Chirality memory of α-methylene-π-allyl iridium species

Article abstract of DOI:10.1039/d1sc02636d

Chirality is one of the most important types of steric information in nature. In addition to central chirality, axial chirality has been catching more and more attention from scientists. However, although much attention has recently been paid to the creation of axial chirality and the chirality transfer of allenes, no study has been disclosed as to the memory of such an axial chirality. The reason is very obvious: the chiral information is stored over three carbon atoms. Here, the first example of the memory of chirality (MOC) of allenes has been recorded, which was realizedviaan optically active alkylidene-π-allyl iridium intermediate, leading to a highly stereoselective electrophilic allenylation with amines. Specifically, we have established the transition metal-mediated highly stereoselective 2,3-allenylation of amines by using optically active 2,3-allenyl carbonates under the catalysis of a nonchiral iridium(iii) complex. This method is compatible with sterically bulky and small substituents on both amines and 2,3-allenyl carbonates and furnishes the desired optically active products with a high efficiency of chirality transfer. Further mechanistic experiments reveal that the isomerization of the optically active alkylidene-π-allyl iridium intermediate is very slow.

Full text of DOI:10.1039/d1sc02636d

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Chirality memory of a-methylene-p-allyl iridium
species†
Cite this: DOI: 10.1039/d1sc02636d
ab
Yifan Cui,ab Yizhan Zhai,‡ab Junzhe Xiao,
‡
Can Li,‡ab Wei-Feng Zheng,‡c
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Chaofan Huang,‡c Guolin Wu,‡c Anni Qin,‡c Jie Lin,‡c Qi Liu,‡ab Huanan Wang,‡c
Penglin Wu,‡c Haibo Xu,‡ab Yangguangyan Zheng ‡c and Shengming Ma
ac
*
Chirality is one of the most important types of steric information in nature. In addition to central chirality,
axial chirality has been catching more and more attention from scientists. However, although much
attention has recently been paid to the creation of axial chirality and the chirality transfer of allenes, no
study has been disclosed as to the memory of such an axial chirality. The reason is very obvious: the
chiral information is stored over three carbon atoms. Here, the first example of the memory of chirality
(MOC) of allenes has been recorded, which was realized via an optically active alkylidene-p-allyl iridium
intermediate, leading to a highly stereoselective electrophilic allenylation with amines. Specifically, we
have established the transition metal-mediated highly stereoselective 2,3-allenylation of amines by using
optically active 2,3-allenyl carbonates under the catalysis of a nonchiral iridium(III) complex. This method
is compatible with sterically bulky and small substituents on both amines and 2,3-allenyl carbonates and
furnishes the desired optically active products with a high efficiency of chirality transfer. Further
mechanistic experiments reveal that the isomerization of the optically active alkylidene-p-allyl iridium
intermediate is very slow.
Received 13th May 2021
Accepted 20th July 2021
DOI: 10.1039/d1sc02636d
rsc.li/chemical-science
Results
Introduction
Optimization of reaction conditions
Memory of chirality (MOC) is a topic of ever-lasting interest in
the storage/transmission of steric information, chiral recogni-
tion, and asymmetric syntheses.1 In addition to enolate chem-
istry,2 some examples of transition-metal catalyzed
stereospecic functionalizations of optically active allylic
derivatives have been recorded.3 However, reports on the
memory of chirality of a-alkylidene-p-allyl metallic species are
very limited: the rapid racemization of such chiral intermediate
via s–p–s-rearrangements has been reported by Tsukamoto
(Scheme 1a).4 Herein, we wish to report the observation of an
excellent memory of chirality (MOC) in the highly stereo-
selective reaction of optically active allenylic methyl carbonates
with amines affording 2,3-allenylic amines in high ee via a-
alkylidene-p-allyl iridium species (Scheme 1b).
In the beginning, due to the importance of amines,5 we were
studying the synthesis of racemic 2,3-allenyl amines. Aer trial
and error, we observed some very attractive results with iridium-
catalysis for the allenylation of benzylamine 2a with racemic
methyl dodeca-2,3-dienyl carbonate 1a. With [Ir(COD)Cl]2 as the
catalyst, a variety of phosphine ligands was screened. PPh3 (Table
aState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, P. R.
China. E-mail: masm@sioc.ac.cn; masm.fudan.edu.cn
bUniversity of Chinese Academy of Sciences, Beijing 100049, P. R. China
cResearch Center for Molecular Recognition and Synthesis, Department of Chemistry,
Fudan University, 220 Handan Road, Shanghai 200433, P. R. China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1sc02636d
Scheme 1 Reaction of optically active a-alkylidene-p-allylic metallic
species.
