Communications
doi.org/10.1002/ejoc.202100783
The cyclization reaction was optimized for the substrate-
PL1-PL5 in Figure 3A). In this paper, we also analyzed the
hydroxylation of unsymmetric 2-susbtituted benzophenones
(PL6-PL9), which were functionalized at the ortho-position of
the unsubstituted ring in a selective fashion (see S.I. for
synthesis of L6-L9). The hydroxylation products derived from 4-
substituted acetophenones (PL10-PL13) and acetonaphthones
(PL14 and PL15) were also obtained with moderate yields (20–
40%). 4-substituted benzaldehydes could also be oxidized but
did not produce the resulting PL products (PL16-PL18) since
these were hydrolyzed to the corresponding 4-substituted 2-
hydroxy-benzaldehydes (see S.I. for details). The products
derived from sp2 CÀ H hydroxylation of butyrophenone (PL19)
and 2-methyl-1-tetralone (PL20) were obtained with excellent
selectivity (i.e., no sp3 CÀ H hydroxylation).
ligand derived from 2-hydroxybenzophenone PL1 (Figure 2).
The reactions were carried out at room temperature and under
air by mixing solutions of PL1 with the metal source and base.
We found that 1 equiv. of CuII(CF3SO3)2 and 5 equiv. of NEt3
were optimal for the formation of the cyclic product (Figure 2,
entries 1 to 4). We also observed that other bases such as TMG
(1,1,3,3-tetramethylguanidine), DBU (1,8-diazabicyclo[5,4,0]
undec-7-ene), TBD (1,5,7-triazabicyclo[4,4,0]dec-5-ene) or
pyridine produced the 2H-1,3-benzoxazine product with smaller
yields (Figure 2, entries 5 to 8). Other CuII sources were also
utilized and we found that CuII(NO3)2 ·3H2O (cheapest Cu salt)
reached the highest yields. Other metal sources (FeII, MnII, NiII,
ZnII and PdII) did not form the cyclization product or did in very
minor yields. Interesting, cyclization in other solvents (THF,
CH2Cl2 and CH3CN) led to similar yields to the ones obtained in
acetone.
After optimizing the cyclization reaction, we decided to
develop a one-pot synthetic protocol to oxidize a series of
substrate-ligands (LX) to the corresponding hydroxylation
products (PLX) and cyclization products (CX) (Figure 3A). The
hydroxylation of the LX systems was performed utilizing
1 equiv. of CuII(NO3)2 ·3H2O, 1 equiv. of NMe4OH and 5 equiv. of
H2O2, which allowed to obtain the PLX products with good
yields. 4,4’-substituted benzophenones were oxidized with
yields similar to the ones reported in our previous work (see
The one-pot sequential hydroxylation-cyclization of the LX
systems to CX was accomplished by performing the hydrox-
ylation with CuII, NMe4OH and H2O2 and, after 30 minutes,
adding 5 equiv. of NEt3 (Figure 3A). The cyclization products
were obtained with modest overall yields (ca. 35%) partially
attributed to hydrolysis of the imine bond in LX and PLX. These
overall yields are also in agreement with the average yield
obtained in the sp2 hydroxylation (ca. 60%) and the optimized
cyclization (ca. 70%). Despite the yields, the CX products were
obtained as sole products by filtering the solutions obtained
after work-up through a basic alumina plug. Using this one-pot
methodology, we synthesized and characterized 15 novel 2-H-
1,3-benzoxazines derived from 4-substituted benzophenones
(C1-C5), 2-substituted benzophenones (C6-C9), 4-substituted
acetophenones (C10-C13), acetonaphthones (C14 and C15),
butyrophenone (C19) and 2-methyl-1-tetralone (C20) (see Fig-
ure 3). For 4-substituted benzaldehydes, we did not observe the
formation of the corresponding cyclization products (C16-C18)
since we believe the PLX imine products are hydrolyzed in the
reaction crude. We attempted to carry out the cyclization of the
independently synthesized PL16 using CuII and NEt3 but no
cyclization was observed and only the products derived from
PL16 hydrolysis could be isolated (see SI).
We also performed the one-pot synthesis of C1 from L1 at a
gram scale (Figure 3B). After hydroxylation with copper,
tetramethylammonium hydroxide and hydrogen peroxide and
cyclization with triethylamine, we were able to isolate C1 by
stirring the reaction crude overnight with a saturated aqueous
solution of Na4EDTA and purifying the resulting organic
products by flash column chromatography in basic alumina
(yield: 26%, 575 mg). The isolated C1 product was transferred
inside the glovebox and it was reacted with 1 equiv. of
[CuI(CH3CN)4]PF6 to produce the corresponding cuprous com-
plex (Figure 3B, right). The resulting complex, [(C1)CuI(CH3CN)]
PF6, was characterized by X-ray diffraction analysis and the CÀ N
distances and NÀ CÀ O angles measured were consistent with
the formulation of C1 as 2H-1,3-benzoxazine product.[7] We also
noticed that in this cuprous complex, the directing group and
the Cu ion were oriented towards the phenyl ring that was not
oxidized, which suggested that after the cyclization reaction a
second hydroxylation process could be promoted. In fact,
hydroxylation of the cyclization product of C1 to PC1 was
accomplished by adding stoichiometric amounts of [CuI-
Figure 2. Optimization of the cyclization reaction conditions.
Eur. J. Org. Chem. 2021, 4536–4540
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