R) 34.9 min, (1R,2S) 40.7 min, other
hexane 20:80, 1 mL/min, 210 nm, T = 25 ºC), (1S,2R) 15.9 min,
(1R,2S) 17.8 min, other diastereomer 25.3 min and 38.1 min;
22
diastereomer 74.5 min and 122.3 min; [α]D = -30 (c = 0.1 in
1
22
CHCl3), dr: 94.8: 5.2, major diastereomer 80% ee; H NMR7
[α]D = -17.6 (c = 0.1 in CHCl3), dr: 88: 12, major
1
1
(CDCl3, 500 MHz): δ 7.43 (d, 2H, J = 7.9 Hz), 7.20-7.19 (m, 71 diastereomer 80% ee, minor diastereomer 18% ee; H NMR
9
11 3H), 7.11 (t, 1H, J = 7.8 Hz), 7.04 (s, 2H), 6.99 (d, 2H, J = 7.9 72 (CDCl3, 600 MHz): δ 7.51 (d, 2H, J = 8.1 Hz), 7.24-7.20 (m,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12 Hz), 6.77 (d, 1H, J = 7.4 Hz), 6.70 (t, 1H, J = 7.4 Hz), 6.59 (d,7
1H), 7.19-7.16 (m, 2H), 7.11 (d, 1H, J = 7.9 Hz), 7.08-7.06 (m,
3H), 7.00-6.92 (m, 4H), 5.34 (d, 1H, J = 8.4 Hz), 5.15 (d, 1H, J
= 7.6 Hz), 5.07-5.06 (m, 1H), 2.37 (d, 1H, J = 3.6 Hz), 2.32 (s,
3H); 13C{1H} NMR (CDCl3, 151 MHz): δ 143.4, 138.5, 136.8,
1
1H, J = 8.2 Hz), 5.70 (d, 1H, J = 9.8 Hz), 4.94 (t, 1H, J = 5.27
Hz), 4.81-4.78 (m, 1H), 3.51 (s, 3H), 2.64 (d, 1H, J = 5.2 Hz),7
2.28 (s, 3H); 13C{1H} NMR (CDCl3, 126 MHz): δ 156.5, 143.0,7
1
1
1
139.9, 137.3, 130.2, 129.2, 129.1, 128.0, 127.9, 127.0, 126.9, 77 134.2, 133.6, 129.8, 129.5, 129.2, 128.9, 128.5, 128.3, 127.2,
17 124.3, 120.6, 110.7, 76.1, 61.2, 55.3, 21.5; m/z (ESI) 420.37
127.0, 126.9, 126.5, 125.8, 75.7, 74.6, 21.6; m/z (ESI) 424.2
[(M+Na)+, 100%], 426.3 [(M+2+Na)+, 35%].
1
1
2
[(M+Na)+, 100%].
7
N-((1S,2R)-2-Hydroxy-1-(4-methoxyphenyl)-2-
1 N-((1S,2R)-1-(4-Chlorophenyl)-2-hydroxy-2-phenylethyl)-
2 4-methylbenzenesulfonamide 18j.
21 phenylethyl)-4-methylbenzenesulfonamide 18h.
22 This compound is novel and was prepared following the general
This compound is novel and was prepared following the general
2
2
2
2
procedure
F
using
N-(1-(4-methoxyphenyl)-2-oxo-2-
procedure
F
using
N-(1-(4-chlorophenyl)-2-oxo-2-
phenylethyl)-4-methylbenzenesulfonamide 14h (0.198 g, 0.50
mmol, 1.0 eq) in MeCN (5 mL), catalyst (R,R)-2 (4.7 mg, 7.5
µmol, 0.015 eq), DABCO (0.280 g, 2.50 mmol, 5.0 eq) and
phenylethyl)-4-methylbenzenesulfonamide 14j (0.200 g, 0.5
mmol, 1.0 eq) in MeCN (5 mL), catalyst (R,R)-2 (4.6 mg, 7.5
7 µmol, 0.015 eq), DABCO (0.280g, 2.50 mmol, 5.0 eq) and
formic acid (56 µL, 1.50 mmol, 3.0 eq) for 24 h when 100%
conversion of ketone achieved (determined by 1H NMR), water
(30 mL) to quench and obtained solid material was filtered and
1 dried to give 18j as a white solid (0.170 g, 0.424 mmol, 84.8%).