‡ These authors contributed equally.
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Table 1 Screening of Ir catalysta
Entry
Ligand (mmol%)
Yield of 3aab (%)
Yield of 4ab (%)
Recovery of 1ab (%)
1
2
3
4
5
6
7
8
PPh3 (7)
13
2
2
1
85
95
99
96
97
99
100
99
100
99
—
dppm (3.5)
DPEphos (3.5)
P(OPh)3 (7)
dppe (3.5)
dppp (3.5)
dppf (3.5)
dppbe (3.5)
Xantphos (3.5)
BINAP (3.5)
Ir pre-catalyst A (3.5)
—
—
—
—
—
—
—
—
—
25
1
—
—
—
—
—
—
26
9
10
11
a
The reaction was conducted using 1a (0.2 mmol) and BnNH2 (0.3 mmol) in 0.4 mL of THF. b Determined by 1H NMR analysis of the crude reaction
mixture using 1,3,5-trimethylbenzene as an internal standard.
1, entry 1) afforded a 13% yield of 3aa, 1% of bis-allenylation expected, the loading of benzylamine greatly affected the
product 4aa, and 85% recovery of 1a. Further screening of selectivity of 3aa/4aa: the addition of 4 equiv. of benzylamine
other phosphine ligands led to poor results (Table 1, entries 2– provided 41% of 3aa, 6% of 4aa, and 38% recovery of 1a (Table
10). To our delight, the utilization of a known cationic Ir(III) pre- 2, entry 4). By running the reaction at 50 ꢀC, the yield was
catalyst A developed by Hartwig and co-workers6 yielded 26% of improved to 70% and no recovery of 1a was detected (Table 2,
3aa and 25% of 4aa with no recovery of 1a (Table 1, entry 11).
entry 7). The reaction at a higher temperature resulted in an
Further optimization was focused on the selectivity of 3aa/ erosion of yield (Table 2, entry 8).
4aa. We rstly increased the amount of Ir pre-catalyst A to
The reactions in other ethers (Table 3, entries 1–3) and
7 mol%, but no improvement was observed (Table 2, entry 2). As chlorinated solvents (Table 3, entries 4 and 5) led to a lower
Table 2 Optimization of reaction conditions for Ir-catalyzed reaction of racemic allenyl carbonate 1a with benzylamine 2aa
Entry
n
T/ꢀC
Yield of 3aab (%)
Yield of 4aab (%)
Recovery of 1ab (%)
1
1.5
1.5
2
4
4
4
4
4
r.t.
r.t.
r.t.
r.t.
r.t.
40
26
24
35
41
45
64
70
65
25
27
28
6
7
8
—
—
—
38
45
11
—
—
2c
3
4
5d
6d
7d
8d
50
60
8
9
a
The reaction was conducted using 1a (0.2 mmol) in 0.4 mL of THF. b Determined by 1H NMR analysis of the crude reaction mixture using 1,3,5-
trimethylbenzene as an internal standard. c 7 mol% Ir pre-catalyst A was used. d The reaction was conducted using 1a (0.2 mmol) in 1.0 mL of THF.
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Table 3 Solvent effecta
Entry
Solvent
Yield of 3aab (%)
Yield of 4aab (%)
Recovery of 1ab (%)
1
2
3
4
5
6
7
8
Ethyl ether
DME
MTBE
DCM
DCE
MeCN
DMF
DMSO
Toluene
THF
54
64
57
50
51
50
35
19
70
70
71d
15
10
13
17
18
18
21
—
9
3
—
—
—
—
—
—
53
—
—
—
9
10
8
9
11c
THF
a
The reaction was conducted using 1a (0.2 mmol) and BnNH2 (0.8 mmol) in 1.0 mL of THF. b Determined by 1H NMR analysis of the crude reaction
mixture using 1,3,5-trimethylbenzene as an internal standard. c The reaction was conducted using allene 1a (1.0 mmol), BnNH2 (4.0 mmol) in 5 mL
of THF. d Isolated yield.
selectivity of 3aa/4aa. Increasing the polarity of aprotic solvents 3pw in 48% isolated yield at 60 ꢀC with 7 mol% Ir catalyst. 4,4-
displayed decreasing yields (Table 3, entries 6–8). Toluene Disubstituted allenyl carbonate 1q also worked to afford
provided a very similar yield and selectivity (Table 3, entry 9). product 3qf.
Scaling the reaction up to 1.0 mmol furnished similar results
A wide range of amines were also tested. Acyclic amines
with 3aa isolated in a 71% yield together with 9% of the bis- bearing different alkyl (2e, 2o, 2q, and 2r), phenyl (12, 5, 6, and
allenylation product (Table 3, entries 10 and 11). Thus, 1a (1 2r), benzyl (2a, 2f, 2k, and 2w), and synthetically useful func-
equiv.), 2a (4 equiv.), and Ir pre-catalyst A (3.5 mol%) in THF at tional groups, such as the allylic (2g and 2o), propargyl (2d and
50 ꢀC was dened as the optimized reaction conditions for 2u) and ester (2c) groups, all furnished the corresponding
further study.
products 3be, 3go, 3iq, 12, 5, 6, 3ir, 3xr, 3aa, 3ga, 3vf, 3wf, 3mf,
3oa, 3pw, 3ag, 3go, 3bd, 3mu, and 3bc in moderate to quan-
titative yields (48–99%). Tryptamine 2j, which contains 3
potential reaction sites, was detected to be allenylated exclu-
sively on the primary amino group as judged by 1H NMR
analysis of the crude product(s). Under standard reaction
conditions, it is not necessary to protect the hydroxyl group
(2k) to afford product 3dk.
Cyclic amines act as widespread skeletons in drug molecules
and natural products. Cyclic amines, such as morpholine 2b,
pyrrolidine 2m, pyrroline 2t, piperidine 2i, piperazine 2h,
1,2,3,6-tetrahydropyridine 2s, tetrahydroisoquinoline (2l and
2p), and tetrahydroquinoline 2v, may all be modied with the
allene unit furnishing the desired products 3bb, 3lb, 3fm, 3im,
3kt, 3ci, 3ah, 3js, 3el, 3hp, 3ol, and 3ov smoothly in 52–96%
yields. Quaternary amine hydrochlorides exist widely in medical
and pharmaceutical science due to their superior water solu-
bility, absorption, and ease of formulation. Both nortropinone
(2x) and 4-piperidinone (2y) furnished the desired products 3tx
and 3uy in the presence of NaHCO3. Hydroxylamine hydro-
chloride 2z could also be allenylated, affording bis-allenylation
product 4uz.
Allenylation of amines
With the optimal conditions in hand, diverse 2,3-allenyl
carbonates and amines were investigated to demonstrate the
scope of this reaction (Scheme 2). Terminal 2,3-allenyl carbon-
ates showed slightly lower reactivities (products 3bb–3be) (part
I). 4-Mono-substituted 2,3-allenyl carbonates were then exam-
ined (part II): R1 may be a 1ꢀ-alkyl group, such as n-C8H17 (1a), n-
C5H11 (1d), n-C6H13 (1t), or a 2ꢀ-alkyl group, i-Pr (1e) and Cy (1f),
smoothly affording products 3aa, 3af, 3ag, 3ah, 12, 3tx, 3dj, 3dk,
3el, 3fm, and 3fn with the corresponding amines. Benzoxy (1c)
and phenyl group (1u) were tolerated (products 3ci, 3uy, and
4uz).
4-Aryl-2,3-allenyl carbonates were next exposed to the opti-
mized reaction conditions (part III): 4-phenyl-2,3-allenyl
carbonate 1g furnished a similar result as compared with 1a
(product 3ga). Substrates with a wide range of functional
groups, such as p-Me (1h), m-OMe (1i), p-F (1j), p-Cl (1k), p-Br
(1l), p-COOMe (1v), p-CF3 (1w), and p-CN (1x), all exhibited
a decent reactivity under the standard conditions (products
3hp, 3im–3ir, 3js, 3kt, 3lb, 3vf, 3wf, and 3xr). 2-Naphthyl (1m)
and 3-thienyl (1o) were also accommodated to afford the target
products 3mf, 3mu, 3ov, and 3oa in 61–90% yields; 3-furyl
substituted allenyl carbonate 1p turned out to be less reactive
and reacted with p-methoxybenzylamine 2w to yield product
In order to demonstrate the scope of the current Ir-catalyzed
2,3-allenylation reaction, we applied this strategy for the late-
stage modication of drug molecules and derivatives of
natural products (part IV). Two commercial drugs for cancer
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Scheme 2 Substrate scope of Ir-catalyzed 2,3-allenylation of amines. Standard conditions: Ir pre-catalyst A (3.5 mmol%), allene (1.0 mmol) and
amine (4.0 mmol) in 5 mL of THF. a5.3 mol% Ir pre-catalyst A was used. b32% of 1b was recovered. c10% of 1b was recovered. d9% NMR yield of
4aa. e5.3 mol% Ir pre-catalyst A was used and the reaction was conducted at 60 ꢀC. f17% NMR yield of 4dk. g7% NMR yield of 4fn. hThe reaction
was conducted using allene (1.0 mmol), amine$HCl (1.2 mmol), and NaHCO3 (1.2 mmol) in 5 mL of THF. i7 mol% Ir pre-catalyst A was used. jThe
reaction was conducted using allene (1.0 mmol), NH2OH$HCl (4.0 mmol), and NaHCO3 (4.0 mmol) in 5 mL of THF and 6% NMR yield of 3uz was
detected. k6% NMR yield of 4ga was detected. l15% of 1o was recovered and 3% NMR yield of 4oa was detected. m7 mol% Ir pre-catalyst A was
used and the reaction was conducted at 60 ꢀC.
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treatment, Getinib and Erlotinib,7 could be directly modied
with an allene unit (products 7 and 8). Furthermore, the ATA
reaction8 of (Æ)-citronellal and cholesterol with propargyl
alcohol conveniently gave the desired allenols, which were
treated with chloroformate to afford the carbonates 1r and 1s.
Subsequent Ir-catalyzed reactions with tetrahydroisoquinolines
and desloratadine9 afforded 2,3-allenyl amines for 3rl, 9, and
3sp with 85–90% yields.
(1)
Encouraged by this result, we further examined the scope of
memory of chirality (Scheme 3). For 4-alkyl-substituted allenyl
carbonate (S)-1a, reactions afforded (S)-3aa in 71% yield and
98% es on a gram-scale with benzylamine 2a and (S)-12 in 85%
yield and 95% es with 4-ethoxycarbonyl aniline, respectively.
The more sterically hindered (S)-1f yielded (S)-3fn in 95% es.
Various 4-aryl-2,3-allenyl carbonates were next investigated:
different substituents on benzene ring, including F ((S)-1j), Cl
((S)-1k), and Br ((S)-1l), were intact under the reaction condi-
tions (products (S)-3js, (S)-3kt, and (S)-3lb). Different types of
acyclic (2a, 2n, 2o, and 2f) and cyclic amines (2s, 2t, and 2b)
showed little inuence on the yields and stereoselectivity.
Paroxetine hydrochloride, a drug used against depression and
social phobia,11 could also be modied with optically active 2,3-
allenyl carbonate ((S)-1d) efficiently to afford the desired
product (Sa,S,R)-10 in high es. Late-stage modication of opti-
cally active derivatives of natural products, (S)-citronellal ((Sa)-
Memory of chirality
Nowadays, optically active 2,3-allenols are readily available from
the EATA reaction.10 Thus, aer unveiling the scope of this
protocol, we were anxious to investigate the memory of chirality
by applying optically active 2,3-allenyl carbonates. Our rst
attempt was the reaction of (S)-1m with dibenzylamine 2f at
room temperature with 3.5 mol% Ir pre-catalyst A (eqn (1)). The
target product could be obtained with 95% yield and an excel-
lent efficiency of chirality transfer (99% es), i.e., the axial
chirality of the allene unit was passed to the axial chirality in the
allenylic amines. To our knowledge, this is the rst example of
such transition metal-involved chirality memory.
Scheme 3 Ir-catalyzed 2,3-allenylation of optically active 2,3-allenyl carbonates with amines. Reaction procedure: to a flame-dried Schlenk
tube (25 mL) were added Ir pre-catalyst A (0.035 mmol)/THF (3 mL), amine (4.0 mmol)/THF (1 mL), and allene (1.0 mmol)/THF (1 mL) sequentially
under an Ar atmosphere. The resulting mixture was stirred at r.t. aEnantioselectivity of the transformation based on the ee of the staring material.
bThe reaction was conducted using allene (6.0 mmol) and amine (24.0 mmol) in 30 mL of THF at 40 ꢀC with a 10% NMR yield of (S,S)-4aa. cThe
reaction was conducted at 0 ꢀC. d8% NMR yield of (S,S)-4fn was detected.e The reaction was conducted using (S)-1d (1.0 mmol),
paroxetine$HCl$21 H2O (1.2 mmol), and NaHCO3 (1.2 mmol) in 10 mL of THF.
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1r) and cholesterol ((Sa)-1s), were sequentially performed, decarboxylation product, 2,3-allenyl methyl ether 11 was also
furnishing the corresponding products (Sa)-3rl and (Sa)-3sp generated with the same level of ee as compared to that of (S)-
smoothly in high yields and excellent d.r. (Scheme 3).
