Zinc salt promoted diastereoselective synthesis of chiral propargylamines using chiral piperazines and their enantioselective conversion into chiral allenes

Article abstract of DOI:10.1002/ejoc.201402766

Zinc chloride catalyzed reactions of chiral piperazine derivatives 4a-d with 1-alkynes and aldehydes give chiral propargylamines in 67-95 % yields with up to 99:1 dr. The chiral propargylamines are converted into chiral allenes by using zinc bromide in sh

Full text of DOI:10.1002/ejoc.201402766

FULL PAPER
DOI: 10.1002/ejoc.201402766
Zinc Salt Promoted Diastereoselective Synthesis of Chiral Propargylamines
Using Chiral Piperazines and Their Enantioselective Conversion into Chiral
Allenes
Mariappan Periasamy,*[a] Polimera Obula Reddy,[a] Athukuri Edukondalu,[a]
Manasi Dalai,[a] Laxman M. Alakonda,[a] and Bantu Udaykumar[a]
Keywords: Synthetic methods / Amines / Allenes / Enantioselectivity / Chirality / Dimerization
Zinc chloride catalyzed reactions of chiral piperazine deriva-
tives 4a–d with 1-alkynes and aldehydes give chiral propar-
gylamines in 67–95% yields with up to 99:1 dr. The chiral
propargylamines are converted into chiral allenes by using
zinc bromide in short reaction times (1–2 h) in high enantio-
selectivities (up to 99%ee) in good yields (up to 89%). The
chiral piperazines are recovered in good yields (79–86%) by
reduction of the imine byproducts in situ by using NaBH4.
Unexpectedly, the chiral aryl-substituted allenes undergo
facile cyclodimerization under neat conditions at 25 °C, in
contrast to an earlier report that cyclodimerization takes
place at 80 °C in benzene, which further illustrates the im-
portance of the two-step procedure reported herein because
the chiral propargylamine may be converted into chiral al-
lene when required.
been developed to access the chiral allenes in very high
enantioselectivity up to 99%ee.
Introduction
Allenes are versatile building blocks and synthons for use
in modern organic synthesis.[1,2] Generally, chiral allenes are
synthesized from enantioenriched propargylic precursors
through transfer of their stereochemical information to all-
enes by SN2 type displacement reactions of chiral proparg-
ylic compounds and (3,3)-sigmatropic rearrangement of
chiral propargyl alcohols.[3] There is growing interest in the
synthesis of chiral allenes by using amines via chiral propar-
gylamines.[4] Chiral propargylamines are also versatile syn-
thetic intermediates for the synthesis of biologically active
skeletons and important structural elements of natural
products.[5] Methods have been reported for the enantiose-
lective synthesis of propargylamine derivatives by using
metal-based chiral ligands such as quinap,[6] pinap,[7] py-
box,[8] and binam diimine[9] as well as diastereoselective
synthesis of chiral propargylamines by using chiral amines
and gold(III) salen complexes.[4a,4c]
Recently, we developed a “chiral amine approach” for
highly enantioselective synthesis of chiral allenes by using
terminal alkynes, aldehydes, and chiral amines promoted by
zinc halides in a single-pot operation.[10a] Thus, the zinc hal-
ide promoted reaction of chiral secondary amines 1–4a, 1-
Scheme 1. Synthesis of chiral allene 7aa by using chiral amines 1–
4a.
This method has a few limitations. Whereas, the C2-sym-
decyne 5a, and benzaldehyde 6a at 120 °C (Scheme 1) has metric chiral amine 1 gave the chiral allene in only 18%ee,
the C1 chiral pyrrolidine derivative 2 afforded the allene
[a] School of Chemistry, University of Hyderabad, Central
University P. O.,
product in 66%ee. The easily accessible and commercially
available chiral amino alcohol 3 yielded chiral allene 7aa in
98%ee, and the reaction has been generalized for a variety
of aldehydes and alkynes. However, the results are highly
dependent on the sequential addition of the reactants and
inadvertent formation of the oxazolidine intermediate 8
Hyderabad 500046, India
E-mail: mpsc@uohyd.ernet.in
http://moodle.uohyd.edu.in/index.php/academics/2011-10-27-
18-38-04/school-of-chemistry/faculty
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402766.
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could lower the enantioselectivity of the allene to port the synthesis of chiral piperazine derivatives 4a–d (Fig-
86%ee.[10a]
ure 2), which enables the synthesis of chiral propar-
The imine byproduct 9 could be isolated and recycled gylamines in a ZnCl2-promoted reaction at 100 °C in 4 h
back to the chiral diphenylprolinol 3 in 75% yield by and their conversion into chiral allenes in a ZnBr2 reaction
NaBH4/CH3OH-mediated reduction. However, careful at 120 °C in 1–2 h.
analysis of the imine product mixture indicated the forma-
tion of 10 (5–10% yield) formed by condensation with the
benzaldehyde present in the medium (Figure 1). The N-
benzylpiperazine derivative 4a gave the chiral allene in
95%ee without the formation of such unwanted sideprod-
ucts.[10a] Therefore, we decided to prepare different chiral
N-benzylpiperazine derivatives for applications in this
transformation, especially for the two-step conversion via
the corresponding propargylamine because this would
avoid the presence of aldehyde substrates that could react
Figure 2. Chiral piperazine derivatives 4a–d.
with the corresponding cyclic imine byproduct after the for-
mation of the allene.[10b] A CuBr-promoted two-step proto-
col is available but this method requires 36 h at 25 °C for
Results and Discussion
the preparation of chiral propargylamines by the reaction
of 2-(dialkylamino)pyrrolidines with 1-alkynes and alde-
hydes in toluene, and a further 18 h at 100 °C for the CuI-
promoted conversion into chiral allenes.[11] Herein, we re-
The diastereomerically pure chiral N-methylcamphanylp-
iperazine derivatives react with aldehydes and 1-alkynes in
the presence of zinc halide to give both enantiomers of the
corresponding chiral allene in a single-pot operation.[12]
However, it is somewhat difficult to recover the chiral N-
methylcamphanylpiperazine. Therefore, the corresponding
N-benzylpiperazines 4b–d were prepared as outlined in
Scheme 2 for use in the present studies. Initial tert-butoxy-
carbonyl (BOC) protection followed by benzylation and
BOC deprotection of the parent piperazines 11 and 14 gave
the N-benzylpiperzines 4b and 4c, respectively, in 90–92%
yields. Whereas, direct benzoylation of the camphanylpiper-
Figure 1. Structures of oxazolidine intermediate 8 and imine by-
products 9 and 10.
Scheme 2. Synthesis of N-benzylpiperazine derivatives 4b–d.
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Synthesis of Chiral Propargylamines, Piperazines, and Allenes
azine 14 at –78 °C followed by reduction with NaBH4/I2 at carbaldehyde 6i reacts with alkynes 5a and 5c to give the
80 °C gave N-benzylcamphanylpiperazine 4d in 78% yield corresponding propargylamines 18aci and 18cai in reason-
(Scheme 2).
able yields and good selectivity. Propargylamine 18cah was
We then carried out detailed studies on the synthesis of obtained in 85% yield with 98:2 dr within 3 h in the reac-
chiral propargylamines and their conversion into chiral all- tion of furfural 6h and 1-decyne 5a with ZnCl2 at 100 °C.
enes. We found that chiral propargylamine 18caa is ob-
tained in 98% yield with 99:1 dr in the zinc chloride cata-
lyzed reaction of 1-decyne 5a, aldehyde 6a, and chiral piper-
azine derivative 4c at 100 °C (Table 1). Chiral propar-
gylamine 18caa was obtained in slightly lower yield by
using other metal halides such as ZnBr2, CuBr, and CuI
under these reaction conditions (Table 1).[13]
Table 1. Synthesis of chiral propargylamine 18caa by using 1-de-
cyne 5a, benzaldehyde 6a, and the chiral N-benzylpiperazine 4c
with metal salts.[a]
En- Metal mol- Time Yield of dr[c]
Yield of
ee [%]
[d]
try
halide
%
[h]
18caa
7caa [%][b]
[%][b]
1
2
ZnCl2
ZnBr2 10
CuBr
CuBr
CuI
10
4
4
4
24
4
98
85
90
95
87
99:1
99:1
98:2
99:1
97:3
–
10
8
–
15
–
Figure 3. ORTEP representation of chiral propargylamine 18aej
(thermal ellipsoids drawn with 50% probability).
99
99
–
3
10
10
10
4[e]
5
99
We then turned our attention to the conversion of chiral
propargylamines into the corresponding chiral allenes. We
have observed that the reaction of chiral propargylamine
18caa with ZnBr2 (0.5 mmol) at 120 °C gave chiral allene
7caa in up to 89% yield with 99%ee. The same procedure
was followed for the conversion of other diastereomerically
[a] Reaction conditions: piperazine 4c (1.0 mmol), 1-decyne
(1.1 mmol), benzaldehyde (1.0 mmol), toluene (3 mL), 100 °C, 4 h.
[b] Isolated yield. [c] dr ratio based on crude 1H NMR spectro-
scopic analysis. [d] ee of allene 7caa was determined by chiral
HPLC analysis. [e] The reaction was carried out at 25 °C for 24 h.
We next investigated the synthesis of various chiral pro- pure propargylamines into the corresponding chiral allenes;
pargylamine derivatives 18 from the corresponding chiral the results are summarized in Table 3.
piperazines 4a–c; the results are summarized in Table 2. Ar-
Chiral propargylamines 18aag, 18caf, and 18cag substi-
ylaldehydes that have an electron-donating group such as tuted with methoxy and methyl groups afforded the corre-
methoxy 6f and para-methyl 6g undergo this reaction to sponding chiral allenes 7aag, 7caf, and 7cag in 72–82%
give the corresponding propargylamines 18aag, 18cag, and yields with up to 99%ee. Propargylamines having chloro,
18caf in 93–97% yields and up to 99:1 dr. Electron-deficient fluoro, or trifluoro substituents were also compatible with
aryl aldehydes 6b–e transformed smoothly into the desired the reaction conditions, affording the corresponding axially
propargylamine derivatives 18aac, 18cad, and 18cae in 89– chiral aryl-substituted allenes 7aac–cae in 69–71% yields
91% yields with up to 98:2 dr. We have also carried out the and up to 99%ee. Propargylamines containing heteroarom-
reaction with various alkynes, aldehydes, and chiral piperaz- atic groups 18aci, 18cah, and 18cai with ZnBr2 (0.5 mmol)
ine derivative 4a under these reaction conditions. Cyano- at 120 °C gave chiral allenes 7cah–cai in 69–73% yields and
and chloro-substituted alkynes 5b and 5c gave the desired up to 99%ee. Propargylamines substituted with cyano or
propargylamines 18aba–aca in 89–92% yields with up to chloro groups afforded the corresponding chiral allenes
99:1 dr. Propargylamines 18ada and 18aej were obtained 7aba and 7aca in 70–71% yields and up to 99%ee. Propar-
in 86 and 92% yield, respectively, with 98:2 and 99:1 dr. gylamines 18ada and 18aej gave the corresponding chiral
Propargylamines 18bfa–bdj were obtained in 67–90% yields allenes 7ada and 7aej in 71–76% yields and up to 99%ee.
with up to 99:1 dr by using the chiral piperazine derivative Propargylamines 18bfa–bdj also afforded the corresponding
4b (Table 2). The configuration at the newly formed ste- chiral allenes 69–89% yields with up to 99%ee (Table 3).
reogenic center in propargylamine 18aej was found to be
We also carried out the allene synthesis by using chiral
S by single-crystal X-ray analysis (Figure 3). Thiophene-2- propargylamine 18daa, with R configuration at the prop-
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Table 2. ZnCl2-promoted synthesis of chiral propargylamines 18 by using 1-alkynes 5, aldehydes 6, and chiral piperazine derivatives 4a–
c.[a,b,c]
[a] Reaction conditions: chiral piperazine (1.0 mmol), 1-alkyne (1.1 mmol), aldehyde (1.0 mmol), toluene (3 mL), 100 °C, 4 h. [b] dr ratio
1
based on crude H NMR spectroscopic analysis. [c] Isolated yield.
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Synthesis of Chiral Propargylamines, Piperazines, and Allenes
Table 3. ZnBr2-promoted synthesis of chiral allenes from chiral propargylamines 18.[a,b,c]
[a] Reaction conditions: propargylamine 18 (1 mmol), toluene (3 mL), ZnBr2 (0.5 mmol). [b] Isolated yield. [c] ee determined by using
chiral HPLC analysis.
argylic stereogenic center. As expected, the S chiral allene
The formation of chiral propargylamines and their con-
7daa was obtained in 83% yield and 99%ee under these version into chiral allenes can be rationalized by the mecha-
conditions (Scheme 3).
nism outlined in Scheme 4. The initially formed alkynylzinc
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Scheme 3. Synthesis of chiral allene (S)-7daa by using propargylamine 18daa.
Scheme 4. Mechanism for formation of (R)-allene by using chiral piperazines 4a–c.
intermediate[14] 20 would react with the favored conformer Brewster rule and also by comparison with reported [α]2D5
21B of the iminium ion derived from aldehyde 6 and chiral values.[15] We have also found that imine byproducts 26b–d
piperazine to give selectively the corresponding propar- could be easily converted in situ into the corresponding chi-
gylamine 23.
ral piperazines 4b–d in 79–86% yield by simple sodium
The corresponding zinc bromide complex of 24 would borohydride mediated reduction (Scheme 5).
then undergo intramolecular hydride shift from the piperaz-
We have observed that the chiral allenes containing aryl
ine skeleton to the acetylinic moiety, leading to the forma- substituents were not stable, and that they readily undergo
tion of alkenylzinc intermediate 25. Subsequently, cleavage cyclodimerization under neat ambient conditions. Pre-
of the C–N bond in intermediate 25 releases the chiral all- viously, it was reported that the 1,3-diphenyl allene 7cea
enes 7 and the imine byproduct 26.
undergoes dimerization at 80 °C in [D6]benzene
All the optically active allenes obtained by using chiral (Scheme 6).[16]
piperazine derivatives 4a–c were levorotatory, from which
Surprisingly, we have observed that under neat condi-
the absolute configurations of the major enantiomer was tions, 1,3-diphenyl allene 7cea undergoes cyclodimerization
assigned as R (Table 3), whereas the optically active allene even at 25 °C in 24 h. Thus, whereas the freshly prepared
7daa obtained with chiral N-benzylcamphanylpiperazine 4d pure chiral allene 7cea sample exhibits an [α]2D5 = –830 (c =
was dextrorotatory, from which the absolute configuration 0.53, CHCl3), the value becomes zero when the product was
of the major enantiomer was assigned as S by the Lowe– kept at 25 °C for 72 h. The 13C NMR spectrum of the prod-
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Synthesis of Chiral Propargylamines, Piperazines, and Allenes
Scheme 5. In situ reduction of imine byproducts 26b–d.
Conclusions
We have developed a simple, practical, and very inexpen-
sive method for the diastereoselective preparation of chiral
propargylamines by using chiral piperazines 4a–d and their
enantioselective conversion into chiral allenes upon reac-
tion with ZnBr2. The surprisingly facile cyclodimerization
reactions observed with aryl-substituted allenes illustrates
the hidden difficulties in handling and storing of allenes.
Scheme 6. Cyclodimerization of 1,3-diphenyl allene 7cea.
uct mixture indicates the presence of the cyclodimerized
products.[16e] We have also found that when freshly prepared
pure chiral 1,3-diphenylallene 7cea was stored in CDCl3
solution, new signals corresponding to the cyclodimerized
products started appearing in the 13C NMR spectrum in
24 h at 25 °C.[17]
We have also observed that the aryl-alkyl-substituted all-
enes also undergo slow cyclodimerization to give a complex
mixture of products under neat conditions at 25 °C within
a week, as indicated by 13C NMR spectroscopic analysis.
Periodic analysis of optical rotations of chiral aryl-substi-
Experimental Section
Synthesis of Chiral Amines 4b–d
tert-Butyl Octahydroquinoxaline-1-carboxylate (12): To a solution
of decahydroquinoxaline (1.40 g, 10.0 mmol) in CH2Cl2 (10 mL),
di-tert-butyldicarbonate (2.2 mL, 10 mmol) was added at 0 °C
slowly by using a syringe under an N2 atmosphere. The reaction
mixture was brought to room temperature slowly and further
stirred for 6 h. Upon completion of the reaction (which was moni-
tuted allenes indicated that in 14 days the optical rotation tored by TLC), the solvent was evaporated under reduced pressure.
Purification of the residue by column chromatography on silica gel
(100–200 mesh; hexane/EtOAc, 50:50) afforded 12 (1.82 g, 76%) as
a colorless viscous liquid; Rf = 0.3 (silica gel; hexane/EtOAc,
50:50); [α]2D5 = –74.29 (c = 0.52, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 3.51–3.47 (m, 2 H), 3.08–2.99 (m, 2 H), 2.98–2.93 (m,
1 H), 2.60 (dt, J = 10.8, 3.6 Hz, 1 H), 2.23–2.19 (d, J = 12.8 Hz, 1
H), 1.82–1.79 (d, J = 12.8 Hz, 1 H), 1.73–1.68 (t, J = 18.4 Hz, 2
H), 1.59–1.46 (m, 2 H), 1.43 (s, 9 H), 1.33–1.08 (m, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 155.5, 79.4, 63.7, 56.2, 44.8, 41.2,
values of the samples became zero. However, when the aryl-
substituted allenes 7caa or 7cac were stored in hexane or
CDCl3 solutions, there was no change in the optical rota-
tion values or 13C NMR signals, even after 14 days. The
mechanism of the facile cyclodimerization of aryl-substi-
tuted allenes under ambient conditions is not clearly under-
stood at this stage. Previously, cyclodimerizations with
some loss in optical activity were reported for chiral allenes
at temperatures of more than 100 °C, and the reaction has
been reported to go through a stepwise mechanism.[18]
33.2, 30.3, 28.5, 25.3, 25.1 ppm. IR (neat): ν = 3320, 2969, 2931,
˜
2854, 1693, 1457, 1413, 1369, 1249, 1150, 1095, 1013, 767 cm–1.
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HRMS (ESI): m/z calcd. for C13H24N2O2 [M + H+] 240.1838;
found 241.1917.
and the mixture was stirred and heated to reflux for 12 h. After
cooling to room temperature, the mixture was filtered to remove
K2CO3 and the solvent was evaporated under reduced pressure.
The residue was extracted with CH2Cl2 (80 mL) and water (20 mL),
and the combined organic extract was washed with brine (20 mL)
and dried with anhydrous Na2SO4. The solvent was evaporated and
the residue was purified by column chromatography, to afforded 16
(3.148 g, 82%) as a colorless liquid; Rf = 0.7 (silica gel; hexane/
EtOAc, 95:5); [α]2D5 = 21.61 (c = 0.70, CHCl3). 1H NMR(400 MHz,
CDCl3): δ = 7.39–7.25 (m, 5 H), 4.18–4.14 (d, J = 16.0 Hz, 1 H),
3.71–3.65 (m, 1 H), 3.32–3.25 (m, 2 H), 2.90–2.86 (d, J = 16.0 Hz,
1 H), 2.72–2.60 (m, 2 H), 2.05–2.03 (m, 1 H), 1.70 (s, 2 H), 1.48–
1.45 (s, 9 H), 1.30 (s, 3 H), 1.16 (s, 2 H), 1.07 (s, 3 H), 0.84 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.5, 139.5, 128.3,
127.9, 126.8, 79.5, 72.4, 71.9, 63.2, 59.2, 53.6, 50.6, 50.0, 45.8, 43.1,
tert-Butyl 4-Benzyl-octahydroquinoxaline-1-carboxylate (13): To a
solution of 12 (1.50 g, 6.25 mmol) in acetonitrile (30 mL) was
added benzyl bromide (0.83 mL,7 mmol), K2CO3 (1.79 g,13 mmol),
and KI (0.498), and the mixture was stirred and heated to reflux for
12 h. After cooling to room temperature, the mixture was filtered
to remove K2CO3 and the solvent was evaporated under reduced
pressure. The residue was extracted with CH2Cl2 (2ϫ 40 mL) and
water (20 mL) and the combined organic extract was washed with
brine (20 mL) and dried with anhydrous Na2SO4. The solvent was
evaporated and the residue was purified by column chromatog-
raphy on silica gel (100–200 mesh; hexane/EtOAc, 50:50) to afford
13 (1.78 g, 86%) as a colorless liquid. We proceeded to next step
without further purification of this product. Rf = 0.6 (silica gel;
hexane/EtOAc, 50:50); [α]2D5 = –71.07 (c = 0.45, CHCl3). 1H
NMR(400 MHz, CDCl3): δ = 7.29–7.28 (d, J = 4.4 Hz, 4 H), 7.23–
7.21 (m, 1 H), 4.01–3.98 (d, J = 13.2 Hz, 1 H), 3.63–3.57 (m, 1 H),
2.82–2.76 (m, 1 H), 2.45–2.40 (m, 1 H), 2.34–2.28 (m, 1 H), 2.21
(s, 2 H), 1.77–1.75 (d, J = 8.8 Hz, 3 H), 1.45 (s, 9 H), 1.32–1.27
(m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.2, 139.4,
128.7, 128.1, 126.7, 79.2, 62.2, 61.9, 56.7, 51.8, 42.9, 30.7, 30.5,
36.0, 28.5, 26.8, 22.3, 20.5, 20.2, 14.5 ppm. IR (neat): ν = 2953,
˜
2887, 2814, 2781, 1691, 1602, 1477, 1452, 1371, 1294, 1232, 1174,
1143, 1109, 1080, 1032, 987 cm–1. HRMS (ESI): m/z calcd. for
C24H36N2O2 [M + H+] 384.2777; found 385.2854.
