Memory of axial chirality in aryl radical phosphanylations

Article abstract of DOI:10.1021/ja105070k

The rate constant for phosphanylation of an aryl radical with trimethylstannyl diphenylphosphane (Me₃SnPPh₂) has been measured as k_phos ≈ 9 × 10⁸ M^-1 s ^-1. Aryl radicals derived from several axially chiral o-haloanilides are trapped by Me₃SnPPh₂ with complete retention of axial chirality as shown by oxidation of the phosphanes to give stable, easily analyzed phosphane oxides or sulfides. Double phosphanylations of o,o′-dihaloanilides followed by treatment with H₂O₂ or S₈ in either order give enantiomers of a mixed diphosphane oxide sulfide. Chemodivergent trapping of diastereomers of an N-(cyclohex-2-enyl) anilide anilide is observed. For one isomer, the cyclization precedes the Me₃SnPPh₂ trapping, while for the other isomer direct trapping with Me₃SnPPh₂ supersedes the cyclization. The products are chiral triaryl phosphanes, oxides, and sulfides that are potentially interesting ligands in asymmetric catalysis.

Full text of DOI:10.1021/ja105070k

Published on Web 07/28/2010
Memory of Axial Chirality in Aryl Radical Phosphanylations
Achim Bruch,† Andrea Ambrosius,† Roland Fro¨hlich,† Armido Studer,*,† David B. Guthrie,‡
Hanmo Zhang,‡ and Dennis P. Curran*,‡
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-UniVersita¨t, Corrensstrasse 40, 48149 Mu¨nster, Germany and
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
Received June 17, 2010; E-mail: studer@uni-muenster.de; curran@pitt.edu
to centrochiral compounds 2 with high fidelity (Figure 2).5-7 This
success shows that cyclization of the intermediate aryl radicals
occurs faster than racemization by rotation around the N-Ar bond.
Clearly, stereospecific intermolecular trapping of axially chiral aryl
radicals as outlined in Figure 1 requires an extremely fast
bimolecular reaction.
Abstract: The rate constant for phosphanylation of an aryl radical
with trimethylstannyl diphenylphosphane (Me3SnPPh2) has been
measured as kphos ≈ 9 × 108 M-1 s-1. Aryl radicals derived from
several axially chiral o-haloanilides are trapped by Me3SnPPh2
with complete retention of axial chirality as shown by oxidation
of the phosphanes to give stable, easily analyzed phosphane
oxides or sulfides. Double phosphanylations of o,o′-dihaloanilides
followed by treatment with H2O2 or S8 in either order give
enantiomers of a mixed diphosphane oxide sulfide. Chemodiver-
gent trapping of diastereomers of an N-(cyclohex-2-enyl)anilide
anilide is observed. For one isomer, the cyclization precedes the
Me3SnPPh2 trapping, while for the other isomer direct trapping
with Me3SnPPh2 supersedes the cyclization. The products are
Figure 2. Axial chirality to centrochirality transfer in aryl radical
cyclizations.
chiral triaryl phosphanes, oxides, and sulfides that are potentially
interesting ligands in asymmetric catalysis.
Radical phosphanylations of aryl halides 3 with trimethylstannyl
diphenylphosphane produce phosphanes 4 in high yields (eq 1).7,8
DFT calculations show that the rate-limiting addition of Me3SnPPh2
Memory of chirality has been observed for various types of
reactions.1 Radical reactions are fast and are therefore prime
candidates for this kind of chirality transfer, yet examples are rare.
Ring strain2 and conformational effects3 have been elegantly used
to transfer chirality from a radical or diradical precursor to the
corresponding product starting with centrosymmetric C-radicals
(Figure 1, top). However, chirality transfer from axially chiral
radicals to axially chiral products has not been reported (Figure 1,
bottom). Central to the challenge is that the intermediate axially
chiral radical must have a significantly lower rotation barrier than
both the precursor and the product.
to a phenyl radical has a high negative reaction enthalpy (∆Eadd
)
-28.2 kcal mol-1). We therefore envisioned that radical phospha-
nylation might be suited for stereospecific trapping of axially chiral
aryl radicals.
We first measured the rate constant for phosphanylation of an
aryl radical by competition kinetics9 with Bu3SnH reduction as the
“clocked” competition process.10 o-Iodoanisole (3, R ) o-OMe,
X ) I) was treated with Bu3SnH (1.0 equiv), Me3SnPPh2 (1.0
equiv), and initiator V-40 in benzene at 80 °C to give a mixture of
anisole and o-anisyldiphenylphosphane (4, R ) o-OMe). From the
product ratio and the known rate constant for reduction of an aryl
radical by Bu3SnH (kred ) 1.2 × 109 M-1 s-1),10 kphos for
phosphanylation was calculated to be 9.4 × 108 M-1 s-1. This large
rate constant encouraged us to study stereospecific trapping of
axially chiral aryl radicals with stannylated phosphines.
Aryl iodides 5a,b were readily prepared as described in the
Supporting Information (SI). They were resolved by preparative
HPLC and were configurationally stable even at 80 °C. To our
delight, treatment of 5a (er ) 96:4) with Me3SnPPh2 (3 equiv) and
AIBN at 75 °C followed by oxidation with H2O2 afforded the
phosphine oxide 6a in 65% isolated yield with perfect memory of
chirality (er ) 96:4, eq 2). The absolute configuration of the
precursor 5a was assigned by X-ray analysis, and the product
configuration follows because the reaction must occur with reten-
tion. In contrast, AIBN-initiated phosphanylation of enantiopure
anilide 5b under the same conditions furnished after S8 oxidation11
Figure 1. Memory of chirality in radical reactions.
Chiral information in axially chiral aryl radicals derived from
iodoanilides of type 14 can be relayed via fast radical cyclizations
† Westfa¨lische Wilhelms-Universita¨t.
‡ University of Pittsburgh.
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C O M M U N I C A T I O N S
Scheme 2. Chemodivergent Phosphanylations
thiophosphine oxide 6b in 60% yield with an enantiomeric ratio of
only 77:23.12 However, phosphanylation at 40 °C by using di-tert-
butyl hyponitrite (DTBH) as an initiator afforded 6b in a 77% yield
with high memory of chirality (98/2).13
To document the power of the method, we focused on sequential
double phosphanylations of axially chiral ortho,ortho′-bishaloanilide
7 (Scheme 1). Selective substitution of iodine and subsequent H2O2
oxidation afforded 8a in 78% yield. Renewed radical phosphany-
lation and S8 treatment provided 9 in a good yield. By reversing
the order of the oxidation processes (S8 oxidation prior to peroxide
treatment) 9 was accessible via 8b, presumably in a stereodivergent
way. Compounds like 9 are potential ligands with soft and hard
Lewis basic coordination sites.
These reactions were performed with racemic 7, which proved
difficult to resolve. However, highly enantiomerically enriched
amide 10 (98:2) was prepared and reacted via 11 to amide 12, which
was isolated with high er (97:3). This proves that excellent memory
of chirality can be achieved in both transformations.
To test that hypothesis, we prepared the readily separable
diastereomeric ortho-iodoanilides 13a and 13b (see SI). Iodide
13a was reacted with Me3SnPPh2 under radical conditions to
provide after oxidation tricycle 14 as the only detectable isomer
in 70% overall yield (Scheme 2). No product of direct phos-
phanylation was detected. Pleasingly, diastereoisomer 13b
underwent aryl radical phosphanylation to give after oxidation
15 in 70% yield. None of the 5-exo-cyclization product was
obtained.14 Under these conditions, phosphanylation is much
slower than cyclization of the radical derived from 13a but much
faster than cyclization of the radical from 13b. All of these
processes are faster than the N-Ar bond rotation that would
interconvert the aryl radicals.
Scheme 1. Double Phosphanylationsa
In conclusion, we show the first examples of stereospecific
intermolecular trapping of axially chiral aryl radicals. The chiral
triarylphosphane products and their derived oxides and sulfides are
potentially interesting ligands in asymmetric catalysis.
Acknowledgment. We thank the Deutsche Forschungsgemein-
schaft (DFG) and the U.S. National Science Foundation (NSF) for
funding. We dedicate this paper to Prof. Bernd Giese on the
occasion of his 70th birthday.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) (a) Fuji, K.; Kawabata, T. Chem.sEur. J. 1998, 4, 373–376. (b) Zhao, H.;
Hsu, D. C.; Carlier, P. R. Synthesis 2005, 1–16.
(2) (a) Buckmelter, A. J.; Powers, J. P.; Rychnovsky, S. D. J. Am. Chem. Soc.
1998, 120, 5589–5590. (b) Buckmelter, A. J.; Kim, A. I.; Rychnosky, S. D.
J. Am. Chem. Soc. 2000, 122, 9386–9390. (c) Rychnovsky, S. D.; Hata,
T.; Kim, A. I.; Buckmelter, A. J. Org. Lett. 2001, 3, 807–810. (d) Dalgard,
J. E.; Rychnovsky, S. D. Org. Lett. 2004, 6, 2713–2716.
(3) (a) Giese, B.; Wettstein, P.; Sta¨helin, C.; Barbosa, F.; Neuburger, M.;
Zehnder, M.; Wessig, P. Angew. Chem., Int. Ed. 1999, 38, 2586–2587. (b)
Seiler, M.; Schumacher, A.; Lindemann, U.; Barbosa, F.; Giese, B. Synlett
1999, 1588–1590. (c) Carroll, G. L.; Allan, A. K.; Schwaebe, M. K.; Little,
R. D. Org. Lett. 2000, 2, 2531–2534. (d) Sinicropi, A.; Barbosa, F.; Basosi,
R.; Giese, B.; Olivucci, M. Angew. Chem., Int. Ed. 2005, 44, 2390–2393.
