Angewandte
Communications
Chemie
The scope with respect to the ketoxime substrates was
Unlike 3i, which was converted into a 10-membered ring, the
further explored by extending the tether length connecting
the aryl azide group (Table 1). When the linker was increased
by one (3i, n = 2), a 10-membered azacyclic compound was
obtained, albeit in moderate yield (4i). Interestingly, the
ketoxime geometry of this product was revealed to be in the
E form as evidenced by X-ray crystallography.[18] The present
expected cyclized compound was not obtained in the reaction
of 6. Instead, an imine-bound rhodacyclic complex (7) was
obtained in quantitative yield. The structure of 7 was fully
characterized by NMR spectroscopy and X-ray crystallogra-
phy[18] (Figure 2). This stable rhodacycle was not converted
À
annulation method, based on an intramolecular C H amina-
tion, allowed to access even larger rings by subjecting
ketoxime substrates tethered with longer linkers (3j–o, n =
3). Again, the 11-membered azacycles were obtained in high
yields irrespective of the electronic influence of the substitu-
ents. A primary kinetic isotope effect (KIE; kH/kD = 2.2) was
observed for the amination of 3j and its deuterated derivative
À
[D5]-3j, implying that C H bond cleavage is likely to be rate-
limiting (see the Supporting Information for details).
Figure 2. ORTEP of 7 with selected bond lengths and angles. Thermal
ellipsoids depicted at the 50% probability level. Hydrogen atoms and
NTf2 anion are omitted for clarity.
We next turned our attention to an analogous type of
substrate equipped with alkyl azides. However, at the
beginning, based on the assumption that the intrinsic rigidity
present in substrates will affect the efficiency of this cycliza-
subsequently into the desired azacycle under various reaction
conditions. Although mechanistic details on the formation of
this unusual complex are not understood at the moment, we
assume that a substrate having the present tether length
makes a geometrical restraint inhibiting the intramolecular
annulation.[16]
À
tion, an intramolecular C H amination with more flexible
alkyl azides was predicted to be more challenging when
compared to that with aryl azides. To examine this hypothesis,
acetophenone ketoxime bearing a 4-azidobutyl moiety (6)
was first treated with a cationic rhodium species (Scheme 3a).
The above result led us to naturally scrutinize more
flexible ketoxime substrates bearing elongated alkyl azides.
When acetophenone ketoxime, tethered with pentyl azide,
was subjected to the standard reaction conditions, a doubly
À
C H aminated dimeric azacyclic compound, 9a, was obtained
in 20% yield at 1008C (Scheme 3b). When the reaction was
carried out at higher concentration (0.8m), the product yield
of the 22-membered ring 9a was improved to 52%. The
formation of 9a was reasoned to take place by a sequential
À
cascade of inter- and intramolecular C H aminations as
depicted in Scheme 3c. Upon the generation of the rhoda-
À
cycle A from 8a, an intermolecular C H amination will occur
preferentially instead of an intramolecular reaction. In fact,
the postulated intermediate B was detected by EI-MS
À
analysis. The second C H bond cleavage of B was believed
to be assisted by an intramolecular hydrogen bond to afford
the rhodacycle C. The final ring formation will proceed by an
À
intramolecular C H amination of C, thus affording 9a. The
moderate yield of 9a is ascribed to side-reactions, such as
À
intermolecular C H amination of C leading to oligomeric
compounds.
The scope with respect to alkyl-azide-tethered ketoximes
(8) was next investigated (Table 2). To our surprise, the
À
reactivity pattern for the formation of doubly C H aminated
dimeric azacycles was observed again with a range of tether
lengths, thus giving rise to azamacrocycles of up to 36-
membered ring products. Functional groups such as bromo,
methoxy, and methyl were compatible with the optimal
reaction conditions, and a number of 22-membered azacyclic
products (9a–d) were obtained in moderate yields. It should
be mentioned that the isolation of the desired azacyclic
products was convenient with the use of the regular silica gel
chromatography. The structure of 9b was confirmed by an X-
ray crystallography[18] and revealed that two intramolecular
Scheme 3. Investigation of the flexible substrate.
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3
These are not the final page numbers!