Cyano(ethoxycarbonothioylthio)methyl benzoate: A novel one-carbon radical equivalent

Article abstract of DOI:10.1021/ol052634m

(Chemical Equation Presented) Cyano(ethoxycarbonothioylthio)methyl benzoate 3 has been prepared and shown to be an excellent one-carbon radical equivalent that can be applied for the introduction of an acyl unit via xanthate transfer radical addition to o

Full text of DOI:10.1021/ol052634m

ORGANIC
LETTERS
2006
Vol. 8, No. 1
147-150
Cyano(ethoxycarbonothioylthio)methyl
Benzoate: A Novel One-Carbon Radical
Equivalent
Sharanjeet K. Bagal, Michiel de Greef, and Samir Z. Zard*
Laboratoire de Synthe`se Organique associe´ au CNRS,
Ecole Polytechnique, 91128 Palaiseau, France
zard@poly.polytechnique.fr
Received October 30, 2005
ABSTRACT
Cyano(ethoxycarbonothioylthio)methyl benzoate 3 has been prepared and shown to be an excellent one-carbon radical equivalent that can be
applied for the introduction of an acyl unit via xanthate transfer radical addition to olefins. The corresponding adducts can be further elaborated.
A rare 1,5-nitrile translocation was also observed during the study.
The generation of acyl radical equivalents and their subse-
quent intra- or, less frequently, intermolecular addition to a
suitably substituted olefin has drawn increasing interest over
the past decade.1 The most commonly encountered form of
such acyl radical equivalents is usually based upon a
dithioacetal (dithiolane, dithiane),2 although oxathianes,2c
acetals,3 and N-alkyl-N-phenylamides4 have shown utility in
this capacity. As part of our ongoing research into novel one-
carbon radical equivalents, we have recently described the
synthetic scope, in this context, of 1,3-dithiane and 1,3-
dithiane 1-oxide radicals generated from the corresponding
xanthates.5 The former radicals only underwent detectable
addition to significantly electron deficient olefins, thereby
reflecting the electron-rich nature of the dative stabilized
radical center. By contrast, 1,3-dithiane 1-oxide radicals
demonstrated smooth addition to a variety of olefins in the
xanthate transfer reaction. This drastic change in reactivity
was most likely due to the nature of the radical center being
modified from a dative to a synergic captodative stabilized
system having enhanced electrophilic character.6 However,
the synthetic scope of 1,3-dithiane 1-oxide radicals was
limited by the corresponding xanthate precursor containing
two nonfixed stereocenters, which led to complex product
mixtures. In addition, the generation of the formyl group re-
quired a two-step protocol. Thus, we now report the synthesis
and utility of cyano(ethoxycarbonothioylthio) methyl ben-
zoate 3 as a new one-carbon radical equivalent that takes
advantage of the captodative effect while having minimal
stereochemical complexity, and which allows facile unmask-
ing of the key formyl function through basic hydrolysis. This
would parallel the use of protected cyanohydrins as acyl
anion equivalents introduced by Stork many years ago.7
The preparation of xanthate 3 commenced with the
efficient alkylation of benzoic acid with chloroacetonitrile
to afford benzoyloxyacetonitrile 1, followed by NBS medi-
ated bromination to generate the corresponding bromide 2
as a mixture with 1 in a 4.5:1 ratio, respectively (Scheme
1). Treatment of the crude product mixture with potassium
O-ethylxanthate then cleanly furnished the desired xanthate
3 in an overall yield of 42%.
(1) For a review of acyl radical chemistry see: Chatgilialoglu, C.; Crich,
D.; Komatsu, M.; Ryu, I. Chem. ReV. 1999, 99, 1991.
(2) (a) Foulard, G.; Brigaud, T.; Portella, C. J. Org. Chem. 1997, 62,
9107. (b) Byers, J. H.; Whitehead, C. C.; Duff, M. E. Tetrahedron Lett.
