Catalytic asymmetric synthesis of optically active allenes from terminal alkynes

Article abstract of DOI:10.1021/ol300296k

CuBr and ZnI₂ have been developed as catalysts or subcatalysts for the efficient asymmetric synthesis of axially chiral allenols with up to 97% ee from readily available propargylic alcohols, aliphatic or aromatic aldehyde, pyrrolidine, and commerically available ligands. The alcohol unit in the terminal alkynes plays a very important role for ensuring high enantioselectivity via coordination.

Full text of DOI:10.1021/ol300296k

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1346–1349
Catalytic Asymmetric Synthesis of
Optically Active Allenes from Terminal
Alkynes
Juntao Ye,† Suhua Li,† Bo Chen,†,§ Wu Fan,‡,§ Jinqiang Kuang,‡,§ Jinxian Liu,‡,§
Yu Liu,‡,§ Bukeyan Miao,‡,§ Baoqiang Wan,†,§ Yuli Wang,‡,§ Xi Xie,‡,§ Qiong Yu,‡,§
Weiming Yuan,‡,§ and Shengming Ma*,†,‡
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, P. R. China
and 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
masm@sioc.ac.cn
Received February 6, 2012
ABSTRACT
CuBr and ZnI2 have been developed as catalysts or subcatalysts for the efficient asymmetric synthesis of axially chiral allenols with up to 97% ee
from readily available propargylic alcohols, aliphatic or aromatic aldehyde, pyrrolidine, and commerically available ligands. The alcohol unit in the
terminal alkynes plays a very important role for ensuring high enantioselectivity via coordination.
Allenes have been becoming more important in organic
synthesis because of extensive exploration on the develop-
ment of new highly selective reactions of allenes.1,2 Of
particular interest, because of the intrinsic axial chirality of
allenes, the axial-to-central chirality transfer strategy has
become an important approach for the synthesis of chiral
products.3 However, the known reports on the synthesis of
axially chiral allenes are still largely limited.2 On the basis
of our recent observation that ZnI2 may promote the
reaction of terminal alkynes, aldehydes, and morpholine
for the synthesis of 1,3-disubstituted allenes,4 we reasoned
that there are two approaches for the easy synthesis of
optically active 1,3-disubstituted allenes from terminal
alkynes and aldehydes: the chiral amine approach and
catalytic asymmetric synthesis of propargylic amine ap-
proach (Scheme 1). In this paper, we wish to report our
recent observation on the realization of such concepts.
In the first place, we tried the following proline-based
commercially available cyclic chiral amines 4ꢀ6 for the
ZnI2-promoted reaction of terminal alkynes based on the
earlier observation by Che et al. under the catalysis of
† Chinese Academy of Sciences.
‡ East China Normal University.
§ These authors contributed equally.
(1) For most recent reviews on the chemistry of allenes, see: (a) Ma, S.
Chem. Rev. 2005, 105, 2829. (b) Ma, S. Aldrichimica Acta 2007, 40, 91. (c)
Brasholz, M.; Reissig, H.-U.; Zimmer, R. Acc. Chem. Res. 2009, 42, 45.
(d) Ma, S. Acc. Chem. Res. 2009, 42, 1679. (e) Alcaide, B.; Almendros, P.;
Campo, T. M. d. Chem.;Eur. J. 2010, 16, 5836. (f) Aubert, C.;
Fensterbank, L.; Garcia, P.; Malacria, M.; Simonneau, A. Chem. Rev.
2011, 111, 1954. (g) Inagaki, F.; Kitagaki, S.; Mukai, C. Synlett 2011,
ꢀ
~
594. (h) Lopez, F.; Mascarenas, J. L. Chem.;Eur. J. 2011, 17, 418.
(2) For reviews on the synthesis of allenes, see: (a) Sydnes, L. K.
Chem. Rev. 2003, 103, 1133. (b) Krause, N., Hashmi, A. S. K., Eds.;
Modern Allene Chemistry; Wiley-VCH: Weinheim, Germany, 2004; Vol. 1
5a
5b
KAuCl4 or AgNO3 salts from L-prolinol-based pro-
pargylic amines. After the extensive combinatorial reactions
of the substrates in our original report4 with amines 4ꢀ6,
it is interesting to note that the reaction of alkyne 1a
with n-BuCHO and the diphenyl-substituted prolinol 6 in
€
and 2. (c) Krause, N.; Hoffmann-Roder, A. Tetrahedron 2004, 60,
11671. (d) Brummond, K. M.; Deforrest, J. E. Synthesis 2007, 795.
(e) Ogasawara, M. Tetrahedron: Asymmetry 2009, 20, 259. (f) Yu, S.;
Ma, S. Chem. Commun. 2011, 47, 5384.
(3) For recent reviews on the chemistry of allenes involving axial-to-
central chirality transfer, see: (a) Ma, S. Acc. Chem. Res. 2003, 36, 701.
(b) Krause, N.; Belting, V.; Deutsch, C.; Erdsack, J.; Fan, H.; Gockel,
€
B.; Hoffmann-Roer, A.; Morita, N.; Volz, F. Pure Appl. Chem. 2008, 80,
1063. (c) Krause, N.;Winter, C. Chem. Rev. 2011, 111, 1994. See also ref 1d.
(4) Kuang, J.; Ma, S. J. Am. Chem. Soc. 2010, 132, 1786.
r
10.1021/ol300296k
Published on Web 02/22/2012
2012 American Chemical Society

