Synthesis of conjugated allenes through copper-catalyzed γ-selective and stereospecific coupling between propargylic phosphates and aryl- or alkenylboronates

Article abstract of DOI:10.1021/ol2033465

A Cu-catalyzed γ-selective coupling reaction between propargylic phosphates and aryl- or alkenylboronates afforded aryl- or alkenyl-conjugated allenes. The reaction showed excellent functional group compatibility in both the propargylic substrates and the boronates. The reaction of an enantioenriched propargylic phosphate proceeded with excellent chirality transfer with 1,3-anti stereochemistry to give axially chiral aryl- and alkenylallenes.

Full text of DOI:10.1021/ol2033465

ORGANIC
LETTERS
2012
Vol. 14, No. 3
816–819
Synthesis of Conjugated Allenes through
Copper-Catalyzed γ-Selective and
Stereospecific Coupling between
Propargylic Phosphates and Aryl- or
Alkenylboronates
Mingyu Yang, Natsumi Yokokawa, Hirohisa Ohmiya,* 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 December 15, 2011
ABSTRACT
A Cu-catalyzed γ-selective coupling reaction between propargylic phosphates and aryl- or alkenylboronates afforded aryl- or alkenyl-conjugated
allenes. The reaction showed excellent functional group compatibility in both the propargylic substrates and the boronates. The reaction of an
enantioenriched propargylic phosphate proceeded with excellent chirality transfer with 1,3-anti stereochemistry to give axially chiral aryl- and
alkenylallenes.
Allenes are important building blocks that have unique
reactivity due to the orthogonal consecutive π-bonds.1,2
Additionally, they are found in many natural products.3,4
Among a number of routes to allenes, the γ-substitution
(formal SN20 displacement) of propargylic alcohol
derivatives with organocuprate reagents is most straight-
forward.5ꢀ8 However, the method often suffers from
problems of functional group compatibility because the
organocopper reagents must be prepared from highly
reactive organometallic reagents such as Grignard or
organolithium reagents.4o,9 Furthermore, the use of sp2-
carbon nucleophiles, such as aryl- or alkenylmetal re-
agents, has not been well exploited due to the poor
nucleophilicity of these reagents relative to that of the
alkylcopper species.9 Therefore, the organocopper-based
method is not generally applicable for the synthesis of aryl-
or alkenyl-conjugated allenes.
Previously, we found that the copper-catalyzed allylꢀ
aryl coupling between allylic phosphates and arylboronates
€
(4) Reviews on the synthesis of allenes: (a) Krause, N.; Hoffmann-Roder,
A. Tetrahedron 2004, 60, 11671–11694. (b) Brummond, K. M.; 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.;
Sawamura, 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. (o)
Ohmiya, H.; Yokobori, U.; Makida, Y.; Sawamura, M. Org. Lett. 2011,
13, 6312–6315. (p) Vyas, D. J.; Hazra, C. K.; Oestreich, M. Org. Lett. 2011,
13, 4462–4465.
(1) Reviews on allenes: (a) Modern Allene Chemistry; Krause, N.,
Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, Germany, 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:
€
Hoffmann-Roder, A.; Krause, N. Angew. Chem., Int. Ed. 2004, 43,
1196–1216.
r
10.1021/ol2033465
Published on Web 01/18/2012
2012 American Chemical Society

