Synthesis of polycyclic spiroindolines by highly diastereoselective interrupted Ugi cascade reactions of 3-(2-isocyanoethyl)indoles

Article abstract of DOI:10.1039/c6cc07459f

We report a highly diastereoselective interrupted Ugi reaction to construct a broad range of structurally congested and stereochemically complex spiroindolines from tryptamine-derived isocyanides. The reaction is facilitated by using fluorinated alcohols (TFE or HFIP) as solvents and tolerates a broad range of amines, aldehydes and 2-isocyanoethylindoles to give polycyclic products in moderate to excellent yields.

Full text of DOI:10.1039/c6cc07459f

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DOI: 10.1039/C6CC07459F.
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Synthesis of polycyclic spiroindolines by highly diastereoselective
interrupted Ugi cascade reactions of 3-(2-isocyanoethyl)indoles
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
Jordy M. Saya, Barry Oppelaar, Răzvan C. Cioc, Gydo van der Heijden, Christophe M. L. Vande
b
a
a
Velde, Romano V. A. Orru and Eelco Ruijter*
DOI: 10.1039/x0xx00000x
www.rsc.org/chemcomm
We report a highly diastereoselective interrupted Ugi reaction to intermediate
construct broad range of structurally congested and give the -adduct
stereochemically complex spiroindolines from tryptamine-derived Mumm rearrangement to give Ugi product
1 is then quickly intercepted by a carboxylate to
4
a
α
2
2 (X = O CR ), which in turn undergoes a
4
. Much research
3
isocyanides. The reaction is facilitated by using fluorinated has been devoted to the development of variations on the Ugi
alcohols (TFE or HFIP) as the solvent and tolerates a broad range reaction to expand the range of resulting products, e.g. by
5
of amines, aldehydes and 2-isocyanoethylindoles to give the combining it with post-condensation reactions. An obvious
polycyclic products in moderate to excellent yields.
point to divert the course of the Ugi reaction is the
introduction of alternative nucleophiles reacting with the
In the pursuit of novel bioactive small molecules, the
development of new synthetic methodology is of high and
continuous interest. Multicomponent reactions (MCRs), in
which three or more reagents are incorporated in the skeleton
of the product, are an effective tool in this quest as they entail
nitrilium intermediate
1 to give other product types. As early
as 1961, Ugi showed that replacing the carboxylic acid by HN
6
3
led to the formation of
α-amino tetrazoles 4. Since then, a
variety of external and internal nucleophiles have been
7
demonstrated to result in a wide range of products. The most
1
high molecular diversity in a single operation. This feature
prominent example of an internal nucleophile is the use of 2-
aminoazines in the Groebke-Bienaymé-Blackburn (GBB)
7b-d
reaction affording fused imidazoles (e.g. 5). Later, Sorensen
allows the rapid and straightforward construction of highly
diverse libraries, which is of prime importance for lead
discovery. Moreover, MCRs are suited to access non-planar
heterocyclic scaffolds which are gaining in popularity in
showed that highly electron-rich anilines can also be used and
8
coined this process an ‘interrupted Ugi reaction’. Although
2
medicinal chemistry. We aim to utilize MCR-based strategies
this reaction may be considered a ‘carba-GBB’ reaction, the
term ‘interrupted Ugi reaction’ covers a much broader range
of transformations.
for the rapid and selective assembly of heterocycles
resembling natural products in terms of complexity and
density of functionalization.
In multicomponent chemistry, isocyanide-based multi-
component reactions (IMCRs) take a unique position. The most
widely studied IMCR is undoubtedly the Ugi reaction, a four-
component reaction between isocyanides, aldehydes, amines,
R
1
R
N
1
N N
O
O
NH
R3
X =
R4
X
X =
N
N
R1
N3
O
O
R4
R3
R3
N
R2
Ugi
HN
R2
azido-
Ugi
HN
R2
3
2
4
3
and carboxylic acids yielding peptide-like compounds. The
X
mechanism of the Ugi reaction is generally believed to involve
the nucleophilic attack of the isocyanide on an in situ-
generated iminium ion (Scheme 1). The resulting nitrilium ion
R1
N
R
1
HN
+
R2
=
N
R1
+ H
N
N
C
H
R3
+
GBB
N
-
H
2
O
3
5
2NH
2
HN
R2
R
R
R3
O
1
this
work
N
N
R1
=
H
2
N
H
R
R3
N
H
or
7
N
N
R2
R2
N
HN
N
H
R1
N
R1
H
H
6
8
Scheme 1 Variations on the Ugi reaction.
