Alternating lodonium-mediated reaction cascades giving indole- And quinoline-containing polycycles

Article abstract of DOI:10.1021/ol800202u

A simple two-step convergent protocol gives direct access to synthetic Intermediate A from ortho-iodoanilines. Intermediate A can be treated with NIS In CH₂CI₂ to Induce novel lodonium mediated domino reaction cascade, which provides direct access to ring-fused Indole compounds B. Simply by changing the reaction conditions, this protocol can be directed down an alternative domino reaction cascade to give various ring fused quinoline compounds C.

Full text of DOI:10.1021/ol800202u

ORGANIC
LETTERS
2008
Vol. 10, No. 10
1967-1970
Alternating Iodonium-Mediated Reaction
Cascades Giving Indole- And
Quinoline-Containing Polycycles
Rosliana Halim, Peter J. Scammells, and Bernard L. Flynn*
Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences,
Monash UniVersity, 381 Royal Parade, ParkVille, VIC 3052, Australia
bernard.flynn@Vcp.monash.edu.au
Received March 4, 2008
ABSTRACT
A simple two-step convergent protocol gives direct access to synthetic intermediate A from ortho-iodoanilines. Intermediate A can be treated
with NIS in CH2Cl2 to induce novel iodonium mediated domino reaction cascade, which provides direct access to ring-fused indole compounds
B. Simply by changing the reaction conditions, this protocol can be directed down an alternative domino reaction cascade to give various ring
fused quinoline compounds C.
Iodocyclization has emerged as an effective protocol in the
preparation of a variety of carbocyclic and heterocyclic ring
Scheme 1
systems.1–5 For example, indoles2 and their O,3 S,4 and Se5
isosteres 2 are readily prepared from phenylacetylenes 1
(Scheme 1). The facile preparation of compounds 1 through
(1) (a) Worlikar, S. A.; Kesharwani, T.; Yao, T.; Larock, R. C J. Org.
Chem. 2007, 72, 1347. and the references cited therein. (b) Alves, D.;
Luchese, C.; Nogueira, C. W.; Zeni, G. J. Org. Chem. 2007, 72, 6726. (c)
Lamanna, G.; Menichetti, S. AdV. Synth. Catal. 2007, 349, 2188. (d) Fischer,
D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Yamamoto, Y. Angew. Chem.,
Int. Ed. 2007, 46, 4764
.
(2) (a) Hoedt, W. M. R.; Koten, G. V.; Noltes, J. G. Synth. Commun.
1977, 7, 61. (b) Barluenga, J.; Trincado, M.; Rubio, E.; Gonzalez, J. M.
Angew. Chem., Int. Ed. 2003, 42, 2406. (c) Amjad, M.; Knight, D. W.
Tetrahedron Lett. 2004, 45, 539. (d) Hessian, K. L.; Flynn, B. L. Org. Lett.
2006, 8, 243. (e) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2006, 71,
Sonogashira coupling and the versatility of the iodo group
in 2 to further substitution, as well as the established capacity
to perform these reactions on solid phases, make this an
extremely powerful method for the construction of these
heterocycles.2–5
In this current study, we have sought to further extend
the utility of this process by exploring the use of an N-(o-
alkynylphenyl)imines 3 in iodocyclization. In particular, we
were interested in the possibility of trapping the intermediate
iminium ion 4 with a tethered nucleophile (Nu), so as to
62.
(3) (a) Banwell, M. G.; Flynn, B. L.; Wills, A. C.; Hamel, E. Aust.
J. Chem. 1999, 52, 767. (b) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli,
F.; Moro, L. Synlett 1999, 1432
.
(4) (a) Flynn, B. L.; Verdier-Pinard, P.; Hamel, E. Org. Lett. 2001, 3,
651. (b) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905. (c) Larock,
R. C.; Yue, D. Tetrahedron Lett. 2001, 42, 6011. (d) Hessian, K. O.; Flynn,
B. L. Org. Lett. 2003, 5, 4377
(5) (a) Kesharwani, T.; Worlikar, S. A.; Larock, R. C. J. Org. Chem.
2006, 71, 2307. (b) Bui, C. T.; Flynn, B. F. J. Comb. Chem. 2006, 8, 163
.
.
10.1021/ol800202u CCC: $40.75
Published on Web 04/24/2008
2008 American Chemical Society

Scheme 2
Table 1. Iodocyclization of N-(o-Alkynylphenyl)imines 3
Derived from Phenylacetylene
yield (%) of
11 from 9
entry
3
methoda
1
2
3
4
5
6
7
3a (R2 ) R3 ) NMe2)
3b (R2 ) H, R3 ) NMe2)
3c (R2 ) H, R3) Ph)
3d (R2 ) R3 ) Ph)
A
A
A/B/C
B
C
B
C
31b
78b
0c
70
62
36
71
3d (R2 ) R3 ) Ph)
3e (R2 ) OMe, R3 ) Ph)
3e (R2 ) OMe, R3 ) Ph)
a Method A: I2, CH2Cl2; Method B: I2, K2CO3, CH3CN; Method C:
NIS, CH2Cl2. b Additional step to cleave the imine portion (5 M KOH,
CH2Cl2) was required. c Decomposition was observed, formation of
benzaldehyde was observed in all reactions.
give ring-fused indole product 5 in a novel tandem reaction
process (Path A, Scheme 2). A fascinating discovery has been
made in the course of this study, where a simple modification
of the reaction conditions employed in the iodocyclization
leads to an alternative reaction path giving ring-fused
quinoline products 6 (Path B, Scheme 2).6
iodocyclization. This reaction was evaluated using different
N-(o-iodophenyl)imines 9a-e, which were coupled to phe-
nylacetylene 10a and the resulting crude products 3a-e
subjected to iodocyclization under different conditions (Table
1). The dimethylamino substituted imines, 3a and 3b, gave
very stable iminium ions after iodocyclization (Method A:
I2, CH2Cl2); these required an additional cleavage step [5 M
KOH(aq)] to give the N-H indole product 11 (31 and 78%,
respectively). Of the other imines trialed, 3c-e (entries 3-7),
only iodocyclization of 3d (Method B: I2, K2CO3, CH3CN)
and 3e (Method C: NIS, CH2Cl2) gave good yields of 11
(Table 1 entries 4 and 7, respectively). In these cases, the
N-H indole 11 was obtained directly, due to rapid in situ
hydrolysis of the iminium ions formed during the iodocy-
clization. As such, they complement the use of N-tosyl and
N-BOC derivatives of o-alkynylanilines 1b, in activating
these substrates toward iodocyclization to give protected
N-H indoles 2 (X ) NH) (Scheme 1).2b,c In view of the
availability of these alternative procedures, we did not further
study this reaction but turned to our main objective of
trapping the iminium ion 4 with an internal nucleophile to
give 5 (Scheme 2).
For the purpose of our investigation, we prepared a series
of N-(o-alkynylphenyl)imines 3 (Scheme 3). These were
Scheme 3
conveniently prepared by condensation of o-iodoanilines 7
with ketones or aldehydes 8 to give N-(o-iodophenyl)imines
9,7 followed by Sonogashira coupling of 9 with acetylenes
10 [1.2 equiv of acetylene, 3 mol% PdCl2(PPh3)2, 8 mol%
CuI, THF/Et3N] to give 3. Most of the imines 3 were
sensitive to hydrolysis and protocyclization; accordingly, the
crude reaction mixtures were generally used in the iodocy-
clization step (Tables 1 and 2).
When 3-isopropoxy-4-methoxyphenylacetylene 10b was
coupled to 9d under Sonogashira conditions (see above) and
the crude product 3f subject to iodocyclization under using
Method C (NIS, CH2Cl2), the cocyclized product isoin-
dolo[2,1-a]indole 5a was obtained in a reasonable overall
yield of 52% from 9d (Table 2, entry 1). This two-step
coupling cocyclization reaction sequence was next investi-
gated using a range of different N-(o-iodophenyl)imines 9c,
9d, and 9f-j and hydroxyl-containing acetylenes 10c-e
(Table 2, entries 2-17). Iodocyclization of the crude coupling
products 3g-u gave the ring fused indoles 5b-p in moderate
to excellent yields from the respective N-(o-iodophenyl)imine
We initially evaluated the capacity of N-(o-alkynylphe-
nyl)imines 3, bearing a non-nucleophilic R4 group to undergo
(6) For an alternative approach to chemoselective indole and quinoline
formation, see ref 2d.
(7) Imine 9a was prepared via nucleophilic substitution of the corre-
sponding iminium chloride as described in the Supporting Information.
1968
Org. Lett., Vol. 10, No. 10, 2008

Scheme 4
Table 2. Iodonium Induced Tandem Cyclization of 3
During our investigations into these cocyclizations reac-
tions, we also employed Method B. Sonogashira coupling
9d to 10d followed by direct iodocyclization of the crude
product 3i using Method B gave the same pyrano fused
indole 5c as that obtained using Method C, albeit in lower
yield (67%) (compare entries 4 and 5 in Table 2). However,
application of Method B to the phenyl-N-(o-alkynylphe-
nyl)imine 3l, obtained from coupling 9c to 10d, did not give
the pyranoindole 5g obtained using Method C but gave the
furanoquinoline 6a in an excellent yield (80%) (compare
entries 8 and 18 in Table 2). This product has resulted from
an oxidative cocyclization reaction (Path B, Scheme 2). The
use of Method B to give a ring fused quinoline was extended
to other systems involving aldimines 9g-i (R2 ) H) and
hydroxyalkynes 10d and 10e to give moderate to good yields
(46-72%) of the furano- and pyrano-fused quinolines over
the two steps (entries 19, 20, and 22-24). In no case was
the corresponding indole compound formed as a byproduct
of this reaction. The ethoxy substituted N-(o-alkynylphe-
nyl)imine 3n failed to give the ring-fused quinoline product
6d but instead underwent rapid decomposition. Attempted
iodocyclization of the N-(o-propynolphenyl)phenylimine
3h using Method B also failed to give either quinoline or
indole 5c using Method B but underwent decomposition
under the reaction conditions (Table 1, entry 3).
a Method B: I2, K2CO3, wet CH3CN; Method C: NIS, CH2Cl2.
b Decomposition of starting material was observed.
9 (43-94%). Only in the case of the phenylaldimine 3h did
the cyclization reaction fail, giving a complex mixture (Table
2, entry 3).
On the basis of observations made during this study, we
have made a number of tentative mechanisitic proposals
(Scheme 4). The propensity for the iodocyclization of
Org. Lett., Vol. 10, No. 10, 2008
1969

aldimines 3 (R2 ) H) using either I2 or NIS to give either 5
or 6, respectively, may arise out of the greater bias of I2,
relative to NIS, to activate the imine in 3 to electrophilic
cyclization than it does the alkyne. Rapid and reversible
single electron extraction from 3 by I2 gives 12. Rotamer
12′ then undergoes a concerted cocyclization reaction to give
13. Alternatively, 12 may first convert to the N-iodoiminium
ion 14 and then cocyclize to give 15. Intermediate 14/15
then loses 2 equivalents of HI giving 6. The HI is sequestered
by the K2CO3 present in the reaction mixture (Method B).
The fact that the diphenylimine 3i gave the pyrano indole
5d under both conditions, Methods B and C (Table 2, entries
4 and 5), probably arises from a much reduced capacity of
the activiated imine 12 to achieve the conformation required
for cyclization (12′/14) due to increased steric interference.
Accordingly, in this case, the reaction flux is directed through
Path A, where I2 acts as an electrophile upon the alkyne.
When Method C is employed, the cyclization proceeds
through Path A, irrespective of the nature of R2 (i.e., for
aldimines and other imines). It is proposed that, relative to
iodine, NIS acts more effectively as an electrophilic π-acid
upon the alkyne than it does as an oxidant upon the imine,
directing the reaction flux through Path A. In Path A, 3 is
initally converted into the cationic intermediate 16. Intramo-
lecular attack by the imine in 16 gives 17, which cyclizes
through its canonical form 17′ to give 5. Alternatively, 16
may give 5 through an asynchronous, concerted reaction
process, transition state A.
Although the stepwise cyclization of 16 through 17/17′
could be used to explain both the monocyclization and
cocyclization reactions to give indoles, it does not fully
explain the pattern of results obtained in this work. We were
struck by the fact that, despite numerous attempts, we were
unable to use Methods B or C to convert aldimine 3c to 11
(Table 1, entry 3), or aldmine 3h to 5c (Table 2, entry 3),
yet all other aldimines 3l,m,n,r,s,t,v bearing a tethered
hydroxyl groups (n ) 2 or 3) cyclized quite efficiently to
give 5 (Method C) or 6 (Method B). The reactions involving
3c and 3h (Methods A-C) all gave a complex mixture of
products. We conclude from this that aldimines 3 (R2 ) H)
are generally unstable under the reaction conditions but that
reversible formation of reactive intermediates 12, 14, and
16 does occur at a rate faster than decomposition. In the
presence of an appropriately tethered nucleophile (n > 1),
these intermediates rapidly undergo cocyclization through
concerted transition states A or 12′/14 to give 5 or 6,
respectively. In both cases (A and 12′/14), the nucleophile
assists cyclization by providing a lower energy pathway to
cocyclization than a stepwise process. In the case of A, this
may be further assisted by the direct development of
aromaticity in the transition state (indole formation) relative
to the transition state leading to the azafulvene intermediate
17.
Transition states A and 12′/14 are not available to 3c
because it lacks a nucleophile. In the case of 3h, transition
state A (n ) 1) is disfavored by Baldwin’s rules as it involves
a 5-endotrigonal cyclization.8 The 6- and 7-endotrigonal
cyclizations that attend the cocyclization of 3l,m,n,r,s,t,v
through transistion state A (n ) 2 or 3) are all favored under
Baldwin’s rule. The ring strain in the transition state of 12′/
14 (n ) 1) going to 13/15 prevents conversion of 3h to a
quinoline 6.
More highly substituted imines (R2/3 * H) are sufficiently
stable to the reaction conditions such that cyclization of 16
to form 17 can occur. Traping of 17/17′ by reaction with
water or an internal nucleophile then gives 11 or 5 (e.g.,
Table 1 entries 4-7 and Table 2 entries 1-2, respectively).
If 17/17′ had formed in the case of the aldimines 3 (R2 )
H) then cyclization of 3h would be expected to proceed at
least as efficiently as the other hydroxyl-containing aldimines
3 (n ) 2 or 3).
In summary, a concise, convergent protocol combining
o-iodoanilines 7, ketones (or aldehydes) 8 and alkynes 10
has been devised that provides for ready access to N-(o-
alkynylphenyl)imines 3, which can be cyclized to give either
ring-fused indoles 5 or quinolines 6 (8 is an aldehyde)
through divergent iodonium induced reaction cascades (Path
A and B, Scheme 2). Formation of 6 most likely involves a
concerted cocyclization process (12′/14), whereas formation
of 5 may be stepwise (17/17′) or concerted (A) depending
on the nature of the nucleophile.
Acknowledgment. We gratefully acknowledge financial
support from the Australian Research Council (LP0562615)
and Bionomics Ltd.
Supporting Information Available: General experimental
procedures and all spectral data for the isolated starting
materials and final products. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL800202U
(8) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734. (b)
Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.; Silberman, L.; Thomas,
R. C. J. Chem. Soc., Chem. Commun. 1976, 736.
1970
Org. Lett., Vol. 10, No. 10, 2008