Catalyst-free intramolecular formal carbon insertion into σ-C-C bonds: A new approach toward phenanthrols and naphthols

Article abstract of DOI:10.1002/anie.201209269

The different reactivity of two kinds of carbonyl groups in keto aldehyde substrates has been exploited for the synthesis of phenanthrols, naphthols, and their heteroatom-containing analogues. Key to this highly efficient and robust methodology is the catalyst-free intramolecular formal diazo carbon insertion of N-tosylhydrazones into keto C-C bonds (see scheme). Copyright

Full text of DOI:10.1002/anie.201209269

Angewandte
Chemie
DOI: 10.1002/anie.201209269
Synthetic Methods
À
Catalyst-Free Intramolecular Formal Carbon Insertion into s-C C
Bonds: A New Approach toward Phenanthrols and Naphthols**
Ying Xia, Peiyuan Qu, Zhenxing Liu, Rui Ge, Qing Xiao, Yan Zhang, and Jianbo Wang*
À
The formal diazo carbon insertion into the carbonyl group is
a valuable tool for the homologation of aldehydes and
ketones.[1,2] The reaction follows two steps: 1) nucleophilic
addition of diazo compound to ketone or aldehyde; 2) 1,2-
shift of R or R’ with instantaneous release of N2 (Sche-
insertion into formyl C H bonds in the synthesis of ketones
has been reported.[7] However, to the best of our knowledge,
the use of N-tosylhydrazones as diazo precursors for the
À
formal carbon insertion into a keto C C bond is without
precedent. Ketones are less reactive than aldehydes, there-
fore, a Lewis acid is usually needed to activate the carbonyl
group of a ketone. However, this method is not compatible
with the basic reaction conditions for the in situ generation of
diazo compounds from N-tosylhydrazones. We conceived that
this problem may be circumvented through an intramolecular
reaction, in which the reactivity of the ketone toward the
diazo nucleophile is enhanced because of steric proximity, so
that activation by a Lewis acid is no longer necessary. In
connection to our recent study on RhII-catalyzed carbene
dimerization,[6] we herein report a catalyst-free intramolecu-
me 1a).[3] The formal carbon insertion into the formyl C H
À
À
lar formal s-C C bond insertion with the internal aldehyde as
the carbon unit, which leads to the efficient formation of
phenanthrol and naphthol derivatives (Scheme 1b).
At the outset, we investigated the reaction of 2’-benzoyl-
biphenyl-2-carbaldehyde (1a) with TsNHNH2 (1.03 equiv) in
toluene at 708C for 30 min (Scheme 2). As expected, only the
Scheme 1. Formal diazo carbon insertion into carbonyl group.
bond has become a general method for ketone synthesis
because of the high efficiency of both steps (Scheme 1a, when
À
R’ = H). On the other hand, the corresponding formal C C
bond insertion (Scheme 1a, when R’ = alkyl or aryl) is more
challenging because of the relatively low reactivity and the
difficulty associated with the selectivity of the 1,2-shift.
Recently, the studies by Kingsbury,[1g,2e,h,j] Maruoka,[1f,2d,f,g,i]
Feng,[1h,2k] and other groups have significantly promoted the
development of this area, particularly the stereocontrol of the
reaction.
Scheme 2. Selective N-tosylhydrazone formation and subsequent cycli-
zation.
A major limitation for the widespread application of this
type of reaction is the use of usually unstable diazo
compounds as nucleophiles. The strategy of in situ generation
of diazo compounds from N-tosylhydrazones, which are easily
available from the corresponding ketones or aldehydes, is
a useful way to circumvent this problem.[4–6] The use of N-
tosylhydrazones as diazo precursors for formal carbon
aldehyde carbonyl group is cleanly converted to the corre-
sponding N-tosylhydrazone 2 because of the reactivity differ-
ence of the two carbonyl groups. Subsequently, NaOMe
(2.5 equiv) was added to the same reaction mixture and
heating was continued for another 30 min at 708C. To our
delight, 10-phenylphenanthren-9-ol (3a) could be isolated in
96% yield. Surprisingly, the conversion of N-tosylhydrazone 2
to 3a can also be carried out at room temperature, although
with diminished yield.
Hydroxy-substituted polycyclic aromatic compounds
(PACs), such as 3a, are highly useful, because they have
wide applications in material science[8a] and medicinal chem-
istry[8b] and are abundant in natural products.[9] Moreover, the
phenolic hydroxy group can be further transformed to various
functional groups.[10,13] However, systematical studies on the
synthesis of hydroxy-substituted PACs are still rare.[11,12] The
experiments shown in Scheme 2 demonstrate the potential of
[*] Y. Xia, P. Qu, Z. Liu, R. Ge, Q. Xiao, Dr. Y. Zhang, Prof. Dr. J. Wang
Beijing National Laboratory of Molecular Sciences (BNLMS) and
Key Laboratory of Bioorganic Chemistry and
Molecular Engineering of Ministry of Education
College of Chemistry, Peking University
Beijing 100871 (China)
E-mail: wangjb@pku.edu.cn
[**] The project is supported by the National Basic Research Program of
China (973 Program, No. 2009CB825300), NSFC (Grant No.
21272010, 20832002).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209269.
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Table 2: Reaction scope of the two aryl rings.[a]
À
intramolecular C C bond insertion in the efficient and
regioselective synthesis of hydroxy-substituted PACs. Con-
sequently, we decided to study the scope of this transforma-
tion.
The scope of this reaction was first explored by testing
a series of 1,2-shifting R group in the biaryl keto aldehyde
substrates. A series of biaryl ketoaldehydes 1a–n can be easily
prepared by Suzuki–Miyaura cross-coupling reactions, start-
ing from readily available starting materials.[13] A variety of
R groups, including aryl, alkenyl, alkynyl, and alkyl groups,
À
were examined, and the expected formal C C bond insertion
process occurred smoothly in all cases (Table 1). When the
Table 1: Reaction scope of the 1,2-shifting group.[a]
[a] Yields of isolated products after purification by column chromato-
graphy on silica gel. [b] The second step was carried out at 908C.
[c] LiOtBu was used instead of NaOMe in the second step.
Next, we examined the substrates with two different
parent aromatic rings (Table 2). The reaction was found
marginally affected by the substituents on the two phenyl
rings. Both electron-withdrawing (5a–b,f,g) and electron-
donating (5d–e,h) groups were tolerated, giving the corre-
sponding substituted 9-phenanthrols in good to excellent
yields. Furthermore, the reaction with substrates that contain
a heteroaryl skeleton afforded the corresponding cyclization
products in good to excellent yields (5i–o).
This method was further applied in the regioselective
formation of polysubstituted naphthols. Both a- and b-
naphthol derivatives could be synthesized with this method
by simply switching the positions of carbonyl groups in the
corresponding ketoaldehyde substrates (Tables 3 and 4).
Here, LiOtBu was proved to be a more suitable base than
NaOMe for the second step. A series of polysubstituted a-
naphthols could be synthesized in good to excellent yields
(Table 3). The substituents on the vinyl aldehyde moiety (R1
and R2) show marginal impact on this transformation,
affording the corresponding isomeric a-naphthols 7a and 7b
in good yields. With regard to the substituents on the aryl
ketone moiety (R3), the reactions also proceed well (7c–f).
Moreover, this methodology can be a good choice for the
formation of carbocyclic ring-fused naphthols (7g–m).
By changing the position of the formyl and keto carbonyl
group on the substrates, b-naphthol derivatives could be
obtained similarly (Table 4). Remarkably, this method can
also be applied in the formation of hydroxy-substituted
benzothiophenes (9n–q).
[a] Yields of isolated products after purification by column chromato-
graphy on silica gel. [b] The second step was carried out at 908C.
[c] LiOtBu was used instead of NaOMe in the second step. [d] The first
step was carried out at 408C.
1,2-shifting group is an phenyl group that bears electron-
donating substituents, the reaction provided the correspond-
ing products in excellent yields (3a–c). On the other hand, the
substrates that bear electron-withdrawing groups afforded the
products in diminished yields (3d,e). Notably, the ortho-
substituted phenyl group on the substrate does not hinder the
À
C C bond migration process (3 f). The heteroaryl, vinyl, and
alkynyl groups also undergo 1,2-shifts to afford the desired
products (3g–j). The low yield after the 1,2-alkynyl shift may
be attributed to the electron deficiency of the alkynyl carbon
atom. To our delight, the reaction with alkyl-substituted
substrates proceeded well by lowering the temperature of the
first step to 408C in order to avoid the formation of N-
tosylhydrazone at the ketone moiety (3k–n). When R is
À
a bulky tert-butyl group, the anticipated C C bond insertion
occurs smoothly, while the subsequent aromatization does not
A plausible mechanism to rationalize this cyclization is
depicted in Scheme 3. The substrate 1a is first converted to
occur (3n).
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Table 3: Reaction scope of the a-naphthols.[a]
Scheme 3. Mechanistic rationale.
the mono(N-tosylhydrazone) 2, which undergoes deprotona-
tion to form tosylhydrazone salt A. From A, two pathways are
possible: a) the corresponding diazo compound B is gener-
ated,[4a,7] then a nucleophilic attack on the keto carbonyl
group forms C, and a 1,2-shift with release of N2 subsequently
affords D; b) A undergoes intramolecular carbon alkylation
(through resonance structure E), which is then followed by
1,2-shift. Current experimental observations indicate that
path b is more likely: 1) the solution does not show the
characteristic red color of diazo intermediate during the
reaction; 2) the reaction can take place at room temperature,
whereas the generation of diazo intermediate from tosylhy-
drazone needs elevated temperatures (usually above
608C).[4a,7] However, rigorous investigation is necessary to
unambiguously establish the reaction mechanism.
[a] Yields of isolated products after purification by column chromato-
graphy on silica gel.
Table 4: Reaction scope of the b-naphthols.[a]
The phenolic hydroxy group can undergo various syn-
thetically useful transformations.[13] To illustrate the potential
application of the products, 3a was converted to dibenzo-
chrysene (DBC).[14] Staring from commercially available
materials, DBC derivative 12 could be readily synthesized in
five steps with an overall yield of 77% (Scheme 4). Deriva-
tives of DBC can be applied to the preparation of sensors,
[a] Yields of isolated products after purification by column chromato-
graphy on silica gel.
Scheme 4. Synthesis of dibenzochrysene derivative.
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À
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À
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Received: November 20, 2012
Published online: January 29, 2013
Keywords: 1,2-shift · cyclization · diazo compounds · insertion ·
.
hydrocarbons
À
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