δ-Sultone formation through Rh-catalyzed C-H insertion

Article abstract of DOI:10.1021/ol701950d

Rhodium-catalyzed reactions of sulfonate ester derivatives are biased strongly toward 1,6-insertion and thus offer a general method for assembling δ-sultones. Two protocols for staging this cyclization reaction are described, which capitalize on the unique ability of either diazo or iodonium ylide intermediates to form Rh-carbene species. The value of these heterocycles for fine chemicals synthesis is demonstrated in both reductive and oxidative reactions that make possible excision of the -SO₃- moiety.

Full text of DOI:10.1021/ol701950d

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4363-4366
δ
-Sultone Formation Through
Rh-Catalyzed C H Insertion
−
Scott A. Wolckenhauer, A. Sloan Devlin, and J. Du Bois*
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
jdubois@stanford.edu
Received August 9, 2007
ABSTRACT
Rhodium-catalyzed reactions of sulfonate ester derivatives are biased strongly toward 1,6-insertion and thus offer a general method for assembling
-sultones. Two protocols for staging this cyclization reaction are described, which capitalize on the unique ability of either diazo or iodonium
ylide intermediates to form Rh-carbene species. The value of these heterocycles for fine chemicals synthesis is demonstrated in both reductive
and oxidative reactions that make possible excision of the SO3 moiety.
δ
−
−
Metal-catalyzed activation of diazo compounds has evolved
as an exceptionally powerful tool for the formation of C-C
bonds.1 Such methods are unique in their ability to func-
tionalize unactivated C-H centers under mild conditions on
substrates bearing a high degree of attendant functionality.
The application of these types of chemistries can lead to
unconventional and inventive strategies to problems in
complex molecule synthesis.2 In this context, intramolecular
diazocarbonyl C-H insertion reactions are most commonly
employed, and typically occur with beneficial levels of
chemo- and regioselectivity.1,3 A hallmark of such processes
is the overwhelming bias toward five-membered-ring forma-
tion. Although substrate conformation, local electronic ef-
fects, and catalyst ligand architecture may override this
intrinsic preference, there is no general paradigm that governs
the application of such controlling elements.2b,4-6 Accord-
ingly, an alternative tactic that would inherently favor six-
membered-ring formation could potentially create opportu-
nities to employ C-H insertion in ways not currently possible
with diazocarbonyl derivatives.
Within the context of studies related to Rh-catalyzed
intramolecular C-H amination, our laboratory has revealed
that six-membered oxathiazinane heterocycles are produced
from sulfamate starting materials through exclusive γ-C-H
insertion.7 The marked contrast of these results vis-a`-vis five-
membered-ring formation observed with carbamate, urea, and
guanidine starting materials intimated that a similar relation-
(1) Reviews: (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds; Wiley-
Interscience: New York, 1998. (b) Davies, H. M. L.; Beckwith, R. E. J.
Chem. ReV. 2003, 103, 2861-2903. (c) Merlic, C. A.; Zechman, A. L.
Synthesis 2003, 1137-1156. (d) Doyle, M. P. In Modern Rhodium-Catalyzed
Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, Germany,
2005; pp 341-355. (e) Taber, D. F.; Joshi, P. V. In Modern Rhodium-
Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim,
Germany, 2005; pp 357-377. (f) Davies, H. M. L. Angew. Chem., Int. Ed.
2006, 45, 6422-6425.
(2) For recent examples, see: (a) Kurosawa, W.; Kan, T.; Fukuyama,
T. J. Am. Chem. Soc. 2003, 125, 8112-8113. (b) Hinman, A.; Du Bois, J.
J. Am. Chem. Soc. 2003, 125, 11510-11511. (c) Davies, H. M. L.; Walji,
A. M. Angew. Chem., Int. Ed. 2005, 44, 1733-1735. (d) Taber, D. F.;
Frankowski, K. J. J. Org. Chem. 2005, 70, 6417-6421. (e) Reisman, S.
E.; Ready, J. M.; Hasuoka, A.; Smith, C. J.; Wood, J. L. J. Am. Chem. Soc.
2006, 128, 1448-1449. (f) Davies, H. M. L.; Dai, X.; Long, M. S. J. Am.
Chem. Soc. 2006, 128, 2485-2490. (g) Tambar, U. K.; Ebner, D. C.; Stoltz,
B. M. J. Am. Chem. Soc. 2006, 128, 11752-11753.
(3) (a) Taber, D. F.; Ruckle, R. E. J. Am. Chem. Soc. 1986, 108, 7686-
7693. (b) Lee, E.; Jung, K. W.; Kim, Y. S. Tetrahedron Lett. 1990, 31,
1023-1026. (c) Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E.; See,
M. M.; Boone, W. P.; Bagheri, V.; Pearson, M. M. J. Am. Chem. Soc.
1993, 115, 958-964. (d) Padwa, A.; Austin, D. J. Angew. Chem., Int. Ed.
1994, 33, 1797-1815. (e) Wang, P.; Adams, J. J. Am. Chem. Soc. 1994,
116, 3296-3305.
(4) (a) Cane, D. E.; Thomas, P. J. J. Am. Chem. Soc. 1984, 106, 5295-
5303. (b) Aburel, P. S.; Romming, C.; Undheim, K. J. Chem. Soc., Perkin
Trans. 1 2001, 1024-1029.
(5) Lee, E.; Choi, I.; Song, S. Y. J. Chem. Soc., Chem. Commun. 1995,
321-322.
(6) (a) Doyle, M. P.; Dyatkin, A. B. J. Org. Chem. 1995, 60, 3035-
3038. (b) Doyle, M. P.; Dyatkin, A. V.; Ene, D. G. J. Am. Chem. Soc.
1996, 118, 8837-8846.
(7) (a) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem.
Soc. 2001, 123, 6935-6936. (b) Wehn, P. M.; Lee, J.; Du Bois, J. Org.
Lett. 2003, 5, 4823-4826.
10.1021/ol701950d CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/21/2007

ship might exist between C-H insertion reactions of diazo-
sulfonyl and diazocarbonyls compounds (Figure 1).8 Interest-
Table 1. Intramolecular C-H Insertion of Diazosulfonates
Figure 1. Substrate design alters positional selectivity.
ingly, the former class of substrates has received almost no
attention in the literature.9,10 Following a recent, analogous
report by Novikov, we now disclose our own findings that
(1) make available substituted six-membered-ring δ-sultones
from diazosulfonates through C-H insertion and (2) enable
the subsequent manipulation of these novel heterocycles to
value-added materials. To further augment this chemistry,
we have also delineated a protocol that obviates preparation
of diazo intermediates, using instead in situ-generated aryl-
iodonium ylides. This latter work borrows from earlier re-
ports by Dauban and Dodd, Mu¨ller, and Charette, and nicely
parallels studies in C-H amination.11-13 As such, selective
methods for δ-sultone generation and the subsequent modi-
fication of these heterocycles should open new pathways for
addressing problems in fine chemicals synthesis.
At the onset of our studies, we were aware of only a single
report that described the application of diazosulfonate esters
for metal-catalyzed alkene cyclopropanation.9,14 While at-
tempts to prepare diazo derivatives from alkyl mesylates met
with varying degrees of success, high-yielding conditions
for the generation of diazosulfonates bearing an R-ester group
were considerably more fruitful. These studies and those of
Novikov have shown that substrates such as 3 may be readily
prepared from ethyl chlorosulfonylacetate 2 followed by
diazo transfer (MeSO3N3, DBU, Figure 2).15-17 Such condi-
a Reactions were conducted by the dropwise addition of a diazosulfonate
solution to a refluxing suspension of 2 mol % of Rh2(OAc)4 in CH2Cl2.
b Product yields are combined for the two diastereomers. Diastereomer ratios
with respect to the C3 center range from 1-3:1. c Reaction performed with
2 mol % of Rh2(esp)2. d Reaction performed with added powdered 3 Å
molecular sieves. e Reaction performed with 2 mol % of Rh2(O2CCPh3)4.
