α-Selective Ni-catalyzed hydroalumination of aryl- and alkyl-substituted terminal alkynes: Practical syntheses of internal vinyl aluminums, halides, or boronates

Article abstract of DOI:10.1021/ja104896b

A method for Ni-catalyzed hydroalumination of terminal alkynes, leading to the formation of α-vinylaluminum isomers efficiently (>98% conv in 2-12 h) and with high selectivity (95% to >98% α), is described. Catalytic α-selective hydroalumination reactions proceed in the presence of a reagent (diisobutylaluminum hydride; dibal-H) and 3.0 mol % metal complex (Ni(dppp)Cl₂) that are commercially available and inexpensive. Under the same conditions, but with Ni(PPh₃)₂Cl₂, hydroalumination becomes highly β-selective, and, unlike uncatalyzed transformations with dibal-H, generates little or no alkynylaluminum byproducts. All hydrometalation reactions are reliable, operationally simple, and practical and afford an assortment of vinylaluminums that are otherwise not easily accessible. The derived α-vinyl halides and boronates can be synthesized through direct treatment with the appropriate electrophiles [e.g., Br ₂ and methoxy(pinacolato)boron, respectively]. Ni-catalyzed hydroaluminations can be performed with as little as 0.1 mol % catalyst and on gram scale with equally high efficiency and selectivity.

Full text of DOI:10.1021/ja104896b

Published on Web 07/15/2010
r-Selective Ni-Catalyzed Hydroalumination of Aryl- and Alkyl-Substituted Terminal
Alkynes: Practical Syntheses of Internal Vinyl Aluminums, Halides, or Boronates
Fang Gao and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received March 11, 2010; E-mail: amir.hoveyda@bc.edu
Abstract: A method for Ni-catalyzed hydroalumination of terminal
alkynes, leading to the formation of R-vinylaluminum isomers
efficiently (>98% conv in 2-12 h) and with high selectivity (95% to
>98% R), is described. Catalytic R-selective hydroalumination re-
actions proceed in the presence of a reagent (diisobutylaluminum
hydride; dibal-H) and 3.0 mol % metal complex (Ni(dppp)Cl2) that
are commercially available and inexpensive. Under the same
promoted by Ni(acac)2.14 The outcome of our screening studies, with
conditions, but with Ni(PPh3)2Cl2, hydroalumination becomes highly
phenylacetylene serving as the substrate, is summarized in Table 1.
ꢀ-selective, and, unlike uncatalyzed transformations with dibal-H,
Reaction with Ni(acac)2 and 1.3 equiv of dibal-H in tetrahydrofuran
generates little or no alkynylaluminum byproducts. All hydrometa-
(thf) at 22 °C for 2 h leads to efficient hydrometalation (entry 1) but
lation reactions are reliable, operationally simple, and practical and
afford an assortment of vinylaluminums that are otherwise not easily
accessible. The derived R-vinyl halides and boronates can be
synthesized through direct treatment with the appropriate electro-
philes [e.g., Br2 and methoxy(pinacolato)boron, respectively]. Ni-
catalyzed hydroaluminations can be performed with as little as 0.1
with a modest preference for the terminal vinylaluminum (68% 1 and
19% 2) along with 13% of 1,3-diene 3. Use of NiCl2 ·6H2O (entry 2)
or Ni(0) complexes (entries 3-4) leads to similarly low selectivity
and significant amounts of 3. With 3 mol % Ni(PPh3)2Cl2 (entry 5),
hydroalumination proceeds with a strong preference for the terminal
vinylaluminum (1:2 ) 93:7) and with <2% of the diene contaminant
(1H NMR analysis). More importantly, as depicted in entries 6-9 of
Table 1, when Ni catalysts bear a bidentate phosphine ligand,
hydrometalation occurs with total reversal of site selectivity. Vinyla-
luminum 2 is formed efficiently (>98% conv) and with >98% R
selectivity when Ni(dppp)Cl2 is used (entry 7).
mol % catalyst and on gram scale with equally high efficiency and
selectivity.
Herein, we demonstrate that commercially available and inexpensive
Ni-based catalysts and diisobutylaluminum hydride (dibal-H) convert
alkyl- or aryl-substituted alkynes to internal (or R-) vinylaluminums
efficiently and with exceptional selectivity (95% to >98% R isomer).
The catalytic protocol offers a one-pot, high yielding and selective
method for conversion of terminal alkynes to R-vinyl halides1 and
boronates2 s valuable entities otherwise prepared by less efficient
routes that are intolerant of several functional groups.3 Moreover, aryl-
substituted terminal ꢀ-vinylaluminums, formed along with substantial
amounts of byproducts in uncatalyzed hydroaluminations, can be
accessed in high yield by the catalytic process.
In the absence of a catalyst, dibal-H reacts with phenylacetylene at
50 °C (hexanes or toluene)15 to afford only ∼50% of the ꢀ-vinyla-
luminum (1) along with 25% styrene and 25% alkynylaluminum (due
to deprotonation of alkyne by the vinylaluminum). In sharp contrast,
alkyne deprotonation is not observed in any of the Ni-catalyzed
reactions (<2%). Thus, in addition to allowing effective control of R
or ꢀ selectivity, Ni complexes enhance hydrometalation rates to the
extent that adventitious deprotonation is eliminated entirely.
Catalytic hydroaluminations can be performed with a considerable
Selective and practical methods for alkyne hydrometalations are of
substantial value.4 The resulting vinylmetals might be utilized to access
vinyl halides and boronates, intermediates critical to catalytic cross-
coupling, one of the most important classes of transformations in
chemical synthesis.5,6 Vinylaluminums are mildly nucleophilic reagents
that can be used in catalytic C-C bond forming processes,7 including
those that are enantioselective.8 Alkyl-substituted vinylaluminums can
be prepared9 by reaction of alkynes with dibal-H;10 the corresponding
processes with aryl alkynes, however, suffer from competitive alkyne
deprotonation, affording significant amounts of alkynylaluminums.11,12
Regardless of varying efficiencies, all existing terminal alkyne hy-
droaluminations favor ꢀ-substituted isomers strongly or, often, exclu-
sively. In contrast, a procedure that directly delivers internal or
R-substituted vinylaluminums (eq 1) reliably and selectively does not
exist. We reasoned that the above shortcomings might be resolved by
rendering alkyne hydroalumination catalytic (eq 1) and that R
selectivity might be achievable through manipulation of a catalyst’s
structure and the energetics of the catalytic cycle.13 An efficient
catalytic hydroalumination might also facilitate metal hydride addition
to such a degree that adventitious alkyne deprotonation is avoided.
To initiate our search for an effective alkyne hydroalumination
catalyst, we focused on Ni complexes, partly based on a report by
Eisch regarding reactions of a small number of disubstituted alkynes
range of aryl alkynes (Table 2), affording R-vinylmetals efficiently
Table 1. Ni-Catalyzed Hydroalumination of Phenylacetylenea
a Reactions performed under N2 atmosphere; <2% alkynyl aluminum
product observed in all cases.b By analysis of 400 MHz 1H NMR spectra
of unpurified mixtures after quench with D2O (0 °C, 30 min); see the
Supporting Information for details.
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J. AM. CHEM. SOC. 2010, 132, 10961–10963 10961

C O M M U N I C A T I O N S
Table 2. R-Selective Ni-Catalyzed Hydroalumination of Arylacetylenesa
access to a wider range of R- and ꢀ-vinylaluminums would substan-
tially expand the utility of such reagents. Cu-catalyzed enantioselective
alkylations in Scheme 1 demonstrate this point. An aryl-substituted
ꢀ-vinylaluminum, obtained through the above Ni-catalyzed process,
can be used to synthesize 1,4-diene 4 with high efficiency and in 96:4
er. In contrast, when the vinylmetal prepared by uncatalyzed hydroalu-
mination is utilized, 26% of the undesired alkyne (vs vinyl) addition
product is generated. Furthermore, synthesis of enantiomerically en-
riched 1,4-dienes 5 and 6 is rendered feasible because the requisite
R-vinylaluminums can now be easily prepared.