1996, 37, 2743. (c) Nishida, A.; Kawahara, N.; Nishida, M.; Yonemitsu,
O. Tetrahedron 1996, 52, 9713. (d) Herrera, A. J.; Studer, A. Synthesis
2005, 9, 1389.
(3) Stien, D.; Crich, D.; Bertrand, M. P. Tetrahedron 1998, 54, 10779.
(4) McDonald, C. E.; Galka, A. M.; Green, A. I.; Keane, J. M.;
Kowalchick, J. E.; Micklitsch, C. M.; Wisnoski, D. D. Tetrahedron Lett.
2001, 42, 163.
Notwithstanding the relatively long and incomplete bro-
mination process (22 h, 2:1 ) 4.5:1) it is nonetheless
(6) Janousek, Z.; Merenyi, R.; Viehe, H. G. Acc. Chem. Res. 1985, 18, 148.
(7) Stork, G.; Maldonado, L. J. Am. Chem. Soc. 1974, 96, 5272.
(5) de Greef, M.; Zard, S. Z. Tetrahedron 2004, 60, 7781.
10.1021/ol052634m CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/14/2005

Table 1. Radical Addition of Xanthate 3 to Olefins a-ma
Scheme 1. Synthesis of Xanthate 3
significant that xanthate 3 can be prepared from cheap and
readily available reagents, on a multigram scale, through a
short 3-step reaction sequence and in reproducible yield.
Moreover, 3 can be stored for many months under an inert
atmosphere without detectable decomposition.
With xanthate 3 in hand, we next investigated its ability
to undergo group transfer radical addition to olefins. The
mechanistic reasoning upon which this work hinges is
outlined in Scheme 2.8 Acyl radical equivalent 4, generated
Scheme 2. Addition of Acyl Radical Equivalent 4 to Olefins
by chemical initiation with lauroyl peroxide (DLP), can be
captured by the olefin to produce an intermediate that reacts
with the starting material 3 in a dithiocarbonate group transfer
propagation step to finally afford a new xanthate adduct 6
(i.e., path B). One important advantage of this system is that
the reaction of captodative radical 4 with its xanthate
precursor 3 (i.e., path A) is degenerate. Without this major
competing pathway radical 4 acquires a relatively long
effective lifetime and should be able to undergo efficient
addition to even unactivated olefin traps.
In practice, we were pleased to observe that xanthate 3
furnished good to excellent yields of adducts 6a-m when
treated with a substoichiometric amount of DLP (5-27%)
and the corresponding olefin a-m (2 equiv) in refluxing 1,2-
dichloroethane (DCE) (Table 1).
To investigate the limitations of the xanthate transfer
reaction a significant range of olefins were screened. Simple
hydrocarbons (entries 1-4) posed no difficulty with excellent
conversion being obtained in each instance. The product
derived from (-)-â-pinene 6c (entry 3) is particularly
interesting since it is formed after initial radical 4 addition
followed by fragmentation of the cyclobutane ring to generate
a tertiary radical to which the xanthate is transferred (Scheme
3). This is the only case for which adduct 6 does not have
a Addition reactions were performed by portionwise addition of DLP
(5%) every 90 min to a refluxing degassed 1 M solution of 3 (1 equiv) in
DCE in the presence of the olefin (2 equiv) until 3 was completely
consumed. b Yields are of isolated products. c Diastereomeric ratio was
measured by NMR spectroscopy after purification by column chromatog-
raphy. d (-)-â-Pinene was utilized. e The isolated yield is moderate due to
a tedious purification of adduct 6k from olefin k.
an identical structure with the generic provided in Scheme
2. Functionality that is widely used in organic synthesis
including ethers, acetals (entries 5 and 6), esters (entries 7
and 8), sulfonamides, amides, N,O-protected amino acids
(entries 9-11), together with complex heterocycles and
sugars9 (entries 12 and 13), may also be tolerated. All adducts
Scheme 3. Formation of Adduct 6c
(8) (a) Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 672. (b)
Quiclet-Sire, B.; Zard, S. Z. Phosphorus, Sulfur Silicon Relat. Elem. 1999,
153-154, 137.
