Cu(I)-Catalyzed Enantioselective Friedel-Crafts Alkylation of Indoles with 2-Aryl-N-sulfonylaziridines as Alkylating Agents

Article abstract of DOI:10.1021/acs.orglett.6b01317

A highly enantioselective Friedel-Crafts alkylation of indoles with N-sulfonylaziridines as alkylating agents has been developed by utilizing the complex of Cu(CH₃CN)₄BF₄/(S)-Segphos as a catalyst. A range of optically act

Full text of DOI:10.1021/acs.orglett.6b01317

Letter
pubs.acs.org/OrgLett
Cu(I)-Catalyzed Enantioselective Friedel−Crafts Alkylation of Indoles
with 2‑Aryl‑N‑sulfonylaziridines as Alkylating Agents
Chen Ge, Ren-Rong Liu, Jian-Rong Gao, and Yi-Xia Jia*
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China
*
S Supporting Information
ABSTRACT: A highly enantioselective Friedel−Crafts alky-
lation of indoles with N-sulfonylaziridines as alkylating agents
has been developed by utilizing the complex of Cu-
(
CH CN) BF /(S)-Segphos as a catalyst. A range of optically
3 4 4
active tryptamine derivatives are obtained in good to excellent
yields and enantioselectivities (up to >99% ee) via a kinetic
resolution process.
n the past two decades, significant progress has been achieved
for catalytic asymmetric Friedel−Crafts alkylation reactions,
used as substrates, [3 + 2] cycloaddition reactions with aziridines
12
I
occurred with excellent enantioselectivities. To the best of our
knowledge, the catalytic asymmetric Friedel−Crafts reaction
with rac-aziridines as alkylating agents has not been reported
until now. As a continuous effort in developing catalytic
and numerous efficient approaches have been established toward
1
the synthesis of optically active aromatic compounds. A range of
alkylating agents have been studied in this transformation, most
2
13
of which are C(sp )-based alkylating agents that contain polar
asymmetric Friedel−Crafts reactions, we report here an
double bonds, such as olefins, aldehydes, ketones, and imines.
The asymmetric 1,2- or 1,4-addition of aromatic systems to the
aforementioned alkylating agents is readily catalyzed by chiral
Lewis acids or organic molecules through a LUMO activation
strategy. In contrast, catalytic asymmetric Friedel−Crafts
enantioselective indole alkylation with racemic N-sulfonylazir-
idines via a nucleophilic substitution pathway using a Cu(I)/(S)-
Segphos complex as a catalyst (Scheme 1). A series of optically
Scheme 1. Enantioselective Friedel−Crafts Alkylation of
Indole with Racemic N-Sulfonylaziridines
3
reactions based on nucleophilic substitution of C(sp )-based
alkylating agents have remained rarely explored. Recently,
2
3
phenolyl methanols, ortho-aminobenzyl alcohol, and indolyl
4
3
methanols or methylamines were employed as C(sp )-based
alkylating agents in the enantioselective indole alkylations,
whereas quinone methides and the extended iminium ions are
mechanistically proposed as intermediates to which the
subsequent addition of indoles is stereoselectively controlled
by chiral Brønsted acid catalysts. So far, only a few examples of
catalytic asymmetric Friedel−Crafts alkylations via nucleophilic
active tryptamine derivatives are afforded in good to excellent
enantioselectivities, and a kinetic resolution of racemic N-
sulfonylaziridines is observed in this reaction.
3
substitution of C(sp ) carbon atoms were documented, which
5
At the outset, 2-phenyl-N-tosylaziridine 4a and 1-methyl-
indole 1 were chosen as the model substrates for condition
optimization. As shown in Table 1, an initial test using 2.2 equiv
of 4a led to the desired product 5 in 57% yield and 55% ee under
the catalysis of the Cu(CH CN) BF /(S)-BINAP complex in
included enantioselective desymmetrization of meso-epoxides
6
and dynamic kinetic resolution of cyclopropanes and α-tosyloxy
7
3
ketones. Therefore, further exploration of suitable C(sp )-based
alkylating agents for catalytic asymmetric Friedel−Crafts
alkylation is in high demand and of great importance.
3
4
4
DCM at 50 °C for 40 h (entry 1). Other chiral diphosphine
ligands were subsequently tested to improve the ee value. It was
found that both (S)-Biphep and (S)-Synphos delivered product 5
in relatively lower enantioselectivities; however, ligand (S)-
Segphos led to a higher ee value (Table 1, entries 2−4). Solvent
effect was then investigated. The enantioselectivity was
remarkably improved to 89% when the reaction was performed
in toluene, albeit with a moderate yield (entry 5). Comparable
results were obtained in THF, whereas poor enantioselectivity
As a versatile building block for the synthesis of nitrogen-
containing biologically active molecules, aziridine has been
employed in a variety of enantioselective nucleophilic ring-
8
opening reactions. Among these, indole has been proven to be a
popular nucleophile in the Friedel−Crafts-type ring-opening
reactions of aziridine, while most of the reported examples are in
their racemic variants or transformations based on chiral
9
,10
aziridines.
The only example of catalytic asymmetric
Friedel−Crafts-type ring opening of aziridines employing
indoles as nucleophiles in a magnesium-catalyzed desymmetriza-
tion of meso-aziridines was reported very recently by Wang and
Received: May 5, 2016
1
1
co-workers. Interestingly, when 3-substituted indoles were
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01317
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Table 2. Scope of Aziridine 4
b
c
entry
1
4 (Ar)
4a (Ph)
4b (4-Br-C H )
yield (%)
ee (%)
7a
7b
7c
7d
7e
7f
73
94(R)
95
d
2
65
6
4
3
4
5
6
7
4c (4-Cl-C H )
73
95
6
4
4d (4-F-C H )
88
91
6
4
t
4e (4- Bu-C H )
75
90
6
4
b
4f (4-AcO-C H )
75 (8:1)
72
88
entry
L*
solvent
t (°C)
time (h)
yield (%)
ee (%)
6
4
4g (3-Me-C H )
7g
7h
7i
92
6
4
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L3
L3
L3
L3
L3
L3
L3
DCM
DCM
DCM
DCM
toluene
THF
50
50
50
50
50
50
50
rt
40
40
40
40
40
40
40
60
72
72
72
57
58
58
50
57
55
57
58
73
47
65
55
49
64
42
89
71
20
93
94
98
87
e
8
4h (3-MeO-C H )
65
86
6
4
e
9
4i (3-Cl-C H )
88
93
6
4
e
1
0
4j (2-Me-C H )
7j
77 (5:1)
87
6
4
1
1
4k (2-naphthyl)
7k
74 (13:1)
80
a
Reaction conditions: 3a (0.2 mmol), 4 (0.44 mmol), Cu-
CH CN) BF (10 mol %), and (S)-Segphos (12 mol %) in toluene
(
(
3
4
4
DCE
b
c
4.0 mL) at rt for 72 h. Ratio of 7/7′ in parentheses. Determined by
toluene
toluene
toluene
toluene
d
e
chiral HPLC. 80 h. At 50 °C.
c
9
rt
d
1
1
0
1
rt
and only compound 7 was isolated; however, in the cases of 4f, 4j,
and 4k, regioisomers 7′ were detected and the ratios of 7/7′ were
,
ce
rt
a
Reaction conditions: indole (1, 0.2 mmol), N-tosylaziridine (4a, 0.44
mmol), Cu(CH CN) BF (10 mol %), and L* (12 mol %) in 4.0 mL
solvent; rt = room temperature. Determined by chiral HPLC. N-
Allylindole 3a (0.2 mmol) was used. N-Benzylindole 2 (0.2 mmol)
was used. Using 10 mol % of Cu(CH CN) PF .
1
determined by their H NMR spectra.
3
4
6
Other N-protecting groups of aziridine were examined and
had a significant effect on the reactivity. Reaction of N-(4-
nitrophenyl)sulfonylaziridine (4l) with N-allylindole at room
temperature afforded product 7l in 78% yield and 85% ee (eq 1),
b
c
d
e
3
4
6
was detected in DCE (entries 6 and 7). As expected, the ee value
was further improved to 93% by decreasing the temperature from
5
0 °C to room temperature, whereas product yield still remained
moderate (entry 8). To enhance the reactivity, the N-protecting
group of indole was then modified. Product 7a was isolated in a
higher yield and an excellent enantioselectivity for the reaction of
N-allylindole 3a with aziridine 4a (entry 9). Despite excellent
enantioselectivity being detected, the yield of 6 was much lower
for the reaction of N-benzylindole 2 (entry 10). In addition,
relatively lower yield and enantioselectivity were observed for the
reaction of N-allylindole 3a with 4a using Cu(CH CN) PF as a
3
4
6
catalyst instead of Cu(CH CN) BF (entry 9 vs 11). To this end,
3
4
4
the optimal conditions were established as follows: Cu-
CH CN) BF (10 mol %) and (S)-Segphos (12 mol %) in
(
3
4
4
toluene at room temperature.
With the optimal conditions in hand, we then examined the
substrate scope of this reaction. As shown in Table 2, a range of
racemic 2-aryl-N-tosylaziridines 4 reacted smoothly with N-
allylindole 3a to afford the desired products in moderate to good
yields and good to excellent enantioselectivities. A series of
functionalities on the benzene ring of N-tosylaziridines 4 were
well-tolerated, whereas the enantioselectivities were influenced
unfavorably by the electron-donating substituents. The ee values
for products 7e−7h containing electron-donating groups were
slightly lower than those of products 7b−7d and 7i that bear
electron-withdrawing substituents (entries 5−8 vs 2−4 and 9). A
lower but good enantioselectivity was also observed for the
reaction of 2-naphthyl-substituted N-tosylaziridine 4k (entry
while lower reactivity and poor enantioselectivity were observed
for N-mesitylsulfonylaziridine (4m). Moreover, no reaction
occurred for N-Boc-aziridine (4n). To further extend the scope
of N-tosylaziridine, 2,2-disubstituted substrate 4n was synthe-
sized and tested in the reaction with N-allylindole. Desired
product 7n bearing a quaternary stereogenic center was obtained
in 48% yield but with poor enantioselectivity (eq 2). However, to
our disappointment, allylic or alkyl N-tosylaziridines (4o, 4p)
and meso-N-tosylaziridines (4q, 4r) were inactive, indicating the
limitation of the present reaction.
We next investigated the substituent effect of N-allylindole,
and the results are summarized in Scheme 2. Reactions of
aziridine 4a with N-allylindoles bearing alkyl, alkoxyl, and
halogen groups at the C5 position proceeded smoothly to afford
the corresponding products 7o−7s in good yields and good to
excellent enantioselectivities. However, lower reactivities were
observed for N-allylindoles containing halogen substituents due
11). Moreover, the reaction of aziridine 4j bearing an ortho-
methylphenyl group led to product 7j in 87% ee, indicating that
enantioselectivity was affected by steric hindrance. Note that in
most of the reactions excellent regioselectivities were observed
B
DOI: 10.1021/acs.orglett.6b01317
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Substituent Effect of N-Allylinodole
In conclusion, we have demonstrated an efficient Cu(I)/(S)-
Segphos-catalyzed enantioselective Friedel−Crafts-type ring-
opening reaction of 2-aryl-N-sulfonylaziridines with indoles in
good yields and good to excellent enantioselectivities, which
provides a reliable approach toward chiral tryptamine derivatives.
It complements the catalytic asymmetric Friedel−Crafts
alkylation reaction based on nucleophilic substitution of
3
C(sp )-based alkylating agents. An efficient kinetic resolution
of racemic N-sulfonylaziridines is observed along with the
asymmetric Friedel−Crafts alkylation reaction.
ASSOCIATED CONTENT
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01317.
a
Reaction conditions: 3 (0.2 mmol), 4a (0.44 mmol), Cu-
CH CN) BF (10 mol %), and (S)-Segphos (12 mol %) in toluene
(
(
3
4
4
Experimental procedure, characterization data, and NMR
spectra for the obtained compounds (PDF)
4.0 mL) for 72 h.
to their lower nucleophilicity, and in these cases, the reactions
needed to be performed at a higher temperature. Therefore, by
improving the temperature to 50 °C, products 7q, 7r, and 7t were
isolated in good yields but with relatively lower ee values (still at a
high level). In addition, the methyl group at the C4 position of N-
allylindole was compatible, and desired product 7u was isolated
in moderate yield and excellent enantioselectivity, which might
indicate that the substituted group of indole had no steric effect
on the reaction.
AUTHOR INFORMATION
■
*
Corresponding Author
E-mail: yxjia@zjut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
As shown in eq 3, a kinetic resolution of N-sulfonylaziridine 4b
was verified. The remaining starting material 4b was isolated in
We are grateful for the financial support from the National
Natural Science Foundation of China (21372202, 21502169, and
2
1522207), the Program for New Century Excellent Talents in
University (NCET-12-1086), and the Natural Science Founda-
tion of Zhejiang Province (LR14B020001 and LQ15B020003).
REFERENCES
■
76% yield and 86% ee in the reaction with 0.4 mmol 4b with 0.2
(1) (a) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int.
Ed. 2004, 43, 550. (b) Poulsen, T. B.; Jørgensen, K. A. Chem. Rev. 2008,
mmol N-allylindole 3a at 50 °C, together with the isolation of 7b
in 94% yield and 92% ee. Synthetic transformations of product 7a
were then conducted. As shown in Scheme 3, the allyl group of
1
2
3
1
08, 2903. (c) You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 38,
190. (d) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010,
9, 4449. (e) Lancianesi, S.; Palmieri, A.; Petrini, M. Chem. Rev. 2014,
14, 7108.
Scheme 3. Product Transformations
(
2) (a) Wilcke, D.; Herdtweck, E.; Bach, T. Synlett 2011, 2011, 1235.
(b) Zhao, W.; Wang, Z.; Chu, B.; Sun, J. Angew. Chem., Int. Ed. 2015, 54,
1
910. (c) Wang, Z.; Wong, Y. F.; Sun, J. Angew. Chem., Int. Ed. 2015, 54,
1
3711.
(
3) Liao, H.-H.; Chatupheeraphat, A.; Hsiao, C.-C.; Atodiresei, I.;
Rueping, M. Angew. Chem., Int. Ed. 2015, 54, 15540.
4) (a) Sun, F.-L.; Zeng, M.; Gu, Q.; You, S.-L. Chem. - Eur. J. 2009, 15,
709. (b) Sun, F.-L.; Zheng, X.-J.; Gu, Q.; He, Q.-L.; You, S.-L. Eur. J.
(
8
Org. Chem. 2010, 2010, 47. (c) Zhuo, M.-H.; Jiang, Y.-J.; Fan, Y.-S.; Gao,
Y.; Liu, S.; Zhang, S. Org. Lett. 2014, 16, 1096. (d) Qi, S.; Liu, C.-Y.;
Ding, J.-Y.; Han, F.-S. Chem. Commun. 2014, 50, 8605. (e) Gong, Y.-X.;
Wu, Q.; Zhang, H.-H.; Zhu, Q.-N.; Shi, F. Org. Biomol. Chem. 2015, 13,
7
993.
indole 7a (>99% ee after recrystallization) was readily removed
in the presence of 5 mol % of RhCl ·3H O in refluxing EtOH for
(5) (a) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Umani-Ronchi, A.
Angew. Chem., Int. Ed. 2004, 43, 84. (b) Boudou, M.; Ogawa, C.;
Kobayashi, S. Adv. Synth. Catal. 2006, 348, 2585. (c) Kokubo, M.; Naito,
T.; Kobayashi, S. Tetrahedron 2010, 66, 1111. (d) Plancq, B.; Lafantaisie,
M.; Companys, S.; Maroun, C.; Ollevier, T. Org. Biomol. Chem. 2013, 11,
3
2
14
1
4 h, which afforded tryptamine derivative 8 in 63% yield.
Deprotection of N-sulfonylamide using Na/naphthalide led to a
free amine 9 in an excellent yield of 97%, which was subsequently
converted to acetylamide 10 in 85% yield. Note that all of these
transformations had no erosion in enantiopurities. Moreover, the
absolute configuration of 7a was determined to be R by the
comparison of its optical rotation value with that reported in ref
7
(
2
463.
6) (a) Wales, S. M.; Walker, M. M.; Johnson, J. S. Org. Lett. 2013, 15,
558. (b) Liu, Q.-J.; Yan, W.-G.; Wang, L.; Zhang, X. P.; Tang, Y. Org.
Lett. 2015, 17, 4014.
(7) Liu, C.; Oblak, E. Z.; Vander Wal, M. N.; Dilger, A. K.; Almstead, D.
15.
K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2016, 138, 2134.
C
DOI: 10.1021/acs.orglett.6b01317
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
8) (a) Pineschi, M. Eur. J. Org. Chem. 2006, 2006, 4979. (b) Wang, P.
A. Beilstein J. Org. Chem. 2013, 9, 1677. (c) Schneider, C. Angew. Chem.,
Int. Ed. 2009, 48, 2082.
(
9) (a) Yadav, J. S.; Reddy, B. V. S.; Abraham, S.; Sabitha, G.
Tetrahedron Lett. 2002, 43, 1565. (b) Rinner, U.; Hudlicky, T.; Gordon,
H.; Pettit, G. R. Angew. Chem., Int. Ed. 2004, 43, 5342. (c) Hudlicky, T.;
Rinner, U.; Finn, K. J.; Ghiviriga, I. J. Org. Chem. 2005, 70, 3490.
(
d) Kaiser, H. M.; Lo, W. F.; Riahi, A. M.; Spannenberg, A.; Beller, M.;
Tse, M. K. Org. Lett. 2006, 8, 5761. (e) Li, Y.; Hayman, E.; Plesescu, M.;
Prakash, S. R. Tetrahedron Lett. 2008, 49, 1480. (f) Cockrell, J.;
Wilhelmsen, C.; Rubin, H.; Martin, A.; Morgan, J. B. Angew. Chem., Int.
Ed. 2012, 51, 9842. (g) Wang, S.; Chai, Z.; Zhou, S.; Wang, S.; Zhu, X.;
Wei, Y. Org. Lett. 2013, 15, 2628. (h) Ghorai, M. K.; Tiwari, D. P.; Jain,
N. J. Org. Chem. 2013, 78, 7121. (i) Tirotta, I.; Fifer, N. L.; Eakins, J.;
Hutton, C. A. Tetrahedron Lett. 2013, 54, 618.
(
10) For a palladium-catalyzed enantioselective N-allylation of indole
with vinyl aziridines through a ring-opening allylic substitution reaction,
see: Trost, B. M.; Osipov, M.; Dong, G. J. Am. Chem. Soc. 2010, 132,
1
(
5800.
11) Yang, D.; Wang, L.; Han, F.; Li, D.; Zhao, D.; Cao, Y.; Ma, Y.;
Kong, W.; Sun, Q.; Wang, R. Chem. - Eur. J. 2014, 20, 16478.
12) (a) Wang, L.; Yang, D.; Han, F.; Li, D.; Zhao, D.; Wang, R. Org.
(
Lett. 2015, 17, 176. (b) Chai, Z.; Zhu, Y.-M.; Yang, P.-J.; Wang, S.;
Wang, S.; Liu, Z.; Yang, G. J. Am. Chem. Soc. 2015, 137, 10088.
(
13) (a) Gao, J.-R.; Wu, H.; Xiang, B.; Yu, W.-B.; Han, L.; Jia, Y.-X. J.
Am. Chem. Soc. 2013, 135, 2983. (b) Weng, J.-Q.; Deng, Q.-M.; Wu, L.;
Xu, K.; Wu, H.; Liu, R.-R.; Gao, J.-R.; Jia, Y.-X. Org. Lett. 2014, 16, 776.
(
c) Wu, L.; Liu, R.-R.; Zhang, G.-Q.; Wang, D.-J.; Wu, H.; Gao, J.-R.; Jia,
Y.-X. Adv. Synth. Catal. 2015, 357, 709. (d) Liu, R.-R.; Ye, S.-C.; Lu, C.-
J.; Zhuang, G.-L.; Gao, J.-R.; Jia, Y.-X. Angew. Chem., Int. Ed. 2015, 54,
1
1205. (e) Wu, H.; Liu, R.-R.; Shen, C.; Zhang, M.-D.; Gao, J.-R.; Jia, Y.-
X. Org. Chem. Front. 2015, 2, 124.
14) Ojima, I.; Kato, K.; Nakahashi, K.; Fuchikami, T.; Fujita, M. J. Org.
Chem. 1989, 54, 4511.
15) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem.,
Int. Ed. 2005, 44, 6576.
(
(
D
DOI: 10.1021/acs.orglett.6b01317
Org. Lett. XXXX, XXX, XXX−XXX