Rapid Construction of Complex 2-Pyrrolines through Lewis Acid-Catalyzed, Sequential Three-Component Reactions via in Situ-Generated 1-Azaallyl Cations

Article abstract of DOI:10.1021/acs.orglett.8b01205

The first Sc(OTf)₃-catalyzed dehydration of 2-hydroxy oxime ethers to generate benzylic stabilized 1-azaallyl cations, which are captured by 1,3-carbonyls, is described. A subsequent addition of primary amines in a sequential three-component re

Full text of DOI:10.1021/acs.orglett.8b01205

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Rapid Construction of Complex 2‑Pyrrolines through Lewis Acid-
Catalyzed, Sequential Three-Component Reactions via in Situ-
Generated 1‑Azaallyl Cations
Marcel Schlegel and Christoph Schneider*
̈
̈
Institut fur Organische Chemie, Universitat Leipzig, Johannisallee 29, 04103 Leipzig, Germany
*
S Supporting Information
ABSTRACT: The first Sc(OTf) -catalyzed dehydration of 2-
3
hydroxy oxime ethers to generate benzylic stabilized 1-azaallyl
cations, which are captured by 1,3-carbonyls, is described. A
subsequent addition of primary amines in a sequential three-
component reaction affords highly substituted and densely
functionalized tetrahydroindeno[2,1-b]pyrroles as single dia-
stereomers with up to quantitative yield. Thus, three new σ-
bonds and two vicinal quaternary stereogenic centers are
generated in a one-pot operation.
he rapid generation of complex heterocyclic compounds
these intermediates has only been reported for a limited number
14,15
T
remains one of the major current challenges of biological
and medicinal chemistry and is central to the discovery of novel
drug candidates. In light of their straightforward and highly atom-
as well as step-economical character, multicomponent reactions
of noncatalyzed transformations to date.
We envisioned tertiary 2-hydroxy oxime ethers potentially
serving as suitable substrates for Lewis acid-catalyzed dehy-
dration, as they would generate resonance-stabilized α-
methoxyimino carbocations A. Based upon their unique
electronic character, which resembles resonance-stabilized allyl
(
MCRs) have proven powerful for furnishing a wide variety of
1
structurally diverse and biologically active heterocycles, and the
development of MCRs that provide pyrroline-derived com-
15
13
cations, they can be described as 1-azaallyl cations. As a
consequence, we envisaged that 1,3-dicarbonyls could capture
them and create a new all-carbon-substituted quaternary
stereogenic center. However, in order to induce a cyclo-
annulation process onto the electrophilic oxime ether, primary
amines might need to be employed to undergo condensation
with the dicarbonyl moiety followed by a 5-exo-trig-cyclization.
This would furnish highly substituted 2-pyrrolines with an aminal
moiety ready for further functionalization. Herein, we now report
our results in this general direction, which have resulted in the
first Lewis acid-catalyzed (2 + 2 + 1)-cycloannulation of in situ-
generated 1-azaallyl cations (Scheme 1).
2
pounds has garnered growing attention in recent years. This is
because they are common structural motifs in natural products
3
4
5
such as anthramycine, sibiromycine, myosmine, and spiro-
6
tryprostatin B, as well as in other pharmaceutically relevant
substrates. Consequently, novel and operationally simple
7
strategies and methodologies for the preparation of these N-
heterocycles are much desired to study their biological activities
in more detail.
The use of tertiary alcohols for the construction of all-carbon
quaternary stereocenters is a highly attractive process in organic
synthesis because water is the sole byproduct. Unfortunately, in
We started our investigations with 2-hydroxy oxime ethers 1,
which were synthesized by a three-step procedure from
commercially available indanones (see the Supporting Informa-
tion (SI) for details). Thus, 1a was treated with methyl
acetoacetate under metal triflate catalysis, and the coupling
product 2a was further condensed with benzylamine in situ to
many cases, such S 1-reactions suffer from severe limitations
N
such as unfavorable steric hindrance, the relatively poor leaving
group character of the hydroxy group, and competitive
8
elimination pathways. Typically, Lewis or Brønsted acids are
used as catalysts, and electron-rich substrates are employed in
9
16
order to stabilize the resulting carbocations. However, the
furnish the desired pyrroline 3a (Table 1). The optimization
dehydration of electronically less activated tertiary alcohols, for
studies initially concentrated on the first step of this sequential
example, with a carbonyl substituent in the α-position, is only
three-component reaction (3CR) generating intermediate 2a.
