Pd-catalyzed cross-coupling of α-(acyloxy)-tri-n -butylstannanes with alkenyl, aryl, and heteroaryl electrophiles

Article abstract of DOI:10.1021/ol102863u

Racemic and scalemic α-(acyloxy)-tri-n-butylstannanes undergo Pd-catalyzed cross-couplings with alkenyl/aryl/heteroaryl iodides, bromides, and triflates in moderate to good yields in THF at 45 °C. Simple aryl iodides and unprotected aza-arenes, two classe

Full text of DOI:10.1021/ol102863u

ORGANIC
LETTERS
2011
Vol. 13, No. 2
344-346
Pd-catalyzed Cross-Coupling of
r-(Acyloxy)-tri-n-butylstannanes with
Alkenyl, Aryl, and Heteroaryl
Electrophiles
Mohan Goli, Anyu He, and J. R. Falck*
Departments of Biochemistry and Pharmacology, UniVersity of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
j.falck@UTSouthwestern.edu
Received November 26, 2010
ABSTRACT
Racemic and scalemic r-(acyloxy)-tri-n-butylstannanes undergo Pd-catalyzed cross-couplings with alkenyl/aryl/heteroaryl iodides, bromides,
and triflates in moderate to good yields in THF at 45 °C. Simple aryl iodides and unprotected aza-arenes, two classes of electrophiles that
typically react sluggishly, are also good substrates. Cross-couplings proceed with retention of configuration at the alkenyl and stannyl-
substituted stereocenters.
The Stille reaction,1 i.e., the transition-metal-mediated cross-
coupling of organostannanes with organic electrophiles, has
achieved wide acceptance2 as an exceptionally mild and
efficient method for the creation of C-C bonds, especially
between sp- and/or sp2-hybridized centers.3 Not surprisingly,
the apparent advantages that would accrue from expanding
the traditional scope and structural confines of the Stille
reaction have attracted much interest.4 In the early 1990′s,
this laboratory5 and others6 explored the utility of tri-n-
butylstannanes for the transfer of stereogenic carbons bearing
heteroatoms and reported the stereospecific palladium/copper
cocatalyzed cross-coupling of scalemic R-alkoxy- and R-ami-
noalkylstannanes with acid chlorides.7,8 Subsequent studies
led to copper-mediated cross-couplings with reactive elec-
trophiles such as allylic and propargylic halides.9 The utility
of this methodology for the construction of chiral ethers and
alcohols was cogently demonstrated during asymmetric total
syntheses of the anticancer agent (+)-goniofufurone10 and
the potent endothelium-derived vasodilator 11,12,15-THE-
(1) Review: Mitchell, T. N. In Metal-Catalyzed Cross-Coupling Reac-
tions, 2nd ed.; de Meijere, A.; Diederich, F., Eds.; Wiley-VCH Verlag
GmbH & Co.: Weinheim, 2004; Vol. 1, Chapter 3.
(2) Recent applications in natural products total synthesis: (a) Masters,
K.-S.; Flynn, B. L. Org. Biomol. Chem. 2010, 8, 1290–1292. (b) Tang, B.;
Bray, C. D.; Pattenden, G.; Rogers, J. Tetrahedron 2010, 66, 2492–2500.
(c) Candy, M.; Audran, G.; Bienayme, H.; Bressy, C.; Pons, J.-M. J. Org.
Chem. 2010, 75, 1354–1359. (d) Amans, D.; Bareille, L.; Bellosta, V.;
Cossy, J. J. Org. Chem. 2009, 74, 7665–7674.
(5) (a) Bhatt, R. K.; Shin, D. S.; Falck, J. R.; Mioskowski, C.
Tetrahedron Lett. 1992, 33, 4885–4888. (b) Belosludtsev, Y. Y.; Bhatt,
R. K.; Falck, J. R. Tetrahedron Lett. 1995, 36, 5881–5882. (c) Falck, J. R.;
Bhatt, R. K.; Reddy, K. M.; Ye, J. Synlett 1997, 481–482.
(6) Linderman, R. J.; Graves, D. M.; Kwochka, W. R.; Ghannam, A. F.;
Anklekar, T. V. J. Am. Chem. Soc. 1990, 112, 7438–7439.
(7) (a) Ye, J.; Bhatt, R. K.; Falck, J. R. J. Am. Chem. Soc. 1994, 116,
1–5.
(8) In 2004, R-sulfonamidoorganostannanes were introduced and shown
to be highly efficacious: Kells, K. W.; Chong, J. M. J. Am. Chem. Soc.
2004, 126, 15666–15667.
(3) Pascual, S.; Echavarren, A. M. In Tin Chemistry; Davies, A. G.,
Ed.; John Wiley & Sons Ltd.: Chichester, 2008; pp 579-606.
(4) For example: (a) Jensen, M. S.; Yang, C.; Hsiao, Y.; Rivera, N.;
Wells, K. M.; Chung, J. Y. L.; Yasuda, N.; Hughes, D. L.; Reider, P. J.
Org. Lett. 2000, 2, 1081–1084. (b) Jarosz, S. Tetrahedron Lett. 1996, 37,
3063–3066.
(9) Falck, J. R.; Bhatt, R. K.; Ye, J. J. Am. Chem. Soc. 1995, 117, 5973–
5982.
(10) Ye, J.; Bhatt, R. K.; Falck, J. R. Tetrahedron Lett. 1993, 34, 8007–
8010.
10.1021/ol102863u  2011 American Chemical Society
Published on Web 12/09/2010

TA.11 On the other hand, comparable unions between
R-heteroatom-substituted triorganostannanes and alkenyl/aryl
electrophiles were conspicuously absent12 and suitable
methodology has been elusive.13 To address this method-
ological gap, we conducted an extensive survey of alternative
reaction parameters including oxygen substituents14 and
herein describe a practical, stereospecific cross-coupling
capable of using a broad range of sp2-hybridized iodides/
triflates/bromides (Scheme 1).
Table 1. Cross-Coupling of R-(Acyloxy)stannanes with
(E)-ꢀ-Iodostyrenea
Scheme 1. Proposed Cross-Coupling
a Reaction conditions: R-(acyloxy)stannane 1 (1 equiv), 2 (1.5 equiv),
Pd(dppe)Cl2 (10 mol %), THF, 45 °C, 8-12 h.
Since esters and alkenyl iodides were identified as the most
promising pairing in our initial evaluations, R-(acetyloxy)s-
tannane 1a and (E)-ꢀ-iodostyrene (2) were selected as the
test system. Screening an extensive collection of transition
metals salts and complexes, tested individually or in com-
bination, revealed palladium complexes were especially
efficacious, and in particular freshly recrystallized Pd-
(dppe)Cl2.15 The yield of adduct 3a increased proportionately
with the amount of Pd(dppe)Cl2 up to 10 mol % (62%; Table
1), but thereafter neither more catalyst nor alterations in mode
of addition improved the outcome.16 Yields of 3a were
patently better in THF as well as the reaction rate compared
to other common solvents, inter alia, toluene, DME, and
DMF; there was no cross-coupling in NMP, acetone, EtOAc,
and CH3CN. In contrast with the experience of others,17
neither sources of fluoride (LiF, TBAF, KF, AlF3, CsF) nor
Lewis acids [MgBr2, AlCl3, FeCl3, ZnBr2, BF3·Et2O,
Sc(OTf)3] have a beneficial effect.
Replacement of the acetate of 3a with a benzoate, i.e.,
3b, resulted in a modest improvement in yield. Electron-
donating substituents (3c-d) had little influence above that
of the parent aromatic 3b and neither did electron-rich
heterocycles like 2-carboxyfuran 3f and 2-carboxythiophene
3g despite the potential for intramolecular coordination in
the transition state. In contrast, electron-withdrawing sub-
stituents (3h-j) offered an additional improvement in adduct
yield and a modest rate enhancement. Because of its better
handling characteristics and lower cost than the polyfluori-
nated aryls 3h,i, p-trifluoromethylbenzoate 3j was used in
subsequent optimization studies.
Having standardized the reaction conditions, we next
explored the scope of the cross-coupling of p-trifluorometh-
ylbenzoate (TFMB) 1j with a panel of representative sp2-
hybridized iodides, triflates, and bromides (Table 2). 3-Io-
dopropenoate 4, despite its proclivity toward loss of HI and/
or isomerization, smoothly cross-coupled using Pd(dppe)Cl2
(catalyst A) to furnish 5 (entry 1) in excellent yield without
complication or loss of the Z-configuration at the alkenyl
center (>98% by 1H/13C NMR), thus precluding a conjugate
addition mechanism. Under the same reaction conditions,
2-iodo-2-cyclohex-2-enone (6), (Z)-iodostyrene (9), (E)-
triflate 12, and unconjugated alkenyl iodide 15 led to adducts
8 (entry 2), 11 (entry 3), 14 (entry 4), and 16 (entry 5),
respectively, although the reaction rates were somewhat
slower than that for 4. TFMB-benzyl alcohols 19 (entry 6),
22 (entry 7), and 24 (entry 8) were obtained analogously
from aryl/heteroaryl iodides 17, 20, and 23, respectively, in
useful yields.
(11) Falck, J. R.; Barma, D.; Mohapatra, S.; Bandyopadhyay, A.; Reddy,
K. M.; Qi, J.; Campbell, W. Bioorg. Med. Chem. Lett. 2004, 14, 4987–
4990.
(12) A catalyst-free cross-coupling of R-sulfur-substituted alkyltriorga-
nostannanes with acid chlorides has been described: Kagoshima, H.;
Takahashi, N. Chem. Lett. 2007, 36, 14–15.
(13) The copper(I) thiophene-2-carboxylate catalyzed cross-coupling of
R-(thiocarbamoyl)tri-n-butylstannanes with sp2-electrophiles was subse-
quently found to be accompanied by a facile Newman-Kwart O f S
rearrangement that in many cases generated the corresponding thiolcar-
bamate as the major product: Falck, J. R.; Patel, P. K.; Bandyopadhyay, A.
J. Am. Chem. Soc. 2007, 129, 790–793. Correction: J. Am. Chem. Soc. 2008,
130, 2372.
(14) Alternative sulfur-containing derivatives (e.g., thioesters, thiocar-
bonates, thiooxamides, thiophosphates) were evaluated, but it was not
possible to completely suppress the rearrangement and still achieve
acceptable yields of cross-coupled adduct (see Supporting Information).
(15) Catalyst quality varied widely with the source as revealed in cross-
coupling yield of 3j, e.g., Aldrich (brown color) mp 222 °C, 10%; TCI
(light brown) mp 255 °C, 40%; Strem (pale yellow) mp 285 °C, 68%; Strem
(recrystallized from EtOH, pale yellow) mp 298 °C, 78%; Strem (recrystal-
lized from DMF/Et2O, pale yellow) mp 301 °C, 81%; lit. mp >300, pale
yellow: Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A.,
Ed.; John Wiley & Sons: New York, NY, 1985; Vol. 3, pp 1675-1676.
(16) Modifications evaluated included reversing the order of reagent
addition and slow addition of reagents via syringe pump.
Comparable couplings of alkenyl and aryl bromides using
Pd(dppe)Cl2 proved more challenging, and only poor yields
of adduct could be obtained. Fortunately, we discovered that
(17) Mee, S. P. H.; Lee, V.; Baldwin, J. E. Chem.sEur. J. 2005, 11,
3294–3308.
Org. Lett., Vol. 13, No. 2, 2011
345

Table 2. Scope of Cross-Coupling Using R-(TFMB)stannane 1ja
Figure 1. Cross-coupling of enantioenriched stannanes.
stereogenic center. This is consistent with prior experience
using other classes of electrophiles but opposite to the
inversion of configuration observed by Kells and Chong8
using scalemic R-(sulfonamido)organostannanes and Pd/Cu
cocatalysis. Analogous coupling of the diastereomeric glyc-
eryl stannane 2721 to give 28 (Figure 1) was also instructive
and revealed the adjacent stereocenter had no apparent
influence on the outcome.
