Free-radical ring contraction of six-, seven-, and eight-membered lactones by a 1,2-shift mechanism. A kinetic and 17O NMR spectroscopic study

Full text of DOI:10.1021/jo982385y

1
762
J . Org. Chem. 1999, 64, 1762-1764
could not be conclusively excluded.1
esters typically prefer the Z conformation1
a â-(acyloxy)alkyl radical could rearrange via the 1,2- or
,3-manifold. On the other hand, an ester constrained
1,13-15
Carboxylate
from which
F r ee-Ra d ica l Rin g Con tr a ction of Six-,
6,17
Seven -, a n d Eigh t-Mem ber ed La cton es by a
,2-Sh ift Mech a n ism . A Kin etic a n d 17
1
O
2
NMR Sp ectr oscop ic Stu d y
to the higher energy E conformation can only access the
transition state for the 1,2-shift, if it exists, failing which
an ion-pair mechanism must be involved (Scheme 2). We
reasoned that this problem might be addressed through
the rearrangements of lactones and proceeded to dem-
onstrate, in the first instance, that lactones are capable
David Crich,*,† Xiaohua Huang,† and
Athelstan L. J . Beckwith‡
Department of Chemistry, University of Illinois at Chicago,
45 West Taylor Street, Chicago, Illinois 60607-7061, and
Department of Chemistry, Australian National University,
Canberra ACT 0200, Australia
8
of undergoing rapid radical ring contractions and expan-
sions.1
8,19
Here, we describe the first examples of confor-
Received December 7, 1998
mationally constrained â-(acyloxy)alkyl radicals under-
going rearrangement by a pure 1,2-shift mechanism
together with its kinetic characterization.
Since 1967,1,2 the mechanism of the â-(acyloxy)alkyl
radical rearrangement and that of its more recent cousins
Our first problem lay in the regiospecific 17O-labeling
of the lactones in either the sp2 or sp3 oxygen. Initial
attempts to form labeled bromohydrins by reaction of
3
,4
5
the â-(phosphatoxy)alkyl, the â-(nitroxy)alkyl, and the
5
â-(sulfonatoxy)alkyl rearrangements has proven to be
a fascinating puzzle that has challenged the ingenuity
of physical organic chemists. On the basis of a large
amount of kinetic and labeling data accrued by several
groups worldwide, we have recently pieced together the
comprehensive mechanistic picture illustrated in Scheme
1
7
20
H
2
O water and NBS across the alkenoic acids, each
prepared by Wittig olefination of benzaldehyde, resulted
in distribution of the label between the bromohydrin and
1
7
the acid as revealed by O NMR spectroscopy of the
subsequent lactones.21 To circumvent this problem, vari-
ous esters were assayed but most led to complications in
the deprotection step. Ultimately, 3 was converted to the
desyl ester22 10, which reacted cleanly with N-bromo-
6
,7
1
.
In this continuum of mechanisms, the slower rear-
rangements take place through a moderately polarized
five-membered cyclic transition state (2,3-shift), whereas
the more rapid ones prefer the three-membered cyclic
transition state (1,2-shift) with its greater separation of
charge. Thus, the mechanism is a function of substrate.
As the migrating group becomes more capable of sup-
porting negative charge and/or the carbon framework of
stabilizing positive charge, a greater proportion of the
three-membered mechanism is to be expected. In the
ultimate situation, when the system is capable of carrying
fully separated charges, ion pair mechanisms and frag-
mentations may occur.8 Unfortunately, while labeling
1
7
succinimide and H
1. Photolysis in aqueous acetonitrile22 provided 6- O
in excellent yield, and this was converted without further
2
O in acetone to give bromohydrin
17
1
1
2
3
purification, using the Yamaguchi protocol, to the
labeled lactone 16.24 O NMR spectroscopy revealed a
single resonance at δ 187.4 fully consistent with the
indicated regiochemistry.21 Unfortunately, application of
the same approach to the lower homologues was foiled
by the instability of the bromohydrin esters. To label the
six-membered ring, the unlabeled lactone 7 was reduced
by DIBAL to the corresponding lactol 12, which was
17
,9
studies have revealed a number of cases of pure 2,3-
2
5
converted to the pentenyl ester 13. Hydrolysis with
shifts,1
0-12
no examples of pure 1,2-shifts have yet been
1
7
H
2
O and NBS then gave the labeled lactol, which was
forthcoming, even though they are expected to be favored
by entropic factors. Labeling studies have brought to light
several systems that proceed to a considerable extent,
and some predominantly, through a 1,2-shift suggesting
the operation of parallel 1,2- and 2,3-shift mechanisms,
but the possibility of caged radical ion pair mechanisms
converted to the corresponding lactone 14 by oxidation
with PCC. Again, 17O NMR spectroscopy demonstrated
(
13) Beckwith, A. L. J .; Duggan, P. J . J . Chem. Soc., Perkin Trans.
2 1992, 1777-1783.
14) Kocovsky, P.; Stary, I.; Turecek, F. Tetrahedron Lett. 1986, 27,
513-1516.
15) Crich, D.; Yao, Q.; Filzen, G. F. J . Am. Chem. Soc. 1995, 117,
(
1
(
†
University of Illinois at Chicago.
Australian National University.
1) Surzur, J .-M.; Teissier, P. C. R. Acad. Sci. Fr. Ser. C 1967, 264,
981-1984.
2) Tanner, D. D.; Law, F. C. J . Am. Chem. Soc. 1969, 91, 7535-
537.
3) Crich, D.; Yao, Q. J . Am. Chem. Soc. 1993, 115, 1165-1166.
4) Koch, A.; Lamberth, C.; Wetterich, F.; Giese, B. J . Org. Chem.
993, 58, 1083-1089.
5) Crich, D.; Filzen, G. F. Tetrahedron Lett. 1993, 34, 3225-3226.
6) Beckwith, A. L. J .; Crich, D.; Duggan, P. J .; Yao, Q. Chem. Rev.
11455-11470.
‡
(16) Schweitzer, W. B.; Dunitz, J . D. Helv. Chim. Acta 1982, 65,
1547-1554.
(
1
7
(17) Wiberg, K. B.; Waldron, R. F.; Schulte, G.; Saunders, M. J . Am.
Chem. Soc. 1991, 113, 971-977.
(
(18) Crich, D.; Beckwith, A. L. J .; Filzen, G. F.; Longmore, R. W. J .
Am. Chem. Soc. 1996, 118, 7422-7423.
(
(
(19) Related rearrangements and fragmentations of â-lactones:
Crich, D.; Mo, X.-S. J . Am. Chem. Soc. 1998, 120, 8298-8304.
1
1
1
7
(
(
(20) 20% O-enriched water was purchased from Isotec Inc., Mi-
amisburg, OH 45342.
997, 97, 3273-3312.
7) Choi, S.-Y.; Crich, D.; Horner, J . H.; Huang, X.; Newcomb, M.;
Whitted, P. O. Tetrahedron 1999, 55, in press.
8) Giese, B.; Beyrich-Graf, X.; Erdmann, P.; Petretta, M.; Schwitter,
(21) Boykin, D. W.; Sullins, D. W.; Eisenbraun, E. J . Heterocycles
1989, 29, 301-305.
(
(22) Givens, R. S.; Matuszewski, B. J . Am. Chem. Soc. 1984, 106,
6860-6861.
(
U. Chem. Biol. 1995, 2, 367-375.
(23) Inanaga, J .; Hirata, K.; Saiki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989-1993.
(
(
9) Crich, D.; Mo, X.-S. J . Am. Chem. Soc. 1997, 119, 249-250.
10) Beckwith, A. L. J .; Thomas, C. B. J . Chem. Soc., Perkin Trans.
(24) Mass spectral analysis of the bromolactones showed the fol-
lowing levels of incorporation: 14, ∼5%; 15, ∼1%; 16, ∼1%. Although
these levels of incorporation are low, they are sufficient given that the
2
1973, 861-872.
11) Beckwith, A. L. J .; Duggan, P. J . J . Am. Chem. Soc. 1996, 118,
2838-12839.
12) Korth, H.-G.; Sustmann, R.; Groninger, K. S.; Leisung, M.;
Giese, B. J . Org. Chem. 1988, 53, 4364-4369.
(
1
7
1
natural abundance of O is only 0.04%.
(25) Lopez, J . C.; Fraser-Reid, F. J . Chem. Soc., Chem. Commun.
1991, 159-161.
(
1
0.1021/jo982385y CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/09/1999

Notes
J . Org. Chem., Vol. 64, No. 5, 1999 1763
Sch em e 1
Sch em e 2
Ta ble 1. Ra te Con sta n ts for Rin g Con tr a ction a t 80 °C
substrate
k (80 °C, s-1)35
5
6
6
7
8
9
(9.9 ( 1.8) × 10
(1.7 ( 0.1) × 10
(1.1 ( 0.1) × 10
group. Thus, the contraction of the six-, seven-, and eight-
membered lactones occurs cleanly by the 1,2-shift mech-
anism. While this was expected for the six- and seven-
membered series, it was less so for the eight-membered
1
4 to be regiospecifically labeled as indicated (δ 365.8).
This protocol could not be applied to the seven- and eight-
membered congeners owing to the instability of the
derivatized lactols. Finally, for the seven-membered
series we had recourse to a more classical method in
series, when a significant proportion of the Z conforma-
tion should be present.2
6-29
Molecular mechanics calcula-
tions (MM2) conducted on the E- and Z-lactone radicals
23 and 24, respectively, indeed found the Z-isomer to be
1
7
which bromohydrin 5 was equilibrated in THF/H
2
O
-1
some 1.7 kcal‚mol lower in energy in qualitative agree-
leading to incorporation of the label into the carboxylate
moiety, before lactonization by the Yamaguchi method.
Fortuitously, exchange of the benzylic alcohol did not
ment with various computational studies2
9-31
on hep-
tanolactone itself. However, the same calculations re-
vealed the C-O-C(dO)-C dihedral angle in 24 to be
around 136°, which places the carbonyl oxygen signifi-
cantly further away from the radical than in the fully
planar system. Again, this observation is qualitatively
occur as 1 O NMR spectroscopy of the subsequent lactone
7
1
5 showed it to be cleanly regiochemically monolabeled
as indicated (δ 376.0).
3
0
in line with earlier calculations on heptanolactone itself.
When the C-O-C(dO)-C dihedral angle in 24 was
constrained to 180° the energy of the system rose
-
1
significantly (by approximately 3.7 kcal‚mol ), which
suggests that the barrier to the 2,3-rearrangement from
the Z conformation will be very high. Taking all things
into consideration, it appears that the initial conforma-
tional mix of radicals 23 and 24 will reflect that of the
starting lactone, i.e., with a slight preponderance of the
Z form (24). Then, owing to the unusually high barrier
for the 2,3-shift, this Z radical rearranges by the 1,2-
mechanism either directly itself or via rapid inversion
to the appreciably populated E conformation (23). A final
conclusion derived from the 17O NMR experiments was
that no scrambling of the label had occurred in the
reduced products.
Working in the unlabeled series, the rates of ring
contraction (Table 1) were determined in benzene at
3
2
reflux using our catalytic adaptation of Newcomb’s
benzeneselenol clock reaction.33 These rate constants are
consistent with those of other radical ester rearrange-
ments that proceed largely, but not exclusively, by the
formal 1,2-shift.1
1,13,34
Finally, using the same radical
Each of the lactones 14-16 was reduced by tributyltin
(26) Huisgen, R.; Ott, H. Tetrahedron 1959, 6, 253-267.
-
3
(27) Clossen, W.; Orenski, P. J . Org. Chem. 1967, 32, 3160-3163.
hydride, in the presence of 10 M benzeneselenol, in
benzene at reflux with AIBN initiation leading, as
(
(
28) Kaiser, E.; Kedzy, F. Prog. Bioorg. Chem. 1976, 4, 239-267.
29) Wiberg, K. B.; Waldron, R. F. J . Am. Chem. Soc. 1991, 113,
1
demonstrated by H NMR spectroscopy, to inseparable
7697-7705.
(
(
30) Allinger, N. L. Pure Appl. Chem. 1982, 54, 2515-2522.
31) Saunders: M.; J im e´ nez-V a´ zquez, H. A. J . Comput. Chem. 1993,
mixtures of the respective rearranged 17-19 and reduced
2
0-22 products. When these mixtures were examined
1
4, 330-348.
17
by O NMR spectroscopy, each rearrangement was found
to have taken place with retention of the labeling
regiochemistry. In no case was any indication found for
scrambling of the label or inversion of the carboxylate
(32) Crich, D.; J iao, X.-Y.; Yao, Q.; Harwood, J . S. J . Org. Chem.
996, 61, 2368-2373.
1
(33) Newcomb, M.; Varick, T. R.; Ha, C.; Manek, M. B.; Yue, X. J .
Am. Chem. Soc. 1992, 114, 8158-8163.
(34) Crich, D.; J iao, X.-Y. J . Am. Chem. Soc. 1996, 118, 6666-6670.

1
764 J . Org. Chem., Vol. 64, No. 5, 1999
Notes
Arrhenius equation (eq 1). It, too, is fully consistent with
the kinetic parameters of other known radical ester
rearrangements.6
log(k, s- ) ) (11.8 ( 0.5) - (9.0 ( 0.8)/2.3RT (1)
1
35
In conclusion, we have prepared three regiochemically
1
7
mono- O-labeled bromolactones and have determined
that each undergoes radical ring contraction by a 1,2-
shift mechanism. Additionally, the kinetic parameters
have been determined.
Ack n ow led gm en t. We thank the ACS-PRF (33076
AC) for partial support of this work.
Su p p or tin g In for m a tion Ava ila ble: Details of prepara-
tion and characterization of all compounds and details and
tables of data for the kinetics. This material is available free
of charge via the Internet at http://pubs.acs.org.
clock method, the rate constants for the contraction of
one example, the seven-membered lactone 8, were de-
termined over an 80° range of temperature leading to the
J O982385Y
(35) Errors are at the 95% confidence interval (2.3σ).