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1
a,b
Table 1 Scope of Aldehydes and Primary Amines
In light of our recent discovery that N-R fragmentation
represents an alternative reaction path from nitrilium
NC
N
H
1
1 to give nitriles (for R = Tr), we considered the
9
O
R2
intermediate
R2
+
H
use of other tailored isocyanides to divert the course of the
classical Ugi reaction. We reasoned that the presence of
tethered C-nucleophiles, notably indoles, could trap the
N
H
H
2
N
TFE,rt
16-24 h
N
R1
N
R
1
9
a
H
8
Br
N
H
N
N
1
.
0,11
Cl
nitrilium intermediate to give spiro intermediates
6
As
Ph
such intermediates also play a role in the Bischler-Napieralski
N
N
N
1
2
N
N
Ph
N
H
H
reaction, they could rearrange to give the corresponding
dihydro- -carbolines Alternatively, spiro iminium
intermediate could undergo a secondary cyclization to give
tetracyclic aminals
H
H
Cl
H
β
7.
8aa
48h, 44%)
8ab
(48h, 37%)
8ac
(48 h, 25%)
c
(
OMe
6
MeO
N
N
N
1
.
3-15
8
As the latter represent a complex,
t-Bu
Bn
t-Bu
natural product-like scaffold with various diversity points, we
opted to pursue it as our primary target.
N
O
N
N
H
N
H
H
N
H
H
H
NH
2
8
ad
11ae
8af
D
ö
mling and Lesma already demonstrated the use of 3-(2-
d
(
24h, 63%)
OMe
(24 h, 37%)
(16 h, 71%)
1
6
isocyanoethyl)indole (9a) in the classical Ugi reaction. In the
absence of a carboxylic acid, we hypothesized that the
envisioned interrupted Ugi cascade would require an acid
catalyst to activate the imine. A related cascade based on
N
N
t-Bu
t-Bu
N
N
N
iPr
N
Bn
H
H
H
H
1
1
conjugate addition of
investigated the reaction of isocyanide 9a and N-benzylidene-
aniline (10) with various Br nsted acids and solvents (for
9
has been reported. Thus, we
8ag
16h, 99%)
8ah
(
(16h, 89%)
8ah
N
N
N
ø
Me
Me
t-Bu
details, see the ESI). However, we found 9a to be unstable
under most conditions. Surprisingly, we found that performing
the reaction in 2,2,2-trifluoroethanol (TFE), a strong hydrogen
bond donor solvent, in the absence of an acid catalyst or other
additives afforded the desired product 8aa in 50% yield as a
N
S
N
OMe
OMe
N
N
N
N
H
H
H
H
H
H
Ph
8
ai
8aj
8ak
(
16h, 70%)
(16h, 73%)
N
(16 h, 83%)
N
N
1
single diastereomer (Scheme 2) as determined by H NMR (dr
N
N
N
N
t-Bu
N
H
N
H
>
19:1). Although various attempts were made to further
H
H
H
H
optimize the reaction conditions, the initial conditions proved
to be optimal (TFE, 0.1 M, rt). 1,1,1,3,3,3-Hexafluoro-
isopropanol (HFIP) was also explored as a solvent. Reaction
rates were drastically increased (i.e. full conversion of 9a
8al
16h, 40%)
8am
8an
(
(16h, 37%)
(16 h, 48%)
a
Reaction conditions: 9a (1 mmol), amine (1.1 mmol), aldehyde (1.1 mmol), TFE (0.1
b
c
d
M), rt. Isolated yields. HFIP (0.1 M) was used as the solvent. With 6-amino-2-
e
picoline as the amine input. Yield based on NMR analysis with internal standard
within 1 h) with similar yields. Nevertheless, we decided to (product unstable to chromatography).
investigate the scope with TFE as the solvent, for its lower
acidity and hence milder conditions.
benzaldehyde and m-chloroaniline (entry 8ac) proved to
require more than 48 h to reach completion. For such
challenging examples the use of HFIP as the solvent is a good
alternative, as even these reactions are complete within 1 h.
Combinations of α-quaternary aliphatic aldehydes and
aliphatic amines proved to be superior in this reaction,
furnishing 8af-8ak typically in good to quantitative yields. For
example, the reaction of 9a with isopropylamine and
pivaldehyde provided 8ag in quantitative yield and high purity
We then moved on to expand the method to a true
multicomponent reaction, reacting 9a with aniline and
benzaldehyde under otherwise identical conditions (TFE, 0.1
M). Although the reaction required more time (48 h) to reach
full conversion of 9a, 8aa was obtained in comparable yield.
We then set out to investigate the reactivity of 9a with a wide
range of amine and aldehyde inputs. Gratifyingly, all
combinations of aliphatic and aromatic amines and aldehydes
afforded the desired pyrroloindolines 8aa-al in moderate to after simple evaporation of the solvent and excess starting
quantitative yield (Table 1). X-Ray crystallographic analysis of materials, a protocol with essentially all features of an ideal
1
8
8
ah allowed us to unambiguously determine the relative synthesis. The reaction also tolerates the use of other
17
19
stereochemistry. Combinations of aromatic aldehydes and aliphatic aldehydes, albeit in lower yields (entries 8al-8an).
aromatic amines were found to afford the products 8aa-ac in
Next, we reacted 9a with pivaldehyde and 6-amino-2-
picoline to investigate the competition between the formation
of 8ae and the GBB reaction. To our surprise, the sole isolable
product was 11ae, resulting from an interrupted Passerini-type
reaction. In the absence of 6-amino-2-picoline, the same
product was obtained in similar yield. Attempts to extend this
reaction to other aldehyde inputs, either led to no conversion
mostly moderate yield. The reaction of 9a with p-chloro-
N
NC
Ph
Ph
+
N
N
TFE, rt
N
H
Ph
N
H
Ph
H
9a
10
8aa (50%)
Scheme 2 TFE-Mediated Interrupted Ugi Reaction.
(
with aromatic aldehydes) or decomposition (with linear
0
2
aliphatic aldehydes).
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a,b
Table 2 Variation of the isocyanide indole ring
Scheme 3
Scope of aldehydes and secondary amines. Reaction
conditions: 9a (1 mmol), amine (1.1 mmol), aldehyde (1.1 mmol), TFE (0.1
a 1
M), rt. Yields refer to isolated yields. H NMR analysis of the crude product
indicated the presence of the other diastereomer (7:1 dr), which could
however not be isolated due to decomposition
.
The limitations of this method were reached when less
activated carbonyl inputs were used. No conversion was
observed with ketones, α,β-unsaturated aldehydes, or hetero-
aromatic aldehydes such as furfural and indole-3-
carboxaldehyde. More electrophilic aldehydes, such as chloral
or phenylglyoxal, did react with the isocyanide, but no clear
product could be identified.
Given the high variability of our interrupted Ugi cascade,
we wondered whether secondary amines could also be used,
since the formation of highly electrophilic iminium species
from aldehydes and secondary amines is plausible in an acidic
solvent like TFE. Evidently, in this case the secondary
a
Reaction conditions: 9 (1 mmol), amine (1.1 mmol), aldehyde (1.1 mmol), TFE
b
(
0.1 M), rt. Isolated yields.
(
12.5), we propose hydrogen bonding to be the mode of imine
activation rather than complete proton transfer, which is
common for the classical Ugi reaction (pK carboxylic acid
4.5). Intermediate can now be trapped by the indole C3
cyclization of intermediate
intermediate may either undergo deprotonation to give
spirocyclic indolenines 12 or rearrangement to give Bischler-
Napieralski products . Pleasingly, we selectively obtained
6
is precluded. Instead,
a
6
~
A
position from either diastereotopic face of the indole ring,
each accessing a different diastereoisomer. Apparently, this
attack is fully diastereoselective in reactions with primary
amines and isocyanides with an unsubstituted indole 2-
7
spiro diimines 12a,b in good yield from the reactions of 9a
with secondary aliphatic amines and unhindered aliphatic
aldehydes (Scheme 3). In contrast, the use of bulky aldehydes
did not lead to product formation, which can be rationalized
by more difficult formation of the iminium ion intermediate.
2
1
position. Lower selectivities were observed in reactions with
secondary amines, while the selectivity was completely lost
with isocyanide 9e bearing a methyl substituent at the indole
Another
notable
observation
was
the
lower
2
-position.
diastereoselectivity in reactions with secondary amines.
Possibly, when primary amines are used, the steric difference
2
2
Since the interrupted Ugi cascade affords a new imine,
1
2
our curiosity was focused toward a possible subsequent
Joullié-Ugi reaction. To our delight, compounds 8aa and 8ac
were smoothly converted to the corresponding Joullié-Ugi
between the –NHR and -R substituents is greater, leading to
higher selectivity.
To gain more insight in the reaction mechanism, and to
demonstrate additional diversification potential, substitution
on the isocyanide indole ring was studied (Table 2). Our results
were generally positive: only combinations of aromatic
aldehydes and anilines proved to be challenging, as 8bb and
products 13a and 13b
,
respectively, with complete
diastereoselectivity. Unfortunately, the Joullié-Ugi reaction of
23
8
1
was found to proceed only when R and R are aromatic.
2
Nevertheless, this simple process allows the introduction of
two new diversity points as well as additional molecular
complexity. Since TFE is also a good solvent for Ugi reactions,
we successfully combined both reactions to achieve a one-pot,
five-component interrupted Ugi/Joullié-Ugi cascade affording
8da could not be isolated. In contrast, the combination of
aliphatic amines and aldehydes afforded the corresponding
products 8ba and 8db in good to excellent yield. The reaction
of 4-methylpiperidine as
combination with isocyanide 1c and piperonal gave 12ca in
4% yield. Interestingly, the reaction of 2-methyl substituted
a secondary amine input in
1
3a in 42% yield.
4
isocyanide 1e with isobutyraldehyde and cyclopropylamine
afforded spiroindolenine 12ea in quantitative yield as a 1:1
diastereomeric mixture. Apparently, substitution of the indole
2-position not only prevents the secondary cyclization, but also
leads to a complete loss of diastereoselectivity.
Having established the synthetic potential of this reaction,
we propose the following mechanism (Scheme 4). After
formation of the imine, nucleophilic attack by the isocyanide
follows to give nitrilium intermediate A. Given the pK of TFE
a
Scheme 4 Proposed reaction mechanism.
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6
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(
(
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8
9
(a) J. S. Schneekloth, J. J. Kim and E. J. Sorensen,
Tetrahedron, 2009, 65, 3096; (b) J. Kim, J. S. Schneekloth and
E. J. Sorensen, Chem. Sci., 2012, 3, 2849.
(a) R. C. Cioc, P. Schuckman, H. D. Preschel, T. Vlaar, E.
Ruijter and R. V. A. Orru, Org. Lett., 2016, 18, 3562; (b) R. C.
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Orru, Chem. – A Eur. J., 2016, 22, 7837.
0 Tron et al. reported a similar approach using 2-aminomethyl-
indoles resulting in a monocyclization reaction: F. La Spisa, F.
Meneghetti, B. Pozzi and G. C. Tron, Synthesis, 2015, 47, 489.
1 Tryptamine-derived isocyanides have been employed in
related cascade reactions involving conjugate addition: (a) X.
Wang, S.-Y. Wang and S.-J. Ji, Org. Lett., 2013, 15, 1954; (b)
X. Zhao, X. Liu, H. Mei, J. Guo, L. Lin and X. Feng, Angew.
Chem. Int. Ed., 2015, 54, 4032.
Scheme 5 One-Pot Interrupted Ugi / Joullié-Ugi Cascade
In conclusion, we report the development of a novel, highly
diastereoselective interrupted Ugi cascade reaction affording
complex tetracyclic pyrroloindolines. This transformation
occurs in a single step from tryptamine-derived isocyanides by
simply excluding the carboxylic acid component in the Ugi
reaction and exploiting the acidity of TFE as imine activator.
The mild conditions allow the rapid synthesis of a diverse array
of polycyclic spiroindolines in moderate to quantitative yield.
Further complexity and diversity generation can be achieved
by an interrupted Ugi/Joullié-Ugi cascade to create unique,
highly functionalized structures.
1
1
1
2 A. Bischler and B. Napieralski, Ber. Dtsch. Chem. Gesellschaft,
893, 26, 1903.
1
The Netherlands Organization of Scientific Research (NWO) 13 Similar scaffolds are can be generated by transition metal-
is acknowledged for financial support. We thank Elwin Janssen
for technical assistance, John Braun and Jurriën Collet for
HRMS measurements, and Dr. Andreas W. Ehlers for NMR
maintenance (all VU Amsterdam). The authors thank Prof. Dr.
Kristof Van Hecke (UGent) for measuring time on the
mediated cyclizations of specific Ugi products; see: (a) L. El
Kaim, L. Grimaud, X.-F. Le Goff, M. Menes-Arzate and L. D.
Miranda, Chem. Commun., 2011, 47, 8145; (b) S. G. Modha,
A. Kumar, D. D. Vachhani, J. Jacobs, S. K. Sharma, V. S.
Parmar, L. Van Meervelt and E. V. Van Der Eycken, Angew.
Chem. Int. Ed., 2012, 51, 9572.
diffractometer, for which funding through the Hercules 14 Comparable scaffolds have been prepared by other cascade
processes: (a) R. Hili and A. K. Yudin, J. Am. Chem. Soc., 2006,
Foundation (project AUGE/11/029 "3D-SPACE: 3D Structural
1
28, 14772. (b) C. de Graaff, L. Bensch, S. J. Boersma, R.C.
Platform Aiming for Chemical Excellence") is acknowledged.
Cioc, M. J. van Lint, E. Janssen, N. J. Turner, R. V. A. Orru and
E. Ruijter, Angew. Chem. Int. Ed., 2015, 54, 14133.
1
1
5 This reaction can also be considered an interrupted Bischler-
Napieralski reaction, as it involves similar intermediates.
6 (a) W. Wang, E. Herdtweck and A. Domling, Chem. Commun.
2010, 46, 770. (b) A. Silvani, G. Lesma, S. Crippa and V. Vece,
Tetrahedron, 2014, 70, 3994.
Notes and references
1
H. Bienaymé, C. Hulme, G. Oddon and P. Schmitt, Chem. Eur.
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6
2
(a) S. Stotani, C. Lorenz, M. Winkler, F. Medda, E, Picazo, R.
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1
1
1
7 See the ESI for detailed information.
8 T. Gaich and P. S. Baran, J. Org. Chem., 2010, 75, 4657.
9 Plausibly, enamine formation leads to decomposition
pathways.
0 Decomposition of 11ae was observed upon concentration in
vacuo at 40°C for several hours, which may account for the
failure of the reaction using other linear aldehydes.
1 At this point, the origin of this stereoselectivity remains
unclear, although steric factors seem to play a minor role at
best. A detailed computational study on the mechanistic
aspects of this reaction is currently ongoing.
M. MacCoss and A. D. G. Lawson, J. Med. Chem., 2014, 57
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2
2
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3
4
2
2 This imine is relatively unreactive as the nucleophile must
attack from the highly crowded bottom face to create the
more favorable cis junction.
4, 54282; (c) G. A. Medeiros, W. A. da Silva, G. A. Bataglion,
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1
3
2
3
When either R or R (or both) were aliphatic, a mixture of
unidentified products was obtained.
32, 7087.
(a) For a review, see: I. Akritopoulou-Zanze and S. W. Djuric,
Heterocycles, 2007, 73, 125; (b) For a recent example, see: C.
5
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