2 TLC: Rf ca 0.2 (7:3, Hexane: EtOAc), less UV active, strong
KMnO4 & PMA reactive; MP: 232-236 ºC; HRMS (ESI):
found [M+Na]+ 424.0747, C21H20ClNNaO3S requires [M+Na]+
424.0745 (error -0.7 ppm); max 3462, 3323, 1314, 1150, 1057,
537 cm-1; Enantiomeric excess determined by HPLC analysis
7 (Chiralpak IC, 250 mm x 4.6 mm column, iPrOH: hexane
20:80, 1 mL/min, 210 nm, T = 25 ºC), (1S,2R) 11.2 min, (1R,2S)
13.9 min, other diastereomer 23.8 min and 45.8 min; [α]D22 = -
114.6 (c = 0.1 in THF), dr: 97.7:2.3, major diastereomer 92%
27 formic acid (56 µL, 1.50 mmol, 3.0 eq) for 24 h when 100%
2
2
conversion of ketone achieved (determined by 1H NMR), water
(30 mL) to quench and obtained solid material was filtered and
dried to give 18h as a brown solid (0.189 g, 0.476 mmol,
1 95.2%). TLC: Rf ca 0.3 (7:3, Hexane: EtOAc), less UV active,
2 strong KMnO4 & PMA reactive; MP: 201-203 ºC; HRMS
(ESI): found [M+Na]+ 420.1238, C22H23NNaO4S requires
[M+Na]+ 420.1240 (error 0.4 ppm); max 3480, 3321, 2972,
1513, 1303, 1151, 1055, 540 cm-1; Enantiomeric excess
determined by HPLC analysis (Chiralpak IC, 250 mm x 4.6 mm
7 column, iPrOH: hexane 20:80, 1 mL/min, 210 nm, T = 25 ºC),
(1S,2R) 25.8 min, (1R,2S) 33.9 min, other diastereomer 60.0
22
min; [α]D = -27.6 (c = 0.1 in CHCl ), dr: 98.2:1.8, major
1
3
1
1
diastereomer 90% ee; H NMR (CDCl , 500 MHz): δ 7.48 (d,
1 1 ee; minor diastereomer >99% ee H NMR (DMSO-d6, 500
3
1 2H, J = 8.0 Hz), 7.21-7.20 (m, 3H), 7.09 (d, 2H, J = 7.8 Hz),
1 2 MHz): δ 8.15 (d, 1H, J = 8.8 Hz), 7.28 (d, 2H, J = 7.8 Hz), 7.23
– 7.19 (m, 3H), 7.14 (d, 2H, J = 7.2 Hz), 7.07-7.06 (m, 4H), 6.99
(d, 2H, J = 8.1 Hz), 5.45 (d, 1H, J = 4.5 Hz), 4.64 – 4.62 (m,
1H), 4.28 (t, 1H, J = 7.5 Hz), 2.28 (s, 3H); 13C{1H} NMR
(DMSO-d6, 126 MHz): δ 142.5, 141.8, 138.4, 137.7, 131.2,
1 7 130.1, 128.9, 127.6, 127.1, 126.9, 126.7, 126.2, 75.1, 62.7, 20.8;
2 6.96 (d, 2H, J = 6.3 Hz), 6.75 (d, 2H, J = 8.3 Hz), 6.60 (d, 2H, J
1
1
= 8.2 Hz), 5.21 (d, 1H, J = 7.4 Hz), 4.95 (s, 1H), 4.49-4.47 (m,
1H), 3.73 (s, 3H), 2.35 (s, 3H), 2.31 (s, 1H); 13C{1H} NMR
1
1
(CDCl , 126 MHz): δ 159.2, 143.2, 139.3, 137.3, 129.5, 129.3,
3
128.4 128.2, 128.0, 127.2, 126.7, 113.5, 76.9, 62.8, 55.3, 21.6;
7 m/z (ESI) 420.4 [(M+Na)+, 100%].
1
m/z (ESI) 424.2 [(M+Na)+, 100%], 426.3 [(M+2+Na)+, 35%].
1
11
N-((1S,2R)-1-(2-Chlorophenyl)-2-hydroxy-2-phenylethyl)-
N-((1S,2R)-2-(4-Chlorophenyl)-2-hydroxy-1-(4-
4-methylbenzenesulfonamide 18i.
111 methoxyphenyl)ethyl)-4-methylbenzenesulfonamide 18k.
112 This compound is novel and was prepared following the
1 This compound is novel and was prepared following the general
2 procedure
F
using
N-(1-(2-chlorophenyl)-2-oxo-2-
11
general procedure
F
using N-(2-(4-chlorophenyl)-1-(4-
phenylethyl)-4-methylbenzenesulfonamide 14i (0.100 g, 0.25
11
methoxyphenyl)-2-oxoethyl)-4-methylbenzenesulfonamide
14k (0.107 g, 0.25 mmol, 1.0 eq) in MeCN (2.5 mL), catalyst
(R,R)-2 (2.3 mg, 3.8 µmol, 0.015 eq), DABCO (0.140 g, 1.25
117 mmol, 5.0 eq) and formic acid (28 µL, 0.750 mmol, 3.0 eq) for
mmol, 1.0 eq) in MeCN (2.5 mL), catalyst (R,R)-2 (2.3 mg, 3.8
11
µmol, 0.015 eq), DABCO (0.140 g, 1.25 mmol, 5.0 eq) and
11
formic acid (28 µL, 0.750 mmol, 3.0 eq) for 48h when 100%
7 conversion of ketone achieved (determined by 1H NMR), water
11
48h when 100% conversion of ketone achieved (determined by
1H NMR), water (20 mL) to quench and obtained solid material
was filtered and dried to give 18k as a white solid (0.095 g,
121 0.220 mmol, 88.2%). TLC: Rf ca 0.2 (7:3, Hexane: EtOAc),
122 less UV active, strong KMnO4 & PMA reactive; MP: 240-243
(30 mL) to quench and DCM (2 X 10 mL) for extraction to
11
generate the crude product which was purified by column
12
chromatography (20% EtOAc in petroleum ether (40-60)) to
1 give 18i as a white solid (0.070 g, 0.174 mmol, 69.8%). TLC:
21
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The Journal of Organic Chemistry
Page 22 of 27
1 ºC; HRMS (ESI): found [M+Na]+ 454.0850, C22H22ClNNaO4S 2 1.50 mmol, 3.0 eq) for 24 h when 100% conversion of ketone
1
2 requires [M+Na]+ 454.0850 (error 0.0 ppm); max 3527, 3235,
1
2
3
4
5
6
7
8
achieved (determined by H NMR), water (30 mL) to quench
1512, 1311, 1238, 1157, 1029, 815, 664, 573, 536 cm-1;
Enantiomeric excess determined by HPLC analysis (Chiralpak
IC, 250 mm x 4.6 mm column, iPrOH: hexane 20:80, 1 mL/min,
210 nm, T = 25 ºC), (1S,2R) 15.8 min, (1R,2S) isomer 19.3 min,
7 other diastereomer 34.9 min and 68.3 min; [α]D22 = -139.2 (c =
and DCM (2 x 10 mL) for extraction to generate the crude
product which was purified by column chromatography (30%
EtOAc in petroleum ether (40-60)) to give 23 as a white solid
7 (0.110 g, 0.395 mmol, 79.0%). TLC: Rf ca 0.4 (6:4, Hexane:
EtOAc), less UV active, strong KMnO4 & PMA reactive; MP:
152-155 ºC; HRMS (ESI): found [M+Na]+ 314.0823,
C15H17NNaO3S requires [M+Na]+ 314.0921 (error -0.5
1
0.05 in THF), dr: >99.9:<0.1, 98% ee; H NMR (DMSO-d6,
7
600 MHz): δ 8.05 (d, 1H, J = 9.5 Hz), 7.26 (d, 2H, J = 8.1 Hz),
1
7.20 (d, 2H, J = 8.3 Hz), 7.13 (d, 2H, J = 8.4 Hz), 7.06 (d, 2H, 71 ppm); max 3486, 3320, 1455, 1407, 1301, 1145, 1056, 981,
9
11 J = 8.0 Hz), 6.98 (d, 2H, J = 8.5 Hz), 6.64 (d, 2H, J = 8.5 Hz), 72 159, 696 cm-1; Enantiomeric excess determined by HPLC
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12 5.42 (d, 1H, J = 4.9 Hz), 4.57-4.55 (m, 1H), 4.18-4.15 (m, 1H)),7
analysis (Chiralpak IC, 250 mm x 4.6 mm column, iPrOH:
1
3.67 (s, 3H), 2.29 (s, 3H); 13C{1H} NMR (DMSO-d6, 1517
MHz): δ 158.1, 141.9, 141.6, 138.6, 131.5, 131.3 129.3, 128.9,7
128.6, 127.5, 126.1, 112.7, 74.7, 62.7, 55.0, 20.9; m/z (ESI)7
454.2 [(M+Na)+, 100%], 456.3 [(M+2+Na)+, 35%].
7
hexane 20:80, 1 mL/min, 210 nm, T = 25 ºC), (1S,2R) 13.9 min,
22
1
1
1
(1R,2S) 16.4 min, other diastereomer 30.8 min; [α]D = -68.3
(c 0.1 in CHCl3), dr: 97.4: 2.6, major diastereomer 95% ee;
1
77 litb above [α]D20 = -22.5 (c 0.98, CHCl3); H NMR (DMSO-d6,
17
500 MHz): δ 7.70 (d, 1H, J = 9.7 Hz), 7.32 – 7.26 (m, 8H), 7.24-
1
1
2
N-((1S,2S)-2-(Furan-2-yl)-2-hydroxy-1-phenylethyl)-4-
7
7.21 (m, 2H), 5.49 (d, 1H, J = 4.9 Hz), 4.75 – 4.73 (m, 1H), 4.36
methylbenzenesulfonamide 18l
– 4.33 (m, 1H), 2.18 (s, 3H); 13C{1H} NMR (DMSO-d6, 126
This compound is novel and was prepared following the general 1 MHz): δ 143.2, 140.3, 128.3, 127.7, 127.7, 127.2, 127.1, 127.0,
21 procedure F using N-(2-(furan-2-yl)-2-oxo-1-phenylethyl)-4- 2 75.3, 63.4, 40.8; m/z (ESI) 314.3 [(M+Na)+, 100%]. The data
22 methylbenzenesulfonamide 14l (0.178 g, 0.5 mmol, 1.0 eq) in
matches the reported data.
2
MeCN (5 mL), catalyst (R,R)-2 (4.7 mg, 7.5 µmol, 0.015 eq),
2
2
2
DABCO (0.280 g, 2.50 mmol, 5.0 eq) and formic acid (56 µL,
N-((1R,2S)-1-Hydroxy-1-phenylpropan-2-yl)-4-
1.50 mmol, 3.0 eq) for 48h when 100% conversion of ketone
methylbenzenesulfonamide 25.
1
achieved (determined by H NMR), water (30 mL) to quench 7 This compound is known and has been previously
27 and DCM (2 x 10 mL) for extraction to generate the crude
characterised.42 This compound was prepared following the
general procedure using 4-methyl-N-(2-oxo-1-
phenylpropyl)benzenesulfonamide (0.152 g, 0.5 mmol, 1.0 eq)
2
2
product which was purified by column chromatography (40%
F
EtOAc in petroleum ether (40-60)) to give 18l as a white solid
(0.165 g, 0.462 mmol, 92.4%). TLC: Rf ca 0.3 (6:4, Hexane: 1 in MeCN (5 mL), catalyst (R,R)-2 (4.7 mg, 7.5 µmol, 0.015 eq),
1 EtOAc), less UV active, strong KMnO4 & PMA reactive; 2 DABCO (0.280 g, 2.50 mmol, 5.0 eq) and formic acid (56 µL,
2 HRMS (ESI): found [M+Na]+ 380.0926, C19H19NNaO4S
requires [M+Na]+ 380.0927 (error 0.4 ppm); max 3460, 1414,
1318, 1156, 1089, 1060, 809, 698, 663, 564 cm-1; Enantiomeric
excess determined by HPLC analysis (Chiralpak IG, 250 mm x
4.6 mm column, iPrOH: hexane 20:80, 1 mL/min, 210 nm, T =
7 25 ºC), (1S, 2S) 23.4 min, (1R,2R) isomer 27.3 min, other
diastereomer 35.3 min and 49.1; dr: 55:45, major diastereomer
1.50 mmol, 3.0 eq) for 48h when 93% conversion of ketone
achieved (determined by H NMR), water (30 mL) to quench
1
and DCM (2 x10 mL) for extraction to generate the crude
product which was purified by column chromatography (50%
7 EtOAc in petroleum ether (40-60)) to give 25 as a white solid
(0.130 g, 0.426 mmol, 85.2%). TLC: Rf ca 0.2 (8:2, Hexane:
EtOAc), less UV active, strong KMnO4 & PMA reactive;
HRMS (ESI): found [M+Na]+ 328.0982, C16H19NNaO3S
1
H NMR (CDCl , 5100
72% ee, minor diastereomer 98% ee;
3
MHz) Diastereomer 1: δ 7.54 (d, 2H, J = 8.3 Hz), 7.32-7.310 1 requires [M+Na]+ 328.0978 (error -1.3 ppm); max 3490, 3265,
1 (m, 1H), 7.14-7.06 (m, 5H), 6.86 (d, 2H, J = 7.2 Hz), 6.22 (1d, 2 2979, 1300, 1153, 1089, 1010, 698, 657, 535 cm-1;
2 1H, J = 1.9 Hz), 6.00 (d, 1H, J = 3.3 Hz), 5.75 – 5.66 (m, 1H1),
4.92-4.89 (m, 1H), 4.77 – 4.75 (m, 1H), 2.67-2.59 (m, 1H), 2.132
(s, 3H); Diastereomer 2: δ 7.48 (d, 2H, J = 8.3 Hz), 7.24 1(s,
1H), 7.14-7.06 (m, 5H), 7.01 (d, 2H, J = 8.0 Hz), 6.19 (d, 1H1, J
Enantiomeric excess determined by HPLC analysis (Chiralpak
IC, 250 mm x 4.6 mm column, iPrOH: hexane 20:80, 1 mL/min,
210 nm, T = 25 ºC), one diastereomer 12.9 min and 18.0 min,
other diastereomer 31.2 min and 88.5 min; dr: 68:32, major
= 5.0 Hz), 6.13 (d, 1H, J = 3.3 Hz), 5.75-5.66 (m, 1H), 4.811– 7 diastereomer 36% ee, minor diastereomer >99% ee.; Major
1
7 4.79 (m, 1H), 4.68 (t, 1H, J = 6.4 Hz), 2.71 (d, 1H, J = 4.9 H1z),
2.33 (s, 3H); 13C{1H} NMR (CDCl3, 126 MHz) bo1th
diastereomers: δ 152.2, 152.1, 143.3, 143.1, 142.4, 142.13,1
diastereomer H NMR (CDCl3, 500 MHz): δ 7.82-7.65 (m,
3H), 7.33-7.22 (m, 6H), 4.93-4.89 (m, 1H), 4.78-4.77 (m, 1H),
3.61-3.54 (m, 1H), 2.63 (d, 1H, J = 4.7 Hz), 2.42 (s, 3H), 0.84
137.5, 137.2, 137.2, 136.2, 129.5, 129.4, 129.4, 128.2, 127.91, 11 (d, 3H, J = 6.9 Hz); 13C{1H} NMR (CDCl3, 126 MHz): δ 143.6,
1 127.8, 127.4, 127.3, 127.2, 127.2, 110.5, 110.4, 108.7, 108.41, 12 140.3, 137.9, 129.9, 128.5, 127.9, 127.2, 126.8, 126.2, 77.2,
2 71.5, 71.1, 61.8, 61.6, 21.5; m/z (ESI) 380.2 [(M+Na)+, 100%1].1
75.8, 55.0, 21.6, 14.9; Minor diastereomer 1H NMR (CDCl3,
500 MHz): δ 7.82-7.65 (m, 3H), 7.33-7.22 (m, 6H), 4.93-4.89
(m, 1H), 4.50-4.48 (m, 1H), 3.46-3.49 (m, 1H), 2.68 (d, 1H, J =
3.0 Hz), 2.42 (s, 3H), 0.96 (d, 3H, J = 6.9 Hz); 13C{1H} NMR
11
11
11
N-((1S,2R)-2-Hydroxy-1,2-
diphenylethyl)methanesulfonamide 23.
This compound is known and has been previously
117 (CDCl , 126 MHz): δ 143.5, 140.4, 137.5, 129.8, 128.6, 128.2,
3
7 characterised.41 This compound was prepared following the
11
11
127.2, 126.6, 126.2, 77.2, 75.8, 55.7, 21.7, 18.0; m/z (ESI)
328.2 [(M+Na)+, 100%]. The data matches the reported data
general
procedure
F
using
N-(2-oxo-1,2-
12
diphenylethyl)methanesulfonamide (0.144 g, 0.5 mmol, 1.0 eq1) 21 N-((1S,2R)-2-Hydroxy-1-phenylpropyl)-4-
in MeCN (5 mL), catalyst (R,R)-2 (4.7 mg, 7.5 µmol, 0.015 eq),
1 DABCO (0.280 g, 2.50 mmol, 5.0 eq) and formic acid (56 µL1, 22 methylbenzenesulfonamide 27.
22
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Page 23 of 27
The Journal of Organic Chemistry
1 This compound is known and has been previously 1 t-Butyl ((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)-2-
2 characterised.43 This compound was prepared following the 2 hydroxyethyl)carbamate 29.
1
2
3
4
5
6
7
8
general
procedure
F
using
4-methyl-N-(2-oxo-1-
This compound is known and has been previously characterised
in racemic form.18a This compound was prepared following the
general procedure F using tert-butyl (2-(3-chlorophenyl)-1-(4-
chlorophenyl)-2-oxoethyl)carbamate 28 (0.379 g, 1.00 mmol,
phenylpropyl)benzenesulfonamide (0.152 g, 0.50 mmol, 1.0 eq)
in MeCN (5 mL), catalyst (R,R)-2 (4.7 mg, 7.5 µmol, 0.015 eq),
DABCO (0.280 g, 2.50 mmol, 5.0 eq) and formic acid (56 µL,
7 1.50 mmol, 3.0 eq) for 24 h when 100% conversion of ketone 7 1.0 eq) in MeCN (10 mL), catalyst (R,R)-20 (10.7 mg, 0.015
1
achieved (determined by H NMR), water (30 mL) to quench
and DCM (2 x 10 mL) for extraction to generate the crude
product which was purified by column chromatography (30%7
mmol, 0.015 eq), DABCO (0.560 g, 5.00 mmol, 5.0 eq) and
formic acid (113 µL, 3.00 mmol, 3.0 eq) for 24 h when 100%
conversion of ketone was achieved (determined by H NMR),
1
1
9
11 EtOAc in petroleum ether (40-60)) to give 27 as a white solid 71 water (50 mL) was dded to quench to quench and the solid
12 (0.125 g, 0.390 mmol, 78.4%). TLC: Rf ca 0.2 (6:4, Hexane: 72 material was filtered and dried to give 29 as a white solid (0.340
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1
1
1
EtOAc), less UV active, strong KMnO4 & PMA reactive;7
g, 0.890 mmol, 89.2%). TLC: Rf ca 0.3 (6:4, Hexane: EtOAc),
less UV active, strong KMnO4 & PMA reactive; HRMS (ESI):
found [M+Na]+ 404.0778, C19H21Cl2NNaO3 requires [M+Na]+
404.0777 (error -0.2 ppm); Enantiomeric excess determined by
77 HPLC analysis (Chiralpak IG, 250 mm x 4.6 mm column,
HRMS (ESI): found [M+Na]+ 328.0978, C16H19NNaO3S7
requires [M+Na]+ 328.0978 (error 1.3 ppm); max 3539, 3310,
7
7
-1
2971, 1316, 1153, 1087, 1054, 807, 701, 566 cm ;
17 Enantiomeric excess determined by HPLC analysis (Chiralpak
7
AD-H, 250 mm x 4.6 mm column, iPrOH: hexane 10:90, 1
iPrOH: hexane 5:95, 1 mL/min, T = 25 ºC), (1S,2R) 11.0 min,
(1R,2S) 21.4 min, other diastereomer 25.5 min and 35.0 min;
1
1
2
7
mL/min, 210 nm, T = 25 ºC), (1S,2R) 25.3 min, (1R,2S) 30.3
22
1
[α]D = –86.6 (c = 0.05 in THF), dr: 99.7:0.3, ee 96.4%; H
1 NMR (DMSO-d6, 600 MHz): δ 7.40-7.27 (m, 9H), 5.53 (d, 1H,
2 J = 4.9 Hz), 4.61 (d, 1H, J = 8.2 Hz), 4.53 (t, 1H, J = 9.0 Hz),
1.20 (s, 9H); 13C{1H} NMR (DMSO-d6, 151 MHz): δ 154.5,
145.9, 140.4, 132.3, 131.4, 129.9, 129.5, 127.6, 126.9, 125.7,
77.9, 74.5, 59.4, 28.1; m/z (ESI) 404.2 [(M+Na)+, 100%], 406.1
[(M+2+Na)+, 60%]. The data matches the reported data.
7
min, other diastereomer 32.5 min and 35.1 min; dr: 75.4:24.6,
21 major diastereomer 97% ee, minor diastereomer 61% ee;
22 Major diastereomer 1H NMR (CDCl3, 500 MHz): δ 7.53-7.51
2
(m, 2H), 7.16-7.03 (m, 7H), 5.63-5.61 (m, 1H), 4.28-4.26 (m,
1H), 4.10-4.06 (m, 1H), 2.33 (s, 3H), 1.84 (d, 1H, J = 6.3 Hz),
1.01 (d, 3H, J = 6.4 Hz); 13C{1H} NMR (CDCl3, 126 MHz): δ
143.2, 137.4, 136.4, 129.4, 128.6, 127.9, 127.8, 127.2, 70.4,
2
2
2
27 62.9, 21.6, 19.6; Minor diastereomer 1H NMR (CDCl3, 500
t-Butyl-((1R,2S)-2-(3-chlorophenyl)-1-(4-chlorophenyl)-2-
hydroxyethyl)carbamate 29.
2
2
MHz): δ 7.53-7.51 (m, 2H), 7.16-7.03 (m, 7H), 5.63-5.61 (m,
1H), 4.14-4.11 (m, 1H), 3.91-3.90 (m, 1H), 2.33 (s, 3H), 2.22
(s, 1H), 1.08 (d, 3H, J = 6.4 Hz); 13C{1H} NMR (CDCl3, 126
1 MHz): δ 143.2, 138.6, 137.4, 129.4, 128.4, 127.8, 127.3, 71.1,
2 64.3, 21.6, 20.1; m/z (ESI) 328.2 [(M+Na)+, 100%].The data
matches the reported data.
This compound is known and has been previously
1 characterised.18a This compound was prepared following the
2 general procedure F using tert-butyl (2-(3-chlorophenyl)-1-(4-
chlorophenyl)-2-oxoethyl)carbamate 28 (0.379 g, 1.00 mmol,
1.0 eq) in MeCN (10 mL), catalyst (S,S)-20 (10.7 mg, 0.015
mmol, 0.015 eq), DABCO (0.560 g, 5.00 mmol, 5.0 eq) and
formic acid (113 µL, 3.00 mmol, 3.0 eq) for 24 h when 100%
7 conversion of ketone achieved (determined by 1H NMR), water
(50 mL) to quench and obtained solid material was filtered and
dried to give 29 as a white solid (0.363 g, 0.952 mmol, 95.2%).
TLC: Rf ca 0.3 (6:4, Hexane: EtOAc), less UV active, strong
t-Butyl-(2-(3-chlorophenyl)-1-(4-chlorophenyl)-2-
oxoethyl)carbamate 28.
7 This compound is known and has been previously
characterised.18a This compound was prepared following the
general
procedure
B
using
tert-Butyl
((4-
1
chlorophenyl)(benzenesulfonyl)methyl)carbamate (2.50 g, 6.56
1 mmol, 1.0 eq) in DCM (50 mL), 3-chlorobenzaldehyde (1.38 1g, 1 KMnO4 & PMA reactive; HRMS (ESI): found [M+Na]+
1 2 404.0778, C H Cl N NaO requires [M+Na]+ 404.0777 (error
2 9.84 mmol, 1.5 eq), 3-Benzyl-5-(2-hydroxyethyl)-4-
methylthiazolium chloride (0.531 g, 1.96 mmol, 0.3 eq) a1nd
triethylamine (9.96 g, 14 mL, 98.4 mmol, 15 eq) for 24 h, wa1ter
17 19
2
4
2
-0.2 ppm); Enantiomeric excess determined by HPLC analysis
(Chiralpak IG, 250 mm x 4.6 mm column, iPrOH: hexane 5:95,
1 mL/min, T = 25 ºC), (1S,2R) 11.0 min, (1R,2S) 21.4 min,
other diastereomer 25.5 min and 35.0 min; dr: >99.9:<0.1, ee
1
(100 mL) to quench and was washed twice with 5% aqueous
HCl (250 mL) to generate the crude product which was purified
1
1 7 96.4%;
7 by column chromatography (10% EtOAc in petroleum ether
1
1
(40-60)) to give 28 as a white solid (1.66 g, 4.38 mmol, 66.7%).
(4S,5S)-5-(3-Chlorophenyl)-4-(4-chlorophenyl) oxazolidin-
2-one 30.