f Reaction performed with 2 mol % of Rh2(O2CC3F7)4 in CCl4. g Product
formed as a ∼3:1 mixture of diastereomers; reported yield is of the mixture.
sponding six-membered δ-sultones in the majority of sub-
strates we have examined (Table 1).19 Of the different
catalysts tested, Rh2(OAc)4 was generally superior.20 As
inferred from the collective data, 3°, benzylic, and 2° C-H
(11) Use of iodonium ylides as carbene precursors was originally
advanced by Varvoglis and Moriarty, see: (a) Hatjiarapoglou, L.; Varvoglis,
A.; Alcock, N. W.; Pike, G. A. J. Chem. Soc., Perkin Trans. 1 1988, 2839-
2846. (b) Moriarty, R. M.; Prakash, O.; Vaid, R. K.; Zhao, L. J. Am. Chem.
Soc. 1989, 111, 6443-6444. For an excellent review on this subject, see:
(c) Mu¨ller, P. Acc. Chem. Res. 2004, 37, 243-251.
(12) For leading references, see: (a) Dauban, P.; Saniere, L.; Tarrade,
A.; Dodd, R. H. J. Am. Chem. Soc. 2001, 123, 7707-7708. (b) Mu¨ller, P.;
Ghanem, A. Org. Lett. 2004, 6, 4347-4350. (c) Moreau, B.; Charette, A.
J. Am. Chem. Soc. 2005, 127, 18014-18015.
(13) Espino, C. G.; Du Bois, J. In Modern Rhodium-Catalyzed Organic
Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, Germany, 2005; pp
379-416.
Figure 2. Preparative method for diazosulfonate substrates.
(14) Thermal reactions of diazosulfonates to generate alkene products
have been reported, see: Berkessel, A.; Voges, M. Chem. Ber. 1989, 122,
1147-1151.
tions provide reliable access from both 1° and 2° alcohols
to the desired diazosulfonates (Table 1).18
Refluxing a CH2Cl2 solution of diazosulfonate with 2 mol
% of Rh2(OAc)4 leads to exclusive formation of the corre-
(15) Sulfonyl chloride 2 was prepared following a modification of a
procedure outlined by: Oliver, J. E.; DeMilo, A. B. Synthesis 1975, 321-
322. See the Supporting Information for details.
(16) Imidazole may be replaced with pyridine in the sulfonylation
reaction. Stronger bases such as Et3N were considerably less effective.
(17) Use of p-acetamidobenzenesulfonyl azide gave poor yield of the
diazo compound and, instead, a significant amount of the alcohol, ROH,
was generated.
(8) (a) Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40, 598-
600. (b) Lee, M.; Mulcahy, J. V.; Espino, C. G.; Du Bois, J. Org. Lett.
2006, 8, 1073-1076.
(9) Ye, T.; Zhou, C. New J. Chem. 2005, 29, 1159-1163.
(10) John, J. P.; Novikov, A. V. Org. Lett. 2007, 9, 61-63.
(18) Purified diazosulfonate derivatives are generally stable for weeks
if stored at -20 °C. In two cases (entries 2 and 4), decomposition was
observed when these materials were left to stand overnight at 23 °C.
4364
Org. Lett., Vol. 9, No. 21, 2007

bonds are all susceptible to functionalization. Qualitative
reactivity trends are, in fact, analogous to those of diazocar-
bonyl compounds.1 In all cases, δ-sultone products were
obtained as epimeric mixtures at the R-ester carbon center.
The bias for diazosulfonates to form six-membered-ring prod-
ucts is noted in entries 3-5, the latter two reactions yielding
novel bridging bicyclic structures.21 Such transannular inser-
tion events are less common with diazocarbonyl derivatives,
and may prove serviceable for installing angular groups at
fused carbon centers in complex polycylic natural products.22
When unsaturated sulfonate starting materials are used,
alkene cyclopropanation is quite efficient and no product of
allylic C-H insertion is obtained (entry 6). In addition, the
cis-fused cyclopropane is generated exclusively. We attribute
the strong bias of the sulfonate group toward the six-
membered products in both σ-C-H and π-bond function-
alization reactions to the close accord between acyclic
sulfonate and δ-sultone C-S-O bond angles (102-
103°).23,24 Insertion to form the five-membered γ-sultone
would force a C-S-O angle deformation of more than 5°.25
Interestingly, distortions in bond length are almost nil (<0.03
Å) between the acyclic and 6-membered cyclic forms.
The utility of diazo compounds notwithstanding, their
preparation with sulfonyl azide reagents and their hazard
potential raise safety concerns. Aryliodonium ylides can
function as surrogates to diazo species and may be prepared
in situ from common hypervalent iodine oxidants.11,12,26
When such species are generated in the presence of a metal
catalyst and an alkene, cyclopropanation is smoothly effected.
The iodonium ylide conditions thus offer salient advantages
over traditional diazo chemistry. On the basis of prior art,
sulfonate esters appeared well-suited as substrates for iodo-
nium ylide chemistry because of the ease of generation and
stability of the R-enolate anion. We were unaware, however,
of any report demonstrating one-pot iodonium ylide forma-
tion and metal-catalyzed C-H bond insertion employing
sulfonate esters or related starting materials (e.g., 1,3-
dicarbonyl derivatives).27
Initial attempts to induce the cyclization of sulfonate 4
employed the commercial oxidant PhI(OAc)2 and catalytic
Rh2(OAc)4 (entry 1, Table 2). Although sultone 5 was
Table 2. In Situ Iodonium Ylide Formation and C-H Insertion
a A ) Rh2(OAc)4; B ) Rh2(oct)4; C ) Rh2(esp)2. Reactions performed
at 25 °C with 1.3 equiv of oxidant, 3.0 equiv of base, and 100 mg of
1
powdered 3 Å molecular sieves. b Product conversion based on H NMR
integration. c Isolated yield in parentheses; product obtained as a 6:1 mixture
of epimers at C3 and >20:1 cis/trans selectivity at C4/C6. d 4-Phenyl-2-
butanol accounted for most of the mass balance in this reaction. e Reaction
performed in C6H6.
generated under these conditions, ∼30% of the starting
material was left unreacted along with a decomposition
product, 4-phenyl-2-butanol (20%). Switching to PhIdO
resulted in a dramatic improvement in the reaction outcome,
as 5 was produced exclusively and could be isolated in 80%
yield (entry 2). This protocol has proven most effective, with
both 3 Å molecular sieves and Cs2CO3 being necessary for
high product conversion. Formation of 5 was depressed in
the absence of sieves or when alternate inorganic bases were
employed. Additionally, it appears that the sparing solubility
of both Rh2(OAc)4 and PhIdO in CH2Cl2 is an important
factor for the success of this process. Circumstantial support
for this conclusion is based on the poor performance of
PhI(OAc)2 and of Rh2(oct)4 and Rh2(esp)2 as catalysts for
the reaction, both of which are completely soluble in
CH2Cl2 (entries 7 and 8).28 The use of benzene as solvent,
however, did not improve the reaction (entry 9).
(19) The addition of powdered 3 Å molecular sieves was found to
improve sultone yields in a few instances, see the Supporting Information
for details.
(20) Other Rh catalysts examined included Rh2(oct)4, Rh2(OPiv)4, Rh2(O2-
CCPh3)4, Rh2(O2CCF3)4, Rh2(NHCOCF3)4, and Rh2(cap)4.
(21) In entry 4, the five-membered-ring product formed through benzylic
C-H insertion was also obtained (42% yield).
(22) For select examples of transannular C-H insertions with diazoke-
tones, see: (a) Ghatak, U. R.; Chakrabarty, S. J. Am. Chem. Soc. 1972, 94,
4756-4758. (b) Spero, D. M.; Adams, J. Tetrahedron Lett. 1992, 33, 1143-
1146. (c) West, F. G.; Eberlein, T. H.; Tester, R. W. J. Chem. Soc., Perkin
Trans. 1 1993, 2857-2859. (d) White, J. D.; Hrnciar, P.; Stappenbeck, F.
J. Org. Chem. 1999, 64, 7871-7884. (e) Wardrop, D. J.; Velter, A. I.;
Forslund, R. E. Org. Lett. 2001, 3, 2261-2264.
(23) A typical γ-sultone C-S-O bond angle is e98°, see: (a) Bil-
lodeaux, D. R.; Owens, C. V.; Sayes, C. M.; Soper, S. A.; Fronczek, F. R.
Acta Cryst. 1999, C55, 2126-2129. (b) Muir, K. W.; Rodger, C. S.; Morris,
D. G.; Ryder, K. S. Acta Cryst. 1998, C54, 1546-1548.
(24) For select X-ray data of acyclic sulfonates and δ-sultones, see: (a)
Ferguson, G.; Schwan, A. L.; Kalin, M. L.; Snelgrove, J. L. Acta Crystallogr.
1997, C53, IUC9700009. (b) Horger, R.; Marsch, M.; Geyer, A.; Harms,
K. Acta Crystallogr. 2005, E61, o3447-o3448.
(25) We have used a similar argument to explain the strong bias for
oxathiazinane dioxide formation in amination reactions of sulfamate esters,
see ref 7a.
Cyclization of sulfonate esters with PhIdO, Cs2CO3, and
catalytic Rh2(OAc)2 is functional with a range of 2° alcohol-
derived materials (Table 3). Highest yields of δ-sultones are
obtained for substrates bearing 3° and benzylic C-H bonds.
The success of these reactions is apparently due to a
combination of effects involving Thorpe-Ingold-type pre-
organization and the established electronic preference of Rh-
carbenoids for 3° and benzylic C-H centers.1,29 In substrates
lacking these structural elements, product yields are dimin-
(27) Mu¨ller has demonstrated Rh-catalyzed C-H insertions of isolated
iodonium ylides: Mu¨ller, P.; Fernandez, D. HelV. Chim. Acta 1995, 78,
947-958.
(28) Rh2(esp)2 ) Rh2(R,R,R′,R′-tetramethyl-1,3-benzenedipropionate)2,
see: Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem. Soc.
2004, 126, 15378-15379. Interestingly, syringe-pump addition of Rh2(oct)4
over a 1 h period to a suspension of 4, PhIdO, Cs2CO3, and 3 Å MS, gave
results comparable to entry 7. The unique effectiveness of Rh2(OAc)4 as a
catalyst for this process is absent a clear explanation at this time.
(29) Jung, M. E.; Piizzi, G. Chem. ReV. 2005, 105, 1735-1766.
(26) (a) Ghanem, A.; Lacrampe, F.; Schurig, V. HelV. Chim. Acta 2005,
88, 216-239. (b) Bonge, H. T.; Hansen, T. Synlett 2007, 55-58.
Org. Lett., Vol. 9, No. 21, 2007
4365

conversion of the sulfonate salt to the sulfonyl chloride with
use of oxalyl chloride is clean and quantitative. Subsequent
treatment of the sulfonyl chloride with Zn(Cu) couple in
THF/AcOH affords the desired ester product.32 Although this
procedure requires two steps, the overall sequence is high
yielding and does not necessitate isolation of the intermediate
sulfonyl chloride. This protocol should help to expand the
potential applicability of C-H insertion methods for sultone
assembly.
Table 3. Rh-Catalyzed C-H Insertion of Sulfonate Esters
Following literature reports, removal of the sulfonyl
linkage was also examined under oxidative conditions.30b,33
Treatment of the potassium enolate derived from sultone 7
with Davis oxaziridine in THF furnishes lactol 8 in 85%
yield (eq 2).34 This transformation presumably involves
O-atom transfer followed by C-S bond cleavage. The
intermediate R-keto ester is then trapped internally by the
pendant alcohol. Sultone ring-opening employing this method
is easily executed, extremely efficient, and well-suited for
application in complex synthesis.
