Diversification of Unprotected Alicyclic Amines by C?H Bond Functionalization: Decarboxylative Alkylation of Transient Imines

Article abstract of DOI:10.1002/anie.202011641

Despite extensive efforts by many practitioners in the field, methods for the direct α-C?H bond functionalization of unprotected alicyclic amines remain rare. A new advance in this area utilizes N-lithiated alicyclic amines. These readily accessible intermediates are converted to transient imines through the action of a simple ketone oxidant, followed by alkylation with a β-ketoacid under mild conditions to provide valuable β-amino ketones with unprecedented ease. Regioselective α′-alkylation is achieved for substrates with existing α-substituents. The method is further applicable to the convenient one-pot synthesis of polycyclic dihydroquinolones through the incorporation of a S_NAr step.

Full text of DOI:10.1002/anie.202011641

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Accepted Article
Title: Diversification of unprotected alicyclic amines via C–H bond
functionalization: Decarboxylative alkylation of transient imines
Authors: Anirudra Paul, Jae Hyun Kim, Scott D. Daniel, and Daniel
Seidel
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Diversification of unprotected alicyclic amines via C–H bond
functionalization: Decarboxylative alkylation of transient imines
Anirudra Paul,[a],+ Jae Hyun Kim,[a],+ Scott D. Daniel,[a] and Daniel Seidel[a],*
Abstract: Despite extensive efforts by many practitioners in the field,
methods for the direct α-C–H bond functionalization of unprotected
alicyclic amines remain rare. A new advance in this area utilizes N-
lithiated alicyclic amines. These readily accessible intermediates are
converted to transient imines through the action of a simple ketone
oxidant, followed by alkylation with a β-ketoacid under mild conditions
to provide valuable β-amino ketones with unprecedented ease.
Regioselective α′-alkylation is achieved for substrates with existing α-
substituents. The method is further applicable to the convenient one-
pot synthesis of polycyclic dihydroquinolones through the
incorporation of a SNAr step.
alkylation with β-ketoacids 3 to provide β-aminoketones 4. In
addition, utilizing o-fluoroaryl-β-ketoacids 5, polycyclic amines 6
can be obtained in a single operation via a process that involves
a subsequent SNAr reaction.
Driven largely by the importance of this class of compounds in
synthetic and medicinal chemistry,[1] the synthesis of substituted
alicyclic amines by means of C–H bond functionalization remains
a highly active area of research.[2,3] In stark contrast to the
numerous advances that have been achieved with 3° or protected
2° amines, highly desirable methods for the direct synthesis of α-
functionalized 2° (i.e. unprotected) alicyclic amines from their
corresponding parent amines remain limited (Scheme 1).[3j,4]
Moreover, α′-C–H bond functionalization of 2° alicyclic amines
with an existing α-substituent is exceptionally challenging,[3j,5,6]
especially with electronically activating substituents that favor
functionalization at the substituted site. Leveraging the known
ability of lithium amides to generate imines upon reaction with
simple ketone oxidants (e.g., 1 → 2, Scheme 1),[7] we recently
developed a new method for the C–H bond functionalization of
Scheme 1. Overview of methods for the C–H bond functionalization of amines
and present strategy.
unprotected alicyclic amines.[8]
Specifically, transient cyclic
imines 2 generated from the oxidation of lithium amides 1 engage
organolithium nucleophiles to provide α-functionalized products.
Regioselective α'-C–H bond functionalization of α-substituted
Mannich reactions and their decarboxylative variants
employing β-keto acids represent valuable tools for the synthesis
of β-amino ketones from imines.[9–11] Despite the utility of the
corresponding products, the use of enolizable cyclic imines in
these reactions has largely remained limited to easily accessible
alicyclic imines such as 1-pyrroline and 1-piperideine.[12–15] This
is likely the result of the limited availability/stability of enolizable
cyclic imines, in particular chiral variants possessing a substituent
in the α-position. In order to determine whether the in-situ-
generation of alicyclic imines via lithium amide oxidation is
compatible with the decarboxylative Mannich process, we
evaluated a range of reaction conditions. Key findings with the
model substrates piperidine and β-keto acid 3a are summarized
in Scheme 2. Following amine deprotonation and treatment with
trifluoroacetophenone to rapidly access 1-piperideine, β-keto acid
3a (1.5 equiv) was added, followed by stirring at room
temperature. Desired β-amino ketone 4a was obtained in 39%
yield. The yield of 4a could be increased to 50% by employing
2.5 equivalents of 3a. Considering that the Li-alkoxide resulting
from the reduction of trifluoroacetophenone may interfere with the
subsequent decarboxylative alkylation,16 the addition of acidic
alicyclic amines was also achieved.[8a]
The scope of the
nucleophile could be expanded to other organometallics such as
Grignard reagents by using Lewis acids to activate the imine
intermediates.[8b] However, α′-C–H bond functionalization of α-
substituted amines proved to be incompatible with Lewis acid
activation, hampering our efforts to further expand the scope of
nucleophiles. Particularly attractive would be new methods in
which α'-C–H bond functionalization is achieved with non-
organometallic nucleophiles. Here we report an approach for the
rapid diversification of transient imines 2 via decarboxylative
[a]
+
Dr. A. Paul, Dr. J. H. Kim, S. D. Daniel, Prof. Dr. D. Seidel
Center for Heterocyclic Compounds, Department of Chemistry
University of Florida, Gainesville, FL 32611 (USA)
E-mail: seidel@chem.ufl.edu
Homepage: http://seidel-group.com/
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
additives was explored.
Indeed, small to appreciable
improvements in yield were observed in all cases. Trifluoroacetic
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10.1002/anie.202011641
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acid (TFA) outperformed acetic acid as an additive, presumably
because lithium acetate is still sufficiently basic to partially
impede the addition process. Under the optimized conditions,
product 4a was obtained in 76% yield.
Scheme 2. Selected optimization reactions.
The scope of the reaction was explored with a broad range of
alicyclic amines and β-keto acids (Scheme 3). Different ring sizes
and substitution patterns on both reaction partners were readily
accommodated. Both aryl and alkyl ketones could be introduced.
Synthetically useful yields of β-amino ketones 4 were obtained in
most cases. Particularly useful are reactions with amines that
contain α-substituents. Regioselective substitution of the α′-
position was observed in all cases. Diastereoselectivities ranged
from poor to excellent (vide infra). Using o-fluoroaryl-β-keto acids
5 and adding an SNAr step without the need for isolating
intermediates enabled the efficient preparation of various
polycyclic dihydroquinolones 6. These species, which are now
available directly from their unfunctionalized amines, are rather
challenging to prepare by other means.[17,18]
Scheme 3. Reaction scope.
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Bull, Synthesis 2019, 51, 3171; v) A. Trowbridge, S. M. Walton, M. J.
Gaunt, Chem. Rev. 2020, 120, 2613.
As shown in Scheme 3, products 4p–4y were obtained
predominantly as trans-diastereomers. The trans-diastereomers
are in fact the kinetic products of these reactions, as it has been
[3]
Selected recent examples of mechanistically diverse methods for amine
C–H bond functionalization: a) Z. Zhao, Y. Luo, S. Liu, L. Zhang, L.
Feng, Y. Wang, Angew. Chem. Int. Ed. 2018, 57, 3792; b) F. Wang, M.
Rafiee, S. S. Stahl, Angew. Chem. Int. Ed. 2018, 57, 6686; c) S.
Greßies, F. J. R. Klauck, J. H. Kim, C. G. Daniliuc, F. Glorius, Angew.
Chem. Int. Ed. 2018, 57, 9950; d) R. J. Griffiths, W. C. Kong, S. A.
Richards, G. A. Burley, M. C. Willis, E. P. A. Talbot, Chem. Sci. 2018, 9,
2295; e) F. I. M. Idiris, C. E. Majeste, G. B. Craven, C. R. Jones, Chem.
Sci. 2018, 9, 2873; f) S.-S. Li, X. Lv, D. Ren, C.-L. Shao, Q. Liu, J. Xiao,
Chem. Sci. 2018, 9, 8253; g) A. F. G. Maier, S. Tussing, H. Zhu, G.
Wicker, P. Tzvetkova, U. Flörke, C. G. Daniliuc, S. Grimme, J. Paradies,
Chem. Eur. J. 2018, 24, 16287; h) K. Mori, R. Isogai, Y. Kamei, M.
Yamanaka, T. Akiyama, J. Am. Chem. Soc. 2018, 140, 6203; i) M.
Shang, J. Z. Chan, M. Cao, Y. Chang, Q. Wang, B. Cook, S. Torker, M.
Wasa, J. Am. Chem. Soc. 2018, 140, 10593; j) A. J. J. Lennox, S. L.
Goes, M. P. Webster, H. F. Koolman, S. W. Djuric, S. S. Stahl, J. Am.
Chem. Soc. 2018, 140, 11227; k) J. Zhang, S. Park, S. Chang, J. Am.
Chem. Soc. 2018, 140, 13209; l) A. M. Nauth, E. Schechtel, R. Dören,
W. Tremel, T. Opatz, J. Am. Chem. Soc. 2018, 140, 14169; m) H.-J.
Jiang, X.-M. Zhong, J. Yu, Y. Zhang, X. Zhang, Y.-D. Wu, L.-Z. Gong,
Angew. Chem. Int. Ed. 2019, 58, 1803; n) M. A. Ashley, C. Yamauchi, J.
C. K. Chu, S. Otsuka, H. Yorimitsu, T. Rovis, Angew. Chem. Int. Ed.
2019, 58, 4002; o) S. Guin, P. Dolui, X. Zhang, S. Paul, V. K. Singh, S.
Pradhan, H. B. Chandrashekar, S. S. Anjana, R. S. Paton, D. Maiti,
Angew. Chem. Int. Ed. 2019, 58, 5633; p) W. G. Whitehurst, J. H.
Blackwell, G. N. Hermann, M. J. Gaunt, Angew. Chem. Int. Ed. 2019,
58, 9054; q) Y. Ma, X. Yao, L. Zhang, P. Ni, R. Cheng, J. Ye, Angew.
Chem. Int. Ed. 2019, 58, 16548; r) R. Grainger, T. D. Heightman,
Steven V. Ley, F. Lima, C. N. Johnson, Chem. Sci. 2019, 10, 2264; s)
D. Vasu, A. L. Fuentes de Arriba, J. A. Leitch, A. de Gombert, D. J.
Dixon, Chem. Sci. 2019, 10, 3401; t) S. Asako, S. Ishihara, K. Hirata, K.
Takai, J. Am. Chem. Soc. 2019, 141, 9832; u) W. Lin, K.-F. Zhang, O.
Baudoin, Nat. Catal. 2019, 2, 882; v) J. Z. Chan, Y. Chang, M. Wasa,
Org. Lett. 2019, 21, 984; w) L. Zhou, Y.-B. Shen, X.-D. An, X.-J. Li, S.-S.
Li, Q. Liu, J. Xiao, Org. Lett. 2019, 21, 8543; x) M. Kataoka, Y. Otawa,
N. Ido, K. Mori, Org. Lett. 2019, 21, 9334; y) M. Lee, A. Adams, P. B.
Cox, M. S. Sanford, Synlett 2019, 30, 417; z) M. Kapoor, P. Chand-
Thakuri, J. M. Maxwell, D. Liu, H. Zhou, M. C. Young, Synlett 2019, 30,
519; aa) K. Ohmatsu, R. Suzuki, Y. Furukawa, M. Sato, T. Ooi, ACS
Catal. 2020, 10, 2627; ab) J. B. Roque, Y. Kuroda, J. Jurczyk, L.-P. Xu,
J. S. Ham, L. T. Göttemann, C. A. Roberts, D. Adpressa, J. Saurí, L. A.
Joyce, D. G. Musaev, C. S. Yeung, R. Sarpong, ACS Catal. 2020, 10,
2929; ac) A. W. Rand, H. Yin, L. Xu, J. Giacoboni, R. Martin-Montero, C.
Romano, J. Montgomery, R. Martin, ACS Catal. 2020, 10, 4671; ad) W.
Liu, T. Babl, A. Röther, O. Reiser, H. M. L. Davies, Chem. Eur. J. 2020,
26, 4236; ae) P. Verma, J. M. Richter, N. Chekshin, J. X. Qiao, J.-Q. Yu,
J. Am. Chem. Soc. 2020, 142, 5117; af) M. M. Walker, B. Koronkiewicz,
S. Chen, K. N. Houk, J. M. Mayer, J. A. Ellman, J. Am. Chem. Soc.
2020, 142, 8194; ag) K. Feng, R. E. Quevedo, J. T. Kohrt, M. S.
Oderinde, U. Reilly, M. C. White, Nature 2020, 580, 621; ah) P. J.
Sarver, V. Bacauanu, D. M. Schultz, D. A. DiRocco, Y.-h. Lam, E. C.
Sherer, D. W. C. MacMillan, Nat. Chem. 2020, 12, 459; ai) J. B.
McManus, N. P. R. Onuska, M. S. Jeffreys, N. C. Goodwin, D. A.
Nicewicz, Org. Lett. 2020, 22, 679; aj) R. Oeschger, B. Su, I. Yu, C.
Ehinger, E. Romero, S. He, J. Hartwig, Science 2020, 368, 736; ak) M.
A. Short, J. M. Blackburn, J. L. Roizen, Synlett 2020, 31, 102; al) A. S.
H. Ryder, W. B. Cunningham, G. Ballantyne, T. Mules, A. G. Kinsella, J.
Turner-Dore, C. M. Alder, L. J. Edwards, B. S. J. McKay, M. N. Grayson,
A. J. Cresswell, Angew. Chem. Int. Ed. 2020, 59, 14986.
established
that
the
corresponding
cis-isomers
are
thermodynamically more stable.[19]
Interconversion of the
diastereomers is possible, presumably via a retro-Mannich or
retro-conjugate addition pathway. Indeed, simply changing the
reaction conditions in the synthesis of product 4p allowed for a
complete reversal of diastereoselectivity in favor of the cis-
isomer (Scheme 4).
Scheme 4. Formation of cis-product.
In summary, we have achieved the α-alkylation of
unprotected alicyclic amines via a decarboxylative Mannich
process involving regioselective C–H bond functionalization.
Adding an SNAr step to the overall reaction sequence, this
process was further extended to the synthesis of polycyclic
dihydroquinolones in a single operation.
Acknowledgements
Financial support from the NIH−NIGMS (Grant
R01GM101389) is gratefully acknowledged.
spectrometry instrumentation was supported by a grant from
the NIH (S10 OD021758-01A1).
Mass
Keywords: C–H bond functionalization • alicyclic amines •
decarboxylative C–C bond formation • Mannich reaction •
annulation
[1]
[2]
a) R. D. Taylor, M. MacCoss, A. D. G. Lawson, J. Med. Chem. 2014, 57,
5845; b) E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014,
57, 10257.
Selected recent reviews on amine C–H bond functionalization: a) K. R.
Campos, Chem. Soc. Rev. 2007, 36, 1069; b) R. Jazzar, J. Hitce, A.
Renaudat, J. Sofack-Kreutzer, O. Baudoin, Chem. Eur. J. 2010, 16,
2654; c) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215; d) E.
A. Mitchell, A. Peschiulli, N. Lefevre, L. Meerpoel, B. U. W. Maes,
Chem. Eur. J. 2012, 18, 10092; e) K. M. Jones, M. Klussmann, Synlett
2012, 23, 159; f) B. Peng, N. Maulide, Chem. Eur. J. 2013, 19, 13274;
g) S. A. Girard, T. Knauber, C.-J. Li, Angew. Chem. Int. Ed. 2014, 53,
74; h) M. C. Haibach, D. Seidel, Angew. Chem. Int. Ed. 2014, 53, 5010;
i) L. Wang, J. Xiao, Adv. Synth. Catal. 2014, 356, 1137; j) C.-V. T. Vo, J.
W. Bode, J. Org. Chem. 2014, 79, 2809; k) D. Seidel, Org. Chem. Front.
2014, 1, 426; l) Y. Qin, J. Lv, S. Luo, Tetrahedron Lett. 2014, 55, 551;
m) D. Seidel, Acc. Chem. Res. 2015, 48, 317; n) J. W. Beatty, C. R. J.
Stephenson, Acc. Chem. Res. 2015, 48, 1474; o) S. Mahato, C. K.
Jana, Chem. Rec. 2016, 16, 1477; p) Y. Qin, L. Zhu, S. Luo, Chem.
Rev. 2017, 117, 9433; q) M.-X. Cheng, S.-D. Yang, Synlett 2017, 28,
159; r) J. C. K. Chu, T. Rovis, Angew. Chem. Int. Ed. 2018, 57, 62; s) L.
Gonnard, A. Guérinot, J. Cossy, Tetrahedron 2019, 75, 145; t) S. Liu, Z.
Zhao, Y. Wang, Chem. Eur. J. 2019, 25, 2423; u) D. Antermite, J. A.
[4]
[5]
P. R. Payne, P. Garcia, P. Eisenberger, J. C. H. Yim, L. L. Schafer, Org.
Lett. 2013, 15, 2182.
The regioselective formation of the less substituted imine from an α-
substituted 2° alicyclic amine has for instance been achieved by the
carefully controlled deprotonation of N-Cl prolinol derivatives and
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related species. Examples: a) B. A. Horenstein, R. F. Zabinski, V. L.
Schramm, Tetrahedron Lett. 1993, 34, 7213; b) R. H. Furneaux, G.
Limberg, P. C. Tyler, V. L. Schramm, Tetrahedron 1997, 53, 2915; c) B.
G. Davis, M. A. T. Maughan, T. M. Chapman, R. Villard, S. Courtney,
Org. Lett. 2002, 4, 103; d) M. A. T. Maughan, I. G. Davies, T. D. W.
Claridge, S. Courtney, P. Hay, B. G. Davis, Angew. Chem. Int. Ed.
2003, 42, 3788.
R. Diodone, A. Fettes, R. Fischer, V. Goeckel, S. Hildbrand, G. Moine,
M. Weber, Org. Process Res. Dev. 2011, 15, 503; f) Y. Pan, C. W. Kee,
Z. Jiang, T. Ma, Y. Zhao, Y. Yang, H. Xue, C.-H. Tan, Chem. Eur. J.
2011, 17, 8363; g) C. Jiang, F. Zhong, Y. Lu, Beilstein J. Org. Chem.
2012, 8, 1279; h) C.-F. Yang, C. Shen, J.-Y. Wang, S.-K. Tian, Org.
Lett. 2012, 14, 3092; i) L. Yin, M. Kanai, M. Shibasaki, Tetrahedron
2012, 68, 3497; j) M. Böhm, K. Proksch, R. Mahrwald, Eur. J. Org.
Chem. 2013, 2013, 1046; k) P. Qian, Y. Dai, H. Mei, V. A. Soloshonok,
J. Han, Y. Pan, RSC Adv. 2015, 5, 26811; l) A. Lahosa, M. Yus, F.
Foubelo, J. Org. Chem. 2019, 84, 7331; m) Y. Zhang, J.-K. Li, F.-G.
Zhang, J.-A. Ma, J. Org. Chem. 2020, 85, 5580; n) H. Zhang, C. Jiang,
J.-P. Tan, H.-L. Hu, Y. Chen, X. Ren, H.-S. Zhang, T. Wang, ACS Catal.
2020, 5698.
[6]
Examples of regioselective α′-C–H bond functionalization of protected
2° alicyclic amines with an existing α-substituent: a) N. Chatani, T.
Asaumi, S. Yorimitsu, T. Ikeda, F. Kakiuchi, S. Murai, J. Am. Chem.
Soc. 2001, 123, 10935; b) H. M. L. Davies, C. Venkataramani, T.
Hansen, D. W. Hopper, J. Am. Chem. Soc. 2003, 125, 6462; c) S. J.
Pastine, D. V. Gribkov, D. Sames, J. Am. Chem. Soc. 2006, 128,
14220; d) J. E. Spangler, Y. Kobayashi, P. Verma, D.-H. Wang, J.-Q.
Yu, J. Am. Chem. Soc. 2015, 137, 11876.
[13] Examples of decarboxylative Mannich reactions of enolizable cyclic
imines: a) E. Anet, G. K. Hughes, E. Ritchie, Nature 1949, 164, 501; b)
C. Schöpf, G. Benz, F. Braun, H. Hinkel, R. Rokohl, Angew. Chem.
1953, 65, 161; c) E. E. van Tamelen, J. S. Baran, J. Am. Chem. Soc.
1956, 78, 2913; d) J. Quick, R. Oterson, Synthesis 1976, 1976, 745; e)
H. Fukawa, Y. Terao, K. Achiwa, M. Sekiya, Chem. Lett. 1982, 11, 231;
f) R. K. Zaidan, P. Evans, Eur. J. Org. Chem. 2019, 2019, 5354.
[14] Examples of Mannich reactions of enolizable cyclic imines: a) M. R.
Monaco, P. Renzi, D. M. Scarpino Schietroma, M. Bella, Org. Lett.
2011, 13, 4546; b) S. Virk, S. V. Pansare, Org. Lett. 2019, 21, 5524.
[15] For the use of nitrones in decarboxylative Mannich reactions, see: V. G.
Lisnyak, T. Lynch-Colameta, S. A. Snyder, Angew. Chem. Int. Ed. 2018,
57, 15162.
[7]
For an early review, see: (a) a) M. Majewski, D. M. Gleave, J.
Organomet. Chem. 1994, 470, 1; Selected key contributions: b) G.
Wittig, H. J. Schmidt, H. Renner, Chem. Ber. 1962, 95, 2377; c) G.
Wittig, A. Hesse, Liebigs Ann. Chem. 1971, 746, 149; d) G. Wittig, A.
Hesse, Liebigs Ann. Chem. 1971, 746, 174; e) G. Wittig, G. Häusler,
Liebigs Ann. Chem. 1971, 746, 185.
[8]
[9]
a) W. Chen, L. Ma, A. Paul, D. Seidel, Nat. Chem. 2018, 10, 165; b) A.
Paul, D. Seidel, J. Am. Chem. Soc. 2019, 141, 8778; c) W. Chen, A.
Paul, K. A. Abboud, D. Seidel, Nat. Chem. 2020, 12, 545.
Selected recent reviews on the Mannich reaction: a) B. Karimi, D.
Enders, E. Jafari, Synthesis 2013, 45, 2769; b) S. Saranya, N. A. Harry,
K. K. Krishnan, G. Anilkumar, Asian J. Org. Chem. 2018, 7, 613; c) D.-J.
Cheng, Y.-D. Shao, ChemCatChem 2019, 11, 2575; d) R. W. Bates, W.
Ko, V. Barát, Org. Biomol. Chem. 2020, 18, 810.
[16] Presumably, the free β-keto acid is required in the alkylation step, with
the corresponding lithium salt being less effective.
[17] Selected methods for the synthesis of polycyclic dihydroquinolones
involving C–H bond functionalization: a) D.-F. Chen, Z.-Y. Han, Y.-P.
He, J. Yu, L.-Z. Gong, Angew. Chem. Int. Ed. 2012, 51, 12307; b) G.
Zhang, S. Wang, Y. Ma, W. Kong, R. Wang, Adv. Synth. Catal. 2013,
355, 874; c) C. Huo, M. Wu, X. Jia, H. Xie, Y. Yuan, J. Tang, J. Org.
Chem. 2014, 79, 9860.
[10] For a review on the use of β-keto acids in synthesis, see: S. Mao, K.
Chen, G. Yan, D. Huang, Eur. J. Org. Chem. 2020, 2020, 525.
[11] Selected reviews on decarboxylative coupling reactions: a) N.
Rodriguez, L. J. Goossen, Chem. Soc. Rev. 2011, 40, 5030; b) Y. Pan,
C.-H. Tan, Synthesis 2011, 2011, 2044; c) S. Nakamura, Org. Biomol.
Chem. 2014, 12, 394; d) J. Xuan, Z.-G. Zhang, W.-J. Xiao, Angew.
Chem. Int. Ed. 2015, 54, 15632; e) P. Liu, G. Zhang, P. Sun, Org.
Biomol. Chem. 2016, 14, 10763; f) T. Patra, D. Maiti, Chem. Eur. J.
2017, 23, 7382; g) Y. Wei, P. Hu, M. Zhang, W. Su, Chem. Rev. 2017,
117, 8864; h) M. Rahman, A. Mukherjee, I. S. Kovalev, D. S. Kopchuk,
G. V. Zyryanov, M. V. Tsurkan, A. Majee, B. C. Ranu, V. N. Charushin,
O. N. Chupakhin, S. Santra, Adv. Synth. Catal. 2019, 361, 2161; i) K.
Hyodo, S. Nakamura, Org. Biomol. Chem. 2020, 18, 2781; j) L.
McMurray, T. M. McGuire, R. L. Howells, Synthesis 2020, 52, 1719.
[12] Examples of decarboxylative Mannich reactions of acyclic and
nonenolizable cyclic imines: a) E. E. van Tamelen, J. S. Baran, J. Am.
Chem. Soc. 1955, 77, 4944; b) A. Ricci, D. Pettersen, L. Bernardi, F.
Fini, M. Fochi, R. P. Herrera, V. Sgarzani, Adv. Synth. Catal. 2007, 349,
1037; c) L. Yin, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2009, 131,
9610; d) J. Baudoux, P. Lefebvre, R. Legay, M.-C. Lasne, J. Rouden,
Green Chem. 2010, 12, 252; e) S. Abrecht, J.-M. Adam, U. Bromberger,
[18] While full consumption of the amine starting materials was typically
observed, a quantitative assessment of the mass balance is not yet
possible. Competing imine-trimer formation cannot be ruled out at
present and intractable polar byproducts are often formed. In case of
α-substituted amine starting materials, small amounts of the
regioisomeric imines were also observed. These species did not
engage in the alkylation reaction and were readily separable from the
target compounds.
[19] a) D. Compère, C. Marazano, B. C. Das, J. Org. Chem. 1999, 64, 4528;
b) F.-X. Felpin, J. Lebreton, J. Org. Chem. 2002, 67, 9192; c) G. Zheng,
L. P. Dwoskin, P. A. Crooks, J. Org. Chem. 2004, 69, 8514; d) J. Ryan,
M. Šiaučiulis, A. Gomm, B. Maciá, E. O’Reilly, V. Caprio, J. Am. Chem.
Soc. 2016, 138, 15798.
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10.1002/anie.202011641
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Anirudra Paul, Jae Hyun Kim, Scott D.
Daniel, and Daniel Seidel
Page No. – Page No.
Diversification of unprotected
alicyclic amines via C–H bond
functionalization: Decarboxylative
alkylation of transient imines
N-lithiated alicyclic amines are converted to transient imines through the action of a
simple ketone oxidant, followed by alkylation with a β-ketoacid under mild
conditions to provide valuable β-amino ketones with unprecedented ease.
Regioselective α′-alkylation is achieved for substrates with existing α-substituents.
The method is further applicable to the convenient one-pot synthesis of polycyclic
dihydroquinolones through the incorporation of a SNAr step.
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