Chiral Br?nsted Acid Catalyzed Dynamic Kinetic Asymmetric Hydroamination of Racemic Allenes and Asymmetric Hydroamination of Dienes

Article abstract of DOI:10.1002/anie.201900955

The first highly efficient and practical chiral Br?nsted acid catalyzed dynamic kinetic asymmetric hydroamination (DyKAH) of racemic allenes and asymmetric hydroamination of unactivated dienes with both high E/Z selectivity and enantioselectivity are described herein. The transformation proceeds through a new catalytic asymmetric model involving a highly reactive π-allylic carbocationic intermediate, generated from racemic allenes or dienes through a proton transfer mediated by an activating/directing thiourea group. This method affords expedient access to structurally diverse enantioenriched, potentially bioactive alkenyl-containing aza-heterocycles and bicyclic aza-heterocycles.

Full text of DOI:10.1002/anie.201900955

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Angewandte
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International Edition
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Accepted Article
Title: Chiral Brønsted Acid-Catalyzed Dynamic Kinetic Asymmetric
Hydroamination of Racemic Allenes and Asymmetric
Hydroamination of Dienes
Authors: Xin-Yuan Liu, Jin-Shun Lin, Tao-Tao Li, Guan-Yuan Jiao,
Qiang-Shuai Gu, Jiang-Tao Cheng, and Ling Lv
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201900955
Angew. Chem. 10.1002/ange.201900955
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10.1002/anie.201900955
Angewandte Chemie International Edition
COMMUNICATION
Chiral Brønsted Acid-Catalyzed Dynamic Kinetic Asymmetric
Hydroamination of Racemic Allenes and Asymmetric
Hydroamination of Dienes
Jin-Shun Lin+, Tao-Tao Li +, Guan-Yuan Jiao+, Qiang-Shuai Gu, Jiang-Tao Cheng, Ling Lv, and Xin-
Yuan Liu*
Abstract: The first highly efficient and practical chiral Brønsted acid-
catalyzed dynamic kinetic asymmetric hydroamination (DyKAH) of
racemic allenes and asymmetric hydroamination of unactivated
dienes with both high E/Z selectivity and high enantioselectivity are
described herein. The transformation proceeds through a new
catalytic asymmetric model involving a highly reactive π-allylic
carbocationic intermediate, generated from racemic allenes or
dienes through a proton transfer mediated by an activating/directing
thiourea group. This method affords expedient access to structurally
diverse enantioenriched, potentially bioactive alkenyl-containing
azaheterocycles and bicyclic azaheterocycles.
highly desirable.
a) Gold(I)-catalyzed dynamic kinetic asymmetric hydroamination of allenes (Widenhoefer, 2007)
Cbz
NHCbz
NHCbz
AuL*
N
L*•[Au2Cl2]
AgX
Me
Ph
Ph
Ph
Ph
R1
Me
Me
Ph
Ph
R1
R1
Z/E 2.0:1~10.1:1
ee 75%~96%
racemic allenes
L* = (S)-3,5-t-Bu-4-MeO-MeOBIPHEP
b) Asymmetric hydroamination of dienes and allenes catalyzed by chiral dithiophosphoric acid (Toste, 2011)
R2
O
S
R2
R2
R2
14 examples
Z/E 3.6:1~1:4.7
yield 67~99%
ee 83~97%
N
H
P
O
N
H
N
H
O
O
SH
N
P
or
S
H
S
prochiral
dienes
prochiral
allenes
c) This work: Brønsted acid-catalyzed dynamic kinetic asymmetric hydroamination (DyKAH) of
racemic unactivated allenes and asymmetric hydroamination of unactivated dienes
R3
N
H
Dynamic kinetic asymmetric transformations (DyKATs) are a
versatile and step-economical strategy for the synthesis of
enantioenriched products with concomitant increase in
molecular complexity from readily available racemic starting
materials in a single step.[1] Over the past few decades, the
synthetic advantages of DyKATs have been well demonstrated
using racemic substituted allenes. Due to the intriguing features
of the two cumulated C=C bonds and the peculiar axial chirality,
racemic substituted allenes are highly valuable synthetic
precursors for the straightforward synthesis of complex
molecules.[2] In this field, several elegant transition-metal-
catalyzed DyKATs of racemic unactivated allenes have been
developed via the activation of the allenyl moiety through
transition-metal coordination.[3] In sharp contrast, although
asymmetric hydroamination of unactivated C=C bonds in
alkenes, allenes, and dienes have been widely developed as an
efficient way to prepare enantioenriched amines,[4] dynamic
kinetic asymmetric hydroamination (DyKAH) that employ
racemic allenes as substrates remain exceedingly scarce.[3b, 3e, 5]
