Electrostatically enhanced phosphoric acids and their applications in asymmetric friedel-crafts alkylations

Article abstract of DOI:10.1021/acs.joc.9b01741

A series of electrostatically enhanced phosphoric acid catalysts were synthesized and studied. These compounds possess two positively charged N-octylpyridinium or triarylphosphonium ion centers at the 3,3′-positions of the (R)-BINOL backbone to enhance re

Full text of DOI:10.1021/acs.joc.9b01741

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Article
Electrostatically Enhanced Phosphoric Acids and Their
Applications in Asymmetric Friedel-Crafts Alkylations
Jie Ma, and Steven Robert Kass
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01741 • Publication Date (Web): 06 Aug 2019
Downloaded from pubs.acs.org on August 8, 2019
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Electrostatically Enhanced Phosphoric Acids and Their Applications in
Asymmetric Friedel-Crafts Alkylations
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Jie Ma 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
BArF
R'
Ar
4
Ar
P
Ar
NO2
cat.
O
(10 mol %)
O
O
NO2
P
cat. =
R
R
R'
+
OH
solvent
N
N
3 Å molecular sieves
H
H
Ar
P
16 examples
up to >99 % conversion
up to 90 % ee
works with >250 mg scale
BArF
Ar
Ar
4
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ABSTRACT
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A series of electrostatically enhanced phosphoric acid catalysts were synthesized and studied.
These compounds possess two positively charged N-octylpyridinium or triarylphosphonium ion
centers at the 3,3'-positions of the (R)-BINOL backbone to enhance reactivity and provide needed
steric bulk for enantioselective transformations. Catalytic activities for Friedel-Crafts alkylations
of indoles with trans-β-nitrostyrenes were studied. Both types of catalysts accelerate reaction
conversions relative to noncharged analogues, and good enantioselectivities up to 90% ee are
observed with the phosphonium ion tagged phosphoric acids. This transformation also can be
scaled up to synthetically useful amounts affording >250 mg of product without losing reactivity
or selectivity.
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INTRODUCTION
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Over the past decade or so a large body of novel Brønsted acids have emerged as effective
organocatalysts for a variety of organic transformations.1 These species are excellent alternatives
to metal-containing catalysts as they typically are moisture and air tolerant, and are considered to
be environmentally friendlier in nature.2 Among these Brønsted acid catalysts, phosphoric acids
bearing a 1,1'-bi-2-naphthol (BINOL) backbone have been extensively investigated. Hundreds of
derivatives have been prepared as they provide a means for carrying out enantioselective acid-
catalyzed processes.3 This includes asymmetric carbon-carbon bond forming transformations4
which are extremely valuable, but can be synthetically challenging to carry out.5
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BINOL-derived phosphoric acids are generally more active catalysts than other chiral Brønsted
acids such as BINOL derivatives,6 thioureas,7 and α,α,α,α-tetraaryl-1,3-dioxolane-4,5-dimethanols
(TADDOLs)8 due to their greater acidities.9 To broaden their scope and develop more reactive
derivatives, several strategies have been employed. These include introducing electron
withdrawing groups into the catalyst backbone,10 modifying the phosphate functional group (e.g.,
to phosphoramides),11 and employing acidic achiral additives.12
More recently, incorporation of positively charged pyridinium ion centers without the
introduction of new hydrogen bond donating sites was found to improve the catalytic abilities of
achiral phenols,13 thioureas,14 and phosphoric acids15 by orders of magnitude. In addition, several
chiral charge-activated thioureas were reported and found to display excellent reactivities and good
enantioselectivities in Friedel-Crafts alkylations of indoles with trans-β-nitrostyrenes.16 Chiral
phosphonium ion-containing (R)-BINOL-derived phosphoric acids were also recently
communicated and found to give good to excellent enantioselectivities in the reactions of indoles
with 2,2,2-trifluoroacetophenones.17 To build upon these efforts a number of new derivatives are
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reported, and both charged and noncharged catalysts were investigated using the reaction
illustrated in eq. 1 as a well-studied test platform (Figure 1). In this regard it is worth noting that
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–
3b previously was used for the reaction of indole with trans-β-nitrostyrene,18 and the PF6 salt of
2a was found to be catalytically inactive for this process.19
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NO2
NO2
cat. (10 mol %)
+
(1)
N
H
N
H
CH2Cl2
3 Å MS
R1
BArF
4
R3
N
n-C8H17
n-C8H17
O
O
O
O
O
O
P
P
OH
N
OH
R3
BArF
4
R1
3a: R3 = 2,4,6-((CH3)2CH)3C6H2
3b: R3 = Si(C6H5)3
1a: R1 = H
1b: R1 = CH3
H3C
BArF
R2
4
BArF
4
P
3
P
O
O
O
O
O
P
P
OH
O
OH
P
P
BArF
4
R2
BArF
3
4
2a: R2 = H
H3C
2b: R2 = CH3
2e
2c: R2 = CH2CH3
2d: R2 = CH2CH2CH3
Figure 1. Catalysts used in this work; different counteranions for 2a were also studied.
RESULTS AND DISCUSSION
Our study was initiated by synthesizing 1a and 1b, two (R)-BINOL-derived phosphoric acids
with N-octylpyridinium groups at the 3,3'-backbone positions. A noncoordinating tetrakis[3,5-
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bis(trifluoromethyl)phenyl]borate anion (BArF –) was incorporated as the counterion because it
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enhances reactivity and solubility in nonpolar media.15,20 Catalytic activities for the Friedel-Crafts
alkylation of indole with trans-β-nitrostyrene were examined at different temperatures in CH2Cl2
with a 10 mol % catalyst loading and 3 Å molecular sieves (MS) to remove adventitious moisture
(Table 1). Disappointingly, the enantioselectivities were poor with the best results of only 21% and
16% ee at -30 ˚C for 1a and 1b, respectively (entries 1-6). These findings led us to examine bulky
triaryl phosphonium ion derivatives 2a-2e as conveniently prepared alternatives.17,19,21
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Table 1. Optimizations of catalysts and reaction conditionsa
entry cat. T (˚C) time (h) yield (%)b ee (%)c
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2
3
4
5
6
7
8
1a
1a
1a
1b
1b
1b
2a
2a
2a
2b
2b
2b
2c
2c
2c
2d
2d
2d
2e
2e
2e
20
0
-30
20
0
-30
20
0
-30
20
0
-30
20
0
-30
20
0
-30
20
0
24
48
73
24
48
73
8
24
46
5
24
46
5
24
46
5
70
58
26
70
64
30
59
50
38
68
75
81
67
71
83
69
73
85
73
63
60
-14
-16
-21
-12
-13
-16
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36
40
50
59
70
36
46
61
34
46
61
47
51
57
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24
46
5
24
46
-30
aReactions were performed with 0.1 mmol indole, 0.2 mmol trans-b-nitrostyrene, 0.01 mmol
catalyst and 10 mg of 3 Å MS in 0.5 mL of CH2Cl2. bIsolated yield. cDetermined by chiral HPLC.
Positive ee values correspond to the S-enantiomer being the major product.
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To our delight, the preliminary screening results for the phosphonium ion-tagged phosphoric
acids (entries 7-21) revealed that they are both more reactive and enantioselective than their
pyridinium ion-containing analogues. Intriguingly they also led to a reversal in the preferred
enantiomer (i.e., the S-enantiomer is favored with catalysts 2a-e)22,23 although this type of finding
has been previously noted and rationalized by steric differences in the chiral pocket.3 The parent
derivative 2a only gave an ee of 35-40% at temperatures ranging from 20 to -30 ˚C (entries 7-9),
but incorporation of p-methyl substituents on each phenyl group led to significant improvements
in the reaction conversions and stereoselectivities (entries 10-12). That is, over the same time
period at -30 ˚C, the isolated yield increased from 38% to 81% and the ee improved from 40% to
70%. A further decrease in temperature to -50 ˚C was not practical in that less than a 10%
conversion was observed after 48 hours. Replacement of the p-methyl groups by larger ethyl or n-
propyl substituents had little impact on the product yield, but led to ~10-15% lower ee values over
the studied temperature range (entries 13-18).