R ca 0.3 (8:2, Hexane: EtOAc), strong UV active; HRM1S1
f
(ESI): found [M+Na]+
402.0633, C H Cl NNaO require1s 11 This compound is known and has been previously
19 19
2
3
1 [M+Na]+ 402.0634 (error 0.4 ppm); max 3379, 1710, 1678,
2 1519, 1494, 1219, 1164, 722, 699, 570 cm ; H NMR (CDCl 1, 12 characterised.18a Carbamate (1S,2R)-29 (product of reduction
-1
1
3
11
by (R,R)-20, 300 mg, 0.787 mmol, 1.0 eq) was dissolved in
pyridine (3 mL) followed by addition of mesic anhydride (411
mg, 2.36 mmol, 3.0 eq) and the resulting mixture was heated to
70 ºC. After 18 h, the mixture was diluted with water (50 mL)
117 and the resulting solid was filtered. The filtrate was checked on
+
500 MHz): δ 7.92 (s, 1H), 7.78 (d, 1H, J = 7.8 Hz), 7.49 (d, 1H,
11
J = 7.8 Hz), 7.36 – 7.27 (m, 5H), 6.19 (d, 1H, J = 7.3 Hz), 6.00
13
1
11
(d, 1H, J = 6.9 Hz), 1.43 (s, 9H); C{ H} NMR (CDCl3, 126
MHz): δ 194.8, 155.0, 136.0, 135.6, 135.3, 134.7, 133.9, 130.12,1
7 129.6, 129.6, 129.1, 127.1, 80.4, 59.6, 28.4; m/z (ESI) 402.2
+
+
11
11
TLC but no trace of product was obtained. The obtained solid
was dissolved in DCM (50 mL) and the organic layer was dried
with MgSO4, filtered and concentrated under reduced pressure
[(M+Na) , 100%], 404.1 [(M+Na) , 60%], 406.0 [(M+2+Na) ,
10%]. The data matches the reported data.
12
121 to generate the crude product which was further purified by
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1 column chromatography (30% EtOAc in petroleum ether (40- 2 N,4-Dimethyl-N-(2-oxo-1,2-
1
2
3
4
5
6
7
8
2 60)) to afford (4S,5S)-30 as a yellow liquid. (0.180 g, 0.586
mmol, 74.5%). TLC: Rf ca 0.3 (Hexane: EtOAc 8:2), strong UV
active; HRMS (ESI): found [M+Na]+ 330.0054,
C15H11Cl2NNaO2 requires [M+Na]+ 330.0059 (error 1.5 ppm);
diphenylethyl)benzenesulfonamide 14aMe. To a stirred
solution of 2-bromo-1,2-diphenylethan-1-one (0.360 g, 1.29
mmol, 1.0 eq) in DCM (20 mL) was added triethylamine (0.156
g, 0.2 mL, 1.54 mmol, 1.2 eq) and the mixture was cooled to 0
1H NMR (CDCl3, 500 MHz): δ 7.42-7.31 (m, 5H), 7.26-7.25 7 ºC in an ice salt bath. Methylamine (0.087 g, 0.13 mL, 2.58
7 (m, 2H), 7.13 (d, 1H, J = 7.6 Hz), 6.07 (s, 1H), 5.20 (d, 1H, J =
7.4 Hz), 4.72 (d, 1H, J = 7.4 Hz); 13C{1H} NMR (CDCl3, 126
MHz): δ 158.4. 139.1, 136.5, 135.4, 135.3, 130.5, 129.7, 129.6,7
mmol, 2 eq) was added dropwise to the reaction mixture which
was stirred at the same temperature for 30 minutes. Once the
reaction mixture started to become a suspension, water (50 mL)
1
127.9, 126.1, 124.1, 85.3, 64.4; m/z (ESI) 330.3 [(M+Na)+, 71 was added and the organic layer was separated. The organic
9
11 100%], 332.2 [(M+2+Na)+, 60%], 334.4 [(M+4+Na)+, 10%]. 72 layer was washed with water (3 x 50 mL) and dried over
º
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12 The data matches the reported data.
7
7
MgSO4. The organic layer was cooled to to 0 C in an ice salt
bath followed by addition of TEA (0.156 g, 0.2 mL, 1.54 mmol,
1.2 eq) and tosyl chloride (0.280g, 1.00 mmol, 0.7 eq) in DCM
and the resulting solution was stirred at RT for 24h. Once the
1
1
1
1
larger-scale reactions (synthesis of compounds 17e and7
18h).
t-Butyl-((1S,2R)-2-(3-chlorophenyl)-2-hydroxy-1-
7
77 reaction was complete (assessed by TLC), water (150 mL) and
17 phenylethyl)carbamate phenylethyl)carbamate 17e.
7
DCM (50 mL) were added and the organic layer was separated.
The aqueous layer was extracted with DCM (3 x 50 mL). The
combined organic layers were washed with brine (50 mL), dried
1
1
2
This was prepared following the general procedure F using tert-7
butyl (2-(3-chlorophenyl)-2-oxo-1-phenylethyl)carbamate 13e
(1.0 g, 2.89 mmol, 1.0 eq) in MeCN (25 mL), catalyst (R,R)-20 1 over MgSO4 and concentrated under reduced pressure to give
21 (31 mg, 0.043 mmol, 0.015 eq), DABCO (1.62 g, 14.5 mmol, 2 the crude product. The crude material was purified by column
22 5.0 eq) and formic acid (328 µL, 8.67 mmol, 1.5 eq) for 24 h.
chromatography (30% EtOAc in petroleum ether (40-60)) to
afford 14aMe as a white solid (0.180 g, 0.474 mmol, 36.8%).
TLC: Rf ca 0.3 (8:2, Hexane: EtOAc), strong UV active; HRMS
(ESI): found [M+Na]+ 402.1124, C22H21NNaO3S requires
7 [M+Na]+ 402.1134 (error 2.6 ppm); H NMR (CDCl3,
500MHz): δ 7.79 (d, 2H, J = 7.3 Hz), 7.63 (d, 2H, J = 8.2 Hz),
7.51 (t, 1H, J = 7.4 Hz), 7.39-7.36 (t, 2H, J = 7.8 Hz), 7.32-7.31
(m, 3H), 7.26 – 7.21 (m, 4H), 6.80 (s, 1H), 2.82 (s, 3H), 2.40 (s,
1 3H); 13C{1H} NMR (CDCl3, 126MHz): δ 190.7, 143.4, 136.6,
2 135.5, 134.3, 133.6, 129.9, 129.6, 129.2, 128.9, 128.8, 128.7,
127.4, 64.5, 31.6, 21.7; m/z (ESI) 402.2 [(M+Na)+, 100%].
