Preparation of α-(2,2-diphenylhydrazino)- and α-(benzyloxyamino)-lactones by radical cyclization: Use of glyoxylic acid diphenylhydrazone and glyoxylic acid 0-benzyloxime

Article abstract of DOI:10.1039/a608236j

Glyoxylic acid diphenylhydrazone (2, Y = NPh₂) and the corresponding O-benzyloxime (2, Y = OBn) are easily esterified in high yield by β-bromo alcohols, and the resulting esters undergo radical cyclization to α-(2,2-diphenylhydrazino) or α-(ben

Full text of DOI:10.1039/a608236j

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Preparation of a-(2,2-diphenylhydrazino)- and a-(benzyloxyamino)-lactones by
radical cyclization: use of glyoxylic acid diphenylhydrazone and glyoxylic acid
O-benzyloxime
Derrick L. J. Clive* and Junhu Zhang
Chemistry Department, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
Glyoxylic acid diphenylhydrazone (2, Y = NPh2) and the
corresponding O-benzyloxime (2, Y = OBn) are easily
esterified in high yield by b-bromo alcohols, and the
efficiently than do the corresponding diphenylhydrazones;
however, in this preliminary work we used diphenylhydrazones.
The ring closure shown for 4 (Scheme 1) requires the indicated
proximity of the carbon radical and the carbon–nitrogen double
bond; this conformation is adequately accessible because of the
sufficiently low rotational barrier about ester C(O)–O single
bonds.10
Our reaction produces lactones bearing an a-nitrogen
substituent (Table 1). When the starting alcohol 1 is cyclic, the
stereochemical outcome at the newly-created ring junction is
determined by the stereochemistry of the original hydroxy-
bearing carbon in 1, but for both cyclic and non-cyclic starting
alcohols the degree of stereoselectivity a to the lactone carbonyl
is low,11 at least under the thermal conditions we have used (see
footnotes to Table 1).
Experiments with indane derivative 15a (see Table 1)
revealed the intervention of a 1,2-acyl migration12 which, in this
case, must be especially fast because of the fact that it leads—
via a readily accessible and favourable geometry—to a benzylic
radical. Entry 6 of Table 1 shows an application to carbo-
hydrates, and also serves as an example of 7-exo closure.
Presumably, favourable geometrical constraints are operating in
this case, but are absent in 9a (6-exo closure), where an
appreciable amount of reduction occurs before cyclization.
All the coupling experiments to generate the radical pre-
cursors 3 were done by addition of DCC (5.5 mmol) and DMAP
(0.5 mmol) to a solution of the appropriate alcohol (5.5 mmol)
and reagent 2 (Y = NPh2 or OBn) (5 mmol) in CH2Cl2. After
6–12 h at room temperature, the esters could be isolated in the
yields shown. The radical cyclizations were conducted by
simultaneously adding toluene solutions‡ (double syringe
pump, 9-10 h) of Bu3SnH (1.73 mmol, 0.173 m) and AIBN
(0.12 mmol, 0.012 m) to a refluxing solution of the substrate
(1.15 mmol, 0.016 m) in the same solvent. At the end of the
addition refluxing was continued for an arbitrary period of 2–3
h (except for 8a, where this period was 5 h).
resulting esters undergo radical cyclization
to
a-(2,2-diphenylhydrazino) or a-(benzyloxyamino) lactones
on treatment with tributyltin hydride; the initial radical can
be formed by homolysis of a carbon–selenium bond as well as
a carbon–bromine bond and, when applied to appropriate
alcohols, the esterification–radical closure sequence can also
be used to make six- or seven-membered lactones.
We report here the synthesis of a-hydrazino lactones (5,
Y = NPh2) and the corresponding O-benzylhydroxylamines (5,
Y = OBn) by the radical cyclization process summarized in
Scheme 1 (X = Br, SePh). The radical precursors 3 are readily
accessible by DCC-mediated coupling of glyoxylic acid
diphenylhydrazone (2, Y = NPh2)1 or O-benzyloxime (2,
Y = OBn)2 with b-bromo or b-(phenylselanyl) alcohols (1,
X = Br or SePh), themselves easily made from alkenes (NBS–
H2O,3 PhSeX4) or epoxides (Me2BBr,5 PhSeNa6). The
glyoxylic acids 2 (Y = NPh2 or OBn) are stable, crystalline
reagents, formed in high yield (90–96%) from glyoxylic
acid.†
Both the coupling reaction (1 + 2 ? 3) and the radical closure
(3 ? 4 ? 5) generally proceed in good yield. Most of our work
has been done with hydrazone acid 2 (Y = NPh2), but related
experiments with the O-benzyloxime acid 2 (Y = OBn) were
also successful; however, we have not made a sufficiently
extensive comparison to identify which series (hydrazone or
oxime) is generally more efficient. Likewise, the superiority of
bromides over selenides for the radical closure step has also not
yet been firmly established.
Formation of carbocycles — specially five-membered rings
— by radical closure onto a carbon–nitrogen double bond is
well-established with oxime ethers,7 but to a much lesser extent
with diphenylhydrazones.8,9 In the case of hydrazones there is
evidence to suggest8a that hydrazone amides and semi-
carbazides 6 (Y = NHCOPh or NHCONHNH2) close more
a-Hydrazino- and a-(hydroxyamino)-g-lactones (cf. sub-
structure 5) are not well-known; neither are the corresponding
d-lactones.13 In principle, these a-substituted lactones can be
modified in various ways and, in the case of 7b for example,
hydrogenolysis (10% Pd–C, THF-aqueous HCl 6 m) gave
homoserine g-lactone hydrochloride14 (81% after crystalliza-
tion from acetone).
All new compounds were characterized by spectroscopic
methods, including accurate mass measurements. The isomers
of 11b (four), 14b (two) and 15b (two) were chromatographic-
X
NY
O
X
NY
O
+
OH
HO
O
1
2
3
R3SnH
AIBN
NHY
O
NY
•
R3SnH
O
O
O
NY
•
5
4
X = Br, SePh, Y = NPh2, OBn
6 Y = NHCOPh, NHCONHNH2
Scheme 1
Chem. Commun., 1997
549

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Table 1 Yields for coupling reaction to form hydrazones or oximes, and for
radical cyclization
Acknowledgment is made to the Natural Sciences and
Engineering Research Council of Canada for financial sup-
port.
Hydrazone or oxime (yield)
Lactone (yield)
NHX
Footnotes
Br
NX
1
† We used the procedure of ref. 2 for both reagents, but simply filtered off
the product, without extraction into CH2Cl2, in the case of the hydrazone.
‡ For 16a ? 16b, benzene was used, in order to demonstrate that the
reaction works also at the reflux temperature of this solvent.
O
O
O
O
7a X = NPh2 (80%)
8a X = OBn (82%)
7b X = NPh2 (75%)
8b X = OBn (51%)
Br
References
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O
12a X = NPh2, Y = Br (90%)
13a X = NPh2, Y = SePh (85%)
14a X = OBn, Y = Br (88%)
Ph2NHN
O
O
O
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NNPh2
15b (70%)b,f
5
Br
O
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O
O
NNPh2
NHNPh2
O
O
SePh
6
H
H
H
O
H
O
O
O
Me
Me
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function)
and
b.
The
isomer
ratio
(1H
NMR)
was
d
e
aa:ab:bb:ba::1:2:2.3:3. Isomer ratio (1H NMR) ca. 1:1. Isomer
ratio (isolation) 1:1. f Isomer ratio (isolation) 1:1.2. g Tentative structural
assignment; the material was obtained mixed with 15b. Isomer ratio (1H
NMR) ca. 1:1.
14 H. R. Snyder, J. H. Andreen, G. W. Cannon and C. F. Peters, J. Am.
Chem. Soc., 1942, 64, 2082.
ally separable, and the relative stereochemistry of each was
established by NOE measurements.
Received, 6th December 1996; Com. 6/08236J
550
Chem. Commun., 1997