Catalytic Asymmetric N-Alkylation of Indoles and Carbazoles through 1,6-Conjugate Addition of Aza-para-quinone Methides

Article abstract of DOI:10.1002/anie.201701947

Catalytic asymmetric N-alkylation of indoles and carbazoles represents a family of important but underdeveloped reactions. Herein, we describe a new organocatalytic strategy in which in situ generated aza-para-quinone methides are employed as the alkylating reagent. With the proper choice of a chiral phosphoric acid and an N-protective group, the intermolecular C?N bond formation with various indole and carbazole nucleophiles proceeded efficiently under mild conditions with excellent enantioselectivity and functional-group compatibility. Control experiments and kinetic studies provided important insight into the reaction mechanism.

Full text of DOI:10.1002/anie.201701947

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Communications
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International Edition: DOI: 10.1002/anie.201701947
German Edition: DOI: 10.1002/ange.201701947
Organocatalysis
Catalytic Asymmetric N-Alkylation of Indoles and Carbazoles through
1,6-Conjugate Addition of Aza-para-quinone Methides
Min Chen and Jianwei Sun*
Abstract: Catalytic asymmetric N-alkylation of indoles and
carbazoles represents a family of important but underdevel-
oped reactions. Herein, we describe a new organocatalytic
strategy in which in situ generated aza-para-quinone methides
are employed as the alkylating reagent. With the proper choice
of a chiral phosphoric acid and an N-protective group, the
Scheme 1. Development of an asymmetric N-alkylation of indoles and
carbazoles with para-aza-quinone methides (P=protective group).
À
intermolecular C N bond formation with various indole and
carbazole nucleophiles proceeded efficiently under mild con-
ditions with excellent enantioselectivity and functional-group
compatibility. Control experiments and kinetic studies pro-
vided important insight into the reaction mechanism.
A
symmetric N-alkylation of indoles and carbazoles repre-
sents a family of important reactions in organic synthesis
owning to the prevalence of these subunits in natural products
and biologically active molecules.[1–4] However, these reac-
tions, particularly intermolecular ones, have remained under-
developed, presumably owing to difficult regiocontrol as
a result of the low nucleophilicity of the N-H motif. Indeed,
direct asymmetric indole N-alkylation has been mainly
limited to substrates with certain substituents.[2] To overcome
these limitations, some indirect strategies have also been
devised.[3] Nevertheless, most of these reactions are limited to
allylation. Furthermore, asymmetric N-alkylation of carba-
zoles has been much less studied,[4] which is in sharp contrast
to the wide utility of carbazoles in medicinal chemistry and
materials science.[1f] In this context, we report herein a highly
efficient strategy for the asymmetric intermolecular N-
alkylation of indoles and carbazoles by means of a 1,6-
addition of aza-p-quinone methides (aza-p-QMs).
Scheme 2. Preliminary results.
based on BINOL and SPINOL backbones were evaluated as
potential catalysts to catalyze not only the dehydration for
in situ generation of the aza-p-QM intermediate, but also the
subsequent asymmetric alkylation.[9] After considerable opti-
mization efforts (see the Supporting Information for details),
we were delighted to find that the reaction proceeded to form
the desired N-alkylation product, albeit with moderate
efficiency and enantioselectivity (Scheme 2). Of particular
note is the absolute regioselectivity. The indole unit reacted at
the 1-position exclusively, thus representing a new example of
asymmetric N-alkylation of indoles. Among all the catalysts
evaluated, catalyst A exhibited the best catalytic performance
with regard to efficiency and enantioselectivity.[10] However,
further tuning of the parameters did not improve the results.
With the aim of further improving the reaction efficiency
and enantioselectivity, we envisioned the possibility of
changing the N-protective group of the alkylating reagent.
As shown in Scheme 3, bulky aliphatic acyl groups, such as
pivaloyl and 1-adamantanecarbonyl groups, proved superior,
with the latter giving excellent enantioselectivity (95% ee).
Other typical N-protective groups, such as Bz, Boc, and Ts,
gave moderate enantioselectivity (see the Supporting Infor-
mation for details). It is worth noting that protection with
a methyl group also resulted in good reactivity, but not
excellent enantioselectivity.