N-(2-Hydroxy-1,2-diphenylethyl)-N,4-
2
When100% conversion of ketone was achieved (determined by
TLC), water (100 mL) was added to quench and DCM (3 x 30
mL) for extraction to generate the crude product which was
purified by column chromatography (20-60% EtOAc in
2
2
2
27 petroleum ether (40-60)) to give 17e as a white solid (0.890 g,
2
2
2.56 mmol, 88.7%). Enantiomeric excess determined by HPLC
analysis (Chiralpak IG, 250 mm x 4.6 mm column, iPrOH:
hexane 7:93, 0.5 mL/min, 210nm, T = 25 ºC), (1S,2R) 20.9 min,
1 (1R,2S) 27.0 min, other diastereomer 37.6 min and 45.4 min;
2 dr: >99.9:<0.1, 95% ee; 1H NMR (DMSO-d6, 500 MHz): δ 7.37
– 7.20 (m, 10H), 5.45 (d, 1H, J = 5.3 Hz), 4.64-4.62 (m, 1H),
4.53 (t, 1H, J = 9.1 Hz), 1.20 (s, 9H); 13C{1H} NMR (DMSO-
d6, 126 MHz): 154.4, 146.1, 141.3, 132.2, 129.4, 128.1, 127.6,
126.9, 126.7, 126.6, 125.7, 77.7, 74.7, 59.9, 28.0.
dimethylbenzenesulfonamide 18aMe.
This compound is novel and was prepared following the
7 general procedure
F
using N,4-dimethyl-N-(2-oxo-1,2-
7
diphenylethyl)benzenesulfonamide 14aMe (0.095 g, 0.25
mmol, 1.0 eq) in MeCN (2.5 mL), catalyst (R,R)-2 (2.3 mg, 3.8
µmol, 0.015 eq), DABCO (0.140 g, 1.25 mmol, 5.0 eq) and
N-((1S,2R)-2-Hydroxy-1-(4-methoxyphenyl)-2-
phenylethyl)-4-methylbenzenesulfonamide 18h.
This compound is novel and was prepared following the general
1
1 1 formic acid (28 µL, 0.750 mmol, 3.0 eq) for 72h. When 50%
1
1 procedure
F
using
N-(1-(4-methoxyphenyl)-2-oxo-2-
1 2 conversion of ketone was achieved (determined by H NMR),
water (30 mL) was added to quench and DCM (2 x 10 mL) for
extraction to generate the crude product which was purified by
column chromatography (50% EtOAc in petroleum ether (40-
60)) to give 18aMe as a white semi solid (0.045 g, 0.118 mmol,
1 7 47.2%). TLC: Rf ca 0.2 (6:4, Hexane: EtOAc), weak UV active,
strong KMnO4 & PMA reactive; HRMS (ESI): found [M+Na]+
404.1293, C22H23NNaO3S requires [M+Na]+ 404.1296 (error -
2 phenylethyl)-4-methylbenzenesulfonamide 14h (0.500 g, 1.26
1
1
mmol, 1.0 eq) in MeCN (10 mL), catalyst (R,R)-2 (12 mg, 0.019
mol, 0.015 eq), DABCO (0.705 g, 6.30 mmol, 5.0 eq) and
1
1
formic acid (174 µL, 3.78 mmol, 3.0 eq) for 24 h. When 100%
conversion of ketone achieved (determined by TLC), water (50
7 mL) was added to quench and the solid product was filtered and
1
1
dried to give 18h as a brown solid (0.455 g, 1.14 mmol, 90.5%).
Enantiomeric excess determined by HPLC analysis (Chiralpak
11
0.4 ppm); Enantiomeric excess determined by HPLC analysis
IC, 250 mm x 4.6 mm column, iPrOH: hexane 20:80, 1 mL/min,
111 (Chiralcel OD-H, 250 mm x 4.6 mm column, iPrOH: hexane
1 210nm, T = 25 ºC), (1S,2R) 19.5 min, (1R,2S) 24.1 min, othe1r 12 25:75, 1 mL/min, 210nm, T = 25 ºC), One diastereomer 10.3
2 diastereomer 46.6 min; dr: 95:5, major diastereomer 89% ee. 1H
11
min and 11.8, other diastereomer 25.6 min and 62.1 min; dr:
83:17, major diastereomer 90% ee, minor diastereomer 35% ee;
1H NMR (CDCl3, 500MHz): Major diastereomer δ 7.58 (d, 2H,
J = 8.2 Hz), 7.25 (d, 2H, J = 7.1 Hz), 7.20 – 7.16 (m, 5H), 7.11-
117 7.10 (d, 2H, J = 7.7 Hz), 7.02 – 7.00 (m, 2H), 5.24 (d, 1H, J =
9.7 Hz), 5.13 (d, 1H, J = 9.7 Hz), 2.89 (s, 3H), 2.37 (s, 3H), 1.61
(br.s., 1H), Minor diastereomer: δ 7.79-7.00 (m, 14H), 5.42 (d,
1H, J = 8.5 Hz), 5.29 (d, 1H, J = 8.5 Hz), 2.59 (s, 3H), 2.34 (s,
121 3H), 1.61 (br.s., 1H); 13C{1H} NMR (CDCl3, 126 MHz) both
122 diastereomers: δ 143.5, 143.0,141.2, 140.4, 136.6, 136.4, 135.6,
NMR (CDCl3, 500 MHz): δ 7.48 (d, 2H, J = 8.0 Hz), 7.21-7.29
11
(m, 3H), 7.09 (d, 2H, J = 8.0 Hz), 6.96 (d, 2H, J = 5.7 Hz), 6.75
11
(d, 2H, J = 8.5 Hz), 6.59 (d, 2H, J = 8.5 Hz), 5.30 (d, 1H, J1=1
7.2 Hz), 4.95 (m, 1H), 4.49-4.46 (m, 1H), 3.72 (s, 3H), 2.38(d,
7 1H, J = 4.0 Hz) 2.34 (s, 3H); 13C{1H} NMR (CDCl3, 126 MHz):
11
δ 159.2, 143.2, 139.3, 137.2, 129.4, 129.3, 128.3, 128.1, 128.10,1
127.2, 126.7, 113.4, 76.8, 62.8, 55.3, 21.6.
