Asymmetric radical addition of ethers to enantiopure N-p-toluenesulfinyl aldimines, mediated by dimethylzinc-air

Article abstract of DOI:10.1021/ol0621093

(Diagram presented) Asymmetric radical addition of ethers to enantiopure aromatic N-p-toluenesulfinyl aldimines has been achieved. The requisite radicals were generated by dimethylzinc-air. Lewis acid activation of the N-p-toluenesulfinyl aldimines follow

Full text of DOI:10.1021/ol0621093

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5729-5732
Asymmetric Radical Addition of Ethers
to Enantiopure N-p-Toluenesulfinyl
Aldimines, Mediated by
Dimethylzinc−Air
Tito Akindele, Yasutomo Yamamoto, Masaru Maekawa, Hiroyuki Umeki,
Ken-ichi Yamada, and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan
tomioka@pharm.kyoto-u.ac.jp
Received August 27, 2006
ABSTRACT
Asymmetric radical addition of ethers to enantiopure aromatic N-p-toluenesulfinyl aldimines has been achieved. The requisite radicals were
generated by dimethylzinc air. Lewis acid activation of the N-p-toluenesulfinyl aldimines followed by radical addition gives a mixture of
−
sulfinamide and sulfonamide products. Subsequent treatment of the mixture with dry m-CPBA affords the sulfonamide product in enantiomerically
enriched form.
The prevalence of chiral amine moieties in natural products,
biologically active compounds, chiral building blocks, aux-
iliaries, and catalysts necessitates the development of novel
methods for their syntheses.1
Our recent reports2 indicated that carbon-centered radicals
generated from ether,3 unfunctionalized cycloalkanes,4 and
primary alkyl iodides,5 in the presence of dimethylzinc and
air, all add to imines to give the adducts in good to excellent
yields. We have also reported the reaction of carbon-centered
radicals generated from ethers, with aldehydes,6 arylamines,
alkoxyamines, and dialkylhydrazines.7 Among the imines that
were investigated, N-sulfonyl imines were most efficient. The
potential application of the radical reaction to the synthesis
of nonracemic oxygenated amine derivatives prompted us
to investigate carbon-centered radical addition of ethers to
enantiopure N-sulfinyl imines.8,9
Although there are numerous examples of asymmetric
anionic additions to N-sulfinyl imines,10,11 to our knowledge,
(6) Yamamoto, Y.; Yamada, K.; Tomioka, K. Tetrahedron Lett. 2004,
45, 795-797.
(7) Yamamoto, Y.; Maekawa, M.; Akindele, T.; Yamada, K.; Tomioka,
K. Tetrahedron 2005, 61, 379-384.
(8) Reviews on asymmetric radical addition to CdN bonds: (a) Friestad,
G. K. Eur. J. Org. Chem. 2005, 3157-3172. (b) Friestad, G. K. Tetrahedron
2001, 57, 5461-5496.
(1) (a) Lee, H.-S.; Kang, S. H. Synlett 2004, 1673-1685. (b) Bergmeier,
S. C. Tetrahedron 2000, 56, 2561-2576.
(2) Review: Yamada, K.; Yamamoto, Y.; Tomioka, K. J. Synth. Org.
Chem. Jpn. 2004, 62, 1158-1165.
(9) For selected recent examples on asymmetric radical addition to Cd
N bonds: (a) Miyabe, H.; Yamaoka, Y.; Takemoto, Y. J. Org. Chem. 2006,
71, 2099-2106. (b) Friestad, G. K.; Draghici, C.; Soukri, M.; Qin, J. J.
Org. Chem. 2005, 70, 6330-6338. (c) Ueda, M.; Miyabe, H.; Sugino, H.;
Naito, T. Org. Biomol. Chem. 2005, 3, 1124-1128. (d) Ferna´ndez, M.;
Alonso, R. Org. Lett. 2003, 14, 2461-2464. (e) Singh, N.; Anand, R. D.;
Trehan, S. Tetrahedron Lett. 2004, 45, 2911-2913. (f) Halland, N.;
Jørgensen, K. A. J. Chem. Soc. Perkin Trans. 1 2001, 1290-1295. (g)
Bertrand, M. P.; Coantic, S.; Feray, L.; Nouguier, R.; Perfetti, P. Tetrahedron
2000, 56, 3951-3961.
(3) (a) Yamada, K.; Yamamoto, Y.; Maekawa, M.; Tomioka, K. J. Org.
Chem. 2004, 69, 1531-1534. (b) Yamada, K.; Yamamoto, Y.; Tomioka,
K. Org. Lett. 2003, 5, 1797-1799. (c) Yamada, K.; Fujihara, H.; Yamamoto,
Y.; Miwa, Y.; Taga, T.; Tomioka, K. Org. Lett. 2002, 4, 3509-3511.
(4) Yamada, K.; Yamamoto, Y.; Maekawa, M.; Chen, J.; Tomioka, K.
Tetrahedron Lett. 2004, 45, 6595-6597.
(5) Yamada, K.; Yamamoto, Y.; Maekawa, M.; Akindele, T.; Umeki,
H.; Tomioka, K. Org. Lett. 2006, 8, 87-89.
10.1021/ol0621093 CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/10/2006

