Titanocene-Catalyzed Regioselective Carbomagnesation of Alkenes and Dienes

Article abstract of DOI:10.1021/jo0354241

A new method for regioselective carbomagnesation of alkenes and dienes has been developed by the use of a titanocene catalyst. This reaction proceeds efficiently at 0 °C in THF in the presence of Cp₂TiCl ₂ by the combined use of organic halides (R-X; R = alkyl, aryl and vinyl) and n-BuMgCl to afford benzyl, α-silylalkyl, or allyl Grignard reagents, which were trapped with various electrophiles. The present reaction involves (i) addition of carbon radicals toward alkenes or dienes in the carbon-carbon bond-forming step and (ii) transmetalation on Ti of benzyl-α-silylalkyl-, or allyltitanocene with n-BuMgCl in the carbon-magnesium bond-forming step. The scope and limitations of this reaction have also been examined.

Full text of DOI:10.1021/jo0354241

Tita n ocen e-Ca ta lyzed Regioselective
Ca r bom a gn esa tion of Alk en es a n d Dien es
Shinsuke Nii, J un Terao, and Nobuaki Kambe*
Department of Molecular Chemistry & Science and
Technology Center for Atoms, Molecules and Ions Control,
Osaka University, Suita, Osaka 565-0871, J apan
tion involves two different types of carbon-carbon bond-
forming processes, i.e., (step A) addition of alkyl radicals
at the terminal vinylic carbon and (step B) electrophilic
trapping of benzylmagnesium intermediates 1 with alkyl
halides (Scheme 1). If step B can be suppressed, this
kambe@chem.eng.osaka-u.ac.jp
Received September 29, 2003
Abstr a ct: A new method for regioselective carbomagnesa-
tion of alkenes and dienes has been developed by the use of
a titanocene catalyst. This reaction proceeds efficiently at 0
°C in THF in the presence of Cp2TiCl2 by the combined use
of organic halides (R-X; R ) alkyl, aryl and vinyl) and
n-BuMgCl to afford benzyl, R-silylalkyl, or allyl Grignard
reagents, which were trapped with various electrophiles. The
present reaction involves (i) addition of carbon radicals
toward alkenes or dienes in the carbon-carbon bond-forming
step and (ii) transmetalation on Ti of benzyl-, R-silylalkyl-,
or allyltitanocene with n-BuMgCl in the carbon-magnesium
bond-forming step. The scope and limitations of this reaction
have also been examined.
SCHEME 1
system would make a unique method of carbomagnesa-
tion to afford the corresponding Grignard reagents 1 from
alkenes and organic halides.
Addition of organometallic reagents of nontransition
metals (M ) Li, Mg, Al, Zn, etc.) across carbon-carbon
unsaturated bonds (carbometalation) is a principal and
important reaction in organic syntheses for the genera-
tion of organometallic compounds having desired carbon
skeletons.1 The most straightforward method for carbo-
magnesation, which has been studied for more than five
decades, is noncatalyzed intermolecular addition of Grig-
nard reagents toward carbon-carbon multiple bonds.
However, this reaction usually requires severe conditions,
and successful examples of its practical application are
quite limited.2 As an attractive alternative methodology
of this transformation, there have been developed several
catalytic reactions using transition metal complexes of
Ni,3a-c Cu,3d Ti,3e Zr,3f-j Mn,3k,l or Fe,3m however, these
reactions also lack generality in the scope of the usable
substrates. Here we disclose a carbomagnesation of
alkenes and dienes catalyzed by titanocene complex
where the carbon moieties of organic halides are intro-
At first, we attempted to obtain an intermediate 1a
(Ar ) Ph, R ) n-octyl) by carrying out the reaction of
styrene (1 mmol) with a limited amount of n-octyl
bromide (1 equiv), Cp2TiCl2 (5 mol %), and a THF solution
of n-BuMgCl (2.1 equiv) at 0 °C for 1 h. After quenching
with H2O, however, this reaction provided only the
corresponding double alkylated product 2a (Ar ) Ph, R
) n-octyl) in 42% yield along with 52% of unreacted
styrene, indicating that the trapping of 1a with n-Octyl
bromide is a rapid process. We then examined the
(3) (a) Duboudin, J .-G.; J ousseaume, B. J . Organomet. Chem. 1972,
44, C1-C3. (b) Snider, B. B.; Karras, M.; Conn, R. S. E. J . Am. Chem.
Soc. 1978, 100, 4624-4626. (c) Snider, B. B.; Conn, R. S. E.; Karras,
M. Tetrahedron Lett. 1979, 19, 1679-1682. (d) Duboudin, J .-G.;
J ousseaume, B.; Bonakdar, A. J . Organomet. Chem. 1979, 168, 227-
232. (e) Akutagawa, S.; Otsuka, S. J . Am. Chem. Soc. 1975, 97, 6870-
6871. (f) Dzhemilev, U. M.; Vostrikova, O. S.; Sultanov, R. M. Izv. Akad.
Nauk SSSR, Ser. Khim. 1983, 218-220. (g) Hoveyda, A. H.; Xu, Z. J .
Am. Chem. Soc. 1991, 113, 5079-5080. (h) Takahashi, T.; Seki, T.;
Nitto, Y.; Saburi, M.; Rouusset, C. J .; Negishi, E. J . Am. Chem. Soc.
1991, 113, 6266-6268. (i) Lewis, D. P.; Muller, P. M.; Whitby, R. J .
Tetrahedron Lett. 1991, 32, 6797-6800. (j) Fischer, R.; Walther, D.;
Gebhardt, P.; Gorls, H. Organometallics 2000, 19, 2532-2540 and
references therein. (k) Okada, K.; Oshima, K.; Utimoto, K. J . Am.
Chem. Soc. 1996, 118, 6076-6077. (l) Tang, J .; Okada, K.; Shinokubo,
H.; Oshima, K. Tetrahedron 1997, 53, 5061-5072. (m) Nakamura, M.;
Hirai, A.; Nakamura, E. J . Am. Chem. Soc. 2000, 122, 978-979.
(4) (a) EtMgBr-mediated intramolecular carbomagnesation of δ-io-
doalkenes involving a radical cyclization process has been reported:
Inoue, A.; Shinokubo, H.; Oshima, K. Org. Lett. 2000, 2, 651-653. (b)
Zr-catalyzed carbomagnesation of styrenes has been developed by using
alkyl tosylates as the electrophilic carbon source: de Armas, J .;
Hoveyda, A. H. Org. Lett. 2001, 3, 2097-2100.
5
duced via a radical mechanism (eqs 1 and 2).4,
Recently, we have developed titanocene-catalyzed double
alkylation of arylalkenes using alkyl halides.6 This reac-
(1) For recent reviews, see: (a) Knochel, P. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
New York, 1991; Vol. 4, pp 865-911. (b) Ley, S. V.; Kouklovsky, C. In
Comprehensive Organic Functional Group Transformations; Katritzky,
A. R., Meth-Cohn, O., Rees, C. W., Eds.; Pergamon Press: New York,
1995; Vol. 2, pp 549-603. (c) Negishi, E.; Choueiry, D. In Comprehen-
sive Organic Functional Group Transformations; Katritzky, A. R.,
Meth-Cohn, O., Rees, C. W., Eds.; Pergamon Press: New York, 1995;
Vol. 2, pp 951-995.
(2) (a) For a recent review, see: Wakefield, B. J . In Organomagne-
sium Methods in Organic Synthesis; Academic Press, Inc.: San Diego,
1995; pp 73-86. (b) Recently, intermolecular carbomagnesation across
vinylsilanes has been developed by exploiting the 2-PyMe2Si group as
a removable directing group; see: Itami, K.; Mitsudo, K.; Yoshida, J .
Angew. Chem., Int. Ed. 2001, 40, 2337-2339.
(5) Some examples have been presented in review articles: (a) Terao,
J .; Kambe, N. J . Synth. Org. Chem. J pn. 2001, 59, 1044-1051. (b)
Terao, J .; Kambe, N. In Latest Frontiers of Organic Synthesis;
Kobayashi, Y., Ed.; Research Signpost, India, 2002; pp 25-48.
(6) (a) Terao, J .; Saito, K.; Nii, S.; Kambe, N.; Sonoda, N. J . Am.
Chem. Soc. 1998, 120, 11822-11823. (b) In the presence of chlorosi-
lanes, carbosilylation products are formed: Nii, S.; Terao, J .; Kambe,
N. J . Org. Chem. 2000, 65, 5291-5297.
10.1021/jo0354241 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/19/2003
J . Org. Chem. 2004, 69, 573-576
573

TABLE 1. Ca r bom a gn esa tion of Alk en es a n d Dien es
w ith Alk yl Ha lid esa
reaction using less reactive organic halides toward SN2
process to suppress step B.
To a mixture of 1,1-diphenylethylene (1 mmol), t-BuCl
(2.0 equiv), and 5 mol % of Cp2TiCl2 was added a THF
solution of n-BuMgCl (3.1 equiv, 3.4 mL). After stirring
for 2 h at 0 °C, the reaction mixture was quenched with
H2O. The NMR analysis of the crude mixture indicated
the formation of the monoalkylated product 3 possessing
a t-Bu group at the terminal carbon in 94% yield (eq 3).
The product was obtained in pure form in 82% yield by
a recycling preparative HPLC using CHCl3 as an eluent.
In a similar manner allylated product 4 was obtained in
66% NMR yield when the reaction mixture was treated
with allyl bromide at 0 °C for 2 h (eq 4). These results
indicate the formation of benzyl Grignard reagent 5.
Under similar conditions, styrene and triethylvinylsilane
also underwent carbomagnesation to give 6 and 7 by use
of secondary alkyl bromides as the alkylating reagents
(Table 1, runs 1 and 2).
Conjugated dienes also underwent carbomagnesation
efficiently. For example, a reaction of 2,3-dimethyl-1,3-
butadiene with tert-amyl chloride under identical condi-
tions afforded an allylic Grignard reagent 8, which was
trapped with PhCOCl to give a sole regioisomer 9 in 92%
isolated yield (run 3). Quenching the reaction mixture
with D2O gave a 35:65 mixture of monoalkylated com-
pounds (10a , b) in 94% total yield which contain a
deuterium at an allylic position (run 4). When stannyl
chloride was used as an electrophile, stannylation took
place regioselectively at the terminal carbon of the
allylmagnesium intermediate due probably to the steric
hindrance of the stannyl group (run 5). A reaction of 2,3-
dimethyl-1,3-butadiene with n-octyl bromide followed by
quenching with H2O gave a mixture of monoalkylated
and double alkylated products.7 So we carried out a
similar reaction employing sterically hindered neopentyl
bromide. Quenching the resulting mixture with
PhCH2Br afforded the desired product in 70% yield as a
single regioisomer (run 6). As for the scope of dienes,
phenyl or benzyl substituted 1,3-butadienes and 1,3-
cyclohexadiene gave the corresponding products in good
to moderate yields (runs 7-9). When internal alkenes,
1-octene, and isoprene were used, reduction of alkyl
a
Alkene or diene (1 mmol), R-X (2 mmol), nBuMgCl (3.1 mmol),
Cp2TiCl2 (0.05 mmol), THF (3.4 mL), 0 °C, 2 h, then electrophile
(1.5 mmol), 0 °C, 2 h. b Isolated yield. NMR yield is in parentheses.
c Reaction was carried out in 10 times scale using 10 mmol of diene.
Diene (10 mmol), R-X (1 mmol), nBuMgCl (2.5 mmol), Cp2TiCl2
d
(0.05 mmol).
halides to alkanes and alkenes proceeded predominantly
and desired products were not obtained.
It should be noted that aryl and vinyl halides can be
employed in the present catalytic system. For example,
a reaction of an excess amount of 2,3-dimethyl-1,3-
butadiene (10 mmol) with 2-bromonaphthalene (1 mmol)
in the presence of Cp2TiCl2 (0.05 mmol) and n-BuMgCl
(2.5 mmol) afforded an 82:18 mixture of monoarylated
compounds (16a , 66%; 16b, 15%) containing a deuterium
at the allylic positions in 81%.8 Introduction of a vinyl
group could also be attained by the use of 2-bromo-
propene under similar conditions and 17 was obtained
in 52% yield after quenching the corresponding allyl-
magnesium intermediate with benzoyl chloride (run
11).
(7) To a mixture of 2,3-dimethyl-1,3-butadiene (87 mg, 1.1 mmol),
n-octyl bromide (366 mg, 1.9 mmol), n-BuMgCl (0.9 M in THF, 3.4 mL,
3.1 mmol) was added Cp2TiCl2 (15 mg, 0.06 mmol) at 0 °C under
nitrogen. After the mixture was stirred for 2 h, H2O was added to the
solution at 0 °C and the products were extracted with ether. Purifica-
tion by HPLC with CHCl3 as an eluent afforded monoalkylated
products CH3(n-C9H19)CdC(CH3)2 and CH3(n-C9H19)CHC(CH3)dCH2
in 30% and 8% yields, respectively, along with dialkylated products
CH3(n-C9H19)CdC(n-C9H19)CH3 and CH3(n-C9H19)(n-C8H17)CC(CH3)d
CH2 in 13% and 9% yields, respectively.
As mentioned above, allylmagnesium chlorides can be
formed by carbomagnesation of conjugate dienes with
alkyl, aryl, and vinyl halides in the presence of Cp2TiCl2
and n-BuMgCl under mild conditions. Aryl- and silyla-
574 J . Org. Chem., Vol. 69, No. 2, 2004

TABLE 2. Ar ylm a gn esa tion a n d Vin ylm a gn esa tion
Usin g Tita n ocen e Ca ta lyst
SCHEME 2
carbon gives 25 which then reacts with Cp2Ti to give 26.
Subsequent transmetalation of 26 with n-BuMgCl affords
a benzylmagnesium chloride 27 and Cp2Tin-Bu which
reacts with n-BuMgCl to regenerate [Cp2Ti-n-Bu2]-MgCl+.
The reaction of dienes would proceed in a similar way
via the formation of allylic intermediates instead of
benzylic ones.
When the reaction of 28 was carried out in the presence
of p-chlorostyrene and Me3SiCl, three-component cou-
pling took place and 29 was obtained as a sole carbosi-
lylation product (eq 5). This result can reasonably be
explained by a similar radical mechanism comprising
intramolecular cyclization of 30 and intermolecular ad-
dition of 31 to p-chlorostyrene.
a
b
Isolated yield based on halide used. Halide (3 mmol), p-
methylstyrene (10 mmol), nBuMgCl (3.1 mmol), electrophile (1
mmol), Cp2TiCl2 (0.05 mmol), THF (3.4 mL), 0 °C, 2 h. c Aryl
bromide (1 mmol), electrophile (2 mmol), nBuMgCl (3.0 mmol),
Cp2TiCl2 (0.05 mmol), THF (3.3 mL), 0 °C, 2 h.
lkenes also afforded the corresponding benzyl- and R-
silylalkylmagnesium chlorides by the use of secondary,
tertiary and sterically hindered primary alkyl halides.
However combination of arylalkenes and aryl or vinyl
halides was unsuccessful resulting in the formation of
complex mixtures of products due probably to the further
reaction of generated benzylmagnesium chloride with
arylalkenes. To suppress this undesirable reaction we
carried out the reaction of p-methylstyrene with 2-bro-
mopropene in the presence of trimethylchlorosilane as
an electrophile. As shown in run 1 (Table 2), desired
product 18 was formed in 74% yield based on the
chlorosilane. 2-Chloronaphthalene also underwent car-
bomagnesation under identical conditions (run 2). When
aryl bromides containing a carbon-carbon double bond
at the appropriate position, such as 20 and 22, were
employed, intramolecular carbomagnesation proceeded
efficiently probably via radical cyclization (vide infra)
giving rise to 21 and 23, respectively, in good yields (runs
3 and 4).
A new method for regioselective carbomagnesation of
alkenes and conjugated dienes has been developed by the
use of a titanocene catalyst. The titanocene complexes
play important roles both in generation of carbon radicals
from organic halides via electron transfer from titanate-
(III) complexes and in transmetalation of titanocene
intermediates with Grignard reagent. The present car-
bomagnesation involves radical mechanisms in the car-
bon-carbon bond-forming step giving rise to benzyl-,
R-silylalkyl-, and allylmagnesium halides with regiose-
lective introduction of alkyl, aryl, and vinyl groups at a
terminal carbon of the alkenes and dienes using the
corresponding organic halides. Grignard reagents gener-
ated by the present method could be trapped with a
variety of electrophiles such as benzoyl chlorides, benzyl
bromide, a chlorostannane, and chlorosilanes.
A plausible pathway of this reaction is outlined in
Scheme 2 for the case of styrene. Electron transfer from
a titanate complex9 [Cp2Ti-n-Bu2]-MgCl+ to an organic
halide forms carbon radical species 24 and Cp2Tin-Bu2
which decomposes to afford Cp2Ti along with butane and
butanes.10 Addition of 24 to a double bond at the terminal
(8) If this reaction was conducted using 1 equiv of 2,3-dimethyl-1,3-
butadiene (1 mmol) with 2-bromonaphthalene (1 mmol) in the presence
of 5 mol % of Cp2TiCl2 and 2.5 equiv of n-BuMgCl, a 82:18 mixture of
monoarylated compounds (16a , 17%; 16b, 6%) containing a deuterium
at the allylic positions were obtained in 23% total yield along with
64% of naphthalene. This result suggests that addition of naphthyl
radical to butadiene is relatively slow and reduction to naphthalene
predominated under these conditions. Debromination of aryl bromides
using Grignard reagents in the presence of Cp2TiCl2 has been
reported: Colomer, E.; Corriu, R. J . Organomet. Chem. 1974, 82, 367-
373.
Exp er im en ta l Section
All reagents were used as purchased without further purifica-
tion. Analytical and purification procedures for NMR, IR, mass,
(9) It is known that Cp2TiCl2 reacts with an excess amount of
Grignard reagents (RMgX) to form anionic titanate complexes [Cp2-
TiR2]-MgX+: Brintzinger, H. H. J . Am. Chem. Soc. 1967, 89, 6871-
6877.
(10) McDermott, J . X.; Wilson, M. E.; Whitesides, G. M. J . Am.
Chem. Soc. 1976, 98, 6529-6536.
J . Org. Chem, Vol. 69, No. 2, 2004 575

GC-MS, elemental analysis, and HPLC were the same as
mentioned previously.6
3-[P h en yl(tr im eth ylsilyl)m eth yl]in d a n (21). To a mixture
of 4-(2-bromobenzene)-1-phenyl-1-butene 20 (246 mg, 0.86 mmol),
Me3SiCl (227 mg, 2.1 mmol), and n-BuMgCl (0.90 M in THF,
3.3 mL, 3.0 mmol) was added Cp2TiCl2 (12 mg, 0.05 mmol) at 0
°C under nitrogen. After the mixture was stirred for 2 h, similar
workup gave an orange crude product (98% NMR yield).
Purification by HPLC with CHCl3 as an eluent afforded 228 mg
(95%) of 21 as a white solid: IR (NaCl) 2954, 2845, 1246, 834,
754, 702 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.27-7.23 (m, 2H),
7.17-7.10 (m, 4H), 7.08-7.00 (m, 1H), 6.84 (t, J ) 7.57 Hz, 1H),
6.43 (d, J ) 7.56 Hz, 1H), 3.77-3.70 (m, 1H), 2.89-2.82 (m, 2H),
2.45-2.37 (m, 1H), 2.32 (d, J ) 10.74 Hz, 1H), 1.97-1.89 (m,
1H), 0.00 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 148.8, 145.1,
144.2, 128.9, 128.8, 126.6, 125.3, 125.0, 124.9, 124.7, 47.7, 43.7,
34.7, 32.4, 0.00; MS (EI) m/z (rel intensity) 280 (M+, 40), 206
(15), 164 (29), 117 (100), 73 (44); HRMS calcd for C19H24Si
280.1647, found 280.1646. Anal. Calcd for C19H24Si: C, 81.36;
H, 8.62. Found: C, 81.16; H, 8.58.
3-Ben zoyl-2,3,5,5-t et r a m et h yl-1-h ep t en e (9): Typ ica l
Exp er im en ta l P r oced u r e. To a mixture of 2,3-dimethyl-1,3-
butadiene (81 mg, 0.99 mmol), tert-amyl chloride (217 mg, 2.05
mmol), and n-BuMgCl (0.90 M in THF, 3.4 mL, 3.1 mmol) was
added Cp2TiCl2 (12 mg, 0.05 mmol) at 0 °C under nitrogen. After
the mixture was stirred for 2 h, benzoyl chloride (212 mg, 1.5
mmol) was added to the solution at 0 °C, and the mixture was
again warmed to 20 °C. A saturated aqueous NH4Cl solution
(50 mL) was added, and the product was extracted with Et2O
(50 mL), dried over MgSO4, and evaporated to give a yellow
crude product (94% NMR yield). Purification by HPLC with
CHCl3 as an eluent afforded 234 mg (92%) of acylated product
9 as a yellow oil: IR (NaCl) 2963, 2879, 1677, 1446, 1178, 699
cm-1 1H NMR (400 MHz, CDCl3) δ 7.90-7.88 (m, 2H), 7.45-
;
7.41 (m, 1H), 7.36-7.31 (m, 2H), 5.15 (s, 1H), 5.04 (s, 1H), 2.25
(d, J ) 14.6 Hz, 1H), 1.88 (d, J ) 14.6 Hz, 1H), 1.74 (s, 3H),
1.47 (s, 3H), 1.28-1.21 (m, 2H), 0.87 (s, 3H), 0.76-0.71 (m, 6H);
13C NMR (100 MHz, CDCl3) δ 204.6, 149.5, 138.0, 131.1, 128.5,
127.6, 111.4, 56.4, 46.7, 37.5, 34.2, 28.4, 27.2, 24.1, 20.6, 8.4;
MS (EI) m/z (rel intensity) 258 (M+, 0.2), 243 (0.9), 229 (1.8),
188 (16), 173 (5), 105 (100), 77 (13), 71 (17), 43 (13); HRMS calcd
for C18H26O 258.1984, found 258.1985. Anal. Calcd for C18H26O:
C, 83.67; H, 10.14. Found: C, 83.48; H, 10.16.
Ack n ow led gm en t. This research was financially
supported in part by the Ministry of Education, Culture,
Sports, Science and Technology of J apan. S.N. is grate-
ful to J SPS for the Research Fellowship Program for
Young Scientists.
This reaction can be applied to large-scale synthesis by
identical operations as above employing 2,3-dimethyl-1,3-buta-
diene (0.83 g, 10.1 mmol), tert-amyl chloride (2.08 g, 20 mmol),
n-BuMgCl (0.83 M in THF, 37.3 mL, 31 mmol), and Cp2TiCl2
(125 mg, 0.5 mmol) to afford a yellow crude product (3.55 g)
which was purified by column chromatography (silica gel,
n-hexane/Et2O 9:1) to give 2.41 g (93%) of 9 as a yellow oil.
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
mental procedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0354241
576 J . Org. Chem., Vol. 69, No. 2, 2004