Stereocontrol in palladium-catalyzed propargylic substitutions: Kinetic resolution to give enantioenriched 1,5-enynes and propargyl acetates

Article abstract of DOI:10.1002/adsc.201300720

Kinetic resolution during the catalytic allyl-propargyl cross-coupling with chiral starting materials can be accomplished with a chiral palladium catalyst. These reactions offer ready access to enantiomerically enriched enyne products from simple, readily

Full text of DOI:10.1002/adsc.201300720

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DOI: 10.1002/adsc.201300720
Stereocontrol in Palladium-Catalyzed Propargylic Substitutions:
Kinetic Resolution to give Enantioenriched 1,5-Enynes and
Propargyl Acetates
Michael J. Ardolino,a Meredith S. Eno,a and James P. Morkena,*
a
Department of Chemistry, Boston College, Chestnut Hill, MA 02467, USA
E-mail: morken@bc.edu
Received: August 9, 2013; Revised: September 27, 2013; Published online: November 13, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300720.
Abstract: Kinetic resolution during the catalytic
allyl-propargyl cross-coupling with chiral starting
materials can be accomplished with a chiral palladi-
um catalyst. These reactions offer ready access to
enantiomerically enriched enyne products from
simple, readily available starting materials.
heteroatom bond forming reactions,[2–4] there are few
asymmetric variants.[3d,5] This deficit is likely due to
two issues: (i) unlike structurally similar (allyl)Pd in-
termediates that are configurationally dynamic,[6] both
B and C are chiral and configurationally static, re-
flecting the configuration of the starting material after
stereospecific SN2’ addition of Pd;[7] (ii) in the absence
of significant steric bias, bond formation generally
occurs from the (allenyl)Pd complex B to furnish
chiral allene products of type D,[8,9] which are known
to be susceptible to racemization by Pd even under
mild conditions.[10] To address these issues, asymmetric
Pd-catalyzed propargyl substitutions have relied on
Keywords: allylation; asymmetric catalysis; asym-
metric synthesis; boron; palladium
Palladium-catalyzed substitutions of propargylic elec- stereospecific couplings with optically enriched prop-
trophiles represent a powerful synthetic method for argyl electrophiles, and are limited in scope to allene
the construction of allene and alkyne containing com- products that are biased against racemization based
pounds [Scheme 1, Eq. (1)].[1,2] These reactions typi- on electronics or sterics.[3d,5]
cally proceed via oxidative addition of Pd(0) with
We recently reported a Pd-catalyzed cross-coupling
propargyl electrophiles of type A to give interconvert- of optically enriched propargyl acetates and allylbor-
ing allenyl (B) and propargyl palladium (C) inter- on reagents to deliver 1,5-enynes [Scheme 1, Eq.
mediates, and yield allene (D) or alkyne (E) contain- (2)].[11] Mechanistically, it appeared that under the in-
ing products upon subsequent reaction. While fluence of a bidentate phosphine ligand (rac-BINAP),
a number of methods have capitalized on these fea- this transformation proceeds by 3,3’-reductive elimi-
tures resulting in catalytic carbon-carbon and carbon- nation from the allyl-allenyl-Pd complex F.[12,13] This
allyl migration is highly regioselective for the configu-
rationally stable propargyl-substituted products of
type E and allows for high stereospecificity for
a range of sterically and electronically diverse electro-
philes. Although this strategy provided a practical
access to synthetically useful intermediates, the need
for enantiomerically pure starting material was
a drawback. A potential solution revealed itself when,
during the course of this study, we observed a small
difference in reactivity of an optically enriched prop-
argyl acetate during reactions catalyzed by complexes
bearing either (R)- or (S)-BINAP. Reasoning that
with a chiral catalyst that can more ably differentiate
matched and mismatched substrates, a kinetic resolu-
tion might result and provide enantiomerically en-
Scheme 1. Palladium-catalyzed propargylic substitutions.
riched 1,5-enynes from racemic starting material.[14]
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Table 1. Optimization of kinetic resolution.
tion even with significantly lower catalyst loadings
(entry 12).[19]
Having developed an active and selective catalyst
system, the resolution of additional propargyl acetates
was explored (Table 2). In addition to the n-alkyl ex-
ample, the reaction tolerated aliphatic substrates with
Table 2. Substrate scope of kinetic resolution.
[a]
Conv.=[ee1/ACHTUNGTRENNUNG(ee1+ee2)], enantiomeric excess determined
by GC analysis on a chiral stationary phase.
s=kfast/kslow =ln[(1ÀConv./100)(1Àee1/100)]/ln[(1ÀConv./
100)(1+ee1/100)].
[b]
[c]
0.75 mol% (R)-3 used in place of Pd2ACTHNUGTRNE(UNG dba)3/ligand.
Although related Pd-catalyzed resolutions of allylic
electrophiles have been reported,[15] such a strategy is
unknown for propargyl systems.[16,17]
Initial experiments with (S)-BINAP (L1), a racemic
mixture of substrate 1, and 0.5 equivalents of
allylBACHTUNGTRENNUNG(pin) in THF at 608C (Table 1, entry 1) offered
moderate selectivity (s=3.8).[18] The selectivity was
relatively unchanged when the reaction was run at
lower temperatures (entries 2 and 3) or in more polar
solvents (entry 4), and decreased when run in the less
polar solvent CH2Cl2 (entry 5). Use of a carbonate
leaving group resulted in lower selectivity (entry 6,
s=1.3), while the pivaloyl ester showed a slight in-
crease in selectivity (entry 7, s=4.9).
The nature of the chiral ligand was found to have
a significant effect on selectivity: with larger 3,5-xylyl
groups on L2 selectivity was diminished compared to
L1, while a small improvement was seen with the
structurally similar MeO-BIPHEP (L3, s=6.6). An
evaluation of other members of the BIPHEP family
revealed a marked jump in selectivity when MeO-
ACHTUNGTRENNUNG(furyl)BIPHEP (L4) was employed (entry 11, s=
18.6). Use of the pre-formed L4-Pd(II)Cl2 complex
[(R)-3] allowed for cleaner and more efficient reac-
[a]
Enantiomer ratios were determined by GC or SFC analy-
sis on chiral stationary phase.
[b]
[c]
[d]
1
Determined by H NMR analysis.
Conv.=[eeI/eeG +eeI)].
s=kfast/kslow =ln[(1ÀConv./100)(1ÀeeI/100)]/ln[(1ÀConv./
100)(1+eeI/100)].
[e]
[f]
Run with 0.5 mol% (R)-3.
Run with (S)-3.
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Stereocontrol in Palladium-Catalyzed Propargylic Substitutions: Kinetic Resolution
protected alcohols, giving similar selectivity for the
benzyl protected substrate (entry 2) and an increased
selectivity with the bulky TBDPS protected alcohol
(entry 3). Pendant aromatic groups were tolerated;
however, the selectivity appeared to be slightly sensi-
tive to the proximity of the aromatic ring (entry 5).
Diminished selectivity was also observed with an un-
saturated R group (entry 6). Use of the (S)-enantio-
Scheme 3. Kinetic isotope effect.
mer of 3 (entry 8) yields the expected reversal of se-
lectivity for both product and recovered substrate. Of
note, aromatic propargyl acetates exhibited signifi- stereochemistry-determining step of the reaction. In
cantly enhanced reactivity (entries 9–14), and re- contrast, a normal secondary isotope effect might be
quired only 1–2 h for the resolution to proceed to expected if the later proposed 3,3’-reductive elimina-
completion. Although s values for the simple phenyl tion were rate-determining.
and p-tolyl substrate (entries 9 and 10) were similar
To gain additional insight into the nature of possi-
to those of the aliphatic substrates, the reaction did ble stereodifferentiation during oxidative addition,
appear sensitive to electronic perturbations to the density functional theory (DFT) calculations were
aromatic ring (entries 11–14).
carried out. The reaction coordinate was examined
The kinetic resolution by allyl-propargyl coupling for the addition of (R)-3 to both the matched (R)-
also proved reliable on a large scale, as the resolution and mismatched (S)-enantiomers of methyl-substitut-
of one gram of 1 shows a nearly identical s value and ed propargyl acetate II (Figure 1). In both cases, re-
regioselectivity [Scheme 2, Eq. (3)] as the example in sults show a strong stabilization upon formation of
Table 2. The ability to recover both enriched product the Pd-alkyne complex (GS) from the free catalyst
as well as enriched starting material in good to high and substrate. This complex exhibits a slightly distort-
yield demonstrates the potential for efficient use of ed square-planar geometry in which the alkyne is
À
À
this resolution in total synthesis applications. In line placed almost parallel to the P Pd P plane and the
with our previous study, the reaction was also tolerant acetate group is directed away from the metal. This is
of b-substituted allylboron reagents: the selectivity in agreement with previous DFT calculations,[23] spec-
and reactivity are nearly unchanged when methallylB- troscopic,[24] and crystallographic[25] data for Pd-
ACHTUNGTRENNUNG
To determine whether the selectivity of the resolu- back donation from the filled Pd d orbitals into the
ꢀ
tion was derived during the oxidative addition or re- C-1 C-2 p* orbital. This back-bonding is strongly sta-
ductive elimination, kinetic isotope effects were stud- bilizing and brings C-1 and C-2 in close proximity to
À
ied (Scheme 3). A competition study between sub- the metal to cause a 308 distortion of the C-1 H and
À
strates 1 and d-1 showed a kH/kD of 0.71 based on re- C-2 C-3 bonds and form a structure that resembles
covered starting material.[20] The magnitude of this a pallada(II)cyclopropene.[26]
secondary inverse isotope effect is similar to what is
From this structure, the calculated transition state
expected for an sp to sp2 hybridization change,[21,22] shows bond formation between Pd and C-3, with
and suggests that oxidative addition is the rate- and a slightly distorted trigonal bipyramidal geometry
about the carbon characteristic of a SN2-type oxida-
tive addition.[27] Natural bond order (NBO) analysis
of the transition state confirms this feature, showing
bonding character between the Pd and an sp2 hybrid-
ized C-3 with concomitant loss of bonding character
between C-3 and the oxygen of the acetate. Such an
addition pathway allows for direct formation of the
h3-allenyl complex Int-a, which could isomerize to the
more stable allenyl-Pd complex Int-b.
Calculated energy differences between both the
ground and transition states for the diasteromeric
matched and mismatched substrate/catalyst complexes
are in good agreement with selectivities observed ex-
perimentally. Key to these observed energy differen-
ces are the interactions of the substituents at the
propargylic carbon of the substrate and the ligand
Scheme 2. Further synthetic utility.
structure. In GSfast, the methyl group is positioned
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Figure 1. DFT optimized structures, reaction coordinate, and simplified stereochemical model for oxidative addition (R)-3
into (R)- and (S)-substrate II. Energy values reported in kcalmolÀ1 relative to GSfast. Calculations performed at the B3LYP-
PCMACHTUNGTRENNUNG(THF)/LANL2DZ-6-31G**, some hydrogen atoms removed for clarity.
into an open quadrant of the C-2 symmetric ligand,
If stereodifferentiation is indeed derived during oxi-
away from the steric bulk of the pseudoaxial furyl dative addition, the resolution should also be opera-
ring (J), whereas in GSslow, the group is positioned tive with nucleophiles other than allyl boronates. In
into this blocked quadrant (K). This interaction is en- this respect, it was considered that a kinetic resolution
hanced during oxidative addition (TSfast and TSslow) as in a Pd-catalyzed reduction of propargyl electrophiles
C-3 is brought closer to the catalyst, resulting in could allow access to optically enriched propargyl
a 1.3 kcalmolÀ1 energy difference between the two acetates utilizing a hydride as an inexpensive nucleo-
transition states.
phile.[28]
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Stereocontrol in Palladium-Catalyzed Propargylic Substitutions: Kinetic Resolution
Table 3. Reduction of propargyl acetates.
development of a kinetic resolution of racemic prop-
argyl acetates to access enantioenriched 1,5-enyne
products. This methodology obviates the need for op-
tically enriched starting materials, and demonstrates
previously unknown catalyst controlled selectivity in
Pd-catalyzed reactions of propargyl electrophiles.
Mechanistic studies of the resolution through labora-
tory and computational experimentation have evinced
that oxidative addition could play the key stereodefin-
ing step. This understanding has allowed for the de-
velopment of a hydrogenolysis to give entry to highly
optically enriched propargyl acetates. In light of the
number of developments in catalyst-controlled asym-
metric manipulations of structurally similar allylic sys-
tems, we hope that the strategies described herein
may find use in other contexts.
Experimental Section
General Procedure for Kinetic Resolution with
Allylboronic Acid Pinacol Ester
[a]
Enantiomer ratios were determined by GC or SFC analy-
An oven-dried vessel equipped with a magnetic stir bar was
charged successively with catalyst 3, (0.75 mol%), THF
[0.5M], the propargyl acetate 1 (1.0 equiv.), allylboronic
acid pinacol ester (0.5 equiv.), and cesium fluoride
(3.0 equiv.) in a dry-box under an argon atmosphere. The
vessel was sealed, removed from the dry-box, and heated to
608C while allowing to stir for 8 h. After this time, the reac-
tion mixture was diluted with diethyl ether, filtered through
a plug of silica gel and concentrated under vacuum.
sis on chiral stationary phase.
Determined by H NMR analysis.
Yield based on theoretical 100% recovery at listed con-
version, average of two or three runs.
s=kfast/kslow =ln[(1ÀConv./100)(1ÀeeI/100)]/ln[(1ÀConv./
100)(1+eeI/100)].
[b]
[c]
1
[d]
[e]
[f]
Run for 1 h.
1.0% catalyst loading.
General Procedure for Kinetic Resolution with
Me4NBHACHTNUGRTENUNG(OAc)3
A survey of various hydride sources revealed that
tetramethylammonium
triacetoxyborohydride
A
ACHTUNGTRENNUNG
An oven-dried reaction vessel equipped with a magnetic stir
bar was charged with catalyst 3, (0.75 mol%), tetramethy-
lammonium triacetoxyborohydride (0.5 equiv.), and THF
sired transformation. This mild hydride source al-
lowed use of catalyst 3 with little modification to re-
action conditions (Table 3). The reaction required [0.5M] in a dry-box under an argon atmosphere. The vessel
was sealed and the contents allowed to stir for five minutes,
over which time the solution turned a deep red color. The
propargyl acetate, 1, (1.0 equiv.) was added, and the vessel
was sealed, removed from the dry-box, and heated to 608C
while allowing to stir for 4.5 h. After this time, the reaction
mixture was diluted with diethyl ether, filtered through
a plug of silica gel and concentrated under vacuum.
shorter reaction times, and showed s values similar to
those with allylB(pin) as the nucleophile. Importantly,
ACHTUNGTRENNUNG
these reactions were clean and allowed facile isolation
of the recovered enriched starting material in good to
excellent yields. The reaction was especially efficient
for aromatic (entries 1 and 2), and unsaturated
(entry 5) substrates, and running these reactions to
slightly higher conversion allowed for easy access to
highly enriched substrate (entry 1c). The hydrogenol-
ysis required longer reaction times for aliphatic sub-
strates (entries 3 and 4), potentially suffering from
slower oxidative additions or the formation of the
non-conjugated allene by-product. Synthetically
useful selectivity could still be achieved for the more
substituted cyclohexyl substrate (entry 4a).
Computational Details
All calculations were performed using Gaussian 09 with all
geometry optimizations, energies and frequencies were cal-
culated at the DFT level utilizing the B3LYP hybrid func-
tional.[29,30] The 6-31G** basis set was used for the elements
C, H, P, and O in conjunction with the LANL2DZ relativis-
tic pseudopotential for Pd. The two oxygens and carbonyl
carbon of the acetate group were augmented with diffuse
functions. All free energies were calculated at 333.15 K. The
PCM model was used to estimate the effect of solvation
(THF).[31] The frequency calculations for transition states
In summary, a subtle difference in reactivity ob-
served during the development of a stereospecific Pd-
catalyzed cross-coupling of optically enriched prop-
argyl acetates and allylmetal reagents has inspired the demonstrated one imaginary frequency each, and were
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found to connected with the correct ground states through
IRC calculations. NBO analysis was carried out with Gaussi-
an NBO version 3.1.[32] The three-dimensional structures
presented in Figure 1 were visualized utilizing CYLview.[33]
1996, 15, 164; d) K. Tsutsumi, T. Kawase, T. Kakiuchi,
S. Ogoshi, Y. Okada, H. J. Kurosawa, Bull. Chem. Soc.
Jpn. 1999, 72, 2687.
[8] a) E. Keinan, M. Peretz, J. Org. Chem. 1983, 48, 5302;
b) C. J. Elsevier, H. H. Mooiweer, H. Kleijnm, P. Ver-
meer, Tetrahedron Lett. 1984, 25, 5571; c) C. J. Elsevier,
P. J. Vermeer, J. Org. Chem. 1985, 50, 3042; d) T.
Moriya, N. Miyaura, A. Suzuki, Synlett 1994, 149;
e) P. H. Dixneuf, T. Guyot, M. D. Ness, S. M. Roberts,
Chem. Commun. 1997, 2083; f) Y. Wang, W. Zhang, S.
Ma, J. Am. Chem. Soc. 2013, 135, 11517.
[9] In mechanistically aligned chemistry, stereospecific ad-
dition of Pd into propargyl electrophiles, followed by
subsequent transmetallation to In, Bi, Sn, Zn, and Yb
forms new chiral metal-allenyl species. These nucleo-
philes can undergo stereospecific SN2’ additions to car-
bonyl compounds to give enantiomerically enriched
propargyl alcohols, see: a) J. A. Marshall, C. M. Grant,
J. Org. Chem. 1999, 64, 8214; b) J. M. Aurreocoechea,
M. Arrare, B. Lꢁpez, Synlett 2001, 872; c) M. Arrate,
A. Durana, P. Lorenzo, ꢂ. R. de Lera, R. ꢂlvarez,
J. M. Aurrecoechea, Chem. Eur. J. DOI:10.1002/
chem.201301170.
Acknowledgements
We thank Dr. Fredrik Haeffner for helpful discussions. MJA
is grateful for American Chemical Society (DOC) and Astra-
Zeneca Fellowships. This work was supported by a grant
from the US National Institutes of Health (NIGMS 64451).
References
[1] For a general review on catalytic propargylic substitu-
tions, see: R. J. Detz, H. Heimstra, J. H. van Maar-
seveen, Eur. J. Org. Chem. 2009, 6263.
[2] For reviews on Pd-catalyzed reactions of propargylic
systems see: a) J. Tsuji, T. Mandai, Angew. Chem. 1995,
107, 2830; Angew. Chem. Int. Ed. Engl. 1995, 34, 2589;
b) S. Ma, A. Zhang, Pure Appl. Chem. 2001, 73, 337;
c) S. Ma, Eur. J. Org. Chem. 2004, 1175; d) L.-N. Guo,
X.-H. Duan, Y.-M. Liang, Acc. Chem. Res. 2011, 44,
111.
[10] a) A. Horvꢃth, J. Bꢄckvall, Chem. Commun. 2004, 964;
b) H. E. Burks, S. Liu, J. P. Morken, J. Am. Chem. Soc.
2007, 129, 8766.
[11] M. J. Ardolino, J. P. Morken, J. Am. Chem. Soc. 2012,
134, 8770.
[3] For a review on Pd-catalyzed cross-couplings of these
systems, see: a) K. Tsutsumi, S. Ogoshi, K. Kakiuchi, S.
Nishiguchi, H. Kurosawa, Inorg. Chim. Act. 1999, 296,
37; for some recent examples, see: b) S. Condon-Guge-
not, G. Linstrumelle, Tetrahedron 2000, 56, 1851; c) T.
Konno, M. Tanikawa, T. Ishihara, H. Yamanaka, Chem.
Lett. 2000, 1360; d) G. A. Molander, E. M. Sommers,
S. R. Baker, J. Org. Chem. 2006, 71, 1563; e) M. Yoshi-
da, M. Higuchi, K. Shishido, Tetrahedron 2010, 66,
2765; f) J. Ye, S. Li, S. Ma, Org. Lett. 2012, 14, 2312.
[4] For some recent examples of Pd-catalyzed carbon-het-
eroatom bond formations in propargyl substitutions,
see: a) Y. Tsuji, M. Taniguchi, T. Yasuda, T. Kawamura,
Y. Obora, Org. Lett. 2000, 2, 2635; b) N. Nishioka, T.
Koizumi, Tetrahedron Lett. 2011, 52, 3662; c) M. Kalek,
J. Stawinski, Adv. Synth. Catal. 2011, 353; d) Z.-S.
Chen, X.-H. Duan, L.-Y. Wu, S. Ali, K.-G. Ji, P.-X.
Zhou, X.-Y. Liu, Y.-M. Liang, Chem. Eur. J. 2011, 17,
6918.
[5] a) C. J. Elsevier, P. M. Stehouwer, H. Westmijze, P. J.
Vermeer, J. Org. Chem. 1983, 48, 1103; b) J. A. Mar-
shall, M. A. Wolf, J. Org. Chem. 1996, 61, 3238; c) M.
Yoshida, T. Gotou, M. Ihara, Tetrahedron Lett. 2004,
45, 5573; d) M. Yoshida, H. Ueda, M. Ihara, Tetrahe-
dron Lett. 2005, 46, 6705.
[6] For reviews on transition-metal catalyzed substitutions
of allylic systems, see: a) B. M. Trost, D. L. Van Vrank-
en, Chem. Rev. 1996, 96, 395; b) Z. Lu, S. Ma, Angew.
Chem. 2008, 120, 264; Angew. Chem. Int. Ed. 2008, 47,
258.
[12] For experimental and computational studies of the 3,3’-
reductive elimination, see: a) M. Mꢅndez, J. M. Cuerva,
E. Gꢁmez-Bengoa, D. J. Cꢃrdenas, A. M. Echavarren,
Chem. Eur. J. 2002, 8, 3620; b) D. J. Cꢃrdenas, A. M.
Echavarren, New J. Chem. 2004, 28, 338; c) M. Perez-
Rodriguez, A. A. C. Braga, A. R. de Lera, F. Maseras,
R. Alvarez, P. Espinet, Organometallics 2010, 29, 4983.
[13] For related allyl-allyl couplings thought to operate
through a 3,3’-reductive elimination, see: a) P. Zhang,
L. A. Brozek, J. P. Morken, J. Am. Chem. Soc. 2010,
132, 10686; b) P. Zhang, H. Le, R. E. Kyne, J. P.
Morken, J. Am. Chem. Soc. 2011, 133, 9716; c) L. A.
Brozek, M. J. Ardolino, J. P. Morken, J. Am. Chem.
Soc. 2011, 133, 16778; d) H. Le, R. E. Kyne, L. A.
Brozek, J. P. Morken, Org. Lett. 2013, 15, 1432.
[14] For some general reviews on kinetic resolutions, see:
a) H. B. Kagan, J. C. Fiaud, Top. Stereochem. 1988, 18,
249; b) E. Vedejas, M. Jure, Angew. Chem. 2005, 117,
4040; Angew. Chem. Int. Ed. 2005, 44, 3974.
[15] For selected examples of Pd-catalyzed resolutions of
non-symmetric allylic systems, see: a) Y. K. Choi, J. H.
Suh, D. Lee, I. T. Lim, J. Y. Jung, M. J. Kim, J. Org.
Chem. 1999, 64, 8423; b) H. J. Gais, O. Bondarev, R.
Hetzer, Tetrahedron Lett. 2005, 46, 6279; c) B. Mao, Y.
Ji, M. FaÇanꢃs-Mastral, G. Caroli, A. Meetsma, B. Fer-
inga, Angew. Chem. 2012, 124, 3222; Angew. Chem. Int.
Ed. 2012, 51, 3168.
[16] For non-enzymatic kinetic resolutions of propargyl al-
cohols, see: a) B. Tao, J. C. Ruble, D. A. Hoic, G. C. Fu,
J. Am. Chem. Soc. 1999, 121, 5091–5092; b) K. Tanaka,
T. Shoji, Org. Lett. 2005, 7, 3561; c) V. B. Birman, L.
Guo, Org. Lett. 2006, 8, 4859; d) X. Li, H. Jiang, E. W.
Uffman, L. Guo, Y. Zhang, X. Yang, V. B. Birman, J.
Org. Chem. 2012, 77, 1722.
[7] a) C. J. Elsevier, H. Kleijn, J. Boersma, P. Vermeer, Or-
ganometallics 1986, 5, 716; b) S. Ogoshi, K. Tsutsumi,
H. J. Kurosawa, J. Organomet. Chem. 1995, 493, C19;
c) M. W. Baize, P. W. Blosser, V. Plantevin, D. G.
Schimpff, J. C. Gallucci, A. Wokcicki, Organometallics
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Stereocontrol in Palladium-Catalyzed Propargylic Substitutions: Kinetic Resolution
[17] Fu and co-workers have reported a stereoconvergent
Ni-catalyzed cross-coupling of racemic propargyl hal-
ides and carbonates with aryl zinc reagents, see:
a) S. W. Smith, G. C. Fu, J. Am. Chem. Soc. 2008, 130,
12645; b) A. J. Oelke, J. Sun, G. C. Fu, J. Am. Chem.
Soc. 2012, 134, 2966.
This analysis confirmed that the GS shown was the
lowest energy conformation about C-2 C3. See the
Supporting Information for more details.
À
[27] A similar alkyne coordination/SN2 oxidative addition
pathway has been proposed by Kurosawa for the addi-
tion of Pt into propargyl chlorides, see: a) S. Ogoshi, Y.
Fukunishi, K. Tsutsumi, H. Kurosawa, J. Chem. Soc.
Chem. Commun. 1995, 2485; b) H. Kurosawa, Pure
Appl. Chem. 1998, 70, 1105; c) H. Kurosawa, S. Ogoshi,
Bull. Chem. Soc. Jpn. 1998, 71, 973.
[18] s=(rate of fast reacting enantiomer)/(rate of slow re-
acting enantiomer); see ref.[13a]
[19] The discrepancies in selectivity for entries 11 and 12
were attributed to a background reaction that occurred
with the Pd
(dba)3 system that might have led to an ar-
[28] review: a) J. Tsuji, T. Mandai, Synthesis 1996, 1; select-
ed examples: b) J. Tsuji, T. Sugigura, M. Yuhara, I.
Minami, J. Chem. Soc. Chem. Commun. 1986, 922; c) J.
Tsuji, T. Sugiuara, I. Minami, Synthesis 1987, 603; d) T.
Mandai, T. Matsumoto, M. Kawada, J. Tsuji, Tetrahe-
dron Lett. 1993, 34, 2161; e) T. Mandai, T. Matsumoto,
M. Kawada, J. Tsuji, J. Organomet. Chem. 1994, 473,
343; f) C. Darcel, S. Bartsch, C. Bruneau, P. H. Dixneuf,
Synlett 1994, 475; g) R. Radinov, S. D. Hutchings, Tetra-
hedron Lett. 1999, 40, 8955; h) H. Ohmiya, M. Yang, Y.
Yamauchi, Y. Ohtsuka, M. Sawamura, Org. Lett. 2010,
12, 1796.
[29] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuse-
ria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V.
Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji,
M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J.
Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M.
Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida,
T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven,
J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M.
Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N.
Staroverov, R. Kobayashi, J. Normand, K. Raghava-
chari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi,
M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gom-
perts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K.
Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,
J. J. Dannenberg, S. Dapprich, A. D. Daniels, ꢇ. Farkas,
J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox,
Gaussian 09, Revision A.02, Gaussian, Inc., Walling-
ford CT, 2009.
tificially high calculated s value for entry 11. This reac-
tion was not seen with 3, and could have been attribut-
ed to the presence of dba or non-ligated palladium spe-
cies.
1
[20] The H NMR ratio of 1:d-1 recovered from the reac-
tion was compared to a sample of the 1:d-1 mixture
prior to reaction. See the Supporting Information for
details on these experiments.
[21] We were unable to find experimental proof that the sp
to sp2 hybridization experiences the same type of in-
verse secondary isotope effect as the sp2 to sp3 hybridi-
zation, however this might be expected based on trends
in bond strength and stretching frequencies. This as-
sumption has been made previously for kinetic isotope
effects in deuterium labeled alkynes: see: a) E. V.
Anslyn, D. A. Dougherty Modern Physical Organic
Chemistry, University Science Books, Sausalito, CA,
2006, p 429; b) J. Impaktschi, J. Mohsseni-Ala, S. Ihlig,
Eur. J. Inorg. Chem. 2003, 4313; c) M. Arndt, K. S. M.
Salih, A. Fromm, L. J. Gooßen, F. Menges, G. Niedner-
Schatterburg, J. Am. Chem. Soc. 2011, 133, 7428.
[22] Our kinetic isotope labeling study does not preclude
the possibility that oxidative addition could be a reversi-
ble step preceding a later rate-determining step. This
phenomenon is known for primary isotope effects, how-
ever secondary equilibrium isotope effects are typically
very small, see a) E. M. Simmons, J. F. Hartwig, Angew.
Chem. 2012, 124, 3120; Angew. Chem. Int. Ed. 2012, 51,
3066; b) ref.[20a], pp 432–444.
[23] a) Q. Cui, D. G. Musaev, K. Morokuma, Organometal-
lics 1998, 17, 1383; b) M. Ahlquist, G. Fabrizi, S.
Cacchi, P. Norrby, Chem. Commun. 2005, 4196.
[24] F. Schager, W. Bonrath, K. Pçrschke, M. Kessler, C.
Krꢆger, K. Seevogel, Organometallics 1997, 16, 4276.
[25] a) H. S. Huh, Y. K. Lee, S. W. Lee, J. Mol. Struct. 2006,
789, 209; b) J. Caeiro, D. PeÇa, A. Cobas, D. Pꢅrez, E.
Guitiꢃn, Adv. Synth. Catal. 2006, 348, 2466.
[30] a) A. D. Becke, Phys. Rev. A 1988, 38, 3098; b) C. Lee,
W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785.
[31] a) S. Miertus, E. Scrocco, J. Tomassi, Chem. Phys. 1981,
55, 117; b) V. Barone, M. Cossi, J. Tomassi, J. Chem.
Phys. 1997, 107, 3210.
[32] D. Glendening, A. E. Reed, J. E. Carpenter, F. Wein-
[26] A conformational analysis was performed in which the
hold, NBO, Version 3.1, E.
[33] C. Y. Legault, CYLview, 1.0b; Universitꢅ de Sher-
brooke, 2009 (http://www.cylview.org).
À
C-2 C-3 bond of the optimized ground state was rotat-
À
À
À
ed 3608 by varying the Pd C-2 C-3 O dihedral angle.
Adv. Synth. Catal. 2013, 355, 3413 – 3419
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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