Nozaki-Hiyama-Kishi reactions catalytic in chromium

Article abstract of DOI:10.1021/ja9625236

A procedure is described which allows for the first time to perform chromium-catalyzed additions of organic halides to aldehydes ("Nozaki-Hiyama-Kishi reactions"). The reactions are mediated by trimethylchlorosilane, and the active Cr²⁺ species is constantly recycled by means of nontoxic, commercial manganese powder as the stoichiometric reductant. This method nicely applies to different substituted aryl, heteroaryl, alkynyl, alkenyl, and allyl halides as well as to alkenyl inflates as the starting materials and rivals its stoichiometric precedent in terms of efficiency, practicability, and chemo- and diastereoselectivity. Specifically, it has been demonstrated that the addition of crotyl bromide to various aldehydes is highly stereoconvergent, i.e. the respective anti-configurated homoallyl alcohols are obtained with excellent diastereomeric excess independent of whether the starting halide is (E)- or (Z)-configurated. In accordance with the likely catalytic cycle, both CrCl₂(cat.) or CrCl₃(cat) turned out to efficiently mediate reactions of this type, with the latter being preferred for practical reasons. Finally, attempts were made to optimize the number of turnovers in chromium. In this context the use of either chromocene (Cp₂Cr) or CpCrCl₂·THF as "pre-catalysts" were found to significantly upgrade the efficiency of such C-C bond formations, with ≤ 1 mol % of chromium being required in these cases for quantitative conversions.

Full text of DOI:10.1021/ja9625236

J. Am. Chem. Soc. 1996, 118, 12349-12357
12349
Nozaki-Hiyama-Kishi Reactions Catalytic in Chromium
Alois Fu1rstner* and Nongyuan Shi
Contribution from the Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1,
D-45470 Mu¨lheim/Ruhr, Germany
ReceiVed July 22, 1996X
Abstract: A procedure is described which allows for the first time to perform chromium-catalyzed additions of
organic halides to aldehydes (“Nozaki-Hiyama-Kishi reactions”). The reactions are mediated by trimethylchlo-
rosilane, and the active Cr2+ species is constantly recycled by means of nontoxic, commercial manganese powder as
the stoichiometric reductant. This method nicely applies to different substituted aryl, heteroaryl, alkynyl, alkenyl,
and allyl halides as well as to alkenyl triflates as the starting materials and rivals its stoichiometric precedent in
terms of efficiency, practicability, and chemo- and diastereoselectivity. Specifically, it has been demonstrated that
the addition of crotyl bromide to various aldehydes is highly stereoconvergent, i.e. the respective anti-configurated
homoallyl alcohols are obtained with excellent diastereomeric excess independent of whether the starting halide is
(E)- or (Z)-configurated. In accordance with the likely catalytic cycle, both CrCl2(cat.) or CrCl3(cat) turned out to
efficiently mediate reactions of this type, with the latter being preferred for practical reasons. Finally, attempts were
made to optimize the number of turnovers in chromium. In this context the use of either chromocene (Cp2Cr) or
CpCrCl2‚THF as “pre-catalysts” were found to significantly upgrade the efficiency of such C-C bond formations,
with e1 mol % of chromium being required in these cases for quantitative conversions.
Introduction
Scheme 1
Since the late 1970s, Nozaki, Hiyama, and co-workers have
pioneered the use of organochromium reagents in organic
synthesis. In a series of seminal papers they have demonstrated
that the addition of organic halides to carbonyl compounds in
a “one-pot” Barbier-type fashion is efficiently and conveniently
mediated by anhydrous CrCl2, which either can be purchased
or may be prepared from CrCl3 and different reducing agents
(Scheme 1).1,2 Later on, the independent and almost simulta-
neous discovery made by Kishi and Nozaki that nickel salts
exhibit a catalytic effect on the formation of the C-Cr bond
has greatly improved the reliablity of such transformations.3,4
These findings were far beyond the scope of earlier investiga-
tions on Cr2+ salts as reagents in organic synthesis5 and have
triggered extensive followup work of many other research
groups.
“Nozaki-Hiyama-Kishi reactions” combine some rather
unique features. As far as the electrophile is concerned, they
are highly aldehyde-selective. With regard to the nucleophile,
however, a wide range of substrates including allyl, propargyl,
alkenyl, alkynyl, and aryl halides, alkenyl triflates, and allyl
sulfonates and phosphates were found to be suitable precur-
sors for the formation of organochromium intermediates.1,4,6-10
Most importantly, however, chromium-induced processes
are distinguished by an unparalleled compatibility with an
X Abstract published in AdVance ACS Abstracts, November 1, 1996.
(1) (a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem.
Soc. 1977, 99, 3179-3181. (b) Hiyama, T.; Okude, Y.; Kimura, K.; Nozaki,
H. Bull. Chem. Soc. Jpn. 1982, 55, 561-568. (c) Takai, K.; Kimura, K.;
Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983, 5281-5284.
(d) Hiyama, T.; Kimura, K.; Nozaki, H. Tetrahedron Lett. 1981, 1037-
1040. (e) Takai, K.; Kuroda, T.; Nakatsukasa, S.; Oshima, K.; Nozaki, H.
Tetrahedron Lett. 1985, 5585-5588.
(2) Reviews: (a) Saccomano, N. A. in ComprehensiVe Organic Synthesis;
Trost B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 1, pp 173-
209. (b) Cintas, P. Synthesis 1992, 248-257. (c) Hodgson, D. M. J.
Organomet. Chem. 1994, 476, 1-5. (d) Hashmi, A. S. K. J. Prakt. Chem.
1996, 338, 491-495. (e) Hoppe, D. In Houben-Weyl, Methods of Organic
Chemistry, “StereoselectiVe Synthesis”; Thieme: Stuttgart, 1995; Vol. E
21, pp 1584-1595. (f) Takai, K. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; pp 1266-1270.
(3) (a) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc.
1986, 108, 5644-5646. (b) Kishi, Y. Pure Appl. Chem. 1992, 64, 343-
350.
(6) Stereoselective reactions of crotylchromium species; cf.: (a) Buse,
C. T.; Heathcock, C. H. Tetrahedron Lett. 1978, 1685-1685. (b) Lewis,
M. D.; Kishi, Y. Tetrahedron Lett. 1982, 23, 2343-2346. (c) Mulzer, J.;
Kattner, L.; Strecker, A. R.; Schro¨der, C.; Buschmann, J.; Lehmann, C.;
Luger, P. J. Am. Chem. Soc. 1991, 113, 4218-4229. (d) Ciapetti, P.; Falorni,
M.; Taddei, M. Tetrahedron 1996, 52, 7379-7390. (e) Mulzer, J.; Kattner,
L. Angew. Chem., Int. Ed. Engl. 1990, 29, 679-680. (f) Mulzer, J.; Schulze,
T.; Strecker, A.; Denzer, W. J. Org. Chem. 1988, 53, 4098-4103. (g)
Mulzer, J.; de Lasalle, P.; Freissler, A. Liebigs Ann. Chem. 1986, 1152-
1171. (h) Evans, D. A.; Sjogren, E. B.; Bartroli, J.; Dow, R. L. Tetrahedron
Lett. 1986, 27, 4957-4960.
(7) Propargyl halides and functionalized allylic substrates: (a) Takai,
K.; Kataoka, Y.; Utimoto, K. Tetrahedron Lett. 1989, 30, 4389-4392. (b)
Place, P.; Delbecq, F.; Gore´, J. Tetrahedron Lett. 1978, 3801-3802. (c)
Fujimura, O.; Takai, K.; Utimoto, K. J. Org. Chem. 1990, 55, 1705-1706.
(d) Wender, P. A.; Wisniewski Grissom, J.; Hoffmann, U.; Mah, R.
Tetrahedron Lett. 1990, 31, 6605-6608. (e) Takai, K.; Nitta, K.; Utimoto,
K. Tetrahedron Lett. 1988, 29, 5263-5266. (f) Auge´, J. Tetrahedron Lett.
1988, 29, 6107-6108. (g) Giammaruco, M.; Taddei, M.; Ulivi, P.
Tetrahedron Lett. 1993, 34, 3635-3638. (h) Auvray, P.; Knochel, P.;
Normant, J. F. Tetrahedron Lett. 1986, 27, 5091-5094.
(4) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.;
Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048-6050.
(5) See the following for leading references on previous work on
organochromium chemistry: (a) Sneedon, R. P. A. Organochromium
Compounds; Academic Press: New York, 1975. (b) Hanson, J. R. Synthesis
1974, 1-8. (c) Kochi, J. K.; Davis, D. D. J. Am. Chem. Soc. 1964, 86,
5264-5271. (d) Kochi, J. K.; Mocadlo, P. E. J. Am. Chem. Soc. 1966, 88,
4094-4096. (e) Barton, D. H. R.; Basu, N. K.; Hesse, R. H.; Morehouse,
F. S.; Pechet, M. M. J. Am. Chem. Soc. 1966, 88, 3016-3021 and lit. cited.
(8) (a) Jubert, C.; Nowotny, S.; Kornemann, D.; Antes, I.; Tucker, C.
E.; Knochel, P. J. Org. Chem. 1992, 57, 6384-6386. (b) Knochel, P; Chou,
T. S.; Jubert, C.; Rajagopal, D. J. Org. Chem. 1993, 58, 588-599. (c)
Nowotny, S.; Tucker, C. E.; Jubert, C.; Knochel, P. J. Org. Chem. 1995,
60, 2762-2772.
S0002-7863(96)02523-1 CCC: $12.00 © 1996 American Chemical Society

12350 J. Am. Chem. Soc., Vol. 118, No. 49, 1996
Fu¨rstner and Shi
array of functional groups in both reaction partners. This
striking chemoselectivity is nicely supplemented by some
favorable stereochemical characteristics: specifically, γ-mono-
substituted allylchromium reagents in general lead to the
corresponding homoallyl alcohols with excellent anti selectivity,
independent of whether the starting halide is (E)- or (Z)-
configurated.1d,6 Finally it should be noted that alkenyl halides
or triflates react with complete retention of their double bond
geometry.4
Scheme 2
It is obvious that this unique profile renders Nozaki-
Hiyama-Kishi reactions particularly well suited for applications
to natural product chemistry. In fact, chromium-induced inter-
or intramolecular C-C bond formations are frequently encoun-
tered as key steps in highly impressive total syntheses of target
molecules of utmost complexity.11
Despite of these favorable distinctions, some major drawbacks
must also be taken into account. Cr2+ is a one-electron donor;
therefore, 2 mol of this reagent/mol of halide are required for
the formation of an organochromium nucleophile; in practice a
huge excess must be employed which is usually in the range of
400-1600 mol %, but examples with up to 100 equiv (!) of
Cr2+ have been reported. Since chromium as well as nickel
salts are physiologically highly suspicious, this precludes any
application of such transformations to industrial processes.
Furthermore, the rather high cost of CrCl2 makes large-scale
syntheses less attractive. Finally, a practical way to control the
configuration of the newly formed chiral center(s) will hardly
emerge from appropriate chiral ligands to chromium, if they
must be used in (over)stoichiometric amounts. An efficient
enantioselective version of the Nozaki-Hiyama-Kishi reac-
tionsalthough highly desirablesis still missing.12
We now report a method which allows for the first time, the
Nozaki-Hiyama-Kishi reactions to be performed catalytic in
chromium, without compromising the scope, practicability,
efficiency, and chemo- and diastereoselectivity of such C-C
bond formations.13 As will be outlined below, a multicompo-
nent redox system accounts for this advancement, which may
help to pave the way for further applications of this valuable
synthetic transformation.
Results and Discussion
Screenings and the Likely Catalytic Cycle. In the first step
of a Nozaki reaction the organic halide reacts with 2 CrCl2,
giving rise to the desired organochromium species A and 1 equiv
of CrX3. The nucleophile then adds to the aldehyde with
formation of the chromium alkoxide B. The high stability of
its O-Cr3+ bond serves as the thermodynamic sink which drives
the conversion but obviously impedes catalysis.
We reasoned that it should be possible to run Nozaki reactions
catalytic in chromium if a ligand exchange between B and an
appropriate additive can be achieved (Scheme 2): for instance,
the renitent chromium alkoxide might be forced to react with
an admixed chlorosilane in view of the pronounced oxophilicity
of silicon. Such a σ-bond metathesis would afford the silyl
ether of the desired product (C) and liberate the second mole
of CrX3. Since it is well precedented that Cr3+ salts can be
reduced to Cr2+ by different reducing agents,1,14 a catalytic cycle
might emerge. This oVerall scenario is depicted in Scheme 2.
However, it should be emphasized that this representation does
not imply that each single step exactly follows the rational
outlined above, but it merely serves as a working hypothesis
awaiting further investigations.
In any case the choice of the stoichiometric reducing agent
is decisive. It must be able to efficiently reduce CrX3 but has
to be inert toward the reducible substrates. Moreover, its salts
should be significantly less toxic than those of chromium. Our
previous work on low-valent titanium chemistry has suggested
the use of Zn/TMSCl for such a purpose.15 This particular
reagent combination, however, has been rapidly ruled out mainly
for two reasons: first, it is well-known that Zn is activated by
chlorosilanes:16 as it may then insert on its own into reactive
substrates such as allyl halides, etc., one would leave the desired
chromium path. Secondly and more seriously, the ZnX2 salt
(9) Heterocycle syntheses: (a) Ledoussal, B.; Gorgues, A.; Le Coq, A.
Tetrahedron 1987, 43, 5841-5852. (b) Hodgson, D. M.; Wells, C.
Tetrahedron Lett. 1994, 35, 1601-1604.
(10) R-Substituted alkylchromium reagents: (a) Takai, K.; Nitta, K.;
Fujimura, O.; Utimoto, K. J. Org. Chem. 1989, 54, 4732-4734. (b)
Nakatsukasa, S.; Takai, K.; Utimoto, K. J. Org. Chem. 1986, 51, 5045-
5046. (c) Knecht, M.; Boland, W. Synlett 1993, 837-838. gem-Dichro-
miumalkyl reagents: (d) Takai, K.; Shinomiya, N.; Kaihara, H.; Yoshida,
N.; Moriwake, T.; Utimoto, K. Synlett 1995, 963-964 and literature cited
therein
(11) See the following for leading references: (a) Nicolaou, K. C.;
Theodorakis, E. A.; Rutjes, F. P. J. T.; Tiebes, J.; Sato, M.; Untersteller,
E.; Xiao, X. Y. J. Am. Chem. Soc. 1995, 117, 1171-1172. (b) Kishi, Y.
Chemtracts-Organic Chemistry 1988, 1, 253-265. (c) Aicher, T. D.;
Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Matelich,
M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. J. Am. Chem. Soc. 1992,
114, 3162-3164. (d) Rowley, M.; Tsukamoto, M.; Kishi, Y. J. Am. Chem.
Soc. 1989, 111, 2735-2737. (e) Aicher, T.; Kishi, Y. Tetrahedron Lett.
1987, 3463-3466. (f) Dyer, U. C.; Kishi, Y. J. Org. Chem. 1988, 53,
3383-3384. (g) Kress, M. H.; Ruel, R.; Miller, W. H.; Kishi, Y.
Tetrahedron Lett. 1993, 34, 5999-6002. (h) Schreiber, S. L.; Meyers, H.
V. J. Am. Chem. Soc. 1988, 110, 5198-5200. (i) Chen, S. H.; Horvath, R.
F.; Joglar, J.; Fisher, M. J.; Danishefsky, S. J. J. Org. Chem. 1991, 56,
5834-5845. (j) White, J. D.; Jensen, M. S. J. Am. Chem. Soc. 1995, 117,
6224-6233. (k) Lu, Y. F.; Harwig, C. W., Fallis, A. G. J. Org. Chem.
1993, 58, 4202-4204. (l) Still, C. W.; Mobilio, D. J. Org. Chem. 1983,
48, 4785-4786. (m) Eckhardt, M.; Bru¨ckner, R.; Suffert, J. Tetrahedron
Lett. 1995, 36, 5167-5170. (n) Dancy, I.; Skrydstrup, T.; Cre´visy, C.;
Beau, J.-M. J. Chem. Soc., Chem. Commun. 1995, 799-800. (o) Brand-
stetter, T.; Maier, M. E. Tetrahedron 1994, 50, 1435-1448. (p) Paquette,
L. A.; Astles, P. C. J. Org. Chem. 1993, 58, 165-169. (q) MacMillan, D.
W. C.; Overman, L. E. J. Am. Chem. Soc. 1995, 117, 10391-10392. (r)
Nicolaou, K. C.; Piscopio, A. D.; Bertinato, P.; Chakraborty, T. K.; Minowa,
N.; Koide, K. Chem. Eur. J. 1995, 1, 318-333. (s) Nakata, M.; Ohashi,
J.; Ohsawa, K.; Nishimura, T.; Kinoshita, M.; Tatsuta, K. Bull. Chem. Soc.
Jpn. 1993, 66, 3464-3474. (t) Eckhardt, M.; Bru¨ckner, R. Liebigs Ann.
1996, 473-488. (u) Aoyagi, S.; Wang, T. C.; Kibayashi, C. J. Am. Chem.
Soc. 1993, 115, 11393-11409. (v) Kato, N.; Okamoto, H.; Takeshita, H.
Bull. Chem. Soc. Jpn. 1995, 68, 2679-2685. (w) Roe, M. B.; Whittaker,
M.; Procter, G. Tetrahedron Lett. 1995, 36, 8103-8106. (x) Nishikawa,
T.; Shibuya, S.; Hosokawa, S.; Isobe, M. Synlett 1994, 485-486. (y)
Hatakeyama, S.; Numata, H.; Osanai, K.; Takano, S. J. Org. Chem. 1989,
54, 3515-3517. (z) Paquette, L. A.; Doherty, A. M.; Rayner, C. M. J.
Am. Chem. Soc. 1992, 114, 3910-3926.
(12) For studies toward this goal, see: (a) Chen, C.; Tagami, K.; Kishi,
Y. J. Org. Chem. 1995, 60, 5386-5387. (b) Cazes, B.; Vernie`re, C.; Gore´,
J. Synth. Commun. 1983, 13, 73-79.
(13) For a preliminary communication, see: Fu¨rstner, A.; Shi, N. J. Am.
Chem. Soc. 1996, 118, 2533-2534.
(14) Wuts, P. G. M.; Callen, G. R. Synth. Commun. 1986, 16, 1833-
1837.

Nozaki-Hiyama-Kishi Reactions
J. Am. Chem. Soc., Vol. 118, No. 49, 1996 12351
Table 1. Control Experiments: Cr2+-Mediated Reaction of
Table 2. Control Experiments: Cr2+-Mediated Reaction of Allyl
Iodobenzene with Octanala
Bromide with Octanala
CrCl2
(mol %)
isolated yield
(%)b
isolated
yield
entry
additives
T (°C)
CrCl2
entry (mol %)
1
2
3
400
7
0
rt
rt
rt
81
78
additives
T (°C) 1a (%)b
Mn, TMSCl
Mn, TMSCl
1
2
3
4
5
6
7
8
400
400
30
15
15
9
20 78c
50 65
<19 (GC)c
a All reactions were carried out with undoped CrCl2 in THF; reaction
time 6 h. b Refers to the yield of the unprotected alcohol 2a obtained
after desilylation of the crude product. c After 90 h reaction time.
Zn, TMSCl
Mn, TMSCl
Mn, ClMe2Si(CH2)3CN
Mn, ClMe2Si(CH2)3CN
Mn, ClMe2Si(CH2)3CN
70 30-40d
50 67
50 72
50 58
50
0
0
0e
0e
denote that it is the chromium salt rather than the Mn(0) which
accounts for the results obtained: neither Mn/R3SiCl nor Mn/
R3SiCl/NiCl2(cat) lead to any product formation in the reaction
of iodobenzene and octanal (GC < 3%) (Table 1, entries 7 and
8). The same holds true for the reaction of allyl bromide with
octanal, where only a tiny amount of product is detected in GC
after extended periods of time (90 h) if the reaction is carried
out in the absence of chromium salts (Table 2, entry 3). In
clear contrast, however, a combination of catalytic amounts of
CrCl2, Mn powder, and a chlorosilane rapidly and cleanly
conVerts these substrates into the desired products. They are
isolated after a final aqueous workup (in the presence of
n-Bu4NF for the more stable silyl ethers) which ensures the
desilylation of the crude product mixture. The yields thus
obtained favorably compare to those of the control experiments
employing overstoichiometric amounts of CrCl2.
Mn, ClMe2Si(CH2)3CN, NiCl2(cat.) 50
a The reactions were carried out in DME/DMF (20/3) unless stated
otherwise, using CrCl2 doped with NiCl2 (∼15%). b After desilylation
of the admixed 1b. c In pure DMF. d Formation of 1-[(trimethyl-
silyl)oxy]-1-octene as side reaction; cf. text. e GC yield < 3%.
accumulating during the course of the reaction is sufficiently
Lewis acidic to convert enolizable aldehydes into the corre-
sponding silyl enol ethers in the presence of TMSCl. Because
they cannot react with an intermediate organochromium species
any more, the yield of the desired product will be unacceptably
low. Our experiments have fully confirmed this assumption:
although some turnovers could by reached in the reaction of
iodobenzene with octanal using CrCl2(cat.)/Zn/TMSCl, com-
pound 1a was obtained in rather poor yield (Table 1, entry 3).
Careful GC analysis showed that 1-[(trimethylsilyl)oxy]-1-
octene was in fact the major product.
Gratifyingly, this catalytic procedure applies to all important
kinds of substrates known to undergo Nozaki-Hiyama-Kishi
reactions. The chemo- and diastereoselectivities observed in
these chromium-catalyzed processes perfectly match those
reported for the stoichiometric set-up. The experience gained
during our study is summarized below.
A likely substitute for zinc is manganese. This metal is very
cheap, its salts are essentially nontoxic, the Lewis acidity of
Mn2+ is significantly lower than that of Zn2+, and the
electrochemical data hold the promise that it will form an
effective redox couple with Cr3+ 17
Particular mention should
.
Cr-Catalyzed Reactions of Aryl and Alkenyl Halides and
Triflates. For an efficient conversion these substrates require
∼15 mol % of CrCl2 which must additionally be doped with
NiCl2. The CrCl2 used should be colorless; pale-green batches
result in lower yields. Reasonable reaction rates are achieved
at 50((3) °C. A mixture of DME/DMF (20/3) turned out to
be the best solvent, although pure DMF was found superior in
the stoichiometric process. The DMF used as the cosolvent
must be thoroughly purified in order to ensure reproducible
results; for details see the Experimental Section.
Although very few examples of stoichiometric Nozaki-
Hiyama-Kishi reactions with aryl halides have been reported
so far,1c we find that our catalytic procedure nicely applies to
this group of substrates. As can be seen from the results
compiled in Table 3, iodobenzene reacts readily with aromatic
as well as with different aliphatic aldehydes in the presence of
CrCl2(cat.)/Mn/chlorosilane. Entry 4 shows that the presence
of an alkyl chloride in the electrophile does not intervene at
all. Similarly, the reaction turned out to be compatible with an
be made of the fact that the oxidative insertion of Mn into
organic halides is largely unknown: commercial Mn powder
reacts only with the most reactive substrates under special
conditions.18,19 This low intrinsic reactivity of metallic Mn
toward organic molecules turned out to be the key for success
in the context of the present study.
As can be seen from Tables 1 and 2, commercial Mn in
combination with TMSCl and catalytic amounts of CrCl2
allowed the first Nozaki-Hiyama-Kishi reactions catalytic in
chromium to be performed. The control experiments clearly
(15) The combination of TiCl3(cat.), Zn, and R3SiCl accounts for the
first carbonyl-coupling reactions catalytic in titanium; cf., (a) Fu¨rstner, A.;
Hupperts, A. J. Am. Chem. Soc. 1995, 117, 4468-4475. For related work
on stoichiometric reactions with TiCl3/Zn, see: (b) Fu¨rstner, A.; Hupperts,
A.; Ptock, A.; Janssen, E. J. Org. Chem. 1994, 59, 5215-5229. (c) Fu¨rstner,
A.; Ptock, A.; Weintritt, H.; Goddard, R.; Kru¨ger, C. Angew. Chem., Int.
Ed. Engl. 1995, 34, 678-681. (d) Fu¨rstner, A.; Weintritt, H.; Hupperts, A.
J. Org. Chem. 1995, 60, 6637-6641. (e) Fu¨rstner, A.; Ernst, A. Tetrahedron
1995, 51, 773-786. (f) Fu¨rstner, A.; Ernst, A.; Krause, H.; Ptock, A.
Tetrahedron 1996, 52, 7329-7344. (g) Review: Fu¨rstner, A.; Bogdanovic,
B. Angew. Chem. 1996, 108, 2583.
(16) (a) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390-2392. For a timely review see: (b) Knochel, P. in ActiVe
Metals. Preparation, Characterization, Applications; Fu¨rstner, A.; Ed.;
VCH: Weinheim, 1996; pp 191-236.
(19) However, highly activated Mn powder prepared by reduction of
manganese salts with either lithium naphthalenide (a) or potassium graphite
laminate (b) is capable to insert into different kinds of organic halides; cf.:
(a) Kim, S. H.; Hanson, M. V.; Rieke, R. D. Tetrahedron Lett. 1996, 37,
2197-2200. (b) Fu¨rstner, A.; Brunner, H., Tetrahedron Lett. 1996, 37,
7009-7012. This latter paper demonstrates that the addition of crotyl-
manganese bromide to aldehydes is diastereodivergent and results in much
lower diastereoselectivity as compared to crotylchromium halide additions.
See also: (c) Hiyama, T.; Obayashi, M.; Nakamura, A. Organometallics
1982, 1, 1249-1251.
(17) Electrochemical redox potentials: Cr3+ + e- h Cr2+ (-0.41 V);
Zn2+ + 2e- h Zn (-0.76 V); Mn2+ + 2e- h Mn (-0.3 V); cf.; Handbook
of Chemistry and Physics; 2nd ed.; CRC press: Boca Raton, FL, 1982.
(18) (a) Cahiez, G.; Chavant, P. Y. Tetrahedron Lett. 1989, 30, 7373-
7376. (b) Hiyama, T.; Sawahata, M.; Obayashi, M. Chem. Lett. 1983, 1237-
1238.

12352 J. Am. Chem. Soc., Vol. 118, No. 49, 1996
Fu¨rstner and Shi
Table 3. Chromium-Catalyzed Reactions of Aryl Iodides, Alkenyl Iodides, and Alkenyl Triflates with Different Aldehydesa
a All reactions were carried out with CrCl2 (15 mol %, doped with NiCl2 cat.), Mn powder (4.2 mmol), aldehyde (2.5 mmol), R-X (5 mmol),
chlorosilane (6 mmol) in DMF/DME (20/3) at 50 °C. b Refers to the product obtained after desilylation (aqueous Bu4NF) of the crude mixture.
c Isolated as the O-acetate after acetylation of the crude product. d 4,4′-Bis(ethoxycarbonyl)diphenyl as byproduct (20% based on I-C6H4COOEt).
Scheme 3
ester group in the nucleophile (entry 6) and can be extented to
heteroaromatic compounds such as 2-iodothiophene (entry 5).
Likewise, alkenyl iodides and alkenyl triflates4,20 reacted
smoothly under our standard conditions. However, we noticed
a subtle influence of the electronic properties of the chosen
aldehyde on the reaction path which has not yet been reported
in the literature. While aliphatic aldehydes, benzaldehyde, and
analogues bearing electron-donating substituents such as an
alkoxy or an acetal group behaved properly leading to the
expected allyl alcohols in good to excellent yields (Table 3,
entries 7-11), some deviation from the known reaction path
was observed with methyl 4-formylbenzoate (14) as the substrate
(Scheme 3).
Although the ester function per se is compatible, its electron-
Some screenings have been performed to see if the turnover
withdrawing character obviously facilitates a single-electron
number of the chromium salt may be improved by replacing
transfer from the low-valent metal salt to the aldehyde group
TMSCl by other additives. As can be seen from the data
included in Tables 1 and 3, the use of ClMe2Si(CH2)3CN did
not significantly upgrade the results, although this particular
of 14. As a consequence, the oxidative insertion of Cr2+ into
the alkenyl triflate 13 has to compete with the formation of the
ketyl radical which undergoes a subsequent pinacol coupling
additive had recently turned out superior in the context of oxo
leading to diol 15 as the major product. However, this
(21) Fu¨rstner, A.; Csuk, R.; Rohrer, C.; Weidmann, H. J. Chem. Soc.,
Perkin Trans. 1 1988, 1729-1734 and lit. cit.
(22) There are some scattered reports in the literature on the use of
observation is in line with previous experiences gathered in
reductive carbonyl coupling reactions which proceed particularly
well with electron-poor arylaldehydes as the substrates.21,22
chromium salts in pinacolization reactions; cf.: (a) Davis, D. D.; Bigelow,
W. B. J. Am. Chem. Soc. 1970, 92, 5127-5130. (b) Conant, J. B.; Cutter,
H. B. J. Am. Chem. Soc. 1926, 48, 1016-1030. (c) Sopher, D. W.; Utley,
J. H. P. J. Chem. Soc., Chem. Commun. 1979, 1087-1088.
(20) Takai, K.; Sakogawa, K.; Kataoka, Y.; Oshima, K.; Utimoto, K.
Org. Synth. 1993, 72, 180-188.

Nozaki-Hiyama-Kishi Reactions
J. Am. Chem. Soc., Vol. 118, No. 49, 1996 12353
Scheme 4
Scheme 7
Scheme 5
Scheme 6a
exclusively whereas the admixed ketone remains completely
unchanged (addition to the ketone < 0.3% in GC).
Of even greater significance is the diastereoselectivity
observed in chromium-catalyzed reactions of crotyl bromides
and related systems. As has been mentioned in the introduction,
Nozaki-Hiyama-Kishi reactions of γ-monosubstitued allyl
halides are distinguished by an excellent preference for the
formation of the anti-configurated homoallyl alcohol regardless
of whether the substrate is (E)- or (Z)-configurated (Scheme
7).1,6,24 In contrast to this pattern of γ-monosubstituted allyl
halides, γ,γ-disubstituted donors follow a stereodivergent course
as has been shown in recent work of Knochel et al.8
The stereoselectiVities obserVed in the reaction of a repre-
sentatiVe set of substituted allylic halides under our standard
catalytic conditions are in full accordance with this literature
precedence (Table 4). Specifically, the anti-selectivity observed
in the reaction of (E)-crotyl bromide (E-23) with different
aldehydes was reproducibly >90:10, i.e. in the same order or
even better than the selectivity reported in the literature for the
respective stoichiometric processes. The analogous transforma-
tions with (Z)-crotyl bromide (Z-23) as the substrate again led
to the anti-configurated product in a diastereomeric ratio of dr
) 90:10. This stereoconvergent behavior clearly reflects the
typical characteristics of a crotyl chromium intermediate1,6 and
therefore provides an additional indication that our procedure
is in fact a chromium-catalyzed rather than a manganese-induced
reaction.19b Final support for this assumption stems from an
experiment with geranyl bromide (28, X ) Br) and benzalde-
hyde as the substrates: In full accord with Knochel’s work,8c
this transformation led to the (S*,S*)-configurated compound
29 as the major product rather than the (S*,R*)-diastereoisomer
with a dr ) 94:6 (Table 5).
Reactions Catalyzed by CrCl3. If the reaction owes its
performance to an efficient Cr2+ h Cr3+ redox process as
suggested by Scheme 2 and substantiated by the results outlined
above, it should proceed no matter at which oxidation state the
catalytic process is started. However, keeping the rather high
cost and the air-sensitivity of CrCl2 in mind, it might consider-
ably upgrade the protocol in practical terms if CrCl2 can be
replaced by CrCl3 as a precatalyst.
A series of experiments using crotyl bromide as the starting
material has unequivocally confirmed this possibility. For
comparative reasons the results obtained have been included in
Table 4 (entries 4, 5, and 8). As can be seen from these data,
(i) the reaction path is again diastereoconvergent, i.e. the use
of (E)- and (Z)-crotyl bromide results in the same anti-
configurated homoallyl alcohol, (ii) the diastereoselectivity
perfectly matches that observed in the CrCl2 cases, and finally
(iii) the isolated yields are as high as or even slightly better
than those obtained in the CrCl2-triggered reactions. An addi-
tional example using methyl 7-oxoheptanoate as the electrophile
a Key: (a) (i) CrCl2 (7 mo %), Mn, TMSCl, THF, room temperature;
(ii) H2O.
amide coupling reactions catalytic in low-valent titanium.15
Obviously its nitrile group is too weak a ligand to chromium to
exert any appreciable effect. Similarly, neither the addition of
catalytic amounts of LiI to the reaction mixture nor replacing
TMSCl by TMSBr, (EtO)3SiCl, or ClMe2SiCH2CH2SiMe2Cl
resulted in better turnovers. For a more successful way to
upgrade the efficiency of the catalytic process by variation of
the chromium source rather than the chlorosilane additive see
the final paragraph of this section.
Cr-Catalyzed Reactions of Alkynyl Halides. The two
examples depicted in Scheme 4 substantiate that our standard
catalytic system works properly with alkynyl iodides as
substrates.1e When performed in THF at room temperature,
good yields of the corresponding propargyl alcohols 17 and 18,
respectively, can be obtained after an aqueous workup of the
crude reaction mixture.
Cr-Catalyzed Reactions of Allyl Halides: Chemo- and
Diastereoselectivity. When allyl halides are used as the sub-
strates, ∼7 mol % of undoped CrCl2 turned out to be sufficient
(Table 2). The presence of trace amounts of nickel salts in the
chromium catalyst is detrimental because it seems to bias Wurtz-
type couplings of these substrates. The reactions can be
conveniently carried out at ambient temperature in THF as the
preferred solvent. The use of substituted allyl halides such as
ethyl 2-(bromomethyl)-2-propenoate (19) does not pose any
problems but leads cleanly to the corresponding R-methylene
γ-lactone 20 after an aqueous acidic workup (Scheme 5).23
It is well established that organochromium reagents in general
react much more readily with aldehydes than with ketones.1,2
The new catalytic protocol also features this clearcut chemose-
lectivity (Scheme 6). In fact, excellent results were obtained
in the chromium-catalyzed reaction of allyl bromide with
octanal, whereas 2-octanone (21) affords 68% isolated yield of
the respective alcohol 22 under the same reaction conditions.
However, if a 1:1 mixture of octanal and 2-octanone is used in
order to probe the relative reaction rates, the aldehyde is attacked
(24) For general reviews on reactions of crotylmetal reagents with
carbonyl compounds and for a pertinent discussion on the origins of the
observed diastereoselection, see: (a) Hoffmann, R. W. Angew. Chem. 1982,
94, 569-580. (b) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207-
2293.
(23) For the synthesis of R-methylene γ-lactones using overstoichiometric
amounts of chromium salts, see: (a) Okuda, Y.; Nakatsukasa, S.; Oshima,
K.; Nozaki, H. Chem. Lett. 1985, 481-484. (b) Mattes, H.; Benezra, C. J.
Org. Chem. 1988, 53, 2732-2737.

