Highly enantioselective synthesis of chiral allenes by sequential creation of stereogenic center and chirality transfer in a single pot operation

Article abstract of DOI:10.1021/ol300717e

Chiral allenes are readily accessed in a single pot operation in the reaction of terminal alkynes, aldehydes, chiral secondary amines, and zinc halides in good yields (up to 77% yield) and excellent enantioselectivities (up to 99% ee) in toluene at 120 °C. The reaction proceeds through initial formation of chiral propargylamine intermediates with creation of a new stereogenic center and subsequent chirality transfer via an intramolecular hydride shift to produce chiral allenes with high enantiomeric purities.

Full text of DOI:10.1021/ol300717e

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Highly Enantioselective Synthesis of
Chiral Allenes by Sequential Creation of
Stereogenic Center and Chirality Transfer
in a Single Pot Operation
Mariappan Periasamy,* Nalluri Sanjeevakumar, Manasi Dalai,
Ramani Gurubrahamam, and Polimera Obula Reddy
School of Chemistry, University of Hyderabad, Central University P. O., Hyderabad - 500 046, India
mpsc@uohyd.ernet.in
Received January 13, 2012
ABSTRACT
Chiral allenes are readily accessed in a single pot operation in the reaction of terminal alkynes, aldehydes, chiral secondary amines, and zinc
halides in good yields (up to 77% yield) and excellent enantioselectivities (up to 99% ee) in toluene at 120 °C. The reaction proceeds through initial
formation of chiral propargylamine intermediates with creation of a new stereogenic center and subsequent chirality transfer via an intramolecular
hydride shift to produce chiral allenes with high enantiomeric purities.
Chiral allenes are versatile synthons with the potential
to provide excellent axis-to-center chirality transfer in
organic synthesis.1 The chiral allene structural motifs are also
present in several biologically active natural products and
pharmaceuticals.2 Many synthetic methods were reported for
the preparation of racemic3 and optically active allenes,4 but
generally the methods available to access enantiomerically
enriched allenes require multistep synthetic operations. Re-
cently, reports have appeared on enantioselective synthesis of
chiral allenes from chiral propargylamines using silver(I) and
gold catalysts involving a two-step synthetic protocol.5 More
recently, synthesis of racemic disubstituted allenes via a ZnI2
promoted reaction of morpholine with aldehydes and term-
inal alkynes has been reported.6a Very recently, a two-step
method for the synthesis of chiral allenes involving prior
preparation of chiral propargylamine intermediates has been
reported.6b We wish to report here a zinc halide promoted
one-pot method for the enantioselective synthesis of chiral
allenes (R)-8 with up to 99% ee, using 1-alkynes, aldehydes,
and readily accessible chiral secondary amines 1À5.7,8
(1) (a) Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.;
Wiley-VCH: Weinheim, 2004. (b) Hashmi, A. S. K Angew. Chem., Int. Ed.
2000, 39, 3590. (c) Bates, R. W.; Satcharoen, V. Chem. Soc. Rev. 2002,
€
31, 12. (d) Krause, N.; Hoffmann-Roder, A. Tetrahedron 2004, 49,
11671. (e) Ma, S. Chem. Rev. 2005, 105, 2829. (f) Brummond, K. M.;
DeForrest, J. E. Synthesis 2007, 795. (g) Ogasawara, M. Tetrahedron:
Asymmetry 2009, 20, 259.
€
(2) Hoffmann-Roder, A.; Krause, N. Angew. Chem., Int. Ed. 2004,
43, 1196.
(3) (a) Rona, P.; Crabbe, P. J. Am. Chem. Soc. 1969, 91, 3289. (b)
ꢀ
ꢀ
Crabbe, P.; Fillion, H.; Andre, D.; Luche, J.-L. J. Chem. Soc., Chem.
Commun. 1979, 859. (c) Nakamura, H.; Kamakura, T.; Ishikura, M.;
Biellmann, J.-F. J. Am. Chem. Soc. 2004, 126, 5958. (d) Karunakar,
G. V.; Periasamy, M. J. Org. Chem. 2006, 71, 7463. (e) Kuang, J.; Ma, S.
J. Org. Chem. 2009, 74, 1763.
(4) (a) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492. (b)
Wan, Z.; Nelson, S. G. J. Am. Chem. Soc. 2000, 122, 10470. (c) Li, C.-Y.;
Sun, X.-L.; Jing, Q.; Tang, Y. Chem. Commun. 2006, 2980. (d) Pu, X.;
Ready, J. M. J. Am. Chem. Soc. 2008, 130, 10874. (e) Liu, H.; Leow, D.;
Huang, K.-W.; Tan, C.-H. J. Am. Chem. Soc. 2009, 131, 7212. (f) Woerly,
E. M.; Cherney, A. H.; Davis, E. K.; Burke, M. D. J. Am. Chem. Soc. 2010,
132, 6941. (g) Yu, S.; Ma, S. Chem. Commun. 2011, 47, 5384.
(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.
r
10.1021/ol300717e
XXXX American Chemical Society

case of phenylacetylene 6g, the chiral amines 2 and 4 gave
the allene (R)-8ga in 48% yield, 46% ee and 48% yield,
94% ee, respectively (Table S2)8 but (S)-DPP 5 gave only a
mixture of unidentifiable products. Since the chiral (S)-
DPP 5 can be readily accessed from (S)-proline7a and both
enantiomers of the DPP 5 are commercially available, we
have examined the scope of this transformation with
various substrates using (S)-DPP 5 (Table 2).
Table 1. Reaction of 1-Decyne 6a and Benzaldehyde 7a with
Chiral Amines 1À5 Promoted by Zinc Halidesa
(S)-DPP 5, ZnBr2, and substituted benzaldehydes 7
react with 1-decyne 6a to give the corresponding (R)-
allenes 8 in 50À70% yields and 82À98% ee (Table 2,
entries 1À7). The chloro and cyano substituted alkynes
6c and 6d react with benzaldehyde 7a to give the allenes
(R)-8ca and (R)-8da in 62% and 69% yields, 93% and 99%
ee, respectively (Table 2, entries 10 and 11). Whereas the
unprotected propargyl alcohol reacts with benzaldehyde 7a to
give only a complex mixture of products under these condi-
tions, the corresponding benzoyl ester leads to the formation
of the N-benzoyl derivative of the (S)-DPP and the corre-
sponding allene was not formed. Fortunately, the p-nitroben-
zyl ether derivative 6e gave the allene (R)-8ea in 64% yield and
99% ee (entry 12, Table 2). Also, the enyne 6f gave the allene
(R)-8fa in 51% yield and 99% ee (entry 13, Table 2).
Thiophene-2-aldehyde 7i also reacts with alkynes 6a, 6c,
and 6d to give the corresponding allenes (R)-8ai, (R)-8ci, and
(R)-8di in reasonable yields and selectivity (entries 14À16,
Table2). Theallene(R)-8aj is obtained in 35% yield and 86%
ee (entry 17, Table 2) after 2 h in the reaction of furfural 7j and
1-decyne 6a with ZnBr2 at 120 οC, but only a complex mixture
of unidentifiable products remained after a 4 h reaction.
The aliphatic aldehydes 7k, 7l, and 7m react with the
4-phenyl-1-butyne 6b, cyano substituted alkyne 6d, and
p-nitrobenzyl propargyl ether 6e to give the allenes (R)-8bk,
(R)-8dl, and (R)-8em in 48%À59% yield and 92%À99%
ee (Table 2, entries 18, 19, and 21). Simple alkynes like
1-decyne 6a react with the aliphatic aldehydes, but chro-
matographic separation of the mixtures containing the
allenic products was somewhat difficult in the absence of
chromophoric groups in these cases. The use of ethyl
propiolate lead to a complex mixture of products in the
reaction with benzaldehyde 6a with the chiral amine 5.
Also, substrates like cinnamaldehyde, N-methyl-2-formy-
lindole, and acetophenone gave only complex mixtures of
unidentifiable products in the reaction with 1-decyne
under the reaction conditions.
ZnX2
time
(h)
yield
(%)b
ee
entry
amine
(equiv)
(%)c
1
2
3
4
5
1
2
3
4
5
ZnI2 (0.5)
ZnI2 (0.5)
ZnI2 (0.6)
ZnI2 (0.6)
ZnBr2 (0.7)
2
2
57
72
55
65
65
18
66
76
95
98
8
4
10
a The reactions were carried out by taking amines 1, 2, 4, 5 (1.0 mmol)
or 3(0.5mmol), ZnX2 and 1-decyne 6a (1.1 or 1.0 mmol with amine 3and 4)
in toluene (3 mL) at 25 οC, heating for 10 min at 120 οC, followed by
addition of the aldehyde (1 mmol) at 25 °C and heating to 120 °C in
45 min and further stirring at 120 °C for the required time. Heating all
components together at 120 °C gives the (R)-allene 8aa in lower ee (by
about 10%). The reaction was stopped as soon as tlc analysis indicated
the absence of benzaldehyde . b Isolated yield. c The % ee was determined
by HPLC analysis on a chiralcel OD-H or OJ-H column.
Initially, we have examined this ZnCl2, ZnBr2, and ZnI2
promoted chiral allene synthesis using chiral secondary
amines 1À5, 1-decyne 6a, and benzaldehyde 7a at 120 οC.
Optimum results obtained are summarized in Table 1, and
the results obtained using different amounts of zinc halides
are given in Table S1 in the Supporting Information.8
Whereas the C2 symmetrical chiral amine 1ÀZnI2 reagent
systemgavethe allene(R)-8aa9 in57% yield withonly 18%
ee, the C1 symmetrical amine 2 afforded the allene (R)-8aa
in higher yield (72%) and selectivity (66% ee) (Table 1,
entries 1 and 2).8 The chiral 2,3-diphenyl-piperazine 3 and
ZnI2 combination gave the allene (R)-8aa in 55% yield
with 76% ee, and the chiral N-benzyl-2,3-diphenyl-piper-
azine 4ÀZnI2 (0.6 equiv) combination gave the allene (R)-
8aa in higher yield (65%) and selectivity (95% ee) (Table 1,
entries 3 and 4). The chiral (S)-diphenyl-prolinol (DPP)
5ÀZnBr2 (0.7 equiv) combination also gave the allene (R)-
8aa in comparable yields and selectivity (65% yield and
98% ee, Table 1, entry 5).
We have also carried out a series of experiments to
isolate the propargylamine intermediates that are expected
to form in this transformation (Schemes 1 and S1).6,8 We
have observed that the propargylamine intermediates are
also readily converted to the allene (R)-8aa upon reaction
with zinc halides (Schemes 1 and S1).8 Also, the imine
byproducts could be easily converted to the starting chiral
amines by simple borohydride reduction without any
change in enantiomeric purity.8
A tentative mechanism outlined in Scheme 2 could be
considered for this transformation based on previous
reports5,6,10 and the relative configuration of chiral
propargylamine intermediates.11 The initially formed alky-
nylzinc species 12 would attack the Re-face of iminium ion
The chiral amines 4 and 5 gave better results in this
transformation compared to the amine 2 (Table 1 and
Table S2 in Supporting Information). Surprisingly, in the
(6) (a) Kuang, J.; Ma, S. J. Am. Chem. Soc. 2010, 132, 1786. (b) 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.
(7) (a) Kanth, J. V. B.; Periasamy, M. Tetrahedron 1993, 49, 5127. (b)
Periasamy, M.; Gurubrahamam, R.; Muthukumaragopal, G. P. Synthesis
2009,1739. (c) Vairaprakash, P.; Periasamy, M. J. Org. Chem. 2006, 71, 3636.
(8) See Supporting Information for details.
(9) (a) Lowe, G. Chem. Commun. 1965, 411. (b) Brewster, J. H. Top.
Stereochem. 1967, 2, 1.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Synthesis of Chiral Allenes 8 by ZnBr2 Promoted Reaction of Chiral Amine 5 with Substituted 1-Alkynes 6 and Aldehydes 7a
a The reactions were carried out by taking amine 5 (1.0 mmol), ZnBr2 (0.7 mmol), and 1-alkyne (1.1 mmol) in toluene (3 mL) at 25 οC following the
sequence of addition of reagents as outlined under Table 1. b Isolated yield. c The % ee was determined by HPLC analysis on a chiralcel OD-H, OJ-H or
OB-H column . d Optically active (R)-allenes were obtained in these cases, but the ee’s could not be determined as the corresponding racemic allenes could
not be resolved using the available OD-H, OJ-H, OB-H, AD-H, or AS-H chiral HPLC column.
14a formed in situ to yield the propargylamine 16. Subse-
quent 1,5-hydride transfer5,6 and elimination of ZnBr2 could
afford the allene (R)-8 and the imine 10 (Scheme 2). The
chiral amines 4 and 5 give better enantioselectivity in this
transformation compared to the amine 2 (Tables 1, 2, and
Table S2) which may be due to coordination of the addi-
tional amino or hydroxyl moieties present in the amines 4
and 5 with the zinc halide in the transition states. Such
hydroxyl moiety coordinations with ZnBr2 in the transitions
states 15 and 17 for the transformation using (S)-DPP 5 are
shown in Scheme 2.
(10) (a) Fischer, C.; Carreira, E. M. Org. Lett. 2004, 6, 1497. (b)
€
Tomooka, C, S.; Fassler, R.; Frantz, D. E.; Carreira, E. M. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5843.
(11) (a) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P.
Angew. Chem., Int. Ed. 2003, 42, 5763. (b) Gokel, G. W.; Marquarding,
D.; Ugi, I. K. J. Org. Chem. 1972, 37, 3052.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 1. Propargylamine Intermediate and Imine Byproduct
Scheme 3. Oxazolidine Intermediate 18 and Its Reaction with
ZnBr2 and 1-Decyne 6a
Interestingly, this oxazolidine intermediate 18 reacts with
1-decyne 6a and ZnBr2 at 120 °C to give the (R)-allene 8aa
only in 85% ee and 52% yield (Scheme 3).
Scheme 2. Plausible Reaction Mechanism
Presumably, when all the components are heated to-
gether, the predominant reaction is between the amino
alcohol DPP 5 and benzaldehyde 7a to give the iminium
ion species 14a (Scheme 2) which could cyclize to give the
oxazolidine 18 (Scheme 3) in the absence of the alkynylzinc
bromide 12. The oxazolidine 18couldthendeprotonatethe
alkyneÀZnBr2 complex1110b (Scheme 2), and the resulting
alkynylzinc species 12 could directly attack the oxazolidine
18, leadingtoadifferent enantioselectivity inthe formation
of the allene 8aa. Further studies on the preparation and
reactions of various intermediates expected to be involved
in this transformation (Schemes 2 and 3) would help in
understanding the mechanism and enantioselectivity.
In summary, since the chiral amines employed here are
readily accessible7,8 and both enantiomers of the DPP 5 are
also commercially available, the methods described for the
synthesis of chiral allenes have good synthetic potential.
Moreover, the methods disclosed here for isolation
of the propargylamine intermediates and subsequent zinc
halide promoted conversion to chiral allenes 8aa
(Schemes 2 and S2) illustrate the scope of this synthetic
protocol for further development.
We have observed that the enantioselectivity is also
affected by the sequence of addition of reagents (Table 1,
footnote a).8 Whereas heating the chiral amine DPP 5,
ZnBr2, and 1-decyne in toluene for 10 min at 120 °C,
followed by addition of the aldehyde at 25 °C and further
stirring at 120 οC for 10 h, gave the (R)-allene 8aa in 65%
yied and 98% ee (Table 1, entry 5), heating all the
components together at 120 °C afforded the (R)-allene
8aa only in 86% ee and 63% yield (Scheme 3). We have
carried out experiments to account for this observation
(Scheme 3). When the amine 5, 1-decyne 6a, and benzal-
dehyde 7awereheated withZnBr2 intoluene at120 °C only
for 15 min, the oxazolidine 1812 was isolated in 30% yield
(Scheme 3). The oxazolidine 18 was also obtained in 62%
yield by heating the amine 5 and benzaldehyde 7a in
toluene at 120 °C for 1 h which further illustrates the ease
of formation of this intermediate upon heating (Scheme 3).
Acknowledgment. We are thankful to the DST (New
Delhi) for a J. C. Bose National Fellowship grant to M.P.
and for the FIST and IRPHA programs. Support of the
UGC under UPE and CAS programs is also gratefully
acknowledged. N.S.K., M.D., R.G., and P.O.R. are
thankful tothe CSIR (New Delhi) for researchfellowships.
Supporting Information Available. Tables S1 and S2,
Scheme S1, experimental procedures, physical constant
1
data, H and 13C NMR data, ORTEP diagram, and
HPLC analysis profiles. This material is available for free
of charge via the Internet at http://pubs.acs.org.
(12) Zuo, G.; Zhang, Q.; Xu, J. Heteroatom. Chem. 2003, 14, 42.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX