Highly selective reactions of unbiased alkenyl halides and alkylzinc halides: Negishi-plus couplings

Article abstract of DOI:10.1021/ol201307y

High yielding stereo- and chemoselective Pd-catalyzed cross-couplings in THF at room temperature of alkenyl iodides and bromides with primary and secondary alkyl zinc iodides have been developed with the aid of N-methyimidazole as the key additive.

Full text of DOI:10.1021/ol201307y

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3822–3825
Highly Selective Reactions of Unbiased
Alkenyl Halides and Alkylzinc Halides:
Negishi-Plus Couplings
Arkady Krasovskiy and Bruce H. Lipshutz*
Department of Chemistry & Biochemistry, University of California, Santa Barbara,
California 93106, United States
lipshutz@chem.ucsb.edu
Received May 15, 2011
ABSTRACT
High yielding stereo- and chemoselective Pd-catalyzed cross-couplings in THF at room temperature of alkenyl iodides and bromides with primary
and secondary alkyl zinc iodides have been developed with the aid of N-methyimidazole as the key additive.
Sp2ꢀsp3 cross-couplings of E- or Z-alkenyl halides with
alkylzinc reagents, as described decades ago by Negishi,
Scheme 1. Negishi Cross-Couplings of Alkenyl Halides with
Alkylzinc Iodides
are among the most important Pd-catalyzed reactions in
synthesis.1 As one of three recently chosen “name” reac-
tions to be awarded the Nobel Prize in Chemistry, these
transformations are sure togain evenfurther in popularity.
One of the most challenging types of Negishi couplings is
that between alkenyl halides and alkylzinc halides. Asso-
ciated with such cross-couplings, issues that may arise
include concomitant formation of undesired byproducts
(Scheme 1), as well as the potential erosion of stereochem-
of Z-alkenyl iodides.3 In this report we disclose new technol-
ogythat allowsfor highly stereoselective cross-couplingsof
alkenyl iodides and bromides with primary and secondary
alkyl zinc iodides. Our approach provides consistent
maintenance of both E- and Z-olefin geometry in the
products, and excellent levels of efficiency, which exceed
results to be expected from traditional additive-free
Negishi cross-couplings,1,2 and even our recently disclosed
methodology.3
As a representative example, (Z)-1-bromooct-1-ene (1-Z)
and n-heptylzinc iodide were coupled using 2 mol % of the
commonly employed catalyst PdCl2(PPh3)2. Although
retention of geometry in the resulting Z-olefin was ob-
served, the reaction led to a mixture of products, including
significant amounts of protio-quench material and the
product of olefin homocoupling (Scheme 1 and Table 1,
istry in the case of a Z-alkenyl halide.2
Recently, we have shown that addition of TMEDA to a
reaction mixture under otherwise standard Negishi condi-
tions1 prevents losses of stereointegrity in cross-couplings
(1) (a) Transition Metals in the Synthesis of Complex Organic
€
Molecules, 3rd ed.; Hegedus, L. S., Soderberg, B. C. G., Eds.; University
Science Books: Sausalito, CA, 2009. (b) Palladium in Organic Synthesis;
Tsuji, J., Ed.; Springer: Berlin, 2005. (c) Negishi, E.-I.; Gagneur, S. In
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E., Ed.; Wiley-VCH: New York, 2002; Vol. 1, p 597. (d) Metal-Catalyzed
Cross-coupling Reactions; Diederich, F., Stang, P. G., Eds.; Wiley-VCH:
New York, 1998.
(2) (a) Negishi, E.-I.; Valente, L. F.; Kobayashi, M. J. Am. Chem.
Soc. 1980, 102, 3298. (b) Negishi, E.-I. Acc. Chem. Res. 1982, 15, 340. (c)
Knochel, P; Singer, R. D. Chem. Rev. 1993, 93, 2117. (d) Negishi, E.-I.;
Hu, Q.; Huang, Z.; Qian, M.; Wang, G. Aldrichimica Acta 2005, 38, 71.
(e) Negishi, E.-I.; Huang, Z.; Wang, G.; Mohan, S.; Wang, C.; Hattori,
H. Acc. Chem. Res. 2008, 41, 1474.
(3) Krasovskiy, A.; Lipshutz, B. H. Org. Lett. 2011, in press.
r
10.1021/ol201307y
Published on Web 07/08/2011
2011 American Chemical Society

entry 1). Among many screened mono- and bidentate
ligands (Figure 1), only conformationally flexible dppf
and DPEPhos (entries 2 and 3), both having large bite
angles,4 proved to be effective for the desired Pd-catalyzed
transformation. While the restricted geometry character-
istic of XantPhos led to stereoretention (entry 4), a poor
yield was obtained.
Table 1. Effect of Catalyst and Additives on Reactions of
Alkenyl Bromide 1 with a Primary and Secondary Alkylzinc
Iodidesa
yield
(%)c
entry
1
catalyst
PdCl2(PPh3)2
Z/Eb
1
2
3
4
5
6
7
Z
Z
Z
Z
Z
Z
Z
99/1
99/1
99/1
98/2
99/1
99/1
99/1
64
PdCl2(dppf)
92
PdCl2(DPEPhos)
94
PdCl2(XantPhos)
72
PdCl2(PPh3)2 þ TMEDAe
PdCl2(PPh3)2 þ N-MeImf
PdCl2(DPEPhos) þ N-MeImf
91
93
>99
(96)d
34
8
E
E
E
E
E
PdCl2(PPh3)2
1/99
1/99
1/99
1/99
1/99
9
PdCl2(DPEPhos)
90
10
11
12
PdCl2(PPh3)2 þ TMEDAe
PdCl2(PPh3)2 þ N-MeImf
PdCl2(DPEPhos) þ N-MeImf
72
82
>99
(95)d
Figure 1. Ligands associated with Pd catalysts screened.
Remarkably, in the presence of N,N,N0,N0-tetramethyl-
ethane-1,2-diamine (TMEDA, 1.1 equiv vs substrate)
or N-methylimidazole5 (N-MeIm, 2.0 equiv vs sub-
strate) under otherwise identical and standard Negishi
conditions1 with the simplest monodentate catalyst PdCl2-
(PPh3)2, virtually complete stereoretention and high
yields were realized (Table 1, entries 5 and 6). The overall
efficiency can be further enhanced using bidentate
ligand-containing catalyst PdCl2(DPEPhos) leading to the
desired cross-coupled product in essentially quantitative
yield (entry 7).
These newly discovered ligand/additive effects can also
be applied to Negishi cross-couplings of (E)-1-bromooct-
1-ene (1-E) with n-heptylzinc iodide. The results obtained
follow the same trend as seen in the case of isomeric
Z-alkenyl bromide 1-Z (entries 8ꢀ12). Complete conver-
sion of starting alkenyl bromide 1-E to the desired product
2-E was observed using the PdCl2(DPEPhos)/N-MeIm
pair (entry 12).
yield
(%)c
entry
1
catalyst
Z/Eb
13
14
15
16
17
18
Z
Z
Z
Z
Z
Z
PdCl2(PPh3)2
ND
<5
<5
40
PdCl2(DPEPhos)
ND
PdCl2(PPh3)2 þ TMEDAe
PdCl2(PPh3)2 þ N-MeImf
PdCl2(DPEPhos) þ N-MeImf
PdCl2(Amphos)2 þ N-MeImf
94/6
96/4
96/4
99/1
69
83
>99
(96)d
19
20
21
22
23
24
E
E
E
E
E
Z
PdCl2(PPh3)2
1/99
1/99
1/99
1/99
1/99
1/99
49
∼10
66
PdCl2(DPEPhos)
PdCl2(PPh3)2 þ TMEDAe
PdCl2(PPh3)2 þ N-MeImf
PdCl2(DPEPhos) þ N-MeImf
PdCl2(Amphos)2 þ N-MeImf
81
93
>99
(98)d
Cross-coupling of secondary alkyl zinc iodides proved to
be more demanding. Use of either PdCl2(PPh3)2 or PdCl2-
(DPEPhos) alone led to only traces of final product (entries
13, 14, 20). Under the best conditions of PdCl2(DPEPhos)/
N-MeIm found for couplings with primary alkylzinc
a Conditions: n-heptylzinc iodide or cyclohexylzinc iodide (1.1 mmol,
1.0 M in THF), alkenyl bromide (1.0 mmol), Pd catalyst (2 mol %).
Reactions were run at 0.33 M at rt, 24 h. b Z/E ratio determined by NMR
and GC on crude material. c GC yield. d Isolated yield. e 1.1 equiv. f 2.0
equiv.
halides (vide supra), full conversion was not observed
(entries 17, 23).
Additional screening of ligands ultimately led to an
(4) Burello, E.; Rothenberg, G. Adv. Synth. Catal. 2005, 347, 1969.
(5) For reports of enhanced reactivity of an alkylzinc reagent in the
presence of N-MeIm, see: (a) Inoe, S.; Furukawa, K. J. Organomet.
Chem. 1972, 37, 25. (b) Inoe, S.; Imanaka, Y. J. Organomet. Chem. 1972,
35, 1. (c) Inoe, S.; Yokoo, Y. J. Organomet. Chem. 1972, 39, 11. (d) Zhou,
J.; Fu, C. G. J. Am. Chem. Soc. 2003, 125, 12527.
(6) (Amphos)2PdCl2 (CAS #887919-35-9) obtained from Johnson
Matthey (Amphos = p-dimethylaminophenyl-di-tert-butyllphosphine):
Guram, A. S.; King, A. O.; Allen, J. G.; Wang, X.; Schenkel, L. B.; Chan,
J.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J.; Reider,
P. J. Org. Lett. 2006, 8, 1787.
6
especially efficient combination: PdCl2(Amphos)2 /N-
MeIm. This catalyst/additive system affords both excellent
yields and essentially total stereoretention (entries 18, 24).
To further explore the scope of these cross-coupling
reactions, several alkenyl halides containing varying
Org. Lett., Vol. 13, No. 15, 2011
3823

conditions developed for these stereoselective cross-
couplings, should allow for the synthesis of a variety of
functionalized isomerically pure alkenes. As illustrated in
Scheme 2, functional groups such as Boc- and an ester are
tolerated within the starting organozinc reagents. Note-
worthy is the high yield and isomeric purity of very
sterically hindered alkene 10 derived from (Z)-1-iodo-
3,3-dimethylbut-1-ene.9 Here again, experiments utilizing
different catalysts and additives, including TMEDA, were
not consistently as effective as the PdCl2(Amphos)2/
N-MeIm combination.10
Table 2. Cross-Couplings of n-Decylzinc Iodide with Repre-
sentative Alkenyl Bromidesa
Scheme 2. Cross-Couplings of Functionalized Reagentsa
a Conditions: n-decylzinc iodide (1.1 mmol, 1.0 M in THF), alkenyl
halide (1.0 mmol), PdCl2(Amphos)2 (2 mol %), N-MeIm (2.0 mmol).
Reactions run at 0.33 M at rt, 3 h (12 h for entries 4 and 5). b Isolated
yield. c From 90% technical grade R-bromostyrene. d n-Decylzinc iodide
(2.4 equiv) used.
substitution patterns were examined (Table 2). Thus, in
addition to the β-substituted alkenyl halides illus-
trated in Table 1, both β,β- (entry 1), R- (entries 2, 3),
and R,β-substituted (entries 4, 5) alkenyl halides coupled
smoothly at room temperature under these newly found
conditions. Also noteworthy is the case of highly labile
(Z)-1-(2-iodoethenyl)cyclohexene (entry 6), found to readily
undergo cross-coupling with complete retention of config-
uration. While both alkenyl bromides and iodides react
smoothly, use of alkenyl iodides is preferred for reactivity
and stability reasons.7
a Conditions: organozinc halide (1.1 mmol, 1.0 M in THF),
alkenyl halide (1.0 mmol), Pd catalyst (2 mol %), TMEDA (1.1
mmol), N-MeIm (2.0 mmol). Reactions were run at 0.33 M at rt, 24
h (3 h for 12). Z/E ratio determined by NMR and GC on crude
material. Isolated yields.
In general, reactions of alkylzinc halides leading to
various undesired products (Scheme 3) has been addressed
by using bidentate ligands to ensure saturation of the
coordination sphere of Pd,11 thus discouraging pathways
such as β-H elimination and homocoupling via ligand
The well-known functional group tolerance of organo-
zinc reagents,8 together with the exceptionally mild
(9) (Z)-1-Iodo-3,3-dimethylbut-1-ene as a starting material was cho-
sen over the corresponding bromide due to the volatility of the latter
compound.
(10) See Supporting Information.
(7) (a) Brown, H. C.; Blue, C. D.; Nelson, D. J.; Bhat, N. G. J. Org.
Chem. 1989, 54, 6064. (b) Ren, H.; Krasovskiy, A.; Knochel, P. Org.
Lett. 2004, 6, 4215.
(8) (a) Rieke, R. D.; Hanson, M. V. Tetrahedron 1997, 53, 1925. (b)
Organozinc Reagents, A Practical Approach; Knochel, P., Jones, P., Eds.;
Oxford: New York, 1999. (c) Handbook of Functionalized Organometal-
lics. Applications in Synthesis; Knochel, P., Ed.; Wiley: Weinheim, 2005.
(11) (a) Zuideveld, M. A.; Swennenhuis, B. H. G.; Boele, M. D. K.;
Guari, Y.; van Strijdonck, G. P. F.; Reek, J. N. H.; Kamer, P. C. J.;
Goubitz, K.; Fraanje, J.; Lutz, M.; Spek, A. L.; van Leeuwen, P. W. N.
M. J. Chem. Soc., Dalton Trans. 2002, 2308. (b) Chass, G. A.; O’Brien,
C. J.; Hadei, N.; Kantchev, E. A. B.; Mu, W.-H.; Fang, D.-C.;
Hopkinson, A. C.; Csizmadia, I. G.; Organ, M. G. Chem.;Eur. J.
2009, 15, 4281.
3824
Org. Lett., Vol. 13, No. 15, 2011

case of secondary alkyl zinc reagents.14 Our preliminary
studies showed that addition of N-methylimidazole also
suppresses this undesired transformation leading to branched
products 13ꢀ14 in excellent yields without detectable forma-
tion of isomerized byproducts (Scheme 4).15
Scheme 3. Sequence Leading to the Desired “Product” When
Pd(0)Ln = PdCl2(Amphos)2/N-Methylimidazole, or Product
Mixtures Using Other Catalysts/Additives
Scheme 4. Cross-Couplings of Aryl Halides with sec-C4H9ZnIa
a Conditions: organozinc halide (1.1 mmol, 1.0 M in THF), aryl
bromide (1.0 mmol), Pd(Amphos)2 (2 mol %), N-MeIm (2.0 mmol), 6 h
at 40 °C for 13 and 3 h at rt for 14. Isolated yields.
In summary, a new catalyst system has been identified
thatoffersa generalsolution tofundamental problems that
can be encountered in Negishi couplings: that is, protio-
quenching and homocoupling that can dramatically im-
pact yields and stereochemical issues, most notably when
Z-alkenyl educts are involved. These “Negishi-Plus” reac-
tions involve a combination of catalytic PdCl2(Amphos)2
together with stoichiometric N-methylimidazole; when
used in THF at room temperature, cross-couplings be-
tween 1° and 2° alkylzinc reagents and variously substi-
tuted alkenyl iodides or bromides take place in high yields.
scrambling. We assume that addition of stoichimetric
amounts of N-methylimidazole, or TMEDA, serves the same
purpose, thus allowing use of simple monodentate ligand-
containing catalysts such as PdCl2(Amphos)2. Presumably,
the presence of these additives in stoichiometric amounts
provides a coordinating ligand for both catalytic palla-
dium12 and stoichiometric zinc.13
Acknowledgment. Financial support provided by the
NIH is warmly acknowledged. We are grateful to Johnson
Matthey for generously supplying PdCl2(Amphos)2 and
Pd(Amphos)2, and to Boulder Scientific for the Cp2ZrCl2
used to make the alkenyl halides used in this study.
It is known that β-H elimination is also responsible for
the formation of isomerized cross-coupled products in the
(12) (a) Szulmanowicz, M. S.; Zawartka, W.; Gniewek, A.; Trzeciak,
A. M. Inorg. Chim. Acta 2010, 363, 4346. (b) Mathews, C. J.; Smith, P. J.;
Welton, T. J. Mol. Catal. A: Chem. 2003, 206, 77.
Supporting Information Available. Experimental pro-
cedures and product spectral data are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) (a) Ross, A. J.; Dreiocker, F.; Schaefer, M.; Oomens, J.; Meijer,
A. J. H. M.; Pickup, B. T.; Jackson, R. F. W. J. Org. Chem. 2011, 76,
1727. (b) Sen Gupta, P. K.; Houk, L. W.; van der Helm, D.; Hossain,
M. B. Acta Crystallogr. 1982, B38, 1818. (c) Citeau, H.; Conrad, O.;
Gulando, D. M. Acta Crystallogr. 2001, E57, m5. (d) Htoon, C.; Ladd,
M. F. C. J. Cryst. Mol. Struct. 1974, 4, 357. (e) Yasuda, H.; Ohnuma, Y.;
Nakamura, A.; Kai, Y.; Yasuoka, N.; Kasai, N. Bull. Chem. Soc. Jpn.
1980, 53, 1101. (f) Andrews, P. C.; Raston, C. L.; Skelton, B. W.; White,
A. H. Organometallics 1998, 17, 779.
(14) (a) Han, C.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 7532.
(b) Kondolff, I.; Doucet, H.; Santalli, M. Organomet. 2006, 25, 5219.
(c) C-alimsiz, S.; Organ, M. G. Chem. Commun. 2011, 47, 5181.
(15) Use of Pd(Amphos)2 instead of PdCl2(Amphos)2 in this case was
nessesary to achieve full conversion.
Org. Lett., Vol. 13, No. 15, 2011
3825