1-Benzyl-5,9,9-trimethyl-decahydro-5,8-methanoquinazoline (4c): To
a solution of 16 (3.072 g, 8.0 mmol) in 1,4-dioxane (20 mL), 6 m
HCl (5 mL) was added slowly by using a syringe over 15 min under
an N2 atmosphere. The resulting mixture was stirred at room tem-
perature for 12 h, then the solvent was evaporated and the residue
was neutralized with 6 n NaOH solution. The organic layer was
extracted with CH2Cl2 and the combined organic extract was
washed with brine (20 mL) and dried with anhydrous Na2SO4. The
solvent was evaporated and the residue was purified by column
chromatography to afford the 4c (2.090 g, 92%) as a yellow liquid;
Rf = 0.4 (silica gel; hexane/EtOAc, 50:50); [α]2D5 = 11.15 (c = 0.44,
CHCl3). 1H NMR(400 MHz, CDCl3): δ = 7.36–7.23 (m, 3 H),
4.34–4.30 (d, J = 16.0 Hz, 1 H), 2.94–2.91 (m, 2 H), 2.80–2.74 (m,
2 H), 2.64–2.60 (m, 1 H), 2.25–2.23 (d, J = 8.0 Hz, 1 H), 1.82–1.78
(m, 2 H), 1.71–1.70 (d, J = 4.0 Hz, 1 H), 1.56 (s, 3 H), 1.46–1.44
(m, 1 H), 1.23–1.18 (m, 2 H), 1.09 (s, 3 H), 0.86 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 140.2, 128.4, 128.2, 128.1, 126.6,
76.2, 61.1, 61.0, 50.9, 50.4, 50.1, 47.4, 41.6, 37.0, 27.1, 22.3, 21.1,
28.5, 25.6, 25.2 ppm. IR (neat): ν = 3084, 3068, 3030, 2975, 2931,
˜
2854, 2794, 1693, 1446, 1402, 1353, 1282, 1249, 1161, 1013, 849,
734, 695 cm–1. HRMS (ESI): m/z calcd. for C20H30N2O2 [M + Na+]
330.2307; found 353.2206.
1-Benzyl-decahydroquinoxaline (4b): To 13 (5.5 mmol 1.83 g) in 1,4-
dioxane (20 mL), 6 m HCl (5 mL) was added slowly by using a
syringe over 15 min under an N2 atmosphere. The resulting mixture
was stirred for 12 h at room temperature, then the solvent was evap-
orated and the residue was neutralized with 6 n NaOH solution
and the organic layer was extracted with CH2Cl2. The combined
organic extract was washed with brine (20 mL) and dried with an-
hydrous Na2SO4. The solvent was evaporated and the residue was
purified by chromatography on basic alumina (100–200 mesh; hex-
ane/EtOAc, 50:50) to obtain 4b (1.16 g, 90%) as a colorless solid;
Rf = 0.2 (silica gel; hexane/EtOAc, 50:50); m.p. 95–96 °C; [α]2D5
=
15.5 ppm. IR (neat): ν = 3281, 3076, 2934, 1554, 1485, 1415, 1379,
–109.81 (c = 0.52, CHCl3). 1H NMR(400 MHz, CDCl3): δ = 7.31–
7.30 (d, J = 4.4 Hz, 4 H), 7.26 (s, 1 H), 4.13–4.10 (d, J = 13.2 Hz,
1 H), 3.16–3.12 (d, J = 13.2 Hz, 1 H), 2.94–2.84 (m, 2 H), 2.73–
2.70 (d, J = 11.6 Hz, 1 H), 2.48–2.42 (m, 1 H), 2.27–2.23 (d, J =
13.2 Hz, 1 H), 2.12 (dt, J = 11.2, 4 Hz, 1 H), 1.87–1.78 (m, 2 H),
1.72–1.70 (d, J = 7.2 Hz, 2 H), 1.38–1.13 (m, 5 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 139.0, 129.1, 128.1, 126.7, 67.0, 60.4, 57.3,
˜
1147, 1055, 808, 692 cm–1. HRMS (ESI): m/z calcd. for C19H28N2
[M + H+] 284.2252; found 285.2329.
Phenyl-(5,9,9-trimethyl-octahydro-5,8-methanoquinazolin-1-yl)meth-
anone (17): To a solution of chiral piperazine 14 (1.940 g, 10 mmol)
and trimethylamine (1.36 mL, 10.0 mmol) in CH2Cl2 (100 mL),
benzoyl chloride (1.270 mL, 10 mmol) was added at –78 °C slowly
(for 30 min) by using a syringe under an N2 atmosphere. The reac-
tion mixture was brought to room temperature slowly and further
stirred for 12 h. Upon completion of the reaction (monitored by
TLC), the solvent was evaporated under reduced pressure and the
residue was washed with NaHCO3. Purification of the residue by
column chromatography afforded 17 (2.771 g, 93%) as a brown
solid. Rf = 0.6 (silica gel; hexane/EtOAc, 60:40); [α]2D5 = 38.67 (c =
0.60, CHCl3). 1H NMR(400 MHz, CDCl3): δ = 7.38–7.28 (m, 5 H),
4.02–3.98 (q, J = 16.0 Hz, 1 H), 3.80–3.78 (d, J = 12.0 Hz, 1 H),
3.50–3.45 (t, J = 20.0 Hz, 1 H), 3.08–3.06 (d, J = 8.0 Hz, 2 H),
2.82–2.79 (d, J = 12.0 Hz, 1 H), 2.57–2.48 (m, 2 H),1.92 (s, 1 H),
1.47–1.45 (t, J = 12.0 Hz, 1 H), 1.20 (s, 4 H), 1.10–1.04 (m, 2 H),
0.84 (s, 3 H), 0.74 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 173.0, 137.2, 131.7, 129.6, 128.2, 127.9, 127.1, 66.2, 60.2, 58.4,
51.2, 48.6, 48.0, 45.8, 42.9, 35.4, 26.5, 21.8, 20.8, 14.1, 11.4 ppm.
53.7, 46.0, 32.8, 29.0, 25.2, 24.9 ppm. IR (KBr): ν = 3254, 3046,
˜
3030, 2980, 2904, 2854, 2794, 1605, 1512, 1446, 1347, 1309, 1254,
1150, 1128, 1084, 1073, 1052, 1002, 827, 756 cm–1. HRMS (ESI):
m/z calcd. for C15H22N2 [M + H+] 230.1783; found 231.1861.
tert-Butyl 4-Benzyl-5,9,9-trimethyl-octahydro-5,8-methanoquinazol-
ine-1-carboxylate (16): To a solution of chiral camphanylpiperazine
14 (1.940 g, 10 mmol) in CH2Cl2 (100 mL), di-tert-butyldicar-
bonate (2.2 mL, 10 mmol) was added at 0 °C slowly (for 10 min)
by using a syringe under an N2 atmosphere. The reaction mixture
was brought to room temperature slowly and further stirred for
6 h. Upon completion of the reaction (monitored by TLC), the
solvent was evaporated under reduced pressure. Purification of the
residue by column chromatography on silica gel (100–200 mesh;
hexane/EtOAc, 50:50) afforded tert-butyl 5,9,9-trimethyl-octahy-
dro-5,8-methanoquinzoline-1-carboxylate 15 (2.941 g, 10 mmol) as
a colorless viscous liquid. To a solution of 15 (2.941 g, 10 mmol)
in anhydrous acetonitrile (30 mL) was added benzyl bromide
IR (KBr): ν = 3314, 3079, 3062, 3024, 2947, 2887, 2739, 1610, 1577,
˜
1445, 1402, 1237, 1160, 1122, 1023, 793 cm–1. HRMS (ESI): m/z
(0.83 mL, 7 mmol), K2CO3 (1.79 g, 13 mmol), and KI (0.498 g), calcd. for C19H26N2O [M + H+] 298.2045; found 299.2123.
6074
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6067–6076

Synthesis of Chiral Propargylamines, Piperazines, and Allenes
1-Benzyl-5,9,9-trimethyl-decahydro-5,8-methanoquinazoline (4d): To
a suspension of NaBH4 (1.9 g, 50 mmol) in THF (50 mL) was
added a solution of I2 (6.32 g, 25 mmol) in THF (40 mL) at 0 °C
under an N2 atmosphere over 30 min. Imide 17 (2.98 g, 10 mmol)
was added to the generated diborane and the mixture was heated
to reflux for 24–36 h. The reaction was brought to room tempera-
ture and quenched with methanol. The solvents were evaporated
and the residue was heated to reflux with 10 n KOH for 6 h. The
mixture was extracted with CH2Cl2 (2ϫ 30 mL) and the combined
organic extract was evaporated to obtain decahydroquinazoline 4d.
The crude amine 4d was purified by chromatography to give 4d
(2.215 g, 78%) as a yellow liquid; Rf = 0.4 (silica gel; hexane/
substituted allenes are given in the Supporting Information (Tables
SI-1 to SI-3).
X-ray Crystallography: X-ray reflections (for 18aej) were collected
with an Oxford CCD X-ray diffractometer (Yarnton, Oxford, UK)
equipped with a Cu-Kα radiation (λ = 1.5406 Å) source. Data re-
duction was performed using the CrysAlisPro 171.33.55 software.
The crystal structure was solved and refined by using Olex2-1.0
with anisotropic displacement parameters for non-H atoms.
Hydrogen atoms were experimentally located through the Fourier
difference electron density map. All C–H atoms were geometrically
fixed by using the HFIX command in the SHELX-TL program of
Bruker-AXS. A check of the final CIF file by using PLATON did
not show any missed symmetry. CCDC-1008592 (for 18aej), con-
tains the 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.
EtOAc, 50:50); [α]2D5
=
18.94 (c
=
0.46, CHCl3). 1H
NMR(400 MHz, CDCl3): δ = 7.31–7.24 (m, 3 H), 4.19–4.16 (d, J
= 12.0 Hz, 1 H), 3.03–3.01 (m, 1 H), 2.91–2.88 (d, J = 12.0 Hz, 1
H), 2.69–2.63 (m, 2 H), 2.11–2.06 (m, 2 H), 1.76 (m, 1 H), 1.64–
1.58 (m, 1 H), 1.54 (s, 3 H), 1.26 (s, 2 H), 0.95 (s, 3 H), 0.85 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 139.2, 128.8, 128.1,
126.8, 97.0, 59.2, 48.8, 48.1, 47.1, 46.6, 41.6, 36.4, 29.7, 26.5, 22.6,
Supporting Information (see footnote on the first page of this arti-
1
cle): Chiral HPLC analysis data, H and 13C NMR spectra for all
new compounds.
20.7, 12.1 ppm. IR (neat): ν = 3377, 3030, 2955, 2879, 2802, 2752,
˜
2687, 2310, 1653, 1604, 1483, 1452, 1388, 1265, 1143, 1109, 1072,
1010, 895 cm–1. HRMS (ESI): m/z calcd. for C19H28N2 [M + H+]
284.2252; found 285.2331.
Acknowledgments
General Procedure for the Preparation of Chiral Propargylamines:
To a 25 mL reaction flask was added ZnCl2 (0.014 g, 10 mol-%),
chiral piperazine 4a–d (1 mmol), 1-alkyne 5 (1.1 mmol), and alde-
hyde 6 (1 mmol) in toluene (3 mL), and the mixture was heated to
100 °C for the given time. The reaction mixture was the brought to
room temperature and, after evaporation of the toluene, the residue
was purified by chromatography on silica gel (100–200 mesh; hex-
ane/ethyl acetate) to obtain the chiral propargylamines 18.
The authors are thankful to the Department of Science and Tech-
nology (DST), New Delhi for a J. C. Bose National Fellowship
(grant to M. P.) and for the support to the School of Chemsitry
under the FIST and IRPHA programs. Support by the University
Grants Commission (UGC) (UPE and CAS programs) is also
gratefully acknowledged. P. O. R., A. E., M. D., L. M. A., and
B. U. K. thank the Council of Scientific and Industrial Research
(CSIR), New Delhi and UGC for research fellowships.
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NMR(400 MHz, CDCl3): δ = 7.83 (s, 1 H), 7.59–7.57 (d, J =
7.4 Hz, 2 H), 7.37–7.21 (m, 10 H), 7.15–7.11 (m, 5 H), 6.92 (s, 1
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= 9.0 Hz, 1 H), 2.90–2.86 (d, J = 13.4 Hz, 2 H), 2.78–2.73 (t, J =
23.1 Hz, 1 H), 2.45–2.38 (m, 3 H), 2.32–2.26 (t, J = 22.7 Hz, 1 H),
1.69–1.58 (m, 4 H), 1.40–1.35 (m, 8 H), 0.91–0.94 (t, J = 13.1 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.2, 140.4, 129.4,
129.1, 128.4, 128.1, 127.9, 126.4, 125.4, 124.8, 122.9, 88.5, 75.1,
73.0, 65.8, 63.5, 57.9, 50.6, 50.2, 48.2, 47.2, 42.9, 36.4, 34.6, 31.8,
31.6, 29.3, 29.1, 29.0, 28.9, 26.2, 25.2, 22.2, 21.0, 18.7, 14.1,
13.8 ppm. IR (neat): ν = 3084, 3062, 3029, 2953, 2925, 2854, 2799,
˜
1604, 1489, 1451, 1330, 1270, 1111, 1073, 1029, 914, 859, 766 cm–1.
HRMS (ESI): m/z calcd. for C40H46N2 [M + H+] 554.3661; found
555.3740. The data for the propargylamine derivatives are given in
the Supporting Information.
General Procedure for the Synthesis of Chiral Allenes from Chiral
Propargylamines 18: Chiral propargylamine (1 mmol) was added
to a stirred suspension of ZnBr2 (0.113 g, 0.5 mmol) in anhydrous
toluene (3 mL) and the mixture was heated for 1–2 h at 120 °C
under a nitrogen atmosphere. The mixture was brought to room
temperature and toluene was removed under reduced pressure. The
crude product was purified on silica gel (100–200 mesh; hexane) to
isolate the chiral allenes 7. The spectroscopic data (see the Support-
ing Information) are consistent with reported data.[10a] The optical
rotation values reported are for freshly prepared samples (see the
Supporting Information). Details on the variation of optical rota-
tion values for aryl-substituted allenes and the NMR spectroscopic
data for mixtures of cyclodimerized products formed from aryl-
Eur. J. Org. Chem. 2014, 6067–6076
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6075

M. Periasamy et al.
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Received: June 17, 2014
Published Online: August 6, 2014
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Eur. J. Org. Chem. 2014, 6067–6076