Highly diastereoselective radical reactions of substituted methylideneimidazolidinones and related systems

Article abstract of DOI:10.1071/CH04054

Stannane-mediated radical addition to tnethylideneimidazolidinones occurs with good to excellent diastereo-selectivity. The stereochemical outcome of addition is highly dependent on the nature of the NI substituent on the imidazolidinone ring.

Full text of DOI:10.1071/CH04054

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CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2004, 57, 629–633
Highly Diastereoselective Radical Reactions of Substituted
Methylideneimidazolidinones and Related Systems∗
George A. Adamson,A Athelstan L. J. Beckwith,A,B and Christina L. L. ChaiA
A Department of Chemistry and Research School of Chemistry, Australian National University,
Canberra ACT 0200, Australia.
B Author to whom correspondence should be addressed (e-mail: beckwith@rsc.anu.edu.au).
Stannane-mediated radical addition to methylideneimidazolidinones occurs with good to excellent diastereo-
selectivity. The stereochemical outcome of addition is highly dependent on the nature of the N1 substituent on
the imidazolidinone ring.
Manuscript received: 27 February 2004.
Final version: 8 April 2004.
Recognition that organic free-radical reactions can pro-
ceed with high chemo-, regio-, and diastereoselectivity[1−4]
has underpinned the development of radical-based method-
ologies, and they now occupy an important place in the
arsenal available to the synthetic organic chemist. How-
ever, the rational exploitation of such reactions requires
identification of the factors that underlie the nature and
degree of selectivity. Although these are now reasonably
well understood for many types of radical reactions includ-
ing additions to acyclic olefinic compounds,[1,2,5] this is
not the case for additions to more complex substrates in
which small structural changes can result in large changes
to the stereochemical outcomes of the reactions.[6−9] The
radical chemistry of the exo-methylidene heterocycles 1
and 2 provides a case in point (Scheme 1). In a typical
example, stannane-mediated cyclohexyl radical addition to
dioxolanone 1 affords mainly the cis product 3 (cis/trans:
7).[6] Other related radical reactions of substrate 1 also exhibit
high cis diastereoselectivity.[6,7] Conversely, treatment of
oxazolidinone 2a with cyclohexyl iodide and tributylstan-
nane gives mainly the trans product 4 (trans/cis: >49).[6,8]
Radical addition reactions of the N-naphthoyl compound
2b also show trans diastereoselectivity,[8] as do those of 2a
with a variety of radicals such as methyl, adamantyl, isobutyl,
perfluoropropyl, methoxymethyl, and tetra(O)acetylglucosyl
(trans/cis: 7–49).[8]
The effect that small changes in substrate structure have
on the diastereoselective outcome is dramatically illus-
trated by comparing the stereochemical outcomes of the
radical addition reactions of N-benzoyloxazolidinone 2a
and N-phenoxycarbonyloxazolidinone 2d. In contrast to the
highly trans diastereoselective reactions that occur with
N-benzoyloxazolidinone 2a, the stannane-mediated reaction
between the cyclohexyl radical and carbamate 2d gives
mainly the cis product 5 (cis/trans: 49).[8] Similar reactions
with carbamates 2e and 2f are also very highly cis diastereo-
selective (cis/trans: >49).[8] As the pure enantiomers of
compounds 1 and 2 are easily prepared, and their adducts
O
O
O
O
O
O
O
O
O
O
O
O
But
But
But
But
But
H
CH2R
CH2R
H
N
N
N
CH2R
H
COR
COPh
CO2Ph
1
2
3
4
5
a R ϭ Ph
R ϭ cyclohexyl
R ϭ cyclohexyl
R ϭ cyclohexyl
b R ϭ 1-naphthyl
c R ϭ CH3
d R ϭ OPh
e R ϭ OCH3
f R ϭ OCH2Ph
Scheme 1.
∗ Dedicated with affection and admiration to Professor Lew Mander on the occasion of his 65th birthday.
© CSIRO 2004
10.1071/CH04054
0004-9425/04/070629

630
G. A. Adamson, A. L. J. Beckwith and C. L. L. Chai
CH3
N
CH3
N
a medium-pressure mercury lamp. The reaction mixture was
treated with aqueous ammonia in order to remove the tin
residues and was then filtered through a plug of silica using
ethyl acetate as eluent. The cis/trans ratio of the products
O
O
But
But
N
N
COPh
CO2Ph
1
was determined by integration of the H NMR spectra. For
6
7
N-benzoyl compounds such as 11 and 12 (Scheme 5), for
which the stereochemistry could be confirmed because we
have X-ray or other data, the signals for the C2 and C5 protons
of the trans isomer were found to be downfield of the compa-
rable signals for the cis isomer. For example, the δH values for
the C2 and C5 protons in the trans compound 11c were 5.67
and 4.27 ppm, respectively, whereas those for the equivalent
protons in the cis isomer 12c were 5.60 and 3.83 ppm. For the
carbamates 13 and 14 the C2 signal for the trans isomer was
also downfield in comparison to that for the cis isomer, but the
signal for the C5 proton was upfield. For example, 14c dis-
playedsignalsfortheC2andC5protonsat5.18and4.20 ppm,
while those for the cis isomer 13c were at 5.05 and 4.41 ppm,
respectively. The preferential formation of adducts 11a and
11b indicates that additions to the N-benzoyl substrate 6 are
highly trans diastereoselective (11a/12a: 21 and 11b/12b:
16). Conversely, stannane-mediated additions to carbamate 7
give mainly cis products (13a/14a: 6 and 13b/14b: 6.8). The
major product in each reaction was isolated by radial chro-
matography, and was characterized by mass spectrometry,
IR, UV, and NMR spectroscopy, as well as elemental analysis.
The isolated yields were 67% for the trans (2S,5S) compound
Scheme 2.
CONHCH3
CH3
(a)
(b)
CONHCH3
CH3
NH2
N
CH3
CH3
O
O
N
N
(c)
(d)
But
But
H
6
H
N
N
CH3
CH3
COPh
H
Scheme 3. Reagents and conditions: (a) ButCHO, pentane, Dean–
Stark, ꢀ, 3 h; (b) CF3CO2H, CH2Cl2, 0◦C, 1 h, NaHCO3/H2O; (c)
PhCOCl, CH2Cl2, Et3N, room temp., 16 h, radial chromatography;
(d) NBS, CCl4, hν, then NaI, acetone, ꢀ, 4 h.
I
I
Br
OAc
OAc
OAc
O
OAc
OAc
OAc
OAc
H
OAc
OAc
H
H
O
O
AcO
AcO
22
11a, [α]D +43.6◦ in CH2Cl2; 69% for the trans (2S,5S) com-
8
9
10
22
pound 11b, [α]D +16.5◦ in CH2Cl2; 61% for the cis (2S,5R)
Scheme 4.
22
compound 13a, [α]D −26.6◦ in CH2Cl2; and 63% for the cis
22
(2S,5R) compound 13b, [α]D −33.3◦ in CH2Cl2.
readily undergo hydrolysis, these reactions afford a useful
method for the enantioselective preparation of α-substituted
hydroxy- and amino-acids.[8,9]
In order to compare the above radical reactions with those
of a related system, as well as to explore further opportuni-
ties for the enantioselective synthesis of substituted alanines
and identify the mechanism by which the nature of the N1
substituent in compounds such as oxazolidinones 2a and 2d
affects diastereoselectivity, we examined the behaviour of the
related imidazolidinones 6 and 7 (Scheme 2).
Preparation of (2S)-methylideneimidazolidinone 6 from
the N-methylamide of l-alanine (Scheme 3) is similar to
the synthesis of oxazolidinones 2,[8−11] and an analogous
sequence of reactions affords the pure (2S)-carbamate 7. As
stannane-mediated radical reactions of sugar-derived radi-
cals with oxazolidinones have been shown to proceed with
high diastereoselectivity,[8] we conducted similar reactions
with imidazolidinones 6 and 7. The unstable iodides 8 and 9
(Scheme 4) to be used as the radical precursors were prepared
from the appropriate pentaacetates.[12,13] As the analogous
preparation of d-xylose triacetate iodide was unsuccessful,
the unstable bromide 10[14] was used instead.
Radical additions of cyclohexyl and isopropyl iodide to
imidazolidinones 6 and 7 were conducted under ‘catalytic
tin’ conditions,[15] whereby the substrate, the radical precur-
sor, tributyltin chloride, sodium cyanoborohydride, and the
initiator (AIBN) in acetonitrile were photolyzed at 30◦C with
Reactions of imidazolidinones 6 and 7 with the radicals
derived from the halo sugars 8, 9, and 10 were conducted
either under catalytic tin conditions or by the slow addition of
a stoichiometric amount of tributylstannane during the reac-
tion. In most cases the catalytic method gave better yields
of the addition adducts. In view of the potential sensitivity
of the resultant products to aqueous ammonia, the workup
procedure to effect the removal of tin residues was modified.
In particular, the reaction mixture was partitioned between
hexane, which preferentially dissolves tin compounds, and
acetonitrile, which retains the more polar adducts.[16] In the
reactions with glucosyl iodide 8 and galactosyl iodide 9 only
a single product was isolated after careful analytical chro-
matography. Unfortunately, 1H NMR spectroscopy could not
beemployedtoassignthestereochemistryofeachoftheprod-
ucts as the protons on the sugar moiety obscured the diagnos-
tic signals from the protons present on the imidazolidinone
nucleus. Accordingly, we turned to circular dichroism (CD)
measurements; these showed that the trans compounds 11a–
11c and 14c gave very similar traces which were easily
distinguishable from those of their cis isomers. As the CD
traces for 15a and 16a, which were formed from the reaction
of N-benzoyl substrate 6 with iodo sugars 8 and 9, respec-
tively, were very similar to those observed for related trans
compounds 11a–11c and 14c, we tentatively assigned the
trans stereochemistry to these products (Scheme 6). In addi-
tion, the stereochemistry of the anomeric sugar carbon was

Diastereoselective Radical Reactions of Substituted Methylideneimidazolidinones
631
CH3
CH3
N
CH3
N
CH3
N
3
O
O
O
O
N
2
4
But
But
But
But
H
CH2R
H
CH2R
1
N
N
N
N
5
CH2R
H
H
CH2R
COPh
COPh
CO2Ph
CO2Ph
11
12
13
14
a R ϭ cyclohexyl
b R ϭ isopropyl
c R ϭ H
Scheme 5.
CH3
N
CH3
N
CH3
N
CH3
O
O
O
O
N
H
But
But
But
But
OAc
O
N
N
N
N
OAc
OAc
CH2
OAc
CH2
CH2
OAc
CH2
OAc
COR
COR
COR
COR
OAc
OAc
OAc
OAc
OAc
O
O
O
17
18
AcO
AcO
OAc
a R ϭ Ph
b R ϭ OPh
15
16
a R ϭ Ph
b R ϭ OPh
Scheme 7.
Scheme 6.
addition reactions of xylosyl radicals.[18] On this basis, we
believe that the two products from 6 detected in a ratio of
1 : 4.8, and characterized by mass spectrometry, UV, IR, and
NMR spectroscopy, as well as elemental analysis, are the
assigned as α because glucosyl and galactosyl radicals usu-
ally form α-anomeric adducts in their reactions with olefinic
substrates.[17] The isolated yields of the pure compounds,
which were characterized by mass spectrometry, UV, IR,
and NMR spectroscopy, as well as elemental analysis, were
22
α-(2S,5S)compoundtrans-17a, [α]D +21.2◦ inCH2Cl2, and
22
the β-(2S,5S) compound trans-18a, [α]D +38.9◦ in CH2Cl2
(Scheme 7).The two products isolated in a ratio of 1 : 1.6 from
22
52% for the (2S,5S) compound trans-15a, [α]D +91.2◦ in
the reaction involving the carbamate 7 are believed to be the
22
CH2Cl2; and 50% for the (2S,5S) compound trans-16a,
α-(2S,5R) compound cis-17b, [α]D −33.9◦ in CH2Cl2, and
22
22
[α]D +71.0◦ in CH2Cl2.
the β-(2S,5R) compound cis-18b, [α]D +62.2◦ in CH2Cl2.
Similarly, the adducts derived from N-carbamate substrate
7 were tentatively assigned as possessing the cis stereochem-
istry. The isolated yields of the pure compounds, which were
characterized by mass spectrometry, UV, IR, and NMR spec-
troscopy, as well as elemental analysis, were 61% for the
Themixtureofanomersobtainedinreactionswithxylosebro-
mide suggests that the conformational rigidity of the xylosyl
radical is much less than that of the glucosyl and galactosyl
radicals.[18]
In summary, present and previous results[6−9] show that
stannane-mediated radical additions to methylidene-2-tert-
butyl-1,3-dioxolanones, oxazolidinones, and imidazolidi-
nones are highly diastereoselective. All reactions reported
for dioxolanone 1 exhibit cis diastereoselectivity, whereas
selectivity in reactions that involve methylideneoxazolidin-
ones and imidazolidinones depends on the nature of the
substituent on N1. In particular, reactions of N-aroyl sub-
strates such as 2a and 6 are highly trans diastereoselective,
while those of N-aryloxycarbonyl substrates such as 2d and
7 are highly cis diastereoselective. The nature of the addend
radical, unlike that of the N1 substituent, appears to exert a
relatively minor influence on the degree but not the direction
of diastereoselectivity.
22
(2S,5R) product cis-15b, [α]D +10.5◦ in CH2Cl2; and 56%
22
for the (2S,5S) product cis-16b, [α]D +21.1◦ in CH2Cl2.
Reactions of xylose bromide 10 with substrate 6 gave
the best yields (57%) when a stoichiometric amount of tri-
butylstannane was added during the reaction. Conversely, the
best yield (47%) obtained for the same reaction with carba-
mate 7 occurred when the catalytic tin method was used. In
each case two adducts were detected and isolated as gums.
Unfortunately, the use of NMR spectroscopy to assign the
stereochemistry of the products was unreliable due to diag-
nostic signal overlap and relatively poor resolution. However,
on the basis of CD measurements and by analogy with the
above results, we tentatively assigned the stereochemistry of
the products from the N-benzoylimidazolidinone 6 as trans
and those from the N-carbamate imidazolidinone 7 as cis.
Differences in the shifts for the NMR signals assigned to
the sugar moieties suggest that the two isomers from each
reaction differ in stereochemistry at the anomeric position,
and that the β-form is the major isomer. The formation of
β-adductshaspreviouslybeenreportedforstannane-mediated
Equilibration experiments in which diastereoisomers 11c
and 12c were treated with lithium tert-butoxide in refluxing
tert-butanol indicated that they are of approximately equal
thermodynamic stability, and empirical calculations on other
pairs of cis and trans isomers such as 11a and 12a gave similar
results.Therefore, we conclude that stereochemical outcomes
must reflect the facial selectivity of hydrogen-atom transfer

632
G. A. Adamson, A. L. J. Beckwith and C. L. L. Chai
CH3
N
O
O
O
N
But
But
•
•
N
CH2R
CH2R
COAr
COPh
19
20
Ar ϭ phenyl or 1-naphthyl
O
X
O
X
But
But
•
•
N
N
CH2R
CH2R
21a
22a
O
PhO
Ph
O
Fig. 1. Preferred conformations of radicals 21a (R = H) and 22a
(R = H).
22
21
a X ϭ NCH3
b X ϭ O
a X ϭ NCH3
b X ϭ O
because of the disposition of the carbonyl group, the aryl
group is close to the C5 radical centre in structure 21a, while
in structure 22a it is close to C2. In both cases the phenyl
ring is substantially twisted out of the plane of the hetero-
cyclic ring and the N1 nitrogen is somewhat pyramidalized.
Inspection of models of intermediate radicals similar to 21a
and 22a, and which are based on the calculated structures and
X-ray data for related species, reveals that the aryl substituent
on the face of the heterocyclic ring anti to the tert-butyl group
will substantially shield the C5 centre in 21a and 21b, and
thereby hamper the approach of a hydrogen-atom transfer
reagent (Fig. 1). Although the substituent in N-carbamate
radicals 22a and 22b and related alkoxycarbonyl species
also lies below the face of the ring anti to the tert-butyl
group, it is situated too far from C5 to impede hydrogen-atom
transfer.
In summary, we have shown that stannane-mediated radi-
cal addition to imidazolidinones 6 and 7 is highly diastereo-
selective and follows the pattern already established for
related reactions of oxazolidinone 2. Also, consideration of
the structural features of the intermediate radicals in these
reactions and those of dioxolanone 1 led us to the following
conclusions.
Scheme 8.
from tributylstannane to the intermediate radicals 19 and 20
(Scheme 8), and that the relative rates of hydrogen-atom
transfer to the syn and anti faces of the intermediate radi-
cals are not under thermodynamic control. This view accords
with the general assumption that hydrogen-atom transfers
from tributylstannane to carbon-centred radicals have early
transition states.[19]
Structural features of the intermediate radicals that may
affect the facial selectivity of hydrogen-atom transfer include
the degree of pyramidalization and the radical stabilization
energies of the intermediates. We expect that captodative
stabilization of phenoxycarbonyl-substituted radicals such as
22 will be less than that of their N-benzoyl counterparts.[20]
However, the dramatic effect that the nature of the N1
substituent has on the stereochemical outcome of radical
reactions that involve methylideneimidazolidinones suggests
that the conformations adopted by the intermediates must be
of prime importance. Therefore, we have commenced a theo-
retical study of radicals 19 and 20, and related species. Thus
far, the results of molecular mechanics and semi-empirical
molecular orbital calculations lead to the same conclusion,
namely that the preferred conformation of radicals that
bear N-aroyl substituents involves the exocyclic N-carbonyl
group lying close to the plane of the heterocyclic ring and
the carbonyl oxygen pointing towards the 2-substituent, as
in structure 21. Conversely, the preferred conformation of
the analogous species, which bears N-aryloxycarbonyl or
N-acyloxycarbonyl substituents, is that the exocyclic car-
bonyl oxygen of the carbamate points away from the 2-
substituent, as in structure 22. It may be significant that
the X-ray crystal structures of compounds 6 and 7, as well
as related compounds,[21] have a trigonal carbon at the
5-position, and show approximately the same orientation
for the carbonyl oxygen as those predicted by theoretical
calculations.
1. The tert-butyl group in radicals derived from dioxolo-
nane 1 sterically hinders the approach of the stannane,
and thereby directs hydrogen-atom transfer to occur at the
anti face of the ring to give cis products such as 3.
2. The steric effect of the aryl substituent in proximity to
the C5 centre in radicals of the general type 21a and 21b
outweighs the steric effect exerted by the tert-butyl group,
and hence the radical transfer occurs syn to the tert-butyl
group to give trans products such as 4 and 11.
3. As the alkyl or aryl substituent is relatively remote from
the C5 centre in radicals such as 22a and 22b, the tert-
butyl group directs hydrogen-atom transfer to occur at
the anti face of the ring to afford cis products such as
5 and 13.
Amoreprecisedeterminationofthestructuralandthermo-
dynamic characteristics of the starting materials and radical
intermediates, as well as the degree to which they effect the
stereochemical outcome of these reactions awaits the results
of further experiments and theoretical studies.
Another significant feature of the theoretically predicted
intermediate radicals, and one which is also supported by
X-raystudies, isthatthephenylringinbothstructures21aand
21b lies below the plane of the imidazolidone ring. However,

Diastereoselective Radical Reactions of Substituted Methylideneimidazolidinones
633
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