In this aspect, only Widenhoefer et al. have reported a gold-
catalyzed DyKAHs of racemic trisubstituted allenes to form 2-
vinyl pyrrolidine products with unsatisfactory Z/E ratios
(2.0:1~10.1:1) (Figure 1a).[3b] Thus, the design and invention of
conceptually different catalytic systems, especially with
organocatalysts for DyKAHs of racemic unactivated allenes is
CH3
Ar
O
N
R4
O
R3
P
R3
N
O
racemic allenes
H
CH3
R4
N
N
S
O
Brønsted
acid
or
CH3
R4
R4
CH3
dienes
H
H
R3
N
27 examples
ee 85%~96%
E/Z > 20:1
allyl cation/N-anion pair
enantioenriched
bicyclic
azaheterocycle
H
R4
yield 52%~91%
Figure 1. Dynamic kinetic asymmetric hydroamination (DyKAH) of racemic
unactivated allenes and asymmetric hydroamination of unactivated dienes
Chiral Brønsted acid, such as chiral phosphoric acid (CPA),
has recently evolved into a fundamentally significant tool for
asymmetric catalysis.[6] Nevertheless, the activation of
unactivated C=C bonds by a chiral Brønsted acid for nucleophilic
attack[7] has been impeded by its inherently low basicity, and
only recently have List’s[7d] and our groups[7c] independently
disclosed highly enantioselective hydrofunctionalizations of
unactivated alkenes using chiral imidodiphosphorimidate and
phosphoric acid catalysts, respectively. Nonetheless, in this field,
organocatalytic hydroamination of allenes and dienes are still
long-standing challenges that remain largely unsolved.[8] To date,
only Toste et al. have reported enantioselective intramolecular
hydroamination of dienes and allenes in the presence of chiral
dithiophosphoric acids via a transient covalently bound chiral
leaving group on the allylic system for excellent stereoinduction
9]
(Figure 1b).[7b,
To address the challenges and inspired by
those advances in activating alkenes with CPA, we became
interested in developing an asymmetric Brønsted acid-catalyzed
hydroamination of C=C bonds. We hypothesized that a DyKAH
of racemic N-(γ-allenyl) species could be achieved through an
intramolecular proton transfer between an amine nucleophile
and a racemic allene in cooperation with CPA to generate a π-
allylic carbocationic intermediate, followed by an SN1-type C–N
bond formation to give the final azaheterocycle (Figure 1c). We
further anticipated that such a key allylic cationic intermediate
could also be generated from dienes catalyzed by chiral
Brønsted acid, which might offer a new catalytic asymmetric
[*] Dr. J.-S. Lin
State Key Laboratory of Chemical Oncogenomics, Key Laboratory of
Chemical Biology, Graduate School at Shenzhen, Tsinghua University,
Shenzhen, 518055, China.
Department of Chemistry, Tsinghua University, Beijing 100084, China.
Dr. J.-S. Lin, Dr. T.-T. Li, G.-Y Jiao, J.-T Cheng, L. Lv, Prof. Dr. X.-Y.
Liu
Department of Chemistry and Shenzhen Grubbs Institute, Southern
University of Science and Technology, Shenzhen 518055, China.
E-mail: liuxy3@sustech.edu.cn
Dr. Q.-S. Gu
Academy for Advanced Interdisciplinary Studies and Department of
Chemistry, Southern University of Science and Technology, Shenzhen
518055, China
4b, 7b, 9-10]
hydroamination of unactivated dienes (Figure 1c).[4a,
[+] These authors contribute equally to this work.
Supporting information for this article is given via a link at the end of
the document.
Given unique chemical properties of racemic unactivated allenes
as well as the intrinsic instability and the high reactivity of the
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10.1002/anie.201900955
Angewandte Chemie International Edition
COMMUNICATION
carbocationic intermediate, we envisioned several essential
challenges that have to be overcome to realize this strategy,[9, 11]
including: (a) how to efficiently generate the highly reactive π-
allylic carbocationic intermediate from racemic unactivated
allenes via a proton transfer catalyzed by CPA; (b) how to
promote the desired hydroamination reaction via the ion-pairing
asymmetric catalysis;[6d, 9, 12] (c) how to minimize the undesired
deprotonation to generate dienes that lack sufficient reactivity;[13]
(d) how to achieve good discrimination between the enantiotopic
that lowering the catalyst loading to 10 mol% led to a slight
decrease in yield and enantioselectivity (entry 16), and no
desired product was detected in the absence of the CPA catalyst
(entry 17).
Table 2. Optimization of the reaction conditions for allene substrates[a,b,c,d]
faces of this π-allylic carbocation via electrostatic interactions
6h, 7d, 11b, 14]
that lack rigidity in the association.[6g,
Herein, we
disclose the first chiral Brønsted acid-catalyzed DyKAH of
racemic unactivated allenes and asymmetric hydroamination of
unactivated dienes via ion-pairing asymmetric catalysis with
excellent stereoinduction. The newly developed catalytic
asymmetric hydroamination can deliver optically enriched
azaheterocycles, which are being intensely investigated due to
their high demand in the pharmaceutical industry (Figure S1 in
SI).[15]
Entry
1
2
3
4
5
6
7
8
CPA
Solvent
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
CHCl3
EtOAc
CH3CN
THF
PhCl
PhCl
Y(%)[b]
76
58
64
17
64
80
6
12
64
60
trace
trace
--[f]
78
E-3A/Z-3A(%)[c]
10:1
13:1
6:1
E-3A ee(%)[d]
(R)-A1
(R)-A2
(R)-A3
(R)-A4
(S)-A5
(S)-A6
(R)-A7
(R)-A8
(S)-A5
(S)-A5
(S)-A5
(S)-A5
(S)-A5
(S)-A5
(S)-A5
(S)-A5
--
−56
−79
−56
−2
83
66
17
33
75
56
To probe the feasibility of our hypothesis, we set out to
explore the effects of different N-protecting groups for their
potentials to efficiently participate in the Brønsted acid-catalyzed
DyKAH of racemic allenes in the presence of CPA in DCM
(Table 1).[7c] Various allene substrates containing free amine,
amide, and Ts-protected amine moieties failed to undergo the
desired DyKAH. Fortunately, the use of urea 1aa’ bearing two
N–H bonds as the nucleophile gave desired product 3AA in high
yield, albeit with moderate enantioselectivity and E/Z selectivity.
This proof-of-principle result encouraged us to further investigate
other urea analogues to improve the stereoselectivity.
Gratifyingly, the use of thiourea substrate 1a led to a remarkable
improvement in E/Z selectivity (10:1).
7:1
13:1
10:1
--[e]
--[e]
9
10:1
6:1
10
11
12
13
14
15[g]
16[g,h]
17[i]
--[e]
50
--[e]
1.3
--[f]
86
--[f]
20:1
20:1
20:1
--[f]
72
94
PhCl
PhCl
70
91
--[f]
--[f]
[a] Reactions were run on a 0.05 mmol scale in solvent (2.0 mL) at 25 °C for
48 h. [b] Yield based on 1H NMR analysis of the crude product. [c] Ratio of E-
3A/Z-3A was determined by 19F NMR analysis of the crude product. [d]
Measured by chiral HPLC analysis. [e] Ratio was not determined. [f] Product
was not detected. [g] 5 Å MS (50 mg) was used. [h] (S)-A5 (10 mol%) was
used. [i] No CPA catalyst.
Table 1. Evaluation of different protecting groups[a,b]
With the optimal reaction conditions being established, we
next explored the substrate scope of the DyKAH (Table 3). First,
various substrates with different N-aryl groups all reacted
smoothly to afford the corresponding products 3A–3C in 56–
74% yields with 90–94% ee and excellent E/Z selectivity. The
absolute configuration of 3A was determined to be S by X-ray
crystallography analysis (Figure S2 in SI).[16] Next, diverse N-(γ-
allenyl) thioureas bearing different substituents on the allenyl
aryl rings, including electron-withdrawing (F or Cl) or -donating
groups (OMe, Me, OPh, or vinyl) at different positions (meta or
para), were found to be suitable substrates and afforded the
expected products 3D–3L in 52–75% yields with outstanding E/Z
selectivity and enantioselectivity, showcasing the excellent
tolerance of substituents with distinct electronic properties.
Importantly, substrate 1h bearing a vinyl group that is often
reactive in transition-metal-mediated transformations was also
converted to the product 3H. Notably, the acetal group was
stable in the presence of the acidic catalyst despite the general
acid lability of this protecting group, and 3I was obtained in an
excellent result. Moreover, the protocol could be extended to an
achiral allene with two terminal methyl groups ， and the
expected product 3M (confirmed by X-ray study, Figure S3 in SI)
was obtained in a good result. Additionally, N-(γ-allenyl) urea
[a] Yields are based on 1H NMR analysis of the crude products and the E-3/Z-
3 ratio was determined by 1H NMR, [b] Ee values were determined based on
HPLC analysis.
To improve the stereoselectivity, we then screened various
SPINOL- and BINOL-derived CPAs (entries 2–8 in Table 2) and
found that (S)-A5 gave both high E/Z selectivity and
enantioselectivity (entry 5). A subsequent solvent screening
indicated that solvent had a significant influence on the reactivity
and stereoselectivity (entries 9–14), and PhCl was identified as
the most efficient solvent as it provided 3A with excellent
stereoselectivity (entry 14). The use of 5 Å molecular sieves as
an additive further enhanced the stereoselectivity and thus, it
gave the best result (entry 15). Further investigation revealed
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10.1002/anie.201900955
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COMMUNICATION
Table 4. Substrate scope of the asymmetric hydroamination of dienes[a,b,c,d]
was also well-tolerated to give the expected product 3AA. With
the broad substrate scope, this approach constitutes an
excellent alternative to the previously developed gold(I)-
catalyzed DyKAH of racemic unactivated allenes.
S
S
Ar
Ar1
R1
R1
Ar1
N
R1
R1
N
(S)-A5 (15 mol%)
N
N
H
O
O
H
H
P
H
O
OH
PhCl, 25 °C
Me
R2
Ar
Table 3. Substrate scope of the DyKAH of racemic allenes[a,b,c,d]
R2
(S)-A5: Ar = 1-Naphthyl
2
3, E/Z > 20:1
Substrate scope for Ar1
CF3
S
Ar
S
X
Ar1
Ph
Ph
S
S
Ar1
N
(S)-A5 (15 mol%)
Ph
Ph
N
O
O
O
N
H
N
H
H
P
N
5 Å MS, PhCl, 25 °C
S
Ph
Ph
N
N
X
OH
Ph
Ph
N
H
H
H
C
Me
H
H
Me
N
CF3
Ph
Ph
N
Ar
H
R1
3, E/Z > 20:1
R1
Me
Me
H
(S)-A5: Ar = 1-Naphthyl
1
Ph
Ph
Me
Substrate scope for substituents on the Ar1
3B, X = CF3, 91%, 96% ee (36 h)
3C, X = CN, 81%, 93% ee (24 h)
3N, X = Cl, 73%, 92% ee (120 h)[e]
3O, X = CF3, 84%, 93% ee (30 h)
3P, X = F, 55%, 91% ee (120 h)
Ph
CF3
X
S
3A, 92%, 96% ee (24 h)
S
N
Substrate scope for R1 and R2
Ph
Ph
N
CF3
H
N
CF3
Ph
Ph
N
CF3
CF3
H
H
S
H
Me
S
S
N
CF3
Ph
Ph
N
Me
Ph
H
N
CF3
N
CF3
N
Ph
Ph
N
3B, X = CF3, 56%,[e] 91% ee (120 h)
H
Ph
3A, 72%, 94% ee (48 h)
H
H
H
H
n
3C, X = CN, 74%, 90% ee (120 h)
Me
Me
Me
Substrate scope for substituents on the R1
CF3
CF3
Ph
Me
3M, 80%, 77% ee (72 h)
CF3
S
S
3Q, n = 1, 76%, 88% ee (12 h)
3R, n = 2, 78%, 91% ee (12 h)
3S, R3 = 4-OMe, 89%, 88% ee (12 h)
3T, R3 = 4-F, 88%, 90% ee (12 h)
3K, R3 = 4-Cl, 83%, 96% ee (12 h)
3F, R3 = 3-Cl, 66%, 96% ee (40 h)
S
N
CF3
Ph
N
N
H
CF3
Ph
Ph
N
H
N
CF3
Ph
Ph
Ph
N
H
H
H
H
Me
Me
Me
O
Me
Me
R2
O
[a] Reaction conditions: 2 (0.10 mmol) and (S)-A5 (15 mol%) in PhCl (4.0 mL)
at 25 °C. [b] Isolated yields. [c] E/Z ratio was determined by 1H NMR analysis
of the crude product. [d] Determined by chiral HPLC analysis. [e] Run at 30 °C.
R2
3I, 77%, 96% ee (48 h)[f]
3D, R2 = Me, E/Z = 16:1, 70%, 93% ee (24 h)
3E, R2 = OMe, 64%, 94% ee (24 h)
3F, R2 = Cl, 69%, 94% ee (96 h)
3G, R2 = F, 52%,[e] 93% ee (120 h)
3H, R2 = vinyl, 70%, 94% ee (72 h)
3J, R2 = Me, 72%, 94% ee (12 h)
3K, R2 = Cl, 75%, 96% ee (90 h)
3L, R2 = OPh, 72%, 85% ee (3 h)
furnish the corresponding products 3F, 3K and 3S–3T in 66–
89% yields with 88–96% ee. Additionally, it is striking to note
that substrate 2m possessing an allenyl methyl substituent was
also suitable for this reaction to give expected product 3M.
CF3
CF3
S
O
N
CF3
Ph
Ph
N
N
CF3
Ph
Ph
N
H
H
a
H
H
CF3
CF3
CF3
Me
Me
S
S
S
Me
3M, 75%, 85% ee (72 h)[g]
Ph
3AA, E/Z = 7:1, 75%, 84% ee (24 h)
Ph
Ph
(S)-A5, 5 Å MS
CF3
PhOCF3 (1.0 eq.)
PhCl, 25 °C, 11 h
Ph
Ph
N
H
N
H
N
CF3
Ph
Ph
N
N
H
N
H
CF3
H
H
C
CH3
C
CH3
[a] Reaction conditions: 1 (0.10 mmol), (S)-A5 (15 mol%), and 5 Å molecular
sieves (100 mg) in PhCl (4.0 mL) at 25 °C. [b] Isolated yields. [c] The ee
values were determined by HPLC analysis. [d] The E/Z ratios were determined
by crude 19F NMR. [e] Run at 35 °C. [f] Na2SO4 (100 mg) was added. [g] Using
CHCl3 (1.0 mL) as solvent and 5 Å molecular sieves (100 mg) and CG50 resin
(100 mg) as additives.
Me
PhOCF3: internal standard
Ph
Ph
Ph
recovered (-)-1a (87% ee)
recovered (+)-1a (88% ee)
(-)-1a (92% ee)
(+)-1a (98% ee)
3A, E/Z > 20:1, 52%, 90% ee
3A, E/Z > 20:1, 56%, 93% ee
CF3
b
CF3
S
S
Ph
Ph
N
CF3
Ph
Ph
N
N
N
CF3
(S)-A5 (15 mol%)
H
H
H
Next, we examined the hydroamination reaction of N-(γ-
dienyl) thiourea 2a in the presence of (S)-A1 (Table S1 in SI).[7c]
As expected, the reaction smoothly delivered the desired 2-vinyl
pyrrolidines 3A albeit with low E/Z selectivity (4:3). After
considerable optimization efforts, (S)-A5 was identified as the
most efficient catalyst, providing E-3A in an almost quantitative
yield with excellent enantioselectivity and E/Z selectivity. Next,
we investigated the scope of the catalytic asymmetric
hydroamination of dienes. Gratifyingly, the reaction of dienes
having different N-aryl groups proceeded smoothly to provide
the desired products 3A–3C and 3N–3P in 55–92% yields with
91–96% ee (Table 4). We next explored the scope for the
tethering groups, and observed good tolerance of cyclic N-(γ-
dienyl) thioureas containing five to six-membered rings, affording
the enantioenriched spiro-products 3Q–3R in high yields with
outstanding ee. Meanwhile, we found that a variety of N-(γ-
dienyl) thioureas with electron-rich or -poor substituents on the
allenyl aryl ring were viable substrates in this transformation to
H
PhCl, 25 °C
Ph
Me
Ph
3A, E/Z > 20:1, 93%, 96% ee, 24 h
E-2a
Z-2a
3A, E/Z > 20:1, 20%, 90% ee, 120 h
c CPA-catalyzed DyKAH of racemic allenes
X
X
Ar
Ar
*
N
H
N
H
N
H
N
O
O
O
CH3
R1
kS
P
X
CH3
H
O
H
R1
kracS ≈
kracR
kS >> kR
CPA activated
proton transfer
H
N
Ar
X
X
N
CH3
Ar
Ar
Ar
N
H
N
H
N
H
N
CH3
kracR
allyl cation/N-anion pair
CH3
H
R1
R1
X = S,O
Scheme 1. Mechanistic study
To get insights into the reaction mechanism, some control
experiments have been conducted. First, to determine whether
this catalytic stereoconvergent process was a DyKAH or not,[1d]
we carried out asymmetric hydroamination reactions on
enantioenriched allenes (−)-1a (92% ee) and its enantiomer (+)-
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10.1002/anie.201900955
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COMMUNICATION
1a (98% ee). The hydroamination reactions proceeded at similar
rates (Figure S5 in SI), furnishing products E-3A with almost
identical enantioselectivity (Scheme 1a). We also observed
catalytic asymmetric hydroamination strategy involves a highly
reactive π-allylic carbocationic intermediate generated from the
racemic allenes or dienes via an intramolecular proton transfer,
which invokes cooperative multiple hydrogen bonding
interactions between the reacting thiourea group and Brønsted
acid. This protocol could serve as a good complementary
approach to the conventional metal-catalyzed DyKAH of racemic
allenes and asymmetric hydroaminations of dienes, providing
expedient access to a diverse range of enantioenriched alkenyl-
containing azaheterocycles and bicyclic azaheterocycles.
Further studies to expand the scope and to develop the more
challenging intermolecular DyKAH of racemic allenes with this
strategy are currently underway in our laboratory.
similar racemization rates of each enantiomer (kracS ≈ kracR
)
(Schemes 1a and 1c). This result was similar to that in a
previous report,[3b] indicating that the process might involve the
formation of the same prochiral intermediate mediated by
CPA[1d] and the formation rate of product (S)-3A should be
significantly higher than that of (R)-3A (ks >> kR) in the presence
of catalyst (S)-5A (Scheme 1c). Furthermore, the lack of
reactivity using an N-methyl thiourea (Scheme S1 in SI), Bz- or
Ts-amides (Table 1) indicated that the thiourea bearing two N–H
bonds might be essential for the effective activation and
stereoinduction, as reported previously.[7c] Thus, the combined
results favor a DyKAH mechanism, in which racemic allenes
might bind to CPA to produce a prochiral π-allylic carbocation/N-
anion pair during the enantioinduction process.[1d] In addition, Z-
and E-2a showed significantly different reactivity, but almost the
same stereoselectivity for asymmetric hydroamination (Scheme
1b), supporting the involvement of the same π-allylic
Acknowledgements
Financial support from the National Natural Science Foundation
of China (Nos 21722203, 21831002, and 21602098) and
Shenzhen Nobel Prize Scientists Laboratory Project
(C17213101) is greatly appreciated.
carbocationic intermediate. Based on the above mechanistic
7d]
investigations and previous studies,[7c,
we propose that the
DyKAH of racemic unactivated allenes and asymmetric
hydroamination of unactivated dienes proceed through
Keywords: chiral Brønsted acid • dynamic kinetic asymmetric
a
hydroamination • racemic allenes • dienes • chiral pyrrolidines
stepwise mechanism: the CPA forms hydrogen bonding
interactions with the thiourea moiety and thus, indirectly
activates the C=C bonds to form the same π-allylic
carbocation/N-anion pair via an intramolecular proton transfer,[17]
followed by an SN1-type C–N bond formation to give the final
product (Scheme 1c and Figure 1c).
[1]
For selected reviews, see: a) J. Steinreiber, K. Faber, H. Griengl,
Chem. Eur. J. 2008, 14, 8060; b) H. Ito, S. Kunii, M. Sawamura,
Nat. Chem. 2010, 2, 972; c) C. Moberg, Acc. Chem. Res. 2016, 49,
2736; d) V. Bhat, E. R. Welin, X. Guo, B. M. Stoltz, Chem. Rev.
2017, 117, 4528. For selected recent examples, see: d) H. You, E.
Rideau, M. Sidera, S. P. Fletcher, Nature 2015, 517, 351; e) A.
Ortega, R. Manzano, U. Uria, L. Carrillo, E. Reyes, T. Tejero, P.
Merino, J. L. Vicario, Angew. Chem. Int. Ed. 2018, 57, 8225;
Angew. Chem. 2018, 130, 8357; f) P.-J. Yang, L. Qi, Z. Liu, G.
Yang, Z. Chai, J. Am. Chem. Soc. 2018, 140, 17211.
[2]
[3]
For selected reviews, see: a) R. W. Bates, V. Satcharoen, Chem.
Soc. Rev. 2002, 31, 12; b) S. M. Ma, Chem. Rev. 2005, 105, 2829;
c) S. M. Ma, Acc. Chem. Res. 2009, 42, 1679; d) E. Soriano, I.
Fernandez, Chem. Soc. Rev. 2014, 43, 3041.
For selected examples, see: a) B. M. Trost, D. R. Fandrick, D. C.
Dinh, J. Am. Chem. Soc. 2005, 127, 14186; b) Z. Zhang, C. F.
Bender, R. A. Widenhoefer, J. Am. Chem. Soc. 2007, 129, 14148;
c) J. D. Osborne, H. E. Randell-Sly, G. S. Currie, A. R. Cowley, M.
C. Willis, J. Am. Chem. Soc. 2008, 130, 17232; d) R. A.
Widenhoefer, Chem. Eur. J. 2008, 14, 5382; e) H. Li, S. D. Lee, R.
A. Widenhoefer, J. Organomet. Chem. 2011, 696, 316; f) D. N.
Tran, N. Cramer, Angew. Chem. Int. Ed. 2013, 52, 10630; Angew.
Chem. 2013, 125, 10824; g) D. A. Khrakovsky, C. Tao, M. W.
Johnson, R. T. Thornbury, S. L. Shevick, F. D. Toste, Angew.
Chem. Int. Ed. 2016, 55, 6079; Angew. Chem. 2016, 128, 6183. h)
B. M. Trost, D. Zell, C. Hohn, G. Mata, A. Maruniak, Angew. Chem.
Int. Ed. 2018, 57, 12916; Angew. Chem. 2018, 130, 13098.
[4]
Leading reviews on the asymmetric hydroamination: a) T. E.
Mueller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada, Chem. Rev.
2008, 108, 3795; b) S. R. Chemler, Org. Biomol. Chem. 2009, 7,
3009; c) N. Krause, C. Winter, Chem. Rev. 2011, 111, 1994; d) J.
Hannedouche, E. Schulz, Chem. Eur. J. 2013, 19, 4972; e) Y.-M.
Wang, A. D. Lackner, F. D. Toste, Acc. Chem. Res. 2014, 47, 889;
f) L. Huang, M. Arndt, K. Goossen, H. Heydt, L. J. Goossen, Chem.
Rev. 2015, 115, 2596; g) A. L. Reznichenko, K. C. Hultzsch,
Organic Reactions, John Wiley & Sons, 2015, 88, pp. 1–554.
K. L. Butler, M. Tragni, R. A. Widenhoefer, Angew. Chem. Int. Ed.
2012, 51, 5175; Angew. Chem. 2012, 124, 5265.
For comprehensive reviews on asymmetric Brønsted acid catalysis,
see: a) T. Akiyama, Chem. Rev. 2007, 107, 5744; b) M. Terada,
Chem. Commun. 2008, 4097; c) S.-L. You, Q. Cai, M. Zeng, Chem.
Soc. Rev. 2009, 38, 2190; d) M. Terada, Synthesis 2010, 1929; e)
J. Yu, F. Shi, L.-Z. Gong, Acc. Chem. Res. 2011, 44, 1156; f) R. J.
Phipps, G. L. Hamilton, F. D. Toste, Nat. Chem. 2012, 4, 603; g) K.
Brak, E. N. Jacobsen, Angew. Chem. Int. Ed. 2013, 52, 534;
Angew. Chem. 2013, 125, 558; h) M. Mahlau, B. List, Angew.
Scheme 2. Transformations of compounds 3A and 3M.
To demonstrate the synthetic utility of the current protocol,
we treated the products 3A and 3M with BF3·OEt2 to
straightforwardly obtain bicyclic azaheterocycles 4 and 5 bearing
new quaternary stereocenters in high yield (Scheme 2). The
structure of 5 has been unambiguously determined by X-ray
structural analysis (Figure S4 in SI)
[5]
[6]
In summary, a chiral Brønsted acid-catalyzed DyKAH of
racemic unactivated allenes and asymmetric hydroamination of
unactivated dienes with both excellent E/Z selectivity and
enantioselectivity have been developed. Significantly, this new
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Chem. Int. Ed. 2013, 52, 518; Angew. Chem. 2013, 125, 540; i) D.
Parmar, E. Sugiono, S. Raja, M. Rueping, Chem. Rev. 2014, 114,
9047; j) Z. Wang, Z. Chen, J. Sun, Org. Biomol. Chem. 2014, 12,
6028; k) T. Akiyama, K. Mori, Chem. Rev. 2015, 115, 9277.
a) L. Ackermann, A. Altharnmer, Synlett 2008, 995; b) N. D.
Shapiro, V. Rauniyar, G. L. Hamilton, J. Wu, F. D. Toste, Nature
2011, 470, 245; c) J.-S. Lin, P. Yu, L. Huang, P. Zhang, B. Tan, X.
-Y. Liu, Angew. Chem. Int. Ed. 2015, 54, 7847; Angew.
Chem. 2015, 127, 7958; d) N. Tsuji, J. L. Kennemur, T. Buyck, S.
Lee, S. Prévost, P. S. J. Kaib, D. Bykov, C. Farès, B. List, Science
2018, 359, 1501.
[13]
[14]
a) R. Hayashi, R. P. Hsung, J. B. Feltenberger, A. G. Lohse, Org.
Lett. 2009, 11, 2125; b) R. Sanz, D. Miguel, A. Martínez, M.
Gohain, P. García-García, M. A. Fernández-Rodríguez, E. Álvarez,
F. Rodríguez, Eur. J. Org. Chem. 2010, 2010, 7027; c) X. Zhang,
C. Fu, S. Ma, Org. Lett. 2011, 13, 1920; d) C. M. Ting, Y. L. Hsu, R.
S. Liu, Chem. Commun. 2012, 48, 6577.
a) M. Rueping, U. Uria, M.-Y. Lin, I. Atodiresei, J. Am. Chem. Soc.
2011, 133, 3732; b) P.-S. Wang, X.-L. Zhou, L.-Z. Gong, Org. Lett.
2014, 16, 976; c) G. Pupo, F. Ibba, D. M. H. Ascough, A. C. Vicini,
P. Ricci, K. E. Christensen, L. Pfeifer, J. R. Morphy, J. M. Brown, R.
S. Paton, V. Gouverneur, Science 2018, 360, 638.
[7]
[8]
A. L. Reznichenko, A. J. Nawara-Hultzsch, K. C. Hultzsch, in Top.
Curr. Chem., Vol. 343 (Eds.: W. Li, X. Zhang), 2014, pp. 191.
I. Dion, A. M. Beauchemin, Angew. Chem. Int. Ed. 2011, 50, 8233;
Angew. Chem. 2011, 123, 8383.
a) P. W. Roesky, T. E. Muller, Angew. Chem. Int. Ed. 2003, 42,
2708; Angew. Chem. 2003, 115, 2812; b) O. Kanno, W. Kuriyama,
Z. J. Wang, F. D. Toste, Angew. Chem. Int. Ed. 2011, 50, 9919;
Angew. Chem. 2011, 123, 10093.
[15]
[16]
a) A. Mullard, Nat. Rev. Drug Discov. 2015, 14, 77; b) A. Mullard,
Nat. Rev. Drug Discov. 2018, 17, 81; c) S. Arthan, Nat. Rev. Drug
Discov. 2018, 17, 699.
CCDC 1886907 (3A), 1886903 (3M), 1887492 (5) 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.
[9]
[10]
[17]
See Scheme S2 in the SI for an alternative possible reaction
pathway suggested by a reviewer.
[11]
[12]
a) G. C. Fu, ACS Cent. Sci. 2017, 3, 692; b) A. E. Wendlandt, P.
Vangal, E. N. Jacobsen, Nature 2018, 556, 447.
D. Nakashima, H. Yamamoto, J. Am. Chem. Soc. 2006, 128, 9626.
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10.1002/anie.201900955
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Entry for the Table of Contents
COMMUNICATION
J.-S. Lin, T.-T. Li, G.-Y. Jiao, Q.-S. Gu,
J.-T. Cheng, L. Lv, and X.-Y. Liu*
Page No. – Page No.
Chiral Brønsted Acid-Catalyzed
Dynamic Kinetic Asymmetric
Hydroamination of Racemic Allenes
and Asymmetric Hydroamination of
Dienes
New DyKAH model：The first Brønsted acid-catalyzed dynamic kinetic
asymmetric hydroamination of racemic allenes and asymmetric hydroamination of
dienes with both high E/Z selectivity and enantioselectivity is presented. The
transformation proceeds through a new catalytic asymmetric model involving a
reactive π-allylic carbocationic intermediate. This method affords expedient access
to diverse enantioenriched, bioactive azaheterocycles.
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