12354 J. Am. Chem. Soc., Vol. 118, No. 49, 1996
Fu¨rstner and Shi
Table 4. Chromium-Catalyzed Reactions of Crotyl Bromide with Different Aldehydes
entry
crotyl bromide
R
chromium salt
additives
product (% yield)
anti:syn
1
2
3
4
5
6
7
8
(E)-23
(E)-23
(Z)-23
(E)-23
(Z)-23
(E)-23
(E)-23
(E)-23
Ph
Ph
Ph
Ph
Ph
n-C5H11
n-C5H11
CrCl2 (400 mol %)
CrCl2 (7 mol %)
CrCl2 (7 mol %)
CrCl3 (7 mol %)
CrCl3 (7 mol %)
CrCl2 (400 mol %)
CrCl2 (7 mol %)
CrCl3 (7 mol %)
24 (100)
24 (79)
24 (64)
24 (85)
24 (74)
25 (97)
25 (84)
27 (83)
90:10 1d
94:6
90:10
91:9
90:10
96:4 1d
92:8
Mn, TMSCl
Mn, TMSCl
Mn, TMSCl
Mn, TMSCl
Mn, TMSCl
Mn, TMSCl
(CH2)5COOMe
92:8
Table 5. Chromium-Induced Reactions of Geranyl Substrates with Benzaldehyde: Comparision between the Catalytic and the Stoichiometric
Procedures
diastereomeric ratio
entry
X
chromium salt
additives
yield (%)
S*,S*:S*,R*
1
2
OP(O)(OEt)2
Br
CrCl2 (215 mol %)
CrCl2 (7 mol %)
94a
97:3 (ref 8c)
94:6
Mn, TMSCl
79b
a In DMPU as the solvent in the presence of LiI. b In THF as solvent.
Table 6. Nozaki-Hiyama-Kishi Reactions Catalyzed by Chromocene (Cp2Cr) or CpCrCl2‚THFa
product
(isolated yield, %)
entry
R-X
aldehyde
octanal
octanal
octanal
benzaldehyde
octanal
octanal
octanal
MeOOC(CH2)5CHO
hexanal
hexanal
chromium source
dr
1
2
3
4
5
6
7
8
9
allyl bromide
allyl bromide
allyl bromide
(E)-23
Cp2Cr (2%)
Cp2Cr (1%)
Cp2Cr (0.5%)
Cp2Cr (1%)
Cp2Cr (1%)
CpCrCl2‚THF
Cp2Cr (1%)
Cp2Cr (1%)
Cp2Cr (5%)
Cp2Cr (1%)
Cp2Cr (9%)c,d
Cp2Cr (9%)c,d
2a (73)
2a (76)
2a (62)
24 (37)b
26 (76)
26 (92)
26 (60)
27 (76)
17 (80)
17 (56)
9 (71)
(E)-23
(E)-23
(Z)-23
(E)-23
anti:syn ) 77:23
anti:syn ) 78:22
anti:syn ) 65:35
anti:syn ) 78:22
1-iodo-1-hexyne
1-iodo-1-hexyne
2-(triflyloxy)-1-octene
iodobenzene
10
11
12
octanal
octanal
1a (59)
a All reactions were carried out in THF at ambient temperature unless stated otherwise. b Together with 56% isolated yield of the pinacolization
product 1,2-diphenyl-1,2-ethanediol. c The chromium catalyst was additionally doped with NiCl2. d In DME/DMF (20/3) at 50 °C.
has been included in order to verify again the compatibility of
an ester group under these conditions (Table 4, entry 8).
Use of Cp2Cr or CpCrCl2‚THF as Precatalysts: Improved
Turnover Numbers. Aiming at a further reduction of the
amount of chromium in C-C bond formations of this type, we
considered the possibility of improving the turnover number of
the catalyst by fine-tuning its redox potential by means of
appropriate ligands. Much to our surprise, a screening of the
extensive literature on Nozaki-Hiyama-Kishi reactions re-
vealed that this possibility has hardly been considered in the
context of the stoichiometric procedure. A pertinent exception
is a recent publication by Wipf et al., claiming that the
performance of a diphenylchromium-TMEDA complex sig-
nificantly exceeds that of CrCl2.25 However, as the C-Cr bond
in Ph2Cr might not resist TMSCl in our catalytic scenario, we
were looking for other chromium complexes bearing electron-
donating but “dummy” ligands. An obvious choice is chro-
mocene Cp2Cr (Cp ) cyclopentadienyl) which is easily prepared
and also commercially available.26 It is known that chromocene
suffers cleavage of one of the Cp rings on treatment with allyl
halides in THF or other donor solvents with formation of the
respective CpCrX2-solvent complex.27 However, keeping in
mind that our catalytic cycle will proceed regardless of whether
we start with Cr2+ or Cr3+ (Vide supra), the loss of one of the
Cp rings should not matter; the well accessible and somewhat
more stable “CpCrCl2” (either in form of its dimer [CpCrCl2]2
or as the solvent complex CpCrCl2‚THF) may also be considered
a suitable precursor for our purposes.28
From the results summarized in Table 6 it is obvious that
the turnover number may in fact be considerably improved if
CrCl2 is replaced by chromium “precatalysts” bearing Cp rings.
Cp2Cr and CpCrCl2‚THF worked equally well: As little as e1
mol % of these chromium sources turned out to be sufficient in
(25) Wipf, P.; Lim, S. J. Chem. Soc., Chem. Commun. 1993, 1654-1656.
(26) For a convenient preparation, see: (a) Ko¨hler, F. H.; Pro¨ssdorf, W.
Z. Naturforsch. 1977, 32B, 1026-1029. (b) Organometallic Synthesis; King,
R. B., Ed.; Academic Press: New York, 1965; Vol. 1, pp 66-67.
(27) Review: (a) Kalousova, J.; Holecek, J.; Votinsky, J.; Benes, L. Z.
Chem. 1983, 23, 327-331. For leading references on the reaction of
chromocene with allylic halides and similar substrates, see: (b) Fischer, E.
O.; Ulm, K. Chem. Ber. 1962, 692-694. (c) Fischer, E. O.; Ulm, K.; Kuzel,
P. Z. Allgem. Anorg. Chem. 1963, 319, 252-265. (d) Ko¨hler, F. H.; Cao,
R.; Ackermann, K.; Sedlmair, J. Z. Naturforsch. 1983, 38B, 1406-1411.
(28) CpCrCl2‚THF can be conveniently prepared from Cp2Cr and HCl
gas in THF at 0 °C on a large scale; cf.: (a) Klocke, H., Dissertation, Ruhr
Universita¨t Bochum, 1984. (b) For the preparation of the dimer [CpCrCl2]2
by the same reaction using pentane instead of THF as the solvent and for
its use in the synthesis of π-allyl complexes, see: Betz, P.; Do¨hring, A.;
Emrich, R.; Goddard, R.; Jolly, P. W.; Kru¨ger, C.; Romao, C. C.;
Scho¨nfelder, K. U.; Tsay, Y. H. Polyhedron 1993, 12, 2651-2662 and
literature cited.

Nozaki-Hiyama-Kishi Reactions
J. Am. Chem. Soc., Vol. 118, No. 49, 1996 12355
were recorded on a Bruker AC 200 spectrometer at 200.1 MHz (1H)
and 50.3 MHz (13C) in CDCl3. Chemical shifts (δ) are given in ppm
relative to TMS. IR spectra were recorded on a Nicolet FT-7199,
wavenumbers are in cm-1. Mass spectra were recorded on a Varian
CH-5 (70 eV).
Substrates. 2-[[(Trifluoromethyl)sulfonyl]oxy]-1-octene,20 2-[[(tri-
fluoromethyl)sulfonyl]oxy]-1-hexene,20 1-iodo-1-hexyne,31 (Z)-crotyl
bromide (Z-23),32 and methyl 7-oxoheptanoate33 were prepared accord-
ing to the literature procedures cited. 2-Iodo-1-hexene was obtained
upon reaction of 1-hexyne with 9-iodo-9-BBN, followed by debory-
lation with HOAc.34
Representative Procedure for the CrCl2-Catalyzed Reaction of
Aryl and Alkenyl Halides (Triflates) with Aldehydes. 1-(4-Meth-
oxyphenyl)-2-methylene-1-hexanol (11). A solution of 4-methoxy-
benzaldehyde (340 mg, 2.5 mmol), 2-[[(trifluoromethyl)sulfonyl]oxy]-
1-hexene (1.06 g, 4.6 mmol) and TMSCl (0.75 mL, 6.0 mmol) in DMF
(1.5 mL) and DME (5 mL) was dropped into a suspension of Mn
powder (230 mg, 4.2 mmol), CrCl2 (46 mg, 0.38 mmol), and NiCl2
(10 mg, 0.07 mmol) in DME (5 mL) at 50 °C. After being stirred for
5 h at that temperature, the mixture was quenched with water (15 mL)
and extracted with ethyl acetate (150 mL in three portions), and the
combined organic layers were washed with brine. Aqueous n-Bu4NF
(75% w/w) was added, and the solution was stirred at room temperature
until TLC showed complete desilylation of the crude product. Standard
workup followed by flash chromatography with hexane/ethyl acetate
(15/1) as eluent afforded the title compound as a colorless syrup (420
mg, 76%). 1H NMR: δ 0.83 (t, 3H), 1.15-1.45 (m, 4H), 1.72- 2.05
(m, 2H), 2.18 (b, 1H), 3.77 (s, 3H), 4.94 (s, 1H), 5.05 (s, 1H), 5.22 (s,
1H), 6.85 (d, 2H), 7.25 (d, 2H). 13C NMR: δ 13.6, 22.1, 29.6, 31.4,
54.9, 76.4, 108.7, 113.2, 127.7, 134.2, 151.0, 158.8. IR: 3410, 2957,
2931, 2871, 1630, 1611, 1511, 1465, 1249, 1172, 1036, 910, 830. MS:
m/z (relative intensity) 220 (100, [M+]), 177 (13), 163 (26), 137 (86),
109 (17).
The products compiled below were obtained analogously.
Diphenylmethanol (3). This compound was identified by com-
parison with an authentic sample (Aldrich).
1-Phenyl-1-octanol (1a). Colorless syrup. 1H NMR: δ 0.92 (t,
3H), 1.31 (m, 8H), 1.79 (m, 2H), 1.97 (s, 1H), 4.69 (t, 1H), 7.37 (s,
5H). 13C NMR: δ 13.7, 22.3, 25.5, 28.9, 29.2, 31.5, 38.8, 74.3, 125.6,
127.1, 128.0, 144.6. IR: 3360, 1600, 1500, 1450, 1060, 1030, 760,
700. MS: m/z (relative intensity) 206 (3, [M+]), 107 (100), 79 (25),
77 (12).
Phenylcyclohexylcarbinol (4). 1H NMR: δ 0.78-1.45 (m, 6H),
1.48-1.85 (m, 4H), 1.95 (b, 1H), 2.00 (s, 1H), 4.33 (d, 1H), 7.29 (m,
5H). 13C NMR: δ 25.8, 26.1, 28.5, 29.0, 44.6, 79.0, 126.4, 127.0,
127.8, 143.3. IR: 3395, 3028, 2924, 2852, 1603, 1493, 1451, 1259,
1068, 1017, 893, 760, 701, 578. MS: m/z (relative intensity) 190 (4,
[M+]), 107 (100), 79 (28).
reactions of allyl halides with aldehydes. This denotes a
significant advancement compared with the ∼7 mol % of CrCl2
(or CrCl3) which are required otherwise. Similarly, a distinct
although less spectacular reduction of the amount of chromium
could be achieved in reactions of alkenyl triflates as well as
alkynyl and aryl iodides as the substrates.
The increased performance of the CpCr-based catalytic
process, however, is somewhat corroded by a slightly lower
diastereoselectivity. Although the reaction of crotyl bromide
again leads to the preferential formation of the anti-homoallyl
alcohol irrespective of the double bond geometry of the starting
material, the anti:syn ratio is less favorable than in the CrClx-
catalyzed process (x ) 2, 3) but remains still in a preparatively
useful range (Table 6, entries 5-8). Moreover, it clearly
emerged from our study that the Cp2Cr-catalyzed method applies
only to aliphatic aldehydes as substrates, while aromatic ones
are prone to pinacol coupling when exposed to this more
electron-rich metal template (Table 6, entry 4).22
Summary and Outlook. We have described the first
Nozaki-Hiyama-Kishi reactions using catalytic amounts of
chromium salts in combination with the cheap and nontoxic
manganese as a suitable stoichiometric reductant. The process
is mediated by trimethylchlorosilane and meets all criteria set
by the stoichiometric precedent with regard to the scope and
the chemo- and the diastereoselectivity. It has been shown that
either CrCl2 or CrCl3 is a suitable catalyst, with the latter being
preferred for practical reasons. Although the amount of
chromium salt (∼7 mol % for allylic and 15 mol % for aryl
and alkenyl substrates) may still seem inappropriately high for
industrial applications of this method, we consider it to be an
important step forward as compared to the large excess of
chromium salts which are usually employed for reactions of
this type. One of the limiting factors for the turnover number
seems to be an incomplete ligand exchange between the
chromium alkoxide initially formed and the admixed chlorosi-
lane.29 Finally we have gained the insight that different
chromium sources catalyze reactions of this type, with CpCr-
templates being particularly promising. As little as e1 mol %
of either Cp2Cr or CpCrCl2‚THF as the “pre-catalysts” in
combination with Mn and TMSCl account for highly efficient
C-C bond formations. This holds the promise of further
improving the efficiency of the process and may help to endow
the catalyst with a periphery of chiral ligands. Several options
along these lines are actively being pursued in our laboratory.30
1-Acetoxy-6-chloro-1-phenylhexane (5). In this case the product
was isolated after acetylation (Ac2O, pyridine) of the crude reaction
mixture. Colorless syrup. 1H NMR: δ 1.22-1.59 (m, 4H), 1.70-
Experimental Section
General Procedures. All reactions were carried out under Ar using
Schlenk techniques. CrCl2: The CrCl2 used should be colorless; pale-
green batches result in lower yields. Samples of good quality were
purchased from Alfa-Johnson Matthey Co. (99.9% purity). CrCl3
(99%), NiCl2 (98%) and Mn powder (ca. 150 µm) were purchased from
Aldrich and used as received. Cp2Cr and CpCrCl2‚THF were prepared
according to literature procedures.26,28 The solvents were dried by
distillation over the following drying agents and were transferred under
Ar: DME (Na/K alloy), THF (Na/benzophenone). The DMF must be
thorougly purified; best results were obtained by distilling predried DMF
over Desmodur-15 (Bayer AG) and dibutyltin laurate at 70-80 °C under
reduced pressure. TMSCl (Janssen), the commercially available
aldehydes, iodobenzene, iodothiophene, allyl bromide, (E)-crotyl
bromide (E-23), geranyl bromide (28), and ethyl 2-(bromomethyl)-2-
propenoate (19) were distilled prior to use. (Cyanopropyl)dimethyl-
chlorosilane (Aldrich) was used as received. Flash chromatography:
Merck silica gel 60 (230-400 mesh) with hexane/ethyl acetate in
various proportions as eluent. Instrumental analyses: NMR spectra
2.05 (m, 4H), 2.11 (s, 3H), 3.54 (t, 2H), 5.79 (t, 1H), 7.36 (s, 5H). 13
C
NMR: δ 20.9, 24.5, 26.2, 32.0, 35.8, 44.5, 75.5, 126.1, 127.5, 128.1,
140.3, 170.0. IR: 3065, 3033, 2941, 2863, 1737, 1495, 1455, 1372,
1239, 1073, 1024, 964, 760, 700, 650, 553. MS: m/z (relative intensity)
254 (6, [M+]), 212 (34), 149 (39), 117 (35), 107 (100), 43 (84).
1-Phenyl-6-chloro-1-hexanol (6). Obtained upon deacetylation
(MeOH, NaOMe(cat.)) of the acetate mentioned above. Colorless
syrup. 1H NMR: δ 1.21-1.54 (m, 4H), 1.62-1.91 (m, 5H), 3.50 (t,
2H), 4.66 (t, 2H), 7.33 (s, 5H). 13C NMR: δ 24.7, 26.4, 32.1, 38.5,
44.6, 74.1, 125.5, 127.2, 128.1, 144.4. IR: 3374, 3029, 2937, 2860,
1603, 1493, 1454, 1310, 1282, 1201, 1028, 914, 762, 701, 650. MS:
m/z (relative intensity) 184 (2, [M+]), 107 (100), 79 (29).
(31) Negishi, E. I.; Yoshida, T.; Abramovitch, A.; Lew, G.; Williams,
R. M. Tetrahedron 1991, 47, 343-356.
(32) LeBel, N. A.; Balasubramanian, N. J. Am. Chem. Soc. 1989, 111,
3363-3368.
(33) Claus, R. E.; Schreiber, S. L. Org. Synth. 1986, 64, 150-156.
(34) (a) Hara, S.; Dojo, H.; Takinami, S.; Suzuki, A. Tetrahedron Lett.
1983, 731-734. See also: (b) Ko¨ster, R.; Seidel, G. Organometallic
Synthesis; King, R. B., Eisch, J. J., Eds.; Elsevier: Amsterdam, 1988; Vol.
4, pp 440-442.
(29) Complete silylation could not be reached. This seems to be a limiting
factor for the number of turnovers.
(30) Fu¨rstner, A.; Shi, N.; Gamez, P. Unpublished results.

12356 J. Am. Chem. Soc., Vol. 118, No. 49, 1996
Fu¨rstner and Shi
1-(2-Thienyl)-1-octanol (7). Colorless syrup. 1H NMR: δ 0.90
(t, 3H), 1.29 (m, 10H), 1.86 (m, 2H), 2.04 (b, 1H), 4.92 (t, 1H), 6.98
(m, 3H), 7.24 (m, 2H). 13C NMR: δ 13.7, 22.3, 25.4, 28.8, 29.0, 31.4,
39.0, 69.7, 123.3, 124.1, 126.2, 148.7. IR: 3377, 2955, 2927, 1465,
1415, 1378, 1231, 1039, 853, 830, 697. MS: m/z (relative intensity)
212 (10, [M+]), 113 (100), 85 (22).