entry
aryl
temp (°C)
time (h)b
conv (%)c
R:ꢀc
1
o-OMeC6H4
m-OMeC6H4
p-OMeC6H4
m-CF3C6H4
p-CF3C6H4
p-FC6H4
4
22
4
12
2
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
98:2
>98:2
>98:2
95:5
2
3
12
12
2
4
4
5
22
22
22
22
4
22
22
97:3
6
2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
Scheme 1. Applications of Ni-Catalyzed Hydroaluminationsa
7
o-ClC6H4
2
8
o-BrC6H4
o-MeC6H4
3-pyridyl
2
9
12
2
10
11
3-thienyl
2
a Reactions under N2 atmosphere. b Reaction times correspond to
hydroalumination portion of the process (not including D2O quench). c By
1
analysis of 400 MHz H NMR spectra of unpurified mixtures (after D2O);
<2% alkynylaluminum observed.
Table 3. R-Selective Ni-Catalyzed Hydroalumination of Alkylacetylenesa
a Synthesis of 5 and 6 at -15 °C. Ar ) 2,4,6-(i-Pr)3-C6H2.
Ni-catalyzed vinylaluminum synthesis is more efficient than other
alternatives, which involve initial synthesis of a vinyl halide, followed
by metal-halogen exchange (n-BuLi) and treatment with an aluminum
chloride. In addition to being a lengthier route, the latter two-vessel
protocol requires R-vinyl halides prepared from terminal alkynes by
hydroiodation (HI)1c,d or halo-boration (BBr3)/proto-deboration with
15-20 equiv of HOAc),17 which constitute strongly acidic conditions
(specific examples below).
Ni-catalyzed hydroalumination does more than obviate the need for
intermediacy of vinyl halides and the attendant harsh conditions leading
to vinylaluminums; it provides an efficient route for the synthesis of
this valuable class of halogenated building blocks. Treatment of the
R-vinylaluminums with N-bromo- or N-iodosuccinimide furnishes vinyl
bromides or iodides in >98% R-selectivity and 79-88% yield after
chromatography (Scheme 2). Synthesis of R-vinylbromide 7 or iodide
11 would not be feasible through the BBr3/HOAc1a and hydro-
iodation1c,d,18 (concomitant removal of methyl or silyl ether). Vinyl
halide synthesis through Ni-catalyzed hydroalumination is a practical
process. Iodide 8 is obtained in 83% yield and >98% R selectivity
with commercial grade thf and Ni catalyst (not purified); similarly,
the alkyl-substituted iodide formed by catalytic hydroalumination of
1-octyne and treatment with N-iodosuccinimide is obtained in 89%
yield and 96% R selectivity.
a-c See Table 2; 2.3 equiv of dibal-H in entry 2; 3 h for entry 4.
d Performed at 4 °C for 12 h; ∼5% alkyne deprotonation observed.
and selectively. Transformations are performed at 4-22 °C and require
e12 h. Alkynes bearing electron-donating (entries 1-3) or electron-
withdrawing units (entries 4-8) or sterically congested aryl acetylenes
(entries 7-9) are suitable substrates. N- or S-containing heterocyclic
substrates readily undergo hydroalumination with high selectivity
(entries 10-11). Two additional points are noteworthy: (1) None of
the transformations with Ni(dppp)Cl2 generate the alkynylaluminum
side product, which is obtained in significantly larger amounts in the
absence of the catalyst (see above). (2) Reactions can be performed
with commercial grade thf and Ni salts that are used as received (see
below for an example).
