Bimetallic enantioselective approach to axially chiral allenes

Article abstract of DOI:10.1021/ol400822m

An efficient bimetallic Zn(II)/Cu(I)-mediated asymmetric synthesis of simple axially chiral allenes from terminal alkynes and aldehydes was realized by taking advantage of the chiral amine (S)-α,α-diphenylprolinol 3. This one-pot procedure is compatible w

Full text of DOI:10.1021/ol400822m

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Bimetallic Enantioselective Approach
to Axially Chiral Allenes
†
‡
Ruizhi Lu, Juntao Ye, Tao Cao,‡,§ Bo Chen,‡,§ Wu Fan,†,§ Weilong Lin,‡,§ Jinxian
Liu,†,§ Hongwen Luo,†,§ Bukeyan Miao,†,§ Shengjun Ni,‡,§ Xinjun Tang,‡,§ Nan Wang,†,§
Yuli Wang,†,§ Xi Xie,†,§ Qiong Yu,†,§ Weiming Yuan,†,§ Wanli Zhang,†,§ Can Zhu,‡,§
and Shengming Ma*,†,‡
€
Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department of
Chemistry, East China Normal University, 3663 North Zhongshan Lu, Shanghai
200062, P. R. China, and State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Lu, Shanghai 200032, P. R. China
masm@sioc.ac.cn
Received March 26, 2013
ABSTRACT
An efficient bimetallic Zn(II)/Cu(I)-mediated asymmetric synthesis of simple axially chiral allenes from terminal alkynes and aldehydes was
realized by taking advantage of the chiral amine (S)-R,R-diphenylprolinol 3. This one-pot procedure is compatible with broad scopes of both
terminal alkynes and aldehydes, providing axially chiral allenes in practical yields with an excellent enantioselectivity. Control experiments
revealed that CuBr is responsible for the efficient formation of propargylic amine while the combination of CuBr and ZnBr2 plays crucial roles in
the amine-to-allene transformation.
Allenes, which had been considered as highly unstable,
are now becoming more and more important in organic
synthesis, pharmaceuticals, and materials science.1 Thus,
there is an urgent demand for efficient entries to optically
active allenes.2À6 Recently, we have developed a “chiral
amine” approach enabling the synthesis of axially
chiral 1,3-disubstituted allenes directly from terminal
alkynes and aldehydes using (S)-R,R-diphenylprolinol 3
(a, Scheme 1).4 However, extensive study in this group revealed
† East China Normal University.
‡ Chinese Academy of Sciences.
§ These authors contributed equally.
(1) For most recent reviews on the chemistry of allenes, see: (a) Ma,
S. Aldrichimica Acta 2007, 40, 91. (b) Brasholz, M.; Reissig, H.-U.;
Zimmer, R. Acc. Chem. Res. 2009, 42, 45. (c) Ma, S. Acc. Chem. Res.
2009, 42, 1679. (d) Alcaide, B.; Almendros, P.; Campo, T. M. d. Chem.;
Eur. J. 2010, 16, 5836. (e) Aubert, C.; Fensterbank, L.; Garcia, P.;
Malacria, M.; Simonneau, A. Chem. Rev. 2011, 111, 1954. (f) Inagaki,
F.; Kitagaki, S.; Mukai, C. Synlett 2011, 594. (g) Lopez, F.; Mascarenas,
J. L. Chem.;Eur. J. 2011, 17, 418. (h) Yu, S.; Ma, S. Angew. Chem., Int.
Ed. 2012, 51, 3074.
(4) (a) Ye, J.; Li, S.; Chen, B.; Fan, W.; Kuang, J.; Liu, J.; Liu, Y.;
Miao, B.; Wan, B.; Wang, Y.; Xie, X.; Yu, Q.; Yuan, W.; Ma, S. Org.
Lett. 2012, 14, 1346. (b) Ye, J.; Fan, W.; Ma, S. Chem.;Eur. J. 2013, 19,
716.
(5) Periasamy, M.; Sanjeevakumar, N.; Dalai, M.; Gurubrahamam,
R.; Reddy, P. O. Org. Lett. 2012, 14, 2932. However, the calibrated
optically rotations of the same allenes with similar ee values from our
study and the reported data are too different, see the Supporting
Information.
ꢀ
~
(2) For reviews on the synthesis of allenes, see: (a) Sydnes, L. K.
€
Chem. Rev. 2003, 103, 1133. (b) Krause, N.; Hoffmann-Roder, A.
Tetrahedron 2004, 60, 11671. (c) Brummond, K. M.; DeForrest, J. E.
Synthesis 2007, 795. (d) Ogasawara, M. Tetrahedron: Asymmetry 2009,
20, 259. (e) Yu, S.; Ma, S. Chem. Commun. 2011, 47, 5384.
(3) For the synthesis of axially chiral allenes from enantioenriched
propargylamines, see: (a) Lo, V. K.-Y.; Liu, Y.; Wong, M.-K.; Che,
C.-M. Org. Lett. 2006, 8, 1529. (b) Lo, V. K.-Y.; Wong, M.-K.; Che,
C.-M. Org. Lett. 2008, 10, 517. (c) Lo, V. K.-Y.; Zhou, C.-Y.; Wong,
M.-K.; Che, C.-M. Chem. Commun. 2010, 46, 213. (d) Gurubrahamam,
R.; Periasamy, M. J. Org. Chem. 2013, 78, 1463.
(6) For selected most recent examples, see: (a) Vyas, D. J.; Hazra,
C. K.; Oestreich, M. Org. Lett. 2011, 13, 4462. (b) Ohmiya, H.;
Yokobori, U.; Makida, Y.; Sawamura, M. Org. Lett. 2011, 13, 6312.
(c) Uehling, M. R.; Marionni, S. T.; Lalic, G. Org. Lett. 2012, 14, 362. (d)
Yang, M.; Yokokawa, N.; Ohmiya, H.; Sawamura, M. Org. Lett. 2012,
14, 816. (e) Li, Z.; Boyarskikh, V.; Hansen, J. H.; Autschbach, J.;
Musaev, D. G.; Davies, H. M. L. J. Am. Chem. Soc. 2012, 134, 15497.
€
ꢀ ꢀ
(f) Li, H.; Muller, D.; Guenee, L.; Alexakis, A. Org. Lett. 2012, 14,
5880.
r
10.1021/ol400822m
XXXX American Chemical Society

that the substrate scope is very limited: only the A-type of
R-oxy-functionalized alkynes and aliphatic aldehydes
may be applied (a, Scheme 1 and entry 1, Table 1);4 with
1-dodecyne and benzaldehyde, the corresponding allene
(R)-4aa was formed in 31% yield with a much lower
ee (82%) (eq 2, Scheme 1).5 Thus, it is still a challenge to
prepare the optically active simple 1,3-disubstituted
allenes from widely available terminal alkynes with much
less sterically bulky “naked” CH2 units adjacent to the
CÀC triple bond since the oxygen-containing unit
(CH(OY)R1) (eq 1, Scheme 1) acts as the enantioselective-
dictating group based on our previous studies.4 On
the other hand, bimetallic catalysts, which are distinct
from those of their monometallic counterparts, have been
shown to exhibit unique activities in a wide range of
organic transformations.7 Given that Zn(II) salt alone
showed low efficiency for the synthesis of simple axially
chiral allenes, we thus envisaged that the bimetallic
strategy might be a solution for higher reactivity and
enantioselectivity for this reaction. Herein, we report a
highly enantioselective bimetallic asymmetric approach
to axially chiral allenes from both aromatic or aliphatic
aldehydes, less sterically bulky alkynes, and chiral amine
(S)-R,R-diphenylprolinol 3 (b, Scheme 1).
Table 1. Optimization of the Reaction Conditionsa
yield of
entry
x/y
solvent
temp (°C)/t (h)
(R)-4ba (%)b
1
2
3
4
5
50/0
toluene
toluene
toluene
toluene
dioxane
110 °C, 13 h
110 °C, 13 h
120 °C, 8.5 h
100 °C, 24 h
120 °C, 13 h
22c
50/10
50/10
50/10
50/20
53 (96% ee)
55 (92% ee)
30d (98% ee)
50 (98% ee)
a The reactions were carried out with (S)-3 (1.0 mmol), 1-decyne 1b
(1.5 mmol), benzaldehyde 2a (2.0 mmol), and the indicated amounts of
ZnBr2 and CuBr in 3 mL of solvent. b Isolated yield of (R)-4ba based
on (S)-3; ee was determined by chiral HPLC analysis. c NMR yield of
(R)-4ba; ee not determined; 7% of the propargylic amine (S,S)-5ba (vide
infra) was also formed as determined by 1H NMR analysis of the crude
reaction mixture. d 8% of the propargylic amine (S,S)-5ba was formed as
determined by 1H NMR analysis of the crude reaction mixture.
lowering the temperature to 100 °C resulted in a very low
yield of (R)-4ba, although the enantioselectivity improved
slightly (entry 4, Table 1), which is expected. Notably,
when the reaction was carried out with 50 mol % ZnBr2
and 20 mol % CuBr in dioxane at 120 °C, (R)-4ba can
be obtained in comparable yield with 98% ee (entry 5,
Table 1). Therefore, 50 mol % ZnBr2, 10À20 mol %
CuBr, 1.5 equiv of 1-alkyne, and 2 equiv of aldehyde in
toluene at 110 °C (conditions A) or dioxane at 120 °C
(conditions B) for 13 h were established as the standard
conditions for further study.
Scheme 1. Synthesis of Axially Chiral Allenes Using
(S)-R,R-Diphenylprolinol 3
With the optimized reaction conditions in hand, the
generality of the reaction was then explored, and repre-
sentative results are summarized in Table 2. Gratifyingly,
both electron-poor and -rich aromatic aldehydes are com-
patible under the optimized conditions: Aromatic alde-
hydes with a synthetically versatile Br, Cl, or F substituent
at the meta- or para-position all underwent the reaction
smoothly, affording the corresponding allene products
(R)-4bbÀ(R)-4bf in moderate yields with up to 98% ee
(entries 3À7, Table 2); aromatic aldehydes containing an
electron-donating group such as CH3 or MeO can also be
transformed into the desired products (R)-4bgÀ(R)-4bi in
practical yields with 93À98% ee (entries 8À10, Table 2).
Notably, terminal alkyne 1d with a chlorine atom at the
5-position was also tolerated, furnishing (R)-4da in 50%
yield with 93% ee and 43% yield with 99% ee under
conditions A and B, respectively (entry 12, Table 2). More-
over, phenylacetylene 1e and aliphatic aldehyde 2j may
also be employed to afford axially chiral allene (R)-4ej in
moderate yields with 99% ee (entry 13, Table 2). This
protocol may also be extended to the alkynyl benzyl ether
1f, affording axially chiral allene (R)-4fj in modest yield
with 99% ee under the two sets of reaction conditions
(entry 14, Table 2). Interestingly, reactions carried out in
dioxane at 120 °C generally afforded the corresponding
axially chiral allenes with higher enantioselectivity, albeit
After screening numerous additives to ZnBr2 such as
FeCl2, FeCl3, NaBr, LiBr, KBr, HgCl2, AuBr3, etc., we
eventually observed that when 10 mol % CuBr was added
to the reaction mixture of 1.5 equiv of 1-decyne 1b,
2.0 equiv of benzaldehyde 2a, 1.0 equiv of (S)-R,R-diphenyl-
prolinol 3, and 50 mol % ZnBr2, the yield of (R)-4ba
dramatically improved from 22% to 53% (entry 2 vs 1,
Table 1); in addition, the enantiomeric excess also im-
proved to 96% (cf. eq 2 in Scheme 1)! The reaction
temperature was also found to be crucial for this transfor-
mation: Elevating the temperature to 120 °C led to an
erosion in enantioselectivity (entry 3, Table 1) whereas
(7) For selected reviews, see: (a) Negishi, E. Pure Appl. Chem. 1981,
53, 2333. (b) Shibasaki, M., Yamamoto, Y., Eds.; Multimetallic Cata-
lysts in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2004.
B
Org. Lett., Vol. XX, No. XX, XXXX

in a slightly lower yield (conditions B vs conditions A in
Table 2).
Scheme 2. Control and Mechanistic Experiments
Table 2. Bimetallic Zn(II)/Cu(I)-Mediated Asymmetric Synthe-
sis of Axially Chiral Allenes from 1-Alkyne, Aldehyde, and (S)-3a
yield of (R)-4 (%)b/(ee %)c
entry
R1 (1)/R2 (2)
conditions A
conditions B
1
n-C10H21 (1a)/Ph (2a)
n-C8H17 (1b)/2a
4aa, 48 (95)
4ba, 53c (96)
4bb, 44 (95)
4bc, 45 (95)
4bd, 47 (95)
4be, 45 (95)
4bf, 57 (92)
4bg, 53c (93)
4bh, 51c (95)
4bi, 52 (95)
4ca, 46 (96)
4da, 50e (93)
4ej, 51 (99)
4fj, 73 (98)
À
2
50 (98)
42 (98)
41 (96)
À
3
1b/p-BrC6H4 (2b)
1b/m-BrC6H4 (2c)
1b/p-ClC6H4 (2d)
1b/m-ClC6H4 (2e)
1b/p-FC6H4 (2f)
4
5
6
41 (96)
48 (96)
40 (97)
48 (98)
46 (97)d
40 (99)
43 (99)
47 (99)
63 (99)
noted that it is the combination of 50 mol % ZnBr2 and
20 mol % CuBr that efficiently converted the propargylic
amine (S,S)-5ba to (R)-4ba in 53% yield with 98% ee
within 8 h (eq 4, Scheme 2). Therefore, we may safely come
to the conclusion that both ZnBr2 and CuBr are respon-
sible for the more efficient transformation of the chiral
propargylic amine intermediate tothe chiral allene product
with a very high efficiency of central-to-axial chirality
transfer.
The absolute configurations of allenes were assigned
clearly based onthe LoweÀBrewsterrule8 and the previous
studies.4 A model to predict the absolute configuration of
the allene moiety for the highly enantioselective formation
of (R)-4 is shown in Scheme 3.4,9 The alkynylmetal species
6, which was formed by deprotonation of the correspond-
ing alkyne in the presence of CuBr, ZnBr2, and amine,
reacted with the in situ generated iminium ion 7 via Re-face
attack, furnishing highly enantioenriched propargylic
amine intermediate (S,S)-5, which then undergoes highly
stereoselective intramolecular 1,5-hydride transfer and
7
8
1b/p-CH3C6H4 (2g)
1b/m-CH3C6H4 (2h)
1b/m-MeOC6H4 (2i)
n-C6H13 (1c)/2a
9
10
11
12
13
14
Cl(CH2)2CH2 (1d)/2a
Ph (1e)/Cy (2j)
BnOCH2 (1f)/Cy (2j)
a The reactions were carried out with ZnBr2 (50 mol %), CuBr
(20 mol %), (S)-3 (1.0 mmol), 1 (1.5 mmol), and 2 (2.0 mmol) in 3 mL
of solvent unless otherwise noted. b Isolated yield of (R)-4 based on (S)-3;
ee was determined by chiral HPLC analysis. c CuBr (10 mol %) was used.
d (R)-4bi was obtained in 47% yield and 97% ee on a 4 mmol scale of
(S)-3. e Contaminated with minor impurities.
To gain insight into the roles of both ZnBr2 and CuBr,
control experiments were conducted (Scheme 2). When the
reaction was carried out with 50 mol % ZnBr2 in the
absence of CuBr at 110 °C for 13 h, the allene product
(R)-4ba was formed in only 22% yield as determined by 1H
NMR analysis (eq 1, Scheme 2). On the other hand, when
the same reaction was carried out with only 20 mol %
CuBr, (R)-4ba was obtained in only 8% yield with 98% ee
and a 71% yield of propargylic amine (S,S)-5ba3 was
isolated (eq 1, Scheme 2). Based on these experimental
data, we believe that the catalytic amount of CuBrmustplay
a much more important role than the 50 mol % of ZnBr2 in
furnishing the first step efficient and high-yielding forma-
tion of the 5-type propargylic amine ensuring an excellent de
(cf. eq 2 in Scheme 1).
Scheme 3. Proposed Mechanism and Prediction of the Absolute
Configuration of the Allene
Whenthe isolated propargylicamine intermediate (S,S)-
5ba was treated with 50 mol % ZnBr2 for 8 h, (R)-4ba was
obtained in 43% yield with 98% ee, with 31% of (S,S)-5ba
being recovered (eq 2, Scheme 2); as a comparison, with
20 mol % CuBr, (R)-4ba was obtained only in 14% yield
with 97% ee and 65% of the propargylic amine (S,S)-5ba
was recovered after 8 h (eq 3, Scheme 2). These data clearly
indicate that ZnBr2 exhibits a higher activity for trans-
forming the propargyl amine intermediate into the allene
products as compared to CuBr. Importantly, it should be
Org. Lett., Vol. XX, No. XX, XXXX
C

β-elimination to generate the axially chiral allene unit
under the cooperation of Cu(I) and ZnBr2. As indicated
by the aforementioned experimental results, CuBr may
play an exclusive role in the efficient formation of chiral
propargylic amine whereas both CuBr and ZnBr2 are
responsible for the formation of allene products.
In conclusion, we have developed a new bimetallic
asymmetric approach for simple axially chiral allenes from
terminal alkynes and aldehydes by taking advantage of the
readily available and cheap chiral amine (S)-R,R-diphenyl-
prolinol 3. Due to the ready availability of all the starting
materials, the potential of the axially chiral allene
products,1,10 and the respectable yields (>70% per-step
based on the mechanism shown in Scheme 3), this meth-
odology will be of high interest for the synthetic commu-
nity. Further studies to expand the scope of the reaction
and gain a better understanding of the bimetallic system
are ongoing in our laboratory.
(8) (a) Lowe, G. Chem. Commun. 1965, 411. (b) Brewster, J. H. Top.
Stereochem. 1967, 2, 1.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (Grant No.
21232006) and the National Basic Research Program of
China (2011CB808700) is greatly appreciated.
ꢀ
ꢀ
(9) (a) Crabbe, P.; Fillion, H.; Andre, D.; Luche, J.-L. J. Chem. Soc.,
Chem. Commun. 1979, 859. (b) Nakamura, H.; Kamakura, T.; Ishikura,
M.; Biellmann, J.-F. J. Am. Chem. Soc. 2004, 126, 5958. (c) Kazmaier,
U.; Lucas, S.; Klein, M. J. Org. Chem. 2006, 71, 2429. (d) Kuang, J.; Ma,
S. J. Org. Chem. 2009, 74, 1763. (e) Kuang, J.; Ma, S. J. Am. Chem. Soc.
2010, 132, 1786.
Supporting Information Available. Detailed experimen-
tal procedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(10) For selected most recent examples on the application of axially
chiral allenes, see: (a) Cai, F.; Pu, X.; Qi, X.; Lynch, V.; Radha, A.;
Ready, J. M. J. Am. Chem. Soc. 2011, 133, 18066. (b) Butler, K. L.;
Tragni, M.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2012, 51, 5175.
(c) Zeng, R.; Fu, C.; Ma, S. J. Am. Chem. Soc. 2012, 134, 9597. (d)
Adams, C. S.; Boralsky, L. A.; Guzei, I. A.; Schomaker, J. M. J. Am.
Chem. Soc. 2012, 134, 10807.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX