Imidazolethiones: novel and efficient organocatalysts for asymmetric Friedel-Crafts alkylation

Article abstract of DOI:10.1016/j.tetlet.2010.02.160

Imidazolethiones organocatalyzed the asymmetric Friedel-Crafts alkylation of pyrroles with α,β-unsaturated aldehydes was achieved to afford the corresponding adducts in moderate to good yields and good to excellent enantioselectivities. The possible mecha

Full text of DOI:10.1016/j.tetlet.2010.02.160

Tetrahedron Letters 51 (2010) 2505–2507
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Tetrahedron Letters
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Imidazolethiones: novel and efficient organocatalysts for asymmetric
Friedel–Crafts alkylation
*
Xianrui Liang, Jiaoyang Fan, Fei Shi, Weike Su
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Imidazolethiones organocatalyzed the asymmetric Friedel–Crafts alkylation of pyrroles with a,b-unsatu-
Received 28 January 2010
Accepted 26 February 2010
Available online 3 March 2010
rated aldehydes was achieved to afford the corresponding adducts in moderate to good yields and good to
excellent enantioselectivities. The possible mechanism was proposed.
Ó 2010 Elsevier Ltd. All rights reserved.
The asymmetric Friedel–Crafts alkylation of arenes with elec-
tron-deficient alkenes is a powerful C–C bond-forming process in
organocatalytic chemistry.1 The first enantioselective Friedel–
O
S
O
S
O
N
C
N
N
N
C
C
C
N
H
N
H
N
H
Crafts reaction of pyrrole with a,b-unsaturated aldehydes was re-
Ph
Ph
Ph
Ph
Ph
ported by MacMillan using the chiral imidazolidinone catalysts in
2001.2 Chiral Lewis acid complexes3 and other organocatalysts4
have also been explored as the efficient catalysts for the enantiose-
important contribution
lective Friedel–Crafts reaction of pyrrole derivatives with
unsaturated systems.
a,b-
S
N
C
N
C
Among theses catalysts, the effectiveness of imidazolidinone5
has attracted our considerable interest. In 1995, Wiberg groups6
indicated the larger barrier of C–N rotating in thioamide by com-
paring with amide due to the much greater change in charge den-
sity at sulfur, which formed more appropriate resonance structure
I for thioamide (Fig. 1). Initiated by these protocols, we designed a
novel chiral organocatalyst imidazolethione to increase the rigidity
of catalyst structures. We anticipated the more ‘stiffer’ imidazol-
ethiones to help contribute to improving the reaction of stereose-
lectivity as chiral organocatalysts.
N
H
N
H
N
H
Ph
important contribution I
Figure 1.
O
S
N
P2S5 / Al2O3
N
In our initial work, a series of novel imidazolethiones were eas-
ily prepared from the corresponding imidazolidinones with good
yields using P2S5/Al2O3 as a sulfuration agent (Scheme 1). Among
these organocatalysts, the imidazolethiones 2a and 2b exhibited
excellent catalytic activities for the asymmetric Friedel–Crafts
HN
toluene, reflux
HN
R2
R2
R1
R1
2
1a R1=Me, R2=Me
1
2a
2b
R =Me, R =Me
1b R1,R2=-(CH2)4-
1
2
R ,R =-(CH2)4-
alkylation reaction of pyrroles with
a,b-unsaturated aldehydes.
Scheme 1.
A
mixture of N-methyl pyrrole 3a and (E)-3-(4-chloro-
phenyl)acrylaldehyde 4a was performed as a model reaction in
the presence of catalytic amount (20 mol %) of imidazolethione
2a (Scheme 2). Various factors including the kinds of catalysts,
additives, solvents, and temperature were investigated for this
reaction.
Me
N
Cl
CHO
2a
HX
Me
20 mol%
N
+
THF-H2O, -20oC
As revealed in Table 1, the effect of additive acids loading on
reaction efficiency was first evaluated. Negligibly target adducts
Cl
CHO
5a
3a
4a
* Corresponding author. Tel./fax: +86 571 88320752.
E-mail address: pharmlab@zjut.edu.cn (W. Su).
Scheme 2.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.160

2506
X. Liang et al. / Tetrahedron Letters 51 (2010) 2505–2507
Table 1
Table 3
Catalysts screening for the reaction of 3a and 4aa
Friedel–Crafts alkylation of pyrroles 3 with
a,b-unsaturated aldehydes 4 catalyzed by
2a or 2ba
Entry
Catalysts
Additives HX
Time (h)
Yieldb (%)
eec (%)
R1
N
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2b
1a
p-TSA
6
32
32
48
48
48
48
48
78
75
Trace
79
78
85
83
80
57
58
—
90
89
91
90
86
R1
20 mol% cat. 2a or 2b TFA
THF-H2O -20oC
F3CSO3H
PhCOOH
Cl2CHCO2H
Cl3CCO2H
TFA
R2
N
CHO
R2
+
CHO
eeb (%)
3
4
5
TFA
TFA
Entry
Product
R1
R2
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12d
13d
14c
15d
16d
17d
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
p-ClC6H4
p-FC6H4
p-MeOC6H4
p-MeC6H4
C6H5
m-ClC6H4
m-MeC6H4
o-MeOC6H4
o-F3CC6H4
Me
CH3(CH2)2
p-ClC6H4
p-FC6H4
p-MeC6H4
C6H5
48
48
48
48
48
72
72
72
72
56
56
48
48
48
48
48
48
85
80
74
76
85
79
75
73
70
82
80
62
65
56
65
60
71
91
93
94
91
92
90
89
84
85
98
95
63
60
45
53
38
97
a
Reactions conditions: a mixture of 3a (4.5 mmol), 4a (2 mmol), 20 mol % cata-
lysts and 20 mol % additives in THF (4 mL)/H2O (0.6 mL) was stirred at ꢀ20 °C for
the given time.
b
Yields based upon isolation of the corresponding alcohol after NaBH4 reduction.
ee determined by chiral HPLC.
c
or poor enantioselectivities were obtained with 2a in the presence
of p-TSA, CF3SO3H, or PhCO2H (Table 1, entry 1–3), whereas
Cl2CHCO2H, CCl3CO2H, and TFA showed significant activity (Table
1, entries 4–6). Most excitingly, the optimal yield (85%) and enanti-
oselectivity (91%) were accomplished by using 2a-TFA (Table 1, en-
try 6). In addition, catalyst 2b gave a similar result (83% yield, 90%
ee) under the same conditions (Table 1, entry 7). Compared to 2a
and 2b, catalyst 1a offered somewhat lower ee value (86% ee)
(Table 1, entry 8).
Secondly, the influence of solvents and reaction temperature on
this alkylation was examined (Table 2). The results indicated that
CH2Cl2, i-PrOH, and THF were unsuitable for the reaction (Table 2,
entries 1–3). A mixed solvent THF/H2O (85:15) proved to be the
most effective (Table 2, entry 6), while excess water (35%) resulted
in decreasing yield (Table 2, entry 8). Moreover, lower ee was
observed by elevating the reaction temperature (Table 2, entry 9).
H
H
H
H
m-MeC6H4
Me
H
a
Reactions conditions: a mixture of 3 (4.5 mmol), 4 (2 mmol), 20 mol % catalyst
2a and 20 mol % TFA in THF (4 mL)/H2O (0.6 mL) was stirred at ꢀ20 °C for the given
time.
b
Yields based upon isolation of the corresponding alcohol after NaBH4 reduction.
ee determined by chiral HPLC.
Using catalyst 2b.
c
d
Based on the literatures2,5j,7 and preliminary experimental find-
ings, we assumed that the probable mechanism and transition
states might be governed by imidazolethiones. As shown in com-
putational modeling, the catalyst-activated iminium ion 6 formed
selectively the (E)-iminium isomer5b,j,8 to avoid nonbonding inter-
actions with the gem-dimethyl group. Simultaneously, the benzyl
group on the catalyst framework could effectively shield the re-
face of the dienophile, led to stereoselective si-facial nucleophilic
conjugate addition by pyrrole in its enol form (Scheme 3). The
‘stiffer’ imidazolethione was possibly attributed to the enhanced
Encouraged by these initial results, the scope of a,b-unsaturated
aldehydes and pyrroles was explored (Table 3, entries 1–17). Aro-
matic unsaturated aldehydes were well tolerated in the alkylation
of N-metyl pyrrole (Table 3, entries 1–9), in which para-substitu-
tion offered higher yield and ee value (Table 3, entries 1–4) than
meta- or ortho-substitution (Table 3, entries 6–9) on the aryl ring.
More importantly, excellent levels of yields and enantioselectivi-
ties were observed for aliphatic unsaturated aldehydes (Table 3,
entries 10 and 11), which were higher than that of MacMillan’s
imidazolidinone.2 As far as alkylation of pyrrole was concerned,
catalyst 2b was used due to the difficult isolation of products with
catalyst 2a, giving moderate yields and enantioselectivities (Table
3, entries 12–16). In particular, crotonaldehyde offered excellent
ee (Table 3, entry 17) compared with aromatic unsaturated
aldehydes.
S
S
N
N
N
N
X
X
Ph
Ph
R
R
iminium ion complex 6
Table 2
The influence of solvents and temperature on the reactiona
Entry
Solvent (v/v)
Temp (°C)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
i-PrOH
THF
CH2Cl2/i-PrOH (85/15)
THF/i-PrOH (90/10)
THF/H2O (85/15)
THF/H2O (95/5)
THF/H2O (65/35)
THF/H2O (85/15)
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ5
31
trace
42
76
80
85
84
64
83
50
—
NH
R
37
89
80
91
91
88
76
CHO
si-face
re-face
blocked
exposed
H
N
a
Reactions conditions: a mixture of 3a (4.5 mmol), 4a (2 mmol), 20 mol % cata-
lyst 2a and 20 mol % TFA in solvent (4.6 mL) was stirred at ꢀ20 °C for 48 h.
computational iminium ion model 6
Scheme 3.
b
Yields based upon isolation of the corresponding alcohol after NaBH4 reduction.
c
ee determined by chiral HPLC.

X. Liang et al. / Tetrahedron Letters 51 (2010) 2505–2507
2507
MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 9328; (j) Lee, S.; MacMillan, D.
W. C. Tetrahedron 2006, 62, 11413.
6. Wiberg, K. B.; Rablen, P. R. J. Am. Chem. Soc. 1995, 117, 2201. and references cited
herein.
7. (a) Huang, Y.; Waiji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc.
2005, 127, 15051; (b) Ahrendt, K. A.; Borths; MacMillan, D. W. C. J. Am. Chem. Soc.
2000, 122, 4243.
8. (a) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125,
1192; (b) Ouellet, S. G.; Walji, A. M.; MacMillan, D. W. C. Acc. Chem. Res. 2007, 40,
1327; (c) Lelais, G.; MacMillan, D.W.C. New Frontiers in Asymmetric Catalysis;
John Wiley Sons, Inc., 2007; p 313; (d) Northrup, A. B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 2458.
catalytic activity and increased iminium geometry control in the
transition state.
In summary, we developed novel organocatalyst imidazolethi-
ones which were efficient to promote the enantioselective Fri-
edel–Crafts alkylation of pyrroles and
a,b-unsaturated aldehydes
with moderate to excellent yields and high enantioselectivities,
especially for the aliphatic unsaturated aldehydes.9 Further, thriv-
ing area of catalysis concepts and widely applicable reactions
based on these catalysts are going in our studies.
9. Typical procedure for the synthesis of imidazolethione 2a: A mixture of P2S5 (3.0 g,
13.5 mmol) and Al2O3 (5.0 g, 49.0 mmol) was ground continuously in a mortar
until a fine, homogeneous powder was obtained. Then, P2S5/Al2O3 (2 g, 5 mmol)
was added to the solution of imidazolidinone 1a (1.1 g, 5 mmol) in 30 mL
toluene. The reaction mixture was stirred at refluxing for the given time under
nitrogen (monitored by TLC). The reaction mixture was filtrated, the solvent was
evaporated under vacuum, and the residue was purified by flash column
chromatography over silica gel (petroleum ether/CH2Cl2/AcOEt 4:1:1) to afford
the corresponding imidazolethione 2a in 89% yield.
Acknowledgment
We thank the Zhejiang Natural Science Foundation (Y407287)
for financial support.
Supplementary data
(S)-5-Benzyl-2,2,3-trimethylimidazolidine-4-thione (2a): Yellow oil. Yield: 89%;
1H NMR (400 MHz, CDCl3): d (ppm) = 7.30–7.22 (m, 5H), 4.15 (t, J = 6.8 Hz, 1H),
3.50 (dd, J1 = 4.4 Hz, J2 = 14.0 Hz, 1H), 3.17 (dd, J1 = 6.8 Hz, J2 = 14.0 Hz, 1H), 3.16
(s, 3H), 1.78 (br s, 1H), 1.31 (s, 3H), 1.30 (s, 3H); 13C NMR (100 MHz, CDCl3): d
(ppm) = 200.0, 137.1, 129.4, 128.5, 126.8, 83.8, 70.0, 39.3, 30.9, 26.5, 24.7; MS
(EI): m/z (%) = 234(96, M+), 177(94), 176(81), 160(83), 143(100). HRMS (EI) exact
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.02.160.
mass calcd for [C13H18N2S]: 234.1191; found: 234.1196. ½a D20
ꢀ139.2 (c 0.87,
ꢁ
References and notes
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mixture of catalyst 2a (0.4 mmol), TFA (0.4 mmol), and ,b-unsaturated
a
aldehydes (2 mmol) in THF (4 mL) and H2O (0.6 mL) was stirred for 5 min at
room temperature. Then, the pyrroles (4.5 mmol) were added. The reaction
mixture was stirred at ꢀ20 °C for the given time (monitored by TLC). The
resulting solution was added to equal volume of absolute EtOH and excess of
NaBH4 and stirred for 15 min. The reaction was quenched with saturated
aqueous NaHCO3, extracted with CH2Cl2, and dried over anhydrous Na2SO4. The
solvent was evaporated under vacuum, and the residue was purified by flash
column chromatography over silica gel (AcOEt/petroleum ether 1:6) to provide
products 5.
(S)-3-(4-Chlorophenyl)-3-(1-methyl-1H-pyrrol-2-yl)propan-1-ol (5a): Yellow
oil. Yield: 85%. 1H NMR (400 MHz, CDCl3): d (ppm) = 7.22 (d, J = 8.4 Hz, 2H),
7.07 (d, J = 8.4 Hz, 2H), 6.52 (t, J = 2.0 Hz, 1H), 6.12–6.09 (m, 2H), 4.10 (t,
J = 7.6 Hz, 1H), 3.70–3.64 (m, 1H), 3.58–3.54 (m, 1H), 3.28 (s, 3H), 2.34–
2.26 (m, 1H), 2.07–1.99 (m, 1H), 1.54 (br s, 1H); 13C NMR (100 MHz,
CDCl3): d (ppm) = 142.0, 134.3, 132.0, 129.3, 128.7, 122.0, 106.4, 105.9, 60.3,
38.8, 38.7, 33.8; MS (EI): m/z (%) = 249 (22, M+), 206(35), 204(100); HRMS
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(EI) exact mass calcd for [C14H16ClNO]: 249.0920, found: 249.0927. ½ ꢁ
a 2D0
+91.4 (c 0.51, CHCl3). HPLC condition: Chiralcel AS-H column, isopropanol/
hexanes 10:90, flow rate 1.0 mL/min, UV detection at 214 nm,
tmajor = 6.3 min, tminor = 7.1 min, 91% ee.