With 10 mol % Zn(OTf) as catalyst, incomplete conversion of
2
1a to 2a was observed with methyl acetoacetate in different
solvents at room temperature (Table 1, entries 1−4). After
investigation of further reaction conditions (entries 5−7),
10
feasible either under harsh reaction conditions or with adjacent,
11
strongly resonance-stabilizing groups.
Imines with a tertiary hydroxy group have thus far never been
applied in Lewis acid-catalyzed S 1-type reactions with carbon
N
nucleophiles to the best of our knowledge. Although the concept
of generating α-imino carbocations from hydrazones or oxime
Received: April 16, 2018
12,13
ethers was established around 1980,
the synthetic utility of
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01205
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Conceptualization of the Three-Component
Reaction
Scheme 2. Substrate Scope from Various Oxime Ethers 1
a
Table 1. Optimization Studies
a
Reaction conditions: 1 (0.20 mmol), methyl acetoacetate (0.26
mmol), Sc(OTf) (20 μmol), 4 Å MS (50 mg), CHCl (1.0 mL),
3
3
benzylamine (0.40 mmol). Isolated yields after column chromatog-
b
c
raphy. EDG = electron-donating group. Multispot-TLC after first
d
e
step. EWG = electron-withdrawing group. First step occurred at rt to
a
Reaction conditions: 1a (0.20 mmol), methyl acetoacetate (0.26
6
0 °C.
mmol), Sc(OTf) (20 μmol), 4 Å MS (50 mg), solvent (1.0 mL),
benzylamine (0.40 mmol). Isolated yield after column chromatog-
raphy. In CH Cl , THF, toluene, or CHCl . Incomplete conversion
3
b
c
d
analysis (see SI). Further heating to 80 °C in the second step of
the 3CR did not result in a shorter reaction time, but in a
significantly reduced product yield (entry 13). Finally,
condensation of 2a with benzylamine in the absence of Sc(OTf)3
only provided 23% of product 3a together with 74% of recovered
2
2
3
e
f
of 1a. 2,6-Di-tert-butylpyridine (30 mol %) added. No reaction.
g
h
i
Yield of 4.00 mmol scale of 1a in parentheses. At 80 °C. Reaction of
intermediate 2a (0.20 mmol) with benzylamine (2.0 equiv) and 4 Å
MS (50 mg) in CHCl (1.0 mL) at 60 °C.
3
compound 2a (entry 14). Based upon this result, we conclude
however, 10 mol % Sc(OTf) in CHCl at 60 °C was found to be
that Sc(OTf) is the most likely catalyst for both steps of the
3
3
3
18
the optimal catalytic system to form 2a in 97% yield within 3 h
3CR.
(
entry 8). Treatment of 1a with a preformed enaminone from
The substrate scope of the 3CR was initially studied by the
variation of substituents at the 2-hydroxy oxime ether 1. We
picked substituents that would either stabilize or destabilize the
putative 1-azaallyl cations (Scheme 2). In the 3CR with methyl
acetoacetate and benzylamine, oxime ethers 1 containing 2-aryl
groups with electron-donating residues in the meta- or para-
position typically furnished the tetrahydroindeno[2,1-b]pyrroles
3b and 3d−j in excellent overall yield. The ortho-tolyl substituted
2-hydroxy oxime ether 1c gave rise to a mixture of recovered
starting material and decomposition products, which can be
explained by steric repulsion of the ortho-methyl group with the
neighboring substituents in the 1-azaallyl cation intermediate.
Introduction of a highly electron-rich N,N-dimethylamino
phenyl substituent (1k) delivered 3k in a moderate yield of
46% due to some decomposition of the corresponding 1-azaallyl
cation. 2-Hydroxy oxime ethers with benzannulated (1l) or
heteroaryl residues (1m) were also tolerated in the 3CR
providing 3l and 3m in 94% and 66% yields, respectively.
Despite electron-withdrawing aryl-substituents decreasing the
methyl acetoacetate and benzylamine in the presence of a Lewis
acid led to no reaction. Control experiments in the presence of
2
,6-di-tert-butylpyridine (DTBP) as a selective proton scavenger
were performed to distinguish between Lewis acid and “hidden
17
Brønsted acid” catalysis. When DTBP was added to the
Sc(OTf) -catalyzed reaction, no significant change of the
3
reaction time or the product yield was observed (entry 9).
Interestingly, replacement of the Sc(III)-catalyst by TfOH with
or without the addition of DTBP resulted in no reaction in both
cases (entries 10−11). These experiments excluded a Brønsted
acid-catalyzed transformation and supported a Lewis acid-
catalyzed pathway.
After complete formation of intermediate 2a monitored by
TLC, excess benzylamine was added at 60 °C. Product 3a was
obtained as a single diastereomer in 95% yield after 2.5 days. This
result could be reproduced on gram-scale to obtain 1.71 g (97%)
of 3a under identical reaction conditions (Table 1, entry 12). Its
relative configuration was determined by X-ray crystal structure
B
DOI: 10.1021/acs.orglett.8b01205
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope from Various Dicarbonyl
Compounds and Amines
Scheme 4. Derivatization of 3a
a
regioselectively in moderate to good yields. Increasing the steric
2
hindrance of the substituent R from methyl to ethyl or iso-propyl
resulted either in incomplete conversion of the respective
intermediates 2 into the products 3aa and 3ab or in no reaction
with benzylamine (for 3ac). In the latter case, only the
corresponding intermediate 2 was isolated in 81% yield (dr ≈
1
:1). Increasing the temperature of the second step to 90 °C did
not improve the outcome of the 3CR in these cases. Also,
tetrahydroindeno[2,1-b]pyrrole products 3ad−ah were synthe-
sized from 1a, methyl acetoacetate, and functionalized amines
with more than 80% overall yields. With cyclohexylamine, 3ai
was isolated in 60% yield along with 28% of 2a.
Tetrahydroindeno[2,1-b]pyrroles 3 contain an aminal moiety
that is ideally suited for further manipulation. Along these lines,
3
a was reacted with indole as a π-nucleophile in the presence of
1
0 mol % Sc(OTf) at 60−90 °C. The methoxyamino group was
3
cleaved under these conditions to form an iminium ion, which
was attacked by indole. Thus, 2-hydroxy oxime ethers 1 can be
regarded as latent tris-electrophiles. The substitution product 8
was formed in 94% yield with complete retention of the relative
configuration as proven by the crystal structure (see SI for more
a
Reaction conditions: 1a (0.20 mmol), 1,3-dicarbonyl (0.26 mmol),
Sc(OTf) (20 μmol), 4 Å MS (50 mg), CHCl (1.0 mL), amine (0.40
mmol). Isolated yields after column chromatography. First step
required 5 h. Incomplete product formation. No reaction in the
second step at 60−90 °C. 4.0 equiv of amine used.
19
3
3
details). As the aminal 3a could not be directly substituted by
b
other nucleophiles under Lewis acidic conditions, it was
converted into the more reactive hemiaminal 9 by hydrolysis.
The BF ·OEt -promoted Hosomi−Sakurai reaction of 9 with
c
d
e
3
2
allyltrimethylsilane delivered compound 10 in 77% yield and as a
single diastereomer. These reaction conditions were also applied
in a Mannich reaction with a silyl enol ether, as well as a reduction
with triethylsilane to furnish 11 and 12, respectively, with good
reactivity of the 2-hydroxy oxime ethers 1, the products 3n−q
were isolated in excellent yields, but required longer reaction
2
times for the first step. Aryl groups (R ) could also be replaced by
alkyl groups to furnish the tetrahydroindeno[2,1-b]pyrroles 3r−t
in moderate yield. The secondary alcohol 1u, as well as other 2-
hydroxy oxime ethers (4−7) proved to be unreactive under these
reaction conditions or gave rise to decomposition products.
Different 3-oxobutanoic esters were investigated in the
reaction with 1a followed by condensation with benzylamine
to furnish 3u−w in excellent yields (Scheme 3). In addition, 1,3-
diketones provided the tetrahydroindeno[2,1-b]pyrroles 3x−z
yields. Finally, the Sc(OTf) -catalyzed aza-Friedel−Crafts
3
alkylation of 9 with 2-methylfuran provided 13 in 84% yield
(Scheme 4).
In summary, we have developed a highly efficient, chemo- and
diastereoselective synthesis of tetrahydroindeno[2,1-b]pyrroles
3 via (2 + 2 + 1)-cycloannulation of 2-hydroxy oxime ethers 1,
1,3-dicarbonyl compounds, and primary amines through a
putative 1-azaallyl cation as the key intermediate. The optimal
C
DOI: 10.1021/acs.orglett.8b01205
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
protocol for this sequential three-component reaction features a
catalytic and easily scalable process, readily accessible starting
materials, operational simplicity with no necessity for an inert
atmosphere, high functional group tolerance, typically excellent
yields, and complete diastereoselectivity. Moreover, manipu-
lation of the obtained products by substitution of the aminal with
different π-nucleophiles reveals the broad utility of the present
methodology to form complex nitrogen heterocycles. Current
investigations are being directed toward detailed mechanistic
insights into the generation of 1-azaallyl cations and their full
exploitation in novel and stereoselective C−C-bond forming
events.
3649. (g) Rajasekaran, T.; Karthik, G.; Sridhar, B.; Subba Reddy, B. V.
Org. Lett. 2013, 15, 1512−1515. For further examples on efficient
synthesis of pyrrolines, see: (h) Green, M. P.; Prodger, J. C.; Sherlock, A.
E.; Hayes, C. J. Org. Lett. 2001, 3, 3377−3379. (i) Knight, D. W.;
Sharland, C. M. Synlett 2004, 119−121. (j) Dieter, R. K.; Chen, N.; Yu,
H.; Nice, L. E.; Gore, V. K. J. Org. Chem. 2005, 70, 2109−2119.
(
k) Morita, N.; Krause, N. Eur. J. Org. Chem. 2006, 2006, 4634−4641.
l) Martin, R.; Jager, A.; Bohl, M.; Richter, S.; Fedorov, R.; Manstein, D.
lker, H.-J. Angew. Chem., Int. Ed. 2009, 48, 8042−
046. (m) Cai, S.-H.; Wang, D.-X.; Ye, L.; Liu, Z.-Y.; Feng, C.; Loh, T.-P.
(
̈
̈
J.; Gutzeit, H. O.; Kno
8
̈
Adv. Synth. Catal. 2018, 360, 1262−1266.
(3) (a) Bates, H. M.; Kuenzig, W.; Watson, W. B. Cancer Res. 1969, 29,
2195−2205. (b) Hurley, L. H. J. Antibiot. 1977, 30, 349−370. (c) Hurley,
L. H.; Petrusek, R. Nature 1979, 282, 529−531. (d) Hurley, L. H.;
Thurston, D. E. Pharm. Res. 1984, 1, 52−59. (e) Thurston, D. E.; Bose,
D. S. Chem. Rev. 1994, 94, 433−465. (f) Rahman, K. M.; Vassoler, H.;
James, C. H.; Thurston, D. E. ACS Med. Chem. Lett. 2010, 1, 427−432.
(g) Antonow, D.; Kaliszczak, M.; Kang, G.-D.; Coffils, M.; Tiberghien,
A. C.; Cooper, N.; Barata, T.; Heidelberger, S.; James, C. H.; Zloh, M.;
Jenkins, T. C.; Reszka, A. P.; Neidle, S.; Guichard, S. M.; Jodrell, D. I.;
Hartley, J. A.; Howard, P. W.; Thurston, D. E. J. Med. Chem. 2010, 53,
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01205.
Experimental procedures, characterization data, and X-ray
structures of 3a and 9 (PDF)
2
927−2941. (h) Rahman, K. M.; James, C. H.; Bui, T. T. T.; Drake, A.
F.; Thurston, D. E. J. Am. Chem. Soc. 2011, 133, 19376−19385.
i) Antonow, D.; Thurston, D. E. Chem. Rev. 2011, 111, 2815−2864.
4) (a) Leber, J. D.; Hoover, J. R. E.; Holden, K. G.; Johnson, R. K.;
Accession Codes
(
CCDC 1817406−1817407 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
(
Hecht, S. M. J. Am. Chem. Soc. 1988, 110, 2992−2993. (b) Li, W.;
Khullar, A.; Chou, S.; Sacramo, A.; Gerratana, B. Appl. Environ.
Microbiol. 2009, 75, 2869−2878.
(5) Kleinsasser, N. H.; Wallner, B. C.; Harreu
W.; Richter, E. Toxicology 2003, 192, 171−177.
́
s, U. A.; Zwickenpflug,
1EZ, UK; fax: +44 1223 336033.
(
6) (a) Cui, C.-B.; Kakeya, H.; Osada, H. J. Antibiot. 1996, 49, 832−
8
1
35. (b) Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 11505−
1515.
AUTHOR INFORMATION
Corresponding Author
E-mail: schneider@chemie.uni-leipzig.de.
■
*
(7) (a) Williams, C. H.; Lawson, J. Biochem. J. 1998, 336, 63−67.
(b) Miltyk, W.; Pałka, J. A. Comp. Biochem. Physiol., Part A: Mol. Integr.
Physiol. 2000, 125, 265−271. (c) Lee, Y.; Ling, K.-Q.; Lu, X.; Silverman,
R. B.; Shepard, E. M.; Dooley, D. M.; Sayre, L. M. J. Am. Chem. Soc. 2002,
124, 12135−12143. (d) Castellano, S.; Fiji, H. D. G.; Kinderman, S. S.;
Watanabe, M.; de Leon, P.; Tamanoi, F.; Kwon, O. J. Am. Chem. Soc.
ORCID
Christoph Schneider: 0000-0001-7392-9556
Notes
2
(
007, 129, 5843−5845.
The authors declare no competing financial interest.
8) Review on S 1-reactions of tertiary alcohols, see: Chen, L.; Yin, X.-
N
P.; Wang, C.-H.; Zhou, J. Org. Biomol. Chem. 2014, 12, 6033−6048.
ACKNOWLEDGMENTS
(9) For selected examples, see: (a) Shirakawa, S.; Kobayashi, S. Org.
■
́
Lett. 2007, 9, 311−314. (b) Sanz, R.; Miguel, D.; Alvarez-Gutier
Rodríguez, F. Synlett 2008, 2008, 975−978. (c) Sanz, R.; Miguel, D.;
Martínez, A.; Gohain, M.; García-García, P.; Fernandez-Rodríguez, M.
A.; Alvarez, E.; Rodríguez, F. Eur. J. Org. Chem. 2010, 2010, 7027−7039.
d) McCubbin, J. A.; Krokhin, O. V. Tetrahedron Lett. 2010, 51, 2447−
́
rez, J.;
This work was generously supported by the European Social
Fund (ESF) through a fellowship awarded to M.S. and by BASF
and Evonik through the donation of chemicals. We thank Jannik
Knoche (University of Leipzig) for his support in the synthesis of
starting materials, as well as Peter Coburger (University of
Leipzig) for obtaining the X-ray crystal structures.
́
́
(
2
3
2
449. (e) Niggemann, M.; Meel, M. J. Angew. Chem., Int. Ed. 2010, 49,
684−3687. (f) Meyer, V. J.; Niggemann, M. Eur. J. Org. Chem. 2011,
011, 3671−3674. (g) Zhong, X.; Li, Y.; Zhang, J.; Zhang, W.-X.; Wang,
REFERENCES
S.-X.; Han, F.-S. Chem. Commun. 2014, 50, 11181−11184. (h) Suar
A.; Gohain, M.; Fernandez-Rodríguez, M. A.; Sanz, R. J. Org. Chem.
2015, 80, 10421−10430. (i) Croft, R. A.; Mousseau, J. J.; Choi, C.; Bull,
J. A. Chem. - Eur. J. 2016, 22, 16271−16276.
́
ez,
■
(
1) For selected reviews on multicomponent reactions, see:
́
(
(
(
(
a) Isambert, N.; Lavilla, R. Chem. - Eur. J. 2008, 14, 8444−8454.
b) Sunderhaus, J. D.; Martin, S. F. Chem. - Eur. J. 2009, 15, 1300−1308.
c) Toure,
́
B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439−4486.
(10) (a) Chen, L.; Zhou, J. Chem. - Asian J. 2012, 7, 2510−2515.
(b) Chen, L.; Zhou, F.; Shi, T.-D.; Zhou, J. J. Org. Chem. 2012, 77,
4354−4362. (c) Kumar, A.; Singh, T. V.; Thomas, S. P.; Venugopalan, P.
Eur. J. Org. Chem. 2015, 2015, 1226−1234.
(11) For selected examples, see: (a) England, D. B.; Merey, G.; Padwa,
A. Org. Lett. 2007, 9, 3805−3807. (b) Wu, Y.-C.; Li, H.-J.; Liu, L.;
Demoulin, N.; Liu, Z.; Wang, D.; Chen, Y.-J. Adv. Synth. Catal. 2011,
353, 907−912. (c) Ghosh, S.; Kinthada, L. K.; Bhunia, S.; Bisai, A. Chem.
Commun. 2012, 48, 10132−10134. (d) Zhou, F.; Cao, Z.-Y.; Zhang, J.;
Yang, H.-B.; Zhou, J. Chem. - Asian J. 2012, 7, 233−241. (e) Kinthada, L.
K.; Ghosh, S.; De, S.; Bhunia, S.; Dey, D.; Bisai, A. Org. Biomol. Chem.
2013, 11, 6984−6993. (f) Zhou, L.-J.; Zhang, Y.-C.; Zhao, J.-J.; Shi, F.;
Tu, S.-J. J. Org. Chem. 2014, 79, 10390−10398. (g) Tan, W.; Li, X.;
Gong, Y.-X.; Ge, M.-D.; Shi, F. Chem. Commun. 2014, 50, 15901−
d) Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Angew. Chem., Int. Ed. 2011,
0, 6234−6246. (e) de Graaff, C.; Ruijter, E.; Orru, R. V. A. Chem. Soc.
Rev. 2012, 41, 3969−4009. (f) Wang, Y.; Lu, H.; Xu, P.-F. Acc. Chem. Res.
015, 48, 1832−1844.
2) For selected examples on MCR of pyrrolines, see: (a) Clique, B.;
Vassiliou, S.; Monteiro, N.; Balme, G. Eur. J. Org. Chem. 2002, 2002,
493−1499. (b) Xu, H.-W.; Li, G.-Y.; Wong, M.-K.; Che, C.-M. Org.
Lett. 2005, 7, 5349−5352. (c) Cui, S.-L.; Wang, J.; Wang, Y.-G. Org. Lett.
5
2
(
1
2
007, 9, 5023−5025. (d) Magedov, I. V.; Luchetti, G.; Evdokimov, N.
M.; Manpadi, M.; Steelant, W. F. A.; van Slambrouck, S.; Tongwa, P.;
Antipin, M. Y.; Kornienko, A. Bioorg. Med. Chem. Lett. 2008, 18, 1392−
396. (e) Asghari, S.; Qandalee, M. Synth. Commun. 2010, 40, 2172−
177. (f) Sun, Y.; Sun, J.; Yan, C.-G. Tetrahedron Lett. 2012, 53, 3647−
1
2
D
DOI: 10.1021/acs.orglett.8b01205
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
5904. (h) Kinthada, L. K.; Ghosh, S.; Babu, K. N.; Sharique, M.; Biswas,
S.; Bisai, A. Org. Biomol. Chem. 2014, 12, 8152−8173. (i) Babu, K. N.;
Kinthada, L. K.; Ghosh, S.; Bisai, A. Org. Biomol. Chem. 2015, 13,
1
0641−10655. (j) Fan, T.; Zhang, H.-H.; Li, C.; Shen, Y.; Shi, F. Adv.
Synth. Catal. 2016, 358, 2017−2031. (k) Zhuo, M.-H.; Liu, G.-F.; Song,
S.-L.; An, D.; Gao, J.; Zheng, L.; Zhang, S. Adv. Synth. Catal. 2016, 358,
8
08−815. (l) Kinthada, L. K.; Babu, K. N.; Padhi, D.; Bisai, A. Eur. J. Org.
Chem. 2017, 2017, 3078−3091. (m) Kinthada, L. K.; Medisetty, S. R.;
Parida, A.; Babu, K. N.; Bisai, A. J. Org. Chem. 2017, 82, 8548−8567.
(
12) (a) Corey, E. J.; Knapp, S. Tetrahedron Lett. 1976, 17, 4687−4690.
(
b) Shatzmiller, S.; Lidor, R.; Shalon, E.; Bahar, E. J. Chem. Soc., Chem.
Commun. 1984, 795−796.
13) Shatzmiller, S.; Shalom, E.; Bahar, E. J. Chem. Soc., Chem.
Commun. 1984, 1522−1523.
14) (a) Enders, D.; Man, S.-H.; Maaβen, R. Tetrahedron Lett. 1995,
(
(
3
3
1
6, 8007−8010. (b) Creary, X.; Jiang, Z. J. Org. Chem. 1996, 61, 3482−
489. (c) Enders, D.; Maaßen, R.; Han, S.-H. Liebigs Ann. 1996, 1996,
565−1574. (d) Enders, D.; Maaßen, R.; Runsink, J. Tetrahedron:
Asymmetry 1998, 9, 2155−2180. (e) Creary, X.; Wolf, A. J. Phys. Org.
Chem. 2000, 13, 337−343. (f) Creary, X.; Burtch, E. A.; Jiang, Z. J. Org.
̈
̈
Chem. 2003, 68, 1117−1127. (g) Narayan, R.; Frohlich, R.; Wurthwein,
E.-U. J. Org. Chem. 2012, 77, 1868−1879.
15) Creary, X.; Wang, Y.-X.; Jiang, Z. J. Am. Chem. Soc. 1995, 117,
044−3053.
16) Cyclization of the intermediate 2a to form a dihydrofuran was not
(
3
(
observed due to the lower nucleophilicity of the enol form of the β-
ketoester moiety in comparison to the enaminone.
(
17) For selected examples on “hidden Brønsted acid”-catalyzed
processes, see: (a) Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B. Chem. - Eur. J.
004, 10, 484−493. (b) Dang, T. T.; Boeck, F.; Hintermann, L. J. Org.
2
Chem. 2011, 76, 9353−9361. (c) Sandridge, M. J.; McLarney, B. D.;
Williams, C. W.; France, S. J. Org. Chem. 2017, 82, 10883−10897.
Selected examples on Lewis acid catalysis with exclusion of a “hidden
Brønsted acid”-catalyzed pathway: (d) Schneider, A. E.; Beisel, T.;
Shemet, A.; Manolikakes, G. Org. Biomol. Chem. 2014, 12, 2356−2359.
(
e) Schlegel, M.; Schneider, C. J. Org. Chem. 2017, 82, 5986−5992.
(
18) The condensation of β-ketoesters with amines can be catalyzed by
Sc(OTf) , see: Yadav, J. S.; Kumar, V. N.; Rao, R. S.; Priyadarshini, A. D.;
3
Rao, P. P.; Reddy, B. V. S.; Nagaiah, K. J. Mol. Catal. A: Chem. 2006, 256,
2
(
34−237.
19) Compound 8 shows two rotamers in the NMR-spectrum at room
temperature, which were identified by coalescence in high-temperature
NMR experiments (see SI).
E
DOI: 10.1021/acs.orglett.8b01205
Org. Lett. XXXX, XXX, XXX−XXX