Organic Letters
Letter
a
substituents on the newly formed pyridazine ring of products
9la and 9ma were introduced by employing C−H bond
substrates prepared by direct condensation of N-amino-2-
cyanopyrrole and trimethyl orthoformate and N,N-dimethyl-
formamide dimethyl acetal, respectively.
Scheme 4. Scope of Alkynes
We then evaluated variations of the pyrrole and azole
framework within the hydrazone C−H bond substrate 8
(Scheme 3). The hydrazone prepared from N-aminopyrrole
Scheme 3. Variation of the Pyrrole and Azole Framework in
a
Hydrazone 8
a
b
Standard conditions: 8a (0.30 mmol) and 4 (0.60 mmol). Yield of
mixture of regioisomers with regioisomers assigned by 2D NOESY
c
experiments. Cu(OAc)2 in place of AgOAc, omission of PivOH,
dioxane (0.2 M) in place of THF, 140 °C (MW), 1 h. Isolated yields
are reported.
gave 9af in 59% yield with a 1.3:1 regioisomeric ratio. This
example demonstrates that sterics alone play only a modest
role in controlling regioselectivity.
We also envisioned that tricyclic products with a central
pyridazine ring should be accessible by tethering the alkyne to
the hydrazone (Scheme 5). For these intramolecular
a
Standard conditions: 8 (0.30 mmol) and 4a (0.60 mmol). Isolated
yields are reported.
a
Scheme 5. Synthesis of Tricyclic Derivatives 10
provided pyrrolopyridazine 9na without any substituents on
the pyrrole ring. Moreover, in addition to the previously
introduced cyano group (see Scheme 2), 2-acetyl and ester
substituents could also be installed at different sites on the
pyrrole ring as shown for products 9oa to 9qa. Interestingly,
for pyrrolopyridazine 9qa, only one out of the two possible
regioisomers was formed, presumably because the ester
functionality directs C−H activation to the more hindered
proximal site.9 Finally, hydrazones incorporating unsubstituted
and substituted imidazoles were effective coupling partners to
provide products 9ra and 9sa, respectively.10
Next, we investigated the scope of the alkyne coupling
partner (Scheme 4). For couplings with unsymmetrical alkynes
we found that using AgOAc instead of Cu(OAc)2 as the
stoichiometric oxidant provided higher yields of product (see
changing the solvent to THF, and heating conventionally at
120 °C for 16 h also improved the reaction yield for these
alkynes (see Table S1). Employing these conditions, phenyl-
substituted, unsymmetrical alkynes provided pyrrolopyrida-
zines 9ab and 9ac in moderate to good yields. Both 9ab and
9ac were produced in a 6:1 regioisomeric ratio. Under the
same conditions, an unsymmetrical alkynoate coupling partner
provided product 9ad in a more modest yield but as a single
regioisomer. For the symmetrical alkyl-substituted alkyne, 3-
hexyne, Cu(OAc)2 and AgOAc were each evaluated as the
stoichiometric oxidant, with AgOAc affording 9ae in a slightly
higher yield of 79% relative to the 70% observed for
Cu(OAc)2. An unsymmetrical, bisalkyl-substituted alkyne
a
Standard conditions: 8 (0.30 mmol). Isolated yields are reported.
annulations we found that decreasing the reaction concen-
tration to 0.1 M resulted in higher yields, possibly by reducing
competing intermolecular cross-reactivity. As demonstrated for
tricyclic products 10a and 10b, comparable yields were
obtained when either alkyl or aryl substituents were introduced
on the central pyridazine ring.
To maximize the robustness of the reaction at short reaction
times, we evaluated the substrate scope with 5 mol % of
[Cp*RhCl2]2 and often with microwave heating at 140 °C for
1 h (vide supra). However, for performing large-scale
reactions, a lower catalyst loading with conventional heating
would likely be desirable. Therefore, a 1 mmol reaction was
performed with hydrazone 8a and alkyne 4a at a lower catalyst
loading of 1 mol % and with conventional heating at 120 °C
for 16 h (Scheme 6). Pyrrolopyridazine 9aa was obtained in
70% isolated yield, similar to that previously obtained at the
higher 5 mol % loading of [Cp*RhCl2]2 under microwave
heating (see Table 1, entry 13).
Next, we turned our attention to the mechanism. We
performed the reaction using hydrazone 8a and styrene in
C
Org. Lett. XXXX, XXX, XXX−XXX