Samarium(II) iodide promoted fragmentation and sequential reactions of aromatic 1,4-diketones

Full text of DOI:10.1021/jo9919005

2834
J . Org. Chem. 2000, 65, 2834-2836
Resu lts a n d Discu ssion
Sa m a r iu m (II) Iod id e P r om oted
F r a gm en ta tion a n d Sequ en tia l Rea ction s of
Ar om a tic 1,4-Dik eton es
Initial probes made use exclusively of 4-oxo-valerophe-
none (1, R ) H).8 Hoffmann has described the cyclization
reaction of 1,4-diketones to produce 1,2-cyclobutanediol
derivatives (including that derived from 1, R ) H, in a
yield of 88%),9 while Ghosh has described the fragmenta-
tion of some strained systems when incorporating HMPA
into the reaction mixture.6e When following the exact
experimental description of Hoffmann (SmI2 in THF
under reflux),9 we were easily able to repeat those results
(affording the corresponding substituted 1,2-cyclobutane-
diol) with no observable side reactions (eq 1). An analo-
gous reaction was carried out using the p-chloro-
substituted equivalent of 1 (R ) Cl), with similar results.
D. Bradley G. Williams,* Kevin Blann, and
Cedric W. Holzapfel
Department of Chemistry and Biochemistry, Rand Afrikaans
University, P.O. Box 524, Auckland Park 2006, South Africa
Received December 9, 1999
In tr od u ction
Since its introduction by Kagan,1 samarium(II) iodide
has found manifold applications in organic chemistry.
This powerful one-electron reductant has been exten-
sively employed in standard reduction reactions,2 where
it shows remarkable selectivity. Carbon-carbon bond-
forming reactions have been explored in some detail,2-4
as have carbon-heteroatom bond fragmentation reac-
tions.2 The facility with which SmI2 may be incorporated
into reaction sequences involving highly functionalized
compounds is attested by the many publications describ-
ing the employment of this reducing agent in key steps.5
Although much of the research making use of SmI2 has
focused primarily on bond-forming reactions, a number
of fragmentation reactions have been reported. The
majority of said fragmentation reactions have, thus far,
been aimed at carbon-heteroatom bond cleavage.2 A few
accounts of carbon-carbon bond cleavage have been
forthcoming,6 but these have been sparse. In most of
these disclosures, ring-strained systems have been the
subjects of the fragmentation reactions.6a-e In one case,6f
a substrate that possessed little ring strain (a γ-haloester
cyclopentane derivative) was employed, while in another
a 3-oxo-1,4-diene steroid was observed to undergo ring
scission.6g Simple reductive dehalogenation was found to
compete with bond cleavage in the former case. As part
of our continued investigations into reactions promoted
by SmI2, including fragmentation processes,7 we became
interested in cleavage reactions of 1-aryl-1,4-diketones.
We herein wish to report on the carbon-carbon bond
cleavage of a variety of open chain 1-aryl-1,4-diketones.
(1)
In stark contrast, repetition of the above reaction at
room temperature in the presence of HMPA (similar to
the conditions specified by Ghosh6e) afforded a more
complex mixture of products, consisting primarily of
acetophenone and the product of phenyl-carbonyl cou-
pling10 (eq 2; entry 1 of Table 1). The isolation of these
products indicated that the presence of HMPA facilitated
carbon-carbon bond cleavage. The mechanisms of elimi-
nation (fragmentation) reactions from intermediate ketyl-
radicals have previously been described as proceeding via
radicals6a or anions,11 depending on the substrate. The
exact mechanism of the current fragmentation reaction
is currently unknown.
(2)
A plausible explanation for the selectivity for fragmen-
tation over pinacol cyclization observed in the presence
of HMPA might be found in competitive complexation.
It is expected that, in the presence of HMPA, only one of
the carbonyl moieties can coordinate the SmI2-HMPAn
complex,12 while in the absence of HMPA both carbonyl
moieties can coordinate the SmI2-THFn complex,3,13 thus
leading to pinacol cyclization in the latter case and
fragmentation in the former.
(1) Girard, P.; Namy, J . L.; Kagan, H. B. J . Am. Chem. Soc. 1980,
102, 2693.
(2) Molander, G. A. Chem. Rev. 1992, 92, 29.
(3) Molander, G. A. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 1, p 251.
(4) Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307.
(5) For representative examples, see: (a) Kan, T.; Hosokawa, S.;
Nara, S.; Oikawa, M.; Ito, S.; Matsuda, F.; Shirahama, H. J . Org. Chem.
1994, 59, 5532. (b) Corey, E. J .; Wu, Y.-J . J . Am. Chem. Soc. 1993,
115, 8871. (c) Masaki, M.; Collin, J .; Kagan, H. B. Nouv. J . Chim. 1992,
16, 89. (d) Chiara, J . L.; Cabri, W.; Hanessian, S. Tetrahedron. Lett.
1991, 32, 1125. (e) Molander, G. A.; Kenny, C. J . Am. Chem. Soc. 1989,
111, 8236.
(6) For some of the few examples, see: (a) Batey, R. A.; Motherwell,
W. B. Tetrahedron Lett. 1991, 32, 6649. (b) Batey, R. A.; Harling, J .
D.; Motherwell, W. B. Tetrahedron 1996, 52, 11421. (c) Lange, G. L.;
Furlan, L.; MacKinnon, M. C. Tetrahedron Lett. 1998, 39, 5489. (d)
Molander, G. A.; Alonso-Alija, C. Tetrahedron 1997, 53, 8067. (e)
Haque, A.; Ghosh, S. J . Chem. Soc., Chem. Commun. 1997, 2039. (f)
Honda, T.; Naito, K.; Yamane, S.; Suzuki, Y. J . Chem. Soc., Chem.
Commun. 1992, 1218. (g) Ananthanarayan, T. P.; Gallagher, T.;
Magnus, P. J . Chem. Soc., Chem. Commun. 1982, 709.
(7) Grove´, J . J . C.; Holzapfel, C. W.; Williams, D. B. G. Tetrahedron
Lett. 1996, 37, 5817. (b) Grove´, J . J . C.; Holzapfel, C. W.; Williams, D.
B. G. Tetrahedron Lett. 1996, 37, 1305.
(8) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639.
(9) Hoffmann, H. M. R.; Mu¨nnich, I.; Nowitzki, O.; Stucke, H.;
Williams, D. J . Tetrahedron 1996, 52, 11783. (b) Nowitzki, O.; Mu¨nnich,
I.; Stucke, H.; Hoffmann, H. M. R. Tetrahedron 1996, 52, 11799.
(10) Shiue, J .-S.; Lin, C.-C.; Fang, J .-M. Tetrahedron Lett. 1993, 34,
335. (b) Shiue, J .-S.; Lin, M.-H.; Fang, J .-M. J . Org. Chem. 1997, 62,
4643.
(11) Molander, G. A.; Hahn, G. J . Org. Chem. 1986, 51, 1135. (b)
Molander, G. A.; Hahn, G. J . Org. Chem. 1986, 51, 2596.
(12) Hou, Z.; Zhang, Y.; Wakatsuki, Y. Bull. Chem. Soc. J pn. 1997,
70, 149.
(13) Molander, G. A.; Kenny, C. J . Org. Chem. 1988, 53, 2132.
10.1021/jo9919005 CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/07/2000

Notes
J . Org. Chem., Vol. 65, No. 9, 2000 2835
Ta ble 1. Resu lts of F r a gm en ta tion Rea ction s of 1 (R ) H) u n d er Va r iou s Con d ition sa
H
+ source
temp
(°C)
additionb
(SmI2 equiv)
recovery of 1
yield of 3
other products
(%)
entry
(5 equiv)
(%)
(%)
1
25
normal (4.8)
0
28
4 (21)
7 (6)
2
3
4
5
6
7
-78
25
-78
25
25
25
normal (2.4)
normal (3.8)
normal (2.2)
reverse (2.2)
reverse (2.2)
reverse (3.3)
25
8
70
17
41
12
7
10
7
20
33
47
MeOH
MeOH
MeOH
PhOH
PhOH
4 (34)
5 (10)
6 (18)
4 (10)
6 (10)
4 (17)
6 (15)
5 (5)
8
9
PhOH
PhOH
25
25
25
25
normal (4.8)
normal (7.2)
reverse (3.3)
reverse (4.8)
33
0
22
9
10
11
EtOH
(253 equiv)
EtOH
33
15
5
3
4 (10)
a
b
Yields refer to those of isolated products. Addition: “normal” implies the addition of substrate in THF to a solution of SmI2 in
THF/proton source; “reverse” implies SmI2 solution in THF added to the solution of diketone in THF/proton source. In all cases, 8 equiv
of HMPA were added to the SmI2/THF solution.
Upon further investigation, it became clear that the
type and yield of products (Figure 1) isolated14 from the
above reaction were somewhat sensitive to reaction
conditions.
The findings of the preliminary investigations are
summarized in Table 1. The results show changes that
occurred in product distribution with changing reaction
conditions (temperature, proton source, equivalents of
added SmI2). It is of interest to note that, contrary to the
expected preferential reduction of the aromatic ketone,15
the aliphatic alcohol 6 was obtained (as opposed to the
benzylic alcohol) as one of the products when phenol was
employed as a proton source (entries 7-9). The exact
reasons for this reversal of selectivity are unclear, but it
may be the result of protonation (and hence activation)
of the more basic aliphatic carbonyl by this relatively
acidic alcohol.16 It was also of some surprise to note that
products of phenyl-carbonyl coupling were isolated when
the reaction was carried out in the presence of a proton
source, even when that source was relatively acidic
(14) The identities of starting materials and products were con-
F igu r e 1. Products obtained by reaction of 1 with SmI2/THF/
firmed primarily by comparison with previously published data. The
literature references for the individual products are as follows: starting
materials 1, refs 8 and 9 and refs therein; 2, ref 8; 3 (R ) H), data
compared with those of an authentic sample; 3 (R ) p-Cl), The Aldrich
Library of NMR Spectra; The Aldrich Chemical Co. 1974; Vol. VI, p
21, spectrum A.; 3 (R ) o-Cl), Kikukawa, K.; Idemoto, T.; Katayama,
A.; Kono, K.; Wada, F.; Matsuda, T. J . Chem. Soc., Perkin Trans. 1
1987, 1511; 3 (R ) p-OMe), The Aldrich Library of NMR Spectra; The
Aldrich Chemical Co., 1974; Vol. VI, p 27, spectrum B.; 4 (R ) H),
Olah, G. A.; Berrier, A. L.; Prakash, G. K. S. J . Org. Chem. 1982, 47,
3903; 5 (R ) H), Martre, A. M.; Mousset, G.; Pouillen, P.; Prime, R.
Electrochim. Acta 1991, 36, 1911; 6 (R ) H), Chini, M.; Crotti, P.;
Favero, L.; Pineschi, M. Tetrahedron Lett. 1991, 32, 7853; 7 (R ) H),
Mukaiyama, T.; Banno, K.; Narasaka, K. J . Am. Chem. Soc. 1974, 96,
7503; 8 (R ) p-OMe), The Aldrich Library of NMR Spectra; The Aldrich
Chemical Co., 1974; Vol. V, p 11, spectrum B.; 9 (R ) p-OMe), Leimner,
J .; Weyerstahl, P. Chem. Ber. 1982, 115, 3697. As far as can be
established, compound 4 (R ) o-Cl) has not been previously prepared
(CAS online search). As a result of the very low yield of this material,
extensive analytical data are not available. The identity of this product
was established by comparison of available data with those of its
analogue (4, R ) H) and of the starting diketone. Rf 0.2 (hexanes/EtOAc
) 3:1); 1H NMR (300 MHz, CDCl3) δ 7.55 (d, 1H, J ) 1.6 Hz), 7.54 (d,
1H, J ) 8.2 Hz), 7.40 (dd, 1H, J ) 8.2 and 1.6 Hz), 2.64 (s, 3H), 1.56
(s, 6H); MS (EI) m/z (rel intensity) 212 (M+, 10%), 197 (100), 154 (50).
(15) Namy, J . L.; Souppe, J .; Kagan, H. B. Tetrahedron Lett. 1983,
24, 765. (b) Souppe, J .; Danon, L.; Namy, J . L.; Kagan, H. B. J .
Organomet. Chem. 1983, 250, 227.
HMPA.
(entries 6-9) or was present in an overwhelming excess
(entry 10). This observation lends credence to the radical
pathway proposed as a mechanism by Fang,10 as opposed
to the alternative ionic mechanism, for the phenyl-
carbonyl coupling reaction. It is clear from the table that
low temperatures (entries 2 and 4) inhibit the desired
fragmentation reaction. It is also apparent that, while
substantial yields of products of sequential reactions were
obtained (thereby complicating the product mixtures), the
total fragmentation yield was satisfactory in most cases
(up to 75%, entry 7).
The fragmentation methodology was subsequently
applied to various other functionalized aromatic dike-
tones. The results, summarized in Table 2, evidence the
fact that para or ortho substitution on the arene drasti-
cally reduces the complexity of product mixtures and
largely prevents the sequential reactions previously
observed (even though the para position was open in the
ortho substituted substrates, only small amounts of the
corresponding product 4 were obtained). Once again, total
product derived from fragmentation is high in certain
cases (up to 75%, entry 7). Although not shown in Table
(16) One referee suggested that product 6 might have resulted from
an intramolecular Meerwein-Ponndorf-Verley/Oppenauer reaction
after the reduction of the ketone adjacent to the phenyl group by SmI2
as is normally anticipated. We thank the referee for this comment.

2836 J . Org. Chem., Vol. 65, No. 9, 2000
Notes
Ta ble 2. Rea ction of Su bstitu ted Dion es w ith Sm I2
molecules from one) are in general favored by an increase
in the reaction temperature.17
substrate
yield of 3
other products
(%)
entrya
R )
additionb
(%)
Con clu sion
1
2
3
4
5
6
7
p-Cl
p-Cl
p-Cl
o-Cl
o-Cl
p-OMe
p-OMe
normal
normalc
reverse
normal
reverse
normal
reverse
32
56
17
15
10
31
43
The results presented in this note clearly indicate that
the presence or absence of HMPA in the reaction mixture
is the deciding factor that determines the outcome
(reductive fragmentation or cyclization) of the reaction
of 1-aryl-1,4-diketones with SmI2. This represents an-
other example of the dramatic effect that HMPA can have
on the outcome of a Sm(II)-mediated reaction. It has also
been shown that the specific reaction conditions greatly
influence the outcome of said fragmentation and/or
subsequent reactions, as does the substitution pattern
on the arene.
1 (5)
4 (4)
8 (12)
8 (19)
9 (13)
4 (16)
5 (19)
8
H
normal
34
9
10
11
p-Cl
o-Cl
p-OMe
normal
normal
normal
85
26
35
4 (14)
8 (23)
9 (23)
a
Reactions corresponding to entries 1-7 were carried out at
ambient temperature, and those corresponding to entries 8-11
were carried out at the reflux temperature of the mixture.
Exp er im en ta l Section
b
Addition: “normal” implies the addition of substrate in THF to
All reactions were carried out in flame-dried glassware under
a positive pressure of argon. Solvents and cosolvents were
distilled from the appropriate drying agents (THF from sodium-
benzophenone ketyl, HMPA from CaH2, and lower alcohols from
magnesium alkoxide) and were degassed by purging with argon
or using a freeze-pump-thaw routine. Starting materials were
obtained from the Stetter reaction of the corresponding alde-
hydes.8 All solid materials were thoroughly degassed directly
prior to reaction with SmI2 by repetitive evacuation of the gases
and filling of the reaction vessel with argon. SmI2 (0.1 M) was
prepared by the reaction of a suspension of Sm metal in THF
with freshly recrystallized diiodoethane.
Reaction conditions for preparing four-membered rings via the
pinacol coupling reaction have been detailed9 and were employed
here exactly as described. Reaction conditions used for fragmen-
tation reactions have been disclosed6e and were used here as
described.
a solution of SmI2 in THF/proton source (7 equiv); “reverse” implies
SmI2 solution in THF added to the diketone solution in THF/proton
source (7 equiv). In all cases, 8 equiv of HMPA were added to the
SmI2/THF solution, and 3.3 equiv of SmI2 were routinely used.
c Reaction conditions similar to those given in footnote b, but 4.8
equiv of SmI2 were employed.
2, the furyl analogue of dione 1 was also subjected to
these reaction conditions. Apart from a small amount
(7%) of the “para” substituted equivalent of 4, no other
products of fragmentation were observed. Entries 8-11
detail the findings of similar reactions carried out at the
reflux temperature of the reaction mixture. The most
striking feature of the latter set of reactions is the
improvement of the overall fragmentation yield (up to
85%, entry 9) in three of the four cases (all of which were
the more highly substituted systems). The primary
reason for the improved yield seems to be the result of a
diminished competition between the fragmentation reac-
tion and side-reactions (over-reduction, phenyl-carbonyl
coupling, pinacol coupling, etc.). The reason for this
observation may lie in the fact that fragmentation
reactions in which there is a gain in entropy (two
J O9919005
(17) Atkins, P. W. Physical Chemistry, 3rd ed.; Oxford University
Press: Oxford, 1987; chapter 5. (b) Ingold, C. K. Structure and
Mechanism in Organic Chemistry; G. Bell and Sons Ltd.: London,
1953; pp 460-464 (based on information extracted from: Cooper, K.
A.; Highes, E. D.; Ingold, C. K.; Maw, G. A.; MacNulty, B. J . J . Chem.
Soc. 1948, 2049).