proceeded in the presence of KOtBu and water (3 equiv
each) with excellent γ-selectivity and stereospecifity.10b On
the basis of this knowledge, we envisioned that arylboron
compounds could be coupled regioselectively with propar-
gyl alcohol derivatives under copper-catalyzed conditions
for constructing aryl- or alkenyl-conjugated allenes.
Here we report a copper-catalyzed γ-selective coupling
between propargylic phosphates and aryl- or alkenyl-
boronates as an approach to conjugated allenes.10ꢀ13 The
reaction is compatible with various functional groups in
both propargylic phosphates and boronates, affording
functionalized aryl- and alkenylallenes that are difficult
to prepare by other methods. The reaction of enantioen-
riched propargylic phosphates took place with excellent
point-to-axial chirality transfer with anti stereochemistry
to give axially chiral conjugated allenes.
Specifically, the reaction of propargylic phosphate 2a
with 5,5-dimethyl-2-phenyl-1,3,2-dioxaborinane (1a) (2 equiv)
in the presence of CuCl (5 mol %), KOtBu (3 equiv), and
H2O (3 equiv) in CH3CN at 60 °C for 4 h afforded arylallene
product 3aa in 88% isolated yield. The 1H NMR analysis of
the crude product confirmed that no R-substitution product
(alkyne) was formed (γ/R >99:1) (Scheme 1).
The optimum reaction conditions are similar to those of
the copper-catalyzed allylꢀaryl coupling between allylic
phosphates and arylboronates.10b Some noteworthy points
are described below. No reaction occurred in the absence of
CuCl. CuCl2 was as effective as CuCl (82% yield). The use
of a small amount of H2O (3 equiv) is critical: the reaction
without H2O resulted in a complex mixture. The amount of
KOtBu is also critical: reducing it from 3 to 2 equiv
decreased the yield from 88 to 44% under otherwise identi-
cal conditions, and no reaction occurred in the absence of
KOtBu. Reducing the amount of boronate 1a to 1 equiv
caused considerable hydrolysis of 2a. The use of phenyl-
boronic acid pinacol ester in place of the neopentyl glycolato
1a decreased the yield of 3aa (60%). Phenylboronicacid was
also usable instead of 1a, but the yield of 3aa was further
decreased to 40%. Changing the leaving group to diethyl- or
diisopropyl phosphates inhibited the reaction.
(5) Pioneering works on γ-substitution of propargylic alcohol deriv-
atives 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.
(6) Reviews on γ-substitution of propargylic alcohol derivatives with
€
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, Germany, 2004; pp 51ꢀ92. (c) Ogasawara, M.; Hayashi, T. In
Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH:
Weinheim, Germany, 2004; pp 93ꢀ140. (d) Ohno, H.; Nagaoka, Y.;
Tomioka, K. In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K.,
Eds.; Wiley-VCH: Weinheim, Germany, 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.
(9) 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) Yoshida,
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, 4182–4188. (g) Miura, T.; Shimada, M.; Ku, S.-Y.; Tamai, T.;
Murakami, M. Angew. Chem., Int. Ed. 2007, 46, 7101–7103.
Scheme 1
(10) Cu-catalyzed γ-selective and stereospecific allylꢀaryl and
allylꢀalkyl 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.
The reaction showed a range of substrate scope of
arylboronates (1) and propargylic phosphates (2), afford-
ing a variety of allenes (Table 1). Functionalities such as
MeO, CF3, Cl, ketone, ester, and silyl ether in 1 or 2 were
compatible with the Cu system (entries 2ꢀ7).
(11) 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, 4m, and 4o.
The tolerance of the reaction toward steric demand in
both arylboronates (1) and propargylic phosphates (2) is
shown in Table 1, entries 1 and 8ꢀ11. o-Tolylboronate (1b)
was coupled with 2a in a reasonable yield (entry 1). The
propargylic phosphates 2c, 2d, and 2e with Me, MeOCH2,
and bulkier i-Bu groups, respectively, instead of the Bu
group at the γ-position in 2 were phenylated effectively to
afford the corresponding allenes 3ac, 3ad, and 3ae (entries
8ꢀ10). A sterically more demanding R-substituent such as
an i-Pr group was also tolerated (entry 11).
(12) 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, M. Org. Lett. 2011, 13, 1086–1088.
(13) Cu-catalyzed CꢀC bond formations with aryl- and alkenylbor-
on reagents: (a) Takaya, J.; Tadami, S.; Ukai, K.; Iwasawa, N. Org. Lett.
2008, 10, 2697–2700. (b) Ohishi, T.; Nishiura, M.; Hou, Z. Angew.
Chem., Int. Ed. 2008, 47, 5792–5795. (c) Yamamoto, Y.; Kirai, N.;
Harada, Y. Chem. Commun. 2008, 2010–2012. (d) Tomita, D.; Kanai,
M.; Shibasaki, M. Chem. Asian J. 2006, 1, 161–166. (e) Tomita, D.;
Yamatsugu, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131,
6946–6948. (f) Takatsu, K.; Shintani, R.; Hayashi, T. Chem. Commun.
2010, 6822–6824. (g) Takatsu, K.; Shintani, R.; Hayashi, T. Angew.
Chem., Int. Ed. 2011, 50, 5548–5552. (h) Yang, C.-T.; Zhang, Z.-Q.;
Liu, T.-C.; Liu, L. Angew. Chem., Int. Ed. 2011, 50, 3904–3907.
(i) Shintani, R.; Takatsu, K.; Takeda, M.; Hayashi, T. Angew. Chem.,
Int. Ed. 2011, 50, 8656–8659. See also refs 10b and 10c.
The Cu catalyst system was also applicable to the
synthesis of conjugated alkenylallenes (Scheme 2 and
Table 2). Specifically, the treatment of trans-1-hexen-
1-ylboronic acid pinacol ester (1h) (3 equiv) with 2a in the
Org. Lett., Vol. 14, No. 3, 2012
817

Table 1. Synthesis of Arylallenesa
Scheme 2
Table 2. Synthesis of Alkenylallenesa
a Conditions: 1 (0.6 mmol), 2 (0.3 mmol), CuCl2 (10 mol %), H2O
(0.9 mmol), KOtBu (0.9 mmol), CH3CN (3 mL), 30 °C, 12 h. b Conditions:
1 (0.6 mmol), 2 (0.3 mmol), CuCl (5 mol %), H2O (0.9 mmol), KOtBu
(0.9 mmol), CH3CN(3mL),entry1;40°C, entry 2; 30 °C, 12 h. c Isolated yield.
d Isomeric ratio (γ/R >99:1). Determined by 1H NMR or GC analysis.
The use of the neopentylglycol ester derivative as an
alkenylboronate was not effective.14
a Conditions: 1 (0.6 mmol), 2 (0.3 mmol), CuCl (5 mol %), H2O
(0.9 mmol), KOtBu (0.9 mmol), CH3CN (1 mL), 60 °C, 4 h. b Isolated
yield. c Isomeric ratio (γ/R >99:1). Determined by 1H NMR or GC
analysis. d The reaction was carried out for 12 h.
A scope for the synthesis of alkenyl-conjugated allenes is
summarized in Table 2. The protocol was applicable to
the vinylboronate 1i, affording the corresponding vinylal-
lene 3ia (entry 1). Both alkyl and aryl substituents were
tolerated at the β-position in the alkenylboronates (entries
2ꢀ7). The styrylboronate 1j and 1-octenylboronate 1k
underwent the reaction with 2a in reasonable yields (entries
2 and 3). A sterically more demanding t-Bu substituent was
tolerated at the β-position of alkenylboronate (1l) (entry 4).
presence of CuCl2 (10 mol %), KOtBu (3 equiv), and H2O
(3 equiv) in CH3CN at 30 °C for 12 h afforded alkenylal-
lene product 3ha in 71% isolated yield. No R-substitution
product (alkyne) was observed (Scheme 2). Increasing the
amounts of both boronate 1h and KOtBu/H2O to 3 and
4 equiv, respectively, resultedina slightincreaseinthe yield
(77%). In contrast to the reaction of the arylboronates, the
use of CuCl resulted in lower reaction efficiency (61%).
(14) The use of the corresponding neopentylglycol ester derivative
instead of 1k decreased the yield from 72 to 26% (cf. Table 2, entry 3).
818
Org. Lett., Vol. 14, No. 3, 2012

substituents: the reaction afforded phenylallene (S)-(ꢀ)-
3ah (99% ee) without any loss of enantiomeric purity
(Table 3, entry 1).15ꢀ18 The reactions between the alkenyl-
boronates 1h or 1k and (S)-2h (99% ee) also occurred with
excellent chirality transfer to give the corresponding chiral
alkenylallenes (ꢀ)-3hh (98% ee) and (ꢀ)-3kh (99% ee),
respectively (entries 2 and 3). Functional groups such as
indole and tosylamide were tolerated in the alkenylboro-
nate (1), giving the corresponding allenes (ꢀ)-(E)-3nh and
(ꢀ)-(E)-3ph with the high chirality transfer efficiency
unchanged (entries 4 and 5).
Table 3. Synthesis of Chiral Allenes
Scheme 3
The utility of the enantioenriched alkenyl-conjugated
allenes was demonstrated in the intermolecular Dielsꢀ
Alder reaction between (ꢀ)-3hh (98% ee) and electron-
deficient alkenes under the Reich’s conditions, as shown in
Scheme 3.19 The reaction employing N-phenylmaleimide (4)
as a dienophile proceeded with a reasonably high diastereo-
face selectivity (92:8) and complete endo/exo selectivity to
install three stereogenic centers and a geometrically controlled
exocyclic alkene in the 6,5-fused bicyclic framework of 5.
In conclusion, we have developed the Cu-catalyzed
coupling reaction between propargylic phosphates and
aryl- or alkenylboronates as a versatile route to aryl- and
alkenyl-conjugated allenes. The excellent point-to-axial
chirality transfer from enantioenriched propargylic phos-
phates with anti-stereochemistry allows efficient prepara-
tion of axially chiral conjugated allenes. The wide availability
and easy-to-handle nature of aryl- and alkenylboronates, the
simplicity and inexpensiveness of the Cu catalyst system, and
the high regio- and stereoselectivities are attractive features of
this protocol.20
a Conditions: 1a (0.6 mmol), 2h (0.3 mmol), CuCl (5 mol %), H2O
(0.9 mmol), KOtBu (0.9 mmol), CH3CN (1 mL), 25 °C, 12 h. b Conditions:
1 (0.6 mmol), 2h (0.3 mmol), CuCl2 (10 mol %), H2O (0.9 mmol), KOtBu
(0.9 mmol), CH3CN (3 mL), 25 °C, 12 h. c Isomeric ratio (γ/R >99:1).
1
Determined by H NMR or GC analysis. d Isolated yield. e NMR yield.
The purified material was contaminated with alkenylboronate (1).
However, the reaction was inhibited by the R-substitution or
R,β-disubstitution in the alkenylboronates (data not shown).
Various functional groups were tolerated in the alkenyl-
boronates, and thus alkenylallenes (3ma, na, oa) containing
Cl, indole, or CN were synthesized in moderate yields (entries
5ꢀ7). The allylic phosphate (2g) having an isolated terminal
alkene was suitable for this protocol (entry 8).
Excellent R-to-γ chirality transfer with 1,3-anti stereo-
chemistry wasobservedin the reaction betweenthe phenyl-
boronate 1a and the enantioenriched propargylic phosphate
(S)-2h (99% ee), which has R-Me and γ-MOMOCH2
(15) The stereoselectivity in the synthesis of axially chiral allenes from
enantioenriched propargylic substrates with organocuprate reagents is
not always reliable. Racemization of chiral allenes occurs under the
reaction conditions. See: (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.
(16) Alexakis and co-workers descibed stereochemical and mechanis-
tic aspects on 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.
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research (B) (No. 21350020) and for
Young Scientists (B) (No. 21750086), JSPS. M.Y. thanks
the China Scholarship Council for a fellowship.
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.
(19) [4 þ 2]-Cycloaddition of vinylallenes: (a) Reich, H. J.; Eisenhart,
E. K.; Whipple, W. L.; Kelly, M. J. J. Am. Chem. Soc. 1988, 110, 6432–
6433. (b) Spino, C.; Thibault, C.; Gingras, S. J. Org. Chem. 1998, 63,
5283–5287.
(20) After submission of our manuscript, Lalic and co-workers
reported the copper-catalyzed arylation of propargylic phosphates with
arylboronates:Uehling, M. R.; Marionni, S. T.; Lalic, G. Org. Lett.
2012, 14, 362–365.
(17) A review on enantioselective routes to chiral allenes that do not
utilize propargylic compounds: Ogasawara, M. Tetrahedron: Asymme-
try 2009, 20, 259–271.
(18) The absolute configuration of (S)-(ꢀ)-3ah was determined by
transforming it to a known compound. See Supporting Information for
details.
Org. Lett., Vol. 14, No. 3, 2012
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