Scheme 2. Conversion of Terminal Alkynes to R-Vinyl Halidesa
R-Selective catalytic hydroaluminations of alkyl-substituted
alkynes proceed readily and with high selectivity as well (Table
3);16 only in one case (entry 6), ∼5% alkyne deprotonation is
observed (<2% otherwise). Alkynes bearing a linear (entries 1-4),
R- (entries 5-6), or ꢀ-branched (entry 7) alkyl unit can be used.
The same range of substrates shown in Table 2 undergo hydroalu-
mination readily in the presence of Ni(PPh3)2Cl2, proceeding with high
ꢀ-selectivity (85.5% to >98%) and with minimal alkyne deprotonation;
complete data are available in the Supporting Information. Only alkyl-
substituted ꢀ-vinylaluminums, which can be accessed by (uncatalyzed)
reaction of dibal-H with a terminal alkyne, have so far been utilized
in metal-catalyzed enantioselective C-C bond formation.8 Efficient
a Reaction with N-iodosuccinimide under otherwise identical conditions.
See the Supporting Information for experimental details.
9
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C O M M U N I C A T I O N S
Tetrahedron Lett. 1983, 24, 731. (b) Cr-mediated conversion of aldehydes
to iodides: Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408. (c) Terminal alkynes to iodides by hydroiodation (HI formed in situ
from TMSI): Kamiya, N.; Chikami, Y.; Ishii, Y. Synlett 1990, 675. (d)
Ketones and aldehydes to iodides with phosphitohalides: Spaggiari, A.;
Vaccari, D.; Davoli, P.; Torre, G.; Prati, F. J. Org. Chem. 2007, 72, 2216.
(e) Terminal alkynes (no branched alkyl-substituted cases) to iodides by
HI addition (generated from iodine/hydrophosphine): Kawaguchi, S-i.;
Ogawa, A. Org. Lett. 2010, 12, 1893.
Ni-catalyzed hydroalumination and vinyl halide synthesis are
amenable to scale up and require low catalyst loadings. As an example,
with only 0.1 mol % Ni(dppp)Cl2 and with inexpensive Br2 as the
halide source, R-vinyl bromide 12 is obtained in 69% yield after
purification (eq 2; <2% ꢀ).19
(2) For synthesis of various cyclic and acyclic vinylboronates through Pd-
catalyzed cross-coupling reactions involving the corresponding vinyl
bromides and triflates, see: Takagi, J.; Takahashi, K.; Ishiyama, T.; Miyaura,
N. J. Am. Chem. Soc. 2002, 124, 8001.
(3) For R-selective Ru-catalyzed hydrosilylation of alkynes, see: Trost, B. M.;
Ball, Z. T. J. Am. Chem. Soc. 2005, 127, 17644.
(4) For a review on hydroaluminations of alkynes and alkenes, see: Eisch, J. J.
In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Schreiber,
S. L., Eds.; Pergamon, Oxford, 1991; Vol. 8, pp 733.
(5) For representative transformations where vinyl iodides are used in complex
molecule synthesis, see: Liu, X.; Henderson, J. A.; Sasaki, T.; Kishi, Y.
J. Am. Chem. Soc. 2009, 131, 16678, and references cited therein.
(6) For applications of vinylboronates in C-C bond formation, see: (a) Miyaura,
N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Kotha, S.; Lahiri, K.;
Kashinath, D. Tetrahedron 2002, 58, 9633.
R-Vinylboronates can be readily accessed through Ni-catalyzed
alkyne hydroalumination (Scheme 3). Direct subjection of vinylalu-
minums with commercially available and inexpensive methoxy(pina-
colato)borane delivers the desired products in >98% R selectivity and
68-94% yield after purification.20
(7) For example, see: (a) Baba, S.; Negishi, E-i. J. Am. Chem. Soc. 1976, 98,
6729. (b) Negishi, E-i.; Okukado, N.; King, A. O.; Van Horn, D. E.; Spiegel,
B. I. J. Am. Chem. Soc. 1978, 100, 2254. (c) Lipshutz, B. H.; Bu¨low, G.;
Lowe, R. F.; Stevens, K. L. Tetrahedron 1996, 52, 7265. (d) Langille, N. F.;
Jamison, T. F. Org. Lett. 2006, 8, 3761.
Scheme 3. One-Pot Synthesis of R-Vinyl Boronatesa
(8) Allylic alkylations: (a) Lee, Y.; Akiyama, K.; Gillingham, D. G.; Brown,
M. K.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 446. (b) Akiyama,
K.; Gao, F.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2010, 49, 419. Carbonyl
additions: (c) Biradar, D. B.; Gau, H.-M. Org. Lett. 2009, 11, 499.
(9) Vinylmetals (including vinylaluminums) can be accessed through carbo-
metallation of alkynes. For example, see: (a) Wipf, P.; Lim, S. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1068. (b) Fallis, A. G.; Forgione, P.
Tetrahedron 2001, 57, 5899. (c) Lipshutz, B. H.; Butler, T.; Lower, A.;
Servesko, J. Org. Lett. 2007, 9, 3737.
(10) (a) Zweifel, G.; Whitney, C. C. J. Am. Chem. Soc. 1967, 89, 2753. For use
of alkyl-substituted vinylaluminums in Cu-catalyzed allylic alkylations, see:
(b) Reference 8a.
(11) (a) Zweifel, G.; Snow, J. T.; Whitney, C. C. J. Am. Chem. Soc. 1968, 90,
7139. (b) Uhl, W.; Er, E.; Hepp, A.; Ko¨sters, J.; Grunenberg, J.
Organometallics 2008, 27, 3346. (c) Uhl, W.; Er, E.; Hepp, A.; Ko¨sters,
J.; Layh, M.; Rohling, M.; Vinogradov, A.; Wu¨rthwein, E.-U.; Ghavtadze,
N. Eur. J. Inorg. Chem. 2009, 3307.
a Yields refer to purified R-vinylboronates; see the Supporting Informa-
tion for experimental details. B(pin) ) pinacolatoboron.
Several issues that underline the unique attributes of the R-vinyl
boronate synthesis method described herein merit specific mention:
(1) Hydroborations of terminal alkynes with pinacolborane, which
require rigorously dried CH2Cl2,21 or Rh-, Ir-,22 and Zr-catalyzed23
variants, furnish ꢀ-vinyl boronates exclusively or as the major isomer
(<10% R).24 (2) Alkyl-substituted R-vinyl boronates can be accessed
through hydroborations that require stoichiometric amounts of a Cu
complex (1.1 equiv of CuCl, KOAc, LiCl, or a phosphine) and only
in up to 91% selectivity (typically 9-71%).25 (3) R-Vinylboronates
can be synthesized from R-vinylbromides by metal/halogen exchange
(n-BuLi) and subjection to i-propoxypinacolborane.17b Cross-coupling
of vinyl halides with B2(pin)2, promoted by the more costly Pd salts,
also affords R-vinylboronates.2 In addition to being two-vessel
protocols (vs one-pot in Scheme 3), the latter processes require vinyl
halides prepared by severely acidic procedures, rendering several vinyl
halides inaccessible (see above). The present approach furnishes the
vinylmetal directly. Finally, a vinylboronate that bears an aryl halide
(e.g., 15, Scheme 3) cannot be selectively prepared by the aforemen-
tioned metal/halogen exchange/boronate trap or Pd-catalyzed cross-
coupling of the corresponding vinyl halide.
(12) Hydroalumination (dibal-H) of Si-substituted aryl alkynes, which proceeds
efficiently and site selectively, has been introduced to address this
shortcoming. The C-Si bond is removed by protodesilylation. See ref 8b.
(13) For selectivity reversal in Ni-catalyzed H-P and H-S addition to terminal
alkynes, see: Han, L.-B.; Zhang, C.; Yazawa, H.; Shimada, S. J. Am. Chem.
Soc. 2004, 126, 5080.
