Tandem O-H Insertion/[1,3]-Alkyl Shift of Rhodium Azavinyl Carbenoids with Benzylic Alcohols: A Route to Convert C-OH Bonds into C-C Bonds

Article abstract of DOI:10.1021/acs.orglett.6b02459

Alcohols are among the most abundant and commonly used organic feedstock in industrial processes and academic research. The first tandem O-H insertion/[1,3]-alkyl shift reaction reported is between benzylic alcohols and rhodium azavinyl carbenoids derived from N-sulfonyl-1,2,3-triazoles, which provides a strategically novel way of cleaving C-OH bonds and forming C-C bonds. The substrate scope is broad, capable of covering 1°-, 2°-, and 3°-benzylic alcohols. Moreover, it constitutes a new and powerful synthetic method for constructing α-aminoketones. Mechanistic studies suggest that a [1,3]-alkyl shift of oxonium ylides is responsible for cleavage of the C-OH bonds.

Full text of DOI:10.1021/acs.orglett.6b02459

Letter
pubs.acs.org/OrgLett
Tandem O−H Insertion/[1,3]-Alkyl Shift of Rhodium Azavinyl
Carbenoids with Benzylic Alcohols: A Route To Convert C−OH Bonds
into C−C Bonds
Pengbing Mi,† Rapolu Kiran Kumar,† Peiqiu Liao,† and Xihe Bi*,†,‡
†Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department of Chemistry, Northeast Normal
University, Changchun 130024, China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: Alcohols are among the most abundant and commonly used
organic feedstock in industrial processes and academic research. The first
tandem O−H insertion/[1,3]-alkyl shift reaction reported is between benzylic
alcohols and rhodium azavinyl carbenoids derived from N-sulfonyl-1,2,3-
triazoles, which provides a strategically novel way of cleaving C−OH bonds
and forming C−C bonds. The substrate scope is broad, capable of covering 1°-, 2°-, and 3°-benzylic alcohols. Moreover, it
constitutes a new and powerful synthetic method for constructing α-aminoketones. Mechanistic studies suggest that a [1,3]-alkyl
shift of oxonium ylides is responsible for cleavage of the C−OH bonds.
arbon−carbon bond-forming reactions are prevalent and
of fundamental significance in the field of synthetic
made leading contributions to the development of methods for
O−H insertion/[3,3]-sigmatropic rearrangement (Figure 1a),
C
chemistry.1 The utility of the “green” alcohols as the starting
materials for forming carbon−carbon bonds is attracting
massive attention, because they are among the most abundant,
inexpensive, and environmentally benign chemicals. Instead of
the traditional carbocation strategy,2 dependence on the
transition-metal catalysis has significantly expanded the horizon
of this area in the past few decades. Many impressive strategies
have emerged, for example, the ruthenium-catalyzed dehy-
drative C−H functionalization of alcohols,3 the TM-catalyzed
arylation/alkylation of benzyl alcohols with Grignard or
arylboronic reagents,4 the TM-catalyzed C-alkylation of ketones
and secondary alcohols with alcohols by the borrowing of a
hydrogen process,5 sequential O−H insertion/[3,3]- or [2,3]-
sigmatropic rearrangement of rhodium carbenoids with
alcohols,6,7 and the palladium-catalyzed allylic alkylation of
ketones with allylic alcohols.8 While these studies provide
variable routes to exploit alcohols in C−C bond-forming
reactions, the limited scope of alcohol substrates still remains a
major drawback in applying these methods in synthetic
practice.3−8 Consequently, development of new alcohol-based
C−C bond-forming reactions, especially those expanding the
repertoire of the alcohols that can be used, is still a long-
standing research goal.
Figure 1. Tandem O−H insertion/sigmatropic rearrangement of
rhodium carbenoids with alcohols.
while the [2,3]-sigmatropic rearrangement has been mainly
exploited by Jung,7a Wood,7b and Davies7c−h (Figure 1b).
Apparently, the dependence of either allylic or propargylic
alcohols is necessary in all of these reactions. Therefore,
expansion of this elegant strategy to general alcohols remains a
hard task. The thermal [1,3]-alkyl shift of vinyl ethers was
known in 1896 in the seminal report of Claisen11 and recently
Rhodium carbenoid insertion into O−H bonds, followed by
sigmatropic rearrangement, has received considerable attention
as an effective method for the cleavage of C−OH bonds to
form C−C bonds.6,7,9 These reactions are believed to proceed,
mechanistically, via tandem formation of an oxonium ylide and
sigmatropic rearrangement. Both [3,3]- and [2,3]-sigmatropic
rearrangements have been utilized in such a reaction sequence,
especially with applications in natural product synthesis.6a,b,10
The groups of Wood,6a−d Mukarami,6e Fokin,6f and Lee6g have
Received: August 17, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02459
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further developed by means of transition metal catalysis12 or
Brønsted acid catalysis.13 In comparison with [3,3]- and [2,3]-
sigmatropic rearrangement, the [1,3]-alkyl migration is less
developed.9 Here, we for the first time have incorporated a
[1,3]-alkyl shift into the C−OH bond cleavage of alcohols by a
strategically novel O−H insertion/[1,3]-alkyl shift reaction of
benzylic alcohols with rhodium azavinyl carbenoids which were
derived from N-sulfonyl-1,2,3-triazoles (Figure 1c).14 Notably,
1°-, 2°-, and 3°-alcohols are all suitable for this reaction. To the
best of our knowledge, this is the first [1,3]-alkyl shift reaction
developed directly starting from alcohols. In addition, this
reaction constitutes a new and powerful synthetic method for
the synthesis of α-aminoketones.15
a
Scheme 2. Scope of Alcohols
After identifying the optimal conditions (for details, please
see the Supporting Information), we then explored the reaction
scope with regard to N-sulfonyl-1,2,3-triazoles (Scheme 1). N-
ab
,
Scheme 1. Scope of N-Sulfonyl-1,2,3-triazoles
a
Conditions: 1 (0.75 mmol), 2 (0.5 mmol), Rh2(Oct)4 (2 mol %), 4 Å
b
MS (100 mg), toluene (3 mL), 120 °C, under N2, 10 h. Isolated
yields.
a
Tosyl-1,2,3-triazoles substituted at C4 with a phenyl ring
containing electron-donating or -withdrawing groups all
afforded high yields of products (3a−3g, 78−93%). N-Tosyl-
1,2,3-triazoles containing a fused aryl ring, such as naphthyl
(3h, 88%), or an aliphatic cyclic system, such as cyclohexenyl
(3i, 91%), also smoothly participated in the target reaction.
Furthermore, variation of the sulfonyl units of 1,2,3-triazoles
did not affect the reaction efficacy (3j−3m, 89−93% yields).
We next explored the scope of alcohols. As illustrated in
Scheme 2, 3°-benzylic alcohols with electron-withdrawing (4b
and 4c) and electron-donating groups at the o/m/p positions
were well tolerated (4a, 4d−4f, 63−91%). Bulky tertiary
alcohols, such as naphthyl (4g), fluorenyl (4h), and 1,1-
diphenylethanol (4i), also smoothly underwent the target
reaction to offer excellent product yields (81−92%).
Furthermore, benzylic alcohols bearing aliphatic rings, such as
cyclopentane (4j), cyclohexane (4k), and cyclobutane (4n),
proved to be suitable. The structure of 4n was further
confirmed by single-crystal X-ray analysis. Similarly, a range
of 2°-benzylic alcohols were reactive and resulted in the
corresponding products in moderate-to-high yields (5a−5i,
41−81%). Next, the reaction scope was expanded to 1°-
benzylic alcohols, which delivered the desired products (6a−
6c), albeit in slightly decreased yields (51−68%). Alcohols
derived from benzofuran (6d, 63%) and indole (6e, 81%) were
also suitable for the target reaction.
Conditions: 1 (0.75 mmol), 2 (0.5 mmol), Rh2(Oct)4 (2 mol %), 4 Å
b
MS (100 mg), toluene (3 mL), 120 °C, under N2, 10 h. Isolated
yields. The dr values were identified by HPLC analysis.
c
To develop an asymmetric version of this reaction, we tested
a series of chiral rhodium catalysts, including Rh2(S-BNP)4,16
Rh2(S-DOSP)4,17 and Rh2(S-nttl)4,18 but no satisfying results
were obtained. Therefore, we considered achieving high
stereoselectivity by chiral induction using a chiral alcohol.
Pleasingly, the alcohol (R)-1p (97% ee) produced the product
5a′ with high dr and ee values (dr = 10.7:1, ee >99%).
All α-aminoketone products structurally contained a benzylic
motif at the α-carbon, thus providing a handle for further
synthetic derivation. We investigated the cyclization under
various conditions and eventually achieved the conversion of
these α-aminoketones into tetrahydroisoquinolines 7 via
reaction with dimethoxymethane in the presence of H2SO4 at
90 °C (Scheme 3).19 The isoquinoline structure was
B
DOI: 10.1021/acs.orglett.6b02459
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Letter
a b
,
involvement of the rhodium catalyst in the [1,3]-sigmatropic
rearrangement step (eqs 4−6). The β-oxyenamine 9 was
prepared separately and then subjected to the standard reaction
conditions, which delivered 3a in 91% yield, whereas the
reaction without the rhodium catalyst afforded the thermal
dissociation products 8 (63%) and 10 (63%), along with 3a in
small amounts (23%). Finally, a competition experiment was
conducted by adding diphenylmethanol to the rearrangement
reaction of 9, which led to 3a in 83% yield, without formation
of the cross-reaction product 5e. This result further suggests
that the rhodium-catalyzed rearrangement of intermediate 9
occurs through an intramolecular process.
Scheme 3. Synthetic Utility of the Products
Based on these results and related precedents,6,7,12 a plausible
mechanism is proposed (Scheme 5). Initially, N-sulfonyl-1,2,3-
a
Scheme 5. Plausible Mechanism
Reaction conditions: 3 (0.5 mmol), dimethoxymethane (0.5 mL),
b
H2SO4 (0.5 mL) at 90 °C. Isolated yields.
unambiguously confirmed by single-crystal X-ray analysis of
product 7a. Notably, 1,2,3,4-tetrahydroisoquinoline is a
privileged structure in many biological and medicinal
compounds such as Solifenacin, a commercial antimuscarinic
drug.20
We performed extensive experiments to elucidate the
reaction mechanism (Scheme 4). First, we sought to identify
Scheme 4. Mechanistic Investigations
triazole 2a is converted to the α-diazo imine intermediate A via
ring−chain tautomerization. This conversion is followed by
reaction with the rhodium catalyst to afford α-imino rhodium
carbenoid intermediate B, along with release of molecular
nitrogen. Alcohol 1a then adds to the electrophilic carbene
center of B to generate zwitterionic intermediate C. Then,
intermediate C released the rhodium to form the vinyl ether
intermediate 9 which then undergoes a rhodium-induced [1,3]-
alkyl shift to give product 3a.12
In conclusion, we have developed a practical, general method
for the construction of C−C bonds using alcohols and rhodium
carbenoids, generated in situ from N-sulfonyl-1,2,3-triazoles. In
contrast to the [2,3]-alkyl shifts typically observed with
conventional rhodium carbenoids derived from α-diazocarbonyl
precursors, and the [3,3]-alkyl shifts observed for rhodium
azavinyl carbenoids derived from N-sulfonyl-1,2,3-triazoles,
these reactions proceed via an unusual formal [1,3]-alkyl
migration pathway. In addition, this atom-economic reaction
provides a useful tool for the synthesis of a range of densely
functionalized α-aminoketones.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02459.
the source of the oxygen and hydrogen atoms in the products.
A reaction using the oxygen isotope-labeled alcohol [18O]-1j
gives β-aminoketone [18O]-4i (eq 1). Trace amount of water in
the solvent was ruled out as the source of the oxygen atom
through an experiment with H218O, which afforded a H2O-
insertion product, [18O]-8, as in Mukarami’s report (eq 2).21
These results suggest that the hydroxyl group of the alcohol is
the source of the oxygen atom in the β-aminoketones. A
reaction with deuterium-labeled triazole [D]-2a offered product
[D]-3a, and equivalent quantities of deuterium were observed
in both compounds (eq 3). Control experiments validated the
Experimental procedures and spectra copies (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: bixh507@nenu.edu.cn.
Notes
The authors declare no competing financial interest.
C
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Letter
16802. (c) Tayama, E.; Horikawa, K.; Iwamoto, H.; Hasegawa, E.
Tetrahedron 2013, 69, 2745.
ACKNOWLEDGMENTS
■
This work was supported by the NSFC (21522202, 21502017,
21372038), the Ministry of Education of the People’s Republic
of China (NCET-13-0714), the Jilin Provincial Research
Foundation for the Basic Research (20140519008JH),
Fundamental Research Funds for Central Universities
(2412015BJ005, 2412015KJ013, 2412016KJ040), and the Jilin
Province Key Laboratory of Organic Functional Molecular
Design & Synthesis (No. 130028658).
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