148
Org. Lett., Vol. 8, No. 1, 2006

6a-m were isolated as a mixture of two or more diastere-
omers (depending on the stereochemical complexity of the
olefin employed), with low diastereoselectivity being ob-
served overall. It is noteworthy that since 6a-m still
incorporate a xanthate moiety, a variety of further transfor-
mations via radical and nonradical processes is possible.10
The newly introduced formyl group can be unmasked by
initial removal of the xanthate moiety through reduction with
a combination of DLP/2-propanol or tributyltin hydride/
AIBN, followed by hydrolysis (Scheme 4). The isolated
In an attempt to hydrolyze the xanthate group, adduct 6e
was treated with n-butylamine at room temperature (Scheme
5). The corresponding thiol was not isolated with the major
Scheme 5. Cyclization of Adduct 6e
Scheme 4. Reduction of a Selection of Adducts 6a-m
product being a dihydrothiophen-2-imine 12e. Imine 12e was
most likely generated through nucleophilic attack of n-
butylamine onto the xanthate moiety followed by 5-exo-dig
cyclization of the sulfide anion formed onto the pendant
nitrile.14 Subsequent treatment of 12e with aqueous TFA
afforded the corresponding dihydrothiophen-2-one 13e in
good overall yield.12
Transformation of the xanthate group in adducts 6 into a
bromide can be effected with ease by treatment with ethyl-
2-bromo-2-methylpropionate and cumyl peroxide in refluxing
dichlorobenzene (Scheme 6).10e The corresponding bromides
Scheme 6. Xanthate-Bromine Exchange of Adducts 6
yields of reduced material 7 with use of DLP/2-propanol
were greater than via the tinhydride method (72-80%
compared with 40-51%), possibly due to tin-mediated
cleavage of the benzoate group. Interestingly, the reduction
of 6e to 7e via the DLP/2-propanol approach resulted in
modest C-O bond â-scission of the corresponding radical.
Further reduction to N-protected amino alcohols is possible
(e.g., 7b to 10b) via catalytic hydrogenation under acidic
conditions (10% Pd-C, HCl-MeOH) followed by base (K2-
CO3) induced migration of the benzoyl moiety.11,12 The new
formyl group can then be obtained from benzoyloxyaceto-
nitrile by mild hydrolysis (NaOH, MeOH-CHCl3), using
general procedures described in the literature.13 As an
alternative to reduction, the xanthate group can be used to
effect an annulation reaction onto a suitably placed aromatic
ring, as in the efficient conversion of adduct 6i to indoline
aldehyde 9i via the isolated indoline 11i.10
14 were produced in good to excellent yield and as a mixture
of diastereomers in an approximate 1:1 ratio. Initial studies
have shown that upon treatment with base, the bromides 14
can be used as precursors to cyclopropanes (e.g., 14b to
15b).12
With a one-carbon radical equivalent in hand, we briefly
explored the possibility of its application to the construction
of the R-kainic acid skeleton. R-Kainic acid 16 has attracted
considerable interest since it was first isolated in 1953,15 due
to its anthelmintic and neuroexcitory properties.16,17 It was
postulated that xanthate 3 could be utilized to install the C3-
carboxyl and C4-exo-methylene functionalities in a total
(9) 5,6-Dideoxy-1,2-O-isopropylidiene-3-O-methyl-R-D-xylo-hex-5-eno-
furanose was utilized in this case: Josan, J. F.; Eastwood, F. W. Carbohydr.
Res. 1968, 7, 161.
(10) For example, see: (a) Lopez-Ruiz, H.; Zard, S. Z. Chem. Commun.
2001, 24, 2618. (b) Axon, J.; Boiteau, L.; Boivin, J.; Forbes, J. E.; Zard, S.
Z. Tetrahedron Lett. 1994, 35, 1719. (c) Liard, A.; Quiclet- Sire, B.; Saicic,
R. N.; Zard, S. Z. Tetrahedron Lett. 1997, 38, 1759. (d) Cholleton, N.;
Zard, S. Z. Tetrahedron Lett. 1998, 39, 7295. (e) Barbier, F.; Pautrat, F.;
Quiclet-Sire, B.; Zard, S. Z. Synlett 2002, 5, 811.
(13) (a) Vieira, E.; Vogel, P. HelV. Chim. Acta 1983, 66, 1865. (b)
Reymond, J.-L.; Vogel, P. Tetrahedron: Asymmetry 1990, 10, 729. (c)
Allemann, S.; Vogel, P. Synthesis 1991, 11, 923. (d) Konno, S.; Ohba, S.;
Sagi, M.; Yamanaka, H. Heterocycles 1986, 24, 1243. (e) Connors, R.;
Durst, T. Tetrahedron Lett. 1992, 33, 7277. (f) Stierle, D. B.; Faulkner, D.
J. J. Org. Chem. 1980, 45, 4980.
(11) Oaksmith, J. M.; Peters, U.; Ganem, B. J. Am. Chem. Soc. 2004,
126, 13606.
(12) The reported reaction yields are unoptimized.
Org. Lett., Vol. 8, No. 1, 2006
149

Scheme 7. Retrosynthetic Analysis for Kainic Acid 16
Scheme 9. Postulated Mechanism for Formation of 24
zation to generate heterocyclic radical 27, which subsequently
cyclizes onto the nitrile to form bicyclic iminyl radical 28.14
In the absence of a hydrogen atom source, 28 is prone to
â-scission to give radical 29. Xanthate transfer in the usual
fashion (Scheme 2) finally affords the isolated product 24.
The diastereoselective formation of a trans-C3-C4 junc-
tion could result from steric repulsion between the trisub-
stituted olefin and the benzoyloxyacetonitrile group in 26,
which disfavors cyclization to the cis product. Moreover,
cleavage of the C-CdN• bond in 28 is likely to be facilitated
by the neighboring phenylester moiety through a combination
of bond weakening and stabilization of the ensuing radical
29.20e
In conclusion, xanthate 3 has been demonstrated as a
useful alternative to known radical and ionic methods for
the introduction of formyl units. It is reactive toward a variety
of unactivated olefins, with the corresponding adducts being
obtained in excellent yields. Furthermore, it can be introduced
under mild reaction conditions and unmasked to furnish a
variety of structural units.
synthesis of kainic acid (Scheme 7). Radical addition of 3
to diene 21, followed by ring closure and xanthate transfer
would afford the pivotal pyrrolidine 20. Thermal xanthate
elimination to generate olefin 19, hydrolysis of the benzoy-
loxyacetonitrile group to give aldehyde 18, and subsequent
oxidation and deprotection would then culminate in the
preparation of 16 through a rapid 5-step reaction sequence.
The key radical addition and cyclization step was initially
investigated with model diene 22 (prepared by phenylsul-
fonation and alkylation of allylamine). Thus, treatment of a
refluxing 1 M solution of xanthate 3 and diene 22 in DCE
with a substoichiometric amount of DLP generated two
cyclized adducts 23 and 24 that were constitutional isomers
(Scheme 8). To our surprise, what we believe (by NMR and
Supporting Information Available: Experimental pro-
cedures and NMR data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
Scheme 8. Model Studies toward Synthesis of 16
OL052634M
(14) (a) Baldwin, J. E.; Thomas, R. C.; Kruse, L. I.; Silberman, L. J.
Org. Chem. 1977, 42, 3846. (b) Baldwin, J. E.; Cutting, J.; Dupont, W.;
Thomas, R. C.; Kruse, L.; Silberman, L. J. Chem. Soc., Chem. Commun.
1976, 18, 734-741.
(15) Murakami, S.; Takemoto, T.; Shimizu, Z. J. Pharm. Soc. Jpn. 1953,
73, 1026.
