Hydrosilylation-Promoted Furan Diels-Alder Cycloadditions with Stereoselectivity Controlled by the Silyl Group

Article abstract of DOI:10.1021/jacs.9b11909

Herein we describe an unprecedented B(C₆F₅)₃-catalyzed cascade reaction of N-allyl-N-furfurylamides involving an initial intramolecular furan Diels-Alder reaction and subsequent ether cleavage. The reaction has a broad substrate scope, even tolerating a trialkyl-substituted olefin as the dienophile, which has not previously been observed with conventional furan Diels-Alder reactions. In addition, the relative configuration of the product can be controlled by the choice of the silyl group: reactions involving Et₃SiH and ⁱPr₃SiH gave different diastereomers. Control experiments and the computational studies revealed that the steric bulk of the silyl group plays a key role in determining the reaction pathway and thus the relative configuration of the product.

Full text of DOI:10.1021/jacs.9b11909

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Article
Hydrosilylation-Promoted Furan Diels–Alder Cycloadditions
with Stereoselectivity Controlled by the Silyl Group
Zhi-Yun Liu, Ming Zhang, and Xiao-Chen Wang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b11909 • Publication Date (Web): 06 Dec 2019
Downloaded from pubs.acs.org on December 6, 2019
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Hydrosilylation-Promoted Furan Diels–Alder Cycloadditions with
Stereoselectivity Controlled by the Silyl Group
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Zhi-Yun Liu,† Ming Zhang,† and Xiao-Chen Wang*
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry,
Nankai University, Tianjin 300071, China.
†These authors contributed equally to this work.
Correspondence: xcwang@nankai.edu.cn
ABSTRACT: Herein we describe an unprecedented B(C6F5)3-catalyzed cascade reaction of N-
allyl-N-furfurylamides involving an initial intramolecular furan Diels–Alder reaction and
subsequent ether cleavage. The reaction has a broad substrate scope, even tolerating a trialkyl-
substituted olefin as the dienophile, which has not previously been observed with conventional
furan Diels–Alder reactions. In addition, the relative configuration of the product can be controlled
i
by the choice of the silyl group: reactions involving Et3SiH and Pr3SiH gave different
diastereomers. Control experiments and the computational studies revealed that the steric bulk of
the silyl group plays a key role in determining the reaction pathway and thus the relative
configuration of the product.
INTRODUCTION
Heterobicyclic octahydroisoindoles and analogous structural motifs are prevalent in natural
products and drugs, including mitiglinide1, serlopitant2, and perospirone3 (Figure 1a); and
synthetic organic chemists have therefore developed efficient, selective methods for preparation
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of compounds with these motifs. The existing methods include [2+2+2] cycloadditions of 1,6-
enynes with alkenes4,5 or alkynes6,7, and cycloadditions of alkene-8 or alkyne-tethered9
vinylcyclopropanes, both of which are catalyzed by rhodium complexes. However, owing to the
steric and electronic requirements of these metal-catalyzed cycloaddition reactions, many types of
octahydroisoindoles are not accessible via these methods.
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We recently became interested in an alternative approach for one-step synthesis of these
structures: intramolecular furan Diels–Alder reactions of N-allyl-N-furfurylamides to afford
oxygen-bridged hexahydroisoindoles (Figure 1b)10–19. The oxygen bridge and the olefin group of
these products offer handles for further elaboration. Although this approach has been known for a
long time and has been systematically studied, it remains limited in terms of substrate scope. For
example, activating groups, such as halogens on the furan ring11,15,17,18 or electron-withdrawing
groups attached to the olefin10,12,19, are often necessary for good reactivity. The cycloaddition
reactions of unactivated substrates are reversible; even sterically unhindered substrates with a
monosubstituted terminal olefin can undergo a retro-Diels–Alder reaction to regenerate the starting
material16. In addition, unactivated nonterminal olefins are generally unreactive. More important,
unactivated substrates lack a handle (e.g. a carbonyl group) for the association with catalysts,
making external control of the stereoselectivity almost impossible, which may explain the marked
decline in the number of relevant studies over the past decade. However, we have revisited this
old chemistry and now report that the substrate scope can be expanded to include very sterically
hindered dienophiles when the furan Diels–Alder reaction is part of a cascade process involving
borane-catalyzed hydrosilylation (Figure 1c). Surprisingly, stereocontrol was also achieved, for
the first time, by varying the silyl group of the hydrosilane. Experimental evidence and
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computational studies suggest that the reactions proceed via two distinct mechanistic pathways,
depending on the steric bulk of the silyl group.
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a) Drugs containing an octahydroisoindole core:
F
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S
N
CF3
Bn
H
N
O
H
N
H
H
N
OH
O
O
N
O
O
CF3
N
H
Me
O
H
mitiglinide
serlopitant
perospirone
b) Furan Diels-Alder reactions for constructing oxygen-bridged hexahydroisoindoles:
O
N
EWG
PG
Pitfalls
[4+2]
O
N
PG
1) Intrinsic stereoselectivity
2) Limited substrate scope
PG
N
PG
N
Hal
O
O
O
activated
unhindered
c) Hydrosilylation-promoted cascade reaction (this work):
R2
R1
OSiEt3
Et3SiH
R2
R2
R1
R1
Ts
Ts
N
N
Advantages
[4+2]
B(C6F5)3
1) Tunable stereoselectivity
2) Broad substrate scope
Ts
N
O
R2
Ts
N
R1
iPr3SiH
OSiiPr3
O
favored
unfavored
Figure 1. Syntheses and applications of hexahydroisoindoles.
RESULTS AND DISCUSSION
Our interest in borane-catalyzed hydrosilylation arose in the course of our ongoing work on
the development of borane-catalyzed reactions20–24. Pioneering works by the groups of Piers25–27
,
Oestreich28-34, and Sakata35 demonstrated that borane-catalyzed ketone hydrosilylation reactions
proceed via activation of the hydrosilane rather than by activation of a Lewis basic carbonyl group;
this activation mode is consistent with the concept of frustrated Lewis pairs introduced by Stephan
and Erker36–40. Because of this distinct activation mechanism, borane-catalyzed hydrosilylation
reactions should not be interfered with by other simultaneous reactions, as long as hydrosilane
activation is not inhibited; these characteristics present opportunities for the development of new
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cascade processes that take advantage of the orthogonal reactivity. We hypothesized that the
above-described unfavorable [4+2] Diels–Alder cycloaddition reactions of unactivated and
sterically hindered N-allyl-N-furfurylamides might become feasible if the cycloaddition product
underwent a borane-catalyzed hydrosilylative ether cleavage reaction41,42, which would drive the
equilibrium of the cycloaddition reaction toward product formation.
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To investigate this hypothesis, we began by carrying out reactions of furan 1a (Table 1),
whose propensity to undergo a furan Diels–Alder reaction is markedly diminished by the presence
of the methyl group on the olefin. Indeed, when 1a was heated at 120 °C in toluene for 12 h in the
absence of a catalyst, Diels–Alder product 2a was obtained in only 7% yield, with unreacted 1a
accounting for the rest of material (entry 1). However, when the reaction of 1a was carried out in
the presence of Et3SiH and 5 mol % of B(C6F5)3, the proposed cycloaddition/ether cleavage
cascade occurred, giving hexahydroisoindole 3a in 50% yield (entry 2), along with unidentified
products generated by decomposition of the starting material. This result confirmed that the ether
cleavage could shift the equilibrium of the otherwise unfavorable [4+2] cycloaddition reaction
toward product formation. Other hydrosilanes (Ph3SiH, PhMe2SiH, Ph2SiH2, Et2SiH2, and PhSiH3)
failed to improve the yield of 3a (entries 3–7). To our surprise, however, when we tested iPr3SiH
(entry 8), we obtained not 3a but rather 4a (94% yield), a diastereomer with the siloxy group on
the opposite face of the cyclohexene ring relative to that in 3a, as indicated by NMR spectroscopy
and single-crystal X-ray analysis.43 Because all the stereogenic centers are formed during the furan
Diels–Alder reaction, the selectivity of which is controlled solely by the electronic and steric
characteristics of the substrate, we were puzzled and interested to find that the stereochemical
outcome could be influenced by varying the silyl group.
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Table 1. Investigation of different hydrosilanesa
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B(C6F5)3
(5 mol %)
[Si]-H
Me
Me
Me
Me
H
H
H
O[Si]
O[Si]
TsN
O
TsN
TsN
TsN
+
+
toluene
120 °C, 24 h
9
O
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1a
2a
3a
4a
(±)
(±)
(±)
entry
[Si]-H
yield of 2a
7
yield of 3ab
n. d.
50
yield of 4ab
1c
2
None
n. d.
Et3SiH
Ph3SiH
PhMe2SiH
Ph2SiH2
Et2SiH2
PhSiH3
iPr3SiH
n. d.
n. d.
n. d.
n. d.
n. d.
n. d.
n. d.
n. d.
3
41
n. d.
4
26
n. d.
5
trace
n. d.
n. d.
trace
n. d.
6
n. d.
7
n. d.
8d
94
a The reaction was run with 0.2 mmol of 1a, 0.3 mmol of [Si]-H and 5 mol % of B(C6F5)3 in 0.5
mL of toluene in a sealed vial. b NMR yields determined by using CH2Br2 as the internal standard;
n. d. = not detected. c No B(C6F5)3 was added. d Reaction temperature: 110 °C.
Next, we investigated the generality of this silyl-group-controlled cascade process by carrying
i
out reactions of a variety of substrates 1 in the presence of either Et3SiH or Pr3SiH (Table 2).
Reactions of 1a with the two silanes afforded 3a and 4a in 45% and 85% isolated yields,
respectively (entry 1). When the substituent on the E-olefin was changed to n-propyl, i-propyl, or
benzyl (1b–1d), the cascade reaction gave exclusively or predominantly one of the two
diastereomers, depending on which hydrosilane was used (entries 2–4).43 However, reaction of
substrate 1e, which has a bromoethyl substituent, with Et3SiH gave a complex mixture of
i
decomposition products; whereas reaction with Pr3SiH generated 4e in 62% yield (entry 5).
Reactions with 1,1-disubstituted olefins 1f and 1g, which formed products with quaternary carbon
centers, were also feasible (entries 6 and 7). Although the diastereoselectivities were good for
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products 3f, 3g, and 4g, the dr for 4f was relatively low. The reaction of sterically unhindered
5
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substrate 1h was highly selective with Et3SiH but poorly selective with Pr3SiH (entry 8).
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Cyclizations of a substrate with a conjugated diene moiety (1i) occurred preferentially at the
proximal olefin to give hexahydroisoindoles 3i and 4i (entry 9). Surprisingly, the reaction was also
feasible with substrate 1j, which has a highly hindered trisubstituted olefin, demonstrating the
power of this cascade reaction (entry 10). Reactions of a series of substrates with terminal aryl
groups (entries 11–16) proceeded regardless of the electronic nature of the substituents on the
10
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aromatic rings;43 predominantly one diastereomer was obtained with both Et3SiH and Pr3SiH.
Interestingly, when substrates with Z-olefins were tested, reactions with Et3SiH and iPr3SiH gave
the same diastereomer as the major or only product (entries 17 and 18).
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Table 2. Substrate scopea
R3
R2
R1
R3
R2
R3
R2
B(C6F5)3
(5 mol %)
R1
R1
OSiEt3
OSiiPr3
6
7
Ts
N
Et3SiH or iPr3SiH
Ts
N
Ts N
+
or
toluene or DCE
75-130 °C, 24 h
O
8
1
3
4
9
3
4
3
4
entry
substrate
yield of (%)
yield of (%)
entry
substrate
yield of (%)
yield of (%)
10
11
12
13
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30
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60
Me
Me
H
Me
H
H
H
OSiEt3
OSiiPr3
OSiEt3
OSiiPr3
Ts
N
Ts
N
Ts
N
Ts N
1
8
Ts
N
Ts N
O
O
1a
1h
3a
4a
3h
4h
(±)
88% (dr = 2.4:1)
(±)
(±)
(±)
85%
61% (dr = 12:1)
45%
Me
Me
nPr
nPr
H
nPr
Me
H
OSiEt3
OSiiPr3
H
H
Ts
N
Ts
N
OSiiPr3
2
3
4
9
OSiEt3
Ts
N
Ts N
Ts
N
Ts N
O
O
1b
1i
3b
54%
4b
(±)
93%
3i
4i
(±)
67% (E/Z = 5.5:1)
(±)
H
(±)
(E/Z = 5.1:1 )
Me
Me
46% (E/Z = 4.5:1)
iPr
iPr
iPr
Me
Me
Me
Me
H
OSiEt3
OSiiPr3
OSiEt3
OSiiPr3
10
Ts
N
Ts
N
Ts
N
Ts
N
Ts
N
Ts N
O
O
3c
4c
3j
4jb
1c
1j
(±)
(±)
(±)
54%
(±)
36%
53%
43%
Bn
Ar
Bn
Bn
Ar
Ar
H
H
H
H
OSiEt3
OSiiPr3
OSiEt3
OSiiPr3
Ts
N
Ts N
Ts
N
Ts
N
Ts
N
Ts N
O
O
1d
4d
(±)
84%
3d
(±)
1k
11 Ar = Ph (
3k
4k
)
(±) , 62%
(±) , 55%
(E/Z = 8.5:1)
41%
1l
)
3l
4l
12 Ar = p-PhOC6H4
(
(±) , 51%
(±) , 55%
Br
1m
)
3m
, 56%
4m
, 60%
13 Ar = p-MeC6H4
(
(±)
(±)
Br
H
Ts
N
5
OSiiPr3
n. d.
1n
(
3n
(±) , 67%
4n
(±) , 69%
14 Ar = p-FC6H4
)
Ts
Ts
N
N
O
15 Ar = p-BrC6H4 (1o)
3o
4o
(±) , 66%
(±) , 69%
1p
)
3p
4p
16 Ar = p-CF3C6H4
(
(±) , 62%
(±) , 59%
1e
4e
(±)
62%
Et
Et
H
Et
H
Me
Me
OSiEt3
OSiiPr3
OSiEt3
OSiiPr3
Me
Ts
N
6
17
Ts
N
Ts
N
Ts
N
Ts N
O
O
1f
1q
3f
4f
3q
3q'
(±)
46% (dr = 4.1:1)
(±)
(±)
(±)
38%
91% (dr = 8.2:1)
92% (dr = 3.3:1)
nPr
nPr
nPr
H
H
Ph
Ph
OSiEt3
OSiiPr3
OSiEt3
OSiiPr3
Ph
18
7
Ts
N
Ts
N
Ts
N
Ts N
Ts
N
Ts N
O
O
1g
1r
3g
4g
3r
3r'
(±)
64% (dr = 6.8:1)
(±)
90% (dr = 8.4:1)
(±)
37%
(±)
44% (dr = 7:1)
a
See the supporting information for the detailed reaction conditions for each substrate. Isolated
yields are given. Products having very high diastereomeric selectivity (dr > 15:1) were not labelled
with the dr values. b 10 mol % of B(C6F5)3 was used.
To investigate the mechanism of the reaction, and particularly the origin of the silyl-group-
controlled selectivity, we conducted a number of control experiments (Figure 2). First, deuterated
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hydrosilanes were subjected to reactions with 1a. The deuterium of Et3SiD was transferred to the
allylic position of the cyclohexene (Figure 2a), indicating that addition of a hydride to the olefin
unit of the Diels–Alder cycloaddition intermediate might have occurred. In contrast, the deuterium
i
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of Pr3SiD was delivered to the carbon directly connected to the siloxy group (Figure 2b),
suggesting that 4a might be the product of ketone hydrosilylation. Next, we labelled the furan with
deuterium at the 5-position.44 After reaction of deuterated 1a with Et3SiH, the deuterium was still
at that position (Figure 2c), but wheniPr3SiH was used, the deuterium shifted to the adjacent carbon
(Figure 2d). These experiments indicate that the two reactions proceed via different pathways. We
suspected that reactions involving Et3SiH followed our originally intended pathway, that is, a
cascade process involving a furan Diels–Alder cycloaddition and a hydrosilylative ether cleavage;
i
whereas the reaction of Pr3SiH involved a 1,2-hydride migration and possibly a ketone
hydrosilylation.
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a
c
e
g
i
b
Me
Me
Me
Me
H
H
OSiiPr3
D
standard
standard
OSiEt3
H
conditions
conditions
TsN
TsN
TsN
TsN
Et3SiD
iPr3SiD
O
D
O
1a
4a-D
86% yield
(±)
1a
3a-D
40% yield
(±)
d
Me
Me
Me
H
Me
H
10
11
12
13
14
15
16
17
18
19
20
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22
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standard
conditions
standard
conditions
OSiiPr3
H
OSiEt3
TsN
TsN
TsN
iPr3SiH
TsN
D
Et3SiH
(70% D)
O
O
D
D
D
(70% D)
(70% D)
4a-D'
(±)
70% yield
(70% D)
3a-D'
(±)
37% yield
1a-D
1a-D
f
H
B(C6F5)3
(5 mol %)
B(C6F5)3
(5 mol %)
H
H
H
H
O
OSiiPr3
OSiEt3
O
TsN
O
TsN
(±)
TsN
+
TsN
TsN
(±)
iPr3SiH
PhMe
80 °C, 1 h
Et3SiH
DCE
80 °C, 1 h
3h
83% yield
(±)
(±) 4h
2h
2h
5
(±)
81% yield
9% yield
(dr = 2.4:1)
h
H
H
H
OSiiPr3
H
B(C6F5)3
(5 mol %)
B(C6F5)3
(1 equiv)
O
O
O
TsN
O
TsN
TsN
TsN
TsN
(±)
PhMe
80 °C, 1 h
iPr3SiH
PhMe
80 °C, 1 h
5
5
(±)
H
4h
(±)
2h
5
(±)
90% yield
77% yield
(dr = 2.4:1)
j
H
H
OSiiPr3
H
B(C6F5)3
(5 mol %)
iPr3SiH
PhMe
B(C6F5)3
(5 mol %)
O
OSiEt3
TsN
TsN
TsN
Et3SiH
DCE
80 °C, 1 h
5
(±)
4h
(±)
4h'
(±)
(±)
99% yield (dr = 1.6:1)
80 °C, 12 h
11% yield
(dr = 2.4:1)
Figure 2. Mechanistic Studies
We knew that reactions of hydrosilanes with the intermediates generated by the furan Diels–
Alder cycloaddition would provide more information about the overall mechanism, so we prepared
cycloaddition intermediate 2h from sterically unhindered substrate 1h, which was the only
substrate in our data table that afforded a reasonable yield of the cycloaddition intermediate under
thermal conditions (see the supporting information for details). Reaction of 2h with Et3SiH gave
corresponding cascade product 3h in 83% yield after 1 hour at 80 °C (Figure 2e). In contrast,
reaction with iPr3SiH gave only a 9% yield of 4h, and ketone 5 was the main product (Figure 2f).
Furthermore, heating 2h with B(C6F5)3 at 80 °C for 1 hour gave 5 in 90% yield (Figure 2g). These
i
results provide evidence for our suspicion that the cascade reaction with Pr3SiH occurred via
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ketone 5, which was produced by means of B(C6F5)3-promoted ring opening of 2h. Reaction of 5
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with Pr3SiH in the presence of one equivalent of B(C6F5)3 gave 4h in 77% yield after 1 hour
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(Figure 2h), and the selectivity was the same as that observed for the cascade reaction (Table 2,
entry 8). However, the same reaction with only a catalytic amount of B(C6F5)3 (5 mol %) gave a
poor yield of 4h, along with unreacted starting material (Figure 2i). These results suggest that an
excess of 5 relative to the catalyst inhibited the hydrosilylation reaction, probably because 5
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competed with Pr3SiH for coordination with B(C6F5)3. Therefore, in the cascade reaction of 1h
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with Pr3SiH, the concentration of 5 must remain low during the reaction. In another control
experiment, we found that reaction of 5 with Et3SiH gave a mixture of diastereomers with a poor
dr (Figure 2j). Considering that the cascade reaction of 1h with Et3SiH showed excellent
diastereoselectivity (Table 2, entry 8), we concluded that the cascade reaction with Et3SiH
proceeded exclusively via hydrosilylative cleavage of the oxygen bridge, rather than via
hydrosilylation of a ketone intermediate.
On the basis of the above-described experimental results, we propose the reaction
mechanisms shown in Figure 3. In the cascade reaction of 1a with Et3SiH (Figure 3a),
cycloaddition intermediate 2a reacts with borane-activated hydrosilane complex 6 to give ion pair
7, in which the silylium ion is bound to the oxygen bridge. Ring opening and subsequent delivery
of hydride to the allylic carbocation of 8 gives product 3a and regenerates the catalyst. The
calculated free energy profile of this process is shown in Figure 3b. The intramolecular furan
Diels–Alder reaction to afford 2a is endothermic by 1.2 kcal/mol and has an energy barrier of 28.8
kcal/mol (TS1), which is qualitatively in agreement with our experimental observation that the
equilibrium favors the starting material (1a). In addition, exo cycloaddition (TS1) is strongly
favored over endo cycloaddition (TS1’, 39.0 kcal/mol), and therefore a single isomer forms during
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the cycloaddition. Subsequent hydrosilylative ether cleavage (conversion of 2a to 3a) has an
overall barrier of 12.4 kcal/mol (from 2a to TS3), which is much lower than the barrier of the furan
Diels–Alder reaction, indicating that the cycloaddition reaction is rate-limiting. Furthermore, the
final step of the process, hydride addition to the allylic carbocation of 8 to form 3a is barrier-less
and is very exothermic (−44.3 kcal/mol).
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The proposed mechanism for the reaction with Pr3SiH involves two co-existing catalytic
cycles (A and B in Figure 3c). In the cycle A, B(C6F5)3 binds to the oxygen bridge of 2a to form
complex 9, which undergoes ring opening to give zwitterionic intermediate 10. Then a 1,2-hydride
shift gives borane-ketone complex 11. Dissociation of B(C6F5)3 from 11 generates ketone 12,
which enters catalytic cycle B, the borane-catalyzed ketone hydrosilylation reaction. In this cycle,
–
hydride is transferred from HB(C6F5)3 to the silyl-activated carbonyl group of bicyclic species 14
from the less-hindered face (opposite the methyl group), which results in the observed
stereochemical features of 4a. The free energy profile of the overall process is shown in Figure 3d.
Owing to the steric bulk of the silyl group, the mechanism depicted in Figure 3a becomes
energetically unfavorable (from 2a to TS9, 27.4 kcal/mol). Instead, from 2a, B(C6F5)3-mediated
ring opening with 1,2-hydride migration to form borane-ketone complex 11, which is exothermic
(−27.4 kcal/mol) and has a barrier of 13.2 kcal/mol, is the predominant reaction pathway. The
subsequent ketone hydrosilylation reaction has a barrier of 24.7 kcal/mol (from 11 to TS7). The
addition of hydride to the silyl-activated carbonyl group from the less-hindered face is favored by
3.5 kcal/mol (TS8 vs. TS10), in agreement with the excellent diastereocontrol observed in the
reaction of 1a with iPr3SiH. The furan Diels–Alder reaction is again the rate-determining step for
the overall process, and therefore the concentration of ketone intermediate 12 should be low
because the ketone is readily converted to the final product. In fact, the experiment shown in Figure
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2i indicates that the low ketone concentration is essential to prevent catalyst inhibition by excess
ketone.
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9
Notably, the Gibbs free energies shown in Figure 3b and Figure 3d were calculated at 120 °C
(393 K) and 110 °C (383 K), respectively, in accordance with the respective optimal reaction
temperature. We have also calculated the pathway shown in Figure 3d when Et3SiH was applied
in place of iPr3SiH at 120 °C (393 K). The obtained free energy profile is given in the supporting
information as Figure S1. The energy profile indicates that this pathway is less favorable than the
pathway depicted in Figure 3b because of the relatively high energy of TS5 (14.9 kcal/mol at 120
°C) compared to TS3 in Figure 3b (13.6 kcal/mol), which is qualitatively in agreement with the
experimental result.
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5
a
b
CH3
O
CH3
CH3
H
‡
‡
OSiEt3
TsN
B(C6F5)3
O
CH3
CH3
6
7
8
9
N
N
H
H
Et3SiH
TS1
TS1'
SiEt3
‡
3a
39.0
Ts
Ts
O
O
TS1'
Ts
N
Ts
N
G393 K
(kcal·mol-1
)
28.8
2a'
HB(C6F5)3
TS3
CH3
H
TS1


B(C6F5)3
13.1
OSiEt3
Et3Si
H
2a'
13.6
10
11
12
13
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TsN
6
8.8
TS3
6
8
3.0
2.0
1.2
TS2
0.3
0.0
1a
HB(C6F5)3
7
6
2a
8
2a
1a
Et3SiH
B(C6F5)3
CH3
CH3
H
B(C6F5)3
‡
H
Et3Si
H
SiEt3
B(C6F5)3
O
O
Ts
N
TsN
7
TS2
-44.0
HB(C6F5)3
3a
c
CH3
CH3
O
B(C6F5)3
O
H
H
TsN
TsN
iPr3SiH
H
1,2-hydride
shift
12
11

iPr3Si

B(C6F5)3
H
13
CH3
H
B(C6F5)3
O
H
Cycle A
Cycle B
B(C6F5)3
TsN
CH3
10
H
OSiiPr3
HB(C6F5)3
TsN
CH3
2a
1a
CH3
H
B(C6F5)3
H
14
H
OSiiPr3
O
TsN
TsN
9
4a
CH3
d
CH3
iPr3Si
‡
‡
H
H
B(C6F5)3
O
Ts
N
O
N
Ts
CH3
‡
H
28.7
TS1
28.5
O
H
B(C6F5)3
TS10
G383 K
(kcal·mol-1
Ts N
TS9
CH3
‡
)
H
OSiiPr3
13
TS6
HB(C6F5)3
Ts
N
H
14.3
TS5
9.5
TS8
8.0
7.5
TS4
4.3
10
9
TS6
2.7
1.1
2a
0.0
B(C6F5)3
13
-1.6
-5.8
TS10
1a
iPr3SiH
TS7
B(C6F5)3
CH3
CH3
‡
‡
B(C6F5)3
13
-9.3
TS8
B(C6F5)3
H
H
B(C6F5)3
O
O
Ts
N
Ts
N
-21.0
-22.5
14
-26.3
B(C6F5)3
12
B(C6F5)3
‡
TS5
TS4
11
iPr3Si H
B(C6F5)3
CH3
-40.9
4a'
H
O
Ts
N
-42.5
4a
TS7
Figure 3. a, Proposed mechanism of the reaction of 1a with Et3SiH. b, Energy profile of the
reaction with Et3SiH at 393 K. c, Proposed mechanism of the reaction of 1a with iPr3SiH. d, Energy
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profile of the reaction with Pr3SiH at 383 K. DFT calculations were performed using M06-2X-
D3/6-311++G(d,p)/SMD(toluene)//M06-2X/6-31G(d).
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We then explored the synthetic utility of this methodology by carrying out some
transformations of 4a (Figure 4). The tosyl protecting group could easily be removed by reaction
with magnesium to afford free amine 15. In addition, the olefin could be transformed either to
epoxides (trans-16 and cis-16) via oxidation with m-CPBA or to hydroxyl compounds (cis-17 and
trans-17) via hydroboration followed by oxidation. Furthermore, the silyl group could be cleaved
with TBAF to give unprotected hydroxyl compound 18, which could be oxidized with PCC to give
ketone 1245 or hydrogenation over Pd/C to give cis-bicyclic octahydroisoindole 19, in excellent
yields in both cases.
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Me
Me
Me
Me
Me
H
O
H
O
OSiiPr3
OSiiPr3
H
O
Ts
N
Ts N
+
Ts
N
trans-16
(±)
67% yield
cis-16
25% yield
12
(±)
98% yield
(±)
m-CPBA
DCM, rt, 16 h
PCC
DCM, rt, 4 h
Me
Me
H
H
H
OSiiPr3
OSiiPr3
OH
Mg
TBAF
THF
Ts
N
HN
Ts
N
MeOH
reflux, 1 h
0 °C to rt, overnight
18
84% yield
(±)
15
70% yield
4a
(±)
(±)
2) NaOH (aq.)
30% H2O2, 60 °C, 1 h
Pd/C, H2
DCM, rt, 4 h
1) BH3•THF
THF, 0 °C to rt, overnight
Me
H
Me
H
OSiiPr3
OSiiPr3
H
OH
+
Ts
N
Ts
N
Ts
N
H
H
H
OH
cis-17
OH
trans-17
19
(±)
35% yield
(±)
(±)
99% yield (dr >10:1)
35% yield
Figure 4. Transformations of 4a
CONCLUSIONS
In summary, we overcame the narrow substrate scope of intramolecular furan Diels–Alder
reactions of N-allyl-N-furfurylamides by developing a cascade process that involves a borane-
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catalyzed hydrosilylation reaction. Furthermore, the stereoselectivity was controlled by the
hydrosilane. Control experiments and computational studies were performed to elucidate the
mechanism of the reactions, which involve either hydrosilylative ether cleavage or borane-
catalyzed ether cleavage followed by ketone hydrosilylation, depending on the hydrosilane that is
used. Furthermore, the reaction generates structurally interesting and synthetically useful
heterobicyclic compounds, which are not readily accessible by other methods. The chemistry
showcases the power of borane-catalyzed hydrosilylation reactions. Our results can be expected to
lead to the development of additional cascade processes involving borane-catalyzed
hydrosilylation.
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ASSOCIATED CONTENT
Supporting Information. Experimental details, compound characterization data, spectra (PDF),
and X-ray diffraction data (CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*xcwang@nankai.edu.cn
ORCID
Xiao-Chen Wang: 0000-0001-5863-0804
Notes
The authors declare no competing financial interests.
Author Contributions
Z.-Y.L. and M.Z. contributed equally to this work.
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ACKNOWLEDGMENT
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We thank financial support from the National Natural Science Foundation of China (91956106
and 21871147), and the Fundamental Research Funds for Central Universities. We thank Prof.
Xiufang Xu, Prof. Shou-Fei Zhu and Prof. Qian Peng for assistance with DFT calculations.
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44. We were unable to achieve higher than 70% of the deuterium incorporation at the 5-position.
45. Indeed, ketone 12 could be alternatively obtained by reacting 1a in toluene at 110 °C for 24 h
in the presence of 5 mol % of B(C6F5)3 without the addition of any hydrosilanes. However, the
NMR yield of 12 was merely 22% because of the severe decomposition of 1a under these
conditions.
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TOC
R2
R1
OSiEt3
OSiiPr3
Et3SiH
iPr3SiH
R2
R2
R1
R1
Ts
Ts
N
N
[4+2]
B(C6F5)3
Ts
N
O
R2
Ts
N
R1
O
favored
unfavored
Advantages: 1) Tunable stereoselectivity; 2) Broad substrate scope
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