General approach to allenes through copper-catalyzed γ-selective and stereospecific coupling between propargylic phosphates and alkylboranes

Article abstract of DOI:10.1021/ol202866h

Copper-catalyzed γ-selective coupling between propargylic phosphates and alkylboron compounds (alkyl-9-BBN, prepared by hydroboration of alkenes with 9-BBN-H) affords multisubstituted allenes with various functional groups. The reaction of enantioenriched

Full text of DOI:10.1021/ol202866h

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6312–6315
General Approach to Allenes through
Copper-Catalyzed γ-Selective and
Stereospecific Coupling between
Propargylic Phosphates and Alkylboranes
Hirohisa Ohmiya,* Umi Yokobori, Yusuke Makida, and Masaya Sawamura*
Department of Chemistry, Faculty of Science, Hokkaido University,
Sapporo 060-0810, Japan
ohmiya@sci.hokudai.ac.jp; sawamura@sci.hokudai.ac.jp
Received October 24, 2011
ABSTRACT
Copper-catalyzed γ-selective coupling between propargylic phosphates and alkylboron compounds (alkyl-9-BBN, prepared by hydroboration of
alkenes with 9-BBN-H) affords multisubstituted allenes with various functional groups. The reaction of enantioenriched propargylic phosphates to
give axially chiral allenes proceeds with excellent point-to-axial chirality transfer with 1,3-anti stereochemistry.
Allenes have gained increasing attention in organic
synthesis as important building blocks possessing unique
reactivities due to the presence of orthogonal consecutive
π-bonds.1,2 In addition, they are found in many natural
products.3 Among the diverse methods for accessing allenes,4
the γ-substitution (formal SN20 reaction) of propargylic alco-
hol derivatives with organocuprate reagents is the most
straightforward and popular, because it uses readily available
substrates and forms a new CꢀC bond while most of the
other methods rely on the use of more difficult-to-prepare
compounds such as dienes, enynes, cyclopropanes, and
other highly functionalized compounds.5ꢀ8 Unfortunately,
however, unlike the copper-based “SN20-type” reactions of
(1) Reviews on allenes: (a) Modern Allene Chemistry; Krause, N.,
Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004; Vols. 1 and 2.
(2) Reviews on the synthetic applications of allenes: (a) Ma, S. Acc.
Chem. Res. 2003, 36, 701–712. (b) Sydnes, L. K. Chem. Rev. 2003, 103,
1133–1150. (c) Ma, S. Chem. Rev. 2005, 105, 2829–2871. (d) Ma, S. Acc.
Chem. Res. 2009, 42, 1679–1688.
(3) Reviews on allenic natural products and pharmaceuticals: Hoff-
€
(5) Pioneering works on γ-substitution of propargylic alcohol deri-
vatives with organocuprate reagents by Crabee and co-workers: (a)
Rona, P.; Crabbe, P. J. Am. Chem. Soc. 1968, 90, 4733–4744. (b) Rona,
P.; Crabbe, P. J. Am. Chem. Soc. 1969, 91, 3289–3292.
mann-Roder, A.; Krause, N. Angew. Chem., Int. Ed. 2004, 43, 1196–
1216.
(4) Reviews on the synthesis of allenes: (a) Krause, N.; Hoffmann-
€
Roder, A. Tetrahedron 2004, 60, 11671–11694. (b) Brummond, K. M.;
(6) Reviews on γ-substitution of propargylic alcohol derivatives with
DeForrest, J. E. Synthesis 2007, 795–818. (c) Yu, S.; Ma, S. Chem.
Commun. 2011, 5384–5418. For selected examples on the synthesis of
allenes since 2007, see: (d) Deutsch, C.; Lipshutz, B. H.; Krause, N.
Angew. Chem., Int. Ed. 2007, 46, 1650–1653. (e) Hayashi, S; Hirano, K.;
Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2008, 130, 5048–5049. (f)
Ready, J. M.; Pu, X. J. Am. Chem. Soc. 2008, 130, 10874–10875. (g)
Kobayashi, K.; Naka, H.; Wheatley, A. E.; Kondo, Y. Org. Lett. 2008,
10, 3375–3377. (h) Tang, M.; Fan, C.-A.; Zhang, F.-M.; Tu, Y.-Q.;
Zhang, W.-X.; Wang, A.-X. Org. Lett. 2008, 10, 5585–5588. (i) Zhong,
C.; Sasaki, Y.; Ito, H.; Sawamura, M. Chem. Commun. 2009, 5850–5852.
(j) Deutsch, C.; Lipshutz, B. H.; Krause, N. Org. Lett. 2009, 11, 5010–
5012. (k) Kuang, J.; Ma, S. J. Am. Chem. Soc. 2010, 132, 1786–1787. (l)
Bolte, B.; Odabacian, Y.; Gagosz, F. J. Am. Chem. Soc. 2010, 132, 7294–
7296. (m) Ohmiya, H.; Yang, M.; Yamauchi, Y.; Ohtsuka, Y.; Sawa-
mura, M. Org. Lett. 2010, 12, 1796–1799. (n) Xiao, Q.; Xia, Y.; Li, H.;
Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2011, 50, 1114–1117.
€
organocuprate reagents: (a) Krause, N.; Hoffmann-Roder, A. In Mod-
ern Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim,
€
Germany, 2002; pp 145ꢀ163. (b) Hoffmann-Roder, A.; Krause, N. In
Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH:
Weinheim, 2004; pp 51ꢀ92. (c) Ogasawara, M.; Hayashi, T. In Modern
Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH:
Weinheim, 2004; pp 93ꢀ140. (d) Ohno, H.; Nagaoka, Y.; Tomioka, K.
In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-
VCH: Weinheim, 2004; pp 141ꢀ181.
(7) The synthesis of optically active allenes by the SN20 ring opening
reaction of alkynyl-substituted β-lactones: Wan, Z.; Nelson, S. G. J. Am.
Chem. Soc. 2000, 122, 10470–10471.
(8) The synthesis of optically active vinylallenes by 1,5-substitution
of enyne acetates: Krause, N.; Purpura, M. Angew. Chem., Int. Ed. 2000,
39, 4355–4356.
r
10.1021/ol202866h
Published on Web 11/04/2011
2011 American Chemical Society

allylic systems, the corresponding allene synthesis, in
fact, suffers from serious problems in regioselectivity9
and stereoselectivity.10,11 In particular, the reaction of primary
propargylic alcohol derivatives affords alkynes rather than
allenes as a major product (vide infra).9b Additionally, the
stereoselectivity in the synthesis of axially chiral allenes from
enantioenriched propargylic substrates is not always reliable:
while efficient chirality transfers have been reported in many
cases, the transformations are susceptive to the drop of
enantiomeric purity depending on the reaction conditions.
Not only erosion of 1,3-anti stereochemistry but also racemi-
zation of the allene moieties under the reaction conditions are
well documented in the literature.10ꢀ12 Furthermore, the
organocuprate method based on Grignard or organolithium
reagents suffers from the problem of functional group in-
compatibility within the organocuprates.6,13 Accordingly, a
general method that overcomes the above-mentioned pro-
blems is highly desirable.
approach to multisubstituted allenes.14ꢀ16 The substrate
scope is markedly broad in terms of both substitution
patterns and functional group compatibility. Moreover,
the protocol is effective for the stereoselective synthesis of
axially chiralallenes, which occurs throughexcellent point-
to-axial chirality transfer.
Specifically, alkylborane 2a was first prepared through
hydroboration of styrene (1a) with 9-borabicyclo-
[3.3.1]nonane dimer [9-BBN-H]2 in THF at 60 °C (1a/B
1.2:1) (Scheme 1). The alkylborane 2a was converted into
an alkylborate via treatment with t-BuOK (0.2 mmol, 1 M
in THF) at rt for 5 min. Then, CuOAc (10 mol %) and
propargylic phosphate 3a (0.2 mmol) was added to the
mixture, and the resulting solution was heated at 80 °C for
6 h. TheNMR analysisofthe crudeproduct indicated89%
conversion of 3a into allene 4aa and confirmed that no R-
substitution product (alkyne) was formed (γ/R > 99:1).
Silica gel chromatography furnished analytically pure 4aa
in 81% yield.17 The reaction was readily scalable: a gram-
scale reaction with 1.0 g (3.0 mmol) of 3a afforded the
allene 4aa in 85% isolated yield.
Previously we developed the copper-catalyzed allylꢀ
alkyl coupling between allylic phosphates and alkyl-
boranes, which proceeds with excellent γ-selectivity
(>99:1).14a Herein, we report that this copper-catalyzed
protocol is applicable to the reaction between propargylic
phosphates and alkylboranes, providing a versatile
Scheme 1
(9) (a) Macdonald, T. L.; Reagan, D. R. J. Org. Chem. 1980, 45,
4740–4747. Discussion concerning the problem in the synthesis of 1,1-
disubstituted allenes:(b) Varghese, J. P.; Knochel, P.; Marek, I. Org.
Lett. 2000, 2, 2849–2852 and references therein.
(10) Racemization of chiral allenes by organocuprate reagents: (a)
Claesson, A.; Olsson, L.-I. J. Chem. Soc., Chem. Commun. 1979, 524–
525. (b) Elsevier, C. J.; Vermeer, P. J. Org. Chem. 1989, 54, 3726–3730.
(11) Alexakis and co-workers descibed stereochemical and mechan-
istic aspects of the formation of axially chiral allenes through the
reaction between enantioenriched propargylic alcohol derivatives and
organocopper reagents. Ligands for copper such as P(OMe)3 or PBu3
were used to improve the point-to-axial chirality transfer. Additionally,
copper salts, halogens of the Grignard reagents, or leaving groups have a
significant effect on the stereoselectivity. Even with these attempts,
however, the chirality transfer was insufficient or incomplete in many
cases. See: (a) Alexakis, A.; Marek, I.; Mangeney, P.; Normant, J. F.
J. Am. Chem. Soc. 1990, 112, 8042–8047. (b) Alexakis, A.; Marek, I.;
Mangeney, P.; Normant, J. F. Tetrahedron 1991, 47, 1677–1696. (c)
Alexakis, A. Pure Appl. Chem. 1992, 64, 387–392.
Several observations concerning the optimum reaction
conditions are to be noted. Less expensive CuCl was also
effective, providing 4aa in 72% yield, while the use of
Cu(OAc)2 resulted in a significantly reduced yield (43%).
A ligand for the copper is not necessary. The reaction in
the absence of t-BuOK resulted in a lower conversion
(12) Recently reported efficient enantioselective routes to chiral
allenes that do not utilize propargylic compounds: (a) Ogasawara, M.;
Ikeda, H.; Nagano, T.; Hayashi, T. J. Am. Chem. Soc. 2001, 123, 2089–
2090. (b) Han, J. W.; Tokunaga, N.; Hayashi, T. J. Am. Chem. Soc. 2001,
123, 12915–12916. (c) Ogasawara, M.; Ueyama, K.; Nagano, T.; Mizu-
hata, Y.; Hayashi, T. Org. Lett. 2003, 5, 217–219. (d) Hayashi, T.;
Tokunaga, N.; Inoue, K. Org. Lett. 2004, 6, 305–307. (e) Ogasawara, M.;
Nagano, T.; Hayashi, T. J. Org. Chem. 2005, 70, 5764–5767. (f)
Ogasawara, M.; Ngo, H. L.; Sakamoto, T.; Takahashi, T. Org. Lett.
2005, 7, 2881–2884. (g) Trost, B. M.; Fandrick, D. R.; Dinh, D. C. J. Am.
Chem. Soc. 2005, 127, 14186–14187. (h) Ogasawara, M.; Fan, L.; Ge, Y.;
Takahashi, T. Org. Lett. 2006, 8, 5409–5412. (i) Liu, H.; Leow, D.;
Huang, K.-W.; Tan, C.-H. J. Am. Chem. Soc. 2009, 131, 7212–7213. (j)
(14) Cu-catalyzed γ-selective and stereospecific allylꢀaryl and allylꢀ
alkyl couplings with organoboron compounds: (a) Ohmiya, H.; Yokobori,
U.; Makida, Y.; Sawamura, M. J. Am. Chem. Soc. 2010, 132, 2895–2897.
(b) Ohmiya, H.; Yokokawa, N.; Sawamura, M. Org. Lett. 2010, 12, 2438–
2440. (c) Whittaker, A. M.; Rucker, R. P.; Lalic, G. Org. Lett. 2010, 12,
3216–3218. For related studies with palladium catalysts, see also: (d)
Ohmiya, H.; Makida, Y.; Tanaka, T.; Sawamura, M. J. Am. Chem. Soc.
2008, 130, 17276–17277. (e) Ohmiya, H.; Makida, Y.; Li, D.; Tanabe, M.;
Sawamura, M. J. Am. Chem. Soc. 2010, 132, 879–889. (f) Li, D.; Tanaka,
T.; Ohmiya, H.; Sawamura, M. Org. Lett. 2010, 12, 3344–3347. (g) Makida,
Y.; Ohmiya, H.; Sawamura, M. Chem.;Asian J. 2011, 6, 410–414.
(15) Our studies on regioselective transformations of propargylic
alcohol derivatives: (a) Ito, H.; Sasaki, Y.; Sawamura, M. J. Am. Chem.
Soc. 2008, 130, 15774–15775. (b) Ohmiya, H.; Ito, H.; Sawamura, M.
Org. Lett. 2009, 11, 5618–5620. See also refs 4i and m.
(16) Cu-catalyzed conjugate additions with alkylboron compounds
(alkyl-9-BBN): (a) Ohmiya, H.; Yoshida, M.; Sawamura, M. Org. Lett.
2011, 13, 482–485. (b) Ohmiya, H.; Shido, Y.; Yoshida, M.; Sawamura,
M. Chem. Lett. 2011, 40, 928–930. Cu-catalyzed carboxylations with
alkylboron compounds (alkyl-9-BBN) to carbon dioxide: (c) Ohmiya,
H.; Tanabe, M.; Sawamura Org. Lett. 2011, 13, 1086–1088.
(17) For Schemes 1 and 2, Table 1, and eqs 1ꢀ3, unreacted pro-
pargylic phosphates (3) were detected in the crude materials after
removal of the catalyst.
€
Ogasawara, M.; Okada, A.; Subbarayan, V.; Sorgel, S.; Tamotsu, T.
Org. Lett. 2010, 12, 5736–5739. (k) Nishimura, T.; Makino, H.; Nagao-
sa, M.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 12865–12867. For a
review, see: (l) Ogasawara, M. Tetrahedron: Asymmetry 2009, 20, 259–
271.
(13) The transition-metal (Pd, Rh)-catalyzed substitutions of pro-
pargylic derivatives with aryl- or alkenylboron compounds: (a) Moriya,
T.; Miyaura, N.; Suzuki, A. Synlett 1994, 149–152. (b) Yoshida, M.;
Gotou, T.; Ihara, M. Tetrahedron Lett. 2004, 45, 5573–5575. (c) Yoshi-
da, M.; Ueda, H.; Ihara, M. Tetrahedron Lett. 2005, 46, 6705–6708. (d)
Yoshida, M.; Okada, T.; Ihara, M. Tetrahedron 2007, 63, 6996–7002. (e)
Molander, G. A.; Sommers, E. M.; Baker, S. R. J. Org. Chem. 2006, 71,
1563–1568. (f) Murakami, M.; Igawa, H. Helv. Chim. Acta 2002, 85,
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akami, M. Angew. Chem., Int. Ed. 2007, 46, 7101–7103.
Org. Lett., Vol. 13, No. 23, 2011
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(34% yield, 40% convn). The use of a catalytic amount (10
mol %) of t-BuOK furnished the allene in only 24% yield
(44% convn). No reaction occurred with the corresponding
propargylic methyl carbonate and acetate.
The hydroborationꢀcoupling one-pot protocol affords a
variety of allenes (Table 1).17 The reaction tolerates func-
tional groups such as alcohol, phosphate, silyl ether, ester,
methyl ether, acetal and carbamate moieties in the pro-
pargylic phosphates and alkenes (entries 1ꢀ7, 10 and 12).
5, 6, and 12). The reaction of the β-branched alkylborane
(2f), which was prepared from R-methylstyrene (1f), was
also successful to give 4fa as a 1:1 diastereomeric mixture
(entry 8). Unfortunately, however, the use of secondary
alkylborane reagents prepared from internal alkenes re-
sulted in no reaction (data not shown).
Table 1 also displays the substrate scope regarding the
steric demand and substitution patterns in the propargylic
phosphates (3). The Bu group at the γ-position of 3a could
be replaced with Me or MeOCH2 groups without a drastic
change in the yield of allenes 4af and 4ag (entries 9 and 10).
However, a bulky isobutyl group severely inhibited the
reaction, giving only a trace of the allene product (data not
shown). The reaction of a terminal alkyne resulted in a
complex mixture (data not shown). The tertiary pro-
pargylic phosphates 3h and 3i were converted into the
corresponding tetrasubstituted allenes 4ah and 4di, respec-
tively (entries 11 and 12).
Table 1. Synthesis of Tri- and Tetrasubstituted Allenesa
Importantly, the reaction of primary propargylic phos-
phate 3ja also occurred cleanly with excellent γ-selectivity
to afford the corresponding geminally disubstituted term-
inal allene 4aj (Scheme 2a).17 On the other hand, the
cuprate-based reactions between alkyl Grignard reagent
2a0 and propargylic phosphate 3ja or acetate 3jb gave
mixtures of the allene (4aj) and alkyne (5aj) irrespective
of catalytic or stoichiometric use of copper (Scheme 2d).9b
The regiocontrolled synthesis of geminally disubstituted
terminal allenes tolerates functional groups such as chloro
and ester moieties in the substrates (Schemes 2b and c).17
Scheme 2. Synthesis of Geminally Disubstituted Terminal
Allenes from Primary Propargyl Alcohol Derivatives
a The reaction was carried out with 3 (0.4 mmol), alkylborane 2 (1.5
equiv), CuOAc (10 mol %), and t-BuOK (1.0 equiv, 1 M in THF) in THF
at 80 °C for 6 h. Alkylborane 2 was prepared in advance by hydrobora-
tion of 1 with 9-BBN-H dimer in THF at 60 °C for 1 h and was used
without purification. b Isolated yield based on 3. c γ/R > 99:1. Deter-
mined by 1H NMR or GC analysis of the crude product. d Diastereo-
meric ratio (1:1).
The tolerance of the reaction toward steric demand in
alkylboranes (2) was evaluated in Table 1, entries 5, 6, 8,
and 12. The sterically more demanding alkylborane 2d,
which was derived from a terminal alkene (1d) bearing a
tertiaryalkyl substituent, servedasa substrate toaffordthe
corresponding allenes 4da, dd, and di in good yields (entries
The present Cu-catalyzed protocol is effective for the
stereocontrolled synthesis of axially chiral allenes.12 The
stereospecific character of the copper-catalyzed coupling is
6314
Org. Lett., Vol. 13, No. 23, 2011

substantiated in eqs 1ꢀ3.17 The couplings between the
styrene-derived alkylborane 2a or the allylbenzene-derived
alkylborane 2e and the enantioenriched propargylic phos-
phate (R)-3l (99% ee), which has R-Me and γ-MOMOCH2
substituents, proceeded with excellent point-to-axial chir-
ality transfer with 1,3-anti-stereochemistry to afford en-
antioenriched allenes (R)-(þ)-4al (96% ee) or (þ)-4el
(96% ee) (eqs 1 and 2).18 The reaction between the bulkier
alkylborane 2g and a simple chiral propargylic phosphate
(R)-3m (97% ee) also occurred with excellent chirality
transfer to give the corresponding chiral allene (þ)-4gm
(94% ee) (eq 3). Evaluation of reactions with different
reaction times and conversions confirmed that no racemi-
zation of the allene occurred under the reaction conditions.
Thus, the slight decreases in enantionmeric purity are
attributable to a minor pathway with 1,3-syn-stereochem-
istry. This result is in contrast to the observation of
racemization in the cuprate-based allene syntheses.11
Scheme 3
would cause anti-β-elimination of the alkylcopper complex
D to afford (R)-4 and LnCuX. This hypothetical reaction
pathway is based on the neutral and mildly nucleophilic
natureof the organocopper(I) species B. This nature would
render the oxidative addition of the organocopper(I) B to
form a copper(III) intermediate with an η3-allenyl/propar-
gyl ligand less feasible. As a result, the above-mentioned
additionꢀelimination route would becomedominant. This
accounts for the excellent and robust regioselectivity to-
ward the allene formation.
In summary, we have developed a new approach to allenes
through a copper-catalyzed γ-selective cross-coupling reac-
tion between propargylic phosphates and alkylboranes. The
excellent point-to-axial chirality transfer in the copper-cata-
lyzed transformation allows the efficient preparation of axi-
ally chiral allenes from enantioenriched propargylic alcohols.
With broad functional group compatibility and robustness in
terms of γ-selectivity and 1,3-anti stereospecificity, the present
alkylboraneꢀcopper method well complements the conven-
tional cuprate-based route to allenes and will find opportu-
nities for applications in the synthesis of complex molecules.
A possible pathway for the alkylboraneꢀcopper system
can be postulated as illustrated in Scheme 3. A trialkyl-
(alkoxo)borate A is initially formed by the stoichiometric
reaction between an alkylborane 2 and KOtBu.14a Subse-
quently, the B/Cu transmetalation between the borate A
and CuX [X = OP(O)(OEt)2 or OAc] occurs to form an
alkylcopper(I) species B. The alkylcopper species B forms
π-complex C with (R)-3. The regioselective syn-addition of
R1ꢀCu across the CꢀC triple bond of 3 gives alkylcopper
complex D. The regioselectivity in the addition step would
be induced by stereoelectronic effects that stabilize the
developing σ(CβꢀCu) orbital through interactions with
the σ[CRꢀOP(O)(OEt)2] orbital. These orbital interactions
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research (B) and for Young Scientists
(B), JSPS. We thank MEXT for financial support in the
form of a Global COE grant (Project No. B01: Catalysis as
the Basis for Innovation in Materials Science). Y.M.
thanks JSPS for scholarship support.
Supporting Information Available. Experimental de-
tails and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) The absolute configuration of (R)-(þ)-4al was determined by
transforming to a known compound. See Supporting Information for
details.
Org. Lett., Vol. 13, No. 23, 2011
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