Highly stereoselective cobalt-catalyzed allylation of functionalized diarylzinc reagents

Article abstract of DOI:10.1055/s-2007-980344

Functionalized diarylzinc reagents react readily with allylic chlorides or phosphates in the presence of Co(acac)₂ (10 mol%) to give the S _N2 products in high yields and with retention of the double-bond configuration. Functionalities like ester, ketone, or cyano are tolerated. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-980344

LETTER
1383
Highly Stereoselective Cobalt-Catalyzed Allylation of Functionalized
Diarylzinc Reagents
H
ighlyStereoselec
u
tive Cobalt-C
i
a
talyz
l
ed
A
lly
l
lation
a
of Function
u
alized
D
iaryl
m
zinc Reagents e Dunet, Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-Universität München, Butenandtstraße 5–13, 81377 München, Germany
Fax +49(89)218077680; E-mail: Paul.Knochel@cup.uni-muenchen.de
Received 27 February 2007
benzoate 3b was isolated in 72% yield (entry 1 of
Table 2). The reaction proceeded similarly when the zinc
reagent 2b was formed in a two-step procedure (an io-
dine–magnesium exchange,5,6 followed by a transmetalla-
tion with 0.5 equiv of ZnBr2), yielding 3b in 69% yield.
Other functionalities were also tolerated in these cross-
coupling reactions. Thus, the diarylzinc reagent 2c, bear-
ing a cyano functionality, reacted smoothly with geranyl
chloride affording the benzonitrile 3c in 75% yield (entry
2). In a similar manner, di(3-trifluoromethylphenyl)zinc
(2d), and di(2-bromophenyl)zinc (2e) react with geranyl
chloride, leading to the E-dienes 3d–e in 72–87% yields
(entries 3 and 4). Even the bulkier zinc reagent dinaph-
thylzinc (2f) reacted smoothly under our conditions, lead-
ing to the expected diene 3f in 82% yield. Interestingly,
when we performed the allylation with neryl chloride
(1b),7 only Z-dienes were obtained, showing that the con-
figuration of the double bond has been preserved through-
out the process. Thus, when neryl chloride was reacted
with the functionalized diarylzinc reagents 2d, 2g or 2h,
the corresponding Z-dienes 3g–i were isolated in 76–78%
yields (entries 6–8).
Abstract: Functionalized diarylzinc reagents react readily with
allylic chlorides or phosphates in the presence of Co(acac)2 (10
mol%) to give the SN2 products in high yields and with retention of
the double-bond configuration. Functionalities like ester, ketone, or
cyano are tolerated.
Key words: catalysis, allylation, cobalt catalysis, organozinc re-
agents, stereoselective cross-coupling, nocarasin C
Palladium-, nickel- and copper-catalyzed cross-coupling
reactions between allylic substrates and organometallic
reagents are among the most useful reactions catalyzed by
transition metals.1 Less attention has been given to other
transition metals, particularly to cobalt.2 Recently, a ste-
reoselective cobalt(II)-catalyzed cross-coupling reaction
between alkylzinc halides or dialkylzinc reagents and al-
lylic chlorides or phosphates was described.3 It led exclu-
sively to the SN2-substitution products with full retention
of the double-bond configuration. Herein, we wish to re-
port an extension of this method using highly functional-
ized diarylzinc reagents, obtained from the corresponding
aryl iodides via
a
direct iodine–zinc exchange4
(Scheme 1).
We then extended the allylic reaction to the more easily
available allylic phosphates.8 Thus, when di(4-methylcar-
boxyphenyl)zinc (2g) was reacted with geranyl phos-
phate, the expected E-diene 3j was obtained in 68% yield.
In a similar manner, the diene 3k and the pivalate 3l were
isolated in 64–71% yields (entries 10 and 11). Under the
same conditions, neryl phosphate (1d) led to the Z-dienes
3m–o in moderate to good yields (entries 12–14). When
cinnamyl phosphate (1e) reacted with 2g, the configura-
tion of the double bond was also retained, leading to the
expected product 3p in 67% yield (entry 15).
First, we reacted geranyl chloride (1a) with diphenylzinc
in the presence of a cobalt(II) salt. A systematic study
showed that the best results were obtained when geranyl
chloride (1 equiv) was treated with diphenylzinc (2a; 1.3
equiv) in DME, in the presence of Co(acac)2 (10 mol%;
Table 1). In this case, the reaction was complete within
one hour, yielding (E)-(3,7-dimethylocta-2,6-dienyl)ben-
zene (3a) in 87% yield. Then, we investigated the reaction
of the functionalized zinc reagent 2b with geranyl
chloride (1a). Under the same reaction conditions, the
i-Pr2Zn
(0.6 equiv),
Li(acac)
R1
R2
X
FG
R1
R2
(10 mol%)
1
FG
FG
I
Zn
2
NMP, r.t.,
12–18 h
Co(acac)2
(10 mol%),
NMP, 0 °C
4
3 (64–87%)
X = Cl, OP(O)(OEt)2
2
Scheme 1 Cobalt-catalyzed allylation of diarylzinc reagents
SYNLETT 2007, No. 9, pp 1383–1386
0
1.
0
6.
2
0
0
7
Advanced online publication: 23.05.2007
DOI: 10.1055/s-2007-980344; Art ID: G04207ST
© Georg Thieme Verlag Stuttgart · New York

1384
G. Dunet, P. Knochel
LETTER
Table 1 Optimization of the Reaction Conditions
Table 2 Cobalt-Catalyzed Allylation of Diarylzinc Reagents
R1
X
Me
Me
FG
Ph2Zn (1.3 equiv)
[Co] catalyst
R1
R2
Cl
Ph
R2
FG
1
Zn
2
Co(acac)2
(10 mol%),
NMP, 0 °C
solvent, 1 h, 0 °C
Me
Me
2
3
Me
Me
3a
1a
X = Cl, OP(O)(OEt)2
Entry Catalyst
Solvent
NMP
NMP
NMP
NMP
THF
Conversion (%)a
Entry Allyl chloride
Diarylzinc
reagent 2
Product Yield
3
or phosphate 1
(%)a
1
2
3
4
5
6
CoBr2 (10 mol%)
50
1
geranyl chloride (1a)
FG = p-CO2Et 3b
(2b)
72 (69)b
(>98% E)
Co(acac)2 (2.5 mol%)
Co(acac)2 (5 mol%)
Co(acac)2 (10 mol%)
Co(acac)2 (10 mol%)
Ni(acac)2 (1 mol%)
24
R1 = Me
75
R2 = (CH2)2CH=C(Me)2
X = Cl
100 (52,b 82c)
2
3
4
5
6
1a
1a
1a
1a
FG = m-CN
(2c)
3c
3d
3e
75
(>98% E)
65d
39
NMP
FG = m-CF3
(2d)
87
(>98% E)
a GC conversion after 1 h.
b Ph2Zn (0.65 equiv) was used.
c Ph2Zn (1 equiv) was used.
FG = o-Br
(2e)
72
(>98% E)
d Large amounts of homocoupling product were observed.
dinaphthylzinc 3f
(2f)
82
(>98% E)
Diheteroarylzinc reagents can also be used as substrates.
Thus, di(5-iodothiophen-2-yl)zinc (2k) was prepared via
a direct iodine–zinc exchange4 and reacted with geranyl
chloride (1a), yielding the expected E-diene 3q in 77%
yield (Scheme 2). In a similar manner, the thiophene de-
rivative 3r was formed in 78% yield, showing that a keto
function was also tolerated.
neryl chloride (1b)
R1 = (CH2)2CH=C(Me)2
R2 = Me
2d
3g
78
(>98% Z)
X = Cl
7
8
9
1b
FG = p-CO2Me 3h
(2g)
76
(>98% Z)
1b
FG = m-Br
(2h)
3i
76
We have applied this cross-coupling reaction to an ex-
pedient synthesis of nocarasin C,9 a metabolite from the
actinomycete Nocardia brasiliensis, exhibiting some
cytotoxic activity (Scheme 3).
(>98% Z)
geranyl phosphate (1c) 2g
R1 = Me
3j
68
(>98% E)
R2 = (CH2)2CH=C(Me)2
X = OP(O)(OEt)2
After a regioselective iodination of 3-hydroxybenzoic
acid (5), and subsequent methylation with dimethyl sul-
fate in acetone, the corresponding methyl-4-iodo-3-meth-
oxybenzoate (6) was obtained in 60% yield. A direct
iodine–zinc exchange with i-Pr2Zn and Li(acac) in NMP
10
11
12
1c
FG = m-OMe 3k
(2i)
71
(>98% E)
1c
FG = p-OPv
(2j)
3l
64
(>98% E)
Me
neryl phosphate (1d)
R1 = (CH2)2CH=C(Me)2
R2 = Me
2c
3m
70
S
I
Zn
(>98% Z)
S
2
I
X = OP(O)(OEt)2
Me
13
14
15
1d
1d
2f
2i
3n
3o
3p
73
(>98% Z)
Cl
Me
Me
3q (77%)
Co(acac)2
(10 mol%),
NMP, 0 °C
Me
77
(>98% Z)
Me
Me
O
S
1a
cinnamyl phosphate (1e) 2g
R1 = H
67
(100% E)
Me
O
S
Zn
R2 = Ph
Me
2
Me
Me
3r (78%)
X = OP(O)(OEt)2
a Isolated yield of analytically pure compounds.
Scheme 2 Allylation of di(heteroaryl)zinc reagents
b The zinc reagent was prepared through an I–Mg exchange, followed
by a transmetallation with ZnBr2 (0.5 equiv).
Synlett 2007, No. 9, 1383–1386 © Thieme Stuttgart · New York

LETTER
Highly Stereoselective Cobalt-Catalyzed Allylation of Functionalized Diarylzinc Reagents
1385
Weinheim, 2005, Chap. 2.3. (f) Shintani, R.; Hayashi, T. In
Modern Organonickel Chemistry; Tamaru, Y., Ed.; Wiley-
VCH: Weinheim, 2005, Chap. 9.2. (g) Magid, R. M.
Tetrahedron 1980, 36, 1901. (h) Lipshutz, B. H.; Sengupta,
S. Org. React. (N.Y.) 1992, 41, 135. (i) Karlström, A. S. E.;
Bäckvall, J.-E. In Modern Organocopper Chemistry;
Krause, N., Ed.; Wiley-VCH: Weinheim, 2002, 259.
(j) Yorimitsu, H.; Oshima, K. Angew. Chem. Int. Ed. 2005,
44, 4435.
I
OH
1. I2, KI, NH3 (aq)
r.t., 3 h
OMe
2. Me2SO4, K2CO3,
acetone, reflux,
12 h
CO2H
CO2Me
6 (60%)
5
6
Zn
i-Pr2Zn (0.6 equiv),
Li(acac) (10 mol%),
NMP, r.t., 12 h
2
(2) (a) Mizutani, K.; Yorimitsu, H.; Oshima, K. Chem. Lett.
2004, 7, 832. (b) Gomes, P.; Gosmini, C.; Périchon, J.
J. Org. Chem. 2003, 68, 1142. (c) Gomes, P.; Gosmini, C.;
Périchon, J. Org. Lett. 2003, 5, 1043. (d) Yasui, H.;
Mizutani, K.; Yorimitsu, H.; Oshima, K. Tetrahedron 2006,
62, 1410. (e) For cobalt-catalyzed reactions involving
organozinc reagents, see for example: Avedissian, H.;
Berillon, L.; Cahiez, G.; Knochel, P. Tetrahedron Lett. 1998,
39, 6163.
OMe
CO2Me
1a,
Co(acac)2 (10 mol%),
NMP, 0 °C, 3 h
(3) Reddy, K.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1996,
35, 1700; Angew. Chem. 1996, 108, 1812.
Me
OMe
(4) Kneisel, F. F.; Dochnahl, M.; Knochel, P. Angew. Chem. Int.
Ed. 2004, 43, 1017.
(5) Recent review: Knochel, P.; Dohle, W.; Gommermann, N.;
Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A.
Angew. Chem. Int. Ed. 2003, 42, 4302.
(6) For recent advances in halogen–magnesium exchange, see:
(a) Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2004,
43, 3333. (b) Liu, C.-Y.; Knochel, P. Org. Lett. 2005, 7,
2543. (c) Ren, H.; Krasovskiy, A.; Knochel, P. Chem.
Commun. 2005, 543. (d) Ren, H.; Krasovskiy, A.; Knochel,
P. Org. Lett. 2004, 6, 4215.
CO2Me
Me
Me
nocarasin C (3s) (78%)
Scheme 3 Synthesis of nocarasin C
(20 °C, 12 h) afforded the corresponding diarylzinc re-
agent 2m which, when reacted with geranyl chloride in
the presence of Co(acac)2, (10 mol%) led to nocarasin C
(3s) in 78% yield.
(7) Prepared according to: Nowotny, S.; Tucker, C. E.; Jubert,
C.; Knochel, P. J. Org. Chem. 1995, 60, 2762.
(8) Allylic phosphates are readily prepared from the
corresponding allylic alcohols using diethyl
In summary, we have developed an improved cobalt-cat-
alyzed allylation reaction of diarylzinc reagents.10 Under
these reaction conditions, the cross-coupling reactions are
highly stereoselective, and provide the SN2 products with
retention of the double-bond configuration. Functional-
ities like ester, ketone, or nitrile are perfectly tolerated,
which makes this cross-coupling particularly attractive
for the synthesis of polyfunctional target molecules. Ex-
tensions of this method are currently underway in our lab-
oratories.
chlorophosphate (1.05 equiv) and pyridine (2.2 equiv) in
Et2O or CH2Cl2: Nowotny, S.; Tucker, C. E.; Jubert, C.;
Knochel, P. J. Org. Chem. 1995, 60, 2762.
(9) Tsuda, M.; Nemoto, A.; Komaki, H.; Tanaka, Y.; Yazawa,
K.; Mikami, Y.; Kobayashi, J. J. Nat. Prod. 1999, 62, 1640.
(10) Representative Procedure for the Preparation of (E)-
Ethyl 4-(3,7-Dimethylocta-2,6-dienyl)benzoate (3b): In a
dry nitrogen-flushed Schlenk tube equipped with a septum
and a magnetic stirring bar, ethyl 4-iodobenzoate (718 mg,
2.60 mmol) and anhyd Li(acac) (35 mg) were dissolved in
anhyd NMP (3.0 mL) and cooled to 0 °C. Then, i-Pr2Zn
(0.27 mL, 5.9 M solution in Et2O, 1.59 mmol, 0.6 equiv) was
added dropwise. The reaction mixture was stirred at room
temperature until the exchange reaction was complete (12 h).
In a dry nitrogen-flushed Schlenk tube equipped with a
septum and a magnetic stirring bar, geranyl chloride (173
mg, 1 mmol) and Co(acac)2 (27 mg, 10 mol%) were
dissolved in anhyd NMP (0.5 mL) and cooled to 0 °C. The
freshly prepared diarylzinc reagent (1.3 mmol) was added
dropwise. The reaction mixture was stirred at 0 °C, until the
reaction was complete (GC monitoring). Saturated aq NH4Cl
was added, and the mixture was extracted several times with
Et2O. The organic layer was dried (MgSO4) and the volatiles
were removed in vacuo (the mixture was heated to 50 °C
while evaporating under high vacuum for 2 h). Purification
by flash column chromatography (eluent: pentane–Et2O,
98:2) afforded 3b as a pale yellow oil (205 mg 72%). 1H
NMR (400 MHz, CDCl3): d = 7.88 (d, J = 8.2 Hz, 2 H), 7.16
(d, J = 8.6 Hz, 2 H), 5.22–5.27 (m, 1 H), 5.00–5.04 (m, 1 H),
4.28 (q, J = 7.0 Hz, 2 H), 3.33 (d, J = 7.4 Hz, 2 H), 1.96–2.07
(m, 4 H), 1.63 (d, J = 1.2 Hz, 3 H), 1.61 (d, J = 1.2 Hz, 3 H),
1.53 (s, 3 H), 1.31 (t, J = 7.0 Hz, 3 H). 13C NMR (75 MHz,
Acknowledgment
We thank the DFG and the Fonds der Chemischen Industrie for the
generous financial support. We thank Chemetall GmbH (Frankfurt),
Degussa AG (Hanau) and BASF AG for the generous gift of chemi-
cals.
References and Notes
(1) (a) Tamao, K. In Comprehensive Organic Synthesis, Vol. 3;
Trost, B. M.; Fleming, I.; Pattenden, G., Eds.; Pergamon:
Oxford, 1991, Chap. 2.2.10.4. (b) Tsuji, J. Palladium
Reagents and Catalysts; Wiley: Chichester, 1995.
(c) Negishi, E.; Liu, F. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley:
New York, 2002, Chap. III.2.9. (d) Negishi, E.; Liao, B. In
Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; Wiley: New York, 2002, Chap.
III.2.10. (e) Takahashi, T.; Kanno, K. In Modern
Organonickel Chemistry; Tamaru, Y., Ed.; Wiley-VCH:
Synlett 2007, No. 9, 1383–1386 © Thieme Stuttgart · New York

1386
G. Dunet, P. Knochel
LETTER
HRMS (EI): m/z calcd for C17H21F3: 282.1595; found:
CDCl3): d = 165.7, 146.2, 136.1, 130.5, 128.6, 127.2, 127.0,
123.1, 121.0, 59.7, 38.6, 33.2, 25.5, 24.7, 16.7, 15.1, 13.3. IR
(neat): 2968, 2913, 1711, 1605, 1442, 1366, 1252, 1174,
1101, 1029, 769 cm–1. MS (EI): m/z (%) = 286 (8), 243 (16),
241 (24), 218 (22), 189 (22), 145 (61), 143 (31), 123 (81), 69
(100). HRMS (EI): m/z calcd for C19H26O2: 286.1933;
found: 286.1922. (E)-3-(3,7-Dimethylocta-2,6-di-
282.1608. (E)-1-Bromo-2-(3,7-dimethylocta-2,6-di-
enyl)benzene (3e): 1H NMR (400 MHz, CDCl3): d = 7.53 (d,
J = 7.4 Hz, 1 H), 7.21–7.24 (m, 2 H), 7.02–7.08 (m, 1 H),
5.27–5.33 (m, 1 H), 5.08–5.14 (m, 1 H), 3.45 (d, J = 7.4 Hz,
2 H), 2.04–2.17 (m, 4 H), 1.71 (d, J = 0.8 Hz, 3 H), 1.69 (d,
J = 1.2 Hz, 3 H), 1.61 (s, 3 H). 13C NMR (75 MHz, CDCl3):
d = 141.1, 137.5, 132.8, 131.8, 130.2, 127.6, 127.6, 124.9,
124.4, 121.5, 40.0, 34.8, 26.8, 26.0, 18.0, 16.5. IR (neat):
2968, 2913, 1604, 1500, 1442, 1366, 1101, 769 cm–1. MS
(EI): m/z (%) = 294 (2), 292 (2), 251 (9), 249 (9), 145 (17),
144 (87), 143 (23), 129 (47), 128 (19), 123 (100), 69 (78).
HRMS (EI): m/z calcd for C16H21Br: 292.0827; found:
292.0831. (E)-1-(3,7-Dimethylocta-2,6-di-
enyl)benzonitrile (3c): 1H NMR (300 MHz, CDCl3): d =
7.24–7.42 (m, 4 H), 5.17–5.26 (m, 1 H), 4.96–5.05 (m, 1 H),
3.30 (d, J = 7.1 Hz, 2 H), 1.94–2.12 (m, 4 H), 1.62 (s, 3 H),
1.61 (s, 3 H), 1.53 (s, 3 H). 13C NMR (75 MHz, CDCl3): d =
142.2, 136.8, 131.9, 130.8, 130.7, 128.5, 128.0, 123.0,
120.3, 118.1, 111.3, 38.6, 32.7, 25.4, 24.7, 16.7, 15.2. IR
(neat): 3379, 2968, 2924, 2230, 1600, 1582, 1482, 1434,
1379, 1096, 792 cm–1. MS (EI): m/z (%) = 239 (1), 196 (4),
171 (6), 156 (7), 123 (24), 69 (100). HRMS (EI): m/z calcd
C17H21N: 239.1674; found: 239.1661. (E)-1-(3,7-
Dimethylocta-2,6-dienyl)-3-trifluoromethylbenzene
(3d): 1H NMR (600 MHz, CDCl3): d = 7.38–7.43 (m, 2 H),
7.31–7.37 (m, 2 H), 5.28–5.33 (m, 1 H), 5.06–5.11 (m, 1 H),
3.41 (d, J = 7.6 Hz, 2 H), 2.05–2.18 (m, 4 H), 1.72 (d, J = 1.0
Hz, 3 H), 1.68 (s, 3 H), 1.60 (s, 3 H). 13C NMR (75 MHz,
CDCl3): d = 142.9, 137.5, 131.9, 131.8, 130.8 (q, J = 32.5
Hz), 128.9, 125.5 (q, J = 272.6 Hz), 125.2 (m), 124.2, 122.8
(m), 122.2, 39.9, 34.2, 26.7, 25.8, 17.9, 16.5. IR (neat): 2968,
2913, 1442, 1366, 1328, 1156, 1115, 824, 631 cm–1. MS
(EI): m/z (%) = 282 (2), 239 (5), 159 (6), 123 (25), 69 (100).
enyl)naphthalene (3f): 1H NMR (300 MHz, CDCl3): d =
7.92–7.98 (m, 1 H), 7.73–7.80 (m, 1 H), 7.63 (d, J = 7.4 Hz,
1 H), 7.38–7.47 (m, 2 H), 7.23–7.36 (m, 2 H), 5.30–5.38 (m,
1 H), 4.98–5.07 (m, 1 H), 3.71 (d, J = 6.7 Hz, 2 H), 1.95–2.11
(m, 4 H), 1.71 (d, J = 1.5 Hz, 3 H), 1.58 (s, 3 H), 1.51 (s, 3
H). 13C NMR (75 MHz, CDCl3): d = 138.0, 136.6, 134.1,
132.4, 131.7, 128.9, 126.8, 125.9, 125.9, 125.8, 125.7,
124.5, 124.3, 123.1, 40.0, 31.9, 26.9, 25.9, 18.0, 16.5. IR
(neat): 3045, 2966, 2913, 2853, 1597, 1510, 1440, 1396,
1376, 790 cm–1. MS (EI): m/z (%) = 264 (37), 196 (18), 195
(98), 193 (33), 181 (24), 167 (45), 166 (42), 165 (99), 153
(100), 141 (59), 123 (85), 69 (51). HRMS (EI): m/z calcd for
C20H24: 264.1878; found: 264.1886.
Synlett 2007, No. 9, 1383–1386 © Thieme Stuttgart · New York