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To address whether the improvement in the stereoselectivity brought about by the p-methyl
groups is due to steric or electronic effects, the diphenyl(p-tolyl)phosphonium ion-tagged BINOL
phosphoric acid 2e was prepared and investigated. Its steric requirements should be very similar
to those of the unsubstituted phosphoric acid 2a because the Ar3P group can rotate readily enabling
any unfavorable interactions brought about by the methyl group to be minimized. Electronically,
2e should be intermediate in behavior to 2a and 2b since these compounds have 2, 0 and 6 methyl
groups, respectively. The observed enantioselectivities with 2e at 20, 0 and -30 ˚C (entries 19-21)
are between the results for 2a and 2b. This indicates that the larger ee values for 2b compared to
2a are primarily due to the electron donating effects of the six methyl groups in the former
compound.24 Computations are in accord with this suggestion and indicate that the S- enantiomer
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of the Friedel-Crafts alkylation product is favored as was observed. More specifically, B3LYP/6-
31G(d,p) transition state structures leading to both enantiomers were located for the (R)-BINOL-
derived phosphoric acid catalysts with H, PPh3, P(p-CH3C6H4)3 and SiPh3 at the 3 and 3'-positions.
Previously reported geometries with simplified biphenyl-substituted phosphoric acid catalysts by
Hirata and Yamanaka25 and Li and You et al.26 were used as our starting points and subsequent
M06-2X/cc-pVTZ//B3LYP/6-31G(d,p) free energy barriers were obtained. In accord with
experiment, 2b is predicted to be more selective than 2a or 3b (i.e., DG‡(R – S) = 0.60 (2b), 0.35
(2a) and 0.32 kcal mol–1 (3b) as compared to experimental values of 0.88, 0.4127 and 0.51 kcal
mol–1, respectively). The geometries of the transition structures catalyzed by 2a and 2b are very
similar but the ones that lead to the S-enantiomer have C–H •• O interactions that are not present
in the geometry leading to the R-enantiomer (Figure 2).
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a = 1.056
b = 1.436
c = 1.694
d = 2.582
e = 2.869
f = 2.099
a = 1.052
b = 1.449
c = 1.692
d = 2.089
c
b
a
b
a
c
e
d
d
f
Figure 2. Computed B3LYP/6-31G(d,p) transition structures with 2b for the S (left) and R (right)
enantiomers. Most carbon-attached hydrogen atoms were removed for clarity.
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The effect of the counterion was examined next by taking the chloride anion precursor to 1a
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–
–
–
and converting it to the BF4 , PF6 and B(C6F5)4 salts 2f-2h (eq. 2). These species were com-
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Cl
X
P
3
P
3
(1) MX, solvent
3 Å MS, 20 oC, 3h
O
O
O
O
O
O
(2)
P
P
(2) 2.0 M H2SO4
OH
OH
P
P
MX = NaBF4,
KPF6,
Cl
X
NaB(C6F5)4
3
3
2f : X– = BF4
2g: X– = PF6
2h: X– = B(C6F5)4
–
–
–
pared to the BArF – salt 2a at -30 ˚C and their reactivity order is as follows: BF4 < PF6 < B(C6F5)4
–
–
–
4
< BArF – (Table 2). The resulting enantioselectivities also seem to track with this order, and is as
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follows: BF4 ≈ PF6 < B(C6F5)4 < BArF –. This trend follows their hydrogen bond accepting
–
–
–
4
abilities28 and so additional experiments were carried out with BArF – salts. It is worth adding that
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2g was previously reported but was found to be catalytically inactive for a series of transformations
including the reaction of indole with trans-b-nitrostyrene.19 This differs from our finding and may
Table 2. Counteranion screening results.a
entry cat. time (h) yield (%)b ee (%)c
1
2
3
4
2f
48
48
48
46
18
23
33
38
<1
<1
33
40
2g
2h
2a
aReactions were performed at -30 ˚C with 0.1 mmol indole, 0.2 mmol trans-b-nitrostyrene, 0.01
b
mmol of the indicated catalyst and 10 mg of 3 Å MS in 0.5 mL of CH2Cl2. Isolated yield.
cDetermined by chiral HPLC.
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be due to the use of a different solvent (i.e., toluene vs dichloromethane) or partially deprotonated
catalyst in the previous work since the counterion exchange was done after the acidification of the
phosphoric acid.
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Reaction additives and media were explored next at -30 ˚C with 2b as the catalyst (Table 3).
Lower yields and enantioselectivities were found for the reactions carried out without MS or with
additives other than 3 Å MS (entries 2-5). Of the single component solvents that were examined
with 3 Å MS (entries 1 and 6-11), CH2Cl2 gave both the highest yield and ee; 81% and 70%,
respectively. 1,2-Dichloroethane (DCE) and chlorobenzene are somewhat worse media for
Table 3. Reaction medium screening.a
entry solvent
time (h) yield (%)b ee (%)c
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCEh
C6H5Cl
CHCl3
EtOAc
THF
C6H5CN
CH2Cl2/C6H6 1:1
CH2Cl2/C6H5CH3 1:1 47
CH2Cl2/m-xylene 1:1 47
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47
48
48
48
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45
164
164
140
46
81
54
73
62
61
73
77
54
trace
trace
43
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83
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86
88
77
70
67
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57
62
63
64
41
–
2d
3e
4f
5g
6
7
8
9
10
11
12
13
14
15
16
17
–
63
71
66
63
70
72
65
CH2Cl2/CCl4 1:1
CH2Cl2/C6H6 1:2
1,2-DCE/C6H6 1:1
48
50
45
aReactions were performed at -30 ˚C with 0.1 mmol indole, 0.2 mmol trans-b-nitrostyrene, 0.01
mmol of 2b and 10 mg of 3 Å MS (unless otherwise noted) in 0.5 mL of the specified solvent;
mixtures are on a volume to volume basis. bIsolated yield. cDetermined by chiral HPLC. dNo MS
were used. e10 mg of 4 Å MS were used. f10 mg of 5 Å MS were used. g10 mg of 13X MS were
used. hDCE = 1,2-dichloroethane.
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this transformation in terms of both the yield and enantioselectivity, but the results in CHCl3,
surprisingly are much poorer (i.e., a 54% yield and an ee of 41% were obtained; entries 1 and 6-
8). Hydrogen bond accepting solvents such as EtOAc and THF completely deactivate the catalyst
shutting down product formation (entries 9-10). Benzonitrile, a weaker hydrogen bond acceptor
than the two oxygen-containing solvents, does not retard the catalyst as strongly (entry 11) but still
is a very ineffective medium, and affords the product with a 7% lower ee than in CH2Cl2.
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In an attempt to improve these results, a number of binary solvent mixtures with a less polar
component (i.e., benzene, toluene, m-xylene and carbon tetrachloride) were tested (entries 12-17).
A 1:1 (v/v) combination of CH2Cl2 and C6H6 led to a 5% reduction in yield but a 1% increase in
ee relative to the former solvent (entry 12). The opposite trend was observed with a 1:1
CH2Cl2/toluene mixture in that the yield was 2% higher but the ee dropped 4% (entry 13).
Unfortunately, m-xylene was ineffective as a cosolvent in both regards and led to a ~6% decrease
in the yield and ee (entry 14). Carbon tetrachloride and dichloromethane in a 1:1 ratio gave an
improved yield (86%) without affecting the ee (entry 15). Higher proportions of benzene were also
investigated since it is the only cosolvent that led to a higher observed ee. A 1:2 CH2Cl2/C6H6
mixture afforded our best result, an 88% isolated yield and a 72% ee (entry 16). A further increase
in benzene to a 1:3 solvent combination is not feasible because the catalyst does not dissolve in
this medium. Finally, a previously reported 1:1 DCE/C6H6 solvent combination was examined,24
but it led to a reduction in both the yield and enantioselectivity (entry 17). Clearly, different solvent
combinations lead to significant differences presumably due to ion pairing and poorly understood
solvation effects.
Under our optimal conditions, the reactivity of charged catalyst 2b was compared to two
similar and well-established noncharged analogues, (R)-3,3'-bis(2,4,6-triisopropylphenyl)-BINOL
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phosphoric acid (TRIP, 3a) and (R)-3,3'-bis(triphenylsilyl)-BINOL phosphoric acid (3b, Figure
1).29,30 The reactions of indole with trans-β-nitrostyrene were followed at the same three time
points by NMR spectrsocopy, and enantioselectivies were measured by chiral HPLC. Reaction
half-lifes, relative rates and the resulting ee values are given in Table 4. Both TRIP and its 3,3'-
bis(triphenylsilyl) analogue are similarly effective in this transformation with t1/2 = 74 (3a) and 96
h (3b), and ee values of 49% and 48%, respectively (entries 1 and 2). The charged
triarylphosphonium ion-containing catalyst 2b was found to be 6–8 times more reactive and
significantly more selective with an ee of 72% (entry 3).
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Table 4. Comparison of charged and noncharged catalysts.a
entry cat.
t1/2 (h)b krel
ee (%)c
1
2
3
3a
3b
2b
74
96
12
1.3
1.0
7.9
49
48
72
aReactions were carried out at -30 ˚C with 0.1 mmol indole, 0.2 mmol trans-b-nitrostyrene, 0.01
mmol of 2b and 10 mg of 3 Å MS in 0.5 mL of a 1:2 CH2Cl2/C6H6 mixture. bReaction conversions
were determined by NMR spectroscopy. cMeasured by chiral HPLC.
The scope of this reaction was also addressed (eq 3), and the results are summarized in Table
5. Awide range of indoles (4a-4k) and trans-β-nitrostyrenes (5a-5f) bearing electron-donating and
electron-withdrawing groups are tolerated and afford high conversions (75 - >99%) with
enantiomeric excesses ranging from 60-90%. Indoles 4b-4d and 4f with an electron-withdrawing
halogen atom at the 5- or 6-position react more slowly than the parent compound (i.e., 4a) and
afforded ~10% lower conversions after an ~33% longer time period, but had little impact upon the
ee (i.e., the values ranged from 69-73%, entries 1-4 and 6). A chlorine atom at the 7-position
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R5
4
5
6
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9
NO2
NO2
cat. (10 mol %)
R4
R5
R4
+
(3)
N
N
CH2Cl2/C6H6 (1:2)
-30 oC
H
H
4a: R4 = H
4b: R4 = 5-F
6a: R4 = H, R5 = H
6b: R4 = 5-F, R5 = H
5a: R5 = H
5b: R5 = 4-F
5c: R5 = 2-Cl
5d: R5 = 3-Br
5e: R5 = 4-Br
5f: R5 = 4-MeO
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4c: R4 = 5-Cl
4d: R4 = 6-Cl
4e: R4 = 7-Cl
4f: R4 = 5-Br
4g: R4 = 5-MeO
4h: R4 = 6-MeO
4i: R4 = 6-Me
4j: R4 = 7-Me
4k: R4 = 7-Et
6c: R4 = 5-Cl, R5 = H
6d: R4 = 6-Cl, R5 = H
6e: R4 = 7-Cl, R5 = H
6f: R4 = 5-Br, R5 = H
6g: R4 = 5-MeO, R5 = H
6h: R4 = 6-MeO, R5 = H
6i: R4 = 6-Me, R5 = H
6j: R4 = 7-Me, R5 = H
6k: R4 = 7-Et, R5 = H
6l: R4 = H, R5 = 4-F
6m: R4 = H, R5 = 2-Cl
6n: R4 = H, R5 = 3-Br
6o: R4 = H, R5 = 4-Br
6p: R4 = H, R5 = 4-MeO
Table 5. Substrate scope.a
conv.
entry reactants
pdt
time (h)
ee (%)c
(%)b
88
1
2
3
4
5
6
7
8
4a + 5a
4b + 5a
4c + 5a
4d + 5a
4e + 5a
4f + 5a
4g + 5a
4h + 5a
4i + 5a
4j + 5a
4k + 5a
4a + 5b
4a + 5c
4a + 5d
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6j
50
68
66
66
114
68
40
39
47
58
58
64
39
39
64
68
64
72
72
73
70
83
69
68
76
60
90
85
74
65
74
70
79
90
81
75
79
88
78
97
96
92
9
10
11
12d,f
13
14
99
98
>99
>99
>99
>99
91
15e,g 4a + 5e
16d
17h
4a + 5f
4j + 5a
>99
aReactions were carried out at -30 ˚C with 0.1 mmol of the indole, 0.2 mmol of the trans-b-
nitrostyrene, 0.01 mmol of 2b and 10 mg of 3 Å MS in 0.5 mL of a 1:2 CH2Cl2/C6H6 mixture.
bDetermined by NMR spectroscopy. cMeasured by chiral HPLC. dA 1:1 CH2Cl2/C6H6 mixture was
used as the solvent. eA 2:1 CH2Cl2/C6H6 mixture was used as the solvent. fThis reaction was run at
half of the typical concentrations. gThis reaction was run at 2/3 of the usual concentrations in 1 mL
of solvent and with 20 mg of 3 Å MS. hThis reaction was scaled up by a factor of 10.
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(4e) behaved differently in that it had a bigger influence on the rate of the reaction and the
enantioselectivity. That is, significantly more time was needed to produce the product but it also
was formed with an increased ee of 83%. An electron donating methoxy substituent at the 5- or 6-
position (4g and 4h) accelerated the transformation as expected, led to high conversions of 97 and
96%, respectively in shorter time periods, and had little effect (± 4%) on the observed ee (entries
7 and 8). Alkyl groups at the 6- and 7-positions (4i-4k) also led to very efficient transformations
but had little impact on the speed of the transformation (entries 9-11). A methyl group, however,
was found to have the largest influence on the enantioselectivity of all the substituents that were
studied. 6-Methylindole (4i) gave the smallest ee (60%) in the reaction with trans-β-nitrostyrene
whereas its 7-methyl isomer (4j) afforded the highest value (90% ee). 7-Ethylindole (4k) also
displayed good enantioselectivity (85% ee). These results indicate that subtle changes in the
location and size of an indole substituent can influence the enantioselectivity of product formation,
and that incorporation of a chlorine, methyl or ethyl group at the 7-position is particularly favorable
from a stereochemical point of view. Incorporation of electron-withdrawing halogen atoms or an
electron-donating methoxy group into the aromatic ring of trans-β-nitrostyrene led to a few
solubility issues, but in all cases excellent conversions were obtained (entries 12-16). The products
were formed with moderate ee ranging from 70-79% except for 5c, which led to a lower value of
65%, presumably because of the ortho-chlorine atom. The reaction of 4j with 5a was also scaled
up by a factor of 10 (entry 17) to afford >250 mg of product without any loss in the yield or ee.
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1-Methylindole (4l) was explored to investigate the role of the N–H •• O=P hydrogen bond in
the reaction of indole with trans-β-nitrostyrene since this interaction is blocked in this case. This
change resulted in a reduction in the isolated yield from 81% to 5% and in the ee from 70% to 30%
under the same reaction conditions.31 These results indicate that the hydrogen bond between indole
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and the phosphoryl oxygen of the phosphoric acid is important both in terms of the reaction
efficiency and stereoselectivity as previously concluded with noncharged BINOL-derived
phosphoric acids.18,29a A kinetic study with catalytic loadings of 2b ranging from 5-20 mol % was
also carried out. A plot of the relative rates vs. the mol % of the catalyst is linear indicating a first-
order dependence on the catalyst concentration (Figure 3). Alternatively, the same conclusion is
reached by carrying out a normalized time scale analysis.32 Interestingly, even though the
background process is not competitive, the ee was found to correlate with the catalyst loading.
That is, when 5, 10 and 20 mol % of 2b, were used, ee values of 60%, 70% and 73% were observed.
This may be due to the changes in the medium arising from differences in the catalyst concentration
since it is a soluble salt. These results, nevertheless, suggest that the operating mechanism is
analogous to noncharged phosphoric acid derivatives,18 and that a pair of hydrogen bond
interactions play a key role in the efficiency and stereoselectivity of this
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[2b] * t (mM * h)
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2b mol%
Figure 3. Linear least squares fit of relative rates vs the catalyst (2b) mol %; rel. rate = 0.32 x 2b
mol % – 0.840, r2 = 0.986. Relative rates and half-lifes follow: 1.0 and 24 h (5 mol %), 2.1 and
12 h (10 mol %) and 5.7 and 4.2 h (20 mol %). Inset is for the normalized time scale analysis.
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transformation (Figure 4), which is consistent with previous reports of other phosphoric acid
catalysts.33 Our computations also suggest that a pair of aromatic C–H •• ONO interactions are
important in determining the observed enantioselectivity.
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BArF
4
PAr3
N
H
O
P
O
O
O
O H
N
PAr3
O
BArF
4
Figure 4. Proposed Friedel-Crafts alkylation transition state.
CONCLUSION
In summary, we demonstrated the successful synthesis of a series of electrostatically enhanced
pyridinium-containing and phosphonium ion-tagged phosphoric acids, and studied their catalytic
performance in the Friedel-Crafts alkylation of indoles with trans-β-nitrostyrenes. Unfortunately,
the pyridinium-containing phosphoric acids failed to afford high stereoselectivity. On the other
hand, the phosphonium ion-containing phosphoric acids are good catalysts for a wide range of
substrates, promoting higher reactivities and enantioselectivities than their noncharged analogues.
Charge activated organocatalysts consequently continue to show promise in the development of
new hydrogen bond and Brønsted acid catalysts.
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Experimental
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Materials and general methods. All the reagents used in this work were obtained from
commercial sources and used without further purification. Reaction solvents were dried with oven-
activated 3 Å molecular sieves. Proton and carbon chemical shifts are reported in ppm (δ) based
upon internal reference signals from the solvent: CDCl3 (7.26 and 77.0 δ) and CD2Cl2 (5.32 and
54.0 δ). For 19F and 31P, external calibrants were used as follows: CF3COOH (-76.55 δ) and 85%
aqueous H3PO4 (0.00 δ). High-resolution electrospray ionization mass spectra (HRMS-ESI) were
obtained with a TOF instrument using methanol solutions and polyethylene glycol (PEG) or
polypropylene glycol (PPG) as an internal standard. HPLC analyses were carried out on chiral 25
cm x 4.6 mm RegisCell and RegisPack columns.
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(R)-2,2'-Bis(ethoxymethoxy)-1,1'-binaphthyl (7).34 (R)-1,1'-Bi-2-naphthol (0.50 g, 1.75 mmol) was
transferred into a 250 mL round-bottomed flask under a dry nitrogen atmosphere, and 20 mL of
anhydrous THF was added via syringe. The resulting solution was stirred and cooled to -20 ˚C
before adding 0.43 g (3.83 mmol) of potassium tert-butoxide in one portion. This mixture was
stirred for 15 min before 0.35 mL (0.356 g, 3.83 mmol) chloromethyl ethyl ether was syringed in
over 5 min. The resulting solution was allowed to warm to room temperature and stirred for 1 hour,
after which brine (30 mL) was added to quench the reaction and the solvent was removed under
vacuum. Ethyl acetate (30 mL x 3) was used to extract the crude product and the combined organic
material was washed with water (30 mL x 2) and brine (30 mL), dried over MgSO4, and
concentrated to give a yellow oil. Purification by MPLC was carried out using the following
protocol: a hexanes wash with a flow rate of 40 mL min–1 was carried out for 5 min, then the eluent
was switched via a linear gradient over the course of 5 min to 1:1 hexanes/CH2Cl2 and maintained
for 20 min. The last fraction was concentrated to afford 0.47 g (67%) of the product as a colorless
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viscous oil. 1H NMR (500 MHz, CD2Cl2) δ 8.01 (d, J = 9.0 Hz, 2H), 7.94 (d, J = 8.2 Hz, 2H), 7.68
(d, J = 9.1 Hz, 2H), 7.40 (t, J = 7.8 Hz, 2H), 7.28 (t, J = 7.6 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 5.21
(d, J = 7.0 Hz, 2H), 5.09 (d, J = 7.0 Hz, 2H), 3.51-3.36 (m, 4H), 1.07 (t, J = 7.1 Hz, 2H). 13C{1H}
NMR (100 MHz, CDCl3) δ 152.8, 134.0, 129.8, 129.3, 127.8, 126.2, 125.5, 123.9, 121.2, 117.4,
93.8, 63.9, 14.8. HRMS-ESI: calc for C26H26O4Na+ (M + Na+)+ 425.1729, found 425.1748.
(R)-3,3'-dibromo-2,2'-bis(ethoxymethoxy)-1,1'-binaphthyl (8). (R)-2,2'-Bis(ethoxymethoxy)-1,1'-
binaphthyl (7, 3.10 g, 7.70 mmol) was dissolved into 50 mL of diethyl ether in a 250 mL round-
bottomed flask under a dry nitrogen atmosphere, after which n-butyllithium (9.25 mL, 2.5 M in
hexane, 23.1 mmol) was added dropwise at room temperature. The resulting solution was stirred
for 2 h before being cooled to -20 ˚C and slowly adding 1,2-dibromotetrachloroethane (7.52 g,
23.1 mmol) in THF (30 mL). Upon warming to room temperature and stirring overnight, the
reaction was quenched with 30 mL of brine. Removal of the solvents with a rotary evaporator
afforded a residue which was extracted with EtOAc (30 mL x 3). The combined organic material
was washed with 30 mL of water and 30 mL of brine, and then dried over MgSO4. Evaporation of
the solvent under vacuum gave a yellow solid which was purified by MPLC; hexanes were used
for 2 min. then a linear gradient to a 9:1 hexanes/EtOAc mixture was applied over a 3 min period,
and this binary solution was maintained until the product eluted off the column. It was concentrated
under reduced pressure to afford 3.88 g (90%) of a white solid (mp 107 – 113 ˚C). 1H NMR (500
MHz, CDCl3) δ 8.27 (s, 2H), 7.81 (d, J = 8.2 Hz, 2H), 7.43 (t, J = 7.7 Hz, 2H), 7.30 (t, J = 8.2 Hz,
2H), 7.17 (d, J = 8.5 Hz, 2H), 4.91 (d, J = 5.9 Hz, 2H), 4.84 (d, J = 5.9 Hz, 2H), 3.08-2.98 (m, 2H),
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13
2.72-2.62 (m, 2H), 0.60 (t, J = 7.1 Hz, 6H). C{1H} NMR (100 MHz, CDCl3) δ 150.2, 133.0,
132.9, 131.5, 127.2, 127.0, 126.9, 126.5, 126.0, 117.5, 97.9, 64.8, 14.3. HRMS-ESI: calc for
C26H24O4Br2Na+ (M + Na+)+ 582.9919, found 582.9899.
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General procedure for the synthesis of 9a-9b. (R)-3,3'-Dibromo-2,2'-bis(ethoxymethoxy)-1,1'-
binaphthyl (8) (0.70 g, 1.25 mmol), 3-pyridinylboronic acid (0.54 g, 4.37 mmol) [or 5-
methylpyridine-3-boronic acid (0.60 g, 4.37 mmol)] and tetrakis(triphenylphosphine)palladium
(0.14 g, 0.13 mmol) were mixed together in a 250 mL round-bottomed flask and then dissolved in
degassed 1,2-dimethoxylethane (8 mL), after which 3.3 mL of a 2.0 M aqueous Na2CO3 solution
was added. The resulting mixture was refluxed at 93 ˚C with stirring for 16 h and upon cooling to
room temperature the volatiles were removed with a rotary evaporator. Dichloromethane (30 mL
x 3) was used to extract the resulting residue and the combined organic solutions were washed
with 30 mL of saturated NH4Cl and 30 mL of brine before being dried over Na2SO4. Concentration
of this material under vacuum gave a yellow oil that was purified by MPLC using EtOAc as the
eluent. The resulting white solid was dissolved in 5 mL of ethanol and then 1.5 mL of 6.0 M HCl
was added dropwise over 5 min with stirring. After 3 h at room temperature a white precipitate
had formed and the reaction was quenched with 30 mL of aqueous NaHCO3. A rotary evaporator
was used to remove the ethanol and the remaining material was extracted with EtOAc (50 mL x
2). The combined organic layers were washed with water and brine, and then dried over Na2SO4.
Concentration of this solution afforded a viscous yellow liquid that was purified by MPLC with
EtOAc as the eluent.
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(R)-3,3'-Di(3-pyridyl)-2,2'-dihydroxyl-1,1'-binaphthyl (9a). This compound was obtained as a
white solid (0.40 g) in a 73% yield (mp 206 - 212 ˚C). 1H NMR (500 MHz, CD2Cl2) δ 11.42 (s,
2H), 9.10 (s, 2H), 7.72 (d, J = 7.8 Hz, 2H), 7.58 (d, J = 7.1 Hz, 2H), 7.35-7.25 (m, 4H), 7.23-7.15
(m, 4H), 6.77 (dd, J = 5.0 and 7.6 Hz, 2H), 6.58 (d, J = 4.3 Hz, 2H). 13C{1H} NMR (100 MHz,
CD2Cl2) δ 152.7, 150.2, 144.8, 135.7, 135.6, 134.6, 130.5, 129.6, 129.4, 128.9, 127.2, 125.1, 123.5,
+
123.3, 116.1. HRMS-ESI: calc for C30H21N2O2 (M + H+)+ 441.1603, found 441.1588.
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(R)-3,3'-Di[3-(5-methyl)pyridyl]-2,2'-dihydroxyl-1,1'-binaphthyl (9b). This species was obtained
as a white solid (0.42 g) in a 72% yield (mp 201 - 208 ˚C). 1H NMR (500 MHz, CD2Cl2) δ 11.68
(s, 2H), 8.89 (s, 2H), 7.59 (d, J = 8.8 Hz, 2H), 7.52 (s, 2H), 7.33-7.26 (m, 4H), 7.19 (d, J = 9.3 Hz,
2H), 7.17 (s, 2H), 6.30 (s, 2H), 2.03 (s, 6H). 13C{1H} NMR (100 MHz, CD2Cl2) δ 152.9, 147.7,
145.2, 136.0, 135.6, 134.0, 132.7, 130.2, 129.8, 129.7, 128.5, 127.0, 125.1, 123.2, 116.0, 18.7.
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+
HRMS-ESI: calc for C32H25N2O2 (M + H+)+ 469.1916, found 469.1933.
General procedure for the synthesis of 10a-10b. Compound 9a or 9b (0.227 mmol) was added
into a 100 mL round-bottomed flask under an atmosphere of dry nitrogen and then was dissolved
in 15 mL of anhydrous acetonitrile. After stirring for 5 min, 0.164 mL of 1-iodooctane (0.218 g,
0.908 mmol) was syringed into the flask in one portion and the solution was heated to 100 ˚C and
refluxed overnight. Upon cooling to room temperature, the reaction mixture was concentrated
under vacuum. The crude product was dissolved in 5 mL of CH2Cl2 and triturated by adding it
dropwise to 100 mL of hexanes. Filtration of the resulting precipitate and a subsequent wash with
hexanes gave the desired product.
(R)-3,3'-Di(3-N-octylpyridinium)-2,2'-dihydroxyl-1,1'-binaphthyl iodide (10a). A yellow solid
(0.16 g) was obtained in a 77% yield (mp 278 - 282 ˚C). 1H NMR (500 MHz, CD2Cl2) δ 9.98 (s,
2H), 8.86-8.77 (m, 4H), 8.34 (s, 2H), 8.10-8.01 (m, 4H), 7.43 (t, J = 7.2 Hz, 2H), 7.33 (t, J = 7.4
Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 4.80-4.65 (m, 4H), 2.09-1.98 (m, 4H), 1.40-1.18 (m, 22H), 0.82
(t, J = 6.6 Hz, 6H). 13C{1H} NMR (100 MHz, CD2Cl2) δ 149.7, 146.4, 145.6, 145.5, 142.0, 139.6,
135.0, 132.6, 130.1, 129.5, 128.9, 128.5, 125.6, 125.1, 118.6, 62.7, 32.3, 32.2, 29.50, 29.48, 26.5,
+
23.1, 14.4. HRMS-ESI: calc for C46H53N2O2 (M - H+ - 2I–)+ 665.4107, found 665.4139.
(R)-3,3'-Di(3-(N-octyl-5-methyl)pyridinium)-2,2'-dihy-droxyl-1,1'-binaphthyl iodide (10b). A
yellow solid (0.19 g) was obtained in an 88% yield (mp 265 - 270 ˚C). 1H NMR (500 MHz, CD2Cl2)
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δ 9.86 (s, 2H), 8.71 (s, 2H), 8.65 (s, 2H), 8.30 (s, 2H), 8.04 (d, J = 7.9 Hz, 2H), 7.45 (t, J = 7.8 Hz,
2H), 7.35 (t, J = 8.3 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 6.53 (s, 2H), 4.79-4.62 (m, 4H), 2.67 (s,
6H), 2.12-2.00 (m, 4H), 1.42-1.18 (m, 20H), 0.83 (d, J = 6.8 Hz, 6H). 13C{1H} NMR (100 MHz,
CD2Cl2) δ 149.5, 146.2, 144.2, 141.3, 139.8, 139.0, 135.0, 132.5, 130.2, 129.5, 128.9, 125.7, 125.3,
125.1, 118.5, 62.5, 32.3, 32.2, 29.53, 29.51, 26.5, 23.1, 19.2, 14.4. HRMS-ESI: calc for
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+
C48H57N2O2 (M - H+ - 2I–)+ 693.4420, found 693.4401.
General procedure for the synthesis of 11a-11b. Iodide salt 10a or 10b (0.218 mmol) was
dissolved into 20 mL of anhydrous acetonitrile under a N2 atmosphere and 64 µL (0.10 g, 0.654
mmol) of POCl3 was added with stirring in one portion followed by 44 µL (0.044 g, 0.544 mmol)
of anhydrous pyridine. The resulting solution was heated to 90 ˚C and refluxed for 16 h before
cooling to room temperature and adding 0.5 mL of water. This material was heated back to 90 ˚C
for 1 h and then allowed to return to room temperature. Removal of the solvent under vacuum
afforded a residue which was dissolved in 40 mL of CH2Cl2 and washed with 2.0 M HCl (15 mL),
15 mL of brine and then dried over Na2SO4. Rotary evaporation of this material gave a brown oil
that was purified by MPLC. A linear gradient from EtOAc to a 1:1 EtOAc/MeOH mixture over 10
min followed by a 10 min wash with this solution eluted the product. This material was
concentrated under reduced pressure to give the desired compound as a yellow solid.
(R)-3,3'-(4-Hydroxy-4-oxidodinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepine-2,6-diyl)bis(1-
octylpyridin-1-ium) chloride (11a). This compound (0.12 g) was generated in a 69% yield (mp 195
- 202 ˚C). 1H NMR (500 MHz, CD2Cl2) δ 10.38 (s, 2H), 9.11 (d, J = 5.6 Hz, 2H), 8.82 (d, J = 7.7
Hz, 2H), 8.20 (s, 2H), 8.08-7.95 (m, 4H), 7.48 (t, J = 7.3 Hz, 2H), 7.30 (t, J = 7.9 Hz, 2H), 7.19
(d, J = 8.7 Hz, 2H), 4.86-4.60 (m, 4H), 2.19 (bs, OH, 1H) 2.10-1.93 (m, 4H), 1.37-1.15 (m, 20H),
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0.82 (t, J = 6.7 Hz, 6H). C{1H} NMR (100 MHz, CD2Cl2) δ 155.31, 155.26, 153.64, 153.58,
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137.64, 137.58, 137.0, 136.7, 136.6, 129.7, 128.7, 123.9, 123.8, 121.0, 120.9, 63.0, 32.2, 32.1,
29.5, 29.4, 26.6, 23.1, 14.4. 31P NMR (162 MHz, CD2Cl2) δ 5.64. HRMS-ESI: calc for
C46H52N2O4P+ (M - H+ - 2Cl–)+ 727.3665, found 727.3677.