Chemoselective generation of δ-sultones through Rh-
catalyzed C-H insertion makes available a novel class of
heterocycles, which have the potential to serve as valuable
intermediates in synthesis. Sulfonate ester starting materials
are conveniently prepared from 1° and 2° alcohols and may
be subjected to one of two sets of conditions for processing
to the desired sultone. With the ability to modify the cyclized
products through SN2 displacement and enolate R-oxidation
reactions, new strategies for employing Rh-catalyzed C-H
functionalization in complex synthesis may be unveiled.
a Reactions were conducted by addition of iodosobenzene (1.2 equiv),
powdered 3 Å molecular sieves, Cs2CO3 (3 equiv), and 2-4 mol % of
Rh2(OAc)4 to a solution of substrate in CH2Cl2. b Product yields are reported
for the mixture of C3-epimers. Diastereomer ratios with respect to the R-ester
carbon range from 1-6:1.
ished when compared to analogous experiments conducted
with diazo compounds (cf. entries 1 and 3, Tables 1 and 3).
Both base-promoted decomposition of the starting sulfonate
and the adventitious consumption of PhIdO are observed
in reactions that underperform. Nevertheless, the success of
this method for certain substrate types and its facile, single-
step operation make it a worthy compliment to the diazo
chemistry. Further investigations will continue to advance
this technology as a broadly applicable tool for synthesis.
The chemistry of δ-sultones as synthetic intermediates en
route to complex molecules has not been fully exploited.30
As with their smaller-ring counterparts, it is possible to
displace the C-O bond with nucleophiles of varying strength
(eq 1). In our hands, NaCN, NaN3, NaOAc, and thiolates
Acknowledgment. We are grateful to the National
Institutes of Health, Camille and Henry Dreyfus Foundation,
the A. P. Sloan Foundation, Amgen, Boehringer-Ingelheim,
GlaxoSmithKline, Merck, and Pfizer for generous support
of this work.
Supporting Information Available: General experimen-
tal protocols and characterization data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL701950D
(30) For reviews on sultone synthesis and reactivity, see: (a) Roberts,
D. W.; Williams, D. L. Tetrahedron 1987, 43, 1027-1062. (b) Metz, P. J.
Prakt. Chem. 1998, 340, 1-10.
(31) Transformations of this type have almost no precedent in the
literature. Attempts to extrude SO3 upon heating with or without acid gave
no reaction.
(32) Use of Zn dust alone resulted in conversion to the corresponding
sulfinic acid, which proved resistant toward desulfinylation.
(33) For related transformations, see: (a) Little, R. D.; Myong, S. O.
Tetrahedron Lett. 1980, 21, 3339-3342 (b) Hwu, J. R. J. Org. Chem. 1983,
48, 4432-4433. (c) Williams, D. R.; Robinson, L. A.; Amato, G. S.;
Osterhout, M. H. J. Org. Chem. 1992, 57, 3740-3744. (d) Metz, P.;
Fleischer, M.; Fro¨hlich, R. Tetrahedron 1995, 51, 711-732. (e) Doye, S.;
Hotopp, T.; Wartchow, R.; Winterfeldt, E. Chem. Eur. J. 1998, 4, 1480-
1488.
are all found to react with 1° and 2° alcohol-derived sultones
to give the corresponding sulfonate salts. Direct extrusion
of SO3 (or SO42-) from these ring-opened products, however,
proved unfeasible under a variety of conditions investigated.31
Presumably, it is for this reason that sultones have enjoyed
only sparing use as electrophilic reagents. Accordingly, we
have developed a two-step protocol to effect the removal of
(34) Chen, B.-C.; Zhou, P.; Davis, F. A.; Ciganek, E. Org. React. 2003,
62, 1-356.
-
the SO3 moiety from the acyclic products (e.g., 6). Initial
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