Enantioselective Friedel-Crafts Alkylation between Nitroalkenes and Indoles Catalyzed by Charge Activated Thiourea Organocatalysts

Article abstract of DOI:10.1021/acs.joc.7b02411

A series of methylated and octylated pyridinium and quinolinium containing thiourea salts with a chiral 2-indanol substituent are reported. These organocatalysts are positively charged analogues of privileged bis(3,5-trifluoromethyl)phenyl substituted thi

Full text of DOI:10.1021/acs.joc.7b02411

Subscriber access provided by READING UNIV
Article
Enantioselective Friedel-Crafts Alkylation between Nitroalkenes and
Indoles Catalyzed by Charge Activated Thiourea Organocatalysts
Yang Fan, and Steven Robert Kass
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02411 • Publication Date (Web): 22 Nov 2017
Downloaded from http://pubs.acs.org on November 23, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Enantioselective Friedel-Crafts Alkylation between Nitroalkenes
and Indoles Catalyzed by Charge Activated Thiourea
Organocatalysts
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
Yang Fan and Steven R. Kass*
Department of Chemistry, University of Minnesota, 207 Pleasant Street, SE, Minneapolis,
Minnesota 55455, United States
E-mail: kass@umn.edu
Table of Content Graphic
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 34
1
2
3
4
ABSTRACT
5
6
7
8
9
A series of methylated and octylated pyridinium and quinolinium containing thiourea salts
with a chiral 2-indanol substituent are reported. These organocatalysts are positively charged
analogs of privileged bis(3,5-trifluoromethyl)phenyl substituted thioureas, and are found to be
much more active catalysts despite the absence of an additional hydrogen bond donor or acceptor
site (i.e., the presence of a heteroatom-hydrogen or heteroatom). Friedel-Crafts reactions of
trans-β-nitorostyrenes with indoles are examined and good yields and enantioselectivities are
obtained. Mechanistic studies indicate that this is a second-order transformation under the
employed conditions, and are consistent with the dimer of the thiourea being the active catalyst.
Charged organocatalysts, consequently, represent an attractive design strategy for catalyst
development.
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
2
ACS Paragon Plus Environment

Page 3 of 34
The Journal of Organic Chemistry
1
2
3
4
INTRODUCTION
5
6
7
8
9
Small molecule metal-free organocatalysts are commonly exploited in carrying out a wide
variety of chemical transformations.1 Over the past two decades asymmetric control of these
reactions has emerged as one of the most vibrant and challenging research areas in organic
synthesis.2 Hydrogen bond interactions are commonly used in this regard and play a key role in
lowering activation barriers and organizing three-dimensional transition state geometries.3
Thioureas with their two N–H hydrogen bond donating sites have proven to be a particularly
successful functional group motif and continue to be extensively investigated.4
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
Reaction rates often correlate with organocatalyst acidities. That is, faster transformations
typically occur with more acidic species of a given structural type.5 Electron withdrawing groups
are routinely employed because of this, and no substituent has been exploited more than a 3,5-
bis(trifluoromethyl)phenyl ring. Doubly activated N,N′-bis(3,5-bis(trifluoromethyl)phenyl)-
thiourea [(3,5-(CF3)2C6H3NH)2CS, 1] is commonly referred to as Schreiner's thiourea and
represents a milestone in the development of hydrogen bond donating organocatalysts.6 Its
greater catalytic ability leads to faster transformations and has been attributed to an enhanced
acidity due to the presence of four electron withdrawing trifluoromethyl groups and two weak
intramolecular C−H···S hydrogen bonds. The incorporation of the CF3 groups also stabilize the
reactive Z,Z-conformer, increase the structural rigidity and enhance the solubility of the thiourea
in non-polar solvents.7 Replacement of one of the 3,5-bis(trifluoromethyl)phenyl rings with a
chiral moiety leads to a versatile platform for catalyst design and extensive efforts have been
reported in this regard.8
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 34
1
2
3
4
5
6
7
8
9
Inspired by the many remarkable studies carried out with thiourea catalysts, we recently
communicated the synthesis and reactivity of charge-containing derivatives with one or two
cationic N-methylpyridinium ion centers and an appropriate noncoordinating anionic counterion
(2 and 3, Figure 1).9 These achiral compounds were found to lead to rate enhancements of one to
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
CF3
CF3
S
N
N
H
CF3
F3C
H
1
S
S
+
+
+
N
N
N
N
N
N
H
N
CH3
H3C
CH3
H
H
H
–
–
–
BArF
BArF
BArF
4
4
4
2
3
Figure 1. Schreiner's thiourea (1) and previously studied pyridinium ion containing analogs (2
and 3), where BArF – = (3,5-(CF3)2C6H3)4B–.
4
three orders of magnitude relative to Schreiner’s thiourea in several organic transformations
without altering the binding motif or introducing an additional N–H or O–H hydrogen bond
donating site.10,11 For example, the reaction of trans-β-nitrostyrene with N-methylindole (eq. 1)
was found to have a half-life of 29 hours when 10 mol% of 1 was used as the catalyst whereas
this was reduced to 4.5 hours and 4.3 minutes with 2 and 3, respectively. Given that the
incorporation of a single charged center outperformed the presence of four trifluoromethyl
groups, it seemed worthwhile to explore chiral variants of 2 (Scheme 1).
Ph
NO2
NO2
1-3
+
(1)
CDCl3
20 ˚C
N
N
CH3
CH3
4
ACS Paragon Plus Environment

Page 5 of 34
The Journal of Organic Chemistry
1
2
3
CF3
4
5
6
S
S
Chiral moiety
Chiral moiety
+
N
N
N
N
N
CH3
CF3
H
H
H
H
7
8
9
Scheme 1. New chiral design strategy for introducing a charged substituent to enhance 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
acidity and reactivity of a thiourea catalyst in nonpolar media.
A wealth of chiral thioureas with a 3,5-bis(trifluoromethyl)phenyl substituent have been
developed but relatively few have an acidic group on the chiral moiety.12 As these bifunctional
species are expected to be compatible with the strategy illustrated in Scheme 1 (i.e., more acidic
thioureas), we focused our attention on (1S, 2R)-1-amino-2-indanol derivatives (4, Scheme 2).
The enantioselective Friedel-Crafts alkylation of indoles with trans-β-nitroalkenes was chosen as
the test platform because it is a fundamental transformation that leads to increased molecular
complexity via the formation of a new carbon-carbon bond. This reaction is also a perfectly atom
economical process that affords valuable pharmaceutical and biology-based intermediates.13,14
Moreover, this transformation has been frequently used to test new BrØnsted acids and hydrogen
bond catalysts, and was employed by both Herrera et al.8a,15 and Ganesh and Seidel11f to
investigate 5–7.
R3
CF3
H
R2
R1
CH3
+
+
–
S
S
S
BArF
4
H
S
S
N
N
+
BArF
–
+
4
N
N
N
N
N
N
N
N
CF3
N
N
H
N
H
H
H
H
H
H
H
H
BArF
–
BArF
–
OH
OH
OH
OH
OH
4
4
4
4h
5
6
7
a: R1 = CH3, R2, R3 = H
b: R1 = 1-C8H17, R2, R3 = H
c: R1 = CH3, R2, R3 = CH=CHCH=CH
d: R1 = 1-C8H17, R2, R3 = CH=CHCH=CH
e: R1 = CH3, R2 = H, R3 = Ph
f: R1 = 1-C8H17, R2 = H, R3 = Ph
g: R1 = CH3, R2 = H, R3 = 4-t-BuPh
Scheme 2. Chiral thioureas examined in this work (4-5) and previously reported (6-7).
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 34
1
2
3
4
RESULTS AND DISCUSSION
5
6
7
8
9
A series of chiral thiourea hydrogen bond catalysts 4a–4h bearing an N-alkylpyridinium ion
center and a 2-indanol substituent were synthesized starting from commercially available 3- or 4-
aminopyridines. These compounds were formed in a similar fashion as illustrated for 4a in
Scheme 3 by first converting the aminopyridine to its corresponding isothiocyanate. Alkylation
with methyl iodide or octyl triflate was then followed by reaction with (1S, 2R)-1-amino-2-
indanol to afford the thiourea precatalyst (i.e., the iodide or triflate salt). Substitution of the
counterion to the weakly coordinating tetrakis(3,5-bis(trifluoromethyl)phenyl)borate anion
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
(BArF – ) was carried out to give the desired thiourea catalysts except in one instance when a
4
tetrakis(pentafluorophenyl)borate (B(C6F5)4–) salt 4a' was formed; this compound differs from 4a
only in the tetrakis(aryl)borate counterion.
CSCl2, NaHCO3 (aq)
CHCl3
CH3I
+
N
N
EtOAc
N
H3C
NH2
NCS
I–
NCS
8
9
10
NH2
NaBArF
(or NaB(C6F5)4)
4
S
S
OH
CH3CN
+
+
N
N
CH2Cl2
N
N
N
N
H
CH3
CH3
–
I–
H
H
H
BArF
(B(C6F5)4
4
OH
OH
–
)
11
4a (4a')
Scheme 3. Synthetic route for the formation of charge-containing thiourea catalysts 4a and 4a'.
To assess the catalytic performance of these charged thiourea salts, the Friedel-Crafts
alkylation of indole with trans-β-nitrostyrene and 10 mol% of 4a was initially examined under
various conditions (Table 1). At room temperature in chloroform-d this transformation went to
completion over the course of two days with a modest enantiomeric ratio (er) of 75 : 25 (entry
1).16
6
ACS Paragon Plus Environment

Page 7 of 34
The Journal of Organic Chemistry
1
2
3
4
Table 1. Evaluation of 4a Under Various Conditions.a
5
6
7
8
entry cat. loading solvent
(mol%)
temp. t (h) Conversion erc
(˚C)
(%)b
100
81
66
93
91
76
37
4
1
10
10
10
10
10
10
10
10
10
10
10
10
10
10
20
5
CDCl3
20
49
44
45
43
48
48
48
48
75 : 25
74 : 26
70 : 30
86 : 14
89 : 11
91 : 9
9
2
CD2Cl2
20
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
3
C6D5CD3 20
4
CDCl3
CDCl3
CDCl3
CDCl3
CD3CN
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
0
5
-20
-35
-45
-35
-35
-35
-35
-35
-35
-35
-35
-35
-35
6
7
92 : 8
8
-
9d
10e
11f
12g
13h
14i
15
16
17
425 38
85 : 15
88 : 12
90 : 10
-
48
48
48
48
48
29
51
72
52
49
trace
59
91 : 9
52 (54)
91
87 : 13 (77 : 23)
90 : 10
89 : 11
90 : 10
42
1
23
aUnless otherwise indicated, these reactions were carried out with 0.05 mmol of trans-β-
nitrostyrene and 3 equivalents of indole with the specified amount of catalyst in 0.6 mL of
b
1
solvent. Conversions were determined by H NMR analysis of crude reaction mixtures.
cEnantiomeric ratios were determined by chiral HPLC. dThis reaction was carried out with 0.017
e
mmol of trans-β-nitrostyrene (i.e., ~3 x more dilute than in entries 1-8). 1.5 equivalents of
f
g
indole were used. Bu4NBArF (5 mol%) was added. p-Toluenesulfonic acid (10 mol%) was
4
added. Et3NHBArF (10 mol%) was added. 1.5 mg of 3 or 4 Å molecular sieves were utilized;
h
i
4
the latter values are given in parentheses.
Dichloromethane-d2 and toluene-d8 were also used (entries 2 and 3) but this led to lower product
conversions and small decreases in the observed selectivities. Improved ers up to 92 : 8 were
obtained by lowering the temperature to -45 °C (entries 4-7), but since nearly the same
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 34
1
2
3
4
5
6
7
8
9
selectivity was observed at -35 ˚C (i.e., 91 : 9) and the reaction is noticeably faster (i.e., 37% vs
76% at t = 48 h), the higher temperature was adopted for our standard conditions. A change in
the solvent to acetonitrile-d3 led to a conversion of < 5% (entry 8), and this can be attributed to
the polar nature of CD3CN and its ability to serve as a hydrogen bond acceptor with the thiourea
catalyst. Concentrations and the trans-β-nitrostyrene/indole ratio were also varied (entries 9 and
10) but this slowed down the transformation without improving the stereoselectivity.
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
Several additives influence on the reaction were examined as well (entries 11-14). Added salt
in the form of Bu4NBArF (5 mol%) reduced the amount of product formed over a 48 h reaction
4
time period but had little, if any, effect on the er. External acids can activate thioureas as
reported by Herrera et al.,15 but in this case the addition of 10 mol% p-toluenesulfonic acid had
the opposite effect and only a trace of product was observed. We attribute this catalyst
deactivation to protonation of the thiourea or indole and coordination of the resulting tosylate
anion with 4a (i.e., hydrogen bonding to OTs— is detrimental). The use of 3 and 4 Å molecular
sieves to remove adventitious water are also disadvantageous with regard to yield and
stereoselectivity.17 Here too, hydrogen bonding between the oxygen atoms of the molecular
sieves (i.e., an aluminosilicate) and the thiourea catalyst is apt to be the cause. Finally,
triethylammonium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate has no effect on the er but does
lower the yield from 76% to 59%.
Catalytic loadings from 1–20 mol% were examined (entries 6 and 15-17) but have no notice-
able impact on the enantioselectivity of the Friedel-Crafts reaction. Kinetic studies revealed
second-order behavior, first-order in both indole and trans-β-nitrostyrene as one might expect.18
Rate constants and the first half-life’s of the limiting reagent (trans-β-nitrostyrene) are given in
Table 2. The latter values decrease with the amount of catalyst added and span from 140 to 7.0
8
ACS Paragon Plus Environment

Page 9 of 34
The Journal of Organic Chemistry
1
2
3
4
Table 2. Reaction Rate Constants and Half-life’s as a Function of Catalyst Loading.a
5
6
entry cat. loading (mol%) k (M–1h–1) t1/2 (h)
7
8
9
1
2
3
4
1
0.022
0.059
0.15
140
52
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
10
20
21
0.44
7.0
aStandard reaction conditions of ~0.083 M trans-β-nitrostyrene, 0.25 M indole and the indicated
amount of catalyst (4a) in CDCl3 at -35 ˚C were employed. The first half-life (t1/2) of the limiting
reagent (i.e., the styrene) is given since this value changes as the reaction proceeds.
hours at -35 ˚C in going from 1 to 20 mol% of 4a. A plot of the second-order rate constants
versus the square of the catalyst mol% is linear (Figure 2), consistent with previous findings and
suggests that the active catalytic species of the thiourea is dimeric.9,19 To assess this further, the
1H NMR spectra of 4a were recorded from 5.0 to 20.0 mM and both NH signals were found to
move downfield linearly with increasing concentration (Table 3). This is consistent with a
rapidly occurring monomer/dimer equilibrium and suggests that the association constant is small
and the resting state for the catalyst is largely monomeric. It also led us to propose the catalytic
cycle illustrated in Scheme 4.20
0.50
0.40
0.30
0.20
0.10
0.00
0
100
200
300
400
500
(4a mol%)2
Figure 2. A plot of second-order Friedel-Crafts alkylation rate constants versus the square of the
catalyst mol%; a least squares fit of the data affords: k (M–1 h–1) = 0.00103 x (4a mol%)2 + 0.33,
r2 = 0.997.
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 34
1
2
3
4
Table 3. Dilution 1H NMR Data for 4a at Room Temperature in CDCl3.a
5
6
7
[4a] mM
δNH1 (ppm) δNH2 (ppm) ΔδNH2(ppm)
8
9
5.0
6.7
10
10.15
10.15
10.17
10.18
9.01
9.07
9.14
9.30
0.29
0.23
0.16
0.00
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
20
aPresumably NH1 and NH2 in 4a are attached to the pyridinium and indanol rings, respectively. A
plot of ΔδNH2 vs [4a] is linear; ΔδNH2 (ppm) = -0.0185 [4a] + 0.363, r2 = 0.982.
S
–
BArF
CH3
4
+
N
2
N
H
N
H
OH
+
Ph
NO2
BArF
H3C
–
4
S
S
+
N
N
H
N
H
N
H
OH
–
BArF
CH3
–
4
BArF
+
4
N
S
S
N
N
H
N
H
+
N
OH
Ph
N
H
N
H
H3C
OH
NO2
–
BArF
4
+
N
N
N
H
N
H
H
CH3
OH
(rate determining step)
O–
O
Scheme 4. Proposed catalytic cycle for the Friedel-Crafts alkylation of indole with trans-β-
nitrostyrene.
10
ACS Paragon Plus Environment

Page 11 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
To try and gain a better understanding of the structure-reactivity and selectivity correlation in
this enantioseletive Friedel-Crafts alkylation,21 a series of modified catalyst structures 4a–4h and
4a' were examined.22 Variations in the achiral positively charged ring structure, the alkyl group
attached to the aromatic nitrogen atom, and the weakly coordinating counterion were explored.
Screening results for these thiourea catalysts at –35 ˚C with a 10 mol% catalyst loading in CDCl3
are summarized in Table 4. The reaction conversions were found to vary widely (i.e., 23% (71 h)
to 91% (50 h)) whereas the stereoselectivies spanned a narrow range with ers of 88 : 12 to 93 : 7.
For the pyridinium ions, substitution of a methyl group with a larger and more flexible 1-octyl
chain at the formally charged nitrogen center led to a small increase in the ers from 91 : 9 to 93 :
7 (entries 1 vs 2 and 5 vs 6) but larger decreases in the reaction rates. Methylated quinolinium
ion 4c (entry 3) with an expanded π-system and a larger ring system behaved similarly to 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
Table 4. Screening Results for the Friedel-Crafts Alkylation of trans-β-Nitrostyrene with
Indole Using Catalysts 4a-h, 4a', and 5.a
entry catalyst t (h) conversion (%)b erc
1
2
3
4
5
6
7
8
9
10
4a
4b
4c
4d
4e
4f
48
48
49
71
48
46
46
50
45
48
76
41
48
23
83
70
41
91
61
trace
91 : 9
93 : 7
93 : 7
88 : 12
91 : 9
93 : 7
91 : 9
89 : 11
89 : 11
–
4g
4h
4a'
5
aStandard reaction conditions of ~0.083 M trans-β-nitrostyrene and 0.25 M indole were
employed. bConversions were determined by1H NMR on crude reaction mixtures. cEnantiomeric
ratios were determined by chiral HPLC.
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 34
1
2
3
4
5
6
7
8
9
octylated pyridinium ion 4b, but a combination of these two design features (i.e., the larger
quinoline ring and an octyl substituent) in 4d led to the smallest reaction conversion and
stereoselectivity (entry 4). Incorporation of a phenyl substituent at the 5-position of the
pyridinium ion ring in 4a and 4b to afford 4e and 4f, interestingly, improved the reaction rate
without affecting the stereoselectivity (entries 5 and 6). If the para hydrogen on the phenyl ring
of 4e is replaced by a tert-butyl group to afford 4g, then the reaction conversion is reduced
significantly but the er is unaffected (entry 7). The catalyst 4h with a para-pyridinium ion center
proved to be the most efficient catalyst tested but among the least selective (er = 89 : 11, entry 8).
Conjugation of the formally charged center with one of the thiourea NH groups presumably
makes this derivative the most acidic one studied and accounts for its enhanced reactivity.
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
Finally, replacing the weakly coordinating BArF – counterion in 4a with (C6F5)4B– to afford 4a'
4
led to a lower product conversion and er value (entry 9).
All of the N-alkylated positively charged catalysts noted above can be compared to the
performance of 5, an analogous non-charged thiourea with a privileged 3,5-bis(trifluoromethyl)-
phenyl substituent. This latter catalyst is at least one to two orders of magnitude less effective
than 4a–4h and 4a' under the employed reaction conditions as only a trace (< 5%) of the product
was observed. Excellent results with catalyst 5 previously have been reported8a&d but these
reactions were carried out at a higher temperature (–25 vs –35 ˚C) with a larger catalyst loading
(20 vs 10 mol%) and at significantly higher reaction concentrations (0.08 vs 0.0083 M catalyst,
0.40 vs 0.083 M trans-β-nitrostyrene and 0.60 vs 0.25 M indole). It is not surprising,
consequently, that little product conversion with 5 was observed under our reaction conditions.
Similar results to ours were obtained by Ganesh and Seidel with 6 (a protonated 2-pyridine
containing thiourea) and somewhat greater stereoselectivities were observed with 7, a related
12
ACS Paragon Plus Environment

Page 13 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
quinolinium thioamide catalyst.11f All of these findings reveal the advantage of charged catalysts,
and are in accord with our earlier reports on achiral thioureas and phosphoric acids.9,10
To try and further improve the reaction efficiency, several increased reactant concentrations
and altered relative ratios were examined with 4b, 4c, and 4f, the three most selective catalysts
previously identified (Table 5). This was done in part because we worried that by varying 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
Table 5. Results for Catalyzed Friedel-Crafts Alkylations at -35 ˚C Using 4b, 4c or 4f and
Varying Substrate Concentrations After 48 h.a
entry Concentration (M–1)
catalyst (10 mol%)
4c
[βNS]b
0.083
0.17
[indole] 4b
4f
1
2
3
4
0.25
0.25
0.375
0.75
41 (93 : 7)c 48 (93 : 7) 70 (93 : 7)d
56 (90 : 10) 45 (92 : 8) 73 (92 : 8)
60 (95 : 5) 58 (92 : 8) 81 (92 : 8)
99 (92 : 8)e 88 (91 : 9) 91 (92 : 8)
0.25
0.25
1
aReactant conversions were determined by H NMR of the crude reaction mixtures and the
enantiomeric ratios were measured by chiral HPLC. bβNS = trans-β-nitrostyrene. ct= 49 h. dt= 46
h. et= 72 h.
substrate concentrations the overall polarity of the medium would be perturbed since CDCl3 is a
low-polarity solvent, and the stereoselectivity might be negatively impacted. This concern was
not born out in that all three catalysts gave good enantiomeric ratios and there is little variation
with substrate concentration over the range that was examined. Since 4b led to the highest er (95 :
5), this catalyst and the reactant concentrations that led to this result were adopted for examining
the scope of this transformation.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 34
1
2
3
4
5
6
7
8
9
Friedel-Crafts alkylations of a series of substituted trans-β-nitroalkenes and indoles (eq 2)
were found to afford high yields and good enantioselectivities (Table 6). Substituents on the
aromatic ring of the nitrostyrene had relatively little impact upon the reaction rate or the er
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
Ph
R
R
NO2
4b (10 mol%)
NO2
(2)
+
Ar
CDCl3, -35 ˚C
N
N
H
H
Table 6. Reaction Scope for Friedel-Crafts Alkylations Catalyzed by 4b at -35 ˚C Using
Substituted trans-β-Nitroalkenes and Indoles as Illustrated in Eq. 2.a
entry Ar
R
H
t (h)
Yieldb erc
1
2
3
4
5
6
7
8
Ph
71
76
99
93 : 7
91 : 9
Ph
5-OMe 70
Ph
6-OMe 70 (5 d) 99 (99) 95 : 5 (92 : 8)d
Ph
5-Cl
6-Cl
H
72
72
70
72
72
35
32
83
91
85
92 : 8
89 : 11
92 : 8
89 : 11
92 : 8
Ph
4-MeC6H4
2-ClC6H4
3-BrC6H4
H
H
aStandard conditions of 10 mol% catalyst, 0.083 M trans-β-nitrostyrene and 0.25 M indole were
used. bDetermined by1H NMR of the crude reaction mixtures. cMeasurements were carried out
using chiral HPLC. dParenthetical values are for a larger scale reaction with 1.5 mmol of trans-β-
nitrostyrene (220 mg), 2.25 mmol of 6-methoxyindole (330 mg), 10 mol% 4b and 0.075 mmol
(12 mg) of hexamethylbenzene as an internal standard in 6.0 mL of CHCl3 at –35 ˚C. Recycled
catalyst on ~1/3 of this larger reaction scale gave an 85% yield after 47 h with a 91 : 9 er.
14
ACS Paragon Plus Environment

Page 15 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
whereas incorporation of an electron donating methoxy group or an electron withdrawing
chlorine atom on to the indole enhanced and retarded the reactivity, respectively. The
stereoselectivity, however, was only slightly perturbed and gave good results in each case. A 30
times larger scale reaction under similar conditions was also carried out and gave similar results
(parenthetical values in entry 3). The catalyst can also be recovered and reused with little or no
falloff in activity and selectivity.
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
CONCLUSION
Asymmetric Friedel-Crafts alkylations of trans-β-nitrostyrenes with indoles are promoted by
non-protonated positively charged thiourea catalysts (i.e., 4). These atom economical
transformations add molecular complexity via carbon-carbon bond formation in good yields and
enantioselectivities. Mechanistic studies reveal a first-order dependence on both reactants and
second-order behavior of the catalyst under the employed reaction conditions. These results are
consistent with the dimer of the thiourea being the active catalyst and lead to some sensitivity to
sterics in 4 on the yield, whereas the enantiomeric ratios are relatively constant. Incorporation of
a charged center and the use of salts with non-interactive counteranions as a means of activating
catalysts without introducing new N–H or O–H hydrogen bond donating sites offers a promising
avenue for catalyst development. It also suggests a method for improving existing catalytic
platforms by replacing the privileged 3,5-bis(trifluoromethyl)phenyl substituent with a charged
group.
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 34
1
2
3
4
Experimental
5
6
7
General. Commercially obtained chemicals were used as received from Sigma Aldrich and Alfa
8
9
Aesar except for tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (NaBArF ) and deuterated
4
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
solvents. These latter materials came from Matrix Scientific and Cambridge Isotope Laboratories,
respectively. Oven-dried glassware (i.e., flasks, vials and NMR tubes) was employed for all
transformations under an inert atmosphere of argon unless specified otherwise. Thin-layer
chromatography was carried out using precoated 250 mm silica gel 60 Å plates and the separated
compounds were visualized with a hand held UV lamp. A medium pressure liquid
chromatography system with silica gel columns (60 Å, 40-75 µm) was used for purification
purposes. Melting points were obtained with a Uni-Melt apparatus in unsealed tubes and are
1
uncorrected. NMR spectra were obtained with a 500 MHz instrument and the respective H and
13C chemical shifts were referenced in ppm as follows: δ 8.03 and 34.9 (DMF-d7); 7.26 and 77.2
(CDCl3); 5.32 and 53.8 (CD2Cl2); 3.31 and 49.0 (CD3OD); 2.50 and 39.5 (DMSO-d6); 2.05 and
29.8 (acetone-d6); 1.94 and 1.3 (CD3CN); 2.08 (toluene-d8). A FT-IR with an ATR source was
used to obtain IR spectra. High resolution mass spectrometry data were obtained with an ESI
TOF instrument using aqueous methanolic and acetonitrile solutions containing polyethylene
glycol as an internal standard. Enantiomeric ratios (er) were measured with a HPLC and a 25 cm
x 4.6 mm (5 µm) RegisCellTM chiral column. Thiourea 5 was prepared as previously described.8a
5-(4-tert-Butyl)phenylpyridin-3-amine (8g). A mixture of 5-bromopyridin-3-amine (248 mg, 1.43
mmol), Pd(PPh3)4 (50.4 mg, 43.6 µmol), toluene (3 mL), aqueous sodium carbonate (2 M, 3 mL,
6 mmol), and 4-tert-butylphenylboronic acid (285 mg, 1.60 mmol) dissolved in ethanol (3 mL)
was heated at 90 °C overnight. The reaction mixture was then allowed to cool to ambient
temperature and extracted with EtOAc (20 mL × 2). The combined organic material was washed
16
ACS Paragon Plus Environment

Page 17 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification of the
residue by column chromatography (10% EtOAc/hexanes to 10% methanol/EtOAc) afforded 255
mg (79%) of 8g as a white solid (Rf = 0.10 in 33% EtOAc/hexanes, mp 145 – 146 °C). 1H NMR
(500 MHz, CDCl3) δ 8.27 (s, 1H), 8.06 (s, 1H), 7.50 (d, J = 8.3 Hz, 4H), 7.14 (s, 1H), 3.84 (br s,
2H), 1.36 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 151.2, 142.6, 138.8, 136.9, 136.2, 135.2, 126.9,
126.0, 119.8, 34.7, 31.4. IR (ATR source): 3427, 3314 cm-1. HRMS-ESI: calcd for C15H19N2 (M
+ H)+ 227.1543, found 227.1542.
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
3-Isothiocyanatoisoquinoline (9c).23 Thiophosgene (0.58 mL, 7.6 mmol) was slowly added to a
mixture of isoquinolin-3-amine (1.0 g, 6.9 mmol) in water (25 mL) over a period of 5 min at
0 °C and the mixture was subsequently stirred at room temperature for 2 h before being diluted
with water and extracted with EtOAc (25 mL × 3). The combined organic solution was dried
over Na2SO4 and concentrated under reduced pressure with a rotary evaporator. Medium
pressure liquid chromatography of the residue (10 – 20% EtOAc/hexanes) afforded 0.83 g (64%)
of 9c as a white solid (Rf = 0.30 in 10% EtOAc/hexanes, mp 64 – 65 °C). 1H NMR (500 MHz,
CD2Cl2) δ 8.78 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.98 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.74 (t, J
13
= 8.3 Hz, 1H), 7.61 (t, J = 8.8 Hz, 1H). C NMR (126 MHz, CD2Cl2) δ 148.0, 146.3, 138.7,
130.4, 130.2, 129.7, 128.1, 127.7, 127.6, 126.0. IR (ATR source): 2021 cm-1. HRMS-ESI: calcd
for C10H7N2S (M + H)+ 187.0324, found 187.0342.
3-Isothiocyanato-5-phenylpyridine (9e). To a solution of 0.90 g (5.3 mmol) of 3-amino-5-
phenylpyridine24 dissolved in 15 mL of chloroform was added an equal volume of saturated
aqueous NaHCO3 at room temperature. The resulting solution was stirred and 0.50 mL (6.5
mmol) of thiophosgene in 5 mL of CHCl3 was added dropwise. After 2 h, the reaction mixture
was filtered and the aqueous layer was extracted with CH2Cl2 (25 mL × 2). The combined
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 34
1
2
3
4
5
6
7
8
9
organic material was dried over MgSO4 and concentrated under reduced pressure with a rotary
evaporator. Medium pressure liquid chromatography of the residue (5% EtOAc/hexanes)
afforded 0.68 g (61%) of 9e as a yellow solid (Rf = 0.15 in 10% EtOAc /hexanes, mp 51 – 52 °C).
1H NMR (500 MHz, CDCl3) δ 8.72 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 2.5 Hz, 1H), 7.70 (dd, J =
2.0, 2.5 Hz, 1H), 7.56 (d, J = 7.4 Hz, 2H), 7.50 (t, J = 6.9 Hz, 2H), 7.45 (t, J = 6.9 Hz, 1H). 13C
NMR (126 MHz, CDCl3) δ 146.2, 145.4, 139.5, 137.5, 136.1, 130.6, 129.7, 129.4, 128.9, 127.2.
IR (ATR source): 2039 cm-1. HRMS-ESI: calcd for C12H9N2S (M + H)+ 213.0481, found
213.0494.
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
5-(4-tert-Butyl)phenyl-3-isothiocyanatopyridine (9g). To a solution of 0.25 g (1.1 mmol) of 8g
dissolved in 2.5 mL of chloroform was added an equal volume of saturated aqueous NaHCO3 at
room temperature. The resulting solution was stirred and 0.11 mL (1.4 mmol) of thiophosgene in
1 mL of CHCl3 was added dropwise. After 2 h, the reaction mixture was filtered and the aqueous
layer was extracted with CH2Cl2 (10 mL × 2). The combined organic material was dried over
MgSO4 and concentrated under reduced pressure. Medium pressure liquid chromatography of the
residue (5 – 30% EtOAc/hexanes) afforded 0.17 g (57%) of 9g as a yellow solid (Rf = 0.10 in 33%
1
EtOAc/hexanes, mp 113 – 114 °C). H NMR (500 MHz, CDCl3) δ 8.71 (s, 1H), 8.47 (s, 1H),
7.67 (s, 1H), 7.52 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 1.37 (s, 9H). 13C NMR (126 MHz,
CDCl3) δ 152.3, 146.1, 145.2, 139.4, 137.4, 133.2, 130.4, 129.7, 126.9, 126.4, 34.8, 31.4. IR
(ATR source): 2067 cm-1. HRMS-ESI: calcd for C16H17N2S (M + H)+ 269.1107, found 269.1086.
3-Isothiocyanato-1-methylisoquinolinium iodide (10c). In a 6 dram vial, 40 mg (0.22 mmol) of
9c was dissolved in 1 mL of EtOAc and 0.23 mL (3.7 mmol) of methyl iodide was added at 40
oC under argon. The reaction mixture was allowed to stir for 72 h and the resulting precipitate
was filtered, washed with 1 mL of hexanes and dried under vacuum to afford 30 mg (42%) of
18
ACS Paragon Plus Environment

Page 19 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10c as a yellow solid (mp decomposed over 200 °C). 1H NMR (500 MHz, DMSO-d6) δ 9.89 (s,
1H), 9.36 (s, 1H), 8.51 (d, J = 8.8 Hz, 1H), 8.40 (d, J = 7.8 Hz, 1H), 8.27 (dd, J = 7.3, 8.8 Hz,
1H), 8.08 (dd, J = 7.3, 7.8 Hz, 1H), 4.63 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 148.9, 141.2,
140.8, 136.4, 135.5, 130.7, 129.9, 128.6, 125.8, 119.2, 45.6. IR (ATR source): 2000 cm-1.
HRMS-ESI: calcd for C11H9N2S.
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
General procedure for preparing 3-isothiocyanato-N-octylpyridinium ions 10b, 10d and 10f.
In a 6 dram vial, 0.73 mmol of a 3-isothiocyanatopyridine derivative (9a,25 9c or 9e) was
dissolved in 1 mL of CH2Cl2 and 0.39 g (1.47 mmol) of 1-octyl triflate26 was added at room
temperature under argon. The reaction mixture was allowed to stir overnight and concentrated
under reduced pressure. The resulting residue was washed with 2 mL of pentane and dried under
vacuum to afford the corresponding product.
3-Isothiocyanato-1-(1-octyl)pyridinium triflate (10b). An 86% yield (0.25 g) of this product was
1
obtained as a yellow oil. H NMR (500 MHz, CDCl3) δ 8.87 (d, J = 6.3 Hz, 1H), 8.68 (s, 1H),
8.22 (d, J = 8.3 Hz, 1H), 8.07 (dd, J = 6.3, 8.3 Hz, 1H), 4.70 (t, J = 7.3 Hz, 2H), 2.00 (m, 2H),
13
1.20 - 1.40 (m, 10H), 0.87 (t, J = 6.9 Hz, 3H). C NMR (126 MHz, CDCl3) δ 145.3, 142.5,
141.7, 141.2, 134.9, 129.4, 120.5 (q, JC-F = 315 Hz), 63.0, 31.64, 31.58, 29.0, 28.9, 26.0, 22.6,
14.1. IR (ATR source): 2003 cm-1. HRMS-ESI: calcd for C14H21N2S (M –CF3SO2)+ 249.1420,
found 249.1403.
3-Isothiocyanato-1-(1-octyl)isoquinolinium triflate (10d). This product was obtained in a 93%
1
yield (0.30 g) as a yellow solid (mp 50 – 52 °C). H NMR (500 MHz, CDCl3) δ 9.38 (s, 1H),
8.87 (s, 1H), 8.32 (d, J = 8.3 Hz, 1H), 8.30 (d, J = 8.3 Hz, 1H), 8.17 (t, J = 8.3 Hz, 1H), 7.93 (t, J
= 8.3 Hz, 1H), 5.08 (t, J = 7.8 Hz, 2H), 2.02 (m, 2H), 1.01-1.49 (m, 10H), 0.80 (t, J = 6.4 Hz,
3H). 13C NMR (126 MHz, CDCl3) δ 146.7, 144.0, 141.9, 136.5, 136.0, 131.4, 130.8, 130.2,
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 34
1
2
3
1
128.2, 120.7 (q, JF-C = 321 Hz), 118.6, 59.2, 31.7, 30.3, 29.0, 26.4, 22.6, 14.8, 14.1. IR (ATR
source): 1992 cm-1. HRMS-ESI: calcd for C18H23N2S (M – CF3SO2)+ 299.1576, found 299.1569.
3-Isothiocyanato-5-phenyl-1-(1-octyl)pyridinium triflate (10f). This product was obtained
quantitatively (0.36 g) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 9.04 (s, 1H), 8.76 (s, 1H),
8.22 (s, 1H), 7.72 (m, 2H), 7.52 (m, 3H), 4.77 (t, J = 7.8 Hz, 2H), 1.98 (pentet, J = 7.4 Hz, 2H),
1.38-1.12 (m, 10H), 0.83 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 145.5, 142.8, 140.4,
139.1, 138.3, 135.0, 131.9, 131.3, 130.1, 127.7, 120.8 (q, J = 322 Hz), 63.4, 32.0, 31.8, 29.1,
26.1, 22.7, 14.8, 14.2. IR (ATR source): 2010 cm-1. HRMS-ESI: calcd for C20H25N2S (M –
CF3SO2)+ 325.1733, found 325.1740.
4
5
6
7
8
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
General procedure for preparing 3-isothiocyanato-N-methylpyridinium ions 10e, 10g and
10h. In a 6 dram vial, 0.47 mmol of a 3-isothiocyanatopyridine derivative (9e, 9g or 9h)27 was
dissolved in 1 mL of EtOAc and 90 µL (1.4 mmol) of iodomethane was added at room
temperature under argon. The reaction mixture was allowed to stir overnight and the resulting
precipitate was filtered, washed with 2 mL of EtOAc and dried under vacuum to afford the
corresponding product.
3-Isothiocyanato-1-methyl-5-phenylpyridinium iodide (10e). This product was obtained in a 60%
yield (0.10 g) as a pale yellow solid (mp 154 – 155 °C). 1H NMR (500 MHz, DMSO-d6) δ 9.36
(s, 1H), 9.26 (s, 1H), 9.01 (s, 1H), 7.92 (d, J = 6.9 Hz, 2H), 7.62 (m, 3H), 4.37 (s, 3H). 13C NMR
(126 MHz, DMSO-d6) δ 141.8, 141.4, 141.1, 139.4, 138.7, 132.2, 131.7, 130.5, 129.4, 127.5,
48.4. IR (ATR source): 2035 cm-1. HRMS-ESI: calcd for C13H11N2S (M – I)+ 227.0637, found
227.0643.
3-Isothiocyanato-1-methyl-5-(4-tert-butyl)phenylpyridinium iodide (10g). This product was
1
obtained in a 77% yield (0.15 g) as a yellow solid (mp 205 – 207 °C). H NMR (500 MHz,
20
ACS Paragon Plus Environment

Page 21 of 34
The Journal of Organic Chemistry
1
2
3
4
DMSO-d6) δ 9.33 (s, 1H), 9.23 (s, 1H), 8.97 (s, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.8 Hz,
5
6
13
2H), 4.36 (s, 3H), 1.33 (s, 9H). C NMR (126 MHz, DMSO-d6) δ 153.4, 141.6, 141.2, 140.9,
7
8
9
139.3, 138.3, 131.7, 129.4, 127.3, 126.3, 48.4, 34.6, 30.9. IR (ATR source): 1989 cm-1. HRMS-
ESI: calcd for C17H19N2S (M – I)+ 283.1263, found 283.1282.
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
4-Isothiocyanato-1-methylpyridinium iodide (10h). This product was obtained in a 66% yield (86
1
mg) as a yellow solid (mp 152 – 154 °C). H NMR (500 MHz, CD3CN) δ 8.60 (d, J = 5.9 Hz,
2H), 7.74 (d, J = 5.9 Hz, 2H), 4.23 (s, 3H). 13C NMR (126 MHz, DMF-d7) δ 149.6, 145.6, 126.7,
126.1, 66.3. IR (ATR source): 2017 cm-1. HRMS-ESI: calcd for C7H7N2S (M – I)+ 151.0324,
found 151.0335; (M – I)+ 201.0481, found 201.0459.
General procedure for preparing thiourea catalyst precursors 11a-h. In a 6 dram vial, 0.18
mmol of a 3-isothiocyanato-1-alkylpyridinium ion (10a-h) was dissolved in 2 mL of CH3CN or
CH2Cl2 and (1S,2R)-cis-1-amino-2-indanol (27 mg, 0.18 mmol) was added at room temperature
under argon. The reaction mixture was allowed to stir overnight and was then either (a)
concentrated under reduced pressure if no precipitate was present, or (b) filtered if precipitate
was present. In the latter case the resulting residue was washed with 2 mL of pentane and dried
under vacuum to afford the corresponding product.
3-(3-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)thioureido)-1-methylpyridinium iodide (11a).
This compound was obtained in a 90% yield (70 mg) as a pale yellow solid (mp 175 – 178 °C).
1H NMR (500 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.70 (d, J = 5.9 Hz, 1H), 8.64 (d, J = 8.8 Hz, 1H),
8.62 (br s, 1H), 8.06 (dd, J = 5.9, 8.8 Hz, 1H), 7.10 - 7.35 (m, 4H), 5.80 (d, J = 3.9 Hz, 1H), 5.52
(d, J = 3.9 Hz, 1H), 4.57 (t, J = 4.4 Hz, 1H), 4.37 (s, 3H), 3.14 (dd, J = 4.4, 16.1 Hz, 1H), 2.87 (d,
J = 16.1 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 180.6, 141.2, 140.6, 139.73, 139.68, 138.3,
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 34
1
2
3
4
5
6
136.9, 127.6, 127.0, 126.2, 125.1, 124.1, 71.7, 71.6, 61.5, 48.3. IR (ATR source): 3370, 3329,
3265 cm-1. HRMS-ESI: calcd for C16H18N3OS (M – I)+ 300.1165, found 300.1167.
7
8
3-(3-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)thioureido)-1-(1-octyl)pyridinium triflate
9
1
(11b). A 72% yield (71 mg) of 11b was obtained as a pale yellow solid (mp 53 – 55 °C). H
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
NMR (500 MHz, CDCl3) δ 9.98 (s, 1H), 9.69 (s, 1H), 8.38 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 5.9
Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.59 (dd, J = 5.9, 8.8 Hz, 1H), 7.37 (d, J = 6.4 Hz, 1H), 7.17
(m, 3H), 5.85 (dd, J = 4.4, 7.3 Hz, 1H), 4.75 (t, J = 4.4 Hz, 1H), 4.31 (t, J = 7.4 Hz, 2H), 3.11 (dd,
J = 4.9, 16.6 Hz, 1H), 2.92 (d, J = 16.6 Hz, 1H), 1.91 (m, 2H), 1.27 (m, 10H), 0.86 (t, J = 4.9 Hz,
3H). 13C NMR (126 MHz, CDCl3) δ 181.2, 141.4, 140.5, 140.2, 137.0, 136.8, 136.4, 128.3, 127.5,
127.1, 125.4, 124.8, 120.3 (q, JC-F = 320 Hz), 73.3, 62.8, 39.8, 31.8, 31.2, 29.1, 29.0, 26.1, 24.3,
22.7, 14.2. IR (ATR source): 3372, 3266 cm-1. HRMS-ESI: calcd for C23H32N3OS (M – CF3SO2)+
398.2261, found 398.2259.
3-(3-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)thioureido)-1-methylisoquinolinium iodide
(11c). This product was obtained in a 67% yield (58 mg) as a yellow solid (mp 157 – 159 °C). 1H
NMR (500 MHz, CD3OD) δ 10.03 (s, 1H), 9.00 (s, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.31 (d, J = 8.3
Hz, 1H), 8.16 (dd, J = 7.3, 8.3 Hz, 1H), 7.98 (dd, J = 7.3, 8.8 Hz, 1H), 7.44 (d, J = 5.4 Hz, 1H),
7.26 (d, J = 5.4 Hz, 1H), 7.20 (m, 2H), 5.97 (d, J = 4.4 Hz, 1H), 4.74 (dd, J = 4.4, 4.9 Hz, 1H),
13
4.68 (s, 3H), 3.20 (dd, J = 4.9, 16.1 Hz, 1H), 2.98 (d, J = 16.1 Hz, 1H). C NMR (126 MHz,
CD3OD) δ 184.2, 149.1, 142.1, 141.8, 138.2, 137.0, 136.1, 135.4, 131.5, 131.1, 131.0, 129.2,
127.9, 126.5, 125.6, 119.8, 66.9, 64.0, 46.7, 41.0. IR (ATR source): 3372, 3329, 3266 cm-1.
HRMS-ESI: calcd for C20H20N3OS (M – I)+ 350.1322, found 350.1327.
3-(3-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)thioureido)-1-(1-octyl)isoquinolinium
triflate (11d). This product was obtained in a 64% yield (69 mg) as a yellow solid (mp 50 –
22
ACS Paragon Plus Environment

Page 23 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
52 °C). 1H NMR (500 MHz, CD2Cl2) δ 10.16 (s, 1H), 9.91 (s, 1H), 8.46 (s, 1H), 8.02 – 8.10 (m,
3H), 7.99 (d, J = 7.3 Hz, 1H), 7.87 (t, , J = 6.9 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 7.3
Hz, 1H), 6.84 (t, J = 7.4 Hz, 1H), 6.64 (t, J = 7.4 Hz, 1H), 5.73 (t, J = 6.4 Hz, 1H), 4.94 (t, J =
4.4 Hz, 1H), 4.86 (m, 1H), 4.74 (m, 1H), 3.12 (dd, J = 3.9, 16.6 Hz, 1H), 2.97 (d, J = 16.6 Hz,
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
13
1H), 2.10 (m, 2H), 1.52 (m, 2H), 1.19 – 1.44 (m, 8H), 0.87 (t, J = 6.4 Hz, 3H). C NMR (126
MHz, CD2Cl2) δ 182.8, 147.2, 140.4, 140.1, 135.8, 134.9, 133.7, 130.4, 130.0, 129.8, 127.6,
1
126.5, 124.8, 124.6, 124.5, 120.5 (q, JF-C = 321 Hz), 116.3, 73.1, 63.0, 58.5, 39.9, 31.7, 29.8,
29.0, 26.6, 22.6, 18.6, 13.8. IR (ATR source): 3372, 3329, 3266 cm-1. HRMS-ESI: calcd for
C27H34N3OS (M – CF3SO2)+ 448.2417, found 448.2396.
3-(3-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)thioureido)-1-methyl-5-phenylpyridinium
iodide (11e). This product was obtained in a 97% yield (88 mg) as a pale yellow solid (mp 160 –
162 °C). 1H NMR (500 MHz, CD3OD) δ 9.48 (s, 1H), 8.91 (s, 1H), 8.89 (s, 1H), 7.80 (d, J = 7.8
Hz, 2H), 7.60 – 7.45 (m, 3H), 7.40 (d, J = 7.3 Hz, 1H), 7.28 – 7.11 (m, 3H), 5.94 (d, 1H), 4.71 (t,
13
J = 4.4 Hz, 1H), 4.43 (s, 3H), 3.16 (dd, J = 4.4, 16.6 Hz, 1H), 2.95 (d, J = 16.7 Hz, 1H). C
NMR (126 MHz, CD3OD) δ 182.6, 141.9, 141.8, 141.7, 141.4, 138.6, 137.3, 134.9, 134.6, 131.4,
130.7, 129.0, 128.5, 127.7, 126.3, 125.4, 73.6, 63.5, 49.7, 40.9. IR (ATR source): 3329, 3253
cm-1. HRMS-ESI: calcd for C22H22N3OS (M – I)+ 376.1478, found 376.1491.
3-(3-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)thioureido)-1-(1-octyl)-5-phenylpyridinium
triflate (11f). This product was obtained in a 85% yield (95 mg) as a pale yellow solid (mp 73 –
76 °C). 1H NMR (500 MHz, CDCl3) δ 9.97 (s, 1H), 9.46 (s, 1H), 8.78 (s, 1H), 8.37 (s, 1H), 8.02
(d, J = 8.3 Hz, 1H), 7.63 (d, J = 5.4 Hz, 2H), 7.48 (m, 3H), 7.39 (d, J = 6.8 Hz, 1H), 7.20-7.10
(m, 3H), 5.89 (dd, J = 4.9, 6.9 Hz, 1H), 4.79 (t, J = 4.7 Hz, 1H), 4.39 (m, 2H), 3.97 (d, J = 5.9 Hz,
1H), 3.11 (dd, J = 4.9, 16.6 Hz, 1H), 2.88 (d, J = 16.6 Hz, 1H), 1.95 (t, J = 6.4 Hz, 2H), 1.40-
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 34
1
2
3
4
13
1.11 (m, 10H), 0.87 (t, J = 6.4 Hz, 3H). C NMR (126 MHz, CDCl3) δ 181.4, 141.4, 140.9,
5
6
7
8
140.3, 139.8, 135.4, 134.8, 134.2, 132.8, 130.7, 129.9, 128.3, 127.4, 127.1, 125.3, 124.8, 120.3
(q, J = 320 Hz), 73.5, 63.0, 57.6, 39.5, 31.8, 31.4, 29.1, 26.1, 22.7, 14.8, 14.2. IR (ATR source):
3315 cm-1. HRMS-ESI: calcd for C29H36N3OS (M – CF3SO2)+ 474.2574, found 474.2558.
5-(4-tert-Butyl)phenyl-3-(3-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)thioureido)-1-
methylpyridinium iodide (11g). This product was obtained in 75% (82 mg) as a pale yellow solid
(mp 145 – 148 °C). 1H NMR (500 MHz, CDCl3) δ 9.51 (s, 1H), 9.09 (s, 1H), 8.35 (s, 1H), 8.32
(d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.8 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H), 7.50 (d, J = 7.8 Hz, 1H),
7.21 – 7.10 (m, 4H), 5.86 (t, J = 4.9 Hz, 1H), 4.84 (t, J = 4.9 Hz, 1H), 4.23 (d, J = 5.9 Hz, 1H),
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
13
4.20 (s, 3H), 3.14 (dd, J = 4.9, 16.6 Hz, 1H), 3.00 (d, J = 16.6 Hz, 1H), 1.35 (s, 9H). C NMR
(126 MHz, (CD3)2CO) δ 181.9, 154.3, 141.8, 141.6, 140.1, 137.9, 135.6, 133.0, 131.4, 128.5,
127.9, 127.4, 127.2, 125.9, 125.4, 111.0, 73.4, 63.2, 49.8, 40.5, 35.4, 31.4. IR (ATR source):
3242 cm-1. HRMS-ESI: calcd for C26H30N3OS (M – I)+ 432.2104, found 432.2128.
4-(3-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)thioureido)-1-methylpyridinium
iodide
(11h). This product was obtained in a 65% (50 mg) yield as a yellow solid (mp 138 – 140 °C).
1H NMR (500 MHz, CD3CN) δ 10.95 (s, 1H), 8.59 (d, J = 6.9 Hz, 2H), 8.56 (s, 1H), 8.26 (d, J =
7.3 Hz, 2H), 7.67 (d, J = 9.8 Hz, 1H), 7.41 (d, J = 7.3 Hz, 1H), 7.28 (t, J = 7.3 Hz, 1H), 7.22 (t, J
= 7.3 Hz, 1H), 5.90 (dd, J = 4.9, 8.3 Hz, 1H), 4.71 (t, J = 4.9 Hz, 1H), 4.06 (s, 3H), 3.45 (s, 1H),
13
3.19 (dd, J = 4.9, 16.7 Hz, 1H), 2.94 (d, J = 16.6 Hz, 1H). C NMR (126 MHz, DMSO-d6) δ
179.4, 152.5, 145.1, 140.8, 140.7, 127.8, 126.3, 125.2, 124.2, 114.5, 71.6, 61.5, 46.0, 39.9. IR
(ATR source): 3375, 3329, 3268 cm-1. HRMS-ESI: calcd for C16H18N3OS (M – I)+ 300.1165,
found 300.1183.
24
ACS Paragon Plus Environment

Page 25 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
General procedure for preparing thiourea catalysts 4a-h and 4a'. To a 6 dram vial, 21 mg
(24 µmol) of sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate or 17 mg (24 µmol) of
potassium tetrakis(pentafluorophenyl)borate, 24 µmol of a thiourea catalyst precursor (11a, c-h)
and 1 mL of CH2Cl2 were added. This mixture was stirred at room temperature under an argon
atmosphere until the solid material was totally dissolved and a cloudy suspension formed.
Stirring was then stopped and the solution was left undisturbed until a white solid precipitated
and a clear solution formed. The reaction mixture was then filtered and concentrated under
reduced pressure. The resulting residue was washed with 2 mL of pentane and dried under
vacuum to afford the corresponding product.
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
3-(3-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)thioureido)-1-methylpyridinium
tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (4a). The title compound was obtained in an 86%
1
yield (24 mg) as a pale yellow solid (mp 70 – 73 °C). H NMR (500 MHz, CD2Cl2) δ 10.00 (s,
1H), 8.14 (s, 1H), 8.02 (d, J = 5.9 Hz, 1H), 7.75 (s, 8H), 7. 80 – 7.45 (m, 3H), 7.59 (s, 4H), 7.38
(d, J = 7.4 Hz, 1H), 7.28 (m, 3H), 5.96 (s, 1H), 4.78 (d, J =4.9 Hz, 1H), 4.31 (s, 3H), 3.26 (dd, J
13
= 4.9, 16.7 Hz, 1H), 2.95 (d, J = 16.2 Hz, 1H) C NMR (126 MHz, CD2Cl2) δ 180.8, 162.1 (q,
1JB-C = 49.5 Hz), 141.6, 140.1, 139.7, 137.9, 137.7, 136.8, 135.2 (q, 2JB-C = 31.3 Hz), 129.3 (qq,
2
1
3JB-C = 3.0 Hz and JF-C = 31.3 Hz), 128.4, 127.8, 127.7, 125.0, 124.9 (q, JF-C = 272 Hz), 124.7,
117.9 (q, JF-C = 2.0 Hz), 67.5, 62.9, 49.8, 40.4. IR (ATR source): 3334 cm-1. HRMS-ESI: calcd
3
for C16H18N3OS (M – C32H12BF24)+ 300.1165, found 300.1181.
3-(3-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)thioureido)-1-(1-octyl)pyridinium tetrakis
(3, 5-bis(trifluoromethyl)phenyl)borate (4b). This catalyst was obtained in an 81% yield (25 mg)
1
as a pale yellow solid (mp 51 – 53 °C). H NMR (500 MHz, CD2Cl2) δ 10.23 (s, 1H), 8.93 (s,
1H), 7.80 (d, J = 5.9 Hz, 1H), 7.72 (s, 8H), 7.69 (s, 1H), 7.54 (s, 4H), 7.50 (m, 1H), 7.41 (dd, J =
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 34
1
2
3
4
5
6
7
8
9
5.9, 8.3 Hz, 1H), 7.36 (d, J = 7.4 Hz, 1H), 7.20 – 7.33 (m, 3H), 5.95 (s, 1H), 4.81 (s, 1H), 4.35 (t,
J = 6.8 Hz, 2H), 3.29 (d, J = 16.1 Hz, 1H), 2.98 (d, J = 16.0 Hz, 1H), 2.18 (br s, 1H), 2.02 (m,
2H), 1.10 – 1.40 (m, 10H), 0.88 (t, J = 6.4 Hz, 3H). 13C NMR (126 MHz, CD2Cl2) δ 181.0, 162.2
(q, 1JB-C = 49.1 Hz), 141.8, 140.1, 137.3, 136.9, 136.7, 136.6, 136.5, 136.3, 135.3 (q, 2JB-C = 35.3
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
2
1
Hz), 129.3 (qq, 3JB-C = 3.0 Hz and JF-C = 31.3 Hz), 128.4, 128.1, 125.9, 125.0 (q, JF-C = 273
3
Hz), 117.9 (q, JF-C = 2.0 Hz), 74.2, 63.9, 40.4, 31.9, 31.6, 29.2, 29.1, 26.3, 22.9, 22.8, 14.2. IR
(ATR source): 3427, 3300 cm-1. HRMS-ESI: calcd for C23H32N3OS (M – C32H12BF24)+ 398.2261,
found 398.2251.
3-(3-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)thioureido)-1-methylisoquinolinium
tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (4c). This product was obtained in an 86% yield
(25 mg) as a yellow solid (mp 75 – 77 °C). 1H NMR (500 MHz, CD2Cl2) δ 9.95 (s, 1H), 9.35 (s,
1H), 8.74 (s, 1H), 8.00 – 8.15 (m, 3H), 7.92 (t, J = 6.9 Hz, 1H), 7.80 (s, 1H), 7.75 (s, 8H), 7.57 (s,
4H), 7.42 (d, J = 7.4 Hz, 1H), 7.00 – 7.24 (m, 3H), 5.97 (s, 1H), 4.79 (s, 1H), 4.52 (s, 3H), 3.23
(dd, J = 4.4, 16.6 Hz, 1H), 2.94 (d, J = 16.1 Hz, 1H), 2.92 (br s, 1H). 13C NMR (126 MHz,
1
2
CD2Cl2) δ 182.4, 162.1 (q, JB-C = 49.1 Hz), 146.1, 140.2, 137.3, 135.7, 135.2 (q, JB-C = 32.7
3
2
Hz), 134.6, 131.5, 131.3, 130.5, 130.3, 129.8, 129.2 (qq, JB-C = 3.0 Hz and JF-C = 32.8 Hz),
127.6, 127.5, 125.8, 125.1 (q, 1JF-C = 276 Hz), 125.0, 124.7, 117.9 (q, 3JF-C = 2.0 Hz), 74.3, 68.3,
46.3, 40.2. IR (ATR source): 3411, 3317 cm-1. HRMS-ESI: calcd for C20H20N3OS (M –
C32H12BF24)+ 350.1322, found 350.1298.
3-(3-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)thioureido)-1-(1-octyl)isoquinolinium tetra-
kis(3,5-bis(trifluoromethyl)phenyl)borate (4d). This product was obtained in a 67% yield (21 mg)
1
as a yellow solid (mp 56 – 58 °C). H NMR (500 MHz, CD3OD) δ 10.14 (s, 1H), 8.80 (s, 1H),
8.41 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 7.9 Hz, 1H), 8.09 (t, J = 7.4 Hz, 1H), 7.88 (t, J = 7.8 Hz,
26
ACS Paragon Plus Environment

Page 27 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1H), 7.64 (s, 8H), 7.60 (s, 4H), 7.42 (s, 1H), 7.31 - 7.00 (m, 4H), 5.98 (s, 1H), 5.04 (t, J = 6.8 Hz,
2H), 4.74 (d, J = 4.9 Hz, 1H), 3.19 (dd, J = 4.4, 16.1 Hz, 1H), 2.99 (d, J = 16.1 Hz, 1H), 2.12 (m,
2H), 2.01 (br s, 1H), 1.52 (m, 2H), 1.42 – 1.14 (m, 8H), 0.82 (t, J = 6.4 Hz, 3H). 13C NMR (126
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
MHz, CD3OD) δ 184.4, 163.0 (q, JB-C = 50.5, Hz) 148.8, 142.1, 141.8, 138.1, 136.4, 136.0,
3
2
135.4, 131.6, 131.4, 130.6 (qq, JB-C = 3.0 Hz and JF-C = 33.3 Hz), 129.2, 128.0, 127.9, 126.6,
1
1
126.5, 125.9 (q, JF-C = 273 Hz), 125.5, 119.6, 118.6 (q, JF-C = 3.0 Hz), 73.9, 64.1, 59.6, 41.0,
32.9, 31.1, 30.8, 30.3, 27.7, 23.7, 14.5. IR (ATR source): 3287 cm-1. HRMS-ESI: calcd for
C27H34N3OS (M – C32H12BF24)+ 448.2417, found 448.2427.
3-(3-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)thioureido)-1-methyl-5-phenylpyridinium
tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (4e). This product was obtained in an 89% yield
(26 mg) as a yellow solid (mp 68 – 71 °C). 1H NMR (500 MHz, CDCl3) δ 9.63 (s, 1H), 9.24 (s,
1H), 8.49 (s, 1H), 8.10 (s, 1H), 7.71 (s, 8H), 7.65 (s, 1H), 7.56 – 7.41 (m, 5H), 7.53 (s, 4H), 7.32
(d, J = 6.9 Hz, 1H), 7.28 – 7.13 (m, 3H), 5.93 (s, 1H), 4.76 (s, 1H), 4.19 (s, 3H), 3.22 (d, J = 16.2
Hz, 1H), 2.87 (d, J = 15.6 Hz, 1H), 2.53 (s, 1H). 13C NMR (126 MHz, CD2Cl2) δ 180.7, 161.8 (q,
1JB-C = 50.5, Hz), 142.4, 141.3, 139.8, 139.4, 135.4, 135.3, 134.8 (q, JB-C = 31.3 Hz), 134.3,
2
3
2
132.1, 131.5, 131.1, 130.3, 129.9, 128.9 (qq, JB-C = 3.0 Hz and JF-C = 33.3 Hz), 127.3, 126.9,
1
3
124.6 (q, JF-C = 273 Hz), 124.5, 117.5 (q, JF-C = 3.0 Hz), 74.0, 62.6, 49.5, 40.1. IR (ATR
source): 3336 cm-1. HRMS-ESI: calcd for C22H22N3OS (M – C32H12BF24)+ 376.1478, found
376.1479.
3-(3-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)thioureido)-1-(1-octyl)-5-phenylpyridinium
tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (4f). This product was obtained in an 87% yield
(28 mg) as a yellow solid (mp 58 – 61 °C). 1H NMR (500 MHz, CDCl3) δ 9.95 (s, 1H), 9.28 (s,
1H), 8.25 (s, 1H), 8.17 (s, 1H), 7.71 (s, 9H), 7.51 (s, 4H), 7.55-7.40 (m, 5H), 7.36 (d, J = 7.4 Hz,
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 34
1
2
3
4
5
6
1H), 7.32-7.20 (m, 3H), 5.98 (s, 1H), 4.79 (s, 1H), 4.44 (t, J = 6.9 Hz, 2H), 3.27 (d, J = 15.6 Hz,
1H), 2.94 (d, J = 15.6 Hz, 1H), 2.68 (br s, 1H), 2.08 (t, J = 7.3 Hz, 2H), 1.44-1.18 (m, 10H), 0.87
7
8
9
13
1
(t, J = 4.9 Hz, 3H). C NMR (126 MHz, CD3OD) δ 183.0, 162.9 (q, JB-C = 50.5, Hz), 142.4,
142.3, 141.7, 137.5, 137.2, 135.8, 135.3, 134.7, 131.5, 130.8, 130.4 (qq, 3JB-C = 3.0 Hz and 2JF-C
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
= 32.3 Hz), 129.1, 128.5, 127.7, 126.4, 126.0, 125.8 (q, 1JF-C = 272 Hz), 125.4, 118.5 (q, 3JF-C
=
3.0 Hz), 73.6, 63.6, 47.9, 40.9, 32.8, 32.4, 30.1, 30.0, 27.2, 23.6, 14.3. IR (ATR source): 3340,
3163 cm-1. HRMS-ESI: calcd for C29H36N3OS (M – C32H12BF24)+ 474.2574, found 474.2572.
3-(3-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)thioureido)-1-methyl-5-(4-tert-butyl)-
phenylpyridinium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (4g). This product was obtained
1
in an 88% yield (27 mg) as a yellow solid (mp 70 – 72 °C). H NMR (500 MHz, (CD3)2CO) δ
10.22 (s, 1H), 9.72 (s, 1H), 9.15 (s, 1H), 8.94 (s, 1H), 8.27 (s, 1H), 7.81 (s, 8H), 7.77-7.62 (m,
4H), 7.69 (s, 4H), 7.43 (d, J = 6.9 Hz, 1H), 7.29-7.19 (m, 3H), 6.02 (s, 1H), 4.79 (t, J = 5.4 Hz,
1H), 4.71 (s, 3H), 4.55 (s, 1H), 3.25 (dd, J = 4.4, 16.6 Hz, 1H), 2.99 (d, J = 16.6 Hz, 1H), 1.37 (s,
13
1
9H). C NMR (126 MHz, (CD3)2CO) δ 182.3, 162.6 (q, JB-C = 49.5, Hz), 154.7, 141.7, 141.6,
3
2
141.0, 138.7, 137.4, 135.5, 135.0, 131.5, 130.0 (qq, JB-C = 3.0 Hz and JF-C = 31.3 Hz), 128.7,
128.0, 127.6, 127.4, 127.3, 126.1, 125.4 (q, 1JF-C = 273 Hz), 125.3, 118.5 (q, 3JF-C = 3.0 Hz), 73.4,
63.2, 49.7, 44.0, 41.0, 31.3. IR (ATR source): 3325, 3163 cm-1. HRMS-ESI: calcd for
C26H30N3OS (M – C32H12BF24)+ 432.2104, found 432.2107.
4-(3-((1R,2S)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)thioureido)-1-methylpyridinium
tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (4h). This product was obtained in a 73% yield
1
(20 mg) as a pale yellow solid (mp 109 – 111 °C). H NMR (500 MHz, CD3OD) δ 8.49 (d, J =
6.9 Hz, 2H), 8.43 (d, J = 7.4 Hz, 2H), 7.60 (s, 12H), 7.37 (d, J = 7.3 Hz, 1H), 7.29-7.06 (m, 3H),
5.96 (d, J = 4.9 Hz, 1H), 4.74 (t, J = 4.9 Hz, 1H), 4.16 (s, 3H), 3.22 (dd, J = 4.9, 16.6 Hz, 1H),
28
ACS Paragon Plus Environment

Page 29 of 34
The Journal of Organic Chemistry
1
2
3
4
13
1
2.98 (d, J = 16.6 Hz, 1H). C NMR (126 MHz, CD3OD) δ 181.4, 162.9 (q, JB-C = 49.4, Hz),
5
6
7
8
3
2
155.1, 145.8, 141.8, 141.5, 135.8, 130.4 (qq, JB-C = 3.0 Hz and JF-C = 31.3 Hz), 129.2, 127.8,
126.4, 125.8 (q, 1JF-C = 272 Hz), 125.3, 118.5 (q, 3JF-C = 3.0 Hz), 115.9, 73.5, 63.3, 46.6, 41.0. IR
(ATR source): 3229 cm-1. HRMS-ESI: calcd for C16H18N3OS (M – C32H12BF24)+ 300.1165,
found 300.1176.
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
3-(3-((1S,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)thioureido)-1-methylpyridinium
tetrakis(pentafluorophenyl)borate (4a'). This product was obtained in an 87% yield (20 mg) as a
1
pale yellow solid (mp 74 – 77 °C). H NMR (500 MHz, (CD3)2CO) δ 10.16 (br s, 1H), 9.89 (s,
1H), 8.80 (d, J = 6.4 Hz, 1H), 8.73 (d, J = 8.3 Hz, 1H), 8.22 (s, 1H), 8.16 (dd, J = 5.9, 8.4 Hz,
1H), 7.40 (d, J = 7.4 Hz, 1H), 7.30-7.09 (m, 3H), 5.98 (s, 1H), 4.77 (t, J = 4.9 Hz, 1H), 4.65 (s,
3H), 4.57 (s, 1H), 3.23 (dd, J = 4.9, 16.6 Hz, 1H), 2.98 (J = 16.6 Hz, 1H). 13C NMR (126 MHz,
CD2Cl2) δ 180.9, 148.4 (d, Jo-FC = 241 Hz), 140.9 (d, Jp-FC = 196 Hz), 139.5, 137.3, 136.6 (d, Jm-
FC = 242 Hz), 136.3, 136.2, 128.9, 128.2, 127.9, 127.6, 125.9, 124.9, 124.7 (ipso-C), 124.0, 74.6,
62.9, 49.6, 40.2. IR (ATR source): 3331 cm-1. HRMS-ESI: calcd for C16H18N3OS (M –
C24BF20)+ 300.1165, found 300.1185.
Representative procedure for the catalytic enantioselective Friedel-Crafts alkylation of
trans-β-nitroalkenes with indoles (see Eq. 2). Oven-dried NMR tubes were charged with 0.050
mmol of a trans-ß-nitroalkene, 0.15 mmol of the desired indole and 0.005 mmol (10 mol%) of
the catalyst in 0.6 mL of CDCl3 at -35 ˚C under an inert atmosphere. Reaction conversions were
obtained at different times by 1H NMR using the indole and the alkylation product resonances as
indicated in Table S1. Second-order rates constants were obtained using the integrated rate law
(i.e., ln([indole][β-nitrostyrene]0/[β-nitrostyrene][indole]0) = k([indole]0 – [β-nitrostyrene]0)t)
where [β-nitrostyrene]0 and [indole]0 are the initial concentrations and [β-nitrostyrene] and
29
ACS Paragon Plus Environment