Selective substituent transfer from mixed zinc reagents in Ni-catalyzed anhydride alkylation

Article abstract of DOI:10.1021/ol0616337

(Chemical Equation Presented) The use of mixed zinc reagents in Ni-catalyzed anhydride alkylation results in preferential transfer of substituents (Ph > Me > Et ? iPr ～ TMSCH₂) for the ligands bipy, dppe, and iPrPHOX. Utilization of such mixed

Full text of DOI:10.1021/ol0616337

ORGANIC
LETTERS
2006
Vol. 8, No. 19
4307-4310
Selective Substituent Transfer from
Mixed Zinc Reagents in Ni-Catalyzed
Anhydride Alkylation
Jeffrey B. Johnson, Robert T. Yu, Paul Fink, Eric A. Bercot, and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
roVis@lamar.colostate.edu
Received July 3, 2006
ABSTRACT
The use of mixed zinc reagents in Ni-catalyzed anhydride alkylation results in preferential transfer of substituents (Ph > Me > Et
TMSCH2) for the ligands bipy, dppe, and iPrPHOX. Utilization of such mixed species allows the use of 0.55 equiv of the diorganozinc reagent,
.
iPr
∼
effectively transferring both desired substituents when used in conjunction with a suitable second zinc reagent.
The formation of carbon-carbon bonds through transition-
metal-mediated processes has revolutionized organic syn-
thesis.1 The mild reaction conditions required for these cross-
couplings are quite beneficial, as a wide variety of functional
groups are tolerated. Although a variety of activated acyl
species, including acid chlorides,2 thioesters,3 aryl trifluo-
roacetates,4 and acyl cyanides,5 have been applied in the
formation of ketones,6 anhydrides have only recently been
investigated as acylating agents in metal-mediated reactions.7
Goossen8 and Yamamoto9 have independently reported the
palladium-catalyzed cross-coupling of mixed acyclic anhy-
drides with boronic acids, whereas Frost has reported a
rhodium-catalyzed analogue.10 Although these reactions
provide a powerful means of producing ketones, they
inherently lack the ability to influence the formation or
definition of stereocenters. Our group has recently reported
the development of a similar cross-coupling methodology
utilizing cyclic carboxylic anhydrides.11 Alkylation of such
anhydrides with diorganozinc reagents catalyzed by nickel
or palladium provides ketoacid derivatives with stereodefined
backbones (eq 1).
(1) Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-Coupling Reactions;
Wiley-VCH: Weinheim, 1998.
(2) (a) Kosugi, M.; Shimizu, Y.; Migita, T. Chem. Lett. 1977, 1423. (b)
Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636. (c) Milstein,
D.; Stille, J. K. J. Org. Chem. 1979, 44, 1613.
(3) (a) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T.
Tetrahedron Lett. 1998, 39, 3189. (b) Liebeskind, L. S.; Srogl, J. J. Am.
Chem. Soc. 2000, 122, 11260. (c) Wittenberg, R.; Srogl, J.; Egi, M.;
Liebeskind, L. S. Org. Lett. 2003, 5, 3033.
(4) Kakino, R.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc. Jpn. 2001,
74, 371.
(5) Duplais, C.; Bures, F.; Sapountzis, I.; Korn, T. J.; Cahiez, G.;
Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 2968.
(6) Dieter, R. K. Tetrahedron 1999, 55, 4177.
(7) We have recently shown that acid fluorides are also competent cross-
coupling partners: Zhang, Y.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 15964.
(8) (a) Goossen, L. J.; Ghosh, K. Angew. Chem., Int. Ed. 2001, 40, 3458.
(b) Goossen, L. J.; Ghosh, K. Eur. J. Org. Chem. 2002, 3254.
(9) (a) Kakino, R.; Narahashi, H.; Shimizu, I.; Yamamoto, R. Bull. Chem.
Soc. Jpn. 2002, 75, 1333. (b) Kakino, R.; Yasumi, S.; Shimizu, I.;
Yamamoto, A. Bull. Chem. Soc. Jpn. 2002, 75, 137. (c) Yamamoto, A. J.
Organomet. Chem. 2002, 653, 5.
The alkylation of a cyclic anhydride with a diorganozinc
reagent is efficiently catalyzed by Ni and an appropriate
(10) Frost, C. G.; Wadsworth, K. J. Chem. Commun. 2001, 2316.
(11) (a) Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 174. (b)
Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 10248. (c) Bercot,
E. A.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 247.
10.1021/ol0616337 CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/15/2006

ligand. A limitation of this chemistry, however, is that only
one of the two zinc substituents is transferred during reaction.
To address this issue, we turned to the chemistry of Knochel
and co-workers, who have described the use of mixed zinc
reagents.12 As diorganozinc reagents metathesize at room
temperature,13 a species containing one readily transferred
substituent and one slowly transferred substituent can be
prepared from the two parent species. Such mixed zinc
reagents, through various means of generation, have been
utilized for carbonyl additions.14,15 In several cases, mixed
zinc reagents have been used in Cu(I)-mediated conjugate
additions.16,17
independent reagents in the Ni-catalyzed cross-coupling.
Although the relative rate of substituent transfer from Sn
reagents containing a mixture of substituents is quite well-
known (alkynyl > vinyl > aryl > alkyl),18 we are unaware
of any studies examining the relative propensity of akyl and
aryl substituents from zinc in cross-coupling reactions.19 For
this reason, and to further investigate the potential transfer
of both substituents from a parent diorganozinc reagent, we
initiated a thorough evaluation of selective substituent
transfer from diorganozinc reagents in Ni-catalyzed cross-
couplings with anhydrides.
The alkylation of a cyclic anhydride with an organozinc
reagent is efficiently catalyzed by Ni and a number of
appropriate ligands. Catalyst precursors include both Ni(0)
[Ni(COD)2] and Ni(II) [Ni(acac)2] sources, and compatible
ligands include bipy, pyphos (1), 1,2-bis(diphenylphosphino)-
ethane (dppe), and isopropylphosphinooxazoline (iPrPHOX)
(2). Following the precedent of Knochel, these reactions have
been shown to proceed more efficiently in the presence of a
styrene promoter.20
In qualitative experiments, we have observed that the
alkylation of cis-1,2,3,6-tetrahydrophthalic anhydride 3 with
Me2Zn, catalyzed by Ni(COD)2 and bipyridyl (bipy) (Table
1), is complete within 5 min; reaction with Et2Zn requires
Table 1. Mixed Zinc Alkylation of 3 Catalyzed by Ni(COD)2
and Bipy
Our survey of mixed zinc reagents began using Ni(COD)2,
bipy, and styrene to catalyze the alkylation of cis-1,2,3,6-
tetrahydrophthalic anhydride 3. Using a 1:1 ratio of Ph2Zn
and Et2Zn, the alkylation of 3 proceeds in a 91% yield with
19:1 selectivity for transfer of the phenyl group. A sequence
of reactions, performed with Ph2Zn, Me2Zn, Et2Zn, iPr2Zn,
and (TMSCH2)Zn to determine the relative propensity of
substituent transfer from zinc, suggests that Ph is transferred
most readily, followed by Me and Et (Figure 1). Much slower
product ratio
(R:R’)
combined
yield (%)
entry
R
R’
1
Ph
Ph
Ph
Me
Ph
Me
Et
Et
Et
Me
Et
iPr
iPr
19:1
19:1
9:1
91
87
89
75
90
90
78
2a
3
4
5
6
7
3:1
>20:1
>20:1
>20:1
TMSCH2
a Reaction performed with 0.7 equiv of each diorganozinc reagent.
Figure 1. Order of substituent transfer from mixed diorganozinc
reagents.
10 min, and reaction with Ph2Zn requires approximately 20
min. Alkylation of 3 with a 1:1 mixture of Et2Zn and Ph2Zn
provided a surprising result: Ph transfer was favored over
Et transfer by a 19:1 margin. These results indicate that the
mixed zinc reagent, PhZnEt, behaves differently than the
is the transfer of the hindered iPr and CH2TMS substituents.
These observations suggest that aryl transfer is sufficiently
faster than ethyl transfer to allow the use of commercially
available Et2Zn as the source of the nontransferable sub-
stituent.
(12) (a) Berger, S.; Langer, F.; Lutz, C.; Knochel, P.; Mobley, T. A.;
Reddy, C. K. Angew. Chem., Int. Ed. Engl. 1997, 36, 1496. (b) Lutz, C.;
Knochel, P. J. Org. Chem. 1997, 62, 7895.
