A Conjugate Addition Approach to Diazo-Containing Scaffolds with β Quaternary Centers

Article abstract of DOI:10.1002/anie.202004557

Structurally complex diazo-containing scaffolds are formed by conjugate addition to vinyl diazonium salts. The electrophile, a little studied α-diazonium-α,β-unsaturated carbonyl compound, is formed at low temperature under mild conditions by treating β-h

Full text of DOI:10.1002/anie.202004557

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Accepted Article
Title: A conjugate addition approach to diazo-containing scaffolds with
β quaternary centers
Authors: Jian Fang, Evan M Howard, and Matthias Brewer
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A conjugate addition approach to diazo-containing scaffolds with
β quaternary centers
Jian Fang,[a] Evan M. Howard,[a] and Matthias Brewer*[a]
[a]
J. Fang, E. M. Howard, and Prof. Dr. Matthias Brewer
Department of Chemistry
University of Vermont
Innovation Hall, 82 University Place, Burlington, VT 05495, USA
E-mail: Matthias.brewer@uvm.edu
Supporting information for this article is given via a link at the end of the document.
Abstract: Structurally complex diazo-containing scaffolds are formed
by conjugate addition to vinyl diazonium salts. The electrophile, a little
studied α-diazonium-α,β-unsaturated carbonyl compound, is formed
at low temperature under mild conditions by treating β-hydroxy-α-
diazo carbonyls with Sc(OTf)3. Conjugate addition occurs selectively
at the 3-position of indole to give α-diazo-β-indole carbonyls, and
enoxy silanes react to give 2-diazo-1,4-dicarbonyl products. These
reactions result in the formation of tertiary and quaternary centers,
and give products that would be otherwise difficult to form.
Importantly, the diazo functional group is retained within the molecule
for future manipulation. Treating a α-diazo ester indole addition
product with Rh2(OAc)4 caused a rearrangement to occur to give a 2-
(1H-indol-3-yl)-2-enoate. In the case of diazo ketone compounds, this
shift occurred spontaneously on prolonged exposure to the Lewis
acidic reaction conditions.
Scheme 1. Reactions of vinyl cations and vinyl diazonium salts
cyclization reactions.[41,42] These intramolecular reactions
proceed via a vinyl cation intermediate (e.g. 3) which is formed
from a vinyl diazonium precursor (e.g. 2) as shown in Scheme 1.
As part of our studies into the mechanism of the vinyl cation C-H
insertion reaction,[43] we modeled the reaction pathway
computationally, which showed that the Lewis acid mediated
dehydroxylation step was reversible, and that the rate limiting step
of this sequence is formation of the vinyl cation by loss of N2 from
the vinyl diazonium intermediate. This led us to consider that it
might be possible to intercept vinyl diazonium intermediate 2 with
a nucleophile other than OH prior to N2 dissociation to give a more
complex product that still retains the diazo fragment. Despite early
recognition that vinyl diazonium ions might serve as useful
synthetic intermediates,[44] very few studies have emerged to
The diazo group is one of the most versatile functional
groups in synthetic chemistry.[1–5] Apart from being reactive 1,3-
dipoles in their own right,[6–8] the diazo group is a progenitor to
several important reactive intermediates including cations, vinyl
cations,[9] and both free and metal bound carbenes.[10–12]
Chemists have taken advantage of diazo compounds to develop
a variety of important synthetic transformations (for example, C-H
and X-H insertions,[13–17]
cyclopropanation,[18] the Buchner
reaction,[19,20] the Wolff rearrangement,[21] and cycloadditions
based on ylide formation[22–24]) that are frequently used in complex
molecule synthesis.[25] However, the high reactivity of diazo
compounds also makes them fairly labile and they are
incompatible with many reaction conditions including protic and
Lewis acids, strong nucleophiles, reductive conditions, and some
metal catalysts. α-Diazo carbonyl compounds are more stable
than alkyl diazos, but the diazo functional group is typically not
carried through long synthetic sequences due to reactivity
concerns. Incorporating a diazo group into a complex molecule is
not always trivial, and is most often achieved by diazo transfer to
a carbonyl enolate,[26,27] or the oxidation of hydrazine-based
precursor.[28–37] In view of their synthetic utility, alternative
strategies to prepare structurally complex diazo-containing
compounds would be beneficial to the synthetic community.
The addition of a metalated α-diazo carbonyl compound to
a ketone or aldehyde via an aldol-type addition is another way of
incorporating a diazo group into a molecule.[38] We have taken
advantage of this strategy to prepare a variety of β-hydroxy-α-
diazo carbonyls (e.g. 1, Scheme 1), which we have studied in ring
fragmentation,[39] C-H insertion,[40] and other intramolecular
realize
this
potential.[45–50]
Structurally
simple
β,β-
dialkoxyethenediazonium salts that are stable and isolable
because of strongly contributing dialkoxycarbenium resonance
forms have received the most attention, and these are
electrophilic at the alkoxycarbenium carbon.[45–48] Crich and
coworkers[50] recently showed that vinyl diazonium ions react with
phenols to give complex 2,3-dihydrobenzofurans through an
addition cyclization process with loss of N2. However, other than
their use as vinyl cation precursors, no general and useful
synthetic transformations have been developed that take
advantage of vinyl diazonium ions. In this paper we show that
vinyl diazonium ions such as 2 can react with carbon nucleophiles
to give tertiary and all-carbon quaternary centers, while retaining
the diazo functional group within the molecule for future
manipulation. All-carbon quaternary centers are found in a
number of biologically active molecules.[51–53] Many natural
products containing these motifs have been shown to be excellent
1
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medicinal leads if not potent drugs themselves.[54–56] Although
advances in methods to form all-carbon quaterary centers have
been made in recent years[53,57–62] there is still need for new
strategies to prepare these challenging motifs.
To begin our studies, we chose indole as the nucleophile
because indole scaffolds are privileged structural subunits in drug
discovery programs,[63,64] and are present in a large number of
biologically active natural products.[65,66] In addition, indole is fairly
non-basic and is known to react in Lewis acid catalyzed conjugate
addition reactions.[67,68] In our earlier fragmentation and C-H
insertion work, we showed that SnCl4 and (C6F5)3B were effective
Lewis acids and we began our current studies by treating diazo
8 (Scheme 2) with SnCl4 in the presence of indole at -20 °C.
These conditions led to a complex mixture of products that
contained indole addition product 9, albeit in only 5% yield. This
addition is noteworthy because it results in the formation of a new
all-carbon quaternary center under mild conditions. While indole
is known to add to β,β-disubstituted ketones,[67] we are not aware
of any example of indoles reacting with a β,β-disubstituted ester
due to their weaker electrophilicity.[69] Changing the Lewis acid to
(C6F5)3B gave no desired product. However, under identical
reaction conditions, Al(OTf)3 returned 9 in 83% yield, and
Sc(OTf)3 gave 9 in 90% yield. In prior work, we had noted that gas
evolution typically occurs around -20 °C, and we thought that
keeping the reaction cold might be critical to increase the lifetime
of the vinyl diazonium intermediate. We were surprised to observe
that running the reaction at 20 °C still gave the addition product in
79% yield, which shows that addition is faster than vinyl cation
formation even at this higher temperature.
As shown in Table 2, a variety of structurally different β-
hydroxy-α-diazo carbonyl compounds gave the expected 1,4-
conjugate addition reaction with indole in good to excellent yields.
It is noteworthy that starting materials that had a 2° alcohol at the
β position react productively to give addition products with new
tertiary centers (e.g. 22 and 23). It is also noteworthy that a distal
N-tosyl protected amine was compatible with the conditions, and
addition product 24 was formed in 95% yield. Importantly,
changing the diazo fragment from a diazo ester to a diazo ketone
did not affect the outcome of the reaction and β-hydroxy-α-diazo
ketones provided the expected conjugate addition products in
generally high yield (25-31). Again, both tertiary and quaternary
centers were formed in comparable yields.
Table 2. Conjugate addition of indole to various vinyl diazonium intermediates.
Scheme 2. Conjugate addition of indole to a vinyl diazonium ester
We examined a small series of substituted indoles to assess
their ability to act as nucleophiles in this reaction (Table 1).
Electron withdrawing or releasing substituents at the indole’s 5
position were well tolerated and had little effect on the reaction
outcome (10-12). A nitrile substituent at the 4 position, on the
other hand, attenuated reactivity significantly and product 13 was
formed in only 33% yield. This lower yield is likely due to
unfavorable steric interactions. Similarly, 2-methyl indole failed to
add, which again indicates that sterics play an important role in
the reaction. Capping the indole nitrogen with the electron
withdrawing acetyl and tosyl groups also prevented the reaction
from occurring, presumably because these compounds are less
nucleophilic. However, a free indole N-H is not necessary since
N-methyl indole gave the expected addition product 17 in 93%
yield.
Other aromatic nucleophiles were also assessed for their
ability to add to the vinyl diazonium intermediate. Pyrrole proved
to be a willing reaction partner and returned diazo 18 in 85% yield
(Table 1). An nOe NMR spectroscopic study confirmed that the
reaction took place at the 2-position of pyrrole. Substituted phenyl
rings, including phenol, anisole, N-phenylacetamide and furan
failed to add. According to Mayr’s reactivity scales, these systems
have lower nucleophilicity parameters than indole derivatives,
which provides another indication that there is a lower limit to how
weak the nucleophile can be.[70,71] 1H-Benzotriazole was a
moderately effective nucleophile providing 2-substituted
benzotriazole 19 in 49% yield. The 1-substituted benzotriazole
regioisomer was not observed.
For the diazo ketone series we noted a strong
temperature dependence on the outcome of the reaction.
Whereas β-hydroxy-α-diazo esters gave the expected conjugate
addition products at room temperature, β-hydroxy-α-diazo
ketones gave enone products instead (Table 3). These products
were also formed when low temperature reactions that had
formed conjugate addition products (as determined by TLC) were
warmed to room temperature. Treating isolated diazo 28 with
Sc(OTf)3 also gave enone 36, confirming that the enone products
Table 1. Conjugate addition of substituted indoles, pyrrole and benzotriazole
with a vinyl diazonium ester.