there has been only one report12 which likely describes
asymmetric addition of radicals to N-sulfinyl imines. This
report by Lin, Xu, and co-workers describes a SmI2-mediated
reductive cross-coupling reaction between aldehydes and
chiral N-tert-butanesulfinyl imines. The reaction may involve
the addition of radical anion intermeditates.
Scheme 1. Me2Zn-Air-Initiated Asymmetric Radical
Addition of 2 to Imine 1aa and the Conversion of Adduct 3 to
Alcohol 5
We report herein a stereoselective addition of R-alkoxy-
alkyl radicals to chiral N-sulfinyl imines.
The requisite N-sulfinyl imines were synthesized in
enantiomerically pure forms using Davis’ procedure.13 With
the enantiomerically pure N-sulfinyl imines in hand, we
commenced our investigation by treating a solution of (S)-
N-p-toluenesulfinyl benzaldehyde imine (1a) in 2,2-dimethyl-
1,3-dioxolane (2) with dimethylzinc (1 M in hexane) and
air at ambient temperature.3a However, complete consump-
tion of 1a required 12 equiv of dimethylzinc and 70 h, giving
a mixture of sulfonamide 3 and its sulfinamide analogue.
Subsequent treatment of the mixture with dry m-CPBA14,15
produced 3 in 65% yield as a 72:28 mixture of diastereo-
isomers3a (Scheme 1).
The sense of asymmetric induction of the radical addition
reaction was determined by converting adduct 3 into known
a The reaction was carried out using 1a (1 mmol) and 2 (250
equiv). Diastereomeric ratios (dr) were determined by 1H NMR of
crude product. Enantiomeric excess was determined by HPLC
analysis (see the Supporting Information).
(10) For reviews on chemistry of N-sulfinyl imines: (a) Morton, D;
Stockman, R. A. Tetrahedron 2006, 62, 8869-8905. (b) Davis, F. A.; Yang,
B.; Deng, J.; Zhang, J. ARKIVOC 2006, 7, 120-128. (c) Davis, F. A.; Yang,
B.; Deng, J.; Wu, Y.; Zhang, Y.; Rao, A.; Fang, T.; Goswami, R.; Prasad,
K. R.; Nolt, M. B.; Anilkumar, G. Phosphorus, Sulfur, Silicon Relat. Elem.
2005, 180, 1109-1117. (d) Senanayake, C. H.; Krishnamurthy, D.; Lu,
Z.-H.; Han, Z.; Gallou, I. Aldrichim. Acta 2005, 38, 93-104. (e) Zhou, P.;
Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003-8030. (f) Ellman,
J. A. Pure Appl. Chem. 2003, 75, 39-46. (g) Ellman, J. A.; Owens, T. D.;
Tang, T. P. Acc. Chem. Res. 2002, 35, 984-995.
alcohol 516 via diol 4. The prolonged reaction time and
requirement of large amounts of dimethylzinc were initially
attributed to the unexpected poor ability of N-sulfinyl imine
1a as an R-alkoxyalkyl radical acceptor. However, the radical
addition step required 4 h, and 3 equiv of Me2Zn when THF
(6) was used to give adduct 7 in high yield (Table 1, entry
1), thus suggesting that the steric bulk due to the methyl
groups of dioxolane 2 was the reason for the slow reac-
tion.
Ethers that would generate more nucleophilic carbon-
centered radicals as a result of an extra adjacent oxygen atom
were also investigated. With 1,3-benzodioxole (8), adduct 9
was obtained in 43% yield with 51% ee (entry 2). The best
results were obtained when 4,4,5,5-tetramethyl-1,3-dioxolane
(10) was used, giving adduct 11a in 67% yield with 83% ee
(entry 3).17 The higher enantiocontrol observed in the case