12
1 Synthesis and reduction of N-methylated derivative 14aMe.
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The Journal of Organic Chemistry
Asymmetric Transfer Hydrogenation of Aryl Ketones. Adv. Synth.
1 134.8, 133.6, 129.6, 129.5, 129.4, 129.2, 128.8, 128.7, 128.4,
Catal. 2014, 356, 3193-3198. e) Cotman, A. E.; Modec, B.; Mohar, B.
Stereoarrayed 2,3-Disubstituted 1-Indanols via Ruthenium(II)-
Catalyzed Dynamic Kinetic Resolution–Asymmetric Transfer
Hydrogenation. Org. Lett. 2018, 20, 2921-2924. f) Soni, R.; Jolley, K.
E.; Gosiewska, S.; Clarkson, G. J.; Fang, Z,; Hall, T. H.; Treloar, B. N.;
Knighton, R. C.; Wills,.Synthesis of Enantiomerically Pure and
Racemic Benzyl-Tethered Ru(II)/TsDPEN Complexes by Direct Arene
1
2
3
4
5
6
7
8
2 128.3, 128.2, 128.1, 127.6, 127.5, 127.4, 127.2, 66.90, 65.21,
31.05, 31.31, 21.6, 21.5; m/z (ESI) 404.2 [(M+Na)+, 100%].
1
2
ASSOCIATED CONTENT
Supporting Information
Substitution:
Further
Complexes
and
Applications.
M.
7
The Supporting Information contains details of the optimization
reactions, NMR spectra, chiral HPLC spectra and X-ray
crystallographic data for structures CCDC 1988253 and 1988254.
The Supporting Information is available free of charge on the ACS7
7
Organometallics 2018, 37, 48–64. g) Soni, R.; Jolley, K. E.; Clarkson,
G. J.; Wills, M. Direct Formation of Tethered Ru(II) Catalysts Using
Arene Exchange. Org. Lett. 2013, 15, 5110–5113.
9
4) Molecular modelling. a) Dub, P. A.; Gordon, J. C. The mechanism
1
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12
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14
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17
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19
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48
49
50
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53
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Publications website. Experimental procedures, NMR and HPLC 71 of enantioselective ketone reduction with Noyori and Noyori–Ikariya
11
72 bifunctional catalysts. Dalton Trans. 2016, 45, 6756-6781. b) Dub, P.
12 spectra and X-rays.
7
A.; Gordon, J. C. Metal–Ligand Bifunctional Catalysis: The
“Accepted” Mechanism, the Issue of Concertedness, and the Function
of the Ligand in Catalytic Cycles Involving Hydrogen Atoms. ACS
Catal. 2017, 7, 6635-6655.
1
7
7
7
1
AUTHOR INFORMATION
77
5) a) Monnereau, L.; Cartigny, D.; Scalone, M.; Ayad, T.;
Ratovelomanana-Vidal, V. Efficient Synthesis of Differentiated
syn‐1,2‐Diol Derivatives by Asymmetric Transfer Hydrogenation–
Dynamic Kinetic Resolution of α‐Alkoxy‐Substituted β‐Ketoesters.
Chem. Eur. J. 2015, 21, 11799-11806. b) Bai, J.; Miao, S.; Wu, Y.;
Zhang, Y. Asymmetric Reduction of 2‐Chloro‐3‐oxo Esters by
Transfer Hydrogenation. Chin. J. Chem. 2011, 29, 2476-2480. c) Hu,
1
1
Corresponding Author
7
Professor Martin Wills, Department of Chemistry, University of
7
17 Warwick, Coventry, CV4 7AL, UK. m.wills@warwick.ac.uk.
1
2
1
1
2
Author Contributions
The manuscript was written through contributions of all authors.
X.; Zhang, K.; Chang, F.; Liu, R.; Liu, G.; Cheng, T.
A
substitution/dynamic kinetic resolution Asymmetric transfer
–
21 Notes
hydrogenation tandem process for preparation of stereocenters β-
hydroxy sulfones. Mol. Catal. 2018, 452, 271-276. d) Echeverria, P.
G.; Ayad, T.; Phansavath, P.; Ratovelomanana-Vidal, V. Recent
Developments in Asymmetric Hydrogenation and Transfer
Hydrogenation of Ketones and Imines through Dynamic Kinetic
Resolution. Synthesis 2016, 48, 2523-2539.
6) Echeverria, P.-G.; Cornil, J.; Férard, C.; Guérinot, A.; Cossy, J.;
Phansavath, P.; Ratovelomanana-Vidal, V. Asymmetric transfer
hydrogenation of α-amino β-keto ester hydrochlorides through
dynamic kinetic resolution. RSC Adv. 2015, 5, 56815-56819.
7) a) Ishida, K.; Obata, Y.; Akagi, C.; Onuki, Y.; Takayama K.
Practical syntheses of D-erythro and L-threo-ceramide [NDS] and
difference in contribution of each isomer in microstructure of stratum
corneum intercellular lipids. J. Drug Discovery Sci. Technol. 2014, 24,
689-693. b) Touge, T.; Kuwana, M.; Komatsuki, Y.; Tanaka, S.; Nara,
22 The authors declare no conflicting interests.
7
2
2
2
2
Data sharing statement: The research data (and/or materials)
supporting this publication can be accessed at
http://wrap.warwick.ac.uk/.
1
2
27 ACKNOWLEDGMENT
2
2
We thank Warwick University for support of SKG through a
Chancellors International Fellowship. The X-ray diffraction
instrument was obtained through the Science City Project with
support from the AWM and part funded by the ERDF.
7
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