2
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are the result of a Lewis acid mediated rearrangement of the 1,4-
addition products. This same transformation could be effected on
ester derivatives by treatment with Rh2(OAc)4. [72]
To further expand the utility of this conjugate addition
reactivity, we were interested to see if non-aromatic nucleophiles
could add to the diazonium intermediate. Substituting allyl
trimethyl silane in place of indole did not give any desired addition
product. However, we have found that enoxy silanes are effective
nucleophiles. In our initial attempt, we reacted diazo ester 46 with
the TBS enoxy silane of propiophenone (47) in the presence of
Sc(OTf)3, which gave the desired Michael addition product in 23%
yield (Scheme 5). A substantial amount of propiophenone was
formed in this reaction, indicating decomposition of the enoxy
silane under the reaction conditions. In an attempt to suppress
decomposition of the nucleophile, we added 2,6-di-tert-butyl-4-
methylpyridine (DTBMP) to the reaction as a buffer. While this
increased the product yield to 45%, it also resulted in the
formation of an equal quantity of an elimination product (49),
which presumably forms via deprotonation of the vinyl diazonium
intermediate. Future work will tell if deprotonation is a general
problem that limits what nucleophilic partners can be used in this
reaction, but it is noteworthy that pyridine and aniline also
promoted this elimination. To prevent decomposition of the
nucleophile, we looked toward using a more robust enoxy silane.
To date, our best results came from treating diazo ester 46 with
two equivalents of the TIPS enoxy silane of propiophenone (50,
Table 4) and one equivalent of Sc(OTf)3 at -16 °C, which gave the
Michael addition product (48) in 70% yield. A fuller study of the
scope of this Mukaiyama-Michael-like reaction is currently
underway, but our preliminary results (Table 4) show that this
conjugate addition forms a tertiary center adjacent to either a
quaternary (48, 51-53) or tertiary (54-57) center in good yield. This
reaction is noteworthy because the Michael addition of enolates
resembling 50 to unsaturated esters is known to be difficult.[74]
Importantly, while systems that form adjacent tertiary centers
could react to give two diastereomers, keto esters 54 to 57 were
formed as single diastereomers. Efforts to rigorously establish the
relative configuration of these products are on-going.
Table 3. Diazo ketone rearrangement products.
Plausible mechanisms for the formation of 40 and 45
are shown in Schemes
3 and 4. Scandium mediated
dehydroxylation of β-hydroxy-α-diazo carbonyl 1 would provide
vinyl diazonium intermediate 2a, which has a carbocation
resonance form (2b, Scheme 1) that is indicative of the
electrophilicity of the β position. Addition of indole followed by
rearomatization of the indole ring by proton abstraction would give
the addition product (40). The irreversible addition of indole
occurs faster than loss of N2, which explains why including the
nucleophile in the reaction mixture changes the course of the
reaction.
Scheme 5. Michael addition of a TBS enoxy silane nucleophile.
Table 4. Michael addition of a TIPS enoxy silane nucleophile to various vinyl
diazonium esters.
Scheme 3. Mechanism for the formation of addition products
Diazo ketones participate in Lewis acid catalyzed
intramolecular cyclizations with pendent nucleophiles.[73] It is not
clear whether these reactions proceed via complexation of the
Lewis acid with the oxygen or carbon atom of the diazo ketone
functionality, and either could be used to explain the formation of
45 from 41. Scheme 4 shows the oxygen coordination pathway.
Warming diazo ketone 41 to room temperature with the Lewis acid
would give vinyl cation 43, and addition of the adjacent indole
would give spirocyclopropane intermediate 44. Ring opening
would provide the observed enone product 45.
This work demonstrates that α-diazonium-α,β-unsaturated
carbonyl compounds, which are little studied reactive species, are
potent electrophiles. Indole and enoxy silanes are effective
Scheme 4. Mechanism for the formation of enone products
3
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be difficult to form by other means, retain the diazo functional
group, which could be taken advantage of in a variety of
subsequent synthetic transformations. As the indole motif is
present in numerous biologically active natural products, the
reaction described here may enable new strategies for the
synthesis of indole alkaloids. We envision that more structurally
complex enoxy silanes could be employed to form products which
would enable the rapid assembly of chemically rich polycyclic
scaffolds. Further studies are ongoing to establish the full scope
of these conjugate addition reactions, and efforts to render the
conjugate addition enantioselective are being assessed.
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Financial support from the National Science Foundation (CHE-
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Keywords: Conjugate addition • Michael addition • Diazo •
quaternary center • Indole
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4
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Entry for the Table of Contents
Insert graphic for Table of Contents here.
Indole and enoxy silanes readily act as nucleophiles in conjugate addition reactions with vinyl diazonium ions that are formed in situ
by the Lewis acid mediated dehydroxylation of β-hydroxy-α-diazo carbonyls. These reactions, which occur under very mild conditions,
can generate a new quaternary center while the products of these reactions retain the diazo functional group for further synthetic
manipulation.
5
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