1886
J . Org. Chem. 2000, 65, 1886-1888
Sch em e 1
Ma sk ed F or m yla tion w ith
2-Ben zotr ia zolyl-1,3-d ioxola n e, a Novel
F or m yl Ca tion Equ iva len t
Alan R. Katritzky,* Herman H. Odens, and
Michael V. Voronkov
Department of Chemistry, Center for
Heterocyclic Compounds, University of Florida, Gainesville,
Florida 32611-7200
Sch em e 2
Received October 18, 1999
In tr od u ction
The direct introduction of a carbonyl moiety, in its
protected form, into a multifunctional organic molecule
can eliminate an additional protection step and allow the
liberation of the masked moiety at a later stage. Such
approaches to the introduction of carbonyl functionality
are widely used in total synthesis.1 General methods for
the introduction of a masked C-1 aldehyde can be divided
into the three classes according to the nature of the
dithiane and close analogues which form dithiane, re-
quiring vigorous conditions to hydrolyze,12a-d and (iii)
N,N-dialkylformamide acetals used for formylation of
enolates.13
In the present work we investigated the use of new
benzotriazole reagent 2 as a remarkably stable and
versatile electrophilic formylating reagent. We report the
use of 2 for the direct electrophilic introduction of a
masked aldehyde moiety under very mild conditions.
•
reagent C, -C, or +C.
The first is exemplified by radical couplings of tri-
oxanes or 1,3-dioxalanes with carbonyl compounds.2a,b
However, these reactions have limited generality and
some require conditions (e.g., strong oxidants or SmI2)
which may not be suitable for multifunctional substrates.
The second class is the most important and widely
developed.3 It includes reactions of electrophiles with
many R-heteroatom-stabilized formyl anion synthons,
typified by deprotonated 1,3-dithiane,4 the corresponding
sulfones or sulfoxides,5 R-arylthiotrimethylsilanes,6 and
other R-heteroatom-stabilized formyl anion equivalents.7a-d
Although some of the previously developed formylating
reagents required deprotection by heavy metals or harsh
reagents such as m-CPBA,6 or TMSI,8 novel R-hetero-
atom-stabilized formyl anion reagents proved to be
advantageous due to the very mild deprotection condi-
tions required.7a-c,9
The third strategy is based on reactions of formyl
cation equivalents with nucleophiles. Among these, reac-
tions of alkyl orthoformates with organometallics are
classical10a-c and afford the desired dialkyl acetals in 14-
81% yields. Other formyl cation reagents used with
Grignards or organolithiums include (i) R,R-dialkoxy
tetraalkylammonium and N-alkoxymethylpyridinium
salts, which give variable yields,11a,b (ii) 2-chloro-1,3-
Resu lts a n d Discu ssion
The key reagent 2 was prepared from 2-ethoxydi-
oxolane 114 and benzotriazole in 75% yield (Scheme 1).
Upon treatment with various organozinc reagents, 2
produced the corresponding products, in 50-94% yields,
according to Scheme 2.
We used two methods (A and B) for the in situ
generation of organozinc reagent 3. In method A a
commercial Grignard reagent was treated with an equiva-
lent amount of a 1.0 M solution of ZnCl2 in THF and
allowed to stir for 1 h at room temperature. Instead of
using a commercial organomagnesium reagent, method
B was applied to provide the desired organozinc reagent
from the corresponding organohalide. In method B the
organic halide was treated with an equivalent amount
of Zn dust and stirred for 1 h (until turning green) in
THF at reflux. In both methods, the addition of 2 followed
by overnight stirring afforded the desired products 4a -
l. All the sp, sp2, and sp3 nucleophiles tested gave good
yields (e.g., entries 4a -c,e,f, Table 1). We found that the
bulkier secondary alkyl organozinc reagent gave the
corresponding product 4g in 57% yield. Unexpectedly,
product 4l was isolated in 72% yield when organozinc
reagent generated from 2-bromomethylnaphthalene was
employed. The NMR spectra of 4l are significantly
different from those of 4a -k . The two singlets at 5.20
and 5.13 ppm on 1H NMR for 4l suggest a terminal
double bond; furthermore, the H-2 of the dioxolanyl
moiety appeared as a doublet (J ) 4.1 Hz). Hence 4l was
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10.1021/jo991624u CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/01/2000