of optically active propargylic amines.5ꢀ9 Knochel et al.7
reported CuBr-catalyzed synthesis of optically active pro-
pargylic amine from terminal alkyne, aldehyde, and di-
benzyl or diallyl amine with (R)-quinap 7 as the chiral
ligand, affording propargylic amines with 90ꢀ98% ee only
with trimethylsilylacetylene; 25ꢀ89% ee were observed
when alkyl- or aryl-substituted terminal alkynes were used.
Besides, the reaction is very slow, taking 1ꢀ6 days to finish
at room temperature; Carreira et al.8 applied the ligand
(R,S)-N-PINAP 8 and (R,R)-N-PINAP 9 to the same reac-
tion, and higher enantioslelectivities were observed, yet the
substrate scope is limited to i-alkyl carbinals and suffers
from a long reaction time (3ꢀ5 days). In addition, we
were also concerned with whether such optically active
propargylic amines may be converted to chiral allenes
highly stereoselectively in the presence of ZnI2 and whether
the two steps (chiral propargylic amine as well as allene
formations) would share the same solvent.
Scheme 1. Concepts for the Synthesis of Optically Active
Allenes
toluene afforded allene 3aa in 98% ee within 16 h (entry 3,
Table 1).6
After examining a series of secondary amines shown in
Scheme 2, we were pleased to find that when pyrrolidine
was employed, full conversion from terminal alkynes and
aldehydestopropargylic aminescan berealizedwithin12h
at room temperature. However, the second-step reaction
withthe directadditionof ZnI2 isincomplete, albeit there is
a decent conversion. During the preparation of racemic
products, we noticed with control experiments that Cu(I)
should be removed for a fast second step forming the
allene. Thus, after simple filtration through a short
pad of silica gel to remove Cu(I) with ether as the eluent,
the ether was then evaporated, and the subsequent trans-
formation from the crude propargylic amine to the allene
3dc was conducted in the same solvent (toluene) in the
presenceof ZnI2 veryefficiently. NaI was added toensurea
higher yield.
Table 1. Initial Efforts to Synthesize Axially Chiral Allenes
Using Chiral Amines 4ꢀ6: Selected Examplesa
chiral
amine
yield
entry
1
R
R0
of 3 (%)b,c
p-NO2C6H4CH2OH2C n-Bu
(1a) (2a)
p-NO2C6H4CH2OH2C n-Bu
(1a) (2a)
p-NO2C6H4CH2OH2C n-Bu
(1a) (2a)
p-NO2C6H4CH2OH2C n-Bu
4
5
6
6
37 (3aa, 34%
ee)d
tracee,f
2
3
4
46 (3aa, 98%
ee)g
Scheme 2. Amines Screened and Preparation of Racemic 3dc
63 (3aa, 94%
ee)h
26 (3bb)i,f
tracef
(1a)
(2a)
5
6
n-C10H21 (1b)
HOH2C (1c)
Ph (2b)
Cy (2c)
6
6
a The reactions were carried out on 1.0 mmol scale of 1 in 5 mL of
toluene unless otherwise noted. b Isolated yield. c ee was determined by
HPLC analysis using Chiralcel AD-H or OD-H column. d 4 (1.1 equiv)
and toluene (3 mL) were used with 16% 1a recovered. e 5 (1.1 equiv) and
toluene (3 mL) were used with 40% 1a recovered. f ee not determined.
g 19% of 1a was recovered with the reaction time of 16 h. h 3% of 1a was
recovered with the reaction time of 16 h at 130 °C. i NMR yield.
With the optimized protocol shown in Scheme 2, we
examined several chiral ligands including (R)-quinap 7,
(6) This manuscript was originally submitted on December 18, 2011
to J. Am. Chem. Soc. (ja-2011-11789x). Periasamy et al. also submitted a
manuscript containing the information of such a ZnBr2-promoted
reaction with amine 6 to J. Am. Chem. Soc. (ja-2011-11215r); thus, we
did not pursue extending the scope of this reaction.
(7) (a) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P.
Angew. Chem., Int. Ed. 2003, 42, 5763. (b) Gommermann, N.; Knochel,
P. Chem. Commun. 2005, 4175. (c) Gommermann, N.; Knochel, P.
Chem.;Eur. J. 2006, 12, 4380.
Because of the expensive nature of at least stoichiometric
amounts of chiral amine 6 and an unsuccessful attempt
with unprotected propargyl alcohol (entry 6, Table 1), we
decided to pursue the second approach shown in Scheme 1.
It is envisioned that the challenge will be the availability of
a highly enantioselective method for the efficient synthesis
€
(8) (a) Knopfel, T. E.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.;
Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971. (b) For the
synthesis of optically active propaygylic amines using 4-piperidone
hydrochloride hydrate as the amine, see: Aschwanden, P.; Stephenson,
C. R. J.; Carreira, E. M. Org. Lett. 2006, 8, 2437.
(5) (a) Lo, V. K. Y.; Wong, M.-K.; Che, C.-M. Org. Lett. 2008, 10,
517. (b) Lo, V. K.-Y.; Zhou, C.-Y.; Wong, M.-K.; Che, C.-M. Chem.
Commun. 2010, 46, 213.
Org. Lett., Vol. 14, No. 5, 2012
1347

(R,S)-N-PINAP 8, and (R,R)-N-PINAP 9. It was observed
that when (R,R)-N-PINAP 9 was utilized as the chiral
ligand, the reaction went smoothly, affording allene (R)-3dc
in 60% yield; however, the enantiopurity of allene 3dc was
rather low (35%), although a very high enantioselectivity
was observed by Carreira et al. for the preparation of chiral
propargylic amines from structurally very similar aldehydes,
i.e., i-PrCHO or i-BuCHO,8 indicating a low efficiency of
chirality transfer for the ZnI2-promoted allene formation4
(Scheme 3).
Scheme 4. Proposed Mechanism and Prediction of the Absolute
Configuration of the Allene
Scheme 3. Preparation of Optically Active (R)-(ꢀ)-3dc
Table 2. Catalytic Asymmetric Synthesis of Chiral Allenols
from Terminal Propargylic Alcohols, Aldehydes, And Pyrroli-
dinea
Thus, we further reasoned that a hydroxyl group in
propargylic alcohols may improve the stereoselectivity of
the first as well as the second step reaction by the possible
coordination of the hydroxyl oxygen with Cu or Zn
(Scheme 4). Excitingly, this hypothesis is working: the
reaction with unprotected propargylic alcohols did afford
2,3-allenols in moderate yields with a very practical ee. It
was noted that the reaction with the tertiary proparylic
alcohols yielded the axially chiral allenes in highest ee
(Table 2). The scope of the aldehydes is quite general:
s-alkyl (entries 1ꢀ9, Table 2), or s-alkylmethyl carbinal
(entry 10, Table 2), normal aliphatic aldedyde (entry 11,
Table 2), and benzaldehyde (entry 12, Table 2) may all
be used with decent ee; with (R,S)-N-PINAP 8, the enantio-
mers (S)-3ec and (S)-3fc may be conveniently prepared,
indicating that the axial chirality in the ligand is largely
determining the absolute configuration of the allene unit
formed (entries 2ꢀ4, 6, Table 2). Control experi-
ments showed that ZnBr2 and ZnCl2 provided similar levels
of ee with much longer reaction times (entries 3 and 4,
Table 2).
3
1
2
entry
R1, R2
R3
t1/t2 (h) yield (%)b ee (%)c
1
2d
ꢀ(CH2)5ꢀ (1e) Cy (2c)
ꢀ(CH2)5ꢀ (1e) Cy (2c)
12/8
68 (R-3ec)
70 (S-3ec)
58 (S-3ec)
54 (S-3ec)
66 (R-3fc)
71 (S-3fc)
69 (R-3gc)
77 (R-3hc)
50 (R-3ed)
75 (R-3ee)
96
93
94
93
97
95
95
96
95
90
92
93
12/4
3d,e ꢀ(CH2)5ꢀ (1e) Cy (2c)
12/12
12/12
13/2
4d,f ꢀ(CH2)5ꢀ (1e) Cy (2c)
5
Me, Me (1f)
Me, Me (1f)
Cy (2c)
Cy (2c)
6d
7
12/1.5
12/2.5
12/1.5
19/2.7
13/1.5
ꢀ(CH2)4ꢀ (1g) Cy (2c)
Et, Et (1h) Cy (2c)
8
9
ꢀ(CH2)5ꢀ (1e) i-Pr (2d)
ꢀ(CH2)5ꢀ (1e i-Bu (2e)
10
11
12
ꢀ(CH2)5ꢀ (1e) n-C7H15 (2f) 20.5/1.4 54 (R-3ef)
ꢀ(CH2)5ꢀ (1e) Ph (2g)
17/4.5
78 (R-3eg)
a The reactions were carried out on 1.0 mmol scale of 1. b Isolated
yield. c Determined by HPLC analysis using Chiralcel AD-H or OJ-H
column. d (R,S)-N-PINAP 8 was used as the ligand. e ZnBr2 (0.5 equiv)
was used instead of ZnI2 in the absence of NaI with 3% of propargylic
amine recovered. f ZnCl2 (0.5 equiv) was used instead of ZnI2 in the
absence of NaI with 3% of propargylic amine recovered.
5b
Control experiment showed that KAuCl45a and AgNO3
used by Che et al. failed to promote the allene formation
reaction (Scheme 5).
Furthermore, the reaction is not limited to tertiary
proparylic alcohols: the reaction of secondary proparylic
alcohol 1i yielded a pair of diastereoisomers (d.r. = 1:1) in
slightly lower yet high ee (eq 1, Scheme 6). When the
optically active propargylic alcohols with a central chir-
ality such as (S)-1i and (R)-1i were used, all four diaster-
eoisomers (R,S)-3ic, (S,S)-3ic, (R,R)-3ic, and (S,R)-3ic
were prepared by this protocol conveniently with (R,S)-
N-PINAP 8 or (R,R)-N-PINAP 9 as the ligand. The
absolute configurations of allenes were assigned based on
(9) For recent reviews on the synthesis of propargylic amines from
terminal alkynes and aldehydes in the presence of amines, see: (a) Zani,
L.; Bolm, C. Chem. Commun. 2006, 4263. (b) Li, C. Acc. Chem. Res.
2009, 42, 335. (c) Feng, J.; Li, C. Sci. Synth. 2009, 40a, 579.
1348
Org. Lett., Vol. 14, No. 5, 2012

