Novel axially chiral bis-arylthiourea-based organocatalysts for asymmetric Friedel-Crafts type reactions

Article abstract of DOI:10.1016/j.tetlet.2006.07.112

It has been shown that catalytic amounts (10-20 mol %) of novel axially chiral bis-arylthioureas promote the asymmetric organocatalytic Friedel-Crafts type addition of indole and N-methylindole to nitroolefins. The optimum catalyst is capable of promoting the reaction between challenging substrates such as N-methylindole and nitroolefins bearing aliphatic β-substituents with enantioselectivity unprecedented for an organocatalytic system.

Full text of DOI:10.1016/j.tetlet.2006.07.112

Tetrahedron Letters 47 (2006) 7037–7042
Novel axially chiral bis-arylthiourea-based organocatalysts
for asymmetric Friedel–Crafts type reactions
Eimear M. Fleming, Thomas McCabe and Stephen J. Connon*
Centre for Synthesis and Chemical Biology, School of Chemistry, University of Dublin, Trinity College, Dublin 2, Ireland
Received 2 June 2006; revised 11 July 2006; accepted 21 July 2006
Available online 14 August 2006
Abstract—It has been shown that catalytic amounts (10–20 mol %) of novel axially chiral bis-arylthioureas promote the asymmetric
organocatalytic Friedel–Crafts type addition of indole and N-methylindole to nitroolefins. The optimum catalyst is capable of
promoting the reaction between challenging substrates such as N-methylindole and nitroolefins bearing aliphatic b-substituents with
enantioselectivity unprecedented for an organocatalytic system.
ꢀ
2006 Elsevier Ltd. All rights reserved.
The addition of p-excessive heteroaromatic compounds
to activated olefins (a process analogous to the
Friedel–Crafts alkylation reaction1 ) is a reaction of
considerable synthetic utility, which can provide access
to valuable precursors to compounds of biological and
Lewis-basic oxygen atoms potentially allow for activa-
tion of the olefin by the acceptance of two hydrogen
,2
16,17
bonds from a suitably designed catalyst
and, (c)
the versatile nitro moiety is readily amenable to sub-
sequent modification (e.g., reduction to yield substituted
chiral tryptamines).
3
medicinal interest. Over the past five years, a number
of transition-metal complexes incorporating either chi-
4
–12
13
ral bis-oxazoline
or salen ligands have been shown
Ricci et al. have found that bis-arylthioureas 1 (Fig. 1)
effectively promote the addition of p-excessive aromatic
to serve as efficient catalysts for asymmetric variants of
such processes, with the enantioselective addition of
indoles to a wide variety of a,b-unsaturated electrophiles
being the subject of particularly intensive investigation.
McMillan and co-workers first demonstrated the feasi-
bility of complementary organocatalytic strategies with
the development of chiral imidazolidinone salts for the
promotion of enantioselective Friedel–Crafts (FC) alkyl-
1
8a
compounds to nitroolefins.
Very recently the same
group demonstrated that bifunctional catalyst
2
(20 mol %, Fig. 1) promoted the addition of indoles to
nitrostyrenes with high levels of stereoinduction, how-
ever, the corresponding N-alkylated indoles not suscep-
tible to bifunctional catalysis gave near-racemic
products under optimised low-temperature condi-
1
4a
14b
18b
ations of pyrroles and indoles with a,b-unsaturated
aldehydes via iminium ion catalysis, however, since
these seminal studies, the rate of expansion of the scope
of the reaction with respect to the electrophilic compo-
nent has been relatively slow.
tions.
As this report emerged we were engaged in
the design of chiral thioureas for the enantioselective
promotion of FC reactions involving challenging N-
alkyl indoles and nitroolefins. A recent report from
1
9
Jørgensen and co-workers describing the development
of a highly active bis-sulfonamide catalyst 3 (Fig. 1)
capable of promoting the asymmetric addition of
N-methylindole to nitrostyrenes with up to 50% ee
prompted us to report our preliminary results in this
area.
In this context, the addition of indoles to nitroolefins
is an attractive target for asymmetric organocatalyst
design as, (a) the analogous uncatalysed reaction generally
requires solvent-free conditions/elevated temperatures
and is characterised by variable yields and polymerisa-
1
5
tion of the olefin component, (b) the presence of two
Our catalyst design-rationale is straightforward; from
both previous studies in our laboratory on the catalysis
2
0
of the Baylis–Hillman reaction using thiourea deriv-
2
1
atives such as 1 and seminal work by Schreiner on the
*
0
Corresponding author. Tel.: +353 16081306; e-mail: connons@tcd.ie
promotion of Diels–Alder reactions by the same class of
040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.112

7038
E. M. Fleming et al. / Tetrahedron Letters 47 (2006) 7037–7042
CF3
CF3
CF3
Ph
Ph
X
S
Tf NH HN Tf
F3C
N
N
CF3 F3C
N
N
H
H
H
H
OH
1
1
a X = O
b X = S
2
3
Ar
Ar
Ar
O
O
NHR
N
N
OH
OH
Ar
RHN
tBu
OH HO
tBu
t
Bu
tBu
4
R = SO -4-Me-C H
5
6 Ar = 1-naphthyl
2
6
4
Z
W
Br
X
X
O
R
R
R
N
H
N
N
H
N
N
N
H
H
H
H
H
N
H
N
H
H
H
H
N
N
N
N
R
R
R
X
X
O
W
Br
Z
7
X = O, R = SO -4-Me-C H
15 X = O, W = H, Z = H, R = C6F5 19 R = 3,5-(CF ) -C H
3 2 6 3
2
6
4
8
9
X = O, R = cyclohexyl
16 X = O, W = Br, Z = H, R = C6F5 20 R = C6F5
17 X = O, W = Br, Z = Br, R = C6F5
X = O, R = C H5
6
1
1
1
1
1
0 X = O, R = 2,6-(Me) -C H
18 X = S, W = H, Z = H, R = 3,5-(CF ) -C H
2
6
4
3 2
6 3
1 X = O, R = 4-OMe-C H4
6
2 X = O, R = 3,5-(CF ) -C H
3
2
6 3
3 X = S, R = 3,5-(CF ) -C H
3
2
6 3
4 X = O, R = C6F5
Figure 1. Hydrogen bond donating organocatalysts.
2
2
compound —it is clear that replacement of either one,
temperature (entries 10 and 11), at ꢀ30 ꢁC the signifi-
cantly more active 13 gave much improved levels of
selectivity. The superiority (in terms of selectivity) of
decafluoro-catalyst 14 to either 12 or 13 is of inter-
est—to the best of our knowledge the N-pentafluoro-
phenyl moiety has not previously been evaluated as a
substituent in N-aryl urea-based catalysts, regrettably
this is concomitant with a reduction in activity which
renders 14 less convenient to utilise than 12 at lower
temperatures (entries 8–15).
or both N-aryl substituents with an aliphatic moiety
2
3,24
results in greatly attenuated catalyst activity;
therefore designed and prepared axially chiral catalysts
and 7–20, which retain the bis-N-aryl structural motif.
The catalysts were devised to probe the influence of the
steric and electronic characteristics of both the chiral and
achiral N-aryl substituents on catalyst efficacy and
enantioselectivity. Catalysts 4–17 were evaluated in the
asymmetric FC addition of the traditionally challenging
substrate N-methylindole (21) to (E)-b-nitrostyrene (22)
we
4
1
7
2
5
at ambient temperature in CDCl3. The results of these
studies are presented in Table 1.
Our attention next turned to the chiral bis-naphthyl
moiety. Although alteration of this catalyst sector did
(as expected) influence both catalyst efficacy and selec-
In the absence of catalyst, only trace levels of FC adduct
tivity, no single modification led to appreciable improve-
ments in both concurrently. Octahydro-analogues of 13
and 14 (15 and 18, respectively) were significantly less
efficient (yet reasonably selective) catalysts, while mono-
and di-bromo derivatives of 15 (16 and 17, respectively)
gave racemic products (entries 16–19). It is noteworthy
that the activity of urea-based catalyst 12 could be sub-
stantially augmented via the installation of bromo sub-
2
3 were observable after 3 days reaction time (Table 1,
entry 1). The catalytic importance of the thiourea moi-
ety is evident from both the clear superiority (in terms
of efficacy) of 7 over (R)-bis-N-tosyl-BINAM-derivative
4
(Table 1, entries 2 and 5), and the catalytic inactivity
2
6
of diols 5 and 6. Disappointingly, catalysis with
tosyl-urea was completely unselective. Bis-N-
7
0
arylthiourea-based catalysts incorporating either
aliphatic- or electron-rich/sterically hindered aromatic
substituents (8–11, entries 6–9) did furnish 22 with low
enantioselectivity, however these materials were decid-
edly slow promoters of the reaction. In contrast, ana-
logues bearing electron-deficient aromatic substituents
stituents at C-6 and C-6 (catalyst 19, entries 20 and 21).
The results of these studies allow the identification of the
simple thiourea 13 as the catalyst structure possessing
the most practical balance of properties in terms of both
catalytic activity and stereoinductive capability.
(
12–14) proved considerably more active and marginally
more selective catalysts.
To probe the compatibility of the catalyst with sub-
strates with a variety of steric and electronic characteris-
tics we investigated the addition of 21 to both aromatic
and aliphatic nitroalkenes 24–29 catalysed by 13 at low
While urea 12 and its thiourea analogue 13 afforded the
product with similar levels of stereoinduction at room

E. M. Fleming et al. / Tetrahedron Letters 47 (2006) 7037–7042
Table 1. Catalysis of the addition of 21 to 22 by 4–20
7039
Ph
*
NO2
cat. (10 mol%)
CDCl3
NO2
N
Ph
Me
N
Me
2
1
22
23
a
b
Entry
Catalyst
Concn (M)
Temperature (ꢁC)
Time (h)
Conversion (%)
ee (%)
1
2
3
4
5
6
7
8
9
—
4
0.36
0.36
0.36
0.36
0.36
0.36
0.36
0.36
0.36
0.36
0.36
0.36
0.36
0.36
0.72
0.36
0.36
0.36
0.36
0.36
0.36
0.36
0.72
rt
rt
rt
rt
rt
rt
rt
rt
rt
72
72
72
72
20
113
113
113
113
113
20
<2
<2
<2
<2
80 (100)
2
2
14
4
100
66 (100)
88
55 (93)
42
80
23
29
46
15
100
100
93
—
—
—
—
0
7
4.5
10
8
11
12
30
15
34
28
20
0
0
28
5
8
16
23
5
6
c
7
8
9
10
11
12
13
13
14
14
14
15
16
17
18
19
19
20
20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
rt
rt
d
ꢀ30
64
c
rt
113
167
70
ꢀ20
ꢀ20
rt
rt
rt
65
113
113
113
22
70
167
167
ꢀ30
rt
ꢀ20
rt
ꢀ30
38
a
b
c
1
Determined by H NMR spectroscopy.
Determined by HPLC using a Chiralpak AD-H column (250 · 4.6 mm).
Conversion after 166 h in parenthesis.
Conversion after 160 h.
d
temperature (Table 2). Aromatic nitroalkenes bearing
electron-withdrawing functionality (entries 2–3) and ste-
rically hindering ortho-substitution (entry 4) gave FC
adducts 30–32 with similar enantioselectivity to that
obtained using the parent styrene 22, while the electron-
rich heterocyclic analogue 27 underwent conversion to
Naturally this unusual thiourea structure (if indicative
of the active conformation in solution) precludes a sub-
strate binding scenario in which the nitroolefin (and by
extension the transition state of the rate determining
addition step) accepts two hydrogen bonds from a single
thiourea moiety. Binding of the electrophile nitro func-
tionality between thiourea moieties is also unlikely as
3
3 at an appreciable rate at ambient temperature only.
Contrary to the trend observed by Jørgensen using bis-
sulfonamide 3, nitroolefins with aliphatic substituents
the most suitably oriented hydrogen atoms (i.e., H
a
1
9
˚
27
and H , Fig. 2) are separated by 3.53 A, while the
b
(
often more difficult substrates in asymmetric organo-
O–O distance in the nitrostyrene is considerably shorter
(ca. 2.15 A). These preliminary studies therefore support
1
6,19
˚
catalytic Michael reactions)
underwent FC addition
with improved enantioselectivity relative to their aromatic
counterparts in the presence of 13 (entries 6 and 7). Inter-
estingly, the FC addition of indole itself to 22 catalysed
by 13 proceeded slowly, however, adduct 37 was isolated
with 10% ee (Scheme 1) after chromatography due in
the intriguing possibility that the catalytic activity of 13
could be derived from the binding of the substrate/tran-
sition state nitro group to a single thiourea hydrogen
1
9
atom.
1
9
part to a demonstrable silica-catalysed FC reaction
In summary, we have prepared and evaluated a small
library of novel thiourea-based axially chiral organocat-
alysts for the asymmetric addition of N-methylindole to
nitroolefins. Initial screening studies led to the identifica-
which can be problematic in cases involving the purifica-
tion of reaction mixtures where conversion is
incomplete.
3
1
tion of the relatively simple and readily prepared (S)-
13 as the optimal structure. While 13 is less active than
With a view towards better understanding both the
catalyst mode of action and the origins of the stereo-
selectivity in these reactions we determined the X-ray
1
9
the prototype literature organocatalyst 3, it is capable
of the promotion of the addition of N-methylindole 21
to nitrostyrenes in good yield and with comparable
(albeit lower) levels of enantioselectivity. An advantage
associated with the use of 13 in these reactions is its
compatibility with challenging nitroolefin substrates
2
7
crystal structure of 13. To our surprise the structure
indicated that the preferred conformation of the thio-
2
8
21,29,30
urea moiety is s-trans, cis and not the expected
s-cis, cis isomer (Fig. 2).

7040
E. M. Fleming et al. / Tetrahedron Letters 47 (2006) 7037–7042
Table 2. Asymmetric addition of 21 to nitroalkenes catalysed by 13: reaction scope
R
NO2
13
*
CDCl (0.72 M)
NO2
3
N
R
Me
-30 ºC
N
2
1 (2.0 equiv)
Me
a
b
Entry
Substrate
mol % (catalyst)
Product
Time (h)
117
Yield (%)
ee (%)
NO2
NO2
2
2
*
1
10
98
30
23
N
Me
F3C
NO2
NO2
*
c
2
3
4
24
10
140
89
36
3
0
F3C
N
Me
Br
NO2
NO2
*
20
287
54
28
25
31
Br
N
Me
NO2
NO2
*
10
115
78
28
2
6
32
N
Me
NO2
NO2
S
*
d
e
5
10
140
60
12
33
27
S
N
Me
NO2
5
NO2
*
6
20
20
69
76
65
50
43
2
8
34
5
N
Me
NO2
NO2
7
*
120
2
9
35
N
Me
a
b
c
Isolated yield.
Determined by HPLC-Chiralpak AD-H or AS column (250 · 4.6 mm).
Reaction concn 0.36 M.
At rt.
Refers to conversion.
d
e

E. M. Fleming et al. / Tetrahedron Letters 47 (2006) 7037–7042
Ph
7041
11. Yamazaki, S.; Iwata, Y. J. Org. Chem. 2006, 71, 739.
1
3 (20 mol%)
*
1
2. Jia, Y.-X.; Zhu, S.-F.; Yang, Y.; Zhou, Q.-L. J. Org.
Chem. 2006, 71, 75.
CDCl3 (0.72 M)
NO2
2
1
N
H
-
30 °C, 10 d
13. Bandini, M.; Fagioli, M.; Melchiorre, P.; Melloni, A.;
Umani-Ronchi, A. Tetrahedron Lett. 2003, 44, 5843.
14. (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc.
2001, 123, 4370; (b) Austin, J. F.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2002, 124, 1172.
N
H
3
6 (2.0 equiv)
3
7 56%, 10% ee
(
24% eebefore chromatography)
Scheme 1. Asymmetric addition of indole to 21.
1
5. Noland, W. E.; Lange, R. F. J. Am. Chem. Soc. 1959, 81,
203.
1
1
6. For examples of asymmetric organocatalytic addition
reactions to nitroolefins using thioureas see: (a) Okino,
T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003,
1
25, 12672; (b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu,
X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119; (c)
McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed.
2
005, 44, 6367; (d) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem.
Commun. 2005, 4481.
1
7. Reviews: (a) Connon, S. J. Chem. Eur. J. 2006, 12, 5418;
(
b) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2
2
2
3
006, 45, 1520; (c) Takemoto, Y. Org. Biomol. Chem.
005, 3, 4299; (d) Pihko, P. M. Angew. Chem., Int. Ed.
004, 43, 2062; (e) Schreiner, P. R. Chem. Soc. Rev. 2003,
2, 289.
Figure 2.
1
8. (a) Dessole, G.; Herrera, R. P.; Ricci, A. Synlett 2004,
374; (b) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci,
2
A. Angew. Chem., Int. Ed. 2005, 44, 6576.
9. Zhuang, W.; Hazell, R. G.; Jørgensen, K. A. Org. Biomol.
Chem. 2005, 3, 2566.
20. Maher, D. J.; Connon, S. J. Tetrahedron Lett. 2004, 45,
1301.
incorporating b-aliphatic substituents, which undergo
FC addition with 21 in the presence of thiourea 13 with
considerably higher enantioselectivity than the literature
benchmark for an organocatalytic system. Investiga-
tions to determine the solution-phase structure of the
catalyst in order to facilitate further optimisation, and
the evaluation of 13 (and 7–20) as organocatalysts in
other asymmetric carbon–carbon bond forming trans-
formations are underway.
1
1
9
21. Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9, 407.
2
2. For the use of bis-N-arylthioureas in other catalytic
processes see: (a) Curran, D. P.; Kuo, L. H. J. Org.
Chem. 1994, 59, 3259; (b) Curran, D. P.; Kuo, L. H.
Tetrahedron Lett. 1995, 36, 6647; (c) Schreiner, P. R.;
Wittkopp, A. Org. Lett. 2002, 4, 217; (d) Okino, T.;
Hoashi, Y.; Takemoto, Y. Tetrahedron Lett. 2003, 44,
2
817; (e) Hoashi, Y.; Yabuta, T.; Takemoto, Y. Tetrahe-
Acknowledgements
dron Lett. 2004, 45, 9185.
2
2
3. For discussion, see Ref. 21.
Financial support from the Irish Research Council for
Science, Engineering and Technology (IRCSET) is
gratefully acknowledged.
4. Thiourea catalysts for asymmetric Pictet–Spengler reac-
tions which do not incorporate N-aryl substituents:
Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004,
1
26, 10558.
2
5. Preliminary solvent screening studies identified chloro-
References and notes
form-d as the optimal solvent in these catalysed reactions.
3
2
6. Thadani, A. N.; Stankovic, A. R.; Rawal, V. H. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5846.
1
. (a) Friedel, C.; Crafts, J. M. C.R. Hebd. Seances Acad. Sci.
877, 84, 1392; (b) Friedel, C.; Crafts, J. M. C.R. Hebd.
1
27. Crystallographic data for 13 have been deposited with the
Cambridge Crystallographic Data Centre, deposit number
CCDC609063.
Seances Acad. Sci. 1877, 84, 1450.
. Olah, G. A. In Friedel–Crafts Chemistry; Wiley: New
York, 1973.
2
1
28. A single rotameric species was detected in the H NMR
3
. Reviews: (a) Bandini, M.; Melloni, A.; Tommasi, S.;
Umani-Ronchi, A. Synlett 2005, 1199; (b) Bandini, M.;
Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed.
spectrum of 13.
29. For examples of the demonstrable s-cis,cis conformational
preference of thioureas see: (a) Tel, R. M.; Engberts, J. B.
F. N. J. Chem. Soc., Perkin Trans. 2 1976, 483; (b) Etter,
M. C.; Panunto, T. W. J. Am. Chem. Soc. 1988, 110, 5896;
(c) Etter, M. C.; Urba n˜ czyk-Lipkowska, Z.; Zia-Ebrahimi,
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2
004, 43, 550; (c) Jørgensen, K. A. Synthesis 2003, 1117.
4
. Jensen, K. B.; Thorbauge, J.; Hazell, R. G.; Jørgensen, K.
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5
6
7
. Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030.
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. Zhou, J.; Ye, M.-C.; Huang, Z.-Z.; Tang, Y. J. Org. Chem.
30. The X-ray crystal structure of cyclohexyl-substituted urea-
based catalyst 8 exhibited an s-cis,cis urea conformation.
8
˚
2
004, 69, 1309.
The distance between the urea hydrogen atoms is 2.12 A.
3
9
. Zhou, J.; Tang, Y. Chem. Commun. 2004, 432.
31. In a 10 cm flask fitted with a stirring bar under an
1
0. Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcia, J. M.;
atmosphere of N (balloon), bis-3,5-trifluoromethylphenyl
2
Linden, A. J. Am. Chem. Soc. 2005, 127, 4154.
isothiocyanate (276 lL, 1.5 mmol) was added via syringe

7042
E. M. Fleming et al. / Tetrahedron Letters 47 (2006) 7037–7042
0
0
to a solution of (S)-1,1 -binaphthyl-2,2 -diamine (205 mg,
0
J = 8.7 Hz, 2H), 7.71 (br s, 2H), 7.68 (s, 4H), 7.68 (s,
2H), 7.50 (m, 2H), 7.29 (m, 2H), 7.13 (d J = 8.7 Hz, 2H).
3
2 2
.72 mmol) in CH Cl (1.2 cm ). The resulting solution
1
3
was left to stir overnight at room temperature. Removal of
the solvent in vacuo and purification of the product by
column chromatography gave (S)-13 as a white solid
C NMR (CDCl , 100 MHz) 179.8, 138.6, 133.4, 132.6,
3
132.2, 131.7 (q, J = 33.7 Hz), 130.5, 128.6, 128.0, 127.3,
126.9, 125.2, 124.6, 124.2, 122.6 (q, J = 272.9 Hz), 119.5.
2
D
0
ꢀ1
(
546 mg, 91%), mp 137–138 ꢁC, ½aꢁ ꢀ126 (c 0.5, CHCl
3
).
IR (film) m 3265, 1688, 1498, 980 cm . HRMS (ESI) calcd
1
+
H NMR (CDCl , 400 MHz) d = 8.24 (br s, 2H), 8.10 (d,
for [C H F N S +Na] requires 849.0992. Found
3
38 22 12
4 2
J = 8.7 Hz, 2H), 7.97 (d, J = 8.3 Hz, 2H), 7.88 (d,
849.1013.