Tunable arylative cyclization of 1,6-enynes triggered by rhodium(III)-catalyzed C-H activation

Article abstract of DOI:10.1021/ja5072702

Two tunable arylative cyclizations of cyclohexadienone-containing 1,6-enynes are reported via rhodium(III)-catalyzed C-H activation of O-substituted N-hydroxybenzamides. The use of different O substituents, i.e. O-Piv and O-Me, on the directing group allows the formation of either tetracyclic isoquinolones through an N-Michael addition process or hydrobenzofurans through a C-Michael addition process. Mechanistic investigations of these two cascade reactions clearly indicated that the C-H bond cleavage process was involved in the turnover-limiting step. Furthermore, the cyclization products could be subjected to various transformations for elaborating the pharmaceutically and synthetically valuable potential. This is the first example of a rhodium(III)-catalyzed arylative cyclization reaction of 1,6-enynes, and the results extend the application realm of CpRh^III-catalyzed C-H activation cascade reactions.

Full text of DOI:10.1021/ja5072702

Article
pubs.acs.org/JACS
Tunable Arylative Cyclization of 1,6-Enynes Triggered by
Rhodium(III)-Catalyzed C−H Activation
Yuki Fukui,†,‡ Ping Liu,‡ Qiang Liu, Zhi-Tao He, Nuo-Yi Wu, Ping Tian,* and Guo-Qiang Lin*
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, People’s Republic of China
S
* Supporting Information
ABSTRACT: Two tunable arylative cyclizations of cyclohexadienone-containing 1,6-enynes are reported via rhodium(III)-
catalyzed C−H activation of O-substituted N-hydroxybenzamides. The use of different O substituents, i.e. O-Piv and O-Me, on
the directing group allows the formation of either tetracyclic isoquinolones through an Ⓝ-Michael addition process or
hydrobenzofurans through a Ⓒ-Michael addition process. Mechanistic investigations of these two cascade reactions clearly
indicated that the C−H bond cleavage process was involved in the turnover-limiting step. Furthermore, the cyclization products
could be subjected to various transformations for elaborating the pharmaceutically and synthetically valuable potential. This is the
first example of a rhodium(III)-catalyzed arylative cyclization reaction of 1,6-enynes, and the results extend the application realm
of Cp*RhIII-catalyzed C−H activation cascade reactions.
set the stage for intense research activity in the area of
Cp*RhIII-catalyzed C−H activation of O-substituted N-
hydroxybenzamides and related processes.9,10
INTRODUCTION
■
Transition-metal-catalyzed direct C−H bond functionalizations
have recently emerged as a powerful, atom-economical, and
ideal method for the formation of carbon−carbon and carbon−
heteroatom bonds.1 Among such transformations, Cp*RhIII-
catalyzed C−H activation, in combination with its subsequent
cross-coupling with alkynes, alkenes, allenes, arenes, and
heteroatoms, is becoming a rapidly evolving research field.2
Various neutral and anionic functionalities, such as hetero-
cycles,3 ketones,4 and carboxylic acid derivatives,5−7 have been
continually developed as efficient directing groups. As an
elegant and green strategy, the use of an oxidizing directing
group (an internal oxidant) has drawn much attention due to
its dual roles in directing C−H activation and regenerating the
catalyst.
In 2010 and 2011, Fagnou and co-workers successively
described Cp*RhIII-catalyzed redox-neutral coupling of N-
methoxy-/N-(pivaloyloxy)benzamides with alkynes to afford a
wide variety of isoquinolones, which sheds light on the stepwise
C−N bond reductive elimination and N−O bond oxidative
addition mechanism (Scheme 1a).8 Roughly at the same time,
Rovis and co-workers established an oxidative cyclization
between benzamides and alkynes.7a These key seminal findings
In 2012, using alkyne-tethered hydroxamic esters as an
alternative substitution pattern, Park and co-workers sub-
sequently offered a novel approach to isoquinolones, but with
reversed regioselectivity (Scheme 1b).11 In the same year,
Glorius and co-workers identified a new method for the
coupling of N-(pivaloyloxy)benzamides and ethynylboronates
for straightforward access to 2-isoquinolinylboronates.12
Just recently, Glorius and co-workers also successfully
developed the Cp*RhIII-catalyzed C−H activation and 1,3-
diyne strategy for the efficient formation of bis-isoquinolones,13
while Antonchick and co-workers described another elegant
alternative organocatalytic gateway from the coupling of N-
methoxybenzamides and diaryl-alkynes to isoquinolones
through a nitrenium ion process.14
Despite such exciting advances, Cp*RhIII-catalyzed coupling
of O-substituted N-hydroxybenzamides and functionalized
alkynes mainly focused on the C−N bond reductive elimination
Received: July 21, 2014
© XXXX American Chemