Iron-catalysed cross-coupling of halohydrins with aryl aluminium reagents: A protecting-group-free strategy attaining remarkable rate enhancement and diastereoinduction

Article abstract of DOI:10.1039/c2cc34185a

Non-protected halohydrins are cross-coupled with aryl aluminium reagents to produce aryl alkanols in the presence of the iron-bisphosphine catalysts. Remarkable reaction rate enhancement and diastereoinduction are realized by the in situ generated aluminium alkoxides, offering a new method for the reactivity and selectivity control of the iron-catalysed cross-coupling reaction.

Full text of DOI:10.1039/c2cc34185a

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 9376–9378
www.rsc.org/chemcomm
COMMUNICATION
Iron-catalysed cross-coupling of halohydrins with aryl aluminium
reagents: a protecting-group-free strategy attaining remarkable rate
enhancement and diastereoinductionw
Shintaro Kawamura,ab Tatsuya Kawabata,ab Kentaro Ishizukaa and Masaharu Nakamura*ab
Received 11th June 2012, Accepted 23rd July 2012
DOI: 10.1039/c2cc34185a
Non-protected halohydrins are cross-coupled with aryl aluminium
reagents to produce aryl alkanols in the presence of the iron–
bisphosphine catalysts. Remarkable reaction rate enhancement
and diastereoinduction are realized by the in situ generated alumi-
nium alkoxides, offering a new method for the reactivity and
selectivity control of the iron-catalysed cross-coupling reaction.
Fig. 1 FeCl2(SciOPP) 1 and FeCl2(TMS–SciOPP) 2.
The directing effect of non-protected hydroxyl groups (called
neighbouring group participation when the directing group is
near the reaction centre) is recognised as a classical, yet
powerful chemical tool in organic synthesis for controlling
stereo-, regio-, and chemoselectivities as well as reaction rate.1
This synthetic control may also be expected to be operative in
cutting-edge cross-coupling technology,2 but there have been
very few reports on attempts to actively implement it
in designing such reactions.3 In addition to the paucity
of systematic research efforts, the increasing interest in
protecting-group-free syntheses4 prompted us to investigate
the cross-coupling reactions of protected/non-protected halo-
hydrins to eventually find the novel reactivity of organo-
aluminium reagents for iron-catalysed cross-coupling reactions.
Herein, we report a new cross-coupling reaction of non-
activated alkyl chlorides and aryl aluminium reagents, in
which the free hydroxyl group, or more precisely, in situ
generated aluminium-alkoxide, facilitated the reaction and
enhanced the diastereoselectivity.
In contrast to the previous observations, we found unexpectedly
that the iron-catalysed cross-coupling reaction of a non-
protected chlorohydrin proceeded readily when using aryl alumi-
nate as the nucleophile. It should be noted that primary alkyl
chlorides usually show low reactivity in iron-catalysed cross-
coupling reactions (regardless of the presence of a free hydroxyl
group), and require certain elaborate catalysts.6 Thus, we first
reinvestigated the iron–bisphosphine-catalysed cross-coupling of
various phenyl metal nucleophiles by using 6-chloro-1-hexanol 3
as a model substrate, in order to confirm the unexpected unique
reactivity of aryl aluminates (Scheme 1 and Table 1).
As shown in entry 1, PhMgBr (5a)5b,c,7 gave the desired
cross-coupling product 4a in only 4% yield, along with the
formation of 5-hexen-1-ol and 1-hexanol in ca. 30% combined
yield. The reaction with diphenylzinc, Ph2Znꢀ2MgCl2 (5b),8
was sluggish, giving 4a in 6% yield (entry 2). Triphenylzincate
(Ph3ZnꢀMgBr, 5c)8 gave the product in a higher yield than the
neutral diphenylzinc; however, the yield and selectivity of the
reaction were both low (entry 3). When diphenylborate
(Ph2B(pin)Li, 5d)5a was used, no desired product was obtained
(entry 4). While neutral phenyl aluminium (Ph3Alꢀ3MgCl2,
5e)9 resulted in almost complete recovery of halohydrin 3a, the
reaction with phenyl aluminate (Ph4AlꢀMgCl, 5f)9 proceeded
smoothly and selectively to give the desired 4a in 91% yield
We have reported previously that the cross-coupling reac-
tions of alkyl halides with various organometallic reagents
proceed efficiently in the presence of the iron–bisphosphine
catalysts (FeCl2–SciOPPs, Fig. 1).5za However, we did not
observe sufficient reactivity of the catalyst when a free hydro-
xyl group was present in the coupling substrates or when a free
alcohol substrate was added to the reaction mixture. We
assumed that catalyst poisoning resulted from the formation
of inert iron-alkoxide species.5a
b,c
(entries 5 and 6).z We suspected that the efficient reaction
might be explained by the formation of a heteroleptic alumi-
nate species (e.g. Ph3AlORꢀMgCl), which generates an anionic
iron (ferrate) or Fe–Al mixed cluster species that exhibits
the unprecedented reactivity (see mechanistic discussion).10
a International Research Center for Elements Science (IRCELS),
Institute for Chemical Research, Kyoto University, Uji,
Kyoto 611-0011, Japan. E-mail: masaharu@scl.kyoto-u.ac.jp;
Fax: +81-774-38-3186; Tel: +81-774-38-3180
b Department of Hydrocarbon Chemistry, Graduate School of
Engineering, Kyoto University, Uji, Kyoto 611-0011, Japan
w Electronic supplementary information (ESI) available: Additional
data, experimental procedure, and data for new compounds. See DOI:
10.1039/c2cc34185a
Scheme 1 Iron-catalysed cross-coupling reaction of protected or
non-protected halohydrins with various phenyl metal reagents.
c
9376 Chem. Commun., 2012, 48, 9376–9378
This journal is The Royal Society of Chemistry 2012

View Online
Table 1 Reactivity differences between various phenyl metal reagents
and effect of protection of hydroxyl group on the reactivity
Finally, intermediate A is regenerated by transmetalation between
intermediate C and the aryl aluminate.
We next focused on the stereoinduction by the hydroxyl
Yieldb (%)
group in the electrophilic coupling partner. Gonzalez-Bobes–
´
Entrya Halide PhnM (equiv.) 4a or 4bc Alkene Alkane RSM (%)b
Fu3a and Yorimitsu–Oshima3b reported the catalytic diastereo-
selective cross-coupling reactions of protected cyclic 2-halohydrins
using nickel and cobalt catalysts, respectively. In addition,
Knochel et al. recently reported the iron-mediated diastereo-
selective cross-coupling reaction of tert-butyldimethylsilyl-
protected cyclic 2-iodohydrins.3c A protected hydroxyl group
near the reaction centre is thus known to induce diastereo-
selectivity in Ni- and Co-catalysed as well as Fe-mediated cross-
coupling reactions. However, it was unknown whether a
non-protected hydroxyl group, i.e., a metal alkoxide generated
in situ, could give rise to such stereoinduction.
1
2
3a
3a
3a
3a
3a
3a
3b
5a (2.0)
5b (1.0)
5c (1.0)
5d (1.0)
5e (1.0)
5f (1.0)
5f (1.0)
4
6
13
0
0
91
20
12
0
23
9
0
6
17
0
20
0
0
0
20
63
89
30
91
>99
0
52
3
4d
5
6e
7
1
a
b
Reactions were carried out at 80 1C for 12 h. The yields were
determined by 1H NMR analysis and confirmed by GLC analysis.
c
The cross-coupling products 4a and 4b were obtained in entries 1–6
d
and 7, respectively. 20 mol% MgBr2 was added as a co-catalyst.
e
The reaction of phenyl aluminate prepared by transmetalation from
AlCl3 and PhMgBr gave the same result as that prepared from
PhMgCl.
We first compared the diastereoselectivities of the reactions
of non-protected and acetyl-protected trans-4-chlorocyclohexanols
with phenyl aluminate 5f (Table 2, entries 1 and 2). While the
reaction of the protected halohydrin afforded an almost 1 : 1
mixture of diastereomers, that of the non-protected substrate
produced the trans-isomer in 94% yield with high diastereo-
selectivity (93/7). Although the bulkiness of the silyl protecting
groups may have affected the diastereoselectivity slightly,
The reaction of the protected chlorohydrin 3b with phenyl
aluminate, thus, gave a 1 : 1 mixture of the coupling product
and the alkane by-product in only 40% combined yield (entry 7),
and the results of the reactions using the other phenyl metal
reagents were almost the same as those reported previously.6zd
For the further study of the influence of alkoxide in the
reaction, 1-hexanol was added to the iron-catalysed cross-
coupling reaction of the protected halohydrin 3b with phenyl
aluminate 5f. Although the reactions in the absence of alcohol
gave the cross-coupling product in low yield (Table 1, entry 7),
stoichiometric or even 20 mol% 1-hexanol dramatically
improved the reaction to give the desired product in high yield.
The in situ generated aluminium alkoxide did not cause any
Table 2 Diastereoselective cross-coupling of cyclic halohydrins
Yieldb (%)
(trans/cis)
Entrya Halide
Product
1
2
3
R = H
R = Ac
R =
94 (93/7)
96 (55/45)
96 (70/30)c
t
SiMe2 Bu
e
4
5
6
7
Ar =
4-FC6H4
Ar =
4-MeOC6H4
Ar =
2-MeC6H4
Ar =
2-naphtyl
75 (90/10)
93 (89/11)
85 (93/7)
93 (92/8)
catalyst poisoning, but enhanced the reaction.z This observa-
tion also clearly indicates that the formation of aluminium-
alkoxide species is a key to the observed high catalytic activity.
Fig. 2 shows a plausible catalytic cycle inferred from the
above-mentioned results and previous reports published by us
and others. In the initial step, the precatalyst complex
FeCl2(TMS–SciOPP) is transformed into intermediate A through
8
9
Ar =
4-biphenyl
Ar = mesityl 16 (100/0)
94 (93/7)
f
transmetalation with an aryl aluminate (Ar3AlORꢀMgX).z The
intermediate A, which is reminiscent of the bis(m-oxo)phenyl-
aluminium–phenyltitanium complex11 and iron chloride–
aluminium-tert-butoxide complexes,12 is proposed here as a
catalytically active species because of its expected high reac-
tivity towards non-activated alkyl chlorides.6,13 Subsequently,
homolytic cleavage of the C–Cl bond proceeds to give an alkyl
10
91 (92/8)c
11
12
R = H
R = Ac
83 (25/75)
88 (40/60)
g
radical and the ferrate intermediate B.z This is followed by
the recombination of the resulting elusive alkyl radical with
the aryl group on intermediate B, which occurs in a solvent
cage to give the cross-coupling product and intermediate C.6
13
14
R = H
R = Ac
67 (90/10)
20 (69/31)c
15
39 (85/15)c
91 (92/8)c
16
a
Reactions were carried out at 80 1C for 12 h on 0.5 mmol scale.
Isolated yield. The diastereoselectivity of the product was deter-
b
mined by 1H NMR and confirmed by GLC analysis. The yields were
1
determined by H NMR analysis.
c
Fig. 2 Plausible catalytic cycle.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9376–9378 9377

View Online
h
high-level diastereoinduction was not observedz (entry 3).
and the use of functionalized aryl aluminum reagents are currently
underway. (j) The starting material was recovered (ca. 80%).
Various aryl aluminates possessing electron-rich, electron-
deficient, and sterically demanding aromatic groups could
participate in the reaction, and gave the product with high
1 For selected papers on neighbouring group participation, see:
(a) S. Hiraoka, S. Harada and A. Nishida, Tetrahedron Lett.,
2011, 52, 3079; (b) W. Adam, N. Bottke, O. Krebs, I. Lykakis,
M. Orfanopoulos and M. Stratakis, J. Am. Chem. Soc., 2002,
124, 14403.
2 (a) T. Kauffmann, Synthesis, 1995, 745; (b) T. Kauffmann, Angew.
Chem., Int. Ed. Engl., 1996, 35, 386.
´
3 Stereocontrol by electrophile: (a) F. Gonzalez-Bobes and G. C. Fu,
J. Am. Chem. Soc., 2006, 128, 5360; (b) H. Ohmiya, H. Yorimitsu
and K. Oshima, J. Am. Chem. Soc., 2006, 128, 1886;
(c) A. K. Steib, T. Thaler, K. Komeyama, P. Mayer and
P. Knochel, Angew. Chem., Int. Ed., 2011, 50, 3303;
(d) H. Ohmiya, H. Yorimitsu and K. Oshima, Org. Lett., 2006,
8, 3093. Stereocontrol by nucleophile: (e) T. Thaler, B. Haag,
A. Gavryushin, K. Schober, E. Hartmann, R. M. Gschwind,
H. Zipse, P. Mayer and P. Knochel, Nat. Chem., 2010, 2, 125;
(f) T. Thaler, L.-N. Guo, P. Mayer and P. Knochel, Angew. Chem.,
Int. Ed., 2011, 50, 2174. Nitrogen-functionality-assisted enantio-
selective cross-coupling reactions were recently developed by Fu
et al. ; (g) Z. Lu, A. Wilsily and G. C. Fu, J. Am. Chem. Soc., 2011,
133, 8154; (h) A. Wilsily, F. Tramutola, N. A. Owston and
G. C. Fu, J. Am. Chem. Soc., 2012, 134, 5794.
i
diastereoselectivities (entries 4–8).z The reaction of mesityl
aluminate gave the desired product with excellent diastereo-
j
selectivity, albeit in low yield,z showing that the steric demand
of the nucleophile also contributes to the high diastereo-
selectivity (entry 9). The reaction of cis-4-chlorocyclohexanol
also gave the trans-isomer of the cross-coupling product, as in
the case of trans-4-chlorocyclohexanol, suggesting that the
stereochemistry at the newly formed C–C bond is controlled
by that of the in situ generated alkoxide moiety in the radical
recombination step (entry 10). With cis-3-chlorocyclohexanol,
the cis-isomer was obtained as the major product (entries 11
and 12). Acetylated trans-2-chlorocyclopentanol gave the desired
product in low yield with low diastereoselectivity, whereas trans-
2-chlorocyclopentanol gave the product in good yield with high
diastereoselectivity (entries 13 and 14). With trans-2-chlorocyclo-
hexanol, the product was obtained with high diastereoselectivity,
but in low yield because of the side reaction that gave cyclo-
pentyl-(phenyl)methanol (entry 15).14 trans-4-Bromocyclohexanol
gave essentially the same result as that of the corresponding
chloride (entry 16). Because high diastereoselectivities have been
observed when a bulky substituent, such as tert-butyl7e or
siloxyl3a,c groups, is in the cyclic alkyl halide substrates, we
consider that the observed diastereoselective induction is caused
by the bulkiness of aluminium alkoxide: it is likely to exist in the
form of an aluminium alkoxide oligomer, thereby acting as a
sterically demanding substituent.15
4 For selected reviews on protecting-group-free synthesis, see:
(a) R. W. Hoffmann, Synthesis, 2006, 3531; (b) I. S. Young and
P. S. Baran, Nat. Chem., 2009, 1, 193.
5 (a) T. Hatakeyama, T. Hashimoto, Y. Kondo, Y.-i. Fujiwara,
H. Seike, H. Takaya, Y. Tamada, T. Ono and M. Nakamura,
J. Am. Chem. Soc., 2010, 132, 10674; (b) T. Hatakeyama,
Y. Okada, Y. Yoshimoto and M. Nakamura, Angew. Chem., Int.
Ed., 2011, 50, 10973; (c) T. Hatakeyama, Y.-i. Fujiwara, Y. Okada,
T. Itoh, T. Hashimoto, S. Kawamura, K. Ogata, H. Takaya and
M. Nakamura, Chem. Lett., 2011, 1030; (d) T. Hashimoto,
T. Hatakeyama and M. Nakamura, J. Org. Chem., 2012, 77, 1168.
6 S. K. Ghorai, M. Jin, T. Hatakeyama and M. Nakamura, Org.
Lett., 2012, 14, 1066.
7 For selected reviews on iron-catalyzed cross-coupling, see:
(a) C. Bolm, J. Legros, J. Le Paih and L. Zani, Chem. Rev.,
2004, 104, 6217; (b) A. Furstner and R. Martin, Chem. Lett.,
¨
2005, 624; (c) B. D. Sherry and A. Furstner, Acc. Chem. Res., 2008,
¨
In summary, we have demonstrated the unique iron-
catalysed cross-coupling reaction between halohydrins and
aryl aluminates.
41, 1500; (d) W. M. Czaplik, M. Mayer, J. Cvengros and A. J. von
Wangelin, ChemSusChem, 2009, 2, 396. For selected papers, see:
(e) M. Nakamura, K. Matsuo, S. Ito and E. Nakamura, J. Am.
Chem. Soc., 2004, 126, 3686; (f) T. Nagano and T. Hayashi, Org.
The aluminium alkoxide generated in situ through deproto-
nation of the hydroxyl group of halohydrin by aryl aluminate
did not cause the expected catalyst poisoning; instead, in
contrast to the initial expectation, the reaction rate was
enhanced, and high-level diastereoselectivity was induced, thus
providing a first illustration of the synthetic potential of this
protective-group-free strategy in catalytic cross-coupling
reactions.
Lett., 2004, 6, 1297; (g) R. Martin and A. Furstner, Angew. Chem.,
¨
¨
Int. Ed., 2004, 43, 3955; (h) A. Furstner, R. Martin, H. Krause,
G. Seidel, R. Goddard and C. W. Lehmann, J. Am. Chem. Soc.,
2008, 130, 8773.
8 For selected papers on the reaction of arylzinc reagents, see:
(a) M. Nakamura, S. Ito, K. Matsuo and E. Nakamura, Synlett,
2005, 1794; (b) R. B. Bedford, M. Huwe and M. C. Wilkinson,
Chem. Commun., 2009, 600; (c) T. Hatakeyama, Y. Kondo,
Y.-i. Fujiwara, H. Takaya, S. Ito, E. Nakamura and
M. Nakamura, Chem. Commun., 2009, 1216; (d) X. Lin,
F. Zheng and F.-L. Qing, Organometallics, 2012, 31, 1578.
9 S. Kawamura, K. Ishizuka, H. Takaya and M. Nakamura, Chem.
Commun., 2010, 46, 6054.
A grant from the Japan Society for the Promotion of
Science (JSPS) through the ‘Funding Program for Next
Generation World-Leading Researchers (NEXT Program)’,
initiated by the Council for Science and Technology Policy
(CRTP), is gratefully acknowledged.
10 T. L. Cottrell, The Strengths of Chemical Bonds, Butterworth,
London, 2nd edn, 1958.
Notes and references
11 K.-H. Wu and H.-M. Gau, J. Am. Chem. Soc., 2006, 128, 14808.
12 R. Gupta, A. Singh and R. C. Mehrotra, Indian J. Chem., Sect. A:
Inorg., Bio-inorg., Phys., Theor. Anal. Chem., 1993, 32, 310.
13 A ferrate species is proposed as the active species because of its
higher reducing potential compared to neutral species:
M. Uchiyama, Y. Matsumoto, S. Nakamura, T. Ohwada,
N. Kobayashi, N. Yamashita, A. Matsumiya and T. Sakamoto,
J. Am. Chem. Soc., 2004, 126, 8755.
14 (a) M. P. Bedos, C. R. Hebd. Seances Acad. Sci., 1929, 189, 255;
(b) S. M. Naqvi, J. P. Horwitz and R. Filler, J. Am. Chem. Soc.,
1957, 79, 6283.
15 (a) E. J. Campbell, H. Zhou and S. T. Nguyen, Org. Lett., 2001,
3, 2391; (b) J. H. Rogers, A. W. Apblett, W. M. Cleaver, A. N. Tyler
and A. R. Barron, J. Chem. Soc., Dalton Trans., 1992, 3179.
z (a) SciOPP is the abbreviation for Spin-Control-Intended Ortho-
Phenylene bisPhosphine. (b) We interpreted that the reactivity differ-
ence between 5f and 5e is derived from whether or not the reactive
ferrate species A in Fig. 2 is formed with the organoaluminate species.
(c) A study to find effective dummy ligands on aryl aluminate is
ongoing, see ESI.w (d) The result of the reaction of phenyl metal
reagents is shown in ESI.w (e) See details in ESI.w (f) Neutral
FeAr2–SciOPPs, which are the reactive species in the cross-coupling
of alkyl halides previously reported by us (ref. 5), showed poor
reactivities toward primary alkyl chlorides. (g) Radical clock experi-
ments are described in ESI.w (h) The aluminum alkoxide did not
improve the diastereoselectivity as shown in ESI.w (i) Further studies
to reduce the amounts of aryl ligands by screening of dummy ligands
c
9378 Chem. Commun., 2012, 48, 9376–9378
This journal is The Royal Society of Chemistry 2012