(13) von dem Bussche-Hu¨nnefeld, J. L.; Seebach, D. Tetrahedron 1992,
48, 5719.
(14) (a) Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Mun˜iz, K. Angew.
Chem., Int. Ed. 2000, 39, 3465. (b) Traverse, J. F.; Hoveyda, A. H.; Snapper,
M. L. Org. Lett. 2003, 5, 3273.
(15) (a) Tan, L.; Chen, C.-y.; Tillyer, R. D.; Grabowski, E. J. J.; Reider,
P. J. Angew. Chem., Int. Ed. 1999, 38, 711. (b) Forrat, V. J.; Prieto, O.;
Ramo´n, D. J.; Yus, M. Chem.sEur. J. 2006, 12, 4431.
(16) (a) Lipshutz, B. H.; Wood, M. R.; Tirado, R. J. Am. Chem. Soc.
1995, 117, 6126. (b) Jones, P.; Reddy, C. K.; Knochel, P. Tetrahedron
1998, 54, 1471. (c) Schinnerl, M.; Seitz, M.; Kaiser, A.; Reiser, O. Org.
Lett. 2001, 3, 4259. (d) Soorukram, D.; Knochel, P. Org. Lett. 2004, 6,
2409.
As the range of commercially available diorganozinc
nucleophiles is quite limited, we also examined the use of
diorganozinc reagents formed in situ to generate mixed zinc
reagents.21 Nucleophiles prepared from corresponding aryl
(18) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(19) Limited studies have been performed regarding the transfer of
diorganozinc reagents to aldehydes: see refs 14-17.
(20) (a) Giovannini, R.; Stu¨demann, T.; Dussin, G.; Knochel, P. Angew.
Chem., Int. Ed. 1998, 37, 2387. (b) Giovannini, R.; Stu¨demann, T.;
Devasagayaraj, A.; Dussin, G.; Knochel, P. J. Org. Chem. 1999, 64, 3544.
(21) (a) Pen˜a, D.; Lo´pez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa,
B. L. Chem. Commun. 2004, 1836. (b) Kim, J. G.; Walsh, P. J. Angew.
Chem., Int. Ed. 2006, 45, 4175.
(17) (a) Wipf, P.; Ribe, S. J. Org. Chem. 1998, 63, 6454. (b) Jensen, A.
E.; Knochel, P. J. Org. Chem. 2002, 67, 79. (c) Rimkus, A.; Sewald, N.
Org. Lett. 2002, 4, 3289.
4308
Org. Lett., Vol. 8, No. 19, 2006

bromides, n-butyllithium, and ZnCl2 were used without
purification (Table 2). The presence of residual salts (LiCl
ligand provides a relatively similar continuum of transfer
propensity, with Ph transfer occurring more readily than Et
or Me transfer (Table 3, entries 1-3). In this case, however,
Table 2. Use of in Situ Nucleophiles in the Alkylation of 3
Catalyzed by Ni(COD)2 and Bipya,b
Table 3. Alkylation of 3 Catalyzed by Ni(COD)2 with Dppe or
Pyphosa
product ratio combined
entry
R
R’
(R:R’)
yield (%)
product
ratio (R:R’)
combined
yield (%)
entry
ligand
R
R’
1
2
3
4c
5
6
Ph
Ph
Et
18:1
>20:1
19:1
15:1
18:1
1:3
88
83
76
67
79
82
TMSCH2
1
2
3
4
5
6
dppe
dppe
dppe
pyphos
pyphos
pyphos
Ph
Ph
Et
Ph
Ph
Et
Et
10:1
6:1
1:1
1:2
1:2
2:1
64
67
67
82
83
86
p-OMePh
p-OMePh
3,4,5-(OMe)3Ph Et
3,4,5-(OMe)3Ph Ph
Et
Et
Me
Me
Et
Me
Me
a Reaction conditions: 3 (1 equiv), Ni(COD)2 (5 mol %), bipy (6 mol
%), styrene (10 mol %), and R2Zn and R’2Zn (0.7 equiv of each) in THF
at 0-23 °C for 16 h. b R2Zn formed in situ from ArBr, nBuLi, and ZnCl2.
c Reaction performed with Ni(acac)2 (5 mol %).
a Reaction conditions: 3 (1 equiv), Ni(COD)2 (5 mol %), ligand (6 mol
%), styrene (10 mol %), 1.1 equiv of both R2Zn and R’2Zn, THF, 0-23 °C
for 16 h.
and LiBr) proved to have no noticeable effect on the
selectivity of transfer from the mixed zinc reagent, providing
the desired aryl keto acid in at least an 18:1 ratio over the
ethyl adduct. Use of air-stable Ni(acac)2 as the metal source
also selectively provided the desired aryl adduct, providing
a 15:1 ratio with a slightly decreased yield (entry 4). The
electronic influence upon selectivity is illustrated by the
selectivity of Ph transfer over 3,4,5-(MeO)3Ph transfer in a
3:1 ratio (entry 6). It should be noted that for these
experiments only 0.7 equiv of diorganozinc was utilizeds
in numerous examples, this represents transfer of the second
substituent, a phenomenon which does not occur in the
absence of a second diorganozinc reagent.
no selectivity was observed between Me and Et. Yields for
these reactions are also generally lower than those observed
for reactions with bipy.
Reactions run using pyphos as the ligand provide a distinct
shift in the nature of transfer from the mixed zinc reagent
(Table 3, entries 4-6). We observe relatively little substituent
selectivity in any of the combinations tested. These results
suggest that anhydride alkylation catalyzed by the Ni-
pyphos system may proceed through a mechanism distinctly
different from that observed for the Ni-bipy-catalyzed
system or that some combination of ligand electronics and
sterics significantly alters the transmetalation process. The
relative selectivity of Et vs Me is also counterintuitive.
The reaction also proceeds efficiently with more highly
functionalized diorganozinc reagents. The alkylation of cis-
1,2-cyclohexanedicarboxylic anhydride 4 was performed with
a mixture of Et2Zn and (EtCO2CH2CH2)2Zn (eq 4) (Figure
2). Despite their relative similarities, the ester substituent
Table 4. Alkylation of 3 Catalyzed by Ni(COD)2 and
iPrPHOXa
products
(R:R’)
combined
yield (%)
ee (%)
(R adduct)
entry
R
R’
1b
2b
3
Ph
81
79
78
73
69
77
72
77
73
65
22
75
63
74
33
44
35
40
Phc
Ph
Et
Et
Et
TMSCH2
TMSCH2
iPr
10:1
10:1
1.3:1
>20:1
>20:1
>20:1
>20:1
4
Phc
Phc
Phc
Phc
Phc
Phc
5d
6
7d
8
9d
iPr
Figure 2. Addition of functionalized mixed zinc reagents.
a Reaction conditions: 3 (1 equiv), Ni(COD)2 (5 mol %), iPrPHOX (6
mol %), styrene (10 mol %), and R2Zn and R’2Zn (0.7 equiv of each) in
THF, 0-23 °C for 16 h. b Used 1.4 equiv of R2Zn. c R2Zn prepared in situ
from ArBr, nBuLi, and ZnCl2 and used without further purification. d 5
equiv of R’2Zn.
transfers with a 5:1 selectivity over the Et substituent. As
expected, use of (TMSCH2)2Zn as the second zinc reagent
results in nearly complete selectivity for transfer of the ester,
providing the desired product in 71% yield.
After examination of the reaction under our standard
conditions, we set out to determine whether high selectivity
is also observed for other ligands known to facilitate this
reaction in conjunction with Ni(COD)2. Use of dppe as a
Knochel12 and Bolm14 have independently reported that
the use of mixed zinc reagents affects enantioselectivities.
Thus, in alkylation catalyzed by Ni(COD)2 and iPrPHOX,
we explored the effect of mixed zinc reagents on product
Org. Lett., Vol. 8, No. 19, 2006
4309

enantioselectivity in conjunction with our study on the
propensity of substituent transfer. Our results of this study
are shown in Table 4. Although the selectivity of Ph transfer
in the presence of Et2Zn is less than that observed with the
Ni-bipy-catalyzed system, the selectivity for Ph transfer is
nearly complete when iPr2Zn or (TMSCH2)2Zn is the second
zinc reagent. Similar product selectivities are observed using
commercially available Ph2Zn or that prepared from bro-
mobenzene and ZnCl2.
Although initial screens were performed with anhydride
3, other anhydrides, namely, 1,2-cyclohexanedicarboxylic
anhydride (4) and 2,3-dimethylsuccinic anhydride (6), were
also alkylated with mixed zinc reagents (Table 6) under Ni
Table 6. Alkylation of Other Anhydrides with Mixed Zinc
Reagentsa,b
It should be noted that the alkylative desymmetrization
of cyclic anhydrides typically proceeds in lower enantiose-
lectivity with the use of in situ prepared nucleophiles than
with the salt-free commercially available species (entries 1
and 2). The use of mixed zinc species has significant effects
upon alkylation product enantioselectivities. These effects,
however, greatly depend on the relative amount and identity
of the second zinc additive and are currently under further
investigation.
product ratio combined
AH entry ligand
R
R’
(R:R’)
yield (%)
4
1
bipy
Ph
Ph
Et
Et
Et
>20:1
6:1
1:2
15:1
8:1
83
69
73
76
53
68
2
dppe
3
pyphos Ph
6
4c bipy
5c dppe
3,4,5-(OMe)3Ph Et
3,4,5-(OMe)3Ph Et
Mixed zinc reagents were also utilized in the alkylative
desymmetrization of 4-methylglutaric anhydride (5) catalyzed
by Ni(COD)2 and iPrPHOX (Table 5). As in the alkylation
6c pyphos 3,4,5-(OMe)3Ph Et
2:1
a General reaction conditions: AH (1 equiv), Ni(COD)2 (5 mol %), ligand
(6 mol %), styrene (10 mol %), R2Zn and R’2Zn (0.7 equiv of each) in
THF, 0-23 °C, 16 h. b Nucleophile prepared in situ from ArBr, nBuLi,
and ZnCl2. c Used 0.55 equiv of R2Zn and R’2Zn.
Table 5. Alkylation of 5 Catalyzed by Ni(COD)2 and
iPrPHOXa
catalysis. These reactions proceed with selectivities similar
to those observed with anhydride 3. To further explore the
potential of this method, entries 4-6 were performed with
only 0.55 equiv of in situ formed bis(3,4,5-trimethoxyphe-
nyl)zinc. This reaction, particularly under catalysis with bipy,
demonstrates its utility, as both aryl groups are successfully
transferred from approximately 50% of the diorganozinc
reagent in producing the desired product in 76% yield.
With these studies, we have demonstrated the utility of
mixed zinc reagents as nucleophiles in the catalytic alkylation
of carboxylic acid anhydrides and illustrated the relative
transfer propensity of Ph, Et, Me, iPr, and CH2TMS in these
alkylation reactions. The technique of using mixed zinc
reagents with bipy, dppe, or iPrPHOX ligands obviates the
use of an excess of a potentially expensive or difficult to
prepare diorganozinc reagent.
products
(R:R’)
combined
yield (%)
ee (%)
entry
R
R’
(R adduct)
1b
2b
3
Ph
Phc
Ph
Phc
Phc
Et
-
-
72
67
79
63
74
78
74
55
49
54
54
58
62
58
Et
Et
TMSCH2
12:1
17:1
>20:1
4
5
6b
7
Et
TMSCH2
>20:1
a General conditions: 5 (1 equiv), Ni(COD)2 (5 mol %), iPrPHOX (6
mol %), styrene (10 mol %), R2Zn (0.7 equiv), R’2Zn (0.7 equiv), in THF,
0-23 °C, 16 h. b Used 1.4 equiv of R2Zn. c R2Zn prepared in situ from
ArBr, nBuLi, and ZnCl2 and used without further purification.
Acknowledgment. We thank Merck, Amgen, Lilly,
Boehringer-Ingelheim, and Johnson and Johnson for support.
T.R. thanks the Monfort Family Foundation for a Monfort
professorship. T.R. is a fellow of the Alfred P. Sloan
Foundation.
of the succinic anhydrides, a 1:1 ratio of Ph2Zn and Et2Zn
primarily results in Ph transfer. Again, use of iPr2Zn or
(TMSCH2)2Zn with Ph2Zn prepared in situ resulted in
complete selectivity for Ph transfer. Unlike earlier results
with the reaction of succinic anhydrides, the enantioselec-
tivity of the alkylated glutaric anhydrides displays little
dependence upon the nature of the second diorganozinc
reagent.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0616337
4310
Org. Lett., Vol. 8, No. 19, 2006