(14) Eisch, J. J.; Foxton, M. W. J. Organomet. Chem. 1968, 12, P33.
(15) There is <2% reaction when phenylacetylene is treated with dibal-H in thf
(at 22 °C, in 2 h).
(16) In the absence of a catalyst, alkyl-substituted substrates react relatively
efficiently (in contrast to aryl alkynes) with dibal-H to afford ꢀ-vinylalu-
minums (>98% selectivity). Such uncatalyzed reactions proceed to ∼80%
conversion after 6 h at 22 °C and must be heated to 55 °C (2 h) to achieve
∼90% conv. The Ni-catalyzed processes (Ni(PPh3)2Cl2) are complete in
2 h at 22 °C. For data regarding this class of catalytic hydroaluminations,
see the Supporting Information.
(17) (a) Reference 1a. (b) Moran, W. J.; Morken, J. P. Org. Lett. 2006, 8, 2413.
(18) For example, see: Morrill, C.; Funk, T. W.; Grubbs, R. H. Tetrahedron
Lett. 2004, 45, 7733.
(19) In a similar manner, the ꢀ-vinyl bromide derived from vinylaluminum 1 is
obtained in 75% yield from a reaction performed on 10 mmol of
phenylacetylene with 0.5 mol % Ni(PPh3)2Cl2.
(20) Synthesis of R-vinylboronates by an NHC-Cu-catalyzed hydroboration of
a propargyl ether and a propargyl amide was recently reported to proceed
with ∼90% R selectivity:Lee, Y.; Jang, H.; Hoveyda, A. H. J. Am. Chem.
Soc. 2009, 131, 18234.
(21) Tucker, C. E.; Davidson, J.; Knochel, P. J. Org. Chem. 1992, 57, 3482.
(22) (a) Pereira, S.; Srebnik, M. Tetrahedron Lett. 1996, 37, 3283. (b) Ohmura,
T.; Yamamoto, Y.; Miyaura, N. J. Am. Chem. Soc. 2000, 122, 4990.
(23) Wang, Y. D.; Kimball, G.; Prashad, A. S.; Wang, Y. Tetrahedron Lett.
2005, 46, 8777.
Investigations regarding the basis of selectivity reversal in Ni-
catalyzed hydroaluminations26 and applications to other classes of
alkynes as well as hydride sources are in progress.
(24) For a Cu-catalyzed hydroboration of phenylacetylene that affords the
terminal vinylboronate, see: Lee, J.-E.; Kwon, J.; Yun, J. Chem. Commun.
2008, 733. This procedure is ineffective with alkyl-substituted alkynes.
(25) Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2001, 625, 47.
(26) Initial studies indicate that Ni(0) complexes are involved (vs Ni(II)).
Subjection of phenylacetylene to the conditions shown in Table 1, but with
3 mol % Ni(dppp)Cl2 and 6 mol % MeMgI (to generate Ni(0)(dppp)
complex in situ), affords 2 with 97% R selectivity (>98% conv). It is
plausible that reactions proceed via an Al-Ni hydride [(i-Bu)2Al-Ni-H];
addition of Ni-H across the alkyne and subsequent alkenyl-Al reductive
elimination regenerates the Ni(0) complex. See: (a) Eisch, J. J.; Sexsmith,
S. R.; Fichter, K. C. J. Organomet. Chem. 1990, 382, 273. (b) Eisch, J. J.;
Ma, X.; Singh, M.; Wilke, G. J. Organomet. Chem. 1997, 527, 301.
Acknowledgment. Financial support was provided by the NIH
(GM-47480). Mass spectrometry facilities at Boston College are sup-
ported by the NSF (DBI-0619576).
Supporting Information Available: Experimental procedures and
spectral, analytical data for all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) For acyclic R-vinyl halide synthesis, see: (a) Bromoboration/protodeboration
of alkyl-substituted alkynes: Hara, S.; Dojo, H.; Takinami, S.; Suzuki, A.
JA104896B
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