Scheme 5. Control Experiments using KAuCl4 or AgNO3
Figure 1. ORTEP representation of (S,S)-3ic.
In conclusion, we have developed an easy and efficient
synthesis of allenes especially allenols with axial chirality by
using the easily available or commercial starting materials
and ligands. Because of the potentials of these chiral allenes,14
it will be of high interest to the scientific community. In
addition, it is interesting to observe that the alcohol unit in the
terminal alkynes plays a unique role in this transformation,
probably due to its coordination with Cuþ in the propargylic
amine formation step and with Zn2þ in both intermediates A
and B as shown in Scheme 4. Further studies in this area are
being actively pursued in our laboratory.
Scheme 6. Reactions of 2c and Pyrrolidine with Racemic 1i, (S)-
1i, and (R)-1i
Acknowledgment. Financial support from National
Basic Research Program of China (2011CB808700) and
National Nature Science Foundation of China (No.
20732005) is greatly appreciated.
Supporting Information Available. Detailed experimen-
tal procedures, characterization data for all the products,
and the CIF file of (S,S)-3ic. This material is available free
of charge via the Internet at http://pubs.acs.org.
(11) Crystal data for compound (S,S)-3ic: C16H20O, MW = 228.32,
monoclinic, space group P2(1), final R indices [I > 2σ(I)], R1 = 0.0266,
wR2 = 0.0676; R indices (all data): R1 = 0.0267, wR2 = 0.0677; a =
˚
˚
˚
11.7903(3) A, b = 4.71280(10) A, c = 12.0475(3) A, R = 90°, β =
3
˚
93.5840(10)°, γ = 90°, V = 668.11(3) A , T = 133(2) K, Z = 2,
reflections collected/unique: 9051/2212 (Rint= 0.0237), number of ob-
servations [>2σ(I)] 2202, parameters: 163. CCDC 862647 contains the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
ꢀ
ꢀ
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Wang, K. K. J. Org. Chem. 1986, 51, 745. (c) Marshall, J. A.; Wang, X.
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the X-ray diffraction study of (S,S)-3ic (Figure 1).11
A
€
Hoffmann-Roder, A.; Krause, N. Org. Lett. 2001, 3, 2537. (h) Friesen,
model to predict the absolute configuration of the allene
moiety for the highly selective formation of allenes from
terminal alkynes is shown in Scheme 4.4,5,12,13
R. W.; Blouin, M. J. Org. Chem. 1993, 58, 1653. (i) Ma, S.; Zhao, S.
J. Am. Chem. Soc. 1999, 121, 7943. (j) Fu, C.; Li, J.; Ma, S. Chem.
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The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
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