Synthesis of activated alkenylboronates from acetylenic esters by CuH-catalyzed 1,2-addition/transmetalation

Article abstract of DOI:10.1002/anie.200804912

(Chemical Equation Presented) Stuck on an sp² carbon: A new route to geometrically defined α-alkoxycarbonyl-substituted vinylboronates consists of the chemo- and stereoselective 1,2-addition of copper hydride to acetylenic esters followed by stereoretentive transmetalation with pinacolborane. This strategy is applied to the generation of an aryl acrylate intermediate in the synthesis of the antiinflammatory drug naproxen (see scheme).

Full text of DOI:10.1002/anie.200804912

Angewandte
Chemie
DOI: 10.1002/anie.200804912
Synthetic Methods
Synthesis of Activated Alkenylboronates from Acetylenic Esters by
CuH-Catalyzed 1,2-Addition/Transmetalation**
ˇ
ˇ
´
Bruce H. Lipshutz,* Zarko V. Boskovic, and Donald H. Aue*
Boronic esters, boronic acids, and trifluoroborates make up an
especially important class of coupling partners in organome-
tallic chemistry. Vinylboronates, in particular, are useful
intermediates in many reactions, including Suzuki–Miyaura
cross-couplings, rhodium-catalyzed additions to unsaturated
carbonyl derivatives, boron-Heck reactions, and boron-Man-
nich reactions.[1] Several approaches to alkenyl boronates
Scheme 2. CuH-catalyzed 1,2-addition/transmetalation of acetylenic
esters. BDP=1,2-bis(diphenylphosphino)benzene.
have been described (Scheme 1), including: a) quenching
Exposure of acetylenic ester 1 to ligated CuH leads to
rapid syn hydrocupration.[7] In the presence of stoichiometric
pinacolborane,[5f,8] the initially formed a-cuprio ester under-
goes stereoretentive transmetalation,[9] affording isolable 1-
(alkoxycarbonyl)alkenyl pinacol boronates 2 (Scheme 2).
Recent interest in a-functionalization of enoates has focused
on methods for installing either silicon[10] or tin[11] at this site.
The corresponding boronates 2, however, benefit from all of
the virtues associated with boron chemistry, such as stability,
environmental friendliness, and chemoselectivity. This route
to a-boryl-a,b-unsaturated esters also complements existing
methods for the synthesis of b-boryl-a,b-unsaturated esters.[12]
Initially, 1,2-bis(diphenylphosphino)benzene (BDP)[13]
was used as a ligand (1 mol%) for in situ generated CuH, to
form [(BDP)CuH](conditions A, Scheme 2). More conven-
ient, however, is commercially available Strykerꢀs reagent
(SR), [(Ph3P)CuH]6[14] (2 mol%)[15] (conditions B, Scheme 2).
Both formulations led instantaneously to the desired HB
product with excellent Z/E ratios. SR in the presence of
pinacolborane (HBpin) undergoes a color change from red to
dark red or even brown, which suggests the possible
formation of a new species, [(Ph3P)CuH]·HBpin, perhaps
analogous to that proposed for ligated CuH in the presence of
silanes.[16]
Scheme 1. Routes to alkenyl boronates: a) Quenching of alkenyl metal
species. b) Pd-catalyzed halogen/boron exchange. c) Olefin metathesis.
d) Hydroboration.
reactive alkenyl metal species with B(OR)3;[2] b) Pd- or Pt-
catalyzed halogen/boron exchange with HB(OR)2;[3] c) olefin
metathesis;[4] and d) hydroboration (HB) of terminal
alkynes.[5] The latter pathway (d) is regioselective for terminal
alkynes only,[6] and requires subsequent manipulation of the
two alkyl–boron bonds present in the initial adduct, which can
add hours (or even days) to the HB reaction.[6] Herein a newly
developed, general methodology is described, which leads to
these rare coupling partners (2, Scheme 2). This single-pot
process highlights a remarkable copper-to-boron transmeta-
lation on an sp2-like hybridized carbon, directly forming
vinylboronates bearing a valuable a-carboalkoxy group not
otherwise accessible by routes (a)–(d).
