Tertiary Enamide-Triggered SEAr: Domino Allylation and Enamine-Type Addition

Article abstract of DOI:10.1021/acs.orglett.8b03987

Two unprecedented domino reactions are described, starting from ketospiro-enesulfonamides. By treatment with ZrCl₄ and allylsilane, an intramolecular electrophilic aromatic substitution and subsequent allylation is observed. By treatment with TiCl₄ and allylsilane, a double enamine-type reaction takes place, thus creating simultaneously four contiguous stereogenic centers diastereoselectively.

Full text of DOI:10.1021/acs.orglett.8b03987

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Tertiary Enamide-Triggered SEAr: Domino Allylation and Enamine-
Type Addition
́
́
Frederic Beltran and Laurence Miesch*
́
̀
Equipe Synthese Organique et Phytochimie, Institut de Chimie, CNRS-UdS UMR 7177, 4, rue Blaise Pascal CS 90032, 67081
Strasbourg, France
S
* Supporting Information
ABSTRACT: Two unprecedented domino reactions are described, starting from ketospiro-enesulfonamides. By treatment with
ZrCl4 and allylsilane, an intramolecular electrophilic aromatic substitution and subsequent allylation is observed. By treatment
with TiCl4 and allylsilane, a double enamine-type reaction takes place, thus creating simultaneously four contiguous stereogenic
centers diastereoselectively.
Scheme 1. Previous Work on Ketoynamides
ecently,tertiaryenamideshavebecomeshelf-stableenamine
Rvariants. Despite the presence of the electron-withdrawing
group, delocalization of the lone-pair electrons of nitrogen into
the carbon−carbon double bond remains possible, allowing
enamine-type reactivity.1,2 Thus, these unique synthons in
organic synthesis have been successfully used in reactions with
epoxides,3 imines,4 carbonyls,5 nitriliumions,6 orN-acyliminium
ions7 to access nitrogen-containing frameworks pertinent for
assessing biological activities.
Aromaticorganiccompoundsareubiquitousindiverseareasof
research, from medicinal chemistry to biology and materials
science.8 Often, the building of aromatic systems relies on
electrophilic aromatic substitution reactions.9 Since the pioneer-
ing work of Friedel−Crafts,10 persistent attention has been given
to this valuable process.11
We present herein an intramolecular electrophilic aromatic
substitutionpromotedbyatertiaryenesulfonamide.UsingZrCl4,
allylationtakesplace, generatingatetracyclicsystem. Bycontrast,
byusingTiCl4,allylationandsubsequentquenchingofβ-silylated
carbocation by tertiary enamide leads to a spiro pentacyclic
scaffold after a second allylation. The former may serve as an
analogue of the analgesic metathebainone of the morphinan
family.12
latter would react with appropriate electrophiles to functionalize
the nitrogen-containingframework further (Scheme 2a). Where-
asthisapproachfailed,weexploredanactivationofthecarbonylin
the presence of BF3·OEt2 and allylsilane (Scheme 2b).16 Against
allodds,weobserveddirectintramolecularelectrophilicaromatic
substitution triggered by enamine-like activity of the nearby
tertiary enesulfonamide, providing spiro-tetracyclic fused ring
system 2a diastereoselectively, together with pentacyclic ring-
fused system 3a, resulting from a second intramolecular addition
of enamide onto the β-silylated carbocation followed by a second
allylation. X-ray analyses of 2a and 3c confirmed the structures of
Ourresearchinterestinthechemistryofketoynamides13 ledus
to a direct spirocyclization from ketosulfonamides via ketoyne-
sulfonamides when the ynesulfonamides are substituted by an
electron-withdrawing group.14 Using ynesulfonamides substi-
tutedbyanarylgroup,anammoniumsalt-promotedspirocycliza-
tion takes place (Scheme 1).15
To take advantage of the exclusive E-configured tertiary
enesulfonamide, i.e., with a vinylogous nitrogen nucleophile
present in the aza-spiro compounds 1a, we speculated that the
Received: December 15, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03987
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Enamide Functionalization with Electrophile or
Nucleophile
Scheme 3. Scope of Electrophilic Aromatic Substitution/
a
Allylation
Table 1. Screening of Lewis/Brønsted Acids
a
a
entry
Lewis acid
conditions
% yield 2a
% yield 3a
1
2
3
4
5
6
7
8
BF3·OEt2
AlCl3
Me3Al
SnCl2
InCl3
FeCl3
ZnCl2
TiCl4
ZrCl4
HfCl4
Y(OTf)3
p-TsOH
TFA
7 h, 40 °C
10 min, rt
2 h, 40 °C
2 h, 40 °C
4 h, 40 °C
1 h, 40 °C
4 h, 40 °C
15 min, rt
1 h, 40 °C
2 h, 40 °C
5 h, 40 °C
4 h, 40 °C
4 h, 40 °C
73
c
b
b
33
c
14
c
b
b
6
c
a
b
Yield of isolated compounds. CCDC 1866280 contains the
supplementary crystallographic data.