of dioxolane 10 relative to that observed when planar dioxole
8 was used was presumably due to the steric hindrance
caused by the methyl groups. The use of tert-butyl methyl
ether (12) required a large amount of dimethylzinc (30 equiv)
and over 3 days to produce adduct 13 in poor yield and ee
(entry 4).
(11) For latest examples of nucleophilic addition to chiral N-sulfinyl
imines: (a) Sun, X.-W.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2006, 8, 4979-
4982. (b) Denolf, B.; Mangelinckx, S.; To¨rnroos, K. W.; De Kimpe, N.
Org. Lett. 2006, 8, 3129-3132. (c) Kos´ciołowicz, A.; Rozwadowska, M.
D. Tetrahedron: Asymmetry 2006, 17, 1444-1448. (d) Kawe¸cki, R.
Tetrahedron: Asymmetry 2006, 17, 1420-1423. (e) Beenen, M. A.; Wiex,
D. J.; Ellman, J. A. J. Am. Chem. Soc. 2006, 128, 6304-6305. (f) Ding,
C.-H.; Chen, D.-D.; Luo, Z.-B.; Dai, L.-X.; Hou, X.-L. Synlett 2006, 1272-
1274. (g) Morton, D.; Pearson, D.; Field, R. A.; Stockman, R. A. Chem.
Commun. 2006, 1833-1835. (h) Li, Y.; Ni, C.; Liu, J.; Zhang, L.; Zheng,
J.; Zhu, L.; Hu, J. Org. Lett. 2006, 8, 1693-1696. (i) Davis, F. A.;
Ramachandar, T.; Chai, J.; Skucas, E. Tetrahedron Lett. 2006, 47, 2743-
2746. (j) Vela´zquez, F.; Arasappan, A.; Chen, K.; Sannigrahi, M.;
Venkatraman, S.; McPhail, A. T.; Chan, T.-M.; Shih, N.-Y.; Njoroje, F. G.
Org. Lett. 2006, 8, 789-792. (k) Wang, Y.; He, Q.-F.; Wang, H.-W.; Zhou,
X.; Huang, Z.-Y.; Qin, Y. J. Org. Chem. 2006, 71, 1588-1591. (l) Xiao,
X.; Wang, H.; Huang, Z.; Yang, J.; Bian, X.; Qin, Y. Org. Lett. 2006, 8,
139-142. (m) Hansen, D. B.; Starr, M. L.; Tolstoy, N.; Joullie´, M. M.
Tetrahedron: Asymmetry 2005, 16, 3623-3627. (n) McMahon, J. P.;
Ellman, J. A. Org. Lett. 2005, 7, 5393-5396. (o) Rajapakse, H. A.; Young,
M. B.; Zhu, H.; Charlton, S.; Tsou, N. N. Tetrahedron Lett. 2005, 46, 8909-
8912. (p) Garc´ıa Ruano, J. L.; Topp, M.; Lo´pez-Cantarero, J.; Alema´n, J.;
Remuin˜a´n, M. J.; Cid, M. B. Org. Lett. 2005, 7, 4407-4410. (q) Li, Y;
Hu, J. Angew. Chem., Int. Ed. 2005, 44, 5882-5886. (r) Kong, J.-R.; Cho,
C.-W.; Krische, M. J. J. Am. Chem. Soc. 2005, 127, 11269-11276. (s)
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Org. Chem. 2005, 70, 4741-4745.
Having identified an ether that produced the adduct in good
yield and ee, we sought to optimize the reaction conditions.
To this end, activation of the N-sulfinyl imine 1a with boron
trifluoride etherate (1 equiv) led to significant acceleration
of the reaction with increased yield of 86% and comparable
enantioselectivity of 80% after 2.5 h using 3 equiv of
(12) Zhong, Y.-W.; Dong, Y.-Z.; Fang, K.; Izumi, K.; Xu, M.-H.; Lin,
G.-Q. J. Am. Chem. Soc. 2005, 127, 11956-11957.
(13) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.;
Zhang, H. J. Org. Chem. 1999, 64, 1403-1406.
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2774.
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1745-1762.
(17) The use of (R)-N-tert-butanesulfinyl benzaldehyde imine resulted
in a complex mixture of products.
(15) Garc´ıa Ruano, J. L.; Alema´n, J.; Cid, M. B.; Parra, A. Org. Lett.
2005, 7, 179-182.
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Org. Lett., Vol. 8, No. 25, 2006

Table 1. Asymmetric Radical Addition of Other Ethers to 1aa
Table 2. Asymmetric Radical Addition of Ether 10 to
N-Sulfinyl Imines 1a
Me2Zn
entry
1
Ar
(equiv) time (h) 11 yield (%) eeb (%)
1
1a Ph
3
9
3
2
45
5
11a
11b
11c
11d
11e
11f
92
61
77
87
69
71
50
80
75
81
82
74
79
70
2c
3
1b 2-MeC6H4
1c 4-MeC6H4
1d 4-ClC6H4
1e 4-MeOC6H4
1f 2-naphthyl
1g 2-furyl
4
3
5
5d
6e
7f
12
12
18
72
49
180
11g
a Unless otherwise mentioned, 1 (1 mmol), 10 (125 equiv), and BF3‚OEt2
(1 equiv) were used b Determined by HPLC analysis (see the Supporting
Information). c BF3‚OEt2 (3 equiv) was used. d 10 (200 equiv) was used.
e BF3‚OEt2 (4 equiv) was used. f BF3‚OEt2 (6 equiv) was used.
alcohol 516 without epimerization, using a Lewis acid
mediated reductive acetal cleavage strategy (Scheme 2).19
Scheme 2. Conversion to Alcohol 5 and Determination of
Absolute Configuration of 11a
a The reaction was carried out using 1a (1 mmol) and ether (250 equiv).
Enantiomeric excess was determined by HPLC analysis (see the Supporting
Information). b Me2Zn (3 equiv). c Determined by 1H NMR of crude product.
d Me2Zn (6 equiv). e Me2Zn (30 equiv). TsNH2 was obtained in 61% yield.
dimethylzinc.5 A further increase in yield to 92% was
observed when the amount of ether was reduced to 125 equiv
(Table 2, entry 1).18 With the optimized conditions estab-
lished, the scope of the reaction was found to cover a range
of aromatic N-sulfinyl imines subtrates (Table 2). Modest
to high yields with good enantioselectivities of the adducts
were obtained using aromatic N-sulfinyl imines with different
substitition patterns (entries 2 to 5). Having a methyl group
in the ortho-position close to the imine carbon led to longer
reaction time and use of more dimethylzinc and boron
trifluoride etherate (entry 2) relative to having a methyl group
in the para-position (entry 3). The presence of an electron-
withdrawing group in the para-position resulted in the use
of lesser amount of dimethylzinc and shorter reaction time
(entry 4) relative to that of an electron-donating group in
the same position (entry 5). Both polyaromatic and het-
eroaromatic substrates required excess reagents and prolong
reaction time to produce the adducts in moderate yields and
ees (entries 6 and 7).
Hence, the absolute configuration of adduct 11a was
established as (R).
The observed stereoselectivity stems from preferential
attack of the radical from the less sterically hindered si-face
of the imino group of the N-sulfinyl imine (Figure 1).20
Tentatively, the absolute configurations of the other adducts
are assigned as (R) by analogy.
In summary, R-alkoxyalkyl radicals generated from ethers
by dimethylzinc-air, have been stereoselectively added to
enantiomerically pure N-sulfinyl imines. Lewis acid activa-
tion of the N-sulfinyl imine substrates facilitates radical
addition. Studies on the improvement of enantiocontrol,
(19) Both Bro¨nsted acid mediated and oxidative cleavage strategies led
to either decomposition or recovery of starting material along with minimal
product formation.
(20) N-Sulfinyl aldimines preferentially adopt a conformation in which
the oxygen atom and imino group are synperiplanar: (a) Dobrowolski, J.
Cz.; Kawe¸cki, R. J. Mol. Struct. 2005, 734, 235-239. (b) Bharatam, P. V.;
Uppal, P.; Kaur, A.; Kaur, D. J. Chem. Soc., Perkin Trans. 2 2000, 43-50.
(c) Tietze, L. F.; Schuffenhauer, A. Eur. J. Org. Chem. 1998, 1629-1637.
(d) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.; Portonovo,
P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll, P. J. J. Org.
Chem. 1997, 62, 2555-2563.
The utility of the adduct was demonstrated by conversion
of an enantiomerically enriched sample of 11a into known
(18) Adduct 11a was obtained in 73% yield with 73% ee when 60 equiv
of dioxolane 10 was used.
Org. Lett., Vol. 8, No. 25, 2006
5731

Acknowledgment. This research was partially supported
by the 21st Century COE (Center of Excellence) Program
“Knowledge Information Infrastructure for Genome Sci-
ence”, a Grant-in-Aid for Young Scientist (B), and a Grant-
in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations” from the Ministry of Education,
Culture, Sports, Science and Technology, Japan. T.A. thanks
the Japanese Society for the Promotion of Science (JSPS)
for a postdoctoral fellowship.
Figure 1. Rationale of stereochemical outcome.
Supporting Information Available: Experimental details
and characterization of data of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
substrate range, as well as addition of non-oxygenated
carbon-centered radicals will be reported in due course.
OL0621093
5732
Org. Lett., Vol. 8, No. 25, 2006