Sulfinyl-mediated stereoselective overman rearrangements and Diels-Alder cycloadditions

Article abstract of DOI:10.1021/ol301139a

The Overman rearrangement of allylic sulfinyl trichloroacetimidates affords sulfinyl trichloroacetamides with high stereoselectivity and excellent yields. Bis-allylic substrates lead to amido 2-sulfinyl butadiene derivatives in excellent yields, with tota

Full text of DOI:10.1021/ol301139a

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3068–3071
Sulfinyl-Mediated Stereoselective
Overman Rearrangements and
DielsꢀAlder Cycloadditions
ꢀ
Roberto Fernandez de la Pradilla,* Ignacio Colomer, and Alma Viso
´
Instituto de Quımica Organica General, IQOG-CSIC, Juan de la Cierva 3,
28006 Madrid, Spain
ꢀ
iqofp19@iqog.csic.es
Received April 27, 2012
ABSTRACT
The Overman rearrangement of allylic sulfinyl trichloroacetimidates affords sulfinyl trichloroacetamides with high stereoselectivity and excellent
yields. Bis-allylic substrates lead to amido 2-sulfinyl butadiene derivatives in excellent yields, with total chemo- and diastereoselectivity. The
DielsꢀAlder cycloaddition of related dienes is controlled by the sulfoxide moiety.
The synthesis of chiral allylic amines is still a challenge
from different standpoints such as synthetic methodology,1
applications,2 medicinal chemistry,3 and synthesis of natural
products.4 This sustained interest has prompted organic che-
mists to develop a number of routes to these valuable building
blocks. A general approach entails the addition to imines of
suitable nucleophiles such as electron-deficient alkenes (aza-
Morita-Baylis-Hillman,5a R-lithiated vinyl sulfoxides5b,c) or
reductive couplings with alkynes.6 An alternative route relies
on metal-catalyzed allylic aminations, promoted by Ir,7 Pd,8
Pt, and even Fe.9 Finally, the hydroamination of 1,3-dienes is
also an important contribution in this field.10
Aside from the above, the thermal or metal-catalyzed
[3,3]-sigmatropic rearrangement of allylic trichloroacetimidates
(5) (a) Yukawa, T.; Seelig, B.; Xu, Y.; Morimoto, H.; Matsunaga, S.;
Berkessel, A.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 11988–11992
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D. T. S.; Liskamp, R. M. J. Bioorg. Med. Chem. Lett. 2008, 18, 78–84.
(b) Liu, Q.; Qian, W.; Li, A.; Biswas, K.; Chen, J. J.; Fotsch, C.; Han, N.;
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125, 8798–8805. (b) Dickson, D. P.; Wardrop, D. J. Org. Lett. 2009, 11,
1341–1344. (c) Hama, N.; Matsuda, T.; Sato, T.; Chida, N. Org. Lett.
2009, 11, 2687–2690. (d) Kitamoto, K.; Sampei, M.; Nakayama, Y.;
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T.; Miwa, S.; Yamazaki, M.; Sato, T.; Chida, N. Org. Lett. 2011, 13,
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ꢀ
~
and references therein. (b) Viso, A.; Fernandez de la Pradilla, R.; Urena,
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M.; Colomer, I. Org. Lett. 2008, 10, 4775–4778. (c) Viso, A.; Fernandez
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(6) (a) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2004, 43, 3941–
3944 and references therein. (b) Ngai, M.-Y.; Barchuk, A.; Krische, M. J.
J. Am. Chem. Soc. 2007, 129, 12644–12645 and references therein.
(7) (a) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124,
15164–15165. (b) Leitner, A.; Shekhar, S.; Pouy, M. J.; Hartwig, J. F.
J. Am. Chem. Soc. 2005, 127, 15506–15514. (c) Shekhar, S.; Trantow, B.;
Leitner, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 11770–11771.
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r
10.1021/ol301139a
Published on Web 05/25/2012
2012 American Chemical Society

(Overman Rearrangement)11 is perhaps one of the most
general routes to allylic amine derivatives.12 In this paper
we report our preliminary results on the Overman rear-
rangement of sulfinyl allylic trichloroacetimidates that
occur with good diastereoselectivities and complete che-
moselectivity in some cases and maintain the useful alkenyl
sulfoxide fragment.
Enantiopure sulfoxides are synthetically versatile chiral
auxiliaries.13 In recent years, we have pursued novel strate-
gies involving readily available R-hydroxy vinyl sulfoxides
2/3 (Scheme 1)14,15 including the highly diastereoselective
Claisen rearrangement of enol ethers Y to carbonyl deriva-
tives Z with generation of up to two stereogenic centers
while preserving the useful vinyl sulfoxide.16 Building upon
these precedents we decided to undertake a study on the
preparation of trichloroacetimidates 4/5 and their transfor-
mation into enantiopure allylic trichloroacetamides 6ꢀ9
with a stereodefined alkenyl sulfoxide moiety by Overman
rearrangement.
In most cases, the required trichloroacetimidates 4/5
(Table 1) were prepared uneventfully under standard
conditions (Cl3CCN, DBU, CH3CN, rt) in almost quanti-
tative yields after column chromatography from the ap-
1
propiate alcohols 2/3. However, the H NMR spectra of
isomers 5 with R1 = n-Bu indicated clearly that two
inseparable species were present in solution (73:27 mixture,
for 5a). While the major products were clearly the expected
trichloroacetimidates, the minor products were tentatively
assigned sulfurane structures, presumably in equilibrium
with the trichloroacetimidates (see Supporting Information),
since, remarkably, the yields and diastereoselectivities of
the rearrangements are not compromised in those cases
(see below).
After considerable experimentation with solvents and
reaction temperatures, the optimal conditions found for
the Overman rearrangement of trichloroacetimidate 4a
(Table 1) involved heating at 100 °C in DMF in the
presence of a small amount of BHT; thus, a 92:8 mixture
of amides 6a and 7a was obtained in 90% yield (Table 1,
entry 1). Encouraged by this result, we selected substrates
4aꢀd and diastereoisomers 5aꢀd to evaluate the effect of
representative R1 and R2 groups on the viability and
selectivity of the rearrangement, and the results are gath-
ered in Table 1, entries 1ꢀ8. The yields and selectivities
found for these processes were excellent in most cases, with
isomers 5 being slightly more reactive and selective than
isomers 4. In all examples, the predominant resulting
isomer had a Z geometry, in sharp contrast with recent
findings on related unsaturated esters that led mainly to E
isomers.17,18 This methodology nicely complements our
previous synthesis of allylic sulfinyl amine derivatives.5b,c
The influence of the geometry of the vinyl sulfoxide was
then addressed, and Z substrates (()-10b and (()-11b19
were submitted to these conditions to produce E trichloro-
acetamides (()-9b and (()-7b, respectively, as single iso-
mers and in excellent yields (Table 1, entries 9 and 10).
Scheme 1. Proposed Sulfinyl-Mediated Overman
Rearrangement
€
(10) (a) Lober, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc.
2001, 123, 4366–4367. (b) Pawlas, J.; Nakao, Y.; Kawatsura, M.;
Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 3669–3679. (c) Qin, H.;
Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2006,
128, 1611–1614. (d) Brouwer, C.; He, C. Angew. Chem., Int. Ed. 2006, 45,
1744–1747.
(11) For recent reviews of allylic trichloroacetimidate rearrangement,
see: (a) Overman, L. E.; Carpenter, N. E. Org. React. 2005, 66, 1–107.
(b) Majumdar, K. C.; Bhattacharyya, T.; Chattopadhyay, B.; Sinha, B.
(14) Vinyl sulfoxides 1 are available in one step by the procedure of
Craig: Craig, D.; Daniels, K.; MacKenzie, A. R. Tetrahedron 1993, 49,
11263–11304. Lithiation and trapping with aldehydes leads to the
substrates of this study 2/3. In most cases 2 and 3 are readily inter-
converted by a Mitsunobu protocol.
