Complex Hydroindoles by an Intramolecular Nitrile-Intercepted Allylic Alkylation Cascade Reaction

Article abstract of DOI:10.1021/acs.orglett.8b00499

Bisnucleophilic reagents derived from malononitrile, ketones, benzaldehydes, and nitromethane can react with bisallylic electrophiles via a nitrile-intercepted allylic alkylation cascade reaction to yield complex hydroindole architectures. Also noteworthy

Full text of DOI:10.1021/acs.orglett.8b00499

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Complex Hydroindoles by an Intramolecular Nitrile-Intercepted
Allylic Alkylation Cascade Reaction
Peter Vertesaljai, Ion Ghiviriga, and Alexander J. Grenning*
Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, Florida 32611, United States
S
* Supporting Information
ABSTRACT: Bisnucleophilic reagents derived from malononitrile, ketones, benzaldehydes, and nitromethane can react with
bisallylic electrophiles via a nitrile-intercepted allylic alkylation cascade reaction to yield complex hydroindole architectures. Also
noteworthy is that the only stoichiometric byproducts from the preparation and reaction of the bisnucleophile and biselectrophile
are water, acetic acid, and bicarbonate, making it a potentially “green” platform for multistep complex molecule synthesis. These
scaffolds can be converted into hydrooxindoles by a unique olefin isomerization followed by Witkop−Winterfeldt-like oxidation.
Scheme 1. Initial Proposal: Cascade Allylic Alkylation To
Access Terpenoid Scaffolds
omplex hydroindoles (e.g., perhydroindoles/octahydroin-
Cdoles, and hexahydroindoles) are common in nature and
drug molecules (Figure 1).1 The diversity of structure results in
innumerous bioactivities and creative synthetic solutions for
many specific targets.2
Figure 1. Representative hydroindole-containing natural and unnatural
products.
Our research program aims to discover tunable routes to
complex natural product architectures.3 Key requirements for
tunable/modular synthesis include abundance of starting mate-
rials, efficiency (yield and step count), and simplicity of syn-
thetic operations.4 Strategies that can adhere to these key
requirements may streamline natural-product-inspired drug dis-
covery. With this in mind, we were attracted to building blocks
1, molecules prepared by operationally simple and eco-friendly
condensation reactions5 and a catalytic asymmetric Michael
addition (Scheme 1A).6 At the outset, we envisaged that these
substrates could serve as platforms for tunable terpenoid syn-
thesis (Scheme 1B,C). Specifically, cascade bisallylic alkylation
of 1 with buten-1,4-diol derivative 2a or related reagents would
yield arylated 6,7 ring systems by Pd-catalyzed deconjugative
α-alkylation7 to form [I-a] followed by nitronate alkylation8 to
afford 3.
To test the proposal, 1a was prepared racemically by amine-
catalyzed Michael addition.6,9 Interestingly, the reaction of 1a
with 1,4-diol derivative 2a gave hydroindole 4a as a separable
mixture of three diastereomers. Under a variety of conditions,
this was the exclusive product (Table 1). The optimal protocol
discovered for hydroindole synthesis was 1:2.5 1a:2a, 5 mol %
Pd(PPh3)4, and Cs2CO3 as a base in dichloromethane at room
temperature for 24 h. We also found that many other solvents
worked modestly to reasonably well (entries 1−3). The reac-
tion could be accelerated at a higher temperature, though the
Received: February 12, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00499
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of the Nitrile-Intercepted Cascade Allylic Alkylation Reaction
entry
Pd(0) (10 mol %)
base (1.1 equiv)
equiv of 2a
solvent
time (h)
temp. (°C)
yield (%)
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd/BINAP
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
1.1
1.1
1.1
1.1
1.1
1.1
2.5
2.5
2.5
THF
24
24
24
24
12
24
24
24
24
rt
rt
rt
rt
50
rt
rt
rt
rt
31
43
39
48
27
19
67
56
55
DMF
Tol
CH2Cl2
THF
THF
CH2Cl2
CH2Cl2
CH2Cl2
K3PO4
yield in this experiment was modest (entry 5). Monodentate
ligands on the Pd metal center appear to be more effective
than bidentate ligands, as suggested by the result examining rac-
BINAP/Pd2dba3 (entry 6). Also, other mild inorganic bases
promoted the hydroindole synthesis as well (entries 8 and 9).
Unfortunately, all optimization attempts resulted in diastereo-
meric mixtures. As a final point, 6/7 bicycloalkanes (the initial
targets; Scheme 1) were never observed in our optimization
studies.
Scheme 3. Scope of Hydroindole Synthesis
Hydroindole 4a is presumed to be prepared from 1a and 2a
by a Pd-catalyzed deconjugative α-allylation to form [I-a′], an
intramolecular nitrile−nitronate coupling reaction (“Pinner-
like” transformation) to form [I-b], and then an intramolec-
ular allylic alkylation reaction between the resultant enamine
and Pd−π-allyl electrophile (Scheme 2). In one mechanistic
Scheme 2. Reaction Sequence Yielding Hydroindole 4a
a
b
Diastereomeric ratios were determined after purification. Dia-
stereomers were separable and individually characterized. See the
c
Supporting Information. Isolated as a mixture of two diastereomers.
d
See the Supporting Information. A diastereomer was isolated pure.
Two diastereomers were inseparable by silica gel chromatography.
e
Two diastereomers were isolated pure. Two diastereomers were
inseparable by silica gel chromatography.
product, the diastereomers could be isolated independently and
characterized by detailed NMR analysis.9 The stereochemistry
of each diastereomer was unequivocally established by a com-
bination of H−1H coupling constants, H−13C coupling con-
stants, and quantitative NOEs.9,11 In regard to the scope, the
reaction could be performed with substrates derived from
cyclohexanones (4a−d) or cycloheptanone (4e). The cyclohexyl
series also explored various substitution patterns, including a
gem-dimethyl group (4b), a heterocycle (4c), and an additional
stereocenter (4d). Scaffolds bearing diverse aryl/alkenyl groups
could also be prepared from different benzaldehyde derivatives
(4f−h), such as 2-bromophenyl (4f) and 2,5-dimethoxyphenyl
(4g). The styrenyl-containing product (4h) can be traced back
to cinnamaldehyde.
1
1
experiment, we found that 1a undergoes a Pinner-like trans-
formation to afford enamine 5a under mildly basic conditions.6b
The facile Pinner-like transformation is initially surprising, but
the high nitrile electrophilicity of dialkylmalononitriles has been
previously noted in the literature.6b,d,10
With the optimized conditions in hand, we next examined the
scalability and scope of the cascade transformation (Scheme 3).
Regarding the former, 2.5 g of 4a was prepared without change
from the optimal protocol as a mixture of diastereomers. For this
B
DOI: 10.1021/acs.orglett.8b00499
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Through the course of the studies, several other notable experi-
ments were performed to examine the scope (Schemes 4 and 5).
nature with powerful biological activities (e.g., lysergic acid/ergot
natural products).12 The stereochemistry-determining events of
this transformation include desymmetrization of the diaster-
eotopic nitriles and the Pd-catalyzed allylic alkylation step,
likely by a double inversion mechanism, and can potentially
be rationalized by the conformations [I-c] and [I-d] shown in
Scheme 4.
Scheme 4. Reduced Substrates Yield Single Diastereomers of
Hydroindoles and Hydroquinolines by Cascade
Transformation
We next examined acyclic starting materials for nitrile-
intercepted cascade allylic alkylation reactivity (Scheme 5).
Substrate 8a derived from diethyl ketone was a competent
reactant, yielding the desired product in 34% yield as a mixture
of separable diastereomers. The reactants 8b and 8c underwent
only deconjugative alkylation because the olefin geometry from
deconjugative alkylation precluded the cascade transformation.
However, by reduction first, hydroindole synthesis was rein-
stated, albeit in modest yield. In this case, the NaBH4 reduction
step to prepare 10a was not diastereoselective because of the
remoteness of the stereocenter, and the cascade transformation
yielded hydroindole 11a in 17% yield as a single diastereomer
(34% based on one diastereomer of 10a). An additional 9% of
product was isolated as an unassigned mixture of four diaste-
reomers. Although we were pleased that the transformation was
successful, it is clear that acyclic starting materials are less
efficient than their cyclic counterparts and may benefit from
further optimization in the future.
Having outlined the scope and limitations of the transfor-
mation, we set out to examine the reactivity of these scaffolds
(Scheme 6). Under standard hydrogenation conditions, only
Scheme 6. Functional Group Interconversion Reactions
Scheme 5. Examination of Acyclic Substrates
the terminal alkene was reduced, yielding 12. The other alkenes
and nitro group survived unscathed. Under basic conditions, we
uncovered an unexpected isomerization of the terminal olefin
to the enamine 13. We suspect that the isomerization involves
double deprotonation; the imine−nitronate [I-e] is generated
first, and then the fully conjugated dianion [I-f] is formed.
Hydrolysis then yields the isomerized product 13. This is ana-
logous to nitronate dianion chemistry, which also is interest-
ing and underexplored.13 Finally, mCPBA-promoted Witkop−
Winterfeldt-like oxidation of enamine 13 yields hydrooxindole
14 with excellent efficiency.14 Thus, hydroindole scaffolds 4 can
efficiently be converted into hydrooxindoles over this unique
two-step sequence.
First, 6a, prepared by a high-yielding (90%) and diastereo-
selective (>20:1 dr) NaBH4 reduction of 1a, underwent the
cascade reaction diastereoselectively. To reiterate, the cascade
reaction with alkylidene-containing substrates 1 is not diaste-
reoselective, whereas the reduced version (6a) yielding 7a is
(Table 1 vs Scheme 4). Intrigued by this result, we explored the
reaction with bisallylic reagent 2b and found a similar result
yielding hydroquinoline 7b as a single diastereomer. Notably,
complex hydroquinolines, like hydroindoles, are ubiquitous in
In conclusion, we serendipitously uncovered a cascade reac-
tion yielding hydroindoles and hydroquinolines. All of the start-
ing materials needed to assemble the heterocycles are abun-
dant: malononitrile, ketones, benzaldehydes, nitromethane, and
C
DOI: 10.1021/acs.orglett.8b00499
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(6) (a) Xue, D.; Chen, Y-Ch.; Wang, Q.-W.; Cun, L. F.; Zhu, J.;
Deng, J.-G. Org. Lett. 2005, 7, 5293−5296. (b) Poulsen, T. B.; Bell, M.;
Jørgensen, K. A. Org. Biomol. Chem. 2006, 4, 63−70. (c) Jiang, L.;
Zheng, H.-T.; Liu, T.-Y.; Yue, L.; Chen, Y.-C. Tetrahedron 2007, 63,
5123. (d) Xue, D.; Li, J.; Zhang, Z.-T.; Deng, J.-G. J. Org. Chem. 2007,
72, 5443. (e) Chen, W.-Y.; Ouyang, L.; Chen, R.-Y.; Li, X.-S. Synth.
Commun. 2012, 42, 2585.
(7) (a) Nakamura, H.; Iwama, H.; Ito, M.; Yamamoto, Y. J. Am.
Chem. Soc. 1999, 121, 10850. (b) Grossman, R. B.; Varner, M. A. J.
Org. Chem. 1997, 62, 5235. (c) Vertesaljai, P.; Navaratne, P. V.;
Grenning, A. J. Angew. Chem., Int. Ed. 2016, 55, 317.
(8) (a) Wade, P. A.; Morrow, S. D.; Hardinger, S. A. J. Org. Chem.
1982, 47, 365. (b) Nemoto, T.; Jin, L.; Nakamura, H.; Hamada, Y.
Tetrahedron Lett. 2006, 47, 6577. (c) Gietter-Burch, A. A. S.;
Devannah, V.; Watson, D. A. Org. Lett. 2017, 19, 2957. (d) Gildner,
P. G.; Gietter, A. A. S.; Cui, D.; Watson, D. A. J. Am. Chem. Soc. 2012,
134, 9942.
(9) See the Supporting Information for more specific details.
(10) (a) Su, W.; Ding, K.; Chen, Z. Tetrahedron Lett. 2009, 50, 636−
639. (b) Longstreet, A. R.; Campbell, B. S.; Gupton, B. F.; McQuade,
D. T. Org. Lett. 2013, 15, 5298.
buten-1,4-diol derivatives and related bisallylic electrophiles.
As such, structural variation can easily be achieved. Though
nondiastereoselective in the original protocol (Scheme 3), we
uncovered a diastereoselective route when the starting material’s
alkylidene is reduced (Scheme 4). Furthermore, the hydroindole
scaffolds 4 can be converted into oxindoles by a unique iso-
merization/oxidation sequence.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00499.
Experimental procedures, compound characterization data
(1H NMR, 13C NMR, and HRMS), and copies of 1H and
13C NMR spectra (PDF)
Stereochemistry elucidation (PDF)
AUTHOR INFORMATION
■
(11) Butts, C. P.; Jones, C. R.; Towers, E. C.; Flynn, J. L.; Appleby,
L.; Barron, N. J. Org. Biomol. Chem. 2011, 9, 177.
Corresponding Author
*grenning@ufl.edu
ORCID
(12) Wallwey, C.; Li, S.-M. Nat. Prod. Rep. 2011, 28, 496.
(13) (a) Tanaka, S.; Kohmoto, S.; Yamamoto, M.; Yamada, K.
Nippon Kagaku Kaishi 1989, 10, 1742. (b) Yamada, K.; Tanaka, S.;
Kohmoto, S.; Yamamoto, M. J. Chem. Soc., Chem. Commun. 1989, 2,
110.
(14) (a) Mentel, M.; Breinbauer, R. Curr. Org. Chem. 2007, 11, 159.
(b) Yang, Y.; Bai, Y.; Sun, S.; Dai, M. Org. Lett. 2014, 16, 6216.
(c) Klare, H. F. T.; Goldberg, A. F. G.; Duquette, D. C.; Stoltz, B. M.
Org. Lett. 2017, 19, 988.
Alexander J. Grenning: 0000-0002-8182-9464
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the College of Liberal Arts and Sciences and the
Department of Chemistry at the University of Florida for
startup funds. We also thank the Mass Spectrometry Research
and Education Center and their funding source (NIH S10
OD021758-01A1).
REFERENCES
■
(1) For a review related to alkaloids, see: (a) Kochanowska-
Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489. For
selected papers related to the representative molecules in Figure 1, see:
(b) Goetz, M.; Boegri, T.; Gray, A. H.; Strunz, G. M. Tetrahedron
1968, 24, 2631−2643. (c) Morita, H.; Takatsu, H.; Shen, Y.-C.;
Kobayashi, J. Tetrahedron Lett. 2004, 45, 901−904. (d) Fridrichsons,
J.; Mathieson, A. M. Tetrahedron Lett. 1960, 1, 18−21. (e) Pfaffli, P.;
Hauth, H. Helv. Chim. Acta 1978, 61, 1682−1695. (f) Inubushi, Y.;
Sasaki, Y.; Tsuda, Y.; Yasui, B.; Konita, T.; Matsumoto, J.; Katarao, E.;
Nakano, J. Tetrahedron 1964, 20, 2007−2023.
(2) For a review related to alkaloid synthesis, see: (a) Crossley, S. W.
M.; Shenvi, R. A. Chem. Rev. 2015, 115, 9465. For selected recent
syntheses of hydroindole-containing alkaloids, see: (b) Shemet, A.;
Carreira, E. M. Org. Lett. 2017, 19, 5529. (c) Gan, P.; Pitzen, J.; Qu, P.;
Snyder, S. A. J. Am. Chem. Soc. 2018, 140, 919. (d) Wang, N.; Liu, J.;
Wang, C.; Bai, L.; Jiang, X. Org. Lett. 2018, 20, 292. (e) Zuo, X.-D.;
Guo, S.-M.; Yang, R.; Xie, J.-H.; Zhou, Q.-L. Org. Lett. 2017, 19, 5240.
(f) Xie, X.; Wei, B.; Li, G.; Zu, L. Org. Lett. 2017, 19, 5430. (g) Huber,
T.; Preuhs, T. A.; Gerlinger, C. K. G.; Magauer, T. J. Org. Chem. 2017,
82, 7410. For diversity-oriented hydroindole synthesis, see: (h) Oguri,
H.; Schreiber, S. L. Org. Lett. 2005, 7, 47.
(3) (a) Lahtigui, O.; Emmetiere, F.; Zhang, W.; Jirmo, L.; Toledo-
Roy, S.; Hershberger, J. C.; Macho, J. M.; Grenning, A. J. Angew.
Chem., Int. Ed. 2016, 55, 15792−15796. (b) Fereyduni, E.; Grenning,
A. J. Org. Lett. 2017, 19, 4130. (c) Scott, S. K.; Grenning, A. J. Angew.
Chem., Int. Ed. 2017, 56, 8125.
(4) (a) Grenning, A. J. Synlett 2017, 28, 633−639. (b) Gaich, T.;
Baran, P. S. J. Org. Chem. 2010, 75, 4657.
(5) Cope, A. C. J. Am. Chem. Soc. 1937, 59, 2327.
D
DOI: 10.1021/acs.orglett.8b00499
Org. Lett. XXXX, XXX, XXX−XXX