[4-(Ethoxycarbonyl)phenyl]phenylmethanol (8). Colorless syrup.
1H NMR: δ 1.36 (t, 3H), 2.65 (b, 1H), 4.33 (q, 2H), 5.84 (s, 1H), 7.31
(m, 5H), 7.43 (d, 2H), 7.99 (d, 2H). 13C NMR: δ 14.0, 60.6, 75.5,
125.9, 126.3, 127.5, 128.3, 129.4, 143.0, 148.3, 166.1. IR: 3461,
3062, 3030. 2982, 1716, 1700, 1611, 1453, 1413, 1368, 1279, 1176,
1106, 1019, 873, 755, 701. MS: m/z (relative intensity) 256 (16, [M+]),
211 (14), 183 (13), 177 (30), 165 (11), 151 (100), 123 (32), 105 (63),
77 (27).
mL), and the mixture was stirred for another 3 h to ensure complete
desilylation of the crude silyl ether. A standard extractive workup with
ethyl acetate followed by flash chromatography with hexane/ethyl
acetate (30/1) afforded the title homoallyl alcohol as a colorless syrup
(320 mg, 79%). The isomeric ratio of the crude product is threo:erythro
) 94:6 (GC).1d,35 Threo-isomer. 1H NMR: δ 7.22-7.36 (m, 5H),
5.81 (ddd, 1H, J ) 7.9, 9, 17), 5.22 (dd, 1H, J ) 1, 17), 5.16 (dd, 1H,
J ) 2, 9), 4.35 (d, 1H, J ) 7.9), 2.53 (m, 1H), 2.19 (s, 1H, OH), 0.85
(d, 3H, J ) 6.7). 13C NMR: δ 142.5, 140.7, 128.2, 127.6, 126.5, 116.7,
77.9, 46.2, 16.5. IR: 3425, 3065, 3030, 2975, 2931, 2872, 1639, 1604,
1494, 1454, 1417, 1372, 1197, 1021, 915, 761, 701. MS: m/z (relative
intensity) 162 (0.1, [M+]), 107 (100), 79 (58), 77 (25). Diagnostic
data of the erythro-isomer. 1H NMR: δ 4.57 (d, J ) 5.4), 0.99 (d, J
) 6.9). 13C NMR: δ 44.7, 14.0.
7-Methylenepentadecan-8-ol (9). Colorless syrup. 1H NMR: δ
0.88 (m, 3H), 1.29-1.55 (m, 23H), 2.00 (m, 2H), 4.05 (t, 1H), 4.83
(d, 1H), 5.00 (d, 1H). 13C NMR: δ 13.7, 22.3, 25.4, 27.7, 28.9, 29.2,
31.0, 31.4, 31.5, 35.2, 75.2, 108.7, 152.0. IR: 3354, 2956, 2927, 2857,
1646, 1466, 1378, 1122, 1047, 1020, 900, 724. MS: m/z (relative
intensity) 240 (3, [M+]), 169 (12), 155 (18), 141 (29), 127 (26), 123
(20), 95 (17), 81 (35) 71 (100).
2-Methylene-1-phenyl-1-octanol (10). Colorless syrup. 1H
NMR: δ 0.85 (t, 3H), 1.18-1.51 (m, 8H), 1.75-2.08 (m, 3H), 4.98
(s, 1H), 5.16 (s, 1H), 5.27 (s, 1H); 7.33 (m, 5H). 13C NMR: δ 13.7,
22.2, 27.4, 28.7, 31.3, 31.5, 77.0, 109.3, 126.4, 127.3, 128.0, 141.9,
150.9. IR: 3376, 3029, 2956, 2928, 2858, 1647, 1493, 1454, 1038,
1026, 903, 841, 763, 699. MS: m/z (relative intensity) 218 (38, [M+]),
147 (24), 133 (100), 129 (10), 120 (50), 107 (46), 105 (33), 91 (10),
79 (29), 77 (19), 55 (21).
2-Methylene-1-[3,4-(methylenedioxy)phenyl]-1-hexanol (12). Col-
orless syrup. 1H NMR: δ 0.85 (t, 3H), 1.17-1.46 (m, 4H), 1.65-
2.04 (m, 3H), 4.95 (s, 1H), 5.04 (s, 1H), 5.24 (s, 1H), 5.93 (s, 2H),
6.80 (m, 3H). 13C NMR: δ 13.6, 22.1, 29.6, 31.3, 76.7, 100.6, 106.8,
107.6, 108.9, 120.0, 136.0, 146.7, 147.4, 150.8. IR: 3390, 2957, 2930,
2873, 1650, 1503, 1487, 1442, 1247, 1094, 1041, 951, 933, 809. MS:
m/z (relative intensity) 234 (100, [M+]), 177 (14), 151 (67), 123 (11),
93 (15).
Representative Procedure for the CrCl2-Catalyzed Reaction of
Alkynyl Halides with Aldehydes. 5-Dodecyn-7-ol (17). To a stirred
suspension of CrCl2 (26 mg, 0.21 mmol), NiCl2 (9 mg, 0.7 mmol),
and Mn powder (120 mg, 2.1 mmol) in THF (7 mL) were added
successively hexanal (125 mg, 1.25 mmol) and 1-iodo-1-hexyne (520
mg, 2.5 mmol). After the mixture was stirred for 6 h at ambient
temperature, water (10 mL) was added and the stirring continued for
3 h until the silyl ether was quantitatively cleaved. The mixture was
extracted with ethyl acetate in three portions (30 mL each), the
combined organic layers were washed with brine, dried over Na2SO4,
and evaporated, and the residue was purified by flash chromatography
with hexane/ethyl acetate (10/1) as eluent, affording the title compound
as pale yellow syrup (180 mg, 79%). 1H NMR: δ 4.38 (tt, 1H, J ) 2,
6.4), 2.25 (dt, 2H, J ) 2, 6.8), 1.78 (s, 1H, OH), 1.34-1.75 (m, 12H),
0.95 (t, 3H), 0.94 (t, 3H). 13C NMR: δ 85.1, 81.0, 62.4, 37.8, 31.1,
30.4, 24.5, 22.2, 21.5, 18.0, 13.6, 13.2. IR: 3346, 2957, 2933, 2861,
2232, 1466, 1432, 1379, 1329, 1261, 1148, 1109, 1026, 914. MS: m/z
(relative intensity) 182 (0.2, [M+]), 153 (2), 139 (4), 125 (18), 111
(100), 55 (17).
The following products have been obtained analogously.
1-Undecen-4-ol (2a). Colorless syrup. 1H NMR: δ 0.81 (m, 3H),
1.21 (m, 8H), 1.38 (m, 2H), 2.00-2.34 (m, 3H), 3.63 (m, 1H), 5.05
(m, 1H), 5.13 (m, 1H), 5.69-5.90 (m, 1H). 13C NMR: δ 13.7, 22.3,
25.3, 28.9, 29.2, 31.5, 36.4, 41.5, 70.5, 117.6, 134.5. IR: 3357, 3077,
2957, 2928, 2856, 1641, 1466, 1438, 1378, 1342, 1126, 1074, 1044,
994, 912. MS: m/z (relative intensity) 170 (0.3, [M+]), 129 (24), 111
(22), 69 (100), 55 (36).
2-Methylene-4-(2-phenyl-1-ethyl)butyrolactone (20). Colorless
syrup. 1H NMR: δ 1.82-2.13 (m, 2H), 2.58 and 3.04 (dtAB system,
2H, J ) 2.5, 7.8, 17), 2.76 (m, 2H), 4.52 (m, 1H), 5.62 (t, J ) 2.5,
1H), 6.23 (t, J ) 2.5, 1H), 7.15-7.34 (m, 5H). 13C NMR: δ 31.0,
33.2, 37.7, 76.2, 121.8, 125.9, 128.1, 128.2, 134.3, 140.3, 169.9. IR:
3027, 2932, 2861, 1762, 1665, 1603, 1497, 1454, 1398, 1342, 1278,
1265, 1164, 1128, 1023, 937, 814, 752, 701, 627. MS: m/z (relative
intensity) 202 (18, [M+]), 117 (100), 91 (71).
3-Methyl-1-nonen-4-ol (25). Threo:erythro ) 92:8 (GC).36 Color-
less syrup. Threo-isomer. 1H NMR: δ 5.68-5.85 (m, 1H), 5.04-
5.15 (m, 2H), 3.36-3.44 (m, 1H), 2.22 (virt-hex, 1H), 1.68 (s, 1H,
OH), 1.31-1.49 (m, 10H), 1.03 (d, 3H, J ) 6.9), 0.90 (vt, 3H, J )
6.4). 13C NMR: δ 140.4, 116.0, 74.7, 44.0, 34.2, 31.9, 25.4, 22.6,
16.2, 14.0, 13.7. IR: 3382, 3076, 2959, 2931, 2860, 1639, 1460, 1417,
1378, 1260, 1121, 1096, 1000, 912. MS: m/z (relative intensity) 156
(6, [M+], 101 (43), 99 (24), 83 (100), 56 (88), 55 (74), 43 (18), 41
(22). Diagnostic data for the erythro-isomer. 1H NMR: δ 1.02 (d, J
) 6.9). 13C NMR: δ 140.8, 115.0.
(1S*,2S*)-2,6-Dimethyl-2-ethenyl-1-phenyl-5-hepten-1-ol (29). Col-
orless syrup.8c Isomeric ratio S*,S*:R*,S* ) 94:6 (GC). Major isomer.
1H NMR: δ 7.30-7.40 (m, 5H), 5.92 (dd, 1H, J ) 10.8, 17.5), 5.33
(dd, 1H, J ) 1.5, 10.8), 5.15 (dd, 1H, J ) 1.5, 17.5), 5.05-5.22 (m,
1H), 4.47 (s, 1H), 2.02 (br s, 1H, OH), 1.92 (q, 2H), 1.71 (d, 3H, J )
1), 1.61 (s, 3H), 1.22-1.56 (m, 2H), 0.98 (s, 3H). 13C NMR: δ 143.6,
140.1, 130.9, 127.7, 127.1, 127.0, 124.4, 115.5, 79.7, 45.6, 37.2, 25.3,
22.5, 17.3, 15.9. IR: 3448, 3083, 3030, 2969, 2925, 2857, 1637, 1604,
1493, 1453, 1413, 1375, 1189, 1083, 1048, 1012, 915, 730, 703. MS:
m/z (relative intensity) 244 (0.6, [M+]), 138 (31), 123 (36), 107 (100),
95 (80), 82 (11), 79 (55), 77 (28), 69 (97), 41 (40).
4-Methyl-1-decen-4-ol (22). 1H NMR: δ 5.85 (X part of ABX,
1H), 5.05-5.16 (AB part of ABX, 2H), 2.22 (d, 2H, J ) 7.4), 1.60 (br
s, 1H, OH), 1.28-1.50 (m, 10H), 1.16 (s, 3H), 0.89 (vt, 3H). 13C
NMR: δ 133.8, 118.1, 71.8, 45.9, 41.5, 31.5, 29.5, 26.3, 23.4, 22.2,
13.7. IR: 3395, 3076, 2959, 2932, 2859, 1641, 1465, 1376, 1141,
1103, 1081, 1046, 998, 913. MS: m/z (relative intensity) 152 (5), 129
(49), 95 (13), 85 (21), 69 (61), 55 (27), 43 (100).
1-Phenyl-2-heptyn-1-ol (18). Obtained according to the procedure
outlined above as a pale yellow syrup. 1H NMR: δ 7.24-7.55 (m,
5H), 5.42 (t, 1H, J ) 1), 2.26 (dt, 3H, J ) 1, 6.8), 1.32-1.60 (m, 4H),
0.91 (t, 3H, J ) 7). 13C NMR: δ 141.0, 128.2, 127.8, 126.3, 87.3,
79.6, 64.5, 30.3, 21.6, 18.2, 13.2. IR: 3374, 3064, 3031, 2958,
2933, 2872, 2280, 2227, 1603, 1493, 1454, 1430, 1379, 1328, 1192,
1135, 1002, 758, 726, 698, 635. MS: m/z (relative intensity) 188 (100,
[M+]), 187 (24), 145 (53), 131 (21), 117 (24), 115 (23), 105 (14), 91
(20), 77 (23).
Representative Procedure for CrCl3-Catalyzed Reactions. Meth-
yl 7-Hydroxy-8-methyl-9-decenoate (27). To a stirred suspension of
CrCl3 (27 mg, 0.17 mmol) and Mn (230 mg, 4.2 mmol) in THF (10
mL) were added successively methyl 7-oxoheptanoate (390 mg, 2.5
mmol), (E)-crotyl bromide (675 mg, 5.0 mmol), and TMSCl (0.75 mL,
6.0 mmol) at ambient temperature. Water was added after a reaction
time of 6 h, and the stirring was continued for another 3 h to ensure
Representative Procedure for the CrCl2-Catalyzed Reaction of
Allyl Halides with Aldehydes. 2-Methyl-1-phenyl-3-buten-1-ol (24).
To a stirred suspension of CrCl2 (22 mg, 0.18 mmol) and Mn (230
mg, 4.2 mmol) in THF (10 mL) was added successively benzaldehyde
(265 mg, 2.5 mmol), (E)-crotyl bromide (675 mg, 5.0 mmol), and
TMSCl (0.75 mL, 6.0 mmol). The mixture was stirred for 6 h at
ambient temperature, the reaction was quenched by adding water (10
(35) The stereochemical assignment was made according to the data given
in ref. 1d and in the following references: (a) Fujita, K.; Schlosser, M.
HelV. Chim. Acta 1982, 65, 1258-1263. (b) Gambaro, Marton, D.; Peruzzo,
V.; Tagliavini, G. J. Organomet. Chem. 1982, 226, 149-155.
(36) Stereochemical assignment by comparison with the data reported
in the following: Furlani, D.; Marton, D. J. Chromatogr. 1986, 369, 313-
320.

Nozaki-Hiyama-Kishi Reactions
J. Am. Chem. Soc., Vol. 118, No. 49, 1996 12357
complete desilyation of the crude product mixture. A standard
extractive workup (EtOAc) followed by a flash chromatography with
hexane/ethyl acetate (4/1) afforded the title compound as colorless syrup
(450 mg, 83%). Threo:erythro ) 92:8 (GC). Threo-isomer. 1H
NMR: δ 5.66-5.84 (m, 1H), 5.04-5.13 (m, 2H), 3.67 (s, 3H), 3.38
(m, 1H), 2.31 (t, 2H, J ) 6.5), 2.17 (m, 1H), 1.78 (s, 1H, OH), 1.20-
1.70 (m, 8H), 1.02 (d, 3H, J ) 6.9). 13C NMR: δ 173.9, 139.9, 115.8,
74.2, 51.1, 43.8, 33.6, 28.8, 28.7, 25.0, 24.5, 15.9. IR: 3462, 3076,
2936, 2861, 1740, 1639, 1457, 1437, 1419, 1370, 1256, 1203, 1174,
1002, 913. MS: m/z (relative intensity) 159 (18), 127 (100), 81 (76),
55 (29). Diagnostic data of the erythro-isomer. 13C NMR: δ 140.6,
114.9, 43.1, 13.7.
Representative Procedure for Cp2Cr-Catalyzed Reactions. To
a suspension of Cp2Cr (9 mg, 0.05 mmol) and Mn powder (230 mg,
4.2 mmol) in THF (7 mL) were added successively allyl bromide (0.42
mL, 5.0 mmol), octanal (0.39 mL, 2.5 mmol), and TMSCl (0.75 mL,
6.0 mmol). The dark blue suspension slowly turned gray due to the
precipitation of white manganese salts. After the mixture was stirred
overnight at ambient temperature, water (10 mL) was added and the
stirring continued for another 2 h to ensure quantitative desilylation of
the crude product. An extractive workup as described above followed
by flash chromatography (hexane/ethyl acetate ) 30/1) afforded alcohol
2a as colorless syrup (312 mg, 73%). The spectroscopic data are in
full agreement with those compiled above.
CpCrCl2‚THF (13 mg, 0.05 mmol) in THF (10 mL) were added octanal
(0.78 mL, 5.0 mmol), (E)-crotyl bromide (1.02 mL, 10.0 mmol), and
TMSCl (1.5 mL, 12 mmol). The suspension was stirred for 6 h at
ambient temperature, the reaction was quenched by adding water (10
mL), and the stirring was continued (2 h) until TLC showed complete
desilylation of the crude product mixture. A standard extractive workup
as described followed by flash chromatography (hexane/ethyl acetate
) 30/1) gave compound 26 as a colorless syrup (853 mg, 92%). The
diastereomeric ratio of the crude product was determined by GC as
anti:syn ) 78:22 in analogy to ref 36. Threo-isomer. 1H NMR: δ
5.68-5.89 (m, 1H), 5.03-5.14 (m, 2H), 3.39-3.50 (m, 1H), 2.21-
2.35 (m, 1H), 1.15-1.63 (m, 13H), 1.07 (d, 3H, J ) 6.9), 0.91 (t, 3H).
13C NMR: δ 140.0, 115.8, 74.4, 43.7, 33.9, 31.5, 29.3, 28.9, 25.4,
22.3, 15.9, 13.7. IR: 3379, 3077, 2959, 2928, 2856, 1639, 1459, 1418,
1378, 998, 912. MS: m/z (relative intensity) 184 (0.5, [M+]), 129 (12),
111 (18), 69 (99), 56 (100). Diagnostic data of the erythro-isomer.
13C NMR: δ 140.8, 114.7, 43.1.
Acknowledgment. Generous financial support by the Fonds
der Chemischen Industrie, Frankfurt, is acknowledged with
gratitude. We would like to thank Prof. P. W. Jolly and his
co-workers at this institute for a generous gift of Cp2Cr and
CpCrCl2‚THF.
Representative Procedure for CpCrCl2‚THF-Catalyzed Reac-
tions. To a suspension of Mn powder (460 mg, 8.4 mmol) and
JA9625236