Chiral Phosphoric Acid-Catalyzed Enantioselective Formal [3+2] Cycloaddition of Azomethine Imines with Enecarbamates

Article abstract of DOI:10.1002/chem.201601548

The first catalytic asymmetric inverse electron demand 1,3-dipolar cycloaddition of azomethine imines with enecarbamates has been developed. Isoquinoline-fused pyrazolidines containing two or three contiguous stereogenic centers were obtained in high yields with excellent regio-, diastereo-, and enantioselectivities. The pyrazolidine ring can be opened to install an aminal, α-amino nitrile, or homoallylamine function with an excellent control of the newly generated stereogenic center. Access to aminobenzo[a]quinolizidine is also documented. Acid catalysis: The first catalytic asymmetric inverse electron demand 1,3-dipolar cycloaddition of azomethine imines with enecarbamates has been developed. Isoquinoline-fused pyrazolidines containing two or three contiguous stereogenic centers were obtained in high yields with excellent regio-, diastereo-, and enantioselectivities (see scheme).

Full text of DOI:10.1002/chem.201601548

DOI: 10.1002/chem.201601548
Communication
&
Synthetic Methods |Hot Paper|
Chiral Phosphoric Acid-Catalyzed Enantioselective Formal [3+2]
Cycloaddition of Azomethine Imines with Enecarbamates
Yang Wang, Qian Wang, and Jieping Zhu*[a]
Abstract: The first catalytic asymmetric inverse electron
demand 1,3-dipolar cycloaddition of azomethine imines
with enecarbamates has been developed. Isoquinoline-
fused pyrazolidines containing two or three contiguous
stereogenic centers were obtained in high yields with ex-
cellent regio-, diastereo-, and enantioselectivities. The pyr-
azolidine ring can be opened to install an aminal, a-amino
nitrile, or homoallylamine function with an excellent con-
trol of the newly generated stereogenic center. Access to
aminobenzo[a]quinolizidine is also documented.
Scheme 1. Enantioselective IED 1,3-DCs of electron-rich alkenes with azome-
thine imines.
1,3-Dipolar cycloadditions (1,3-DCs) of azomethine imines with
cloadducts with a penta-substituted pyrazolidine unit (R2 =
alkenes/alkynes are useful methods for the assembly of five-
membered heterocycles.[1] The resulting dihydropyrazoles or
alkyl). The utility of this chemistry was further illustrated by the
pyrazolidines are structural motifs found in natural products
and bioactive compounds.[2] Although enantioselective normal
electron demand (NED) 1,3-DCs of azomethine imines with
electron-deficient alkenes are well established,[3] the inverse
electron demand (IED) cycloaddition between azomethine
imines and electron-rich alkenes is far less developed.[4,5] Enol
ether 1a and enol thioether 1b have been successfully em-
ployed as electron-rich olefins in the enantioselective IED 1,3-
DCs, whereas enamides/enecarbamates have not been used
thus far. Indeed, it has been reported that enamides 2a and
2b[6] were incompetent dipolarphiles in the attempted enan-
tioselective [3+2] cycloadditions with N-acyl hydrazone
(Scheme 1).[7] Assuming that the activation mode of azome-
thine imines might be different from that of N-acyl hydrazones,
we set out to investigate the IED [3+2] cycloadditions be-
tween azomethine imines 3 and enecarbamates 4. We report
herein that in the presence of a chiral spinol-derived phospho-
ric acid,[8,9] heteroannulation between 3 and 4 occurs smoothly
to afford the isoquinoline-fused aminopyrazolidines 5 in high
yields with excellent regio-, diastereo-, and enantioselectivities
(Scheme 1). Conditions for the cycloaddition involving b-substi-
tuted enecarbamates have also been optimized leading to cy-
post-transformation of the resulting cycloadduct to functional-
ized tetrahydroisoquinolines and benzoquinolizidine. It is im-
portant to note that in Maruoka’s chiral dicarboxylic acid-cata-
lyzed heteroannulation of C,N-cyclic azomethine imines with
tert-butyl vinyl ether, the reaction is exo-selective.[4a] However,
our reaction is NHCbz-endo selective; therefore, indicating a sig-
nificant mechanistic deviation from Maruoka’s reaction.
The C,N-cyclic azomethine imine 3a (R1 =H) and benzyl N-
vinyl carbamate 4a (R2 =H) were chosen as model substrates.
After initial survey of the solvents, reaction temperatures, and
concentrations using 6a as a catalyst (0.1 equiv; Figure 1), we
chose to perform the reaction in CH2Cl2 (0.1m) at À208C for
catalyst screening. As shown in Table 1, all chiral phosphoric
[a] Dr. Y. Wang, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique FØdØrale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201601548.
Figure 1. Structures of chiral phosphoric acids.
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Table 1. Survey of reaction conditions.[a]
Table 2. Scope of asymmetric IED 1,3-DC with benzyl N-vinyl carbama-
te.[a]
Entry
Catalyst
t [h]
Conv. [%]
d.r.
e.r.[b]
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6 f
6g
6h
6i
6j
7
8
9
36
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
69.9:30.1
68.1:31.9
67.9:32.1
65.3:34.7
51.7:48.3
57.9:42.1
61.9:38.1
64.1:35.9
55.1:44.9
65.1:34.9
53.3:46.7
53.3:46.7
80.0:20.0
93.9:6.1
Entry
Product 5
Yield [%][b]
d.r.
e.r.[c]
1
2
3
4
R1 =H (5a)
80
75
79
77
80
68
83
70
72
76
81
72
76
d.r.
97.6:2.4
95.3:4.7
98.6:1.4
94.9:5.1
94.2:5.8
97.5:2.5
95.4:4.5
95.1:4.9
95.4:4.6
98.3:1.7
96.5:3.5
97.8:2.2
98.8:1.2
R1 =5-Me (5b)
R1 =6-Me (5c)
R1 =7-Me (5d)
R1 =8-Me (5e)
R1 =7-MeO (5 f)
R1 =7-F (5g)
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
5
6[d]
7
9
8
9
10
11
12
13
R1 =7-Cl (5h)
R1 =5-Br (5i)
R1 =6-Br (5j)
R1 =7-Br (5k)
R1 =5-CO2Me (5l)
R1 =6-CF3 (5m)
10
11
12
13
14
15
16
10a
10b
10c
97.6:2.4
94.9:5.1
[a] Reaction conditions: 3a (0.10 mmol), 4a (0.20 mmol), and (S)-10b
(0.01 mmol) in DCM (c 0.1m) at À208C. [b] Isolated yield. [c] Determined
by SFC analysis on a chiral stationary phase. [d] t=48 h.
[a] Reaction conditions: 3a (0.10 mmol), 4a (0.20 mmol), and (S)-phos-
phoric acid (0.01 mmol) in DCM (c 0.1m) at À208C. [b] Determined by
SFC (supercritical fluid chromatography) analysis on a chiral stationary
phase.
(entries 3, 10, and 13). The absolute configuration of 5j was
determined by X-ray crystallographic analysis[13] and those of
other adducts were assigned accordingly.
acids (CPAs) are capable of catalyzing the [3+2] cycloaddition
between 3a and 4a to afford the desired adduct 5a in excel-
lent yield and diastereoselectivity (d.r.>19:1). However, the
enantioselectivity varied significantly depending on the back-
bone structure of CPAs. With (S)-binol-derived CPAs (6a–6j)
having different steric and electronic properties as catalyst, 5a
was isolated with an e.r. of 69.9:30.1 at best (entries 1–10). The
more acidic N-triflyl phosphoramide 7[10] was also inefficient for
this purpose (entry 11), so was the bulky imidodiphosphoric
acid 8[11] (entry 12). An improved enantioselectivity was ob-
served with the octahydro-(S)-binol-derived CPA 9 (e.r.: 80:20;
entry 13). A breakthrough came when STRIP (6,6’-bis(2,4,6-tri-
To further explore the scope of this novel catalytic enantio-
selective 1,3-DCs, both (Z)- and (E)-benzyl N-prop-1-en-1-yl car-
bamates (Z)-4b (R2 =Me) and (E)-4b (R2 =Me) were synthe-
sized[14] and submitted to our standard conditions. Although
the reaction of (E)-4b with 3a afforded a mixture of two dia-
stereomers, the reaction of (Z)-4b gave a single diastereomer,
albeit with low conversion and a negligible e.r. (55.3:44.7).
Therefore, screening of CPAs using (Z)-4b as dipolarphile was
carried out that allowed us to identify H8-binol-based CPA 9 as
a suitable catalyst. Under optimized conditions (3a (0.1 mmol),
(Z)-4b (0.2 mmol), 9 (0.01 mmol, 0.1 equiv), CH2Cl2 (c 0.1m),
À208C, 4 days), the cycloadduct 5n was isolated as a single
diastereomer in 91% yield with an e.r. of 96:4 (Table 3, entry 1).
To the best of our knowledge, this represents the first example
of IED 1,3-DCs between the C,N-cyclic azomethine imine and
the electron-rich internal double bond.
isopropylphenyl)-1,1’-spirobiindan-7,7’-diyl
hydrogenphos-
phate, 10a) was employed as a catalyst to afford 5a with an
e.r. of 93.9:6.1 (entry 14).[12] Encouraged by this result, a series
of (S)-spinol-derived CPAs were synthesized. Among them, the
previous unknown CPAs 10b and 10c were found to be the
most promising. With 10b as a catalyst (0.1 equiv), the reaction
of 3a with 4a afforded 5a in 80% yield with an e.r. of 97.6:2.4
(entry 15).
As shown in Table 3, a wide range of C,N-cyclic azomethine
imines containing electron-withdrawing or -donating substitu-
ents at different positions of the aromatic ring reacted with
(Z)-4b to afford the corresponding cycloadducts 5o–5t in ex-
cellent yields with excellent diastereo- and enantioselectivities
(entries 2–7). Other b-substituted enecarbamates (Z)-4c (R2 =
Et), (Z)-4d (R2 =iPr), and (Z)-4e (R2 =Bn) underwent 1,3-DC
with 3j to provide the corresponding cycloadducts in excellent
yields and diastereoselectivities, albeit with slightly reduced
enantioselectivities (entries 8–10). We note that increasing the
size of R2 substituent decelerated the reaction. Therefore, reac-
tions involving (Z)-4d (R2 =iPr) and (Z)-4e (R2 =Bn) had to be
performed at room temperature that led to a decreased enan-
With optimized conditions in hand (10b (0.1 equiv), CH2Cl2
(c 0.1m), À208C, 24 h), the generality of the reaction was next
examined (Table 2). A remarkably broad range of C,N-cyclic
azomethine imines 3 could be converted to the corresponding
cycloadducts 5 in excellent yields and enantioselectivities. Elec-
tron-donating (entries 2–6) and -withdrawing substituents (en-
tries 7–13), irrespective of their positions on the aromatic ring,
were well tolerated, providing the endo adducts with uniformly
high diastereo- and enantioselectivities. It was nevertheless
noted that a substituent at the C6-position of the azomethine
imine gave in general a slightly higher e.r. of the cycloadducts
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molecular attack of the enecarbamate to the Si-face of the azo-
methine imine would afford intermediate B that upon aminal
formation afforded the cycloadduct 5. In line with this hypoth-
esis, benzyl N-methyl-N-vinyl carbamate, which lack the NH
function, failed to react with 3a under our standard condi-
tions.
Table 3. Scope of asymmetric IED 1,3-DC of azomethine imines with (Z)-
b-substituted enecarbamates.[a]
Post-functionalization of cycloadducts 5 was next investigat-
ed to illustrate the synthetic potential of this novel IED 1,3-di-
polar cycloaddition. Treatment of 5a with SmI2 in MeOH at
room temperature[15] afforded chiral aminal 11 (98%) as the
only diastereoisomer through selective cleavage of the NÀN
bond (Scheme 3).[16] Taking advantage of the aminal function
Entry
Product 5
Yield [%][b]
d.r.
e.r.[c]
1[d]
2[e]
3
4
5
6
7
8[f]
9[f,g]
10[f,h]
R1 =H; R2 =Me (5n)
91
89
93
91
92
94
90
93
89
95
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
96.0:4.0
98.1:1.9
98.9:1.1
97.5:2.5
97.8:2.2
98.6:1.4
97.0:3.0
93.6:6.4
89.6:10.4
90.0:10.0
R1 =7-Me; R2 =Me (5o)
R1 =8-Me; R2 =Me (5p)
R1 =7-MeO; R2 =Me (5q)
R1 =5-Br; R2 =Me (5r)
R1 =6-Br; R2 =Me (5s)
R1 =7-Br; R2 =Me (5t)
R1 =6-Br; R2 =Et (5u)
R1 =6-Br; R2 =iPr (5v)
R1 =6-Br; R2 =Bn (5w)
[a] Reaction conditions:
3 (0.10 mmol), 4 (0.20 mmol), and (S)-9
(0.01 mmol) in DCM (c 0.1m) at À208C. [b] Isolated yield. [c] Determined
by SFC analysis on a chiral stationary phase. [d] t=5 d. [e] t=48 h. [f] 3 Š
MS was added. [g] RT, 48 h. [h] RT, 24 h.
Scheme 3. Reductive cleavage of the NÀN bond of the cycloadduct.
in 5, its Lewis acid-mediated diastereoselective functionaliza-
tion was examined. Reaction of 5a with TMSCN (10.0 equiv) in
the presence of an excess of BF3·Et2O afforded a-amino nitrile
12 in 51% yield with a d.r. of >19:1 (Scheme 4). The relative
stereochemistry of 12 was determined without ambiguity by
its X-ray crystallographic analysis. Using allyltrimethylsilane as
nucleophile, allylamine 13 was similarly prepared in 69% yield
with a d.r. of >19:1. Subsequent SmI2-mediated reductive NÀN
bond cleavage[15] of 13 provided C1-substituted tetrahydroiso-
quinoline 14 with a 1,3-diamine unit in 97% yield.[17] The tetra-
tioselectivity. Gratefully, addition of molecular sieves was found
to be beneficial in these cases (entries 8–10).
The absolute configuration of 5s was determined by X-ray
crystallographic analysis. The fact that the reaction between
(E)-4b and 3a under optimized conditions afforded the cyclo-
adduct in a lower yield with much reduced enantioselectivity
(major isomer: yield 67%, e.r. 59:11; minor isomer: yield 25%,
e.r. 81.5:18.5) excluded the possibility of the isomerization of
(Z)-4b to (E)-4b before the annulation process. In addition, re-
submitting the cycloadduct 5a to the standard conditions did
not cause the epimerization of the aminal stereogenic center.
Therefore, the observed trans relationship between R2 and the
NHCbz groups in cycloadduct 5 indicated that the present IED
1,3-DCs between 3 and (Z)-4b most probably went through
a stepwise mechanism. We assumed that the CPA acted as a bi-
functional catalyst activating both the nucleophile and the
electrophile via transition state A (Scheme 2). A pseudo-intra-
Scheme 2. Stereochemical outcome and X-ray structure of 5s.
Scheme 4. Synthetic transformations of the cycloadduct.
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acid-catalyzed enantioselective inverse electron demand 1,3-di-
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imines and enecarbamates. The reaction afforded functional-
ized isoquinoline-fused pyrazolidines in high yields with excel-
lent regio-, diastereo-, and enantioselectivities. The utility of
this transformation was illustrated by the subsequent conver-
sion of the resulting cycloadducts to a diverse set of C1-substi-
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Y.W. is the recipient of a Marie Curie International Incoming
Fellowship (PIIF-GA-2013-622134) of the 7th Framework Pro-
gram of the European Union. We are grateful to Dr. Rosario
Scopelliti for performing X-ray structural analysis.
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Keywords: azomethines
·
carbamates
·
cycloaddition
·
organocatalysis · tetrahydroisoquinolines
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Received: April 4, 2016
Published online on May 2, 2016
Chem. Eur. J. 2016, 22, 8084 – 8088
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim