Catalytic Asymmetric Umpolung Allylation of Imines

Article abstract of DOI:10.1021/jacs.6b05288

Here we report an iridium-catalyzed asymmetric umpolung allylation of imines as a general approach to prepare 1,4-disubstituted homoallylic amines, a fundamental class of compounds that are hitherto not straightforward to obtain. This transformation proceeds by a cascade involving an intermolecular regioselective allylation of 2-azaallyl anions and a following 2-aza-Cope rearrangement, utilizes easily available reagents and catalysts, tolerates a substantial scope of substrates, and readily leads to various enantioenriched, 1,4-disubstituted homoallylic primary amines.

Full text of DOI:10.1021/jacs.6b05288

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Communication
Catalytic Asymmetric Umpolung Allylation of Imines
Jie Liu, Chao-Guo Cao, Hong-Bao Sun, Xia Zhang, and Dawen Niu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 19 Sep 2016
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Catalytic Asymmetric Umpolung Allylation of Imines
Jie Liu‡, ChaoꢀGuo Cao‡, HongꢀBao Sun, Xia Zhang, Dawen Niu*
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Department of Emergency, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University,
and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
Supporting Information Placeholder
SCHEME 1. a) Classical methods of making homoal-
lylic amines. b) Umpolung functionalization of imines
(Rare). c) An allylation/2-aza-Cope rearrangement
sequence to chiral homoallylic amines (This work).
ABSTRACT: Here we report an iridiumꢀcatalyzed
asymmetric umpolung allylation of imines as a general
approach to prepare 1,4ꢀdisubstituted homoallylic
amines, a fundamental class of compounds that are hithꢀ
erto not straightforward to obtain. This transformation
proceeds by a cascade involving an intermolecular regiꢀ
oselective allylation of 2ꢀazaallyl anions and a following
2ꢀazaꢀCope rearrangement, utilizes easily available reaꢀ
gents and catalysts, tolerates a substantial scope of subꢀ
strates, and readily leads to various enantioenriched, 1,4ꢀ
disubstituted homoallylic primary amines.
Because chiral amine units are present in a large numꢀ
ber of pharmaceuticals, agrochemicals, and ligands to
transition metals, synthetic methods for building these
motifs have been pursued actively.1 Currently, attack of
carbonꢀbased nucleophiles to imines (as electrophiles)
constitutes one of the most frequently utilized strategies
to access chiral amines.2 For example, numerous elegant
catalytic asymmetric methods2 have been developed to
prepare enantioenriched homoallylic amines (1+2 to 4
via 3, Scheme 1a). Within this regime, a 1,2ꢀ
disubstituted product 4 is usually formed when a linear
allylmetal reagent such as 23 is employed as the nucleoꢀ
phile, as explained by transition states 3. 4 However,
catalytic, enantioselective approaches to make 1,4ꢀ
disubstituted homoallylic amines (cf. 10 in Scheme 1c)
Many factors may have hampered the development of
such umpolung processes in Scheme 1b. For example,
the products of these reactions (e.g., 7) contain the same
(imine) functional group as the starting materials (e.g.,
5) and therefore may undergo deprotonation (to give 2ꢀ
azaallyl anions) under the reaction conditions too, an
event that will deteriorate the stereointegrity of the iniꢀ
tially formed products. 12 Moreover, while imines (as
electrophiles) have only one reactive carbon center, 2ꢀ
azaallyl anions (as nucleophiles) contain two, as reflectꢀ
ed by the two resonance structures 6 and 6'. From the
perspective of product diversity, selective functionalizaꢀ
tion at the Cα (to form 7) over the Cα' position (to form
7') is preferred. However, achieving such regioselectiviꢀ
ty could be nonꢀtrivial. Recently, breakthroughs in the
enantioselective arylation10 and Michael addition11 of 2ꢀ
azaallyl anions have been reported, and each was acꢀ
complished through sophisticated design of chiral cataꢀ
lysts or ligands. The asymmetric umpolung allylation of
imines, which will lead to valuable homoallylic amines,
is still an unmet challenge. Here we report a general,
with general substrate scope are still rare to date 5
.
The umpolung6 functionalization of imines, in which
imines serve as nucleophiles via the intermediacy of 2ꢀ
azaallyl anions,7 represents a new paradigm for amine
synthesis (5 to 7 via 6/6', Scheme 1b). This strategy may
not only obviate the generation and use of sensitive orꢀ
ganometallic reagents and/or activated imine species (cf.
1 and 2 in Scheme 1a), but also readily lead to primary
amines—arguably the most synthetically versatile class
of amines under mild conditions. Moreover, through
unconventional ways of bond connections, the umꢀ
polung reactions may give products that are traditionally
challenging to prepare. In spite of these advantages, apꢀ
plication of the umpolung reaction mode of imines in
synthesis,7ꢀ 11 especially in the context of asymmetric
catalysis, remains scarce.
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TABLE 2. Substrate scope for imine reaction partnera
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TABLE 1. Condition optimization for asymmetric um-
polung allylation reaction of imine 11a
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iridiumꢀbased approach to accomplish the catalytic,
asymmetric umpolung allylation of imines (5+8 to 10
via 9, Scheme 1c). The overall process consists of a Cα'ꢀ
selective allylation of imine 5 that gives terminal alkene
9 first, and a following facile, stereospecific 2ꢀazaꢀCope
rearrangement13 of 9 that delivers the Cαꢀfunctionalized
product 10 ultimately. The whole transformation, which
often occurs in tandem, utilizes readily available starting
materials and displays significant substrate scope. This
reaction provides a solution to the synthesis of enantiꢀ
oenriched, 1,4ꢀdisubstituted homoallylic amines.
branchꢀselective allylation of 2ꢀazaallyl anion 12/12'
occurred at the (more encumbered) Cα' position selecꢀ
tively8iꢀj,10 to deliver 14 first; and (ii) intermediate 14
underwent a 2ꢀazaꢀCope rearrangement19 spontaneously
at 25 °C to yield 15. Each of these two outcomes might
have resulted from the unique properties of the fluorenyl
group in 11, which could both control the regioselectiviꢀ
ty of the allylation step (through stabilizing the negative
charge at Cα' position) and facilitate the 2ꢀazaꢀCope
rearrangement [through conjugation with the C=N bonds
in the transition state (TS) and product]. The enantioꢀ
meric excess (ee) of 15 obtained under entry 1 condiꢀ
tions was moderate. We surmised that the strong amide
base (LiHMDS) used is capable of deprotonating prodꢀ
uct 15 and responsible for its compromised ee. Guided
by this thinking, we screened a few weaker bases. While
the use of metal alkoxides gave inferior results (entry 2
and 3), the use of organic base 1,1,3,3ꢀ
tetramethylguanidine (TMG, entry 4) or 1,8ꢀ
diazabicycloundecꢀ7ꢀene (DBU, entry 5) afforded 15
with excellent enantiocontrol, with the latter furnishing
15 also in high yield. However, further tuning down the
basicity of the reaction medium by the use of trialkylaꢀ
mine bases resulted in almost no product formation (enꢀ
try 6 and 7). In the presence of DBU, we also examined
the behaviors of other commonly used ligands in this
reaction (L2–L4,20 entry 8–10), and found that L2 proꢀ
vided 15 with excellent results as well. Nonetheless, we
used L1 in most of the following reactions for its simꢀ
plicity.
We commenced our study of the umpolung reaction of
imines by investigating the iridiumꢀmediated allylation
of Nꢀfluorenyl imine 11 with tertꢀbutyl cinnamyl carꢀ
bonate (13, Table 1). Imine 118iꢀj,10,14 was selected as our
substrate for multiple reasons. First, it could be prepared
readily and efficiently by the condensation between 9Hꢀ
fluorenꢀ9ꢀamine and benzaldehyde, without the need for
chromatography. Besides, because of the aromatic
stablibilization of the resulting fluorenyl anion (cf. 12'),
the Cα'ꢀH bond of 11 is fairly acidic and can be deproꢀ
tonated under mildly basic conditions15 (11 to 12/12').
We used iridiumꢀbased catalysts in this study for their
outstanding performances in conducting selective allylaꢀ
tion of various types of nucleophiles, as demonstrated by
other groups13a,16 and recently by our group17 as well. In
practice, we subjected 11 and 13 to the standard iridiumꢀ
catalyzed allylation reaction conditions using L118 as the
chiral ligand and LiHMDS as base (entry 1, Table 1).
Under these conditions, we found that, somewhat to our
surprise, product 15 (as the E isomer) was directly
formed in a clean fashion. The direct formation of the
linear (1,4ꢀdisubstituted) product 15 under the catalysis
of an iridium complex that usually mediates branchꢀ
selective allylation was rationalized by (i) the initial
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TABLE 3. Substrate scope for allylic carbonatesa
With optimal reaction conditions established, we conꢀ
1
tinued to explore the scope of this transformation (Table
2 and 3). It is noteworthy that the products of these reacꢀ
tions were readily hydrolyzed to give primary amines,
and isolated as the corresponding HCl salt or NꢀBoc
amines. As shown in Table 2, a broad array of Nꢀ
fluorenyl imines 16 participated in this reaction effiꢀ
ciently. For example, we found this reaction could be
performed on a 4 mmol scale, using 1.5 mol%
[Ir(COD)Cl]2, with minimal effects on the yield and seꢀ
lectivity (15'). Moreover, imines containing electronꢀ
neutral (17a), electronꢀrich (17b-c) or electronꢀdeficient
(17d-g) aromatic rings all proved to be competent reacꢀ
tion partners. Notably, product 17f could be derived to a
potential pesticide in one step (Figure S2 in SI). Further,
imines with sterically demanding groups (17h-j) underꢀ
went this transformation smoothly, and gave the Cαꢀ
functionalized products in high selectivities. Besides,
imines originated from cinnamyl aldehyde (17k) or aliꢀ
phatic aldehydes (17l-n) are also tolerated when L2 was
used as the ligand. Importantly, imines with various hetꢀ
eroaryl groups, including furan (17o), thiophene (17p-
q), pyrrole (17r), thiazole (17s), imidazole (17t), pyraꢀ
zole (17u), pyridine (17v), quinoline (17w), indole
(17x), and azaindole (17y) can all be accommodated,
underscoring the generality of this transformation. Lastꢀ
ly, this reaction displayed good regioselectivity for most
substrates in this Table, although in the cases of 17c, 17f,
and 17g, formation of the corresponding branched isoꢀ
mers (~10%) [by the initial Cα (as opposed to Cα') atꢀ
tack] was also observed (see SI).
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To further demonstrate the synthetic utility of this
method, we have made 19t (see SI for Xꢀray structure), a
precursor to an intermediate used in the synthesis of entꢀ
sertraline21 (Table 3). Likewise, our method is well suitꢀ
ed for the preparation of 21, an agonist of neuronal nicoꢀ
tinic receptor (NNR).22 Some additional applications of
this reaction can be seen in Figure S2 of SI.
This transformation demonstrated a broad scope with
respect to the allylic carbonate reaction partner (18) as
well. As summarized in Table 3, cinnamyl carbonates
containing electronꢀdonating (19b) or withdrawing
groups (19c-e) could engage in this reaction, and those
with functional groups such as halogen atoms (19a),
esters (19d), ketones (19e), silyl ethers (19q), and aceꢀ
tonides (19r-s) were also tolerated. In addition, allylic
carbonates bearing a heterocycle, such as dioxolane
(19f), furan (19g), thiophene (19h), thiazole (19i), pyriꢀ
dine (19j-k), indole (19l), azaindole (19m), and quinoꢀ
line (19n) partook in this reaction, delivering the correꢀ
sponding amine products in good yields and selectiviꢀ
ties. Intriguingly, when aliphatic allylic carbonates were
used, the reaction stalled after the first allylation step,
and the branched products 19o'-s' were accumulated
without further rearranging to the final linear products
under the reaction conditions (i.e., at 25 °C for 24 h).
The isolation of 19o'-s' supports our proposed reaction
pathway (Table 1). The fact that 19o'-s' undergo rearꢀ
rangement at slower rates than compound like 14 (Table
1) is congruent with the notion that, compared with aryl
groups, alkyl groups are less able to stabilize the correꢀ
sponding TS structures. Nonetheless, desired products
19o-s could be obtained cleanly upon heating of 19o'-s'
(See SI).
In conclusion, through developing an iridiumꢀ
catalyzed asymmetric umpolung allylation of imines, we
have established a general protocol to prepare 1,4ꢀ
disubstitued homoallylic amines, a class of compounds
that are not straightforward to obtain using traditional
methods. This transformation proceeded by a regioselecꢀ
tive allylation reaction of 2ꢀazaallyl anions and a facile
(and often spontaneous) 2ꢀazaꢀCope rearrangement. This
reaction permitted the use of a remarkable range of subꢀ
strates, including those with electrophilic functional
groups, bulky substituents, or nitrogenꢀcontaining heterꢀ
ocycles, yielding various 1,4ꢀdisubstituted homoallylic
amines in high yields and enantioselectivities. Besides
its immediate synthetic utility, we expect this method
will inspire new development in the area of asymmetric
umpolung functionalization of imines.
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website.
Experimental procedures and compound characterization are provided
(PDF).
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Corresponding Author
* Eꢀmail: niudawen@scu.edu.cn
Notes
The authors declare no competing financial interest.
Author Contributions
All authors have performed the experiments and given apꢀ
proval to the final version of the manuscript. / ‡These auꢀ
thors contributed equally.
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ACKNOWLEDGMENT
This investigation was supported by the startꢀup grant from
West China Hospital, Sichuan University, and 1000 Talents
Plan Program. J.L. was partially supported by NSFC (No.
81573290). We thank Professor Thomas R. Hoye (UMN)
and Jason J. Chruma (SCU, China) for helpful discussions.
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Am. Chem. Soc. 2006, 128, 11038–11039. (c) Rueping, M.; Anꢀ
tonchick, A. P. Angew. Chem. Int. Ed. 2008, 47, 10090–10093. (d)
Ren, H.; Wulff, W. D. J. Am. Chem. Soc. 2011, 133, 5656–5659. (e)
Ren, H.; Wulff, W. D. Org. Lett. 2013, 15, 242–245. (f) Goodman, C.
G.; Johnson, J. S. J. Am. Chem. Soc. 2015, 137, 14574–14577.
(20) (a) Alexakis, A.; Polet, D. Org. Lett. 2004, 6, 3529–3532. (b) Liu,
W.ꢀB.; Zheng, C.; Zhuo, C.ꢀX.; Dai, L.ꢀX.; You S.ꢀL. J. Am. Chem.
Soc. 2012, 134, 4812–4821. (c) Defieber, C.; Ariger, M. A.; Moriel,
P.; Carreira, E. M. Angew. Chem. Int. Ed. 2007, 46, 3139–3143.
(21) (a) Kalshetti, R.; Venkataramasubramanian, V.; Kamble, S.;
Sudalai, A. Tetrahedron Lett. 2016, 57, 1053–1055.
(6) Seebach, D. Angew. Chem. Int. Ed. 1979, 18, 239–258.
(7) (a) Kauffmann, T.; Köppelmann, E.; Berg, H. Angew. Chem., Int.
Ed. 1970, 9, 163. (b) Cram, D. J.; Guthrie, R. D. J. Am. Chem. Soc.
1966, 88, 5760–5765. The anions generated from glycinate ester
imines are not considered in this report. For a review, see: (c)
O’Donnell, M. J. Aldrichimia Acta 2001, 34, 3–15.
(8) (a) Burger, E. C.; Tunge, J. A. J. Am. Chem. Soc. 2006,
128,10002–10003. (b) Yeagley, A. A.; Chruma, J. J. Org. Lett. 2007,
9, 2879–2882. (c) Fields, W. H.; Chruma, J. J. Org. Lett. 2010, 12,
316–319. (d) Li, Z.; Jiang, Y.ꢀY.; Yeagley, A. A.; Bour, J. P.; Liu, L.;
(22) Dull, G. M.; Munoz, J. A.; Genus, J.; Bhatti, B. S.; Young, J. A.;
Bencherif, M.; James, J. W.; Williams, M. G.; Jordan, Kristen, Lipꢀ
piello, P. M.; FordhamꢀMeier, B. Novel Salt Forms of (2S)ꢀ(4E)ꢀNꢀ
methylꢀ5ꢀ[3ꢀ(5ꢀmethoxypyridin)yl]ꢀ4ꢀpentenꢀ2ꢀamine
WO2009018367 A2, February 5, 2009.
ACS Paragon Plus Environment

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Journal of the American Chemical Society
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5

a. Classical methods of making chiral homoallylic aminesa
Journal of the American Chemical Society
Page 6 of 9
M
(FG)N
‡
R
FG
NH2
R'
R
N
(FG)N
M
R'
+
or
1
R
M
H
R
2
3
4
R'
R'
(+ other isomers)
3
M = Zn, B, Si, Sn, etc.
1
2
4
(after FG removal)
(electrophile) (nucleophile)
5
6
b. Umpolung functionalization of imines (rare and challenging)
7
Ar
Ar
8
Ar
N
9
Ar
N
α'
10
11
12
C
R
Ar
α
R
6
- H+
C+
7 (desired)
α'
13
Ar
N
14
15
16
17
18
19
20
α
Ar
Ar
Ar
R
α'
+
Ar
N
C
N
5
α
6'
(nucleophile)
R
R
7' (undesired)
c. Umpolung allylation/rearrangement sequence to chiral homoallylic amines (This work)
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22
R'
2-aza-
Cope
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H
Ar
α'
R'
allylation
NH2
+
5
α
Ar
N
R
R'
ACS Paragon Plus Environment
[Ir]/L
hydrolysis
α
R
OBoc
(cf. 4)
8
9
10

= FluH
Journal of the American Chemic=aFl lSuociety
Page 7 of 9
- H+
–
H
1
2
N α'
α'
N
N
+ H+
α
α
11
3
Ph
Ph
Ph
12
12'
4
5
Flu
N
[Ir(COD)Cl]2
L1-L4
2-aza-
Cope
6
BocO
α
H
7
8
9
10
11
12
Ph
α'
α
N
Ph
Ph
THF (0.1 M)
Base, 25 °C, 24 h
Ph
Ph
15
13
14
Base
Entry
Ligand
Entry Base Ligand Yield
ee
Yield ee
13
14
15
16
17 3
18
1
2
88% 50%
84% 17%
48% 3%
69% 96%
99% 95%
6
7
3%b
< 2%b
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
N.D.
N.D.
LiHMDS
KOtBu
LiOtBu
TMG
DABCO
Et3N
8
99% 96%
–85%
DBU
4
9
43%
38% 24%
DBU
19
20
21
22
5
10
DBU
DBU
aConditions: 10 (0.11 mmol), 12 (0.1 mmol), [Ir(COD)Cl] (3 mol%), L (6 mol%). bStarting
2
materials recovered. Yields were determined by 1H NMR spectroscopy with 1,3,5-trimethylbenzene
as internal standard; Ee's were determined by HPLC analysis.
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24
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NR2 =
R'
Me Me
N
R'
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O
P NR2
Me
N
N
O
ACS Paragon Plus Environment
L1: R' = H
L1-L4
L2: R' = OMe
L3
L4

FluH
BocO
Journal of the American Chemical Society
NH3Cl
NHBoc
Page 8 of 9
[Ir(COD)Cl]2, L1
N
+
α
or
α
R
R
α
R
THF (0.1–0.2 M), DBU
25–50 °C, 24 h
(See SI for workup methods)
1
2
Ph
12
16
17
Ph
Ph
=
R
3
4
5
6
7
8
9
ee
Yield
R'
Cl
17a
Br
85% 94%
Cl
17b MeO 91% 97%
17cc Me2N 84% 95%
17d CF3 60% 93%
17e CO2Me 66% 92%
R'
15' b
(4 mmol)
17a-e
17fc
91% IY, 94% ee
72% IY, 94% ee
10
11
12
Me
Me
NC
13
14
15
16
Ph
Me
17gc
17h
17i
17j
17kd
81% IY, 94% ee
71% IY, 94% ee
85% IY, 97% ee
83% IY, 90% ee 72% IY, 97% ee
17
18
19
20
21
22
Me
Me
17ld
Me
Me
17nd
O
S
Ph
17md
17o
17p
89% IY, 94% ee
81% IY, 99% ee
92% IY, 99% ee
74% IY, 97% ee 90% IY, 96% ee
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Me
24
25
26
27
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N
S
S
Me
N
N
Me
N
Me
Ph
N
N
Me
17q
Me
Cl
Trityl
17r
17s
86% IY, 91% ee
17t
17u
93% IY, 90% ee
78% IY, 96% ee
88% IY, 97% ee 88% IY, 99% ee
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N
N
Ts
17y
N
N
N
Ts
17v
73% IY, 94% ee
17w
17x
82% IY, 96% ee
81% IY, 93% ee
55% IY, 96% ee
37
aConditions: 16 (0.33 mmol), 12 (0.3 mmol), [Ir(COD)Cl]2 (3 mol%), L1 (6 mol%). Isolated
38
yields (IY) of the N-Boc amines or HCl salts were reported; ‡Ee's of imine products were
39
determined by HPLC analysis. b 4 mmol scale using [Ir(COD)Cl] (1.5 mol%), L1 (3 mol%),
ACS Paragon Plus Environment
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THF (0.2 M), 28 °C. c Branched isomer was also formed; the reported yield refers to that of
41
the major isomer. d The reactions were run using L2 as ligand. See SI for experimental details.
42

NHBoc
NH3Cl
BocO
FluH
Page 9 of 9
[Ir(COD)Cl] , L1
Journal of the America2n Chemical Society
Ph
N
+
or
Ph
α
THF (0.1–0.2 M), DBU
Ph
25–35 °C, 24 h
(See SI for workup methods)
R
11
1
2
R
R
19
18
=
R
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
ee
R'
Br
yield
19a
95% 96%
91% 90%
92% 93%
O
S
19b MeO
19c CF3
O
O
19f
94% IY
91% ee
19g
19h
19d CO2Me 88% 95%
19e C(=O)Me 92% 93%
R'
19a-e
92% IY
97% ee
85% IY
96% ee
N
N
S
N
N
N
N
Ts
Ts
OMe
N
19i
82% IY
96% ee
19j
19k
19l
19m
74% IY
94% ee
19n
83% IY
97% ee
81% IY
92% ee
70% IY
94% ee
84% IY
90% ee
18
19
20
21
22
Me
Me
O
O
Toluene
H
nPr
OPh
19o
OTBS
110 °C
t1/2 = 0.5–4 h
N
Ph
R
19p
19q
19r (R-L1) 19s (S-L1)
73% IY 71% IY
76% IYa
94% ee
82% IY
93% de
85% IY
94% de
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24
19o'-s' (isolable)
95% ee 90% ee
25
NH3Cl
NHMe
NFluH
NHMe
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1) [Ir(cod)Cl]2, L2
then, Boc2O
1
Me
Me
16l
1) Et3N, Boc2O
(89% IY, 99% ee)
4
OBoc
+
2) NaH, MeI
3) PPA (ref. 21)
2) NaH, MeI
3) HCl, MeOH
(ref. 22)
32
Cl
N
Cl
OMe
33
34
Cl
19t
Cl
ent-sertraline
(+ C4-epimer)
N
21
(agonist of NNR)
92% IY, 95% ee
OMe
35
20
(see SI for X-ray)
36
ACS Paragon Plus Environment
Conditions: 11 (0.33 mmol), 18 (0.3 mmol), [Ir(COD)Cl]2 (3 mol%), L1 (6 mol%). Isolated yields (IY)
37
were reported; ‡Ee's and de's were determined by HPLC analysis. aThe TBS group was removed during
38
39
workup. NNR: neuronal nicotinic receptor. See SI for experimental details.