Scheme 4. Scope of the Domino Reaction Providing
Pentacyclic Adducts
a
b
b
32
84
b
b
c
51
5
b
b
c
d
9
10
11
12
13
c
c
a
b
Yield of isolated compounds. Starting material was totally
recovered. Degradation was observed. Concentration in starting
c
d
material 1a was 35 mM instead of 70 mM.
Table 2. Optimization of the Formation of Adduct 3a
a
a
entry
x (equiv)
concentration (mM)
% yield 2a
% yield 3a
1
2
3
4
5
2
5
5
10
10
70
70
130
130
260
32
15
17
9
51
59
62
78
81
8
a
Yield of isolated compounds.
boththetetra-andpentacyclicazaspiroadductsobtained(CCDC
1866279 and CCDC 1895442 contain the supplementary
crystallographic data for both structures).
Anintramolecularelectrophilicaromaticsubstitutiontriggered
by the delocalization of tertiary enamide electrons into the
benzene ring is exceedingly rare. To the best of our knowledge,
a
b
Yield of isolated compounds. CCDC 1895442 contains the
supplementary crystallographic data.
B
DOI: 10.1021/acs.orglett.8b03987
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
well as Brønsted acids (Table 1, entries 12 and 13) were not
beneficial for this reaction. Finally, ZrCl4 promotes the selective
formation of tetracyclic compound 2a, whereas the pentacyclic
adduct 3a predominated by treatment of 1a with the stronger
Lewis acid TiCl4. It should be noted that the formation of the
pentacyclic fused ring system 3a occurred in a totally
diastereoselective and regioselective manner, creating four new
contiguous stereogenic centers in one strike. Having found that
TiCl4 favors the formation of pentacyclic adduct 3a, we tried to
optimize this reaction further (Table 2).
Althoughincreasingtheamountofallylsilane(Table2,entry2)
favored bridged compound 3a, enhancing the concentration of
thesubstrateandusing5equivofallylsilane(Table2, entry3)led
to more pentacyclic derivative 3a, albeit with a lower selectivity.
Enhanced selectivity (3a vs 2a) could be obtained by increasing
the amount of allylsilane (Table 2, entry 4). Quadrupling the
concentration of spiro-enesulfonamide 1a and working with 10
equivofallylsilane(Table2,entry5)wasthemostefficientwayto
obtain bridged compound 3a with the highest yields and
selectivity. With suitable reaction conditions for high selectivity
in hand, we explored first the scope of the sequential electrophilic
aromatic substitution reaction/allylation reaction (Scheme 3).
Within the aryl unit, electron-withdrawing 4-OCF3 (2b), 4-F
(2c), 2-Cl (2d), and 2-F (2e) substitutions were tolerated.
Naphthyl enesulfonamide 1h and heteroaryl compound 1i were
Scheme 5. Attempt To Form the Tetracyclic Adduct
this phenomenon has been observed only once, by the group of
Wang, in an 8-endo-epoxide arene cyclization.17 Unexpectedly, a
second nucleophilic attack of the tertiary enamide took place,
providing 3a with total regio- and diastereoselectivity.
Considering the possibility of a Lewis acid−allylsilylation-
promoted sequence to form spirocyclic fused ring systems
diastereoselectively, we sought conditions to target the exclusive
formation of either the tetracyclic system or the pentacyclic
system.
To do so, we screened several Lewis acids as well as Brønsted
acids (Table 1).
Among the tested Lewis acids, only BF3·OEt2 (Table 1, entry
1), InCl3 (Table 1, entry 5), TiCl4 (Table 1, entry 8), and ZrCl4
18
(Table1,entry9)ledtobothtetracyclicadduct2aandpentacyclic
compound 3a. Other Lewis acids, such as AlCl3, Me3Al, SnCl2,
ZnCl2, FeCl3, and HfCl4 (Table 1, entries 2, 3, 4, 6, 7, and 10), as
Scheme 6. Proposed Mechanisms
C
DOI: 10.1021/acs.orglett.8b03987
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suitablecandidates,althoughthelatterledtopolycyclicderivative
2i with a moderate yield. Surprisingly, unsymmetrically aryl-
substituted compounds (meta derivatives 1f and 1g) underwent
enamide-triggered aromatic substitution and subsequent allyla-
tion in a totally regioselective manner, affording exclusively 9-
hexahydro-1H-benzo[f ]cyclopenta[d]indoles 2f and 2g with
goodyields.Theprotocolwasextendedtospiro-enesulfonamides
derived from cyclohexanones (1j and 1k), wherein fused
spirocyclic ring systems 2j and 2k could be obtained with 73
and70%yield,respectively.Spiro-enesulfonamide1lcontaininga
7−5ringsystemdidnotundergocyclization, probablybecauseof
the increased distance between the two carbons of the new C−C
bondtobeformed,thusdelineatingonelimitationofthisreaction.
Successful formation of pentacyclic adduct 3a with TiCl4 and
allylsilane prompted us to investigate the pertinence of this
domino reaction (Scheme 4). Within the aryl unit, electron-
withdrawing 4-OCF3 (1b), 4-F (1c), 2-Cl (1d), and 2-F (1e)
substitution was tolerated, providing bridged compounds 3a−e.
Although the domino reaction proceeded with unsymmetri-
cally substituted aryl compounds (meta derivatives 1f and 1g), in
thiscase moderateyields of 3f, 3f′and 3g, 3g′ wereobtainedwith
moderate selectivity. Cyclohexyl derivative 3j was found to be a
goodcandidateforthisreaction,whereasgem-dimethylderivative
1k met with less success, undergoing only electrophilic aromatic
substitutionandsubsequentallylation.Likewise,2-thienyladduct
2i was obtained exclusively by treatment with TiCl4. With
naphthyl spiro-enesulfonamide 1h, an erosion of selectivity with
respect to the formation of polycyclic compounds formed was
observed, and in this case, 3h and 2h were isolated by treatment
with TiCl4.
stitution/enamine-like addition/allylation, where four contig-
uous stereogenic centers were created simultaneously.
ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.8b03987.
Experimental procedures, synthesis of starting materials,
and compound characterization data (PDF)
1H and 13C NMR spectra for new compounds (PDF)
Accession Codes
CCDC 1866279−1866280 and 1895442 contain the supple-
mentary crystallographic 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 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lmiesch@unistra.fr.
ORCID
Laurence Miesch: 0000-0002-0369-9908
Notes
The authors declare no competing financial interest.
With respect to the mechanism of this process and to verify
whether enesulfonamide is essential for the reaction to proceed,
reduced419 wastreatedwithTiCl4 andallylsilane.Intramolecular
cyclization reaction was not observed, and only starting material
was recovered (Scheme 5).
To explain the formation of these spiro-polycyclic-fused ring
systems, the mechanism outlined in Scheme 6 is proposed.
Activation of ketone 1a by a Lewis acid provides alkoxide A.
Subsequent intramolecular electrophilic aromatic substitution
assisted by the tertiary spiro-enesulfonamide affords imidium
intermediate B followed by rearomatization to afford C.
Ionization of the alkoxide/Lewis acid complex of C leads to
tertiary carbocation D.16 At this point, two pathways can be
considered,dependingontheLewisacidinvolved:18,20PathwayA
involves allylsilane addition on the convex face of molecule D′.
Because zirconium(IV) has an ionic radius much larger than that
oftitanium(IV),21 theZr−Clbondmaybemorelabile,promoting
β-silyl elimination to form polycyclic system 2a. In pathway B,
allylsilane adds to D″, providing F. In this case, the enamine-like
reactivity of F is faster than β-elimination of the silicon moiety,
thus leading to bridged compound G. A second molecule of
allylsilane subsequently adds to the iminium ion from the less
hindered side of G, thus ending with the production of 3a after β-
silyl elimination.
In conclusion, we have developed a tandem intramolecular
electrophilic aromatic substitution followed by allylation to form
aza-tetracyclic fused spiranic ring systems diastereoselectively by
treatment with ZrCl4. A diverse array of various aryl-substituted
fused spiro-enesulfonamides were obtained. Unsymmetrically
substituted aryl compounds led to 9-hexahydro-1H-benzo[f]-
cyclopenta[d]indoles exclusively. Cyclization with TiCl4 and
allylsilaneaffordedpentacyclicbridgedderivativeswithcomplete
diastereoselectivity by consecutive electrophilic aromatic sub-
ACKNOWLEDGMENTS
■
́
Support for this work was provided by CNRS and Universite de
Strasbourg. F.B. thanks M.R.T. for a research fellowship.
REFERENCES
■
(1)Wang,M.-X.Chem.Commun.2015,51,6039andreferencestherein
.
(2) Xu, X.-M.; Zhao, L.; Zhu, J.; Wang, M.-X. Angew. Chem., Int. Ed.
2016, 55, 3799.
(3)(a)Yang,L.;Zheng,Q.-Y.;Wang,D.-X.;Huang,Z.-T.;Wang,M.-X.
Org. Lett. 2008, 10, 2461. (b)Cossey, K. N.; Funk, R. L. J. Am. Chem. Soc.
2004, 126, 12216.
(4) (a) Tong, S.; Yang, X.; Wang, D.-X.; Zhao, L.; Zhu, J.; Wang, M.-X.
Tetrahedron 2012, 68, 6492. (b) Suga, S.; Nishida, T.; Yamada, D.;
Nagaki, A.; Yoshida, J.-I. J. Am. Chem. Soc. 2004, 126, 14338.
(5) (a) Yang, L.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. J. Am. Chem.
Soc. 2009, 131, 10390. (b) Yang, L.; Lei, C.-H.; Wang, D.-X.; Huang, Z.-
T.; Wang, M.-X. Org. Lett. 2010, 12, 3918. (c) Tong, S.; Wang, D.-X.;
Zhao, L.; Zhu, J.; Wang, M.-X. Angew. Chem., Int. Ed. 2012, 51, 4417.
(6) (a) Lei, C.-H.; Wang, D.-X.; Zhao, L.; Zhu, J.; Wang, M.-X. J. Am.
Chem.Soc.2013,135,4708.(b)Lei,C.-H.;Wang,D.-X.;Zhao,L.;Zhu,J.;
Wang, M.-X. Chem. - Eur. J. 2013, 19, 16981. (c) Lei, C.-H.; Zhao, L.;
Wang, D.-X.; Zhu, J.; Wang, M.-X. Org. Chem. Front. 2014, 1, 909.
(7) Andna, L.; Miesch, L. Org. Lett. 2018, 20, 3430.
(8) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
Rev. 2002, 102, 1359.
(9) (a) Friedel−Crafts and Related Reactions; Olah, G. A., Ed.; Wiley:
New York, 1963. (b) Friedel−Crafts Chemistry; Olah, G. A., Ed.; Wiley:
New York, 1973. (c) Friedel−Crafts Alkylation Chemistry: A Century of
Discovery; Roberts, R. M., Khalaf, A. A., Eds.; Dekker: New York, 1984.
(10) Friedel, C.; Crafts, J. M. Comptes Rendus 1877, 84, 1392.
(11) (a) Galabov, B.; Nalbantova, D.; Schleyer, P. v. R.; Schaefer, H. F.,
III Acc. Chem. Res. 2016, 49, 1191. (b) Arene Chemistry: Reaction
MechanismsandMethodsforAromaticCompounds;Mortier,J.,Ed.;Wiley:
Hoboken, NJ, 2016.
D
DOI: 10.1021/acs.orglett.8b03987
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(12) (a) Small, L. F.; Meitzner, E. J. Am. Chem. Soc. 1933, 55, 4602.
(b) Bentley, K. W.; Dyke, S. F.; Marshall, A. R. Tetrahedron 1965, 21,
2553. (c) Pschorr. Ber. Dtsch. Chem. Ges. 1905, 38, 3160.
(13) Heinrich, C. F.; Fabre, I.; Miesch, L. Angew. Chem., Int. Ed. 2016,
55, 5170.
(14) Beltran, F.; Fabre, I.; Ciofini, I.; Miesch, L. Org. Lett. 2017, 19,
5042.
(15) Beltran, F.; Andna, L.; Miesch, L. Org. Chem. Front. 2019, 6, 373−
376.
(16) De, S. K.; Gibbs, R. A. Tetrahedron Lett. 2005, 46, 8345.
(17) (a) Yang, L.; Wang, D.-X.; Pan, J.; Zheng, Q.-Y.; Huang, Z.-T.;
Wang, M.-X. Org. Biomol. Chem. 2009, 7, 2628. (b) Yang, L.; Deng, G.;
Wang, D.-X.; Huang, Z.-T.; Zhu, J.-P.; Wang, M.-X. Org. Lett. 2007, 9,
1387.
(18) Franck-Neumann, M.; Miesch, M.; Gross, L. Tetrahedron Lett.
1990, 31, 5027.
(19) Zheng, P.-F.; Ouyang, Q.; Niu, S.-L.; Shuai, L.; Yuan, Y.; Jiang, K.;
Liu, T.-Y.; Chen, Y.-C. J. Am. Chem. Soc. 2015, 137, 9390.
(20) (a) Franck-Neumann, M.; Miesch, M.; Gross, L. Tetrahedron Lett.
1992, 33, 3879. (b) Harrowven, D. C.; Dainty, R. F. Tetrahedron Lett.
1997,38,7123.(c)Harrowven,D.C.;Dainty,R.F.Tetrahedron1997,53,
15771. (d) Shi, M.; Jiang, J.-K.; Cui, S.-C. Molecules 2001, 6, 852.
(21) Selectivities in Lewis Acid Promoted Reactions; Schinzer, D., Ed.;
Springer: Dordrecht, The Netherlands, 2012.
E
DOI: 10.1021/acs.orglett.8b03987
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