5212
K. F. Biegasiewicz et al. / Tetrahedron Letters 55 (2014) 5210–5212
probes have received the most attention.7,8 Herein, we outline a
general approach to a synthesis of a library of isoflavonoids that
could be used in labeling and other syntheses.
in synthesizing 5-hydroxyisoflavonoids (9–12), however we had
no luck utilizing the outlined scheme for 6-hydroxyisoflavonoids
(13–16). This was unsuccessful in the first step of our pathway;
that is, the formation of the enamine and protection of the hydro-
xyl. We attempted this in molar ratios of 1:1 up to 50:1 of aceto-
phenone to DMF-DMA. In addition, we explored different
temperatures and reaction times. Our best result yielded only
10% of crude product. We therefore explored initial protection of
6-hydroxyl. Although we were able to selectively protect one of
the hydroxyls of 2,6-dihydroxyacetophenone simply by manipula-
tion of reagent ratios with silyl protecting groups and benzyl; in
both cases the subsequent enamine formation was unsuccessful.
Ultimately, as with genistein, we found success with MOM-protec-
tion. Therefore, after the initial MOM-protection with chloro-
methyl methyl ether and N,N-diisopropylethylamine in CH2Cl2
(Step pre-1), we obtained the protected acetophenone, which we
used without additional purification to obtain the enamine (Step
1). This went further through a ring closure/iodination reaction
(Step 2) followed but the Suzuki cross-coupling (Step 3). Simple
refluxing in concentrated HCl for one hour afforded the desired
6-hydroxyisoflavonoids (13–16) in moderate to good yields (Step
4).
Recently we demonstrated the total synthesis of daidzein9,10
and genistein11 from acetophenone derivatives in four and five
steps, respectively. Our synthesis of daidzein involved the forma-
tion of the enamine from its corresponding acetophenone using
N,N-dimethylformamide dimethylacetal (DMF-DMA). This had
the serendipitous effect of also protecting the 4-hydroxyl as its
methyl ether. We have subsequently explored this latter event in
a greater detail.12 Unfortunately, when we attempted this with
the 2,4,6-trihydroxyacetophenone, we were unsuccessful and thus
needed to employ MOM-protection to ultimately obtain the
desired genistein. In light of this, we decided to initially attempt
to synthesize our library of isoflavonoids in a similar route as we
had for daidzein and thus only employ MOM-protection if neces-
sary (Scheme 1).
With this in mind we began with the synthesis of the simplest of
all the isoflavonoids (Table 1), 3-phenylchromen-4-one (1). Indeed,
when 2-hydroxyacetophenone was reacted with DMF-DMA the
corresponding enamine was obtained in 99% yield (Step 1). Simi-
larly, when we performed the one-pot, two-step ring closure and
iodination via addition of I2 in MeOH, the 3-iodochromone was pro-
duced in near quantitative yield (Step 2). As with both daidzein9,10
and genistein,11 we utilized a green approach for the Suzuki cou-
pling demonstrated by Liu et. al.13 By employing poly(ethylene gly-
col) 10,000 (PEG 10,000) as the ligand, along with Pd(OAc)2, Na2CO3
in MeOH, and phenylboronic acid, we performed the cross-coupling
reaction to obtain phenylchromen-4-one (1) in 95% yield (Step 3).
To our delight, our synthetic route also allowed for the use of alter-
nate arylboronic acids to produce other isoflavonoid derivatives.
Thus, using 2-, 3-, or 4-hydroxyphenylboronic acid afforded 20-
hydroxyisoflavonoid (2: 59%), 30-hydroxyisoflavonoid (3: 87%),
and 40-hydroxyisoflavonoid (4: 92%), respectively. Of note, as the
hydroxyl group moves further away from the reactive boronic acid
site the yield of the coupling reaction increased. This trend was also
observed for the other members of the library (Table 1).
In conclusion, we have presented a three- to five-step synthetic
route to a host of isoflavonoid derivatives. The key synthetic steps
involve enamine formation (Step 1), ring closure/iodination (Step
2), and Suzuki cross-coupling (Step 3). Additional steps beyond
these are either deprotection (Step 4) or protection/deprotection
(Step pre-1/Step 4).
Acknowledgments
K.F.B., J.S.G., and R.P. would like to thank the Niagara University
Academic Center for Integrated Sciences, as well as the Rochester
Academy of Science for financial support. D.A.R. and R.P. would
also like to thank the Western New England University, College
of Pharmacy for generous financial support.
We next focused on the introduction of hydroxyls on Ring A of
the isoflavonoid (Fig. 1). We decided to use commercially available
acetophenones, including 2,3-, 2,4-, 2,5-, and 2,6-dihydroxyaceto-
phenone; however, we ultimately did not utilize the 2,3-dihy-
droxyacetophenone variant as we found this to be too cost
prohibitive. Therefore, as with our synthesis of daidzein, we began
with the enamine formation/O-methylation with DMF-DMA on the
2,4-dihydroxyacetophenone (Step 1). After the one pot-two step
ring closure and iodination (Step 2), we were in the position to per-
form the cross-coupling with phenylboronic acid as well as with its
2-, 3-, and 4-hydroxy derivative (Step 3). In all four examples we
successfully synthesized the 4-methoxyisoflavonoids in moderate
to excellent yields (66–98%). Unlike the aforementioned series,
which yielded isoflavonoids in three steps, we still needed to
demethylate our products. We attempted this with AlCl3,14
BCl3,15 and TMSI,16 but as with our synthesis of daidzein only HI
refluxed for 4 h proved successful (Step 4). This ultimately afforded
us the series of 4-hydroxyisoflavonoids (5–8).
References and notes
Using the same methodology as described above we set out to
complete the synthesis of our library (9–16). We were successful