Asymmetric acyl-Mannich reaction of isoquinolines with α-(diazomethyl)phosphonate and diazoacetate catalyzed by chiral Br?nsted acids

Article abstract of DOI:10.1039/d0cc03201h

An efficient asymmetric acyl-Mannich reaction of isoquinolines with α-(diazomethyl)phosphonate and diazoacetate has been developed using chiral spiro phosphoric acids as catalysts. This reaction allowed the construction of a series of chiral 1,2-dihydroisoquinolines bearing a tertiary stereocenter at the C1 position with up to 98% yield and 99% ee.

Full text of DOI:10.1039/d0cc03201h

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DOI: 10.1039/D0CC03201H
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Asymmetric Acyl-Mannich Reaction of Isoquinolines with α-
(Diazomethyl)phosphonate and Diazoacetate Catalyzed by Chiral
Brønsted Acids
Wei Wu,a Yan Wang,a Jing Guo,a Liu Cai,a Yuan Chen,a Yanmin Huang*b and Yungui Peng*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
An efficient asymmetric acyl-Mannich reaction of isoquinolines diazoacetate at the C1 position, which can be further
with α-(diazomethyl)phosphonate and diazoacetate has been transformed into promising densely functionalized compounds
developed using chiral spiro phosphoric acids as catalysts. This containing
both
dihydroi-soquinoline
and
β-
reaction allowed the construction of a series of chiral 1,2- aminophosphonate10 or β-aminocarbonate11 substructures
dihydroisoquinolines bearing a tertiary stereocenter at the C1 with potential biological activities. Herein, we report the
position with up to 98% yield and 99% ee.
asymmetric
acyl-Mannich
reaction
of
α-
(diazomethyl)phosphonate or diazoacetate with isoquinolines.
The study commenced with the model reaction of 1a and 2a
with 3a. After initial trials, the asymmetric acyl-Mannich
proceeded smoothly using chiral phosphoric acid (SPA)12 Ia (10
mol %) as catalyst in toluene at 0 °C, affording desired 4a′ in
13% yield with 10% ee (Table 1, entry 1). A series of chiral SPAs
were investigated (see supporting information, SI). SPA Id
showed good stereocontrol, affording 57% ee (entry 4). The
enantioselectivity was increased dramatically when 5 Å
molecular sieves (MS) were added as a water scavenger,
achieving up to 75% ee (entry 5). Changing the nitrogen
acylation reagent from (Boc)2O (2a) to diethyl pyrocarbonate
(DEPC) (2b) further increased the enantioselectivity of product
4a to 83% ee (entries 5 and 6). We further modified the SPA
and increased its steric hindrance by introducing substituents
on the middle phenyl ring. The best enantioselectivity was
achieved using Ie as catalyst. Using the best catalyst, the
reaction parameters, including the reaction temperature,
catalyst loading, the effect of nitrogen acylating reagent, alkyl
of α-(diazomethyl)phosphonate ester, the amounts of additive
5Å MS, substrate ratio and solvents were optimized (see SI).
The optimal reaction conditions were identified, as follows:
Catalyst, Ie; ratio of 1a/2b/3a, 1.5:1.5:1.0; solvent, toluene;
temperature, –30 °C; additive, 5Å MS.
With optimal reaction conditions in hand, we proceeded to
investigate the scope of the acyl-Mannich reaction with
various isoquinolines. The results are summarized in Table 2.
Isoquinolines with both electron-withdrawing and electron-
donating substituents on the aryl rings were tolerated in the
asymmetric acyl-Mannich reaction (Table 2, entries 2–15). In
general, moderate to excellent yields and excellent
enantioselectivities were achieved, irrespective of whether the
isoquinolines had electron-withdrawing (entries 3, 4 6–8 and
15) or electron-donating (entries 2, 5, and 9–14) groups.
Compounds containing the 1,2-dihydroisoquinoline skeleton
have shown various biological and pharmacological
properties,1-3 such as drug transport through the highly
impermeable blood–brain barrier,1 antitumor2 and antiviral
activity.3 Therefore, much effort has been focused toward the
development of efficient methodologies to synthesize 1,2-
dihydroisoquinoline derivatives, especially those bearing a
tertiary stereocenter at the C1 position.4,5 Among these, the
addition of nucleophiles to iminium or acyliminium ions
formed in situ by the dearomatization6 of isoquinoline via N-
alkylation or N-acylation5 has been demonstrated as an
efficient method for the construction of 1-substituted
dihydroisoquinoline derivatives. However, the nucleophiles
have been mainly limited to TMSCN,5a-c terminal alkynes,5d silyl
ketene acetals,5e,f organolithium reagents,5g indoles,5h-j
aldehydes,5k silyl phosphites5l and o-acylated azalactones.5m
α-Diazo compounds, such as α-(diazomethyl)phosphonate7
and diazoacetate,8 have been successfully employed as
nucleophiles in a series of asymmetric reactions. Accordingly,
we became interested in whether the asymmetric version of α-
diazo compounds as nucleophile additions to iminium or
acyliminium ions formed by the dearomatization of
isoquinoline could be realized.9 Therefore, a series of chiral
dihydroi-soquinolines bearing a tertiary stereocenter are
available
by
grafting
(diazomethyl)phosphonate
or
a
Key Laboratory of Applied Chemistry of Chongqing Municipality, School of
Chemistry and Chemical Engineering, Southwest University, Chongqing 400715,
China. E-mail: pengyungui@hotmail.com, pyg@swu.edu.cn.
b
College of Chemistry and Life Science, Guangxi Teachers Education University,
Nanning 530001, China.E-mail: huangyanmin828@gxtc.edu.com.
†
Electronic Supplementary Information (ESI) available: NMR, HRMS (ESI),
enantioselectivities measurement and X-Ray crystal structure data (CIF) for
compounds 4g and 9c. CCDC 1812008 and CCDC 1974617. See DOI:
10.1039/x0xx00000x
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Table 1 Catalyst screening for the asymmetric acyl-Mannich reactiona
Table 2 Acyl-Mannich reactions of (diazomethyl)phosphonate with isoquinolinesa
View Article Online
DOI: 10.1039/D0CC03201H
R1
O
(MeO)2P
O
R1
O
(R'OC) O
O
(MeO)2P
SPA (10 mol %)
Ie (10 mol %)
tol, -30 oC, 5 Å MS
NCO2R'
N2
+
+
+
N
NCO2Et
N2
2
+
(EtOC)2O
tol, T
N
N2
N2
3a
2a: R' = tBu
2b: R' = Et
R
(MeO)2(O)P
4a': R' = tBu; 4a: R' = Et
(MeO)2(O)P
4
1
3a
2b
R1
H
1a
Entry
1
t (h)
yield (%)b
ee (%)c
92
Ia: R = Ph
48
62
86
93
71
94
90
93
48
48
56
56
96
4a, 98
4b, 92
4c,81
4d, 72
4f, 84
4g, 62
4h, 83
4i, 58
4j, 71
4k, 91
4l, 98
4m, 97
4n, 59
Ib: R = 4-tBuC6H4
O
O
O
Ic: R = 2-Me-4-tBuC6H3
2
4-Ph
5-Cl
94
P
Id: R = 4-(3, 4, 5-F3C6H2)-C6H4
OH
3
93
Ie: R = 3,5-(Me)2-4-(3,4,5-F3C6H2)-C6H2
4
5-Br
92
R
5
5-OMe
6-F
89
Entry
SPA
Ia
T (°C)
t (h)
96
yield of 4 (%)b
4a′, 13
4a′, 29
4a′, 31
4a′, 32
4a′, 77
4a, 78
ee (%)c
10
6
95
1
2
0
0
7
6-Cl
95
Ib
Ic
120
96
36
8
6-Br
90
3
0
14
9
6-OMe
6-Me
6-Et
84
4
Id
Id
Id
Ie
0
35
57
10
11
12
13
91
5d
0
48
75
91
6d,e
7d,e
8d,e,f
0
48
83
6-iPr
6-tBu
90
0
48
4a, 85
85
84
Ie
30
48
4a, 98
92
14
15
7-OMe
7-Br
91
91
4o, 70
4p, 65
73
97
a
Reactions were conducted using 1a (0.1 mmol), 2a (0.1 mmol), 3a (0.1 mmol),
SPA (10 mol %) in toluene (1.0 mL) at 0 °C. bIsolated yield. Determined by HPLC
c
aPerformed with 1 (0.15 mmol), 2b (0.15 mmol), 3a (0.10 mmol), 5 Å MS (150
mg), and Ie (10 mol %) in toluene (1.0 mL) at 30 °C. bIsolated yield. cDetermined
by HPLC analysis.
analysis. dWith 5 Å MS (150 mg). e2b was employed instead of 2a. 1a/2b/3a =
f
1.5:1.5:1.0.
Halogen-substituted isoquinolines were also compatible with
the reaction, and the resulting products were useful for further
functional group transformations. In addition to the electronic
properties of substituents on the isoquinoline moiety, the
substituent position also greatly influenced the reaction
outcome. When the substituents were at the isoquinoline C4–
C7 positions, good yields and enantioselectivities were
achieved. However, when the substituents were at the
isoquinoline C8 position, poor results or even no reaction were
observed, irrespective of their electronic properties. This was
presumably due to steric hindrance from the groups at C8
this reaction, we evaluated a number of isoquinolines with α-
diazoacetate. The results are summarized in Table 3. The
substrate bearing a C4-substituted phenyl group reacted
smoothly, affording product 6b in 96% yield with 98% ee (entry
2). Isoquinolines bearing either electron-withdrawing (entries
3–5 and 7–9) or donating groups (entries 6 and 10–13) at the
C5 or C6 positions were tolerated, affording decent yields
(71%–93%) with excellent enantioselectivities (95%–99% ee).
However, the isoquinoline with a strong donating group (OMe)
at the C6 position gave the same excellent enantioselectivity
(97% ee), but in only 41% yield (entry 14). This might be due to
the strongly donating conjugate effect of the OMe group
greatly increasing the stability of the imine ion formed in situ,
which would reduce the reactivity toward nucleophile addition
by ethyl diazoacetate. Changing the diazoacetate alkyl group
from Et to Me, iPr, and tBu afforded the corresponding
products in high yields with excellent enantioselectivities
(entries 15–17).
blocking
the
nucleophile
addition
of
α-
(diazomethyl)phosphonate to the imine ion formed in situ.
This was the limitation of the methodology.
Encouraged by the asymmetric acyl-Mannich reaction of
isoquinolines with α-(diazomethyl)phosphonate, we were
interested in whether this catalytic system could be employed
in the reaction of alkyl diazoacetate 5 with isoquinolines (Table
3). As expected, 6a was delivered in 78% yield with 86% ee
when 1a, DEPC (2b), and 5a were reacted under the optimized
reaction conditions for α-(diazomethyl)phosphonate (Table 3,
in parenthesis of entry 1). As this reaction outcome was not so
gratifying, additional chiral SPA catalysts were explored, and
the reaction conditions further optimized (see SI). Excellent
results (90% yield, 98% ee) were achieved when the reaction
was conducted with Ic (10 mol %) as catalyst in toluene at –20
°C with 5 Å MS as additive and a 1a/2b/5a ratio of 1.5:1.5:1
(Table 3, entry 1). To demonstrate the substrate generality of
The reaction was also performed on a larger scale (4 mmol),
affording 4d in 70% yield with 92% ee (see SI).
Treating 4a with P(Bu)3 gave chiral hydrazone 7a.13 In the
presence of DBU, the hydrogenation of 4a under Pd/C catalysis
afforded β-isoquinoline phosphonate 8a in 82% yield without
affecting the enantioselectivity (92% ee) (Scheme 1).7b-c, 14
The absolute configurations of the acyl-Mannich products
were determined by X-ray analysis of compounds 4g (see SI),
from which the configurations of all other products were
deduced.
2 | J. Name., 2012, 00, 1-3
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Table 3 Acyl-Mannich reaction of α-diazocarbonate with isoquinolinesa
O
O
View Article Online
O
Ie (10 mol %)
tol, -30 oC, 5 Å MS
(MeO)2P
D
H
DOI: 10.1039/D0CC03201H
NCO2Et
(a)
+
+
(EtOC)2O +
R1
R1
N
O
COR2
N2
3a'
O
(MeO)2(O)P
N2
Ic (10 mol %)
tol, -20 oC, 5 Å MS
4a
NCO2Et
1a
2b
(EtOC) O
+
+
2
97% yield, 92% ee
N
N2
O
(MeO)2P
N2
CO2R2
Ie (10 mol %)
tol, -30 oC, 5 Å MS
5a: R2 = Et
t (h)
22 (48)
42
1
2b
6
(b)
NCO2Et
D/H
(EtOC)2O +
N
N2
3a
entry
1d
2
R1, R2
H, Et
yield (%)b
6a, 90 (78)
6b, 96
6c, 80
6d, 91
6e, 93
6f, 90
ee (%)c
(MeO)2(O)P
N2
4
D/H
1a' (D > 95%)
2b
98 (86)
98
98% yield, 92% ee, D > 95%
O
4-Ph, Et
5-Br, Et
5-Cl, Et
(MeO)2P
H
O
Ie (10 mol %)
tol, -30 oC, 5 Å MS
(c)
+
NCO2Et
NCO2Et
OEt
3
36
98
N2
3a
(MeO)2(O)P
N2
4
72
98
1ab
1
4a
72 h, 95% yield, 92% ee
Ie (10 mol %)
tol, -30 oC, 5 Å MS
5
5-NO2, Et
5-OMe, Et
6-F, Et
70
96
(MeO)2P
+
H
(CH3CO)2O or
(CF3CO)2O
(d)
no reaction
+
N
6
16
99
N2
3a
7
64
6g, 87
6h, 92
6i, 88
97
Scheme 2 Control experiments.
8
6-Cl, Et
6-Br, Et
6-Me, Et
6-Et, Et
6-iPr, Et
6-tBu, Et
6-OMe, Et
H, Me
88
97
9
46
98
Ar
10
11
12
13
14
15e
16e
17e
64
6j, 71
98
NCO2Et
N2
N
O
O
P
60
6k, 97
6l, 78
98
1a
O
O
88
97
OH
(MeO)2P
O
(2b)
(EtOC)2O
4a
36
6m, 75
6n, 41
6o, 98
6p, 85
6q, 91
95
Ar
100
96
97
NCO2Et
OEt
O
(MeO)2P
EtOH
95
N
N
1ab
H, iPr
96
98
O
H
H, tBu
96
98
Ar
(MeO)2P
H
O
P
N
aPerformed under argon using 1 (0.15 mmol), 2b (0.15 mmol), 5 (0.10 mmol), 5 Å
MS (150 mg), and Ic (10 mol %) in toluene (1.0 mL) at 20 °C. bIsolated yield.
cDetermined by HPLC analysis. dData in the parenthesis was in the catalysis of Ie
(10 mol %) in toluene (1.0 mL) at 30 °C. ePerformed at 30 °C.
O
O
N2
3a
O
O
O
Ar
TS
Scheme 3 Proposed reaction mechanism.
N
P(O)(OMe)2
N2
P(O)(OMe)2
NCO2Et (b)
P(O)(OMe)2
NCO2Et
H2N
acylisoquinolinium ion gave an intermediate similar to 1ab,
NCO2Et
(a)
which played an important role in achieving the subsequent
7a: 96% yield, 92% ee
4a: 92% ee
8a: 82% yield, 92%
ee
transformation. Therefore, we proposed
a
plausible
(a) P(Bu)3, THF, 25 oC, 2 h; (b) H2 (balloon), Pd/C (1 mol %), DBU (20 mol %),
EA/MeOH = 4/1
mechanism similar to that reported in the literature15 (Scheme
3). First, isoquinoline (1a) reacts with 2b to form intermediate
1ab. Protonation of the 1-ethoxyl group in 1ab aided by chiral
phosphoric acid, followed by the release of EtOH, then gives a
2-ethoxycarbonylisoquinoline iminium ion. This forms an ion
pair with the anion of the chiral phosphoric acid, which
induces the enantioselective nucleophile addition of 3a at its
Si-face. Finally, the phosphoryl oxygen function, a Brønsted
Scheme 1 Product derivatization.
To gain insight into the mechanism, we employed -
deuterated diazophosphonate (3a′) as nucleophile, which
resulted in no deuterium observed in product 4a (Scheme 2a).
When isoquinoline deuterated at the 1-position (1a′) was
applied to the reaction, the deuterium ratio in the product was
the same as in the start material (Scheme 2b). This result
showed that the D/H ratio at the 1-position of isoquinoline
was not affected during the reaction. The reaction of 1ab with
3a was next investigated to establish optimal reaction
conditions, affording 4a with good yield and enantioselectivity
(Scheme 2c). When (CH3CO)2O and (CF3CO)2O were employed
for isoquinoline activation, no reaction was observed (Scheme
2d). This might be attributed to the lower electrophilicity of
the 2-acetylisoquinoline acetate formed in situ. When dialkyl
pyrocarbonate was used as an activating agent, the
nucleophilic addition of the alkoxide formed in situ to the
basic
site,
abstracts
the
-hydrogen
from
-
(diazomethyl)phosphonate to give product 4a. This explains
why -deuterated diazophosphonate (3a′) gave the same level
of enantioselectivity as observed using 3a.
In conclusion, we have reported an unprecedented
asymmetric
acyl-Mannich
reaction
of
(diazomethyl)phosphonate or diazoacetate with isoquinolines
catalyzed by chiral phosphoric acids. A series of chiral α-diazo-
β-isoquinoline phosphonates and carbonates were obtained in
excellent yields (up to 98%) with excellent enantioselectivities
(up to 99% ee). These products could be further transformed
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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G. Peng, Org. Lett. 2012, 14, 2126. (e) T. P. Du, F. Du, Y. Q.
into 1-substituted dihydroisoquinoline derivatives by merging
with β-aminophosphonates or β-aminocarbonates.
This work was supported by the National Science
Foundation of China (21472151), Natural Science Foundation
of Chongqing (cstc2019jcyj-msxmX0414), and Fundamental
Research Funds for the Central Universities (XDJK2019AA003).
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Conflicts of interest
There are no conflicts to declare
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DOI: 10.1039/D0CC03201H
R
R
O
EWG
NCO2Et
EWG
SPA (10 mol %)
+
+
(EtOC)2O
N
N2
5 Å MS, tol, -30 o
C
N2
EWG = PO(OMe)2;
CO2Et
up to 98% yield
99% ee
-Diazo--isoquinoline derivatives were obtained in excellent yields and
enantioselectivities by asymmetric acyl-Mannich reaction of
(diazomethyl)phosphonate or diazoacetate with isoquinolines.