Aza-QMs are useful species in organic synthesis, biolog-
ical processes, materials science, and drug development.[5]
Having noticed their high reactivity toward nucleophiles, we
envisioned that these species may serve as versatile alkylating
reagents for the difficult asymmetric N-alkylation of indoles
and carbazoles, provided that asymmetric induction by
a suitable chiral catalyst could be achieved (Scheme 1).[6–8]
We started our exploration of the reaction with 2,3-
dimethylindole, hoping to intrinsically favor N-alkylation
over the more common C-alkylation (Scheme 2). An N-acetyl
para-aminobenzylic alcohol was employed as the model
precursor to aza-p-QM. Different chiral phosphoric acids
[*] Dr. M. Chen, Prof. J. Sun
Department of Chemistry
The Hong Kong University of Science and Technology
Clear Water Bay, Kowloon, Hong Kong SAR (China)
E-mail: sunjw@ust.hk
With the optimized conditions in hand, next we examined
the reaction scope. A wide range of substituted indoles
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201701947.
À
participated smoothly in the intermolecular C N bond
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The product absolution configuration was confirmed by X-ray
crystallography (3u). Notably, many of these products were
obtained in essentially enantiopure form. It is also worth
noting that the p-aminobenzylamine motif is a widely
observed subunit in many biologically important molecules.[11]
While 3-substituted indoles use the 1-position as the
nucleophilic site for the reaction, we were interested in
knowing how 3-unsubstituted indoles react. Indeed, with the
above standard conditions, the reaction with 2-phenylindole
gives exclusive reaction at the 3-position, but with diminished
enantioselectivity (75% ee). Nevertheless, we further opti-
mized the reaction and found that the use of dichloromethane
as the solvent and 3 ꢀ molecular sieves as additive led to
improved enantioselectivity (Table 1). A brief survey of some
analogous nucleophiles indicated that aryl, alkenyl, and alkyl
substitution at the 2-position of the indole nucleophile does
not significantly influence on the efficiency and enantiose-
lectivity.[12] Steric hindrance in close proximity to the reactive
site is also well tolerated.
Scheme 3. Evaluation of different protective groups.
formation reaction, providing the corresponding indole-
derived chiral anilines with excellent efficiency and enantio-
selectivity (Scheme 4). More importantly, a range of variously
substituted carbazoles are also suitable nucleophiles (2o–2y).
The scope with respect to the aza-p-QM precursors is equally
broad (Scheme 5). Heterocycles like thiophene can also be
incorporated into the product. Substitution with an aliphatic
group at the benzylic position also provided good enantiose-
lectivity. The mild conditions mean that a diverse set of
functional groups is tolerated, including aryl halides, esters,
nitriles, ethers, olefins, alkynes, and silyl-protected alcohols.
Table 1: Scope with respect to 3-unsubstituted indoles.[a]
Entry
R
5
Yield [%][b]
ee [%][b]
1
2
3
4
5
Ph
5a
5b
5c
5d
5e
99
99
98
95
96
84
82
88
89
94
1-cyclohexenyl
Bn
iPr
tBu
[a] 1a (0.2 mmol), 4 (0.23 mmol), 3 ꢀ MS (10 mg), CH2Cl2 (8.0 mL).
[b] Yield of isolated product.
To further demonstrate the utility of the process, we
carried out representative derivatizations of the product 3d.
Reduction of the amide smoothly gave chiral aniline 6
(Scheme 6). The N-acyl protective group can be efficiently
removed in the presence of SmI2 and Et3N to form the free
amine 7 (Scheme 6). Notably, the optical purity remained
unchanged after these transformations.
To probe the reaction mechanism, particularly whether
the key aza-p-QM intermediate is involved, we carried out
some control experiments. We synthesized the N-methylated
substrate 1a’, which is not capable of generating the aza-p-
QM intermediate. In fact, 1a’ did not react under the standard
conditions, which is consistent with the intermediacy of aza-p-
QM (Scheme 7). Furthermore, when substrate 1a was sub-
jected to the standard conditions in the absence of a nucleo-
phile, we were able to isolate a dimeric product 9, which was
presumably formed through alcohol addition to the aza-p-
QM intermediate (Scheme 8). Further addition of a nucleo-
phile to the reaction mixture still led to the desired product
formation with comparably high enantioselectivity, albeit
with slow conversion compared with the standard method.
This observation indicates that the formation of 9 is reversible
and the reverse conversion of 9 into the aza-p-QM is slow.
Scheme 4. Scope with respect to indoles and carbazoles.[a] [a] 1a
(0.2 mmol), 2 (0.28 mmol), 5 ꢀ MS (50 mg), toluene (8.0 mL). The
reactions for 2o–2y were run with 2 (0.4 mmol) and (R)-B1 without
MS at 08C, which led to products with opposite configuration. Yields
of isolated product are shown. [b] Run in the dark. [c] Run with
0.6 mmol of 2 for 72 h. [d] Run at 08C.
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Scheme 5. Scope with respect to aza-p-QMs.[a] [a] 1a (0.2 mmol), 2 (0.28 mmol), 5 ꢀ MS (50 mg), toluene (8.0 mL). Yield of isolated product is
provided. The reactions for 4p–4t were run with 2 (0.4 mmol) and (R)-A without MS at 08C, which led to products with opposite configuration.
Yield of isolated product is provided. [b] Run at 08C. [c] Run with 2 equivalents of nucleophile and 15 mol% of (S)-A for 72 h. [d] Run with
0.6 mmol of 2,3-dimethylindole. [e] The remained substrate accounts for the mass balance.
Scheme 6. Representative derivatizations of the product 3d.
Scheme 8. Mechanistic evaluation of the involvement of aza-p-QM.
Scheme 7. Mechanistic evaluation using N-methylated substrate 1a’.
To gain further insight into the mode of catalyst activa-
tion, we found that the enantiopurity of the product shows
a linear relationship with that of the catalyst (Figure 1). This
result may suggest that only one catalyst molecule is involved
in the enantiodetermining transition state. We thus propose
a transition state in which the catalyst plays a bifunctional role
to activate both the aza-p-QM and the nucleophile. In this
way, remote stereocontrol is expected. Indeed, this remote
control is highly effective in view of the observed excellent
enantiocontrol.[13]
In summary, we have developed a new strategy for the
efficient asymmetric N-alkylation of indoles and carbazoles,
an important but underdeveloped reaction. This process
employs highly reactive in situ generated aza-para-quinone
Figure 1. Absence of nonlinear effects and the proposed transition
state.
methides as the alkylating reagent. With the proper choice of
a chiral phosphoric acid and N-protective group, the inter-
À
molecular C N bond formation with various indole and
carbazole nucleophiles proceeded with excellent efficiency
and enantioselectivity. The mild reaction conditions mean
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zewicz, S. L. Zultanski, J. C. Peters, G. C. Fu, Science 2016, 351,
681 – 684.
that the reaction tolerates a wide range of functional groups.
The use of alcohol precursors for in situ generation of the
unstable aza-para-quinone methide intermediates makes this
process particularly easy to handle. Control experiments
provided important insight into the reaction mechanism,
suggesting that the chiral acid catalyst serves not only as
a promoter for the in situ formation of the key aza-para-
quinone methide intermediate, but also as a bifunctional
catalyst in the subsequent enantiodetermining step.
[5] Reviews and highlights of QMs and aza-QMs: a) A. B. Turner,
Q. Rev. Chem. Soc. 1964, 18, 347 – 360; b) H.-U. Wagner, R.
Gompper in The Chemistry of the Quinonoid Compounds, Vol. 2
(Ed.: S. Patai), Wiley, New York, 1974, chap. 18, pp. 1145 – 1178;
c) M. G. Peter, Angew. Chem. Int. Ed. Engl. 1989, 28, 555 – 570;
Angew. Chem. 1989, 101, 572 – 587; d) K. Wojciechowski, Eur. J.
Org. Chem. 2001, 3587 – 3605; e) T. Itoh, Prog. Polym. Sci. 2001,
26, 1019 – 1059; f) Quinone Methides (Ed.: S. E. Rokita), Wiley,
Hoboken, NJ, 2009; g) M. M. Toteva, J. P. Richard, Adv. Phys.
Org. Chem. 2011, 45, 39 – 91; h) A. Parra, M. Tortosa, Chem-
CatChem 2015, 7, 1524 – 1544; i) A. A. Jaworski, K. A. Scheidt, J.
Org. Chem. 2016, 81, 10145 – 10153.
Acknowledgements
[6] We are not aware of any asymmetric reactions of aza-p-QMs.
Achiral and racemic examples: a) P. Bongsup, R. Lonnie, D.
Joanna, Tetrahedron 2000, 56, 7379 – 7388; b) M. Canepa, M. A.
Fox, J. K. Whitesell, J. Org. Chem. 2001, 66, 3886 – 3892; c) K.
Tanaka, W. Ohashi, H. Okada, Y. Chujo, Tetrahedron Lett. 2014,
55, 1635 – 1639; d) M. S. Markoulides, C. G. Efthymiou, A. J.
Tasiopoulos, N. Chronakis, Synlett 2015, 2659 – 2662.
Financial support was provided by Hong Kong RGC
(16311616, 16304115, ECS605812, M-HKUST607/12) and
Shenzhen STIC (JCYJ20160229205441091). We thank Dr.
Herman Sung for assistance in structure determination.
[7] Representative reviews (a–b) and examples of o-QMs (c–o) and
p-QMs (p–t): a) L. Caruana, M. Fochi, L. Bernardi, Molecules
2015, 20, 117333 – 111764; b) Z. Wang, J. Sun, Synthesis 2015,
3629 – 3644; c) D. Wilcke, E. Herdtweck, T. Bach, Synlett 2011,
1235 – 1238; d) O. El-Sepelgy, S. Haseloff, S. K. Alamsetti, C.
Schneider, Angew. Chem. Int. Ed. 2014, 53, 7923 – 7927; Angew.
Chem. 2014, 126, 8057 – 8061; e) C.-C. Hsiao, H.-H. Liao, M.
Rueping, Angew. Chem. Int. Ed. 2014, 53, 13258 – 13263; Angew.
Chem. 2014, 126, 13474 – 13479; f) C.-C. Hsiao, S. Raja, H.-H.
Liao, I. Atodiresei, M. Rueping, Angew. Chem. Int. Ed. 2015, 54,
5762 – 5765; Angew. Chem. 2015, 127, 5854 – 5857; g) W. Zhao, Z.
Wang, B. Chu, J. Sun, Angew. Chem. Int. Ed. 2015, 54, 1910 –
1913; Angew. Chem. 2015, 127, 1930 – 1933; h) Z. Wang, F. Ai, Z.
Wang, W. Zhao, G. Zhu, Z. Lin, J. Sun, J. Am. Chem. Soc. 2015,
137, 383 – 389; i) G. C. Tsui, L. Liu, B. List, Angew. Chem. Int.
Ed. 2015, 54, 7703 – 7706; Angew. Chem. 2015, 127, 7814 – 7818;
j) J.-J. Zhao, S.-B. Sun, S.-H. He, Q. Wu, F. Shi, Angew. Chem.
Int. Ed. 2015, 54, 5460 – 5464; Angew. Chem. 2015, 127, 5550 –
5554; k) Y. Luan, S. E. Schaus, J. Am. Chem. Soc. 2012, 134,
19965 – 19968; l) J. Izquierdo, A. Orue, K. A. Scheidt, J. Am.
Chem. Soc. 2013, 135, 10634 – 10637; m) H. Lv, W.-Q. Jia, L.-H.
Sun, S. Ye, Angew. Chem. Int. Ed. 2013, 52, 8607 – 8610; Angew.
Chem. 2013, 125, 8769 – 8772; n) Y. Huang, T. Hayashi, J. Am.
Chem. Soc. 2015, 137, 7556 – 7559; o) W. Guo, B. Wu, X. Zhou, P.
Chen, X. Wang, Y.-G. Zhou, Y. Liu, C. Li, Angew. Chem. Int. Ed.
2015, 54, 4522 – 4526; Angew. Chem. 2015, 127, 4605 – 4609;
p) W. D. Chu, L. F. Zhang, X. Bao, X. H. Zhao, C. Zeng, J. Y. Du,
G. B. Zhang, F. X. Wang, X. Y. Ma, C. A. Fan, Angew. Chem. Int.
Ed. 2013, 52, 9229 – 9233; Angew. Chem. 2013, 125, 9399 – 9403;
q) L. Caruana, F. Kniep, T. K. Johansen, P. H. Poulsen, K. A.
Jørgensen, J. Am. Chem. Soc. 2014, 136, 15929 – 15932; r) Z.
Wang, Y. F. Wong, J. Sun, Angew. Chem. Int. Ed. 2015, 54,
13711 – 13714; Angew. Chem. 2015, 127, 13915 – 13918; s) N.
Dong, Z.-P. Zhang, X.-S. Xue, X. Li, J.-P. Cheng, Angew. Chem.
Int. Ed. 2016, 55, 1460 – 1464; Angew. Chem. 2016, 128, 1482 –
1486; t) K. Zhao, Y. Zhi, T. Shu, A. Valkonen, K. Rissanen, D.
Enders, Angew. Chem. Int. Ed. 2016, 55, 12104 – 12108; Angew.
Chem. 2016, 128, 12283 – 12287.
Conflict of interest
The authors declare no conflict of interest.
Keywords: alkylation · asymmetric catalysis ·
aza-quinone methides · nucleophilic addition · organocatalysis
[1] Selected reviews on the utility of indoles and carbazoles: a) S.
Cacchi, G. Fabrizi, Chem. Rev. 2005, 105, 2873 – 2920; b) M.
Shiri, Chem. Rev. 2012, 112, 3508 – 3549; c) M. Bandini, A.
Eichholzer, Angew. Chem. Int. Ed. 2009, 48, 9608 – 9644; Angew.
Chem. 2009, 121, 9786 – 9824; d) R. J. Sundberg, Indoles, Aca-
demic Press, London, 1996; e) A. J. Kochanowska-Karamyan,
M. T. Hamann, Chem. Rev. 2010, 110, 4489 – 4497; f) A. W.
Schmidt, K. R. Reddy, H.-J. Knçlker, Chem. Rev. 2012, 112,
3193 – 3328.
[2] Selected examples of asymmetric N-alkylation of indoles: a) M.
Bandini, A. Eichholzer, M. Tragni, A. Umani-Ronchi, Angew.
Chem. Int. Ed. 2008, 47, 3238 – 3241; Angew. Chem. 2008, 120,
3282 – 3285; b) L. M. Stanley, J. F. Hartwig, Angew. Chem. Int.
Ed. 2009, 48, 7841 – 7844; Angew. Chem. 2009, 121, 7981 – 7984;
c) H.-L. Cui, X. Feng, J. Peng, J. Lei, K. Jiang, Y.-C. Chen,
Angew. Chem. Int. Ed. 2009, 48, 5737 – 5740; Angew. Chem.
2009, 121, 5847 – 5850; d) B. M. Trost, M. Osipov, G. Dong, J.
Am. Chem. Soc. 2010, 132, 15800 – 15807; e) Q. Cai, C. Zheng, S.-
L. You, Angew. Chem. Int. Ed. 2010, 49, 8666 – 8669; Angew.
Chem. 2010, 122, 8848 – 8851; f) Y. Xie, Y. Zhao, B. Qian, L.
Yang, C. Xia, H. Huang, Angew. Chem. Int. Ed. 2011, 50, 5682 –
5686; Angew. Chem. 2011, 123, 5800 – 5804; g) H.-G. Cheng, L.-
Q. Lu, T. Wang, Q.-Q. Yang, X.-P. Liu, Y. Li, Q.-H. Deng, J.-R.
Chen, W.-J. Xiao, Angew. Chem. Int. Ed. 2013, 52, 3250 – 3254;
Angew. Chem. 2013, 125, 3332 – 3336.
[3] Examples of indirect formation of chiral N-alkyl indoles: a) W.-
B. Liu, X. Zhang, L.-X. Dai, S.-L. You, Angew. Chem. Int. Ed.
2012, 51, 5183 – 5187; Angew. Chem. 2012, 124, 5273 – 5277; b) X.
Dou, W. Yao, C. Jiang, Y. Lu, Chem. Commun. 2014, 50, 11354 –
11357; c) K. Xu, T. Gilles, B. Breit, Nat. Commun. 2015, 6, 7616;
d) Q.-A. Chen, Z. Chen, V. M. Dong, J. Am. Chem. Soc. 2015,
137, 8392 – 8395.
[8] Examples of asymmetric reactions of aza-o-QMs: a) C. Wang,
J. A. Tunge, J. Am. Chem. Soc. 2008, 130, 8118 – 8119; b) Q.-Q.
Yang, Q. Wang, J. An, J.-R. Chen, L.-Q. Lu, W.-J. Xiao, Chem.
Eur. J. 2013, 19, 8401 – 8404; c) A. Lee, A. Younai, C. K. Price, J.
Izquierdo, R. K. Mishra, K. A. Scheidt, J. Am. Chem. Soc. 2014,
136, 10589 – 10592; d) G. Li, H. Liu, G. Lv, Y. Wang, Q. Fu, Z.
Tang, Org. Lett. 2015, 17, 4125 – 4127; e) H.-H. Liao, A.
Chatupheeraphat, C.-C. Hsiao, I. Atodiresei, M. Rueping,
[4] We are only aware of one general study on asymmetric N-
alkylation of carbazoles: Q. M. Kainz, C. D. Matier, A. Bartos-
4
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Angew. Chem. Int. Ed. 2015, 54, 15540 – 15544; Angew. Chem.
[11] a) P. L. Kotian, Y. S. Babu, M. Wu, V. R. Chintareddy, V. S.
2015, 127, 15760 – 15765; f) A. Chatupheeraphat, H.-H. Liao, S.
Mader, M. Sako, H. Sasai, I. Atodiresei, M. Rueping, Angew.
Chem. Int. Ed. 2016, 55, 4803 – 4807; Angew. Chem. 2016, 128,
4882 – 4887; g) M. Kretzschmar, T. Hodꢁk, C. Schneider, Angew.
Chem. Int. Ed. 2016, 55, 9788 – 9792; Angew. Chem. 2016, 128,
9941 – 9946; h) K. Bera, C. Schneider, Chem. Eur. J. 2016, 22,
7074 – 7078.
Kumar, W. Zhang, Patent CA2941380 A1, 2015; b) S. E.
Draheim, N. J. Bach, R. D. Dillard, D. R. Berry, D. G. Carlson,
N. Y. Chirgadze, D. K. Clawson, L. W. Hartley, L. M. Johnson,
N. D. Jones, E. R. McKinney, E. D. Mihelich, J. L. Olkowski,
R. W. Schevitz, A. C. Smith, D. W. Snyder, C. D. Sommers, J.-P.
Wery, J. Med. Chem. 1996, 39, 5159 – 5175; c) A. Tafi, R. Costi,
M. Botta, R. Di Santo, F. Corelli, S. Massa, A. Ciacci, F. Manetti,
M. Artico, J. Med. Chem. 2002, 45, 2720 – 2732.
[9] Seminal reports and selected reviews on chiral phosphoric acid
catalysis: a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew.
Chem. Int. Ed. 2004, 43, 1566 – 1568; Angew. Chem. 2004, 116,
1592 – 1594; b) D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004,
126, 5356 – 5357; c) T. Akiyama, Chem. Rev. 2007, 107, 5744 –
5758; d) M. Terada, Synthesis 2010, 1929 – 1982; e) D. Parmar, E.
Sugiono, S. Raja, M. Rueping, Chem. Rev. 2014, 114, 9047 – 9153;
f) T. James, M. van Gemmeren, B. List, Chem. Rev. 2015, 115,
9388 – 9409.
[12] With the standard method, unsubstituted indole reacted at the 3-
position with excellent yield but moderate enantioselectivity
(94% yield, 56% ee).
[13] Substrate kinetic resolution was observed (s = 6.3). During the
progress of the reaction, the product ee remained constant. The
absolute stereochemistry of the product is influenced by the
configuration of the catalyst, but not that of the substrate. These
observations are consistent with the intermediacy of aza-p-QM.
[10] Catalyst Awas first reported by List and co-workers: L. Kçtzner,
M. J. Webber, A. Martꢁnez, C. De Fusco, B. List, Angew. Chem.
Int. Ed. 2014, 53, 5202 – 5205; Angew. Chem. 2014, 126, 5303 –
5306.
Manuscript received: February 22, 2017
Revised: March 1, 2017
Final Article published: && &&, &&&&
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Communications
Organocatalysis
An organocatalytic strategy for the asym-
metric N-alkylation of indoles and carba-
zoles was developed in which in situ
generated aza-para-quinone methides are
employed as the alkylating reagent. With
the proper choice of a chiral phosphoric
acid and N-protective group (P), the
M. Chen, J. Sun*
&&&& — &&&&
Catalytic Asymmetric N-Alkylation of
Indoles and Carbazoles through 1,6-
Conjugate Addition of Aza-para-quinone
Methides
À
intermolecular C N bond formation with
various indole and carbazole nucleo-
philes proceeds under mild conditions
with excellent efficiency and enantiose-
lectivity.
6
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