Double Activation Catalysis for α′-Alkylidene Cyclic Enones with Chiral Amines and Thiols

Article abstract of DOI:10.1002/chem.201702183

Cooperative catalysis has contributed greatly to the progress of asymmetric synthesis. However, double-activation catalysis has been less explored, especially for covalently tethered species. Here, we present a double-activation strategy for α′-alkylidene cyclic enone substrates that uses a chiral primary amine and 2-mercaptobenzoic acid to promote regio- and chemoselective addition to generate the complex interrupted iminium ion species. Significantly enhanced reactivity and enantioselectivity were observed for β-regioselective Michael addition and Friedel–Crafts alkylation with malononitriles and indoles, respectively, which produced a spectrum of chiral cyclic adducts with an exo-alkylidene group. Moreover, a HRMS study detected a few key covalently tethered intermediates among the substrates and catalysts, which helped elucidate the catalytic mechanism.

Full text of DOI:10.1002/chem.201702183

A Journal of
Accepted Article
Title: Double Activation Catalysis for α´-Alkylidene Cyclic Enones with
Chiral Amines and Thiols
Authors: Ying-Chun Chen, Zhou-Xiang Wang, Zhi Zhou, Wei Xiao, Qin
Ouyang, and Wei Du
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To be cited as: Chem. Eur. J. 10.1002/chem.201702183
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Double Activation Catalysis for -Alkylidene Cyclic Enones with
Chiral Amines and Thiols
Zhou-Xiang Wang,[a] Zhi Zhou,[a] Wei Xiao,[a] Qin Ouyang,[b] Wei Du,[a] and Ying-Chun Chen*[a,b]
Dedication ((optional))
Abstract: Cooperative catalysis has contributed greatly to the
progress of asymmetric synthesis. Nevertheless, the double
activation catalysis has been less explored, especially in a covalently
tethered pattern. Here we present a double activation strategy for -
alkylidene cyclic enone substrates with a chiral primary amine and 2-
mercaptobenzoic acid, through regio- and chemoselective additions
to generate the complex interrupted iminium ion species. Significantly
enhanced reactivity and enantioselectivity have been observed in the
-regioselective Michael addition and FriedelCrafts alkylation
reactions with malononitriles and indoles, respectively, producing a
spectrum of chiral cyclic adducts with an exo-alkylidene group.
Moreover, high resolution mass spectroscopy study has finely
List, while the enantiocontrol was induced by a counteranion from
a chiral phosphoric acid.[5] Importantly, in 2010, the Jacobsen
group developed an asymmetric Povarov reaction through a
network of noncovalent interactions between imines and a
Brønsted acid promoted by a chiral urea.[6] In contrast, there are
fewer double activation catalysis instances involving covalent
interactions. Shi[7] and Miller[8] independently investigated
asymmetric MoritaBaylis Hillman reaction via a double HOMO-
raising activation strategy; however, moderate enantioselectivity
was generally obtained. Therefore, the development of new
successful covalent double activation catalysis requires
thoughtful design and insightful mechanism elucidation.
detected
a few key covalently tethered intermediates among
substrates and two catalysts, which is helpful for elucidating the
catalytic mechanism.
Introduction
Cooperative catalysis is termed that two or more catalysts activate
one or two substrates concertedly, which has been widely applied
in asymmetric synthesis over the past years.[1] In general,
cooperative catalysis can be classified as synergistic catalysis,
cascade catalysis, and double activation catalysis. In the case of
synergistic catalysis, two substrates are activated by different
catalysts simultaneously through separate catalytic cycles to
furnish
a
single chemical transformation.[2] In cascade
(tandem/relay) catalysis, the first catalyst decreases the energy
barrier of substrates to produce the intermediates, which are
further accelerated by the second catalyst.[3] While the strategy of
synergistic catalysis has attracted extensive attention and been
well exploited as well as cascade catalysis, double activation
catalysis,[4] in which either the nucleophile or the electrophile is
activated by two catalysts, has been barely explored in
asymmetric catalysis. An early example of asymmetric allylation
of aldehydes through Pd and amine activation was reported by
Scheme 1. Different double activation modes of -alkylidene cyclic enones via
cooperative amine/thiol catalysis.
Recently, we disclosed that 2-mercaptobenzoic acid could
regioselectively add to an -alkylidene 2-cyclopentenone, and
the resulting intermediate I could isomerize to intermediate II.
Subsequently, a HOMO-raised dienamine species III could be
generated with a chiral amine catalyst, and underwent an ,-
regioselective [4+2] cycloaddition reaction with an activated
alkene to deliver a bridged product (Scheme 1).[9] Therefore, the
cooperative catalysis of thiols[10] and primary amines[11] led to an
unusual reaction pathway with -alkylidene 2-cyclopentenone
substrates. We speculated that the double activation of such
dienones with amine and thiol catalysts would have other
potential to expand their applications. It could be envisioned that
the iminium ion IV between a cyclic dienone and an amine might
have a relatively low reactivity toward a nucleophile because of
the polyconjugated system; in contrast, -regioselective sulphur
[a]
Z.-X. Wang, Z. Zhou, W. Xiao, Dr. W. Du, Prof. Dr. Y.-C. Chen
Department of Medicinal Chemistry
West China School of Pharmacy, Sichuan University
Chengdu, 610041 (China)
Fax: (+) 86 28 85502609
E-mail: ycchen@scu.edu.cn
[b]
Prof. Dr. Q. Ouyang, Prof. Dr. Y.-C. Chen
College of Pharmacy
Third Military Medical University
Chongqing, 400038 (China)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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addition of 2-mercaptobenzoic acid to an -alkylidene cyclic
enone might produce an interrupted iminium ion V after reaction
with a chiral amine, thus a more effective -regioselective Michael
addition would be furnished accordingly. In addition, the
stereogenically tethered sulphide moiety might increase the steric
effect, leading to further enhanced enantioselectivity in the
asymmetric addition step.
reported previously via aminocatalysis, we initially explored the
reaction of -benzylidene 2-cyclohexenone[13] 1a and
malononitrile 2a catalyzed by amine C1 and trifluoroacetic acid
A1 in toluene. Only trace amounts of product could be detected
at 50 C after 12 h (Table 1, entry 1). A moderate conversion was
observed when benzoic acid A2 was used, but the
enantioselectivity for the -regioselective adduct 3a was very poor
(Table 1, entry 2). A high ee value was obtained with a racemic
acid A3, albeit in a low yield (Table 1, entry 3). In sharp contrast,
both yield and enantiocontrol were significantly improved when 2-
mercaptobenzoic acid 4 (20 mol%) was added, indicating that the
cooperative catalysis of a thiol was crucial for the current reaction
(Table 1, entries 4 and 5). It should be noted that the -
regioselective product was not detected in the above reactions.
Moreover, the same enantioselectivity was achieved by using
amine C2 or C3 in combination with acid A3, albeit with lower
yields (Table 1, entries 6 and 7). Slightly better data were afforded
catalyzed by amine C1, thiol 4 and salicylic acid A4 (Table 1, entry
8). Further solvent screenings (Table 1, entries 911) verified that
an excellent ee value with a high yield was gained in mesitylene,
even at a gram scale (Table 1, entry 11). Similar results could be
obtained by reducing the loadings of amine C1, while a longer
time was required (Table 1, entry 12).
Results and Discussion
Table 1.Screening conditions of asymmetric Michael addition of
malononitrile 2a to 2,2-dienone 1a.[a]
Table 2. Reaction scope of malononitriles 2 and 2,2-dienones 1.[a]
Entry
1[d]
2[d]
3[d]
4
C
A
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
Yield (%)[b]
ee (%)[c]
/
C1
C1
C1
C1
C1
C2
C3
C1
C1
C1
C1
C1
A1
A2
A3
A2
A3
A3
A3
A4
A4
A4
A4
A4
trace
45
15
Entry
1
R
N
1
1
1
1
1
1
1
1
1
1
1
1
0
0
0
t (h)
18
18
18
18
18
18
18
18
18
48
48
18
48
96
96
Yield (%)[b]
3a, 85
3b, 91
3c, 83
3d, 73
3e, 84
3f, 78
ee (%)[c]
98
24
88
Ph
82
91
2
3-ClC6H4
2-BrC6H4
4-BrC6H4
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
2-Naphthyl
2-Thienyl
n-Pentyl
Phenylethyl
c-Hexyl
97
5
80
94
3
>99
98
6
74
95
4
7
40
94
5
90
8
82
95
6
98
9
80
94
7
3g, 93
3h, 70
3i, 83
99
10
11[e]
12[f]
o-xylene
mesitylene
mesitylene
80
98
8
>99
96
85 (86)
85
98 (97)
94
9
10[e]
11
12[e]
13
14
15
3j, 50
93
[a] Unless noted otherwise, reactions were performed with 2,2-dienone 1a
(0.05 mmol), malononitrile 2a (0.075 mmol), catalyst C (20 mol%), acid A
(40 mol%) and thiol 4 (20 mol%)in solvent (0.5 mL) at 50 °C for 12 h. [b]
Yield of isolated product. [c] Determined by HPLC analysis on a chiral
stationary phase. [d] In the absence of thiol 4. [e] Data in parentheses were
obtained at 5.5 mmol scale. [f] With C1 (5 mol%), acid A (10 mol%) and thiol
4 (20 mol%) for 96 h. DCE = 1,2-dichloroethane.
3k, 72
3l, 53
90
96
Ph
3m, 46
3n, 58
3o, 35
90
4-BrC6H4
4-MeOC6H4
90
As the asymmetric Michael additions of malononitrile to ,-
unsaturated ketones, including simple cyclic enones, have been
86
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16[e]
17[f]
18[f]
i-Propyl
0
1
0
48
20
48
3p, 40
3q, 88
3r, 81
81
93
81
Ph
Table 3.FriedelCrafts Reaction scope of alkylations of indoles 5 with 2,2-
dienones 1.[a]
Ph
[a] Unless noted otherwise, reactions were performed with 2,2-dienone 1
(0.1 mmol), malononitrile 2a (0.15 mmol), catalyst C1 (20 mol%), acid A4
(40 mol%) and thiol 4 (20 mol%) in mesitylene (1.0 mL) at 50 °C. [b] Yield of
isolated product. [c] Determined by HPLC analysis on a chiral stationary
phase. [d] The absolute configuration of 3a was determined by X-ray
analysis.[15] The other products were assigned by analogy. [e] With 1 (0.15
mmol) and 2a (0.1 mmol). [f] 2b was used at 35 °C .
Entry
1[d]
2
R
R1, R2
H, H
n
1
1
1
1
1
1
1
1
1
1
1
1
1
0
0
0
0
0
t (h)
96
72
48
48
48
48
72
48
24
24
72
72
48
48
48
48
48
96
Yield (%)[b]
6a, 60
6a, 94
6b, 91
6c, 91
6d, 89
6e, 68
6f, 60
ee (%)[c]
85
Consequently, we explored the generality of asymmetric
Ph
Michael additions of malononitriles
alkylidene cyclic enones under the double activation of
amine C1 and thiol in the presence of acid A4. The results
are summarized in Table 2. In general, 2,2 -dienones with a
2 to a diverse range of -
Ph
H, H
94
1
4
3
4-ClC6H4
3-BrC6H4
4-MeC6H4
2-MeOC6H4
n-Butyl
c-Hexyl
Ph
H, H
95

4
H, H
84
-aryl or a -heteroaryl group could be well tolerated, and
moderate to high yields with excellent enantioselectivity were
5
H, H
83
obtained smoothly (Table 2, entries 1–9). 2,2
a linear or a branched -alkyl group exhibited lower reactivity,
but high enantiocontrol was retained (Table 2, entries 10 12).
-dienones with
6
H, H
84

7[e]
8[e]
9[f]
10[f]
11
12
13
14
15
16
17
18
H, H
91
On the other hand, it was found that only fair to moderate
conversions were attained when a few -alkylidene
cyclopentenones were utilized probably due to the more
crowded structures, and the enantioselectivity was also
H, H
6g, 52
6h, 92
6i, 93
88
CH3, H
Ph, H
H, 6-Br
H,6-CH3
H, 5-MeO
H, H
80
slightly decreased (Table 2, entries 13

16).[14]
A
Ph
86
propargylmalononitrile 2b showed higher reactivity, and
good results were obtained (Table 2, entries 17 and 18).[12b]
Ph
6j, 55
90
The successful double activation strategy of amine and thiol for
-alkylidene cyclic enones promoted us to investigate other -
functionalization reactions. As illustrated in Table 3, the
FriedelCrafts (FC) reaction of indole 5a (R1 = R2 = H) with -
benzylidene 2-cyclohexenone 1a proceeded sluggishly under the
catalysis of amine C1 and acid A3 in toluene at 50 C, and a
moderate yield with a good ee value for product 6a was obtained
after 96 h (Table 3, entry 1).[16] As expected, the reactivity was
dramatically enhanced by adding catalytic amounts of 2-
mercaptobenzoic acid 4, giving 6a in 94% yield after 72 h with
outstanding enantioselectivity (Table 3, entry 2).[17] Subsequently,
we explored the reaction scope and limitations of the new FC
reaction. In general, moderate to high yields and enantio-
selectivity were obtained for cyclohexenones 1 with diverse -
alkylidene groups in reactions with indole 5a (Table 3, entries 28).
In addition, indoles with either a 2-methyl or a 2-phenyl group
showed high reactivity in reactions with dienone 1a, delivering
products 6h and 6i with good enantioselectivity, respectively
(Table 3, entries 9 and 10). Although lower reactivity was
observed for indoles with a substituent on the aryl ring, the
enantiocontrol was satisfactory (Table 3, entries 1113).
Moreover, we tested the reactions between indole 5a and a few
-alkylidene cyclopentenones, and moderate enantioselectivity
was generally afforded (Table 3, entries 1418).[14]
Ph
6k, 51
6l, 57
94
Ph
88
Ph
6m, 80
6n, 82
6o, 66
6p, 98
6q, 32
85
4-BrC6H4
4-MeOC6H4
3-Furyl
i-Propyl
H, H
79
H, H
77
H, H
74
H, H
73
[a] Unless noted otherwise, reactions were performed with 2,2-dienone 1
(0.1 mmol), indole 5 (0.2 mmol), catalyst C1 (20 mol%), acid A3 (40 mol%)
and thiol 4 (20 mol%) in toluene (1.0 mL) at 50 °C. [b] Yield of isolated
product. [c] Determined by HPLC analysis on a chiral stationary phase. [d]
In the absence of thiol 4. [e] With 2,2-dienone 1 (0.12mmol) and indole 5
(0.1 mmol) at 35 °C. [f] At 35 °C.
the intermediate I. Subsequently, chiral amine C1 may react
with a more stereogenically matched enone I to afford the key
iminium ion V, which can be attacked by malononitrile 2a from
Si-face. Subsequently, elimination of thiol 4 from adduct VI
occurs, delivering the imine intermediate VII, which can be
finally hydrolyzed to produce adduct 3a and amine C1.
Pleasingly, the key intermediates I, V, VI and VII have been
successfully detected by high resolution mass spectroscopy
(HRMS) study, verifying that the current reaction would
proceed in a covalent double activation catalytic pathway.[14]
We proposed a plausible catalytic cycle to gain more insight into
the catalytic mechanism. As outlined in Scheme 3, thiol 4 may
reversibly and -regioselectively add to 2,2-dienone 1a, giving
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Significantly enhanced reactivity and enantioselectivity have been
observed in the subsequent -regioselective Michael additions
with malononitriles and FriedelCrafts alkylations with indoles,
respectively, furnishing a spectrum of chiral cyclic products with
an exo-alkylidene group in moderate to excellent enantio-
selectivity. Moreover, a few key species via covalent double
activation catalysis have been successfully elucidated based on
high resolution mass spectroscopy analysis. Currently, the
development of more asymmetric reactions with multifunctional
dienone substrates via amine and thiol cooperative catalysis is
under way.
Experimental Section
General
For the synthesis of starting materials, full characterization data, NMR
spectra, and HPLC traces, see the Supporting Information.The research
data underpinning this publication can be accessed at DOI:
General procedure for asymmetric Michael additions of
malononitriles to 2,2-dienones
2,2-Dienone 1 (0.1 mmol), malononitrile 2 (0.15 mmol), catalyst C1 (20
mol%), acid A4 (40 mol%) and 2-mercaptobenzoic acid 4 (20 mol%) were
added into a vial equipped with a magnetic stir bar. Mesitylene (1.0 mL)
was added. The mixture was stirred at the indicating temperature and
monitored by TLC. After completion, the resulting crude residue was
purified by column chromatography on silica gel eluting with (EtOAc/
petroleum ether = 1/30–1/8) to afford the product 3.
Some Z-configured isomers will be generated from the previously formed
E-products 3 upon standing. 1H NMR, 13C NMR and HPLC data refer to
the products 3 with an E-configuration.
Scheme 2.HRMS study of the key intermediates in the Michael addition cycle
via double activation catalysis.
Moreover, preliminary density functional theory (DFT)
computational calculations were performed to clarify the catalytic
reactivity of double activation. As showed in Figure 1, owing to the
interruption of thiol addition, the carbon at β-site (0.024) in the
stereogenically optimized intermediate V has a more positive
natural population analysis (NPA) charge than that at β-site
(0.045) in the polyconjugated iminium ion IV, suggesting it
should be easier to be attacked by a nucleophile.[16]
(S,E)-2-(4-Benzylidene-3-oxocyclohexyl)malononitrile (3a)
Obtained as a yellow solid in 85% yield after flash chromatography and the
enantiomeric excess was determined to be 98% by HPLC analysis on
chiralpak ID column (40% 2-propanol/n-hexane, 1 mL/min), UV 254 nm,
tmajor = 11.21 min, tminor = 8.56 min; [α]D20 = +208.4 (c = 1.24 in CHCl3); 1H
NMR (400 MHz, CDCl3): δ (ppm) 7.64 (s, 1H), 7.46–7.35 (m, 5H), 3.77 (d,
J = 5.6 Hz, 1H), 3.24 (d, J = 16.4 H z, 1H), 3.00–2.90 (m, 1H), 2.81–2.73
(m, 1H), 2.73–2.66 (m, 1H), 2.64 (d, J = 8.6 Hz, 1H), 2.47 (dd, J = 16.8,
12.4 Hz, 1H), 2.30–2.21 (m, 1H); 13C NMR (150 MHz, CDCl3): δ (ppm)
196.0, 138.5, 134.7, 132.7, 130.4, 129.4, 128.6, 111.0, 110.8, 42.6, 36.7,
28.5, 26.9, 26.6; ESI-HRMS: calcd. for C16H14N2O+Na+ 273.0998, found
273.0999.
General procedure for asymmetric FriedelCrafts alkylations of
indoles with 2,2-dienones
Figure 1.The geometries and NPA charges of iminium ions IV and V.
2,2-Dienone 1 (0.1 mmol), indole 5 (0.2 mmol), catalyst C1 (20 mol%),
acid A3 (40 mol%) and 2-mercaptobenzoic acid 4 (20 mol%) were added
into a vial equipped with a magnetic stir bar. Toluene (1.0 mL) was added.
The mixture was stirred at the indicating temperature and monitored by
TLC. After completion, the resulting crude residue was purified by column
chromatography on silica gel eluting with (EtOAc/petroleum ether = 1:15)
to afford the product 6.
Conclusions
In conclusion, we have disclosed that a chiral primary amine
and 2-mercaptobenzoic acid can covalently react with -
alkylidene cyclic enones regio- and chemoselectively, leading to
the formation of the interrupted iminium ion intermediates.
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Some Z-configured isomers will be generated from the previously formed
E-products 6 upon standing. 1H NMR, 13C NMR and HPLC data refer to
the products 6 with an E-configuration.
Angew. Chem. 2017, 129, 2129; d) T. Miao, Z.-Y. Tian, Y.-M. He, F. Chen,
Y. Chen, Z.-X. Yu, Q.-H. Fan, Angew. Chem. Int. Ed. 2017, 56, 4135;
Angew. Chem. 2017, 129, 4199.
[4]
For non-asymmetric versions, see: a) M. Rubina, M. Conley, V.
Gevorgyan, J. Am. Chem. Soc. 2006, 128, 5818; b) Y. Shi, S. M.
Peterson, W. W. Haberaecker III, S. A. Blum, J. Am. Chem. Soc. 2008,
130, 2168; c) T. Ema, Y. Miyazaki, S. Koyama, Y. Yano, T. Sakai, Chem.
Commun. 2012, 48, 4489; d) H. Noda, K. Motokura, W.-J. Chun, A. Miyaji,
S. Yamaguchi, T. Baba, Catal. Sci. Technol. 2015, 5, 2714.
S. Mukherjeem, B. List, J. Am. Chem. Soc. 2007, 129, 11336.
a) H. Xu, S. J. Zuend, M. G. Woll, Y. Tao, E. N. Jacobsen, Science 2010,
327, 986; b) for a similar strategy, see: Y. Wang, T.-Y. Yu, H.-B. Zhang,
Y.-C. Luo, P.-F. Xu, Angew. Chem. Int. Ed. 2012, 51, 12339; Angew.
Chem. 2012, 124, 12505.
(S,E)-2-Benzylidene- 5-(1H-indol-3-yl)cyclohexan-1-one (6a)
Obtained as a yellow solid in 94% yield after flash chromatography and the
enantiomeric excess was determined to be 94% by HPLC analysis on
Chiralcel OD-H column (40% 2-propanol/n-hexane, 1 mL/min), UV 254 nm,
tmajor = 6.89 min, tminor = 12.33 min; [α]D20 = +123.4 (c = 0.46 in CHCl3);1H
NMR (400 MHz, CDCl3): δ (ppm) 8.05 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H),
7.58 (s, 1H), 7.47–7.29 (m, 6H), 7.23 (t, J = 7.2 Hz, 1H), 7.14 (t, J = 7.2
Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 3.64–3.57 (m, 1H), 3.06 (dd, J = 17.4,
3.6 Hz, 1H), 2.97 (dt, J = 14.8, 4.8 Hz, 1H), 2.892.85 (m, 1H), 2.79 (dd, J
= 14.8, 7.2 Hz, 1H), 2.38–2.25 (m, 1H), 2.07–1.98 (m, 1H); 13C NMR (100
MHz, CDCl3): δ (ppm) 201.7, 136.6, 136.0, 135.9, 135.6, 130.5, 128.7,
128.4, 126.3, 122.3, 120.4, 119.5, 119.4, 119.1, 111.4, 46.6, 32.3, 30.3,
27.5; ESI-HRMS: calcd. for C21H19NO+Na+ 324.1359, found 324.1363.
[5]
[6]
[7]
[8]
a) M. Shi, J.-K. Jiang, C.-Q. Li, Tetrahedron Lett. 2002, 43,127; b) for a
bifunctional stategy, see: L. Zhang, S. Luo, L. Chen, J. Li, J. Cheng, Sci.
China Ser. B-Chem. 2009, 52, 1300.
a) J. E. Imbriglio, M. M. Vasbinder, S. J. Miller, Org. Lett. 2003, 5, 3741;
b) C. E. Aroyan, M. M. Vashinder, S. J. Miller, Org. Lett. 2005, 7, 3849;
c) M.M. Vashinder, J. E. Imbriglio, S.J. Miller. Tetrahedron 2006, 62,
1145.
[9]
Z. Zhou, Z.-X. Wang, Y.-C. Zhou, W. Xiao, Q. Ouyang, W. Du, Y.-C.
Chen, Nat. Chem. 2017, DOI: 10.1038/NCHEM.2698.
Acknowledgements
[10] P. S. Selig, S. J. Miller, Tetrahedron Lett. 2011, 52, 2148.
[11] P. Melchiorre, Angew. Chem. Int. Ed. 2012, 51, 9748; Angew. Chem.
2012, 124, 9886.
We are grateful for the financial support from the NSFC
(21372160 and 21125206).
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Keywords: double activation catalysis • aminocatalysis • thiol
catalysis • Michael addition • FriedelCrafts alkylation
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Crystallographic
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10.1002/chem.201702183
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Zhou-Xiang Wang, Zhi Zhou, Wei Xiao,
Qin Ouyang, Wei Du, and Ying-Chun
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Double Activation Catalysis for -
Alkylidene Cyclic Enones with Chiral
Amines and Thiols
Double activation: Complex iminium ion species are generated among -alkylidene
cyclic enones,
a chiral primary amine and 2-mercaptobenzoic acid regio- and
chemoselectively, leading to significantly enhanced reactivity and enantioselectivity in the
subsequent -regioselective Michael additions with malononitriles and FriedelCrafts
alkylations with indoles.
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