(e) Radical cation reactions: Crich, D.; Brebion, F.; Suk, D.-H. In Topics
in Current Chemistry; Gansa¨uer, A., Ed.; Springer-Verlag: Heidelberg,
2006; Vol. 263, pp 1-38.
a (a) Me3SnPPh2 (1.1 equiv), AIBN (0.3 equiv), 75 °C, 16 h, then H2O2.
(b) Me3SnPPh2 (1.1 equiv), AIBN (0.3 equiv), 75 °C, 16 h, then S8. (c)
Me3SnPPh2 (2.0 equiv), AIBN (0.3 equiv), 75 °C, 24 h, then S8. (d)
Me3SnPPh2 (3.0 equiv), AIBN (0.3 equiv), 75 °C, 24 h, then H2O2. (e)
Me3SnPPh2 (4 equiv), DTBH (0.3 equiv.), 40 °C, 17 h, then H2O2. (f)
Me3SnPPh2 (9 equiv), DTBH (0.3 equiv), 40 °C, 63 h, then S8.
We also pitted this rapid phosphanylation method against a
(4) (a) Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. J. Am. Chem. Soc.
1994, 116, 3131–3132. (b) Curran, D. P.; Liu, W.; Chen, C. H.-T. J. Am.
Chem. Soc. 1999, 121, 11012–11013. (c) Curran, D. P.; Chen, C. H.-T.;
Geib, S. J.; Lapierre, A. J. B. Tetrahedron 2004, 60, 4413–4424.
(5) Petit, M.; Lapierre, A. J. B.; Curran, D. P. J. Am. Chem. Soc. 2005, 127,
14994–14995.
(6) Ionic/organometallic processes: (a) Lapierre, A. J. B.; Geib, S. J.; Curran,
D. P. J. Am. Chem. Soc. 2007, 129, 494–495. (b) Guthrie, D. B.; Curran,
D. P. Org. Lett. 2009, 11, 249–251.
(7) Photochemical reactions: Ayitou, A. J.-L.; Sivaguru, J. J. Am. Chem. Soc.
2009, 131, 5036–5037.
(8) Vaillard, S. E.; Mu¨ck-Lichtenfeld, C.; Grimme, S.; Studer, A. Angew.
Chem., Int. Ed. 2007, 46, 6533–6536.
cyclization. 5-Exo-aryl cyclizations of radicals derived from N-allyl
ortho-iodoanilides occur with rate constants on the order of 109
4c
s-1
.
Hence with appropriate tuning, the radical phosphanylation
and 5-exo cyclization might compete. Highly interesting is the case
where the N-allyl moiety bears an additional stereogenic center
because the 5-exo-radical cyclization of the axially chiral radicals
will occur via two diastereomeric transition states. Phosphanylation
might filter out the higher energy 5-exo pathway resulting in a
chemodivergent process.
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C O M M U N I C A T I O N S
(9) Newcomb, M. In Radicals in Organic Synthesis; Renard, P., Sibi, M., Eds.;
Wiley-VCH: Weinheim, 2001; Vol. 1, pp 317-336.
(10) (a) Chatgilialoglu, C.; Newcomb, M. In AdVances in Organometallic
Chemistry; West, R., Hill, A. F., Eds.; Academic Press: San Diego, 1999;
Vol. 44, pp 67-112. (b) Curran, D. P.; Chen, C. H.-T.; Geib, S. J.; Lapierre,
A. J. B. Tetrahedron 2004, 60, 4413–4424.
(13) The amide C(O)-N bond rotation energy is rather high for compounds 6a
and 6b, and the amide cis-trans isomers could be separated by HPLC; see
also: Ototake, N.; Nakamura, M.; Dobashi, Y.; Fukaya, H.; Kitagawa, O.
Chem.sEur. J. 2009, 15, 5090–5095.
(14) Some dehalogenation of 13b was observed, possibly resulting from
reduction of the intermediate aryl radical with Ph2PH formed by hydrolysis
of the stannylated phosphine. See: Campbell, I. G. M.; Fowles, G. W. A.;
Nixon, L. A. J. Chem. Soc. 1964, 1389–1396.
(11) H2O2 oxidation worked equally well; however, the phosphine oxide could
not be resolved with the HPLC columns tested.
(12) Evidently, the silyl group lowers the rotation barrier in this series, perhaps
by complexation with the amide oxygen. See Keller, A. I. Ph.D. Thesis,
University of Pittsburgh, 2007, Chapter 2.
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