Practical and Asymmetric Reductive Coupling of Isoquinolines Templated by Chiral Diborons

Article abstract of DOI:10.1021/jacs.7b04256

We herein describe a chiral diboron-templated highly diastereoselective and enantioselective reductive coupling of isoquinolines that provided expedited access to a series of chiral substituted bisisoquinolines in good yields and excellent ee's under mild conditions. The method enjoys a broad substrate scope and good functional group compatibility. Mechanistic investigation suggests the reaction proceeds through a concerted [3,3]-sigmatropic rearrangement.

Full text of DOI:10.1021/jacs.7b04256

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Communication
A Practical and Asymmetric Reductive Coupling
of Isoquinolines Templated by Chiral Diborons
Dongping Chen, Guangqing Xu, Qinghai Zhou, Lung Wa Chung, and Wenjun Tang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b04256 • Publication Date (Web): 12 Jul 2017
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A Practical and Asymmetric Reductive Coupling of Isoquinolines
Templated by Chiral Diborons
Dongping Chen,a Guangqing Xu,b Qinghai Zhou,c,d Lung Wa Chung,c Wenjun Tang*,a,b
aSchool of Physical Science and Technology, ShanghaiTech University, Shanghai 200031. bState Key Laboratory of BioꢀOrganic and Natꢀ
ural Products Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciꢀ
ences, 345 Ling Ling Road, Shanghai 200032. cDepartment of Chemistry, South University of Science and Technology of China, Shenꢀ
zhen 518055. dCollege of Chemistry, Nankai University, Tianjin 300071, China
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of diboron compounds in the presence of a heterocyclic comꢀ
ABSTRACT: We herein describe a chiral diboronꢀtemplated
pound. Instead of employing a substituted pyridine for activation
highly diastereoselective and enantioselective reductive coupling
of diboron compounds, we chose isoquinoline as the base for
of isoquinolines which have provided an expedite access to a
series of chiral substituted bisisoquinolines in good yields and
excellent ee’s under mild conditions. The method enjoys a broad
substrate scope and good functional group compatibility. Mechaꢀ
nistic investigation suggests that the reaction proceeds through a
concerted [3,3]ꢀsigmatropic rearrangement.
study (Table 1). When isoquinoline (2a) was treated with 0.5
equiv. of bis(pinacolato)diboron (DB1) in dioxane at rt for 0.5 h,
the reductive coupling product 4 was isolated in an almost perfect
yield (entry 1). The facile and exclusive formation of dl-N,Nꢀ
diborate 4 instead of the meso diastereomer 3 was in sharp conꢀ
trast to the reported reductive coupling methods of isoquinolines
Diboron compounds1 have become increasingly important feed
stocks in organic synthesis thanks to the rapid development of the
with zinc or lowꢀvalent niobium as the reducing reagents, where
significant amounts of meso compounds were formed.10cꢀe No
SuzukiꢀMiyaura crossꢀcoupling2 and various transitionꢀmetal
other sideꢀproducts were observed even when only 0.25 equiv. of
catalyzed borylations.3 In addition, the transitionꢀmetalꢀfree
DB1 was employed (entry 2). The reductive coupling can proceed
o
borylation4 with diboron reagents has built a new dimension of
even at ꢀ40 C without compromising the yield of 4 (entry 3).
However, when the mixture was stirred at rt for 12 h, a diminꢀ
ished yield (75%) of 4 was isolated, suggesting partial decomposiꢀ
tion of 4 with a prolonged reaction time (entry 4).
their synthetic utilities. With the addition of a Lewis base, the
diboron compound can proceed a borylative addition or a diboraꢀ
tion on various π systems (Scheme 1a).4,5 When a pyridine derivaꢀ
tive is employed, a reductive addition6 of bispyridine (Scheme 1b)
or the formation of a persistent radical7 (Scheme 1c) can result
which can proceed further transformations.8 Herein we describe a
transitionꢀmetalꢀfree carbonꢀcarbon bondꢀforming transformation
templated by a chiral diboron compound that have led to a highly
diastereoselective and enantioselective reductive coupling of isoꢀ
quinolines, providing the access to a variety of chiral bisisoquinoꢀ
line diacetamides in good yields and excellent enantioselectivities.
Table 1. Reductive coupling of isoquinoline mediated by
bis(pinacolato)diboron (DB1)
Scheme 1. Transitionꢀmetalꢀfree borylation with diboron
Entriesa
Other conditions
Yield of 4 (%)b
a. Base-promoted borylative addition or diboration of systems
1
2
3
4
/
99
49
98
75
base
B
B
B
B, H
+
X
X = C, N
DB1 (0.25 equiv)
-40 oC, 2 h
12 h
X
b. Reductive addition of bispyridine
aUnless otherwise specified, the mixture was stirred in dioxane at rt
B
+
N
N
B
N
N
B
B
for 0.5 h.
bIsolated yield.
c. Formation of persistent radical
The labile nature of 4 encouraged us to form a stable derivaꢀ
tive of 4 during the reaction. Treatment of 4 with acetyl chloride
led to the successful formation of diacetamide 5a in 90% yield.
To our delight, the derivatization can be done in one pot with the
reductive coupling reaction (Table 2). With this protocol, a varieꢀ
ty of diboron compounds DB1-6 can be applied to form the same
product 5a in various yields (entries 1ꢀ6). Bis(pinacolato)diboron
(DB1) proved to be most effective in terms of yield. In order to
form enantiomerically enriched diacetamide 5a, a series of chiral
diborons DB7-11 were prepared12 and applied to the reaction.
(4S,4'S)ꢀ4,4'ꢀDiphenylꢀ2,2'ꢀbi(1,3,2ꢀdioxaborolane) (DB7) proꢀ
vided the desired product 5a in 93% yield and 39% ee (entry 7).
A sterically more hindered diboron DB8 containing two geminal
methyl groups provided a diminished yield (75%) and a similarly
low ee (37%, entry 8). Gratifyingly, a high yield (87%) and an
excellent ee (93%) were achieved when a diboron DB9 derived
from (1S,2S)ꢀ1,2ꢀdiphenylethaneꢀ1,2ꢀdiol was employed (entry 9).
Only a moderate yield (57%) was obtained when DB10 derived
from (S)ꢀ1,1,2ꢀtriphenylethaneꢀ1,2ꢀdiol was used, albeit with an
excellent ee (94%, entry 10). A diminished ee was afforded when
B
B
N
CN
+
N
CN
B
d. Asymmetric reductive coupling of isoquinolines (this work)
N
B*
B*
B*
B*
R
R
+
H
N
H
N
R
Despite the significance of chiral 1,2ꢀdiamines9 and derivaꢀ
tives in organic synthesis, their efficient preparations remain chalꢀ
lenges. Chiral bisisoquinolines are used as chiral phase transfer
agents or ligand backbones.10 However, the lack of efficient synꢀ
thetic methods has hampered their applications. Low dl/meso
selectivities were often observed in reductive coupling of isoꢀ
quinolines or derivatives.10bꢀe Search for a practical and efficient
asymmetric reductive coupling for the synthesis of chiral bisisoꢀ
quinolines remains an important goal.
During our studies on diboron compounds and related transꢀ
formations,11 we were interested in exploring new transformations
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Table 2. Asymmetric reductive coupling of isoquinoline mediatꢀ
ed by chiral diboron compounds
Table 3. Asymmetric reductive coupling of isoquinolines temꢀ
plated by chiral diboron DB9a
1
2
3
4
5
N
H
N
Ac
Ac
1) solvent, rt
diboron
+
H
N
2) AcCl
6
7
8
9
2a
DB1ꢀ12
5a
entriesa
diboron
DB1
DB2
DB3
DB4
DB5
DB6
DB7
DB8
solvent
yield (%)
90
70
84
9
ee of 5a (%)
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
MTBE
-
-
-
-
-
-
39
37
93
94
82
80
93
99
1
2
3
4
5
6
7
8
9
10
11
12
13b
14
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
6
93
75
87
57
90
35
82
87
DB9
DB10
DB11
DB12
DB9
DB9
aUnless otherwise specified, the reactions were carried out at rt
with 2a (0.5 mmol, 1.0 equiv), diboron (0.375 mmol, 0.75 equiv) in
the designated solvent for 0.5 h, and then AcCl (0.5 mL) was added.
