Enantioselective Friedel-Crafts alkylation of thiophenes with ethyl glyoxylate: Easy access to chiral secondary alcohols

Article abstract of DOI:10.1002/ejoc.201001455

Friedel-Crafts alkylation reactions of ethyl glyoxylate with various thiophenes to give the corresponding chiral secondary alcohols were demonstrated. The majority of these reactions proceeded with good enantioselectivities (up to 91%) and satisfactory is

Full text of DOI:10.1002/ejoc.201001455

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001455
Enantioselective Friedel–Crafts Alkylation of Thiophenes with Ethyl
Glyoxylate: Easy Access to Chiral Secondary Alcohols
Zhong Huang,[a,b] Jingchang Zhang,* Yuqiang Zhou, and Nai-Xing Wang*
[b]
[a]
[a]
Keywords: Sulfur heterocycles / Asymmetric catalysis / Alkylation / Alcohols
Friedel–Crafts alkylation reactions of ethyl glyoxylate with
various thiophenes to give the corresponding chiral second-
ary alcohols were demonstrated. The majority of these reac-
tions proceeded with good enantioselectivities (up to 91%)
and satisfactory isolated yields. Notably, we found that 2-
substituted thiophenes underwent the reaction more
smoothly than unsubstituted and 3-substituted thiophenes.
aromatic amines. Jørgensen and co-workers[6] have reported
the asymmetric reaction of 2-methylthiophene with tri-
Introduction
Sulfur-containing heterocycles have versatile applications
in the areas of materials science, agrochemicals, and
pharmaceuticals due to their unique chemical and bio-
logical properties. Specifically, widely used sulfur-contain-
fluoropyruvate catalyzed by (S)-tBu-BOX-Cu(OTf) . Al-
2
[1]
[2]
though only a low yield (16%) and moderate enantio-
selectivity (79%) were obtained, this study opened the door
to the asymmetric, catalytic Friedel–Crafts alkylation of
thiophenes. Despite these achievements, in view of the great
utility of thiophene-containing compounds, the systematic
exploration of the Friedel–Crafts alkylation reaction of
thiophenes is still highly desirable.
Though thiophenes are less reactive than indoles, furans,
and pyrroles, the Friedel–Crafts alkylation reaction could
be realized to prepare secondary alcohols when an appro-
priate electrophile is chosen to react with the thiophenes.
[
3]
[
3a,3b]
ing pharmaceuticals include penicillin
and cefalotin
and clopidogrel
[
3c,3d]
[3e]
[3f]
sodium
as antibiotics, prasugrel
as antiplatelet drugs, raloxifene hydrochloride as a second-
generation drug for osteoporosis in postmenopausal
[
3g,3h]
women,
aminopeptidase N (APN) as an efficient anti-
[
3i]
cancer drug,
and eprosartan as a antihypertensive
These applications sharply captured our interest
[
3j,3k]
drug.
in sulfur-contained heterocycles, and in particular thio-
phenes.
Building on the knowledge obtained from earlier stud-
The well-known Friedel–Crafts alkylation reaction is one
of the most fundamental and popular carbon–carbon
bond-forming reactions in organic synthesis.[4] The develop-
ment of a catalytic enantioselective method for the facile
synthesis of optically active compounds from electron-rich
aromatic rings reacting with C=O has recently attracted sig-
[5c,5d]
ies,
we explored the use of ethyl glyoxylate as the elec-
trophile and thiophenes as the nucleophiles in Friedel–
Crafts reactions. Expected products with good yields and
high enantiomeric excess values for the majority of the sub-
strates were obtained. To the best of our knowledge, the
study of the Friedel–Crafts alkylation of versatile thio-
phenes with ethyl glyoxylate to give (S)-secondary alcohols
has not been reported.
[
5]
nificant attention. Although asymmetric Friedel–Crafts
reactions have been extensively studied, including the reac-
[5a]
tions of indoles with aromatic aldehydes and ethyl glyox-
[
5b]
[5c,5d]
ylate, aromatic amines with ethyl glyoxylate,
pyrrole
[5e]
with trifluoromethyl ketones, and furan with ethyl glyox-
Results and Discussion
[
5d]
ylate, there are still very few studies that involve the Frie-
del–Crafts reactions of thiophenes.[6,7] This may be due to
the lower activity of the thiophene ring than indole and
With the selected reaction system, we conducted a very
detailed optimization, and the results are summarized in
Table 1. First, we tried the Friedel–Crafts reaction of 2-eth-
ylthiophene (1a) with ethyl glyoxylate (2) at room tempera-
[
a] Technical Institute of Physics and Chemistry,
Chinese Academy of Sciences,
1
IV
ture in the presence of (S)-BINOL (L )/Ti (5 mol-%) as
Beijing, 100080, China
1
Fax: +86-10-62554670
E-mail: nxwang@mail.ipc.ac.cn
the catalyst, which was prepared in situ by mixing L and
Ti(OiPr) in a 1:1 molar ratio in CH Cl for 2 h. The result
4
2
2
[b] Institute of Modern Catalysis,
State Key Laboratory of Chemical Resource Engineering,
Beijing University of Chemical Technology,
Beijing 100029, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001455.
shows that the reaction proceeds very smoothly to give 84%
yield with 26%ee (Table 1, Entry 1). Encouraged by this re-
sult, different commercially available and prepared ligands
2
7
[8]
(L –L , Scheme 1) complexing with Ti(OiPr) were used
4
Eur. J. Org. Chem. 2011, 843–847
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
843

Z. Huang, J. Zhang, Y. Zhou, N.-X. Wang
Table 1. Optimization of the enantioselective Friedel–Crafts reac- terms of both enantioselectivity and reactivity. Although
SHORT COMMUNICATION
IV
[a]
tion of 1a with 2 catalyzed by Ti –ligand complexes.
the enantiomeric excess is not very high (38%ee; Table 1,
Entry 3), the relatively high reactivity of L led us to investi-
3
gate other BINOLs. Unexpectedly, the steric hindrance of
Ј
the 3,5-ditrifluoromethylphenyl group at the 3,3 -positions
5
of BINOL L proved to be very disadvantageous for both
reactivity and enantioselectivity, as the product was ob-
Entry
Ligand
Solvent
Temp. [°C] Yield [%][b]
ee [%][c]
tained in only 16% yield with 3%ee (Table 1, Entry 5).
1
2
1
2
3
4
5
6
7
8
9
L
CH
CH
CH
CH
CH
CH
CH
Cl
2 2
Cl
2 2
Cl
2 2
Cl
2 2
Cl
2 2
Cl
2 2
Cl
2 2
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
84
33
89
19
16
Ͻ10
28
70
31
56
26
30
38
1
Then, we tried L with a partially reduced backbone, but a
2
L
greatly decreased yield and a slightly decreased enantio-
3
L
3
4
selectivity in comparison to those obtained with L were
L
5
obtained. It is well known that the acidity of the catalyst is
L
3
6
L
–5
–7
67
25
14
54
63
80
74
80
80
85
90
–
essential for the Friedel–Crafts reaction. In comparison
7
3
2
L
with L , the acidity of L is greatly weakened because of
3
L
toluene
THF
the electron-donating properties of the partially reduced
3
L
2
IV
3
backbone. The lower catalytic activity of L /Ti might be
1
0
L
CHCl
3
2
1
1
L
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
26
60
65
attributed to its relatively weak acidity. The reaction cata-
1
4
IV
1
2
L
lyzed by L /Ti afforded the product in 19% yield, but with
3
1
3
L
very low enantioselectivity (Table 1, Entry 4). This may be
[
d]
3
1
4
L
0
44
4
[
e]
3
due to the fact that L did not coordinate with Ti(OiPr)
4
1
5
L
0
20
[
f]
3
and thus did not participate in the reaction. The ethoxy
16
L
0
50
3
4
1
7
L
–20
60
groups of L largely decrease its coordination ability, and it
3
1
8
L
–40
–78
–40
–40
–40
83
n.r.
85
64
Ͻ10
can thus not form a hydrogen bond, which is very impor-
3
1
9
L
[5c]
tant in the transition state for the reaction.
The results
[
g]
3
2
0
L
84
87
84
show that L6 and L7 were not good partners with Ti-
(OiPr) for the reaction of thiophenes with glyoxylate.
Therefore, the appropriate assembly of ligands with
Ti(OiPr) and the substituents on the backbone of BINOL
[
h]
3
2
1
L
[
i]
3
22
L
4
[
a] All reactions were performed with the ligand (0.01 mmol),
Ti(OiPr) (0.01 mmol), 2-ethylthiophene (1a, 0.2 mmol), and ethyl
4
4
glyoxylate (2, 0.4 mmol) in solvent (0.5 mL) for 9 h unless other- are the keys to obtaining good yield and enantioselectivity.
wise stated. The absolute configuration was defined according to
Considering that solvent effects could play a very impor-
tant role in enantioselectivity, we examined the reactions in
different solvents (Table 1, Entries 3, 8–10). The use of tolu-
[
7b]
3
b. [b] Isolated yield of 3a after flash chromatography. [c] Deter-
mined by HPLC by using a Chiralcel OD-H column. [d] The molar
ratio of 1a and 2 was 2:1. [e] The molar ratio of 1a and 2 was 1:1.
3
[f] The molar ratio of L and Ti(OiPr)
4
was 2:1. [g] The catalysts ene greatly improved the enantioselectivity to 67%, which
loading was 10 mol-%. [h] The catalysts loading was 2 mol-%. was greater to that obtained in CH Cl , CHCl , and THF.
2
2
3
[i] The aging time of the ligand with Ti(OiPr)
4
was 14 h.
3
To further verify the result that L is more appropriate than
L and L for the reaction system, we used L /Ti and L /
to investigate the asymmetric catalytic reactions. The results Ti as catalysts in toluene, respectively, and expectedly,
1
2
1
IV
2
IV
clearly show that the reactivity and enantioselectivity of the both the ligands gave poorer yields and enantioselectivity
3
reactions are significantly influenced by the nature of the than L (Table 1, Entries 8, 11, 12).
3
IV
ligand, electric effects, and substituents of the BINOL
Subsequently, we examined the use of L /Ti at low tem-
1
3
(
Table 1, Entries 2–7). On the whole, BINOLs L –L and perature. To our delight, further optimization of the reac-
5
4
6
L are obviously more favorable than ligands L , L , and tion conditions revealed that an excellent enantioselectivity
L . Among these BINOLs, L with an electron-withdrawing could be obtained when the reaction temperature was low-
7
3
Ј
group (Br) at the 6,6 -positions is the most favorable in ered to 0 °C (Table 1, Entry 13). Under these reaction con-
Scheme 1. Ligands used in this study.
844
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Eur. J. Org. Chem. 2011, 843–847

Enantioselective F–C Alkylation of Thiophenes with Ethyl Glyoxylate
ditions, we examined the influence of the molar ratio of 1a 3-position (Table 2, Entries 10–12) and unsubstituted thio-
to 2 on the yield and enantioselectivity (Table 1, Entries 14 phene (Table 2, Entry 13).
an 15). When the ratio was 2:1, both the yield and enantio-
Table 2. Substrate scope of the enantioselective Friedel–Crafts reac-
selectivity decreased, and when the ratio was 1:1, though
3
tion of thiophenes 1a–m with ethyl glyoxylate (2) catalyzed by L /
the enantioselectivity had no obvious change, the yield was
IV[a]
Ti .
3
largely decreased. Also, changing the molar ratio of L and
Ti(OiPr) to 2:1 did not have an obvious impact on the
4
enantioselectivity but instead led to a lower yield (Table 1,
Entry 16), probably because the excess amount of the li-
gand could coordinate with Ti(OiPr) , decreasing the acid-
4
ity of the catalyst. Lowering the reaction temperature to
1
2
Temp. Yield of 3 ee [%][c]
–20 °C enhanced the enantioselectivity to 85% (Table 1, En-
Entry
1 (R ; R )
[b]
[°C]
[%]
try 17), although the reaction took a longer time to reach
completion. The best result was obtained when the reaction
was performed –40 °C (90%ee; Table 1, Entry 18). How-
ever, when we lowered the temperature to –78 °C, target
compound 3a was not found in the crude reaction mixture.
The catalyst loading was also studied at –40 °C. Though
raising the catalyst loading to 10 mol-% slightly improved
the yield, the enantioselectivity was decreased. Lowering
the catalyst loading to 2 mol-% decreased both the yield
and the enantioselectivity. Because of these results, we de-
cided to use 5 mol-% of catalyst to explore the scope of the
reaction. In addition, we found that the enantioselectivity
1
2
3
4
5
6
7
8
9
1a (H; Et)
1b (H; Me)
1c (H; MeO)
1d (H; Bn)
1e (H; Ph)
–40
–40
–40
–40
0
0
0
0
0
0
r.t.
r.t.
r.t.
3a, 83
3b, 80
3c, 91
3d, 84
3e, 96
90
88
90
90
91
88
85
85
81
73
4
1f (H; 2,4-dichlorobenzyl)
1g (H; diphenylmethyl)
1h (H; 4-methoxybenzyl)
1i (H; 1-phenylpropyl)
1j (Me; H)
3f, 76
3g, 97
3h, 98
3i, 98
1
0
3j, 75
11
12
1k (MeO; H)
1l (Br; H)
1m (H; H)
3k, Ͻ10
3l, Ͻ10
3m, 20
24
29
1
3
was slightly lowered to 84%, but with less than 10% yield [a] All reactions were performed with L3 (0.01 mmol), Ti(OiPr)
4
(
0
[
0.01 mmol), thiophene 1 (0.2 mmol), and ethyl glyoxylate (2,
when the catalyst aging time was prolonged to 14 h.
With the optimized conditions in hand for the model re-
action of 1a with 2, we explored the scope of the catalytic
enantioselective Friedel–Crafts reaction of readily available
substituted thiophenes 1a–m[ with ethyl glyoxylate (2,
.4 mmol) in toluene (0.5 mL) for 7–72 h at the stated temperature.
b] Isolated yield of 3 after flash chromatography. [c] Determined
by HPLC by using a Chiralcel OD-H column.
9]
Even though the substituents of 1a–i are all at the 2-
Table 2). In all cases, the reactions provided expected sec- position of the thiophene ring, the difference among sub-
ondary alcohols 3a–m with different enantiomeric excess stituents can also affect the reactivity of the thiophenes.
values. However, the position of the substituent on the thio- Therefore, their reactions with 2 were conducted at different
phene ring had a very important impact on the yield and temperatures after our many efforts. Substrates 1a–d with
enantioselectivity (Table 2, Entries 2 and 3 vs. 10 and 11, small electron-donating groups reacted smoothly with 2 at
respectively). When the methyl group was at the 2-position, –40 °C to provide products in good yields (80–91%) with
up to 88%ee was obtained, but when the group was at the good and enantioselectivity (88–90%ee). However, the re-
3-position, the reaction proceed with a lower yield, and the action of 1e–i could with 2 at –40 and –20 °C did not pro-
secondary alcohol was obtained with only 73%ee. This dif- ceed well. For 1e, the phenyl group lowers the charge den-
ference may be caused by the existence of a steric effect of sity of the thiophene ring through π–π conjugation, weak-
the substituent at the 3-position. Moreover, the phenome- ening the nucleophilic ability of the thiophene rings, and
non is more obvious for the reaction of 3-methoxythio- for 1f–i, it is a result of the steric effect of the bulky substit-
phene (1k) with 2, which not only gave the product with uents. We had to raise the temperature to 0 °C for the reac-
low enantioselectivity, but also with an unexpectedly low tion of 1e–i with 2, which gave moderate to high yields with
yield, even though the MeO group is an electron-donating enantioselectivities of more than 80%ee. However, the reac-
group. We believe that the product, containing a hydroxy tion of unsubstituted thiophene did not proceed smoothly
and a methoxy group, forms a six-membered ring with the even at 0 °C, and a significant drop in both yield and
catalyst, which thus inhibits the reaction. This hypothesis enantioselectivity was observed at room temperature. Com-
was confirmed by the experimental details that a very obvi- parison of 1m and 1e (1e has a lower charge density) indi-
3
ous spot belonging to L was found on all the TLC plates cates that the substituent at the 2-position acts as a good
3
for the reactions outlined in Entries 1–10, 12, and 13 guide for the enantioselectivity. We attempted to use the L /
IV
(
Table 2), but this spot was not obvious on the TLC plate Ti catalyst for the reaction of thiophenes with aromatic
for the reaction outlined in Entry 11 (Table 2). From analy- aldehydes such as benzaldehyde, p-nitrobenzaldehyde, p-
sis of 1j and 1k above, it is not difficult to understand the methoxybenzaldehyde, and 2,4-dichlorobenzaldehyde, but
low yield and enantioselectivity for 1l with an electron-with- we did not obtain the target secondary alcohol. This is be-
drawing group (Br). It is highlighted that reactions of thio- cause the electrophilicity of the aromatic aldehyde is not as
phenes with substituents at the 2-position (Table 2, En- strong as that of ethyl glyoxylate, and the nucleophilicity of
tries 1–9) proceed better than those with substituents at the the thiophene is not as strong as that of the corresponding
Eur. J. Org. Chem. 2011, 843–847
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
845

Z. Huang, J. Zhang, Y. Zhou, N.-X. Wang
SHORT COMMUNICATION
Scheme 2. The proposed mechanism for the reaction of 2-ethylthiophene (1a) with ethyl glyoxylate (2).
indole.[5a] 3-Substituted thiophenes cannot undergo nucleo- much more accessible to a nucleophile than the former. Af-
philic reactions at the 5-position because of the lower ter attack, transition state 6 is formed, and then the Ti–
charge density at this position relative to that at the 2-posi- O bond breaks to give target secondary alcohol 3a. This
tion. From the experimental results, it can be concluded asymmetric induction pathway is consistent with the ob-
that the reactivity and enantioselectivity depend on the served S configuration of product 3a.
steric effect and charge density of the electrophile, nucleo-
phile, and catalyst.
[
10]
and Ding[5c] have described a detailed transi- Conclusions
Corey
tion-state model for this type of Friedel–Crafts reaction,
where a hydrogen bond forms in the sterically favorable
configuration in the BINOL ligand. Thus, on the basis of
previous work and our observed enantioselectivity, it is rea-
sonable for us to propose the mechanism for the asymmet-
ric Friedel–Crafts reaction of 2-ethylthiophene (1a) with
In summary, we have demonstrated titanium(IV)/BI-
NOL-catalyzed Friedel–Crafts alkylation reactions of ethyl
glyoxylate with various thiophenes to give the correspond-
ing chiral secondary alcohols. The majority of these reac-
tions proceeded with good enantioselectivities (up to
91%ee) and satisfactory isolated yields. Notably, we found
ethyl glyoxylate as shown in Scheme 2. Complex 4 is formed
3
that 2-substituted thiophenes underwent the reaction more
smoothly than unsubstituted and 3-substituted thiophenes.
after aging L with Ti(OiPr) , and it then combines with
4
ethyl glyoxylate (2) to give five-member ring transition state
5; this makes the Ti–O coordination bond less flexible. The
Ti–O bond is easily broken when the highly polarized C=O
+
Experimental Section
moiety of the formyl group with a δ charge at the carbon
–
atom is attacked by 2-ethylthiophene with a δ charge at its
General Procedure for the Friedel–Crafts Alkylation Reaction of 3a:
3
5-position. In structure 5, because the top face is strongly To a solution of ligand L (0.01 mmol, 4.4 mg) in toluene (0.5 mL)
shielded by the nearby naphthyl subunit, the bottom face is was added Ti(OiPr)
4
in toluene (70 μL, 40 mg/mL) with a microin-
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Eur. J. Org. Chem. 2011, 843–847

Enantioselective F–C Alkylation of Thiophenes with Ethyl Glyoxylate
jector, and the solution was stirred at room temperature for 2 h.
Then, ethyl glyoxylate (2; 0.4 mmol, 40 mg) was added, and the
mixture was stirred at –40 °C for 10 min; then, 2-ethylthiophene
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–40 °C for 9 h. The mixture was filtered through a short pad of
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Acknowledgments
Support for this research was provided by the National Natural
Science Foundation of China (20472090 and 10576034) and the
National 973 Program (No. 2010CB732202)
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Received: October 27, 2010
Published Online: December 29, 2010
Eur. J. Org. Chem. 2011, 843–847
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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