Schwartz's Reagent-Mediated Regiospecific Synthesis of 2,3-Disubstituted Indoles from Isatins

Article abstract of DOI:10.1021/acs.orglett.5b03449

An expeditious, functional group-tolerant synthesis of indoles from isatins is described. Isatins are treated with Grignard reagents to yield oxindoles. These, in turn, are reduced with Schwartz's reagent and subjected to nucleophile addition and dehydrat

Full text of DOI:10.1021/acs.orglett.5b03449

Letter
pubs.acs.org/OrgLett
Schwartz’s Reagent-Mediated Regiospecific Synthesis of 2,3-
Disubstituted Indoles from Isatins
A. Ulikowski and B. Furman*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
S
* Supporting Information
ABSTRACT: An expeditious, functional group-tolerant syn-
thesis of indoles from isatins is described. Isatins are treated with
Grignard reagents to yield oxindoles. These, in turn, are reduced
with Schwartz’s reagent and subjected to nucleophile addition
and dehydration to yield 2,3-disubstituted indoles regiospecifi-
cally. This represents a divergent approach to the synthesis of
these medicinally and synthetically important compounds.
Scheme 1. Different Approaches to the Synthesis of Indoles
ndoles are one of the most enduring motifs in organic
Ichemistry. They form the core of a myriad of natural products
and occur in a number of medicinally relevant compounds.1
Their importance is expressed in the wealth of methods for their
synthesis developed over the years.2 One of the most commonly
used methods is the classic Fisher indole synthesis.3 More
recently, a number of transition-metal-mediated methods have
appeared, the most well-known of which is the Larock indole
synthesis.4
Despite the rich methodology available for their synthesis, the
chemistry of indoles is not free of challenges. Among them,
especially pronounced is the question of regioselectivity in the
synthesis of 2,3-disubstituted indoles.
Scheme 2. Selective Activation of Isatin Carbonyls
The majority of known methods are most suitable for the
synthesis of 2- or 3-monosubstituted indoles. This is problematic,
as 2,3-disubstituted indoles are compounds of marked
importance.5
As most known strategies for the synthesis of indoles involve
the annulation of the azacycle to an existing aromatic ring
(Scheme 1), a possibility of differently annulated regioisomers
arises. Addressing this issue is a priority in modern methods of
indole synthesis.
We envisioned an alternative approach to the regioselective
synthesis of 2,3-disubstituted indoles that involved the differ-
ential activation of the two carbonyl groups present in the isatin
molecule (Scheme 2). Isatins are an ideal substrate for the
synthesis of indoles owing to their ready availability.6,7 We
expected that the ketone group would undergo ready
substitution by a number of nucleophiles, leaving the amide
carbonyl to be manipulated in the next step.
The unique chemistry of Schwartz’s reagent, allowing for the
selective activation of amide carbonyls,8 prompted us to employ
this reagent in the second step of the synthesis to form a reactive
iminium moiety which would allow the addition of a range of
nucleophiles not available in previous work.7 We expected the
partial reduction and addition to proceed in a one-pot manner,
with subsequent dehydration to the indole proceeding
spontaneously under the acidic conditions employed. The
anticipated reaction pathway is shown in Scheme 3. The amide
carbonyl group undergoes reduction with Schwartz’s reagent.
The resulting zirconium complex is decomposed by the action of
added TFA. The addition of the nucleophile yields a hydroxy-
amine, which is then dehydrated in the acidic conditions
employed.
To test our hypothesis, we synthesized a series of oxindoles
containing different functional groups from N-benzylisatin
(Scheme 4). We employed modified literature conditions9 and
Received: December 3, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03449
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Organic Letters
Letter
Scheme 3. Anticipated Reaction Pathway
Scheme 5. Synthesis of Indoles from Oxindoles
Scheme 4. Synthesis of Oxindoles from N-Benzylisatin
Table 1. Yields of Indoles
substrate
product yield (%)
used magnesium−iodine exchange10 to obtain the Grignard
reagents necessary. The 3-substituted oxindoles were produced
in good yields.
We then subjected the synthesized oxindoles to reduction with
Schwartz’s reagent using a modified literature procedure.8c As it
turned out, using more than 1 equiv of the reductant did not
improve the yield. We discovered that cooling the reaction
mixture prior to the addition of Schwartz’s reagent avoided over-
reduction of the sensitive functionalities. Preformed Schwartz’s
reagent was employed as using a reagent generated in situ led to
over-reduction to 2-unsubstituted indoles.
Next, we subjected the reduced substrates to the addition of
the nucleophile in the same pot. The addition of allyltributyl-
stannane, acetophenone enol TMS ether, and indole proceeded
smoothly. In the case of thiophenol it was necessary to use only 1
equiv of the nucleophile. Otherwise, extensive over-reduction to
a 3-monosubstituted indole occurred. Amines were unreactive;
neither pyrrolidine nor p-anisidine gave the expected product.
We are currently working on addressing this issue. The reaction
with dimethyl malonate did not proceed under the standard
conditions, but we were able to obtain the expected effect by the
addition of an excess of TMSOTf. We suspect that this is due to
the additional activation of the nucleophile by the formation of a
ketene acetal in situ. Contrary to our expectations, we normally
isolated a mixture of the target indole and the product of addition
which did not dehydrate spontaneously. We found that simple
treatment of the crude reaction mixture with excess TFA in
CH2Cl2 effected dehydration, converting the mixture into the
desired indole only (Scheme 5). The product was normally
obtained in good to excellent yield (Table 1).
2a
2b
2c
2d
2e
2f
3a, 99
3b, 99
3c, 75
3d, 84
3e, 75
3f, 65
4a, 82
4b, 82
4c, 78
4d, 57
4e, 73
4f, 67
5a, 80
5b, 70
5c, 73
5d, 69
5e, 49
5f, 49
6a, 49
6b, 84
6c, 67
6d, 41
6e, 67
7a, 51
7b, 55
a
7c, 35
7d, 59
b
b
a
6f, 12
a
These products could not be isolated in pure form; yield is estimated
from NMR. No expected product was isolated.
b
and -cyano-substituted substrates. This is probably due to the
more forcing conditions required in the reactions with this
nucleophile. The same probably accounts for the poor yield
when employing the electrophile bearing the acid-sensitive
methoxy group. We believe that these limitations might be
overcome by careful optimization of the reaction conditions. In
the case where TMSCN was employed as the nucleophile, we
observed quite a different reaction outcome. Instead of obtaining
the desired indole, we isolated a compound to which we ascribe
the tetrahydroquinoline structure 8. We suspect that this is due
to the decomposition of zirconocene by cyanide anion with the
release of cyclopentadiene, which reacts with the nascent
iminium salt in the manner of a Povarov reaction11−
fragmentation cascade (Scheme 6). We believe that the observed
unusual anti stereochemistry stems from the minimization of
steric hindrance in the bicyclic intermediate. This represents a
new approach to the diastereoselective synthesis of highly
substituted tetrahydroquinolines.12 We are currently in the
process of investigating the scope of this transformation.
The results show that the method employed is regiospecific in
contrast to classical methods that rely on constructing the five-
membered azacycle from scratch. The excellent functional group
tolerance of this method allows the introduction of varied
substituents to the product structure, allaying the limitations of
previous methods, i.e., especially the work of Lu et al.7 In
comparison to that methodology, the present method allows for
sensitive functionalities to be introduced in the addition step
Only when the nitro-substituted oxindole was subjected to the
reaction with thiophenol did we isolate low amounts of the
desired indole, probably due to over-reduction of the nitro group
by the thiol reagent. In the case of other functional groups the
yields stayed uniformly high. We also did not observe the desired
product in the reactions of dimethyl malonate with the arylnitro-
B
DOI: 10.1021/acs.orglett.5b03449
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Scheme 6. Mechanism of Rearrangement to
Tetrahydroquinoline
REFERENCES
■
(1) (a) Sharma, V.; Kumar, P.; Pathak, D. J. Heterocycl. Chem. 2010, 47,
491. (b) Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C. H.;
Verma, A. K.; Choi, E. H. Molecules 2013, 18, 6620. (c) Zhang, M.-Z.;
Chen, Q.; Yang, G.-F. Eur. J. Med. Chem. 2015, 89, 421. (d) Ishikura, M.;
Abe, T.; Choshi, T.; Hibino, S. Nat. Prod. Rep. 2013, 30, 694.
(e) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010,
110, 4489.
(2) (a) Taber, D. F.; Tirunahari, P. K. Tetrahedron 2011, 67, 7195.
(b) Inman, M.; Moody, C. J. Chem. Sci. 2013, 4, 29. (c) Vicente, R. Org.
Biomol. Chem. 2011, 9, 6469. (d) Gribble, G. W. J. Chem. Soc. Perkin 1
2000, 1045. (e) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215.
(f) Bartoli, G.; Dalpozzo, R.; Nardi, M. Chem. Soc. Rev. 2014, 43, 4728.
(3) (a) Robinson, B. Chem. Rev. 1963, 63, 373. (b) Robinson, B. Chem.
Rev. 1969, 69, 227. (c) Robinson, B. The Fischer Indole Synthesis; Wiley,
1982.
(4) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63, 7652.
(c) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644.
(5) (a) Alex, K.; Schwarz, N.; Khedkar, V.; Sayyed, I. A.; Tillack, A.;
Michalik, D.; Holenz, J.; Díaz, J. L.; Beller, M. Org. Biomol. Chem. 2008,
6, 1802. (b) Arcadi, A.; Cacchi, S.; Carnicelli, V.; Marinelli, F.
Tetrahedron 1994, 50, 437. (c) Pawlak, J. M.; Khau, V. V.; Hutchison,
(Scheme 4) while preserving them in the next synthetic steps.
This represents a marked departure from the previous work,
where mainly hydrocarbon-substituted indoles could be
obtained. The intermediacy of an iminium cation enables the
use of a wider array of nucleophiles than only Grignard reagents,
which have been used under rather forcing conditions.7 The
method described is carried out in a straightforward and rapid
fashion, permitting the synthesis of large libraries of compounds
in a timely manner. A diverse set of nucleophiles can be
employed, including C- and S-nucleophiles, which leads to
greater diversification of the products.
In summary, we have developed an expeditious method of
synthesizing 2,3-disubstituted indoles from commercially
available isatins regiospecifically. The methodology is charac-
terized by high functional group tolerance and employs the
readily available Schwartz’s reagent as the reducing agent. It
opens up an attractive route to a variety of 2,3-disubstituted
indoles and has the potential to aid in the synthesis of
pharmacologically and synthetically relevant indole derivatives.
We have also described a new diastereoselective synthesis of
highly substituted tetrahydroquinolines.
D. R.; Martinelli, M. J. J. Org. Chem. 1996, 61, 9055. (d) Kruger (nee
́
̈
Alex), K.; Tillack, A.; Beller, M. Adv. Synth. Catal. 2008, 350, 2153.
(6) (a) Silva, J. F. M. da; Garden, S. J.; Pinto, A. C. J. Braz. Chem. Soc.
2001, 12, 273. (b) Garden, S. J.; da Silva, R. B.; Pinto, A. C. Tetrahedron
2002, 58, 8399.
(7) Dou, X.; Yao, W.; Wen, S.; Lu, Y. Chem. Commun. 2014, 50, 9469.
(8) (a) Spletstoser, J. T.; White, J. M.; Tunoori, A. R.; Georg, G. I. J.
Am. Chem. Soc. 2007, 129, 3408. (b) Schedler, D. J. A.; Li, J.; Ganem, B. J.
Org. Chem. 1996, 61, 4115. (c) Oda, Y.; Sato, T.; Chida, N. Org. Lett.
2012, 14, 950. (d) Nakajima, M.; Oda, Y.; Wada, T.; Minamikawa, R.;
Shirokane, K.; Sato, T.; Chida, N. Chem. - Eur. J. 2014, 20, 17565.
(9) Connolly, T. J.; Durst, T. Can. J. Chem. 1997, 75, 542.
(10) (a) Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.; Vu, V.
A.; Knochel, P. Synthesis 2002, 2002, 565. (b) Calí, P.; Begtrup, M.
Synthesis 2002, 2002, 63. (c) Sapountzis, I.; Knochel, P. Angew. Chem.,
Int. Ed. 2002, 41, 1610.
(11) (a) Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656. (b) Kouznetsov,
V. V. Tetrahedron 2009, 65, 2721. (c) Fochi, M.; Caruana, L.; Bernardi,
L. Synthesis 2014, 46, 135.
(12) Sridharan, V.; Suryavanshi, P. A.; Menen
2011, 111, 7157.
́
dez, J. C. Chem. Rev.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03449.
1
Detailed synthetic procedures, characterization, and H
and 13C spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: furbar@icho.edu.pl.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this research, provided by the National
Science Centre, Grant No. OPUS 2013/11/B/ST5/01188, is
gratefully acknowledged.
C
DOI: 10.1021/acs.orglett.5b03449
Org. Lett. XXXX, XXX, XXX−XXX