(16) (a) Watase, H.; Tomiie Y.; Nitta, I. Nature 1958, 181, 761. (b)
McGeer, E. G.; Olney, J. W.; McGeer, P. L. Kainic Acid as a Tool in
Neurobiology; Raven Press: New York, 1978. (c) Shinozaki, H. In
Excitatory Amino Acid Receptors. Design of Agonists and Antagonists;
Krogsgaard-Larsen, P., Hansen, J. J., Eds.; Ellis Horwood: New York, 1992.
(17) For reviews on the syntheses of kainoids, see: (a) Hashimoto, K.;
Shirahama, H. J. Synth. Org. Chem. Jpn. 1989, 47, 212. (b) Parsons, A. F.
Tetrahedron 1996, 52, 4149. For total synthesis of R-kainic acid using
radical cyclization, see: (c) Baldwin, J. E.; Moloney, M. G.; Parsons, A.
F. Tetrahedron 1990, 46, 7263. (d) Hatakeyama, S.; Sugawara, K.; Takano,
S. J. Chem. Soc., Chem. Commun. 1993, 2, 125. (e) Hannessian, S.;
Ninkovic, S. J. Org. Chem. 1996, 61, 5418. (f) Bachi, M. D.; Melman, A.
J. Org. Chem. 1997, 62, 1896. (g) Miyata, O.; Ozawa, Y.; Ninomiya, I.;
Aoe, K.; Hiramatsu, H.; Naito, T. Heterocycles 1997, 46, 321. (h) Cossy,
J.; Cases, M.; Pardo, D. G. Tetrahedron 1999, 55, 6153. (i) Miyata, O.;
Ozawa, Y.; Ninomiya, I.; Naito, T. Tetrahedron 2000, 56, 6199.
(18) Adduct 23 was isolated as a mixture of four diastereomers. However,
the low yield of 23 does not permit an accurate diastereomeric ratio to be
stated within experimental error.
HRMS analysis) to be the expected product 23 was the minor
component (9%) while the major product 24 (45%) was a
pyrrolidine derived from a rare 1,5-nitrile translocation. Both
adducts were isolated as a mixture of four diastereomers after
purification by column chromatography.12,18 The structure
of 24 was confirmed by tributyltin hydride/AIBN mediated
xanthate reduction, which afforded heterocycle 25 in reason-
able yield and as a mixture of two separable diastereomers in
a 25a:25b 3:1 ratio.19 The major diastereomer exhibits a trans
relationship between the C3 and C4 substituents based upon
NOESY analysis. Dilution of the reaction mixture from 1 to
0.5 M offered no improvement on the isolated yields of 23
and 24 and did not alter the observed diastereomeric ratio.19
A number of groups have recently reported 1,4 and 1,5
nitrile translocation reactions in radical processes although
the latter mode is far less commonplace.20 It is likely that
the mechanism for formation of 24 from 3 and 22 is similar
to that originally proposed by Kalvoda (Scheme 9).21 Thus,
the initially formed radical 26 is subject to 5-exo-trig cycli-
(19) The diastereomeric ratio 25a:25b 3:1 was determined after purifica-
tion by column chromatography.
(20) (a) For rates of radical addition to nitriles see: Griller, D.; Schmid,
P.; Ingold, K. U. Can. J. Chem. 1979, 57, 831. For examples of nitrile
translocations see: (b) Curran, D. P.; Seong, C. M. Tetrahedron 1992, 48,
2175. (c) Beckwith, A. L. J.; O’Shea, D. M.; Westwood, S. W. J. Am.
Chem. Soc. 1988, 110, 2565. (d) Rychnovsky, S. D.; Swenson, S. S.
Tetrahedron 1997, 53, 16489. (e) Bowman, W. R.; Bridge, C. F.; Brookes,
P. Tetrahedron Lett. 2000, 41, 8989. (f) Callier, A.-C.; Quiclet- Sire, B.;
Zard, S. Z. Tetrahedron Lett. 1994, 35, 6109.
(21) (a) Kalvoda, J. HelV. Chim. Acta 1968, 51, 267. (b) Kalvoda, J.
Chem. Commun. 1970, 16, 1002.
150
Org. Lett., Vol. 8, No. 1, 2006