Selective Synthesis of Six Products from a Single Indolyl α-Diazocarbonyl Precursor

Article abstract of DOI:10.1002/anie.201605337

Indolyl α-diazocarbonyls can be selectively cyclized to give six distinct products through the careful choice of catalyst and reaction conditions. A range of catalysts were used, including complexes of Rh^II, Pd^II, and Cu^II, as well as SiO₂, to promote diazo decomposition and subsequent cyclization/rearrangement through a range of mechanistic pathways.

Full text of DOI:10.1002/anie.201605337

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201605337
German Edition: DOI: 10.1002/ange.201605337
Diazo Compounds
Selective Synthesis of Six Products from a Single Indolyl
a-Diazocarbonyl Precursor
Michael J. James, Peter OꢀBrien, Richard J. K. Taylor,* and William P. Unsworth*
Abstract: Indolyl a-diazocarbonyls can be selectively cyclized
to give six distinct products through the careful choice of
catalyst and reaction conditions. A range of catalysts were used,
a single a-diazocarbonyl, of the form 1, by a series of mild
rhodium(II)-, palladium(II)-, copper(II)-, and SiO -catalyzed
2
processes, as discovered through a mix of careful reaction
design and serendipity (Figure 1).
II
II
II
including complexes of Rh , Pd , and Cu , as well as SiO , to
2
promote diazo decomposition and subsequent cyclization/
rearrangement through a range of mechanistic pathways.
T
he ability to access structurally diverse compounds is the
cornerstone of lead generation in the pharmaceutical and
[
1]
agrochemical industries. In most cases, such compounds are
generated using organic synthesis, and over the years,
a
number of reliable and predictable methods have
[1,2]
emerged.
The importance of such methods cannot be
over-stated, but nonetheless, there is also value in the
examination of reaction systems which react less predict-
[
3]
ably. Reactive precursors known to participate in a wide
range of synthetic transformations can significantly stream-
line the synthesis of diverse compounds by allowing multiple
products to be generated from a single precursor, provided
their reactivity can be controlled.
With this in mind, we initiated the research described
herein, focusing on the reactions of indolyl a-diazocarbonyl
Figure 1. Catalyst-selective synthesis: six scaffolds from one precursor.
[
4]
compounds. The utility of diazo precursors in diversity-
orientated synthesis was elegantly demonstrated by Warriner,
Our studies began with the three-step synthesis of the
[
3]
Nelson and co-worker in 2014, who exploited the unpre-
dictable reactivity of a-diazoamides to generate product
mixtures for bioassays. In our research we have taken an
alternative approach, using a different reaction system, and
focused on controlling the “unpredictable” nature of diazo-
carbonyl reactivity by catalyst variation. The ability to access
several distinct products from a common precursor is
synthetically important, and such research can also lead to
advances in the study of catalysis and mechanism. With this as
motivation, we challenged ourselves to uncover a reaction
system capable of delivering as many product scaffolds as
possible from a single precursor by varying the catalyst and
a-diazocarbonyl 1a from the commercially available acid 2a
[8]
(Table 1), which was then treated with a range of potential
catalysts (10 mol%) in CH Cl2 at room temperature for
2
16 hours. Selected results are given in Table 1 (for full details,
see the Supporting Information).
A number of catalysts able to promote diazo decompo-
sition and cyclization were uncovered. Five identifiable
products were observed in total, with mechanistically related
products grouped to aid the subsequent discussion: the
spirocyclic indolenine 3a and a,b-dicarbonyl 4a (group A),
C2 annulated indole 5a and carbazole 6a (group B), and
isomeric indole 7a (group C). As expected, many of the
catalysts afforded complex mixtures of products, as exempli-
fied by the reactions of the rhodium(II)- and copper(II)-based
catalysts (Table 1, entries 1–4). However, more promising
catalysts were also found and they enabled the selective
synthesis of group A products 3a and 4a [Rh oct )], group B
[
5]
reaction conditions. Most reported methods of this type
[
6]
allow the selective synthesis of two distinct products, with
protocols able to deliver three or more products being much
[7]
more rare. However, herein we report the catalyst-selective
synthesis of six structurally distinct cyclic scaffolds from
2
4
redox isomers 5a and 6a [Pd(MeCN) (BF ) or Cu(OTf) ],
4
4
2
2
and the rearrangement product 7a (SiO ), and these catalysts
were therefore selected for further optimization.
2
[
*] M. J. James, Prof. P. O’Brien, Prof. R. J. K. Taylor, Dr. W. P. Unsworth
Department of Chemistry, University of York
York, YO10 5DD (UK)
To the best of our knowledge, the [Rh oct ]-catalyzed
2
4
[
9]
procedure to form 3a represents the first reported synthesis
of a spirocyclic indolenine from a diazocarbonyl precursor,
although C3 functionalization of indoles using diazocarbonyl
so this outcome was not
wholly unexpected. However, the formation of the oxidized
E-mail: richard.taylor@york.ac.uk
[
10]
william.unsworth@york.ac.uk
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
[
11,12]
compounds has been reported,
[13]
1002/anie.201605337.
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Table 1: Initial catalyst screening.
We propose that both reactions start with the formation of
[
15]
the rhodium carbenoid A,
which then reacts with the
nucleophilic indole to form the spirocycle B, before under-
going protodemetallation to furnish 3a (Scheme 2). Then, in
[
a]
[b]
Entry
Catalyst
Product composition [%]
1
a
3a
4a
5a
6a
7a
1
2
3
4
[Rh (OAc) ]
–
–
–
–
50
55
–
20
15
60
–
15
–
20
–
15
20
–
2
4
[Rh esp ]
10
20
65
2
2
mix
Cu(MeCN) OTf
4
Cu(MeCN) PF6
15
20
–
4
5
A
B
C
[Rh oct ]
–
95
5
–
–
–
2
4
6
7
Pd(MeCN) (BF )
4 2
Cu(OTf)2
–
–
–
–
–
–
95
70
5
30
–
–
4
Scheme 2. Proposed mechanism for the formation of 3a and 4a.
8
SiO (1 g/g)
–
–
–
–
–
>90
2
[
a] Reactions performed with 0.05 mmol of 2a and 10 mol% catalyst in
the presence of oxygen, we propose that 3a forms the
CH Cl (0.1m) under argon at RT for 16 h. [b] Calculated using the
2
2
[8a]
1
intermediate endoperoxide D,
rebound process (3a!C!D),
possibly by a radical
before fragmenting as
H NMR spectrum of the unpurified reaction mixture. esp=a,a,a’,a’-
[
16]
17]
tetramethyl-1,3-benzenedipropanoate, oct=octanoate, p-ABSA=p-
acetamidobenzenesulfonyl azide, T3P=propane phosphonic acid
anhydride, Tf=trifluoromethanesulfonyl.
[
shown to afford the product 4a. Additional evidence for
this mechanism (including an X-ray structure for a related
endoperoxide) can be found in the Supporting Information.
While 4a could be isolated in good yield, it was found to
be relatively short-lived as it degraded during silica gel
chromatography and upon storage, but pleasingly, we were
able to exploit its high reactivity to deliver two new oxindole
scaffolds, 8a and 9a (Scheme 3). Thus, two highly diastereo-
selective intramolecular aldol-type reactions were developed
using either Brønsted-acidic or Brønsted-basic conditions.
product 4a was much more surprising, with the structure of
this product confirmed by X-ray crystallography.
[14]
It was
found that the selective synthesis of either product could be
achieved, with the reaction outcome being dependent on the
presence of air in the reaction. By switching the reaction
solvent from CH Cl to chloroform, reducing catalyst loading
to 5 mol%, and performing the reaction under oxygen-free
conditions, 3a was isolated in 92% yield (Scheme 1). Fur-
thermore, carrying out the same reaction in a flask open to air
was sufficient to completely switch the selectivity to effi-
ciently furnish 4a.
2
2
Scheme 1. Selective synthesis of 3a and 4a.
Scheme 3. Stereoselective formation of 8a and 9a.
2
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Both reactions were performed in one pot, thus requiring only
Finally, the scope of all six procedures was tested on five
a solvent switch to THFand the addition of an excess of either
TFA or tBuOK. Under acidic conditions 4a was selectively
converted into the syn-diastereoisomer 8a in 99% yield, and
we propose this to be the result of hydrogen bonding between
the oxindole and a,b-dicarbonyl moieties (E). Conversely,
under basic conditions, the anti-diastereoisomer 9a was
formed, and we propose that it results from a reactive
conformation of the form F, in which the destabilizing steric
interactions are lower than those in E, and the carbonyl
dipoles are opposed. Both product structures were confirmed
diazocarbonyl substrates (1a–e), thus delivering 30 discrete
products in total (Scheme 6). The spirocycles 3a–e were each
formed in good yield, with variable diastereomeric ratios, and
is likely due to epimerization of the a-keto stereocenter
during chromatography. The other five procedures were all
well tolerated by the same precursor set. The spirocyclic
oxindoles 8a–e and 9a–e, as well C2 annulation products 5a–
e, 6a–e, and 7a–e were formed in generally good yields, and is
pleasing given that no additional optimization was performed
[23]
for any of these reactions.
[
14]
by X-ray analysis.
In summary, we report a novel catalyst-controlled
approach to form six structurally diverse products from
a single a-diazocarbonyl precursor. While other catalyst-
Next, the palladium(II)- and copper(II)-catalyzed reac-
tions were optimized, thus allowing selective formation of the
C2-annulated product 5a and carbazole 6a using Pd(MeCN)4-
[
5–8]
selective synthesis systems are known,
we know of no
(
(
BF4)2 (5 mol%) and Cu(OTf) (20 mol%), respectively
other capable of delivering the level of scaffold diversity by
simply varying the catalyst and reaction conditions. Given the
importance and diversity of the compound classes accessible,
the methods are expected to be of much synthetic inter-
2
[
18,19]
Scheme 4).
A key difference between these reactions is
[
24,25]
est,
while the novel reactivity and mechanistic informa-
tion uncovered is likely to be useful to researchers studying
catalysis. These discoveries (some of which were serendip-
itous) were made as a result of challenging the methodology
in terms of the number of products which could be selectively
formed. Much as natural product synthesis has long been used
[
26]
to inspire the invention of new synthetic processes,
we
believe that the same principles apply in catalyst-selective
synthesis.
Scheme 4. Selective formation of 5a and 6a. TFA=trifluoroacetic acid,
THF=tetrahydrofuran.
Acknowledgments
that it is necessary to perform the carbazole-forming reaction
under oxygen at 508C. It is difficult to unambiguously
determine whether these reactions proceed by direct nucleo-
philic attack from the indole C2 or by initial C3 attack
We wish to thank the University of York (M.J.J. and W.P.U.)
and the Leverhulme Trust (for an Early Career Fellowship,
ECF-2015-013, W.P.U.) for financial support and Dr. A. C.
Whitwood for X-ray crystallography.
[20]
followed by a 1,2-migration. Based on related precedent,
and the observation that 3a can be converted into a mixture
Keywords: cyclizations · diazo compounds · indoles ·
of 5a and 6a upon reaction with Cu(OTf) , the latter appears
spirocycles · synthetic methods
2
more likely.
The silica-promoted C2-annulation reaction required
minimal deviation from the initial screen. The compound 7a
was prepared in good yield by reacting 1a with an equivalent
weight of SiO in CH Cl (Scheme 5). The reaction likely
2
2
2
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Scheme 6. Catalyst-selective synthesis of six products from a single indolyl a-diazocarbonyl precursor (yields are those of products isolated after
column chromatography).
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Angewandte
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Received: June 3, 2016
Published online: && &&, &&&&
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5
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Communications
Diazo Compounds
Pick a catalyst: Indolyl a-diazocarbonyls
can be selectively cyclized to give six
distinct products through the careful
choice of the catalyst and reaction con-
ditions. A range of catalysts were used,
M. J. James, P. O’Brien, R. J. K. Taylor,*
W. P. Unsworth*
&&&& — &&&&
II
II
II
Selective Synthesis of Six Products from
a Single Indolyl a-Diazocarbonyl
Precursor
including complexes of Rh , Pd , and Cu
as well as SiO , to promote diazo
2
decomposition and subsequent cycliza-
tion/rearrangement through a range of
mechanistic pathways.
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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