Control experiments confirmed that net HB does not take
place in the absence of CuH. Likewise, a mixture of alkynoate
and pinacolborane did not give rise to HB to any noticeable
extent, even after prolonged reaction times (several hours).
Triphenylphosphine alone led to no reaction under these
typical conditions.
For successful HB reactions, substrate concentrations on
the order of 1m in THF appeared to be crucial.[17] Lower
concentrations (0.1m) unexpectedly yielded the correspond-
ing Z-enoate as the only reaction product, as protonation
occurred faster than transmetalation. Examples of successful
conversions of various educts 1 into products 2 are illustrated
in Figure 1. The nature of the alkyl ester residue appeared not
to be of consequence, even when highly hindered (e.g., 2-
adamantyl, 9). The expected Z-boronates were favored,
although this selectivity is somewhat ligand-dependent. For
ˇ
ˇ
´
[*] Prof. B. H. Lipshutz, Z. V. Boskovic, Prof. D. H. Aue
Department of Chemistry and Biochemistry
University of California, Santa Barbara
Santa Barbara, CA 93106 (USA)
E-mail: lipshutz@chem.ucsb.edu
aue@chem.ucsb.edu
[**] Financial support from the NSF and Zymes, LLC is warmly
acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804912.
Angew. Chem. Int. Ed. 2008, 47, 10183 –10186
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Figure 2. Molecular structure of vinylboronic acid 11, depicting two
adjacent molecules (see Scheme 3, R=nC5H11, R’=Me). Thermal
ellipsoids are set at 50% probability. B orange, C gray, H blue, O red.
Figure 1. Isolable products from acetylenic ester precursors, with PPh3
or BDP as a ligand for in situ generated CuH. TMS=trimethylsilyl;
Ad=adamantyl; THP=tetrahydropyranyl.
However, exposure to selected transition metal catalysts, such
as [Rh(OH)cod] (0.1 mol%, cod = cyclooctadiene) promoted
transmetalation, and in the presence of water led to facile a-
protonation or deuteration (13, Scheme 4, path a). Sequential
example, only Z-boronates, such as 3 and 5, resulted from
reaction with [(BDP)CuH] and HBpin. Terminal acetylenes,
such as propynoates, were unfortunately deprotonated to
their copper acetylides, thereby inhibiting HB. Whereas
boronates 3–10 are all isolable by chromatography, small
amounts were lost as a result of protonolysis. Therefore, yields
did not fully reflect the efficiency of the initial CuH-catalyzed
event.
The readily obtained pinacol boronates, such as 3 and 5,
were smoothly converted into their corresponding boronic
acids 11 by hydrolytic cleavage using sodium periodate in an
acetone/water mixture (Scheme 3).[18] In the case of crystal-
line boronic acid 11 (R = nC5H11, R’ = Me), single-crystal X-
ray diffraction confirmed the expected Z-geometry resulting
from syn hydrocupration (Figure 2). Application of Moland-
erꢀs conditions readily transformed boronic acid 11 (R = R’
Et) to potassium organotrifluoroborate 12.[19]
Scheme 4. Functionalization of 1-(alkoxycarbonyl)alkenyl pinacol boro-
nate 2. a) [Rh(OH)cod] (0.1 mol%), dioxane (R=nPr, R’=Me), D2O;
b) Br2, DCM, then NaOMe, MeOH (R=R’=Et); c) Et2Zn, THF, À788C
to RT, hexanal (R=R’=Et, R’’=nC5H11); d) H2O2, H2O, KOH, 08C
(R=nPr, R’=Me).
The newly formed boronates 2 were unexpectedly stable
to acid (both aqueous HCl and refluxing HOAc), compared
with the usual lability of vinylic boron-containing species.
treatment of boronate 2 with bromine followed by NaOMe in
a one-pot reaction afforded the corresponding alkenyl
bromides 14 with predominant inversion of configuration.[20]
The presence of base, however, led to partial olefin isomer-
ization (Z/E ratio: 5:1; Scheme 4, path b). Transmetalation
with zinc and subsequent addition to aldehydes allowed for an
alternative to the Baylis–Hillman reaction (15; Scheme 4,
path c).[21] Standard treatment of 2 with alkaline hydrogen
peroxide led to a-ketoesters 16 (Scheme 4, path d).
Net hydroarylation of an alkyne was achieved when a
boronic ester, such as 5 (Scheme 5), was subjected to Suzuki–
Miyaura conditions, catalyzed by 1,1’-bis(di-tert-butylphos-
phino)ferrocene palladium(II) chloride (2 mol%; path C).
The couplings proceeded in minutes, and the resulting
styrenes 17–19 retained their original double-bond geometry.
Scheme 3. Conversion of pinacol boronates into coupling partners 11
and 12.
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structures of 21a and 21b have a much larger effect on the
overall energy difference. Thus, the computed free energy
difference between methyl acrylate (analogous to 21a) and its
enol (analogous to 21b) is 43.7 kcalmolÀ1.
Further calculations indicated that the reaction proceeds,
initially, via a weakly bound p-complex 20, which rearranges
to 21a via a transition state involving hydrogen transfer
(Figure 3), with a calculated free-energy barrier of only
Scheme 5. Pd-catalyzed couplings in a water/THF mixture 7/1 v/v (C)
or water (D). dtbpf=1,1’-bis(di-tert-butylphosphino)ferrocene;
PTS=polyoxyethanyl-a-tocopheryl sebacate
Figure 3. Transition state 20 in the addition of (PH3)CuH to methyl
propiolate. C gray, Cu orange, H white, O red, P magenta.
Both electron-poor and electron-rich aryl bromides reacted
with equal effectiveness. Opportunities also exist to conduct
such reactions in neat water, in the presence of the micelle-
forming amphiphile polyoxyethanyl-a-tocopheryl sebacate
(PTS, 2 mol%, path D).[22]
The stereoselectivity of the HB reaction suggests a
mechanism (Scheme 6) in which the 1,2-addition forms a
carbon-bound copper intermediate 21a,[23] rather than the
7.2 kcalmolÀ1, compared to 21.8 kcalmolÀ1 for CuH addition
in the absence of a chelating PH3 ligand. An alternative
mechanism, via 21b and a 6-membered transition state to
À
form the B C bond in 2, appears unlikely in view of the high
calculated free energy of 21b, and is not consistent with the
derived boronate stereochemistry.
Access to a-aryl enoates offers a new pathway to the key
intermediate 24, which is utilized industrially in the synthesis
of the antiinflammatory drug naproxen (Scheme 7). Readily
available propiolate 22 undergoes CuH-catalyzed HB to form
a-boron enoate 8, followed by a Suzuki–Miyaura reaction.
Cross-coupling of 8 with naphthyl bromide 23 was effective
either in THF (conditions C, Scheme 5; 92%) or in neat water
in the presence of PTS (conditions D; 87%), although in the
latter case sonication was required, to overcome the low
solubility in water of 23. The vinylic trimethylsilyl group was
cleanly cleaved with sulfuric acid in refluxing THF to afford
Scheme 6. Stereoselective addition-transmetalation leading to boro-
nates 2. L=PH3.
oxygen-bound intermediate 21b. This result was at first
À
surprising, based upon the assumption that the Cu O bonds
À
would be stronger than Cu C bonds, and prompted a
computational investigation of this reaction. High-level
ab initio calculations indicated that 21b, is significantly less
stable than 21a (R = H, L = PH3, R’ = CH3), by 29.5 kcal
molÀ1.[24] Similarly, the stabilities of the boron analogues
(R’’ = H) were found to differ by a comparably large free
energy, 23.2 kcalmolÀ1. Although our computed bond ener-
À
À
gies confirmed that Cu C (or B C) bonds are weaker than
À
À
Cu O (or B O) bonds, other energetic differences in the
Scheme 7. Synthesis of intermediate 24, en route to naproxen.
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Communications
[8] Catecholborane seems to be incompatible with SR.
[9] a) B. H. Lipshutz, P. Papa, Angew. Chem. 2002, 114, 4762 – 4764;
Angew. Chem. Int. Ed. 2002, 41, 4580 – 4582; b) D. Zhao, K.
Oisaki, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2006, 128,
14440 – 14441.
[10] a) A. J. Mueller, M. P. Jennings, Org. Lett. 2007, 9, 5327 – 5330;
b) A. J. Mueller, M. P. Jennings, Org. Lett. 2008, 10, 1649 – 1652.
[11] a) Y. Shi, S. M. Peterson, W. W. Haberaecker, S. A. Blum, J. Am.
Chem. Soc. 2008, 130, 2168 – 2169; b) L. T. Leung, S. K. Leung, P.
Chiu, Org. Lett. 2005, 7, 5249 – 5252.
aryl acrylate 24, which can be subsequently hydrolyzed and
hydrogenated with Noyoriꢀs ruthenium-based catalyst to give
naproxen.[25]
In summary, a new route has been developed to geo-
metrically defined vinylboronates bearing an activating
alkoxycarbonyl substituent in the a-position. The method
consists of catalytic chemo- and stereoselective 1,2-additions
of CuH to acetylenic esters, and subsequent facile in situ
transmetalation with pinacolborane. The application of this
method to the synthesis of the antiinflammatory drug
naproxen demonstrated its potential.
[12] J.-E. Lee, J. Kwon, J. Yun, Chem. Commun. 2008, 733 – 734.
[13] B. A. Baker, Z. V. Boskovic, B. H. Lipshutz, Org. Lett. 2008, 10,
289 – 292.
[14] a) W. S. Mahoney, D. M. Brestensky, J. M. Stryker, J. Am. Chem.
Soc. 1988, 110, 291 – 293; b) W. S. Mahoney, J. M. Stryker, J. Am.
Chem. Soc. 1989, 111, 8818 – 8823.
[15] Reducing copper and ligand content to 0.2 mol% and 0.3 mol%,
respectively, lengthened the reaction times from minutes to
several hours.
Experimental Section
General Procedure for Hydroboration of Alkynoates using Strykerꢀs
Reagent: In a flame-dried 100 mL round bottom flask under an argon
atmosphere, a bright red solution of Strykerꢀs reagent [(PPh3)CuH]6
(140 mg, 0.428 mmol, 2.1 mol%), and triphenylphosphine (100 mg,
0.38 mmol, 2 mol%) in THF (20 mL) was cooled in an ice bath and
pinacolborane (3.20 mL, 22.05 mmol, 1.10 equiv) was added in one
portion and stirred for 5 min, which caused the solution to darken.
Methyl octynoate (3.08 g, 3.35 mL, 20.00 mmol, 1 equiv) was then
added dropwise over 5 min. The solvent was evaporated under
reduced pressure and the residue subjected to chromatography on
silica gel, using 7% EtOAc in hexanes, to afford the product (4.79 g,
17.00 mmol, 85%).
[16] B. H. Lipshutz, W. Chrisman, A. Lower, J. Am. Chem. Soc. 2003,
À
125, 8779 – 8789. Such Cu B species are well-known; see H.
Zhao, L. Dang, T. B. Marder, Z. Lin, J. Am. Chem. Soc. 2008,
130, 5586 – 5594; D. S. Laitar, E. Y. Tsui, J. P. Sadighi, J. Am.
Chem. Soc. 2006, 128, 11036, and references therein. Borylcup-
ration: T. Kajiwara, T. Terabayashi, M. Yamashita, K. Nozaki,
Angew. Chem. 2008, 120, 6708 – 6712; Angew. Chem. Int. Ed.
2008, 47, 6606 – 6610.
[17] Alkynones do not lead to HB products akin to 2 under these
conditions. Interestingly, under transfer hydrogenation condi-
tions using a ruthenium hydride at high substrate concentrations,
1,2-addition across the alkyne occurs as an undesired side
reaction, to form an a-ruthenium complex; see K. Matsumura, S.
Hashiguchi, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1997, 119,
8738 – 8739.
[18] a) T. Itoh, K. Hirai, H. Tomioka, J. Am. Chem. Soc. 2004, 126,
1130 – 1140; b) M. Nambo, R. Noyori, K. Itami, J. Am. Chem.
Soc. 2007, 129, 8080 – 8081.
Received: October 8, 2008
Published online: November 25, 2008
Keywords: boronates · copper · cross-coupling · hydroboration ·
.
P ligands
[1] Boronic Acids (Ed.: D. G. Hall), Wiley-VCH, Weinheim, 2005.
[2] a) H. C. Brown, N. G. Bhat, Tetrahedron Lett. 1988, 29, 21 – 24;
b) K. Itami, T. Kamei, J.-i. Yoshida, J. Am. Chem. Soc. 2003, 125,
14670 – 14671; c) T. E. Cole, R. Quintanilla, Organometallics
1991, 10, 3777 – 3781.
[3] a) J. Takagi, K. Takahashi, T. Ishiyama, N. Miyaura, J. Am.
Chem. Soc. 2002, 124, 8001 – 8006; b) M. Murata, T. Oyama, S.
Watanabe, Y. Masuda, Synthesis 2000, 778 – 780.
[19] G. A. Molander, N. Ellis, Acc. Chem. Res. 2007, 40, 275 – 286. See
also S. Darses, J.-P. Genet, Chem. Rev. 2008, 108, 288 – 325.
[20] H. C. Brown, T. Hamaoka, N. Ravindran, J. Am. Chem. Soc.
1973, 95, 6456 – 6457.
[21] F. Langer, L. Schwink, A. Devasagayaraj, P.-Y. Chavant, P.
Knochel, J. Org. Chem. 1996, 61, 8229 – 8243.
[22] B. H. Lipshutz, T. B. Petersen, A. R. Abela, Org. Lett. 2008, 10,
1333 – 1336.
[4] C. Morrill, R. H. Grubbs, J. Org. Chem. 2003, 68, 6031 – 6034.
[5] a) R. W. Hoffmann, S. Dresley, Synthesis 1988, 103 – 106; b) P.
Martinez-Fresneda, M. Vaultier, Tetrahedron Lett. 1989, 30,
2929 – 2932; c) A. Kamabuchi, T. Moriya, N. Miyaura, A. Suzuki,
Synth. Commun. 1993, 23, 2851 – 2859; d) H. C. Brown, S. K.
Gupta, J. Am. Chem. Soc. 1975, 97, 5249 – 5255; e) A. V. Kalinin,
S. Scherer, V. Snieckus, Angew. Chem. 2003, 115, 3521 – 3526;
Angew. Chem. Int. Ed. 2003, 42, 3399 – 3404; f) C. E. Tucker, J.
Davidson, P. Knochel, J. Org. Chem. 1992, 57, 3482 – 3485; g) X.
He, J. F. Hartwig, J. Am. Chem. Soc. 1996, 118, 1696 – 1702.
[6] M. Gravel, B. B. Toure, D. G. Hall, Org. Prep. Proced. Int. 2004,
36, 573 – 580.
[23] J. Klein, R. M. Turkel, J. Am. Chem. Soc. 1969, 91, 6186 – 6187.
[24] Free energy differences for copper species were calculated by
using a G2(MP2)-like procedure at the CCSD(T)/6-311 + G-
(2df,2pd)//MP2/6-311 + G(d,f) level, using thermodynamic
terms from B3LYP/6-311 + G(d,p) frequencies scaled by 0.99
for zero-point energies and 0.96 for thermal and entropy terms.
For the boronic acids, the level of theory is effectively CCSD(T)/
aug-cc-pVTZ//MP2/6-31 + G(d,f) with B3LYP/6-311G(d,p) fre-
quencies.
[25] a) Hydrolysis: S. J. Mahmood, C. Brennan, M. M. Hossain,
Synthesis 2002, 1807 – 1809; b) Asymmetric hydrogenation: T.
Ohta, M. Takaya, M. Kitamura, K. Nagai, R. Noyori, J. Org.
Chem. 1987, 52, 3174 – 3176; c) A. S. C. Chan, S. A. Laneman,
US Patent 5198561, 1993.
[7] a) J. F. Daeuble, C. McGettigan, J. M. Stryker, Tetrahedron Lett.
1990, 31, 2397 – 2400; b) H. C. Brown, G. A. Molander, J. Org.
Chem. 1981, 46, 645 – 647.
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