ꢀ
~
(15) (a) Fernandez de la Pradilla, R.; Colomer, I.; Urena, M.; Viso, A.
ꢀ
Org. Lett. 2011, 13, 2468–2471. (b) Fernandez de la Pradilla, R.;
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Castellanos, A.; Osante, I.; Colomer, I.; Sanchez, M. I. J. Org. Chem.
Synthesis 2009, 2117–2142.
For representative reports, see:
2009, 74, 170–181.
(c) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597–599. (d) Overman,
L. E. J. Am. Chem. Soc. 1976, 98, 2901–2910. (e) Overman, L. E. Acc.
Chem. Res. 1980, 13, 218–224. See also: (f) Wai, J. S.; Fisher, T. E.;
Embrey, M. W. Tetrahedron Lett. 1995, 36, 3461–3464.
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(16) (a) Fernandez de la Pradilla, R.; Montero, C.; Tortosa, M. Org.
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Lett. 2002, 4, 2373–2376. (b) Fernandez de la Pradilla, R.; Montero, C.;
Tortosa, M.; Viso, A. Chem.;Eur. J. 2009, 15, 697–709.
(17) See ref 11 in: Lee, S. I.; Moon, S. Y.; Hwang, G.-S.; Ryu, D. H.
Org. Lett. 2010, 12, 3234–3237. The relative configuration of final
products 6 and 8 was assigned from their Z geometry (NOE), the relative
configuration of the starting materials, and the accepted mechanism for
the Overman rearrangement.
(18) The rearrangement of the sulfone analog of 5a afforded an 80:20
Z/E mixture of the sulfones related to 8a and 9a, with identical data to
those obtained by oxidation of 8a and 9a. See Supporting Information.
(19) Racemic (Z)-sulfinyl alcohols were prepared from the corre-
sponding alkynyl sulfides (Kabanyane, S. T.; MaGee, D. I. Can. J.
Chem. 1992, 70, 2758ꢀ2763) by Pd-catalyzed hydroestannylation
(Magriotis, P. A.; Brown, J. T.; Scott, M. E. Tetrahedron Lett. 1991,
32, 5047ꢀ5051), tinꢀlithium exchange, condensation with an aldehyde,
and diastereoselective oxidation with m-CPBA. For an enantioselective
synthesis of (Z)-sulfenyl alcohols, see: Berenguer, R.; Cavero, M.;
(12) For recent advances in the catalytic enantiocontrol of the [3,3]-
sigmatropic rearrangement of trichloroacetimidates, see: (a) Calter, M.;
Hollis, T. K.; Overman, L. E.; Ziller, J.; Zipp, G. G. J. Org. Chem. 1997,
62, 1449–1456. (b) Donde, Y.; Overman, L. E. J. Am. Chem. Soc. 1999,
121, 2933–2934. (c) Anderson, C. E.; Overman, L. E. J. Am. Chem. Soc.
2003, 125, 12412–12413 and references therein. (d) Jiang, G.; Halder, R.;
Fang, Y.; List, B. Angew. Chem., Int. Ed. 2011, 50, 9752–9755.
(e) Wanniarachchi, Y. A.; Kogiso, Y.; Slaughter, L. M. Organometallics
2008, 27, 21–24.
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Synthesis 2006, 1899–1930. (c) Pellissier, H. Tetrahedron 2006, 62, 5559–
5601. (d) Mellah, M.; Voituriez, A.; Schulz, E. Chem. Rev. 2007, 107, 5133–
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5209. (e) Carreno, M. C.; Hernandez-Torres, G.; Ribagorda, M.; Urbano,
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A. Chem. Commun. 2009, 6129–6144. (f) Wojaczynska, E.; Wojaczynski, J.