In conclusion, we have demonstrated the stereospecific Pd-
mediated cross-coupling TFMB-protected R-hydroxystan-
nanes with alkenyl/aryl/heteroaryl iodides/triflates/bromides
including secondary cycloalkenyl and unactivated aryl
iodides in THF under mild conditions.22 When combined
with the recently introduced methodology for the synthesis
of racemic and scalemic R-hydroxystannanes,19 we anticipate
the foregoing methodology will find wide utility in the
synthesis of heteroatom-substituted stereogenic centers.
a Reaction conditions: 1j (1 equiv), electrophile (1.5 equiv), Pd catalyst
(10 mol %), THF, 45 °C, 8-12 h. b Catalyst A ) recrystallized Pd(dppe)Cl2,
catalyst B ) chloro(2-di-tert-butylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-
biphenyl)[2-(2-aminoethyl)phenyl] palladium(II).
the Buchwald pallacyclic catalyst18 chloro(2-di-tert-bu-
tylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-ami-
noethyl)phenyl] palladium(II) (t-BuXphos) restored efficacy
(Table 2). While reaction times were modestly increased for
bromides 10, 13, 18, and 21, adduct yields were generally
comparable or even slightly better than those seen with
alkenyl iodides/triflates. The exception was (Z)-bromostyrene
(10) which likely reflects this electrophile’s greater steric
hindrance.
To ascertain the stereochemistry of the C-C bond forma-
tion, enantioenriched benzoate 25 (98% ee), readily prepared
from the corresponding aldehyde via the one-pot procedure
of He and Falck,19 was added to phenyl iodide using the
standard conditions (Figure 1). Saponification of the resultant
benzoate 26 gave rise to the known20 1,3-diphenylpropan-
1(R)-ol (98% ee via chiral HPLC), thus demonstrating
complete retention of configuration at the stannyl-substituted
Acknowledgment. Financial support provided by the
RobertA.WelchFoundation(GL625910)andNIH(GM31278,
DK38226). Dr. E. R. Fogel (CRO Laboratories, Inc.) is
thanked for useful insights.
Supporting Information Available: Synthetic procedures,
1
analytical data, chiral HPLC chromatograms, and H/13C
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL102863U
(21) Mohapatra, S.; Bandyopadhyay, A.; Barma, D. K.; Capdevila, J. H.;
Falck, J. R. Org. Lett. 2003, 5, 4759–4762.
(22) Cross-Coupling Procedure: A Schlenk tube is charged with R-(acy-
loxy)-tri-n-butylstannane (0.16 mmol) and recrystallized Pd(dppe)Cl2 (0.016
mmol, 10 mol %), when using an alkenyl/aryl/heteroaryl iodide/triflate, or
chloro(2-di-tert-butylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-
aminoethyl)phenyl] palladium(II) (t-BuXphos), when using an aryl/het-
eroaryl/alkenyl bromide, and then degassed via four alternating high-vacuum
argon cycles. After dissolving in anhydrous THF (3 mL) under an argon
atmosphere, a solution of electrophile (0.24 mmol) in THF (2 mL) is added
via syringe and the mixture is warmed to 45 °C. After 6-12 h, the reaction
mixture is diluted with Et2O (10 mL) and filtered through a short pad of
neutral alumina. The filter cake is washed with Et2O (2 × 20 mL), and the
combined organic filtrates are washed with water and brine and evaporated
in Vacuo. Chromatographic purification (SiO2) of the residue furnishes the
cross-coupled adduct in the indicated yield (Tables 1 and 2).
(18) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc.
2008, 130, 6686–6687.
(19) He, A.; Falck, J. R. Angew. Chem., Int. Ed. 2008, 47, 6586–6589.
(20) (a) Node, M.; Nishide, K.; Shigeta, Y.; Shiraki, H.; Obata, K. J. Am.
Chem. Soc. 2000, 122, 1927–1936. (b) Anthony, R.; Stoner, H. E. J.;
Peterson, M. J.; Grover, V. K. J. Org. Chem. 2003, 68, 8092–8096.
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