Fe/Cr- and Co/Cr-mediated catalytic asymmetric 2-haloallylations of aldehydes

Article abstract of DOI:10.1021/ja045557j

The first example to couple aldehydes and 3-bromo-2-halopropenes in a catalytic asymmetric manner is reported. The coupling reaction is effected by the use of a chiral sulfonamide-Cr complex (prepared in situ from 1d, CrBr₃, Fe(III) or from Co(II), Et₃N, and Mn), TMSCl, and 2,6-lutidine. The method reported here is operationally simple and scalable, furnishing 3-halohomoallylic alcohols with a synthetically useful level of enantiomeric excess. Copyright

Full text of DOI:10.1021/ja045557j

Published on Web 09/10/2004
Fe/Cr- and Co/Cr-Mediated Catalytic Asymmetric 2-Haloallylations of
Aldehydes
Michio Kurosu, Mei-Huey Lin, and Yoshito Kishi*
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford Street,
Cambridge, Massachusetts 02138
Received July 23, 2004; E-mail: kishi@chemistry.harvard.edu
Scheme 1
In connection with our efforts to develop a practical synthesis
of the marine natural product halicondrin B and its analogues, we
reported a synthesis of the C14-C26 segment by using Ni/Cr- and
Co/Cr-mediated catalytic asymmetric coupling reactions (Scheme
1).1 We have realized the possibility that the C14-C19 building
block could be obtained through a catalytic asymmetric 2-haloal-
lylation (see the reaction highlighted by a box in Scheme 1). Otera
reported that 2-bromoallylation of aldehydes with 2,3-dibromopro-
pene is effectively achieved by using Sn/HBr.2 However, no method
is known to synthesize 3-halohomoallylic alcohols in a catalytic
asymmetric manner.3 In this communication, we report Fe/Cr- and
Co/Cr-mediated catalytic asymmetric 2-haloallylations of aldehydes.
We reported that sulfonamides such as 1a,b are effective in Ni/
Cr- and Co/Cr-mediated catalytic asymmetric vinylation and
alkylation reactions in a catalytic asymmetric manner.1 To achieve
Cr-mediated asymmetric haloallylation reactions, we first screened
Table 1. Catalytic Asymmetric Allylations of Aldehydesa
the sulfonamide ligands for the coupling of heptanal (3a) with allyl
bromide (2a) under the reaction conditions using (1) a Cr-ligand
complex (10 mol %) generated from a sulfonamide and CrCl3‚3THF
in the presence of Et3N and Mn and (2) TMSCl as a chromium-
alkoxide dissociating reagent.4 Through this screening, it became
evident that a sulfonamide with R3 ) H is far superior to the
corresponding sulfonamide with R3 ) Me (cf, 1c vs 1a). We then
optimized the ligand 1c, from which three excellent sulfonamides
1d-f emerged.5 However, as 1d can be synthesized in two steps
from commercially available inexpensive 2-aminobenzonitrile, we
a All reactions were done with 10 mol% of the catalyst at 0 °C. b Ee of
the products was established by 1H-NMR analysis of its Mosher ester. c The
reaction completed within 12 h.
used 1d for further studies. Interestingly, an addition of 2,6-lutidine
was found to improve asymmetric inductions significantly.6 Under
the optimized conditions, the allylation of 3a with 2a gave the
corresponding homoallylic alcohol 4a in 93% yield with 93%
enantiomeric excess (ee) in the presence of 10 mol % of the catalyst
(Entry 1 in Table 1). It is worthwhile noting that a satisfactory
result was obtained even with 4 mol % of the catalyst (85% yield,
93% ee).7
We then investigated catalytic asymmetric 2-haloallylation.
Disappointingly, under the optimized conditions given in Table 1,
2,3-dibromopropene (5a) did not give the desired products. The
reactivity of 5a against the reducing metals was electronically and
sterically attenuated by the bromine at the â-position. To enhance
the reactivity of the ligand 1d-Cr complex, we attempted to replace
CrCl3 with CrBr3.9 However, due to its extremely poor solubility
in THF, CrBr3 remained unchanged in the presence of 1d, Mn,
and Et3N even at 70 °C. Interestingly, in the presence of iron tris-
(2,2,6,6-tetramethyl-3,5-heptanedione) (Fe(TMHD)3),10 CrBr3 was
reduced to a low-valent Cr species and formed a complex with the
ligand 1d.11 Gratifyingly, 2-bromoallylation of 6a with 5a in the
presence of 10 mol % of the complex (generated from 1d, Fe-
(TMHD)3, CrBr3, Mn, and Et3N (all in THF) and TMSCl and 2,6-
lutidine) afforded, after selective TMS-desilylation, the desired
product 7a in 75% yield with 93% ee (entry 1 in Table 2). Even
with 5 mol % of the catalyst, the 2-bromoallylation smoothly
proceeded to give the desired product in 70% with 92% ee. The
same reaction of a functionalized aldehyde 6b gave an equally
satisfactory result (entry 2). In demonstrating the applicability of
The optimized conditions were then applied to γ,γ-dimethylallyl
bromide (2b) and methallyl bromide (X ) Br in 2c). The rate of
catalytic allylation with γ-substituted allyl bromides was not
noticeably different from that observed for allyl bromide.8 On the
contrary, the rate with â-substituted allyl bromides was significantly
decreased compared to that of allyl bromide. For example, the
catalytic allylation with methallyl bromide under the conditions
developed for 2a proceeded but sluggishly (ca. 30% conversion
after 48 h). However, the coupling reaction was completed within
12 h using methallyl iodide (2c) (entry 4).
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J. AM. CHEM. SOC. 2004, 126, 12248-12249
10.1021/ja045557j CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Asymmetric 2-Haloallylationsa
complex is formed from Fe(III) or Co(II)/CrBr3/1d/Mn/Et3N (vide
ante). A transmetalation between the 1d/Cr(II) complex and the
metalloallyl species should result in the 1d/allyl-Cr(III) complex
which is identical (except for a difference in the allyl vs vinyl) to
the complex suggested for the catalytic Ni/Cr-mediated couplings.1
This complex would then undergo the addition to aldehydes through
a six-centered transition state.16
In conclusion, we have developed a novel Fe/Cr- and Co/Cr-
mediated 2-haloallylation that allows, for the first time, aldehydes
and 2-haloallyl halides to couple in a catalytic asymmetric manner.
The coupling reactions are operationally simple and scalable and
furnish products with a synthetically useful level of enantiomeric
excess. This method will provide direct and economical access to
valuable synthetic intermediates.
a All reactions were done with 10 mol% of the catalyst at 0 °C.
b Fe(TMHD)3 was used. c Co(Pc) was used. d This reaction was done under
the conditions specified in Table 1. e ee of the product was established by
chiral HPLC analysis or by 1H NMR analysis of its Mosher ester. f For
determination of absolute chemistry, see Supporting Information. g Trans
isomer. h The aldehyde was not completely consumed. i 6a ) 3a (in Table
1), 6b ) 3b.
Acknowledgment. We thank the National Institutes of Health
(CA 22215) and Eisai Research Institute for generous financial
support.
Supporting Information Available: Experimental details. This
material is available free of charge via the Internet at http://pubs.acs.org.
Scheme 2. Proposed Mechanism for the Fe/Cr- or Co/
Cr-Mediated Reactions
References
(1) (a) Wan, Z.-K.; Choi, H.-W.; Kang, F.-A.; Nakajima, K.; Demeke, D.;
Kishi, Y. Org. Lett. 2002, 4, 4431. (b) Choi, H.-W.; Nakajima, K.;
Demeke, D.; Kang, F.-A.; Jun, H.-S.; Wan, Z.-K.; Kishi, Y. Org. Lett.
2002, 4, 4435 and references therein.
(2) Mandai, T.; Nokami, J.; Yano, T.; Yoshinaga, Y.; Otera, J. J. Org. Chem.
1984, 49, 172.
(3) For a stoichiometric enantioselective synthesis of bromohomoallylic
alcohols with the chiral borane and 2-bromoallyltributyltin reagents, see:
Corey, E. J.; Yu, C.-M.; Kim, S. S. J. Am. Chem. Soc. 1989, 111, 5495.
(4) (a) Fu¨rstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 2533. (b) Fu¨rstner,
A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349.
(5) The ligands 1e and 1f gave a slightly better asymmetric induction than
1d, but the difference was insignificant.
(6) Other amines including pyridine, 2,6-di-tert-butylpyridine, quinoline, and
acridine were found to be ineffective in improving ee. The exact role of
2,6-lutidine is not clear at this time.
(7) For Cr-mediated catalytic asymmetric allylations, see: (a) Bandini, M.;
Cozzi, P. G.; Melchiorre, P.; Morganti, S,; Umani-Ronchi, A. Org. Lett.
2001, 3, 1153. (b) Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A. Angew.
Chem., Int. Ed. 2000, 39, 2327. (c) Inoue, M.; Suzuki, T.; Nakada, M. J.
Am. Chem. Soc. 2003, 125, 1140.
these reaction conditions for other functionalized aldehydes, we
noticed that 2,6-lutidine not only improves the enatioselectivity (vide
ante) but also acts as an acid scavenger. In the absence of 2,6-
lutidine, 2-bromoallylation of the TBS-protected aldehyde 6c gave
the product accompanied with a significant amount of the diol,
whereas in the presence of 2,6-lutidine the 2-bromoallylation
reaction gave the expected product 7c without contamination of
the TBS-deprotected byproduct (entry 3). The applicability of these
reactions was tested for several additional types of aldehydes. As
summarized in Table 2, saturated and R-branched aldehydes gave
90% or better ee’s (entries 1-5). However, R,â-unsaturated and
aromatic aldehydes gave slightly lower ee (83-87%) (entries 6-8).
We then applied the conditions developed for 2-bromoallylation
to 2-iodoallylation and were pleased to observe that 2-iodo-3-
bromopropene (5b) gave the expected product with good enantio-
selectivity (entry 9). However, its chemical yield was only modest.12
We wished to improve its overall efficiency. In this regard, we
noticed that an active chromium-bromide complex can be formed
via cobalt phthalocyanine (CoPc) and that the Co/Cr-mediated
system enhanced the reaction rate.13 Gratifyingly, the Co/Cr-
mediated reaction was very effective in the 2-iodoallylation of 6b
with 5b (entry 10). On the contrary, 2-chloroallylation is best
achieved with 2-chloro-3-bromopropene (5c) under the CrCl3‚3THF
conditions given in Table 1 (entry 12).
(8) Catalytic allylation completed within 12 h with crotyl bromide, prenyl
bromide (entry 3 in Table 1), and 1,3-dibromopropene.
(9) We expected that CrBr3 would exhibit higher reduction potential than
CrCl3. For a similar concept for Ti species, see: Mukaiyama, T.;
Kagayama, A.; Igarashi, K. Chem. Lett. 2000, 336. In addition, we
expected that CrBr3 and CrCl3 might behave differently due to the
difference in their Lewis acidity.
(10) Fe(DBM)3 was also found to be equally effective.
(11) The progress of the complex formation could be monitored by a change
of solution color that turned into dark green.
(12) The iodoallylation reactions between 6b and 5b (2.5 equiv) under the
conditions of Otera2 gave the expected product but in poor yield (∼10%).
(13) Co/Cr-Mediated 2-bromoallylation of 6b was significantly faster than the
corresponding Fe/Cr-mediated 2-bromoallylation with a lower ee (89%).
(14) (a) Tamura, M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93, 1487. (b) Kochi,
J. K. Pure Appl. Chem. 1980, 52, 571 and references therein, (c) Takai,
K.; Nitta, K.; Fujimura, O.; Utimoto, K. J. Org. Chem. 1989, 54, 4732.
(15) The Fe/Cr mediated iodoallylation of 6b with 5d affored a 1:2.6 mixture
of 7j and 7k, thereby indicating that a metallotropic rearragement takes
place. However, the observed product ratio may suggest that this metallo
allyl species is not completely symmetrized before the C-C bond-
formation. Because Cr-mediated allylation reactions are known to go
through a six-membered cyclic transition state,16 this observation may
suggest that Fe facilitates the oxidative addition of 5d.
Mechanistically, the Fe/Cr- and Co/Cr-mediated 2-halo-allyl-
ations might involve sequences of steps depicted in Scheme 2. Both
low-valent Co and Fe species are known to facilitate radical
formation from alkyl halides.13,14 The bromine or iodine at the
â-position appears to play an important role in forming and/or
stabilizing the allyl radical generated in the Fe/Cr/Mn- or Co/Cr/
Mn-multimetallic system.15 On the other hand, the 1d/Cr(II)
(16) (a) Buse, C. T.; Heathcock, C. H. Tetrahedron Lett. 1978, 19, 1685. (b)
Hiyama, T.; Kimura, K.; Nozaki, H. Tetrahedron Lett. 1981, 22, 1037.
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