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~
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´
Org. Lett., Vol. 14, No. 12, 2012
3069

Table 1. Scope of the Sulfinyl-Mediated Overman
Rearrangementa
Table 2. Overman Rearrangement of Bis-allylic Substratesa
major
entry
SM
4a
R1
R2
producta
dr (yield %)b,c
entry
SM
4e
R1
R3
producta
yield %
1
2
n-Bu
n-Bu
n-Bu
n-Bu
Ph
Et
Et
Ph
Ph
Et
Et
Ph
Ph
Ph
Ph
6a
92:8 (90%)
96:4 (90%)
70:30 (75%)
100:0 (92%)
100:0 (83%)
100:0 (91%)
100:0 (51%)
100:0 (91%)
100:0 (85%)
100:0 (95%)
1
2
n-Bu
n-Bu
Ph
H
12e
91%
99%
92%
98%
92%
95%
80%
97%
88%
95%
5a
8a
5e
H
12e
3
4b
6b
3
4f
H
12f
4
5b
8b
4
5f
Ph
H
12f
5
4c
6c
5
4g
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
Ph
Ph
Me
Me
Me
Me
12g
6
5c
Ph
8c
6
5g
13g
7
4d
Ph
6d
7
4h
12h
8
5d
Ph
8d
8
5h
13h
9
(()-10b
(()-11b
n-Bu
n-Bu
(()-9b
(()-7b
9
(()-10h
(()-11h
(()-14h
(()-15h
10
10
a Reactions were performed in DMF with a catalytic amount of BHT
at 100 °C. b Ratio determined by 1H NMR analysis of crude reaction
mixtures. c Combined yield after chromatography.
a Reactions were performed in DMF with a catalytic amount of BHT
at 100 °C.
unstable to purification on silica gel and, therefore, the
yields are reported from the starting alcohols. Finally,
geometric isomers (()-10h and (()-11h, as crude products,
were submitted to the rearrangement conditions to afford
respectively the E,Z aminodienes (()-14h and (()-15h as
single isomers.
These results may be tentatively accounted for in terms
of diastereomeric transition states derived from chairlike
reactive conformations AꢀD (Figure 1). For E vinyl
sulfoxides 5aꢀd, with an S-cis alkene and SdO bonds,21
while conformer B would have a severe R1ꢀR2 1,3-diaxial
interaction and the p-Tol group would point toward the
incoming unsaturated moiety for the rearrangement, con-
former A would display a favorable arrangement of stereo-
controlling elements.
Having established the generality of the methodologywe
examined the behavior of bis-allylic substrates with the
expectation that the different natures of the alkenes poten-
tially involved in the rearrangement could provide a useful
level of chemoselectivity, often elusive in the known ex-
amples of this transformation.20 In this manner, diaster-
eomeric trichloroacetimidates 4e and 5e (R3 = H),
prepared smoothly from the alcohol precursors, were
submitted to the standard reaction conditions, to produce
excellent yields of aminodiene 12e with complete chemos-
electivity (Table 2, entries 1 and 2). Likewise, phenyl-
substituted diene 12f was obtained in excellent yields and
as a single isomer from acetimidates 4f and 5f (Table 2,
entries 3 and 4).
Encouraged by these results, the creation of an addi-
tional stereocenter by placing a substituent at the reactive
alkene (R3 ¼ H) was examined, and to our delight, the
rearrangement took place with complete chemo- and
stereoselectivity to produce dienes 12g, 13g, 12h, and 13h
in excellent yields (Table 2, entries 5ꢀ8). It should be
pointed out that these trichloroacetimidates (4g, 5g, 4h,
and 5h) were used as crude products since they were
In the case of Z vinyl sulfoxides 10b, the process appears
to be primarily controlled by A1,2 strain rather than 1,3-
diaxial interactions with conformer C displaying a severe
1,2-strain between the p-Tol and R2 moieties that results in
high stereoselectivity to produce the E rearrangement
product 9, presumably through conformer D.22 For bis-
allylic substrates, the process seems to follow the accepted
stereochemical outcome for the [3,3]-sigmatropic Over-
man rearrangement albeit with unprecedented complete
chemoselectivity.
(20) Chemoselective Overman rearrangement on bis-allylic trichloro-
acetimidates continues to be a challenge, since poor selectivity (60:40)
has been achieved. See: (a) Birtwistle, D. H.; Brown, J. M.; Foxton,
M. W. Tetrahedron 1988, 44, 7309–7318. (b) Commerc-on, A.; Ponsinet,
G. Tetrahedron Lett. 1990, 31, 3871–3874. See also ref 11a and 11d.
(21) Tietze, L. F.; Schuffenhauer, A.; Schreiner, P. R. J. Am. Chem.
Soc. 1998, 120, 7952–7958.
(22) A similar trend is followed for isomers 4 and 11.
3070
Org. Lett., Vol. 14, No. 12, 2012

spectral data to those found before. These results conclu-
sively establish that the stereochemical outcome of the
DielsꢀAlder cycloaddition of our sulfinyl dienes is primar-
ily controlled by the chiral sulfur atom.
Scheme 2. Sulfinyl-Directed DielsꢀAlder Cycloadditions
Figure 1. Stereochemical outcome.
At this stage we pursued exploratory experiments on the
behavior of our sulfinyl amido dienes in diastereoselective
DielsꢀAlder processes, and the results are summarized in
Scheme 2.23 The reaction between our diastereomeric
dienes (()-14h and (()-15h with N-phenylmaleimide
(NPM) in toluene at rt afforded excellent yields of R-endo
cycloadducts (()-16 and (()-17 respectively as single iso-
mers and preserving the valuable alkenyl sulfoxide moiety.
Oxidation with MMPP gave the related sulfonyl cycload-
ducts (()-18 and (()-19 respectively as single isomers.
To determine the intrinsic stereodirecting capabilities of
the chiral allylic amide residue under these conditions,24 we
examined the cycloaddition between amido sulfonyl diene
(()-20, prepared by oxidation of (()-15h, that gave rise to
a 66:34 mixture of (()-19 and (()-ent-18,25 with identical
In conclusion, the first examples of the Overman rear-
rangement of allylic sulfinyl trichloroacetimidates to afford
sulfinyl trichloroacetamides have been described. The re-
arrangement of bis-allylic substrates involves exclusively the
alkene that does not bear the sulfinyl substituent to afford
amido 2-sulfinyl butadienes. Selected examples of these
dienes undergo highly diastereoselective DielsꢀAlder cy-
cloadditions controlled exclusively by the chiral sulfur atom.
We are currently exploring the scope, limitations, and
synthetic applications of these methodologies.
Acknowledgment. This research was supported by MI-
CINN (CTQ2009-07752). We also thank MEC for a
fellowship to I.C.
(23) For related work on DielsꢀAlder with sulfinyl dienes, see:
ꢀ
(a) Fernandez de la Pradilla, R.; Montero, C.; Viso, A. Chem. Commun.
ꢀ
1998, 409–410. (b) Fernandez de la Pradilla, R.; Montero, C.; Tortosa,
M.; Viso, A. Chem.;Eur. J. 2005, 11, 5136–5145. For a review of
´
general aplications of sulfoxides in cycloadditions see: (c) Garcıa Ruano,
J. L.; Cid de la Plata, B. Top. Curr. Chem. 1999, 1–126.
(24) (a) Kozikowski, A. P.; Nieduzak, T. R.; Springer, J. P. Tetra-
hedron Lett. 1986, 27, 819–822. (b) Kozikowski, A. P.; Nieduzak, T. R.;
Konoike, T.; Springer, J. P. J. Am. Chem. Soc. 1987, 109, 5167–5175.
(c) Crisp, G. T.; Gebauer, M. G. J. Org. Chem. 1996, 61, 8425–8431.
(25) The ent nomenclature is used to facilitate comparison of the
data.
Supporting Information Available. Experimental pro-
cedures, compound characterization, NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
3071