The mixture was stirred for additional 5 min before workꢀup. The
absolute configuration of 5a was determined by its Xꢀray crystallogꢀ
raphy. bThe mixture was stirred for 5 min before the addition of
AcCl.
aUnless otherwise specified, the reactions were carried out at rt
with 2b-u (0.2 mmol, 1.0 equiv), diboron (0.15 mmol, 0.75 equiv) in
MTBE (1 mL) for 0.5 h, and then AcCl (0.5 mL) was added. The
mixture was stirred for additional 5 min before workꢀup.
products 5b-d in good yields and excellent enantioselectivities. A
series of 6,6’ꢀdisubstituted bisisoquinoline diacetamides 5e-i were
successfully formed in moderate yields and excellent ee’s. Subꢀ
stituents such as bromo, phenyl, methyl, thiophenyl, and furyl
groups were well tolerated. 7,7’ꢀDisubstituted bisisoquinoline
diacetamides 5j-l were also smoothly formed. A series of 8,8’ꢀ
disubstituted bisisoquinoline diacetamides 5m-q were also preꢀ
pared in high enantioselectivities. Products containing electronicꢀ
donating substituents such as alkyl or methoxy groups at 4,4’ꢀ
positions 5r-t were formed in excellent ees, while no reaction was
observed on an isoquinoline bearing a bromo or trifluoromethyl
substituent at 4ꢀposition. No reaction was observed on a 1ꢀ, or 3ꢀ
substituted isoquinonline, probably due to the enhanced steric
hindrance. Excitingly, dihydroisoquinoline was also a good subꢀ
strate to provide 5u in 63% yield and 73% ee.
DB11 was applied as the diboron species (entry 11). The diboron
DB12 prepared from a chiral pinanediol only provided a low yield
(35%) and a moderated ee (80%, entry 12). We then employed
DB9 as the reagent for further optimization. When 2a and DB9
were stirred at rt for only 5 min, a similarly high yield and enantiꢀ
oselectivity was achieved (entry 13). Finally, switch of solvent
from dioxane to MTBE further enhanced the chiral induction, and
product 5a was isolated in 99% ee and 87% yield, whose absolute
configuration was determined by Xꢀray crystallography (entry 14).
We then looked into the substrate scope of the reductive couꢀ
pling with DB9 as the chiral diboron reagent. A variety of quinoꢀ
line derivatives with different substituents at various positions
were applicable to form a series of chiral bisisoquinoline diacꢀ
etamides in moderate to high yields and excellent ee’s (up to
99%). It should be noted that no meso compounds were formed
on all the substrates studied. As shown in Table 3, the reductive
coupling was applicable to 5ꢀsubstituted isoquinolines to provide
Scheme 2. Mechanistic investigation
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compound as the template. Lastly, DFT (M06 method) calculaꢀ
(1)
N
H
N
Bpin
Bpin
1
2
tions were performed on reaction of DB9 and 2a (Figure 1 and
Figure S1 in SI). The computed most favorable pathway initiates
with coordination of two 2a to chiral diboron DB9 to cooperativeꢀ
ly activate the BꢀB bond, followed by a concerted [3,3]ꢀ
sigmatropic rearrangement via 6ꢀmembered chairꢀform TSINTa-4a
with a low barrier of 10.8 kcal/mol in solution to afford reductive
coupling product 4a (∆Gsol = ꢀ38.2 kcal/mol). The formation of
ent-4a requires a higher barrier than 4a by 2.1 kcal/mol, mainly
due to steric congestion of the two Ph groups and a lower stability
of ent-4a (ꢀ35.3 kcal/mol). The formation of a meso product
would require a boatꢀform and higherꢀenergy transition state (16.2
kcal/mol). These results are consistent with the experimental obꢀ
servations, and show how the chiral diboron template guides the
formation of the observed chiral coupling product.
dioxane
rt, 0.5 h
H
+
(Bpin)2
N
3
4
5
2a
(1 equiv)
4
tempo (0.75 equiv): 94% yield
(0.75 equiv)
cyclohexa-1,4-diene (0.75 equiv): 96%
6
(2)
7
8
N
H
Bpin
Bpin
MTBE
rt, 1 h
(Bpin)2
+
N
N
Bpin
H
N
9
Bpin
2q
(1.0 equiv) (2.0 equiv)
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
rac-4q
90% yield
not observed
NC
N
O
B
O
(0.2 equiv)
(3)
B1-N1(B2-N2):
pentane, rt, 4h
B1-N1(B2-N2):
1.518 Å
30% yield
1.539 Å
(PhCOO)2
(1.0 equiv)
(Bpin)2
+
C1-N1(C2-N2):
C1-N1(C2-N2):
1.349 Å
(1.0 equiv)
O
B
N
1.342 Å
O4
O1
B1
(0.2 equiv)
O
C2
C1
C2
B2
N2
N1
O3
N1
O2
O1
2.365 Å
pentane, rt, 4h
O3
O4
C1
N2
not observed
B1
B2
O2
EPR study
B1-B2: 2.029 Å
C1-C2: 2.701 Å
B1-B2: 1.906 Å
C1-C2: 2.766 Å
(4)
O3-B1-B2-O4: 58.4°
O1-B1-B2-O2: ꢀ42.4°
TSINTaꢀ4a
0.0/0.0
0.0/0.0
G‡
M06/6ꢀ31G* (kcal/mol)
Esol Gsol
Eint Edist
TSINTaꢀentꢀ4a
3.3/2.1
-1.4/4.7
a. (Bpin)2 in dioxane
b. 4 in dioxane
c, (Bpin)2 and 2a in dioxane
sol
/
10.8
/
d. (Bph)2 and 4-CNPy in dioxane
Figure 1. DFTꢀcomputed energies and structures of the two most
lowest (reductive coupling) concerted [3,3]ꢀsigmatropic rearꢀ
rangement transition states with the key geometrical parameters.
(Bpin)2
4
46% yield
(0.3 equiv)
+
(5)
2a (1.0 equiv)
Scheme 3. Scalability and derivatization of 5a
+
O
MTBE, rt, 1h
N
H
N
Bpin
O
B
O
B
H
N
H
N
O
O
O
O
O
H
B
B
O
B
O
DB13
(0.3 equiv)
8
7
not observed
52% yield
A series of experiments were conducted in order to elucidate the
mechanism of the asymmetric reductive coupling (Scheme 2).
Firstly, the reductive coupling was performed in the presence of a
radical quencher tempo or cyclohexaꢀ1,4ꢀdiene and the coupling
product 4 was isolated without deterioration of the yield; Secondꢀ
ary, 8ꢀallylisoquinoline (2q) was subjected for reductive coupling.
Only racꢀ4q was isolated and no formation of compound 6 or
related cyclic products was observed; Thirdly, both 4ꢀ
cyanopyridine and isoquinoline were used as catalyst for the radiꢀ
cal coupling reaction between (PhCOO)2 and B2pin2. Phenylꢀ
boronic ester was formed as reported with 4ꢀcyanopyridine as an
additive,7a whereas no coupling was observed with isoquinoline
as the additive, indicating no involvement of radical intermediates;
Fourthly, an EPR experiment of the mixture of isoquinoꢀ
line/B2pin2 revealed no radical signals, while a mixture of 4ꢀ
cyanopyridine/B2pin2 (g = 2.0038, 298 K) cleared showed radical
signals as reported by Zhu & Li.7a All the above experiments sugꢀ
gested no involvement of a radical intermediate in the diboronꢀ
templated reductive coupling, which was in contrast to the radical
formation in 4ꢀcyanopyridine/B2pin2 system.7 To test whether
only a single diboron was involved in the reductive coupling, both
B2pin2 (DB1) and DB13 were subjected in one pot for reductive
coupling of isoquinoline and only products 4 and 7 were isolated
with no formation of the crossꢀover product 8. This result indicatꢀ
ed that the reductive coupling occurred with a single diboron
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43
44
45
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49
50
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53
54
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In order to demonstrate the practicality of this method, the reꢀ
ductive coupling was performed at a gram scale and product 5a
was obtained in 98% ee and 77% isolated yield (Scheme 3). Deꢀ
spite the requirement of a stoichiometric amount of DB9 for the
reaction, the chiral diol 9 was recovered in 95% yield, which
could be easily converted back to DB9. The chiral bisisoquinoꢀ
lines are versatile building blocks for further transformation. For
example, 5a could be hydrogenated and hydrolyzed under acidic
conditions to provide chiral diamine 10. Alternatively, it could be
transformed to an acyclic diamine derivative 11 by ozonolysis.
Bromination of 5a provided product 12, which was not accessible
3
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directly by reductive coupling. Excitingly, borylations13 at 3,3’ꢀ
positions were realized under rhodium catalysis with BIꢀDIME14
as the ligand to form 13 in an acceptable yield.
(m) Li, H.; Shangguan, X.; Zhang, Z.; Huang, S.; Zhang, Y.;
Wang, J. Org. Lett. 2014, 16, 448.
6. Ohmura, T.; Morimasa, Y.; Suginome, M. J. Am. Chem. Soc.
2015, 137, 2852.
1
2
3
4
5
6
7
8
9
In conclusion, we have discovered a chiral diboronꢀtemplated
highly diastereoselective and enantioselective reductive coupling
of isoquinolines, which have provided an expedite access to a
series of chiral substituted bisisoquinoline diacetamides in good
yields and excellent enantioselectivities under mild conditions.
This simple and practical method enjoys a broad substrate scope
and good functional group compatibility. Mechanistic investigaꢀ
tion suggests that the reaction proceeds through a concerted [3,3]ꢀ
sigmatropic rearrangement via a 6ꢀmembered chairꢀform transiꢀ
tion state. Because of the synthetic versatility of chiral bisisoquinꢀ
olines, this method is expected to facilitate further development of
chiral diamine chemistry and applications in asymmetric catalysis.
7. (a) Wang, G.; Zhang, H.; Zhao, J.; Li, W.; Cao, J.; Zhu, C.; Li,
S. Angew. Chem., Int. Ed. 2016, 55, 5985. (b) Wang, G.; Cao,
J.; Gao, L.; Chen, W.; Huang, W.; Cheng, X.; Li, S. J. Am.
Chem. Soc. 2017, 139, 3904. (c) Köster, R.; Bellut, H.; Ziegler,
E. Angew. Chem., Int. Ed. 1967, 6, 255.
8. For radicalꢀrelated coupling, (a) Zhang, L.; Jiao, L. J. Am.
Chem. Soc. 2017, 139, 607. (b) Mfuh, A. M.; Doyle, J. D.;
Chhetri, B.; Arman, H. D.; Larionov, O. V. J. Am. Chem. Soc.
2016, 138, 2985. (c) Chen, K.; Zhang, S.; He, P.; Li, P. Chem.
Sci. 2016, 7, 3676. (d) Zhang, J.; Wu, H.ꢀH.; Zhang, J. Eur. J.
Org. Chem. 2013, 6263. (e) Mo, F.; Jiang, Y.; Qiu, D.; Zhang,
Y.; Wang, J. Angew. Chem., Int. Ed. 2010, 49, 1846.
10
11
12
13
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15
16
17
18
19
20
21
22
23
24
25
26
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28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9. Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed.
1998, 37, 2580.
Supporting Information
10. (a) Elliott, I. W., Jr.; McGriff, R. B. J. Org. Chem. 1957, 22,
514. (b) Nielsen, A. T. J. Org. Chem. 1970, 35, 2498. (c) Siegꢀ
fried, M.ꢀA.; Hilpert, H.; Rey, M.; Dreiding, A. Helv. Chim. Ac-
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J. Chem. Soc., Perkin Trans. 2, 2002, 201. (e) Arai, S.; Takita,
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11. (a) Hu, N.; Zhao, G.; Zhang, Y.; Liu, X.; Li, G.; Tang, W. J. Am.
Chem. Soc. 2015, 137, 6746. (b) Tang, W.; Keshipeddy, S.;
Zhang, Y.; Wei, X.; Savoie, J.; Patel, N. D.; Yee, N. K.; Senaꢀ
nauyake, C. H. Org. Lett. 2011, 13, 1366.
12. For previous reports on chiral diboron, see: (a) Clegg, W.; Joꢀ
hann, T. R. F.; Marder, T. B.; Norman, N. C.; Orpen, A. G.;
Peakman, T. M.; Quayle, M. J.; Rice, C. R.; Scott, A. J. J.
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H. C. J. Organomet. Chem. 2007, 692, 784.
13. (a) Cuenca, A. B.; Fernández, E. Top. Organomet. Chem. 2016,
1. (b) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J.
M. Hartwig, J. F. Chem. Rev. 2010, 110, 890.
14. (a) Tang, W.; Capacci, A. G.; Wei, X.; Li, W.; White, A.; Patel,
N. D.; Savoie, J.; Gao, J. J.; Rodriguez, S.; Qu, B.; Haddad, N.;
Lu, B. Z.; Krishnamurthy, D.; Yee, N. K.; Senanayake, C. H.
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Full experimental and computational details, characterization
data, NMR spectra of 2, 4, 5 and related intermediates, chiral
HPLC of 5a-u and related chiral intermediates, cif files of 4, 5a,
DB9. This information is available free of charge via the Internet
at http://pubs.acs.org/.
Corresponding Author
tangwenjun@sioc.ac.cn
Notes
The authors declare no competing financial interest.
Acknowledgments
The work is supported by the Strategic Priority Research Program
of the Chinese Academy of Sciences XDB20000000, CAS
(QYZDYꢀSSWꢀSLH029), NSFCꢀ21432007, 21572246, and
K.C.Wong Education Foundation.
References
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J. J.; Fernández, E. Chem. Soc. Rev. 2012, 41, 3558. (c)
Dewhurst, R. D.; Neeve, E. C.; Braunschweig, H.; Marder, T. B.
Chem. Commun. 2015, 51, 9594.
5. For recent examples: Diboration of olefins, (a) Fang, L.; Yan,
L.; Haeffner, F.; Morken, J. P. J. Am. Chem. Soc. 2016, 138,
2508. (b) Blaisdell, T. P.; Caya, T. C.; Zhang, L.; SanzꢀMarco,
A.; Morken, J. P. J. Am. Chem. Soc. 2014, 136, 9264. (c) Bonet,
A.; PubillꢀUlldemolins, C.; Bo, C.; Gulyás, G.; Fernández, E.
Angew. Chem., Int. Ed. 2011, 50, 7158. Borylation of Michael
acceptors, (d) Rodomkit, S.; Hoveyda, A. H. Angew. Chem., Int.
Ed. 2014, 53, 3387. (e) Wu, H.; Radomkit, S.; O’Brien, J. M.;
Hoveyda, A. H. J. Am. Chem. Soc. 2012, 134, 8277. (f) Bonet,
A.; Gulyás, H.; Fernández, E. Angew. Chem., Int. Ed. 2010, 49,
5130. Diboration or borylation of alkynes, (g) Morinaga, A.;
Nagao, K.; Ohmiya, H.; Sawamura, M. Angew. Chem., Int. Ed.
2015, 54, 15859. (h) Nagashima, Y.; Hirano, K.; Takita, R.;
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Borylation of allylic alcohols, (k) Miralles, N.; Alan, R.; Szabó,
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Borylation of imines, (l) Solé, C.; Gulyás, H.; Fernández, E.
Chem. Commun. 2012, 48, 3769. Borylation of diazo compouds,
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