3mf. It is notable that the treatment of (S)-1m with 27% of pre-
catalyst A for 12 h followed by the addition of dibenzylamine
still formed (S)-3mf in 74% ee, which may be attributed to the
much slower rate of racemization (Scheme 4b). Malcolmson
et al.13 had reported that the rapid racemization of optically
active 2,3-allenyl amine happened even in the presence of
a chiral palladium catalyst (Scheme 4c and d). However, the
treatment of the optically active product (S)-3mf under the
standard reaction conditions did not lead to racemization
(Scheme 4e). Moreover, no racemization of (S)-3mf or genera-
tion of (S)-3mr was observed in the scrambling experiment,
indicating that the nucleophilic attack of amine is irreversible
under the current Ir-catalyzed reaction conditions (Scheme 4f).
Based on the mechanistic experiments, a catalytic cycle is
proposed as shown in Scheme 5. At rst, the oxidative addition
Mechanistic studies
The absolute conguration of (S)-3mf was conrmed by
preparing this same product by following a known procedure.12
To gain insight into the mechanism, a series of experiments was
carried out.
Firstly, we le a period of time for the racemization of the
optically active alkylidene-p-allyl iridium intermediate as (S)-
1m was treated with different amounts of Ir pre-catalyst A for as
long as 12 h followed by the addition of the nucleophile
dibenzylamine 2f. As showed in Scheme 4a, the level of race-
mization is linear with the loading of the Ir pre-catalyst A. With
the increased loading of the Ir pre-catalyst A, the
Scheme 4 Mechanistic studies. The reaction procedure for the data in (a): to a flame-dried Schlenk tube were added Ir pre-catalyst A (x mol%)/
THF (1.5 mL), and (S)-1m (0.5 mmol)/THF (0.5 mL) sequentially under an Ar atmosphere. The resulting mixture was stirred at room temperature
for 12 h. Dibenzyl amine 2f (2.0 mmol)/THF (0.5 mL) were then added sequentially under an Ar atmosphere. The resulting mixture was stirred at
room temperature.
Scheme 5 Proposed catalytic cycle.
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of Ir(I)-h2-(S)-1 I leads to the formation of optically active alky-
lidene-p-allyl Ir(III) II, accompanied by the release of a carbonate
anion. The chirality is memorized in this intermediate since the
isomerization to form the allylic Ir intermediate V is very slow.
The subsequent irreversible attack of amine results in the
formation of Ir(I)-h2-2,3-allenyl aminylium ion III, which is
much faster than the attack of methoxy in the carbonate anion
aer releasing carbon dioxide. The subsequent coordination of
another (S)-1 with Ir(I) in III regenerates I and releases the 2,3-
allenyl ammonium ion VI to complete the catalytic cycle. With
the aid of a carbonate anion, the nal product (S)-3 could be
afforded by the deprotonation of VI, accompanied by the release
of carbon dioxide and methanol.
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Conclusions
In conclusion, although racemizations of the optically active
alkylidene-p-allylic transition metal complexes are very
common, leading to the erasure of the chiral information in the
starting materials and have been extensively applied to the
asymmetric syntheses of optically active allenes,14 we have
recorded here the rst example of chirality memory involving
alkylidene-p-allylic transition metal species and developed
a robust highly stereoselective approach for asymmetric allene
synthesis. Such a chirality memory involving iridium will be
critical for the storage and transmission of the axial chirality in
optically active allenols, which are readily available from prop-
argylic alcohols and aldehydes. Further studies with other
nucleophiles in this area are being actively pursued in our
laboratory.
Data availability
The ESI† include experimental details, specic rotation data,
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of the experiments, contributed equally to this work. Y. C. and
S. M. checked the experimental data. Y. C. and S. M. wrote the
manuscript with contributions from the other authors.
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Conflicts of interest
6 S. T. Madrahimov, Q. Li, A. Sharma and J. F. Hartwig, J. Am.
Chem. Soc., 2015, 137, 14968.
There are no conicts to declare.
7 W. D. Travis, E. Brambilla, M. Noguchi, A. G. Nicholson,
K. R. Geisinger, Y. Yatabe, D. G. Beer, C. A. Powell,
G. J. Riely, P. E. Van Schil, K. Garg, J. H. M. Austin,
H. Asamura, V. W. Rusch, F. R. Hirsch, G. Scagliotti,
Acknowledgements
Financial support from National Natural Science Foundation of
China (Grant No. 21690063 & 21988101) is greatly appreciated.
© 2021 The Author(s). Published by the Royal Society of Chemistry
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