a Reaction conditions B: 3aa (0.2
mmol), 4a (0.4 mmol),
[Cp*IrCl2]2 (5 mol %),
AgSbF6 (20 mol %), PivOH (0.2 mmol) and Oxidant (0.6
mmol) in solvent (2 mL) at a temperature under argon for 24 h.b Isolated yield.
Afterwards, we further investigated the corresponding substrate scope
under the standard condition B. As shown in Scheme 3, the 7-methyl
substituted tetrahydrocarbazol-4-one derivative 3ja was easily
transformed into 5b in a moderate efficiency, whera
electron-withdrawing trifluoromethyl (5c ) may be unfavorable in
a lower 22% yield. When replacing methyl with Bn, n- Bu and Et at
R2 position, the expected products5d -5f and 5k were well obtained,
respectively, and p -methylphenyl enriched the diversity of
R3 substituent (5g ). Besides, a series of
substituted thiophenes and furans were also tolerated, where
electron-rich thiophene rings had higher reaction efficiencies
(5h -5n ).
Scheme 3. Substrate Scope for5 a,b
a Reaction conditions B: 3aa ,3ja , 3la , 3na, 3oa, 3pa, 3ai (0.2 mmol),4a -g (0.4 mmol),
[Cp*IrCl2]2 (5 mol %),
AgSbF6 (20 mol %), PivOH (0.2 mmol) and AgOPiv (0.6
mmol) in dioxane (2 mL) under argon for 24 h.b Isolated yield.
Encouraged by the success ofC5 -(hetero)arylation of 3aa , we
subsequently achieved its C5 -alkylation
(6 ), C5 -alkenylation (7 ) andC5 -amidation (8 ) by treating3aa with tert -butyl-3-ethyl 2-diazomalonate,
3-buten-2-ol and 3-phenyl-1,4,2-dioxazolidin-5-one, respectively (Scheme
4). The structures of products 7 and 8 were
unambiguously established by the single crystal X-ray diffraction
analyses (see Figures S3 and S4 in the Supporting Information). These
transformations will provide simpler routes for the synthesis of
highly-functionalized tetrahydrocarbazol-4-one derivatives, which could
be further modified to obtain biologically active compounds.
Scheme 4. The C5 -alkylation,
alkenylation and amidation of 3aa .
To further evaluate the application potential of the prepared
carbazolone derivatives, we first performed a gram-scale preparation of3sa in 48% isolated yield (Scheme 5a). Then, 3aa was
used a universal precursor to synthesize potentially active molecules
through functional group conversion (Scheme 5b). First, 3aa was
reacted with Pb(OAc)4 in dichloromethane (DCM) at room
temperature for 12 h to give the unexpected oxidation product9 . Surprisingly, both double bond and carbonyl group of3aa were reduced to afford tetrahydrocarbazole 10 in
61% yield when treating 3aa with NaBH3CN in
acidic solution. Moreover, the carbonyl group of 3aa was easily
reacted with hydroxylamine hydrochloride to yield oxime, which further
underwent a Beckmann rearrangement reaction under PPA and gave the
ring-expanding lactam 11 in 70% yield. More importantly,
carbazolone derivatives 3 could be used to prepare Ondansetron
(12a ) and its analogues (12b and 12c ), a
marketed drug treating vomiting caused by chemotherapy and radiotherapy,
through simple two step reactions (Scheme 5c).[15]Notably, our methods and products could find great applications in drug
synthesis.
Scheme 5 . Gram-scale Preparation and Conversion of 3 .
To gain insight into the reaction mechanism, we subsequently performed
some mechanistic experiments. First, the H/D exchange experiment under
the standard condition A showed that the C–H activation was reversible
(Scheme 6a). Then, the intermolecular competition experiment was
performed between N -methyl-N -(p-tolyl)nitrous amide1e andN -methyl-N -(4-(trifluoromethyl)phenyl)nitrous amide1g , and the mole ratio of 3ea /3ga was up to
2.6, indicating that the electron-donating substituent may be more
conducive to the reaction (Scheme 6b).
Scheme 6 . Preliminary Mechanistic Investigations
On the basis of the preliminary mechanistic experiments and literature
precedents, a conceivable reaction mechanism was proposed in Scheme 7.
First, the catalyst is activated in the presence of
AgBF4 and PivOH. Then, the active catalyst Ibreaks the ortho C–H bond of 1a to form a five-membered
Rh intermediate II , which subsequently captures 2a and
gives the Rh-carbene species IV with the release of IPh. The
intermediate IV undergoes a cyclohexanedione carbene migration
insertion into C(Ar)- Rh bond and a sequential protonation, providing
the intermediate VI and the active Rh. Finally, the
intermediate VI undergoes an intramolecular enol
interconversion and cyclization to afford the carbazolone derivative3aa , accompanying by the departure of a molecule of
HNO2.
Scheme 7 . Proposed Reaction Mechanism.
Conclusions
In conclusion, we have developed a Rh(III)-catalyzed C–H activation ofN -nitrosoanilines and iodonium ylides to construct novel
tetralydrocarbzol-4-one scaffolds, which provided valuable templates for
sequential C-H functionalization such as alkylation, alkenylation,
amidation and (hetero)arylation at C5 -position
of tetralydrocarbzol-4-one with diverse coupling partners. The protocol
showed mild reaction conditions and good functional group tolerance.
This transformation enabled the multiple C–H modification of
pharmaceuticals, and the concise construction of biologically active
molecules.
Experimental