Stereospecific cross-coupling of α-(thiocarbamoyl)organostannanes with alkenyl, aryl, and heteroaryl iodides

Article abstract of DOI:10.1021/ja064948q

Racemic and scalemic PTC-protected α-hydroxystannanes cross-couple with alkenyl/aryl/heteroaryl iodides in moderate to good yields using copper(I) thiophene-2-carboxylate (CuTC) in THF at or below room temperature. Simple aryl iodides and 1-iodocyclohexen

Full text of DOI:10.1021/ja064948q

Published on Web 01/10/2007
Stereospecific Cross-Coupling of
r-(Thiocarbamoyl)organostannanes with Alkenyl, Aryl, and
Heteroaryl Iodides
J. R. Falck,* Paresh K. Patel, and Anish Bandyopadhyay
Contribution from the Departments of Biochemistry and Pharmacology, UniVersity of Texas
Southwestern Medical Center, Dallas, Texas 75390
Received July 12, 2006; E-mail: j.falck@utsouthwestern.edu
Abstract: Racemic and scalemic PTC-protected R-hydroxystannanes cross-couple with alkenyl/aryl/
heteroaryl iodides in moderate to good yields using copper(I) thiophene-2-carboxylate (CuTC) in THF at or
below room temperature. Simple aryl iodides and 1-iodocyclohexene, 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.
successes, alkenyl9 and aryl10 electrophiles were refractory and
little, if any, cross-coupled adduct could be isolated. Conse-
Introduction
Cross-couplings of organostannanes mediated by transition
metals have emerged over the past quarter century as one of
the premier procedures for the creation of carbon-carbon bonds,
especially with sp and sp2-hybridized electrophiles.1 Their
numerous advantages, inter alia, applicability to a wide variety
of substrates, high stereospecificity, mild and neutral reaction
conditions, and compatibility with most functional groups, make
them especially suitable for the preparation of complex and/or
labile molecules.2 In the early 1990s, our laboratory3 and others4
explored the utility of organostannanes for the transfer of
stereogenic carbons bearing heteroatoms and described the
palladium-mediated cross-coupling of scalemic R-alkoxy- and
R-acyloxyalkylstannanes with acid chlorides.5 We subsequently
extended this to allylic and propargylic electrophiles and to
R-nitrogen-substituted alkylstannanes.6 The utility of this meth-
odology for the construction of chiral ethers and alcohols was
cogently demonstrated during asymmetric total syntheses of the
anticancer agent (+)-goniofufurone7 and the potent endothelium-
derived vasodilator 11,12,15-THETA.8 In stark contrast to these
quently, we initiated a systematic investigation of this variant
of the Stille reaction (eq 1) and report herein our progress.
Results and Discussion
The initial objective, i.e., the identification of a catalyst or
promoter11 competent to cross-couple R-hydroxystannanes with
alkenyl and aryl electrophiles at room temperature, was
conducted using pyrrolidinylthiocarbamoyl (PTC)-protected
stannane 3 and E-alkenyl iodide 4 as the test system. Evaluation
of a wide variety of transition metal salts and complexes, either
individually or in combination, revealed copper salts12,13 were
uniquely suitable and, in particular, commercial copper(I)
(1) Review: Mitchell, T. N. In Metal-Catalyzed Cross-Coupling Reactions,
2nd ed.; de Meijere, A.; Diederich, F., Eds.; Wiley-VCH Verlag GmbH &
Co.: Weinheim, 2004; Vol. 1, Chapter 3.
(9) Recent examples of alternative chiral allylic alcohol syntheses: (a)
Berkessel, A.; Roland, K.; Neudoerfl, J. M. Org. Lett. 2006, 8, 4195-
4198. (b) Evans, D. A.; Aye, Y. J. Am. Chem. Soc. 2006, 128, 11034-
11035. (c) Hilt, G.; Hess, W.; Harms, K. Org. Lett. 2006, 8, 3287-3290.
(10) Recent examples of alternative chiral benzylic alcohol syntheses: (a) Yang,
S.-D.; Shi, Y.; Sun, Z.-H.; Zhao, Y.-B.; Liang, Y.-M. Tetrahedron:
Asymmetry 2006, 17, 1895-1900. (b) Zhu, D.; Yang, Y.; Hua, L. J. Org.
Chem. 2006, 71, 4202-4205. (c) Grasa, G. A.; Zanotti-Gerosa, A.; Hems,
W. P. J. Organomet. Chem. 2006, 691, 2332-2334.
(11) Since CuTC is used in stoichiometric amounts and apparently consumed
to some extent, a reviewer suggested the term promoter instead of catalyst.
(12) Catalysis or promotion of the Stille reaction by copper salts in combination
with other transition metals or alone is well established: (a) Liebeskind,
L. S.; Fengl, R. W. J. Org. Chem. 1990, 55, 5359-5364. (b) Wipf, P.
Synthesis 1993, 537-557. (c) Piers, E.; McEachern, E. J.; Burns, P. A. J.
Org. Chem. 1995, 60, 2322-2323. (d) Wang, Y.; Burton, D. Org. Lett.
2006, 8, 1109-1111.
(13) Transmetalation of organostannanes with higher order cuprates is also
known: Behling, J. R.; Babiak, K. A.; Ng, J. S.; Campbell, A. L.; Moretti,
R.; Koerner, M.; Lipshutz, B. H. J. Am. Chem. Soc. 1988, 110, 2641-
2643.
(2) Recent applications in natural products total synthesis: (a) Nicolaou, K.
C.; Koftis, T. V.; Vyskocil, S.; Petrovic, G.; Tang, W.; Frederick, M. O.;
Chen, D. Y.-K.; Li, Y.; Ling, T.; Yamada, Y. M. A. J. Am. Chem. Soc.
2006, 128, 2859-2872. (b) Snyder, S. A.; Corey, E. J. J. Am. Chem. Soc.
2006, 128, 740-742. (c) Schnermann, M. J.; Boger, D. L. J. Am. Chem.
Soc. 2005, 127, 15704-15705.
(3) (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.
(4) Linderman, R. J.; Graves, D. M.; Kwochka, W. R.; Ghannam, A. F.;
Anklekar, T. V. J. Am. Chem. Soc. 1990, 112, 7438-7439.
(5) Ye, J.; Bhatt, R. K.; Falck, J. R. J. Am. Chem. Soc. 1994, 116, 1-5.
(6) Falck, J. R.; Bhatt, R. K.; Ye, J. J. Am. Chem. Soc. 1995, 117, 5973-
5982.
(7) Ye, J.; Bhatt, R. K.; Falck, J. R. Tetrahedron Lett. 1993, 34, 8007-8010.
(8) Falck, J. R.; Barma, D.; Mohapatra, S.; Bandyopadhyay, A.; Reddy, K.
M.; Qi, J.; Campbell, W. Bioorg. Med. Chem. Lett. 2004, 14, 4987-4990.
9
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J. AM. CHEM. SOC. 2007, 129, 790-793
10.1021/ja064948q CCC: $37.00 © 2007 American Chemical Society

Cross-Coupling of
R
-(Thiocarbamoyl)organostannanes
A R T I C L E S
Table 1. Cross-Coupling of PTC-Protected R-Hydroxystannanes with Vinyl Iodidesa
a See standard cross-coupling procedure. b Stannane 3 is racemic; 8 and 18 are >98% optically pure. c Conducted at 0 °C. d Stannane (2.5 equiv), iodide
(1 equiv). e Ratio based on weight of pure, isolated adduct. f Conducted at 23 °C. g Conducted at -20 °C. h Determined by integration of chiral HPLC
chromatogram.
thiophene-2-carboxylate14 (CuTC; Liebeskind promoter15), albeit
in stoichiometric amounts. The yield of adduct 5 increased as
the portion of CuTC was raised: 0.1 equiv (51%), 0.5 equiv
(64%), 1.0 equiv (73%), and 1.5 equiv (84%; Table 1, entry
1); more than 1.5 equiv of CuTC did not improve the outcome.16
The remainder of the material balance was carbamothioate 1,
the result of an SfO rearrangement.17 Control experiments
showed 1 was generated almost quantitatively in ca. 15 min
when 3 was exposed to CuTC under identical conditions in the
absence of an electrophile. Yields of 5 were similar in many
common solvents, inter alia, THF, DMF, NMP, toluene,
acetone, dioxane, and EtOAc. However, the reaction rate was
patently faster in THF (typically 10-60 min at rt) compared
with the other aforementioned solvents; thus, it was used as
the routine solvent in all subsequent experiments. In contrast
to the experience of others,18 sources of fluoride (LiF, TBAF,
KF, AlF3, CsF) did not have a significant effect nor did Lewis
acids [MgBr2, AlCl3, FeCl3, ZnBr2, BF3‚Et2O, Sc(OTf)3].19
(14) We speculate that CuTC is more effective than other copper salts because
it is bidentate and can establish a highly coordinated intermediate, e.g., i,
that resists â-elimination. This may explain, in part, why simple aryl iodides
and 1-iodocyclohexene are satisfactory coupling partners, in contrast to
the experience of Allred and Liebeskind (see ref. 15).
Once we had secured a promising promoter and standardized
the reaction conditions, we next explored the scope of the cross-
coupling using a panel of representative alkenyl iodides (Table
(15) The Liebeskind laboratory developed CuTC and adroitly exploited it for
the cross-coupling of organostannanes with aryl and alkenyl iodides: Allred,
G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748-2749.
(16) Little, if any, tri-n-butylstannyl iodide or distannane is observed in the crude
product at the end of the reaction. In light of the report by Allred and
Liebeskind (ref. 15) that tri-n-butylstannyl thiophene-2-carboxylate is
produced in their reactions, we speculate that the tri-n-butylstannyl
byproduct is sequestered in this form. It would follow, therefore, that
stoichiometric amounts of CuTC would be required, and this is what we
found empirically to achieve maximum yields.
(17) Lewis acid catalyzed Newman-Kwart rearrangement: Fujii, K.; Shuto,
Y.; Kinoshita, Y. Agric. Biol. Chem. 1990, 54, 2379-2384.
(18) Mee, S. P. H.; Lee, V.; Baldwin, J. E. Chem. Eur. J. 2005, 11, 3294-
3308.
(19) Kagoshima, H.; Shimada, K. Chem. Lett. 2003, 32, 514-515.
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A R T I C L E S
Falck et al.
Table 2. Cross-Coupling of PTC-Protected R-Hydroxystannanes with Aryl/Heteroaryl Iodidesa
a See standard cross-coupling procedure. b Stannane 3 is racemic and 8 is >98% optically pure. c Stannane added over 0.5 h. d >98% de via NMR of
crude product.
1). Notably, 3 and (+)-glyceryl stannane 8 added smoothly to
Z-iodide 6 and E-iodide 4, respectively, affording Z-allylic
alcohol 7 (entry 2) and E-allylic alcohol 9 (entry 3) with
complete stereospecificity at the alkenyl centers (>98% by 1H/
13C NMR), thus precluding a radical chain mechanism. The latter
cross-coupling was complete in less than 10 min at rt. Retention
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792 J. AM. CHEM. SOC. VOL. 129, NO. 4, 2007

Cross-Coupling of
R
-(Thiocarbamoyl)organostannanes
A R T I C L E S
of configuration at the stannyl-substituted stereogenic center,
as indicated by the erythro-coupling20 (J2,3 ≈ 4.8 Hz) in the 1H
NMR of 9, was consistent with prior experience using other
classes of electrophiles,5,6 but opposite to the inversion of
configuration observed by Kells and Chong using scalemic
R-(sulfonamido)organostannanes and Pd/Cu cocatalysis.21 Not
surprisingly, transmetalation of 8 with lithium or magnesium
prior to conversion to an organocopper intermediate failed to
give 9 and instead led to 2 (>90%) via facile â-elimination.22
In the case of di-iodide 10, there was a modest preference
for addition to the less hindered side furnishing 11 as a 4:1
Z/E-mixture (entry 4). The Z/E-ratio improved to 9:1 at 0 °C.
Repetition of the coupling at rt using an excess of stannane 3
gave rise to an excellent yield of adduct 11, but had no influence
on the stereochemistry. Other kinds of alkenyl iodides, e.g.,
cyclohexenyl14 12, R-keto 14, and â-iodostyrene (16), behaved
analogously generating 13 (entry 5), 15 (entry 6), and 17 (entry
7), respectively, in synthetically useful yields. The coupling in
entry 8 was more challenging since enantioenriched stannane
18 is both acyclic and nonbiased (i.e., unlike 8, it has no other
chiral centers to influence the stereochemical outcome). At rt,
19 was secured in good yield, but only 90% ee. As anticipated,
the enantioselectivity could be elevated by lowering the tem-
perature, 91% ee or 95% ee at 0 °C or -20 °C, respectively,
albeit with some consequential effects on the yield and reaction
time. The cross-coupling of 20 (entry 9) also merits attention
as an indicator of the mildness of the reaction conditions. Despite
the proclivity of 20 toward loss of HI and/or isomerization, its
union with 3 proceeded without complication or loss of the
Z-configuration to give 21.
m-cyano substituent seemed to have minimal effect (entry 12)
while a p-methoxy (entry 13) had the anticipated equal but
opposite influence of that observed with electron-withdrawing
groups (Vide supra). A variety of heteroaryl iodides, despite
concerns that they might retard coupling by sequestering the
promoter, were gratifyingly reactive. Indole 45, thiophene 47,
and uracil 49 were readily transformed into 46 (entry 14), 48
(entry 15), and 50 (entry 16), respectively, within 30 min or
less at rt under the standard reaction conditions.
Standard Cross-Coupling Procedure. A solution of PTC-
protected R-alkoxystannane (0.19 mmol) in anhydrous THF (2
mL) was added to a stirring suspension of CuTC (0.28 mmol)
and alkenyl/aryl/heteroaryl halide (0.28 mmol) in anhydrous
THF (2 mL) under an argon atmosphere at the temperature
indicated in Table 1 and 2. The heterogeneous mixture turned
reddish-green as the reaction progressed. After TLC monitoring
indicated all stannane was consumed (see Table 1 and 2 for
times), the reaction mixture was diluted with Et2O (20 mL) and
filtered through a small bed of alumina. The filter bed was
washed with fresh Et2O (5 mL), and the combined filtrates were
concentrated under reduced pressure. Chromatographic purifica-
tion of the residue on SiO2 gave the cross-coupled adduct in
the indicated yield (Tables 1 and 2).
Conclusions
The Liebeskind promoter (CuTC) rapidly and stereospecifi-
cally cross-couples racemic and scalemic PTC-protected R-hy-
droxystannanes with alkenyl/aryl/heteroaryl iodides including
secondary cycloalkenyl and unactivated aryl iodides in THF at
ambient temperature. It is anticipated that the foregoing
methodology will be compatible with a wide range of func-
tionality and be of general utility in the synthesis of heteroatom-
substituted stereogenic centers. Toward this end, preliminary
results demonstrate CuTC can also mediate the cross-coupling
of alkenyl bromides with PTC-protected R-hydroxystannanes.
These data and extensions to other classes of electrophiles will
be reported in due course.
The applicability of aryl and heteroaryl iodides as electro-
philes was also evaluated, and the results are summarized in
Table 2. The simple, unactivated electrophile iodobenezene14
(22) provided acceptable yields of 23 (entry 1) and 24 (entry
2) from 3 and 8, respectively. The presence of electron-
withdrawing substituents boosted the efficiency somewhat. Thus,
benzyl alcohols 26, 28, 30, 31, and 33 were accessed in 70%
or better yield from aryl iodides 25 (entry 3), 27 (entry 4), 29
(entries 5 and 6), and 32 (entry 7), accordingly. Even the more
sterically demanding o-chloro 34, o-benzoyl 36, and o-nitro 39
aryl iodides reacted well to give 35 (entry 8), 37/38 (entries 9
and 10), and 40 (entry 11) all in comparable amounts. A
Acknowledgment. Financial support provided by the Robert
A. Welch Foundation and NIH (GM31278, DK38226). Dr.
Elaine R. Fogel is warmly thanked for insightful discussions.
Supporting Information Available: Synthetic procedures,
analytical data, chiral HPLC chromatograms, and 1H/13C spectra
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(20) Ja¨ger, V.; Schro¨ter, D.; Koppenhoefer, B. Tetrahedron 1991, 47, 2195-
2210
(21) Kells, K. W; Chong, J. M. J. Am. Chem. Soc. 2004, 126, 15666-15667.
(22) (a) Dieter, R. K.; Oba, G.; Chandupatla, K. R.; Topping, C. M.; Lu, K.;
Watson, R. T. J. Org. Chem. 2004, 69, 3076-3086. (b) Tomooka, K.;
Shimizu, H.; Nakai, T. J. Organomet. Chem. 2001, 624, 364-366.
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