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(R)-5,5'-(4-Hydroxy-4-oxidodinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepine-2,6-diyl)bis(3-
methyl-1-octylpyridin-1-ium) chloride (11b). This compound (0.15 g) was produced in an 83%
yield (mp 194 - 200 ˚C). 1H NMR (500 MHz, CD2Cl2) δ 10.25 (s, 2H), 9.19 (s, 2H), 8.62 (s, 2H),
8.20 (s, 2H), 8.02 (d, J = 8.2 Hz, 2H), 7.47 (t, J = 7.1 Hz, 2H), 7.30 (t, J = 8.5 Hz, 2H), 7.21 (d, J
= 8.6 Hz, 2H), 4.72 (t, J = 7.3 Hz, 4H), 2.63 (s, 6H), 2.54 (bs, OH, 1H), 2.15-1.95 (m, 4H), 1.45-
1.14 (m, 20H), 0.82 (t, J = 6.8 Hz, 6H). 13C{1H} NMR (100 MHz, CD2Cl2) δ 147.2, 146.5, 144.7,
142.6, 139.7, 138.8, 133.9, 132.5, 131.0, 129.4, 128.1, 127.6, 127.3, 126.4, 124.0, 62.6, 32.3, 32.1,
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29.6, 29.5, 26.7, 23.1, 19.0, 14.4. P NMR (162 MHz, CD2Cl2) δ 6.19. HRMS-ESI: calc for
C48H56N2O4P+ (M - H+ - 2Cl–)+ 755.3978, found 755.4002.
General procedure for the synthesis of 1a-1b. Chloride salt 11a or 11b (0.0755 mmol), sodium
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (0.141 g, 0.159 mmol) and 3 Å molecular sieves
(0.10 g) were mixed in a 23 x 85 mm vial, and then 7 mL of CH2Cl2 was added. The resulting
solution was stirred at room temperature for 3 h before being filtered through a 0.45 µm
polytetrafluoroethylene (PTFE) membrane. The filtered solution was washed with 2.0 M H2SO4
(7 mL x 2) and water (7 mL x 3), and then was dried over Na2SO4 before being concentrated to
afford the product.
(R)-3,3'-(4-Hydroxy-4-oxidodinaphtho[2,1-d:1',2'-f][1,3,-2]dioxaphosphepine-2,6-diyl)bis(1-
octylpyridin-1-ium) tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (1a). A yellow solid (0.17 g)
was formed in a 92% yield (mp 77 - 81 ˚C). 1H NMR (500 MHz, CD2Cl2) δ 9.54 (s, 2H), 8.90 (d,
J = 7.8 Hz, 2H), 8.29 (d, J = 5.9 Hz, 2H), 8.12 (s, 2H), 8.06 (d, J = 8.3 Hz, 2H), 8.00 (dd, J = 5.9
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and 7.9 Hz, 2H), 7.77 (s, 16H), 7.65-7.57 (m, 10H), 7.47 (t, J = 8.3 Hz, 2H), 7.35 (d, J = 8.8 Hz,
2H), 4.62-4.44 (m, 4H), 2.60 (bs, OH, 1H) 2.07-1.93 (m, 4H), 1.36-1.21 (m, 20H), 0.84 (t, J = 6.9
Hz, 6H). 13C{1H} NMR (100 MHz, CD2Cl2) δ 162.4 (q, J = 48.9 Hz), 147.1, 145.7, 145.4, 141.4,
140.7, 140.5, 135.5, 134.0, 133.1, 131.3, 129.5 (qq, J = 2.92 and 31.4 Hz), 128.6, 127.9, 127.7,
127.2, 125.9, 125.2 (q, J = 270 Hz), 124.1, 118.2 (septet, J = 3.64 Hz), 63.9, 32.1, 32.0, 29.4, 29.3,
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26.6, 23.0, 14.2. F NMR (376 MHz, CD2Cl2) δ -62.68. P NMR (162 MHz, CD2Cl2) δ 6.76.
HRMS-ESI: calc for C46H52N2O4P+ (M - H+ - 2BArF –)+ 727.3665, found 727.3679.
4
(R)-5,5'-(4-Hydroxy-4-oxidodinaphtho[2,1-d:1',2'-f][1,3,-2]dioxaphosphepine-2,6-diyl)bis(3-
methyl-1-octylpyridin-1-ium) tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (1b). A yellow solid
1
(0.17 g) was generated in a 91% yield (mp 54 - 58 ˚C). H NMR (500 MHz, CD2Cl2) δ 9.06 (s,
2H), 8.55 (s, 2H), 8.21 (s, 2H), 8.13 (s, 2H), 8.06 (d, J = 7.8 Hz, 2H), 7.74 (s, 16H), 7.63 (t, J =
7.1 Hz, 2H), 7.56 (s, 8H), 7.48 (t, J = 8.5 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 4.83 (bs, OH, 1H),
4.45 (t, J = 7.3 Hz, 4H), 2.55 (s, 6H), 2.07-1.90 (m, 4H), 1.36-1.17 (m, 20H), 0.82 (t, J = 6.8 Hz,
6H). 13C{1H} NMR (100 MHz, CD2Cl2) δ 162.3 (q, J = 49.6 Hz), 147.6, 143.9, 142.5, 141.6, 141.3,
139.0, 135.4, 133.65, 133.63, 131.7, 129.5 (qq, J = 2.92 and 31.4 Hz), 128.4, 127.3, 125.47, 125.45,
125.2 (q, J = 270 Hz), 123.58, 123.56, 118.1 (septet, J = 3.64 Hz), 63.7, 32.1, 32.0, 29.4, 29.3,
19
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26.6, 23.0, 19.1, 14.2. F NMR (376 MHz, CD2Cl2) δ -62.76. P NMR (162 MHz, CD2Cl2) δ
5.68. HRMS-ESI: calc for C48H56N2O4P+ (M - H+ - 2BArF –)+ 755.3978, found 755.3998
4
General procedure for the synthesis of 2f-2g. In a 23 x 85 mm vial, (R)-(4-hydroxy-4-
oxidodinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepine-2,6-diyl)bis(triphenylphosphonium) chlor-
ide (0.188 g, 0.200 mmol), sodium tetrafluoroborate (0.046 g, 0.420 mmol) or potassium
hexafluorophosphate (0.077 g, 0.420 mmol) and 3 Å molecular sieves (0.50 g) were mixed
together and then 3 mL of methanol was added. After stirring at room temperature for 2 h, 10 mL
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of CH2Cl2 was added and the reaction was stirred for an additional 1 h before filtering the solution
through a 0.45 µm PTFE membrane. The solvent was removed under vacuum and the residue was
redissolved in 8 mL of CH2Cl2. It was then washed twice with 8 mL of 2.0 M H2SO4 and three
times with 8 mL of water before being dried over Na2SO4. Concentration of the solution under
reduced pressure afforded the desired product.
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(R)-(4-Hydroxy-4-oxidodinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepine-2,6-diyl)bis(triphenyl-
phosphonium) tetrafluoroborate (2f). A yellow solid (0.141 g) was afforded in a 67% yield (mp
233 – 236 ˚C). 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 16.3 Hz, 2H), 7.87 (d, J = 7.7 Hz, 2H),
7.83-7.72 (m, 18H), 7.68-7.62 (m, 12H), 7.57-7.48 (m, 4H), 7.28 (d, J = 8.3 Hz, 2H), 1.25 (bs, OH,
1H). 13C{1H} NMR (100 MHz, CDCl3) δ 150.7 (d, J = 9.9 Hz), 141.0 (d, J = 8.4 Hz), 136.2 (d, J
= 2.4 Hz), 135.03, 134.95 (d, J = 10.5 Hz), 131.0, 130.0 (d, J = 13.1 Hz), 129.8, 129.2 (d, J = 14.3
Hz), 127.0, 126.5, 124.5 (d, J = 10.1 Hz), 118.9 (d, J = 90.4 Hz), 110.8 (d, J = 91.0 Hz). 19F NMR
(376 MHz, CD2Cl2) δ -154.11. 31P NMR (162 MHz, CD2Cl2) δ 22.93, 0.87. HRMS- ESI: calc for
C56H40O4P3 (M - H+ - 2BF4 ) 869.2134, found 869.2103.
+
– +
(R)-(4-Hydroxy-4-oxidodinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepine-2,6-diyl)bis(triphenyl-
phosphonium) hexafluorophosphate (2g). A yellow solid (0.177 g) was produced in a 76% yield
(mp 225 – 230 ˚C). 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 16.3 Hz, 2H), 7.88 (d, J = 7.7 Hz,
2H), 7.81-7.72 (m, 18H), 7.68-7.62 (m, 12H), 7.58-7.50 (m, 4H), 7.28 (d, J = 8.3 Hz, 2H), 2.11
13
(bs, OH, 1H). C{1H} NMR (100 MHz, CDCl3) δ 144.7 (d, J = 8.6 Hz), 141.0 (d, J = 8.4 Hz),
136.2 (d, J = 2.9 Hz), 135.1, 135.0 (d, J = 10.6 Hz), 131.0, 130.1 (d, J = 13.2 Hz), 129.8, 129.2 (d,
J = 14.4 Hz), 127.0, 126.5, 124.5 (d, J = 7.0 Hz), 118.9 (d, J = 90.5 Hz), 110.7 (d, J = 91.1 Hz).
19F NMR (376 MHz, CDCl3) δ -73.62 (d, J = 712 Hz). 31P NMR (162 MHz, CDCl3) δ 22.94, 0.77,
+
– +
-144.43 (septet, J = 712 Hz). HRMS- ESI: calc for C56H40O4P3 (M - H+ - 2PF6 ) 869.2134, found
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(R)-(4-Hydroxy-4-oxidodinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepine-2,6-diyl)bis(triphenyl-
phosphonium) tetrakis(pentafluorophenyl)borate (2h). In a 23 x 85 mm vial, (R)-(4-hydroxy-4-
oxidodinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepine-2,6-diyl)bis(triphenylphosphonium)
chloride (0.188 g, 0.200 mmol), potassium tetrakis(pentafluorophenyl)borate (0.302 g, 0.420
mmol) and 3 Å molecular sieves (0.50 g) were mixed together and then 8 mL of CH2Cl2 was added.
The solution was stirred at room temperature for 3 h and then filtered through a 0.45 µm PTFE
membrane. It was subsequently washed twice with 2.0 M H2SO4 and three times with water before
being dried over Na2SO4. Removal of the CH2Cl2 gave 2h as a yellow solid (0.337 g) in a 76%
yield (mp 178 – 182 ˚C). 1H NMR (500 MHz, CD2Cl2) δ 8.10 (d, J = 16.5 Hz, 2H), 7.91 (d, J =
8.1 Hz, 2H), 7.84-7.77 (m, 6H), 7.77-7.69 (m, 12H), 7.69-7.59 (m, 14H), 7.54 (d, J = 8.1 Hz, 2H),
7.29 (d, J = 8.5 Hz, 2H), 2.20 (bs, OH, 1H). 13C{1H} NMR (100 MHz, CD2Cl2) δ 149.7 (d, J = 9.4
Hz), 148.7 (d, J = 236.4 Hz), 142.5 (d, J = 8.5 Hz), 138.8 (d, J = 242.9 Hz), 136.9 (d, J = 231.2
Hz), 135.7 (d, J = 3.0 Hz), 136.7, 135.5 (d, J = 10.5 Hz), 132.0, 130.6 (d, J = 13.1 Hz), 130.5,
130.2 (d, J = 14.3 Hz), 128.1, 127.0, 124.7 (d, J = 6.9 Hz), 124.2 (m), 119.1 (d, J = 90.6 Hz), 110.6
(d, J = 91.2 Hz). 19F NMR (376 MHz, CD2Cl2) δ -133.12, -163.39 (t, J = 20.4 Hz), -167.38 (t, J =
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17.1 Hz). 31P NMR (162 MHz, CD2Cl2) δ 22.81, 0.89. HRMS- ESI: calc for C56H40O4P3 (M - H+
– +
- 2B(C6F5)4 ) 869.2134, found 869.2116.
General procedure for the Friedel-Crafts alkylations. A 23 x 85 mm vial was charged with a
catalyst (10 mol %) and 3 Å molecular sieves (10 mg), and then was sealed followed by a 1 min
purge with dry nitrogen. After adding 250 µL of CH2Cl2 via syringe, the resulting solution was
cooled if the reaction was being carried out at subambient temperature. Indole (0.100 mmol) and
trans-β-nitrostyrene (0.200 mmol) were dissolved in 250 µL of CH2Cl2 and this solution was then
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added dropwise over 10-15 s. The reaction mixture was shaken and the transformation was allowed
to proceed over the course of 5-164 h. Reaction conversions were determined by removing 1-2
drops of the reaction mixture and dissolving it in 0.5 mL of CDCl3 after flowing dry nitrogen over
the sample for ≤ 15 s to evaporate the CH2Cl2. Upon completion of reaction, the solution was
injected on to a 4 g silica gel column followed by 0.2-0.3 mL of CH2Cl2 that had been used to rinse
the molecular sieves. MPLC purification was carried out first with hexanes (1 min) followed by a
linear gradient to 100% CH2Cl2 over the course of 7 min, and then this solvent was maintained
until all of the components eluted off the column. Racemic reference materials were obtained in
the same way using diphenylphosphate as the reaction catalyst.
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Analytical data for the Friedel-Crafts products. 3-(2-Nitro-1-phenylethyl)-1H-indole (6a).18 1
H
NMR (500 MHz, CDCl3) δ 8.10 (bs, NH, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.39-7.30 (m, 5H), 7.29-
7.24 (m, 1H), 7.23-7.18 (m, 1H), 7.12-7.06 (m, 1H), 7.03 (d, J = 2.5 Hz, 1H), 5.20 (t, J = 8.2 Hz,
1H), 5.07 (dd, J = 7.7 and 12.6 Hz, 1H), 4.95 (dd, J = 8.4 and 12.5 Hz, 1H). 13C{1H} NMR (100
MHz, CDCl3) δ 139.2, 136.5, 128.9, 127.7, 127.5, 126.1, 122.7, 121.6, 119.9, 118.9, 114.4, 111.4,
79.5, 41.5. HRMS-ESI: calc for C16H13N2O2 (M - H+)– 265.0977, found 265.0971. Enantiomeric
–
excess was determined with a Regiscell column (75:25 hexanes/iPrOH, 1.0 mL min–1, 20 ˚C, 250
nm, τmajor = 17.0 min, τminor = 20.1 min).
5-Fluoro-3-(2-nitro-1-phenylethyl)-1H-indole (6b).35 Reaction conversion was determined by
relative integration of the 1H NMR signals at δ 6.42 (4b) and 4.78 (6b). Enantiomeric excess was
measured with a Regiscell column (92:8 hexanes/iPrOH, 1.0 mL min–1, 20 ˚C, 254 nm, τmajor
56.1 min, τminor = 48.2 min).
=
5-Chloro-3-(2-nitro-1-phenylethyl)-1H-indole (6c).18,36 Reaction conversion was determined by
relative integration of the 1H NMR signals at δ 6.41 (4c) and 4.82 (6c). Enantiomeric excess was
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measured with a Regiscell column (80:20 hexanes/iPrOH, 1.0 mL min–1, 20 ˚C, 250 nm, τmajor
16.8 min, τminor = 13.8 min).
=
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6-Chloro-3-(2-nitro-1-phenylethyl)-1H-indole (6d).37 Reaction conversion was determined by
relative integration of the 1H NMR signals at δ 6.43 (4d) and 4.82 (6d). Enantiomeric excess was
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measured with a Regiscell column (85:15 hexanes/iPrOH, 1.0 mL min–1, 20 ˚C, 250 nm, τmajor
21.2 min, τminor = 19.8 min).
=
7-Chloro-3-(2-nitro-1-phenylethyl)-1H-indole (6e). A yellow solid was isolated with a mp of 58 -
62 ˚C. 1H NMR (500 MHz, CDCl3) δ 8.32 (bs, NH, 1H), 7.37-7.29 (m, 5H), 7.29-7.26 (m, 1H),
7.20 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 7.00 (t, J = 7.8 Hz, 1H), 5.17 (t, J = 8.0 Hz, 1H),
5.06 (dd, J = 8.0 and 12.5 Hz, 1H), 4.95 (dd, J = 8.0 and 12.5 Hz, 1H). 13C{1H} NMR (100 MHz,
CDCl3) δ 138.8, 133.8, 129.0, 127.71, 127.691, 127.688, 127.5, 122.1, 120.8, 117.6, 116.9, 115.6,
79.4, 41.5. HRMS-ESI: calc for C16H12N2O2Cl– (M - H+)– 299.0587 and 301.0558, found 299.0577
and 301.0553. Reaction conversion was determined by relative integration of the 1H NMR signals
at δ 6.60 (4e) and 4.95 (6e). Enantiomeric excess was measured with a Regiscell column (75:25
hexanes/iPrOH, 1.0 mL min–1, 20 ˚C, 250 nm, τmajor = 34.7 min, τminor = 39.6 min).
5-Bromo-3-(2-nitro-1-phenylethyl)-1H-indole (6f).18 Reaction conversion was determined by
relative integration of the 1H NMR signals at δ 6.40 (4f) and 4.82 (6f). Enantiomeric excess was
measured with a Regiscell column (75:25 hexanes/iPrOH, 1.0 mL min–1, 20 ˚C, 250 nm, τmajor
12.1 min, τminor = 10.8 min).
=
5-Methoxy-3-(2-nitro-1-phenylethyl)-1H-indole (6g).36 Reaction conversion was determined by
relative integration of the 1H NMR signals at δ 6.39 (4g) and 4.84 (6g). Enantiomeric excess was
measured with a Regiscell column (75:25 hexanes/iPrOH, 1.0 mL min–1, 20 ˚C, 250 nm, τmajor
12.9 min, τminor = 11.4 min).
=
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6-Methoxy-3-(2-nitro-1-phenylethyl)-1H-indole (6h). A white solid was isolated with a mp of 82
- 85 ˚C. 1H NMR (500 MHz, CDCl3) δ 7.96 (bs, NH, 1H), 7.35-7.29 (m, 4H), 7.29-7.24 (m, 2H),
6.92 (dd, J = 0.8 and 2.3 Hz, 1H), 6.83 (d, J = 2.2 Hz, 1H), 6.74 (dd, J = 2.3 and 8.8 Hz, 1H), 5.14
(t, J = 8.1 Hz, 1H), 5.05 (dd, J = 7.7 and 12.4 Hz, 1H), 4.92 (dd, J = 8.3 and 12.5 Hz, 1H), 3.82 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 156.9, 139.2, 137.3, 128.9, 127.7, 127.5, 120.5, 120.3,
119.6, 114.4, 110.0, 94.7, 79.6, 55.6, 41.6. HRMS-ESI: calc for C17H16N2O3Na+ (M + Na+)+
319.1059, found 319.1074. Reaction conversion was determined by relative integration of the 1H
NMR signals at δ 6.39 (4h) and 4.92 (6h). Enantiomeric excess was measured with a Regiscell
column (75:25 hexanes/iPrOH, 1.0 mL min–1, 20 ˚C, 250 nm, τmajor = 20.7 min, τminor = 16.6 min).
6-Methyl-3-(2-nitro-1-phenylethyl)-1H-indole (6i). This compound was isolated as a colorless
viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.94 (bs, NH, 1H), 7.41-7.28 (m, 5H), 7.28-7.23 (m,
1H), 7.15 (s, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 5.17 (t, J = 8.0 Hz, 1H), 5.06
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(dd, J = 7.7 and 12.5 Hz, 1H), 4.94 (dd, J = 8.4 and 12.5 Hz, 1H), 2.44 (s, 3H). C{1H} NMR
(100 MHz, CDCl3) δ 139.2, 136.9, 132.6, 128.9, 127.7, 127.5, 123.9, 121.7, 120.9, 118.5, 114.3,
111.3, 79.5, 41.6, 21.6. HRMS-ESI: calc for C17H15N2O2 (M - H+)– 279.1134, found 279.1149.
–
Reaction conversion was determined by relative integration of the 1H NMR signals at δ 6.51 (4i)
and 4.94 (6i). Enantiomeric excess was measured with a Regiscell column (75:25 hexanes/iPrOH,
1.0 mL min–1, 20 ˚C, 250 nm, τmajor = 13.1 min, τminor = 12.0 min).
7-Methyl-3-(2-nitro-1-phenylethyl)-1H-indole (6j).18 Reaction conversion was determined by
relative integration of the 1H NMR signals at δ 6.57 (4j) and 4.95 (6j). Enantiomeric excess was
measured with a Regispack column (97:3 hexanes/iPrOH, 1.0 mL min–1, 20 ˚C, 250 nm, τmajor
40.1 min, τminor = 35.6 min).
=
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7-Ethyl-3-(2-nitro-1-phenylethyl)-1H-indole (6k).38 Reaction conversion was determined by
relative integration of the 1H NMR signals at δ 6.58 (4k) and 4.96 (6k). Enantiomeric excess was
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measured with a Regispack column (97:3 hexanes/iPrOH, 1.0 mL min–1, 20 ˚C, 250 nm, τmajor
33.3 min, τminor = 29.7 min).
=
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3-(1-(4-Fluorophenyl)-2-nitroethyl)-1H-indole (6l).39 Reaction conversion was determined by
relative integration of the 1H NMR signals at δ 6.47 (4a) and 4.79 (6l). Enantiomeric excess was
measured with a Regiscell column (75:25 hexanes/iPrOH, 1.0 mL min–1, 20 ˚C, 250 nm, τmajor
18.1 min, τminor = 22.8 min).
=
3-(1-(2-Chlorophenyl)-2-nitroethyl)-1H-indole (6m).40 Reaction conversion was determined by
relative integration of the 1H NMR signals at δ 6.47 (4a) and 5.64 (6m). Enantiomeric excess was
measured with a Regiscell column (75:25 hexanes/iPrOH, 1.0 mL min–1, 20 ˚C, 250 nm, τmajor
20.5 min, τminor = 13.3 min).
=
3-(1-(3-Bromophenyl)-2-nitroethyl)-1H-indole (6n).40 Reaction conversion was determined by
relative integration of the 1H NMR signals at δ 6.47 (4a) and 4.81 (6n). Enantiomeric excess was
measured with a Regiscell column (75:25 hexanes/iPrOH, 1.0 mL min–1, 20 ˚C, 250 nm, τmajor
20.2 min, τminor = 27.7 min).
=
3-(1-(4-Bromophenyl)-2-nitroethyl)-1H-indole (6o).40 Reaction conversion was determined by
relative integration of the 1H NMR signals at δ 6.47 (4a) and 4.81 (6o). Enantiomeric excess was
measured with a Regiscell column (75:25 hexanes/iPrOH, 1.0 mL min–1, 20 ˚C, 250 nm, τmajor
21.7 min, τminor = 27.0 min).
=
3-(1-(4-Methoxylphenyl)-2-nitroethyl)-1H-indole (6p).18 Reaction conversion was determined by
relative integration of the 1H NMR signals at δ 6.47 (4a) and 4.79 (6p). Enantiomeric excess was
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measured with a Regiscell column (80:20 hexanes/iPrOH, 1.0 mL min–1, 20 ˚C, 250 nm, τmajor
25.3 min, τminor = 27.9 min).
=
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3-(2-Nitro-1-phenylethyl)-1-methylindole (6q).41 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 8.0
Hz, 1H), 7.45-7.27 (m, 7H), 7.16 (t, J = 7.0 Hz, 1H), 6.91 (s, 1H), 5.25 (t, J = 8.1 Hz, 1H), 5.09
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(dd, J = 7.6 and 12.6 Hz, 1H), 4.98 (dd, J = 8.5 and 12.6 Hz, 1H), 3.75 (s, 3H). C{1H} NMR
(100 MHz, CDCl3) δ 139.3, 137.2, 128.8, 127.6, 127.4, 126.4, 126.2, 122.1, 119.3, 118.9, 112.6,
109.4, 79.4, 41.4, 32.6. HRMS-ESI: calc for C17H16N2O2Na+ (M + Na+)+ 303.1109, found
303.1118. Enantiomeric excess was measured with a Regiscell column (95:5 hexanes/iPrOH, 1.0
mL min–1, 20 ˚C, 250 nm, τmajor = 59.6 min, τminor = 56.6 min).
Computations. DFT calcuations were carried out with Gaussian 0942 at the Minnesota
Supercomputer Institute for Advanced Computational Research. Full B3LYP/6-31G(d,p)
geometry optimizations were performed and subsequent vibrational frequencies and M06-2X/cc-
pVTZ single point energies were computed.43,44 Stationary points that correspond to energy
minima have no imaginary frequencies while those that correspond to transition structures have
one negative value.
Supporting Information
Illustrated synthetic route for the preparation of pyridinium ion-containing phosphoric acids 1a
and 1b, kinetic data, NMR spectra, HPLC chromatograms, computed geometries and energies and
the complete citation to ref. 42. This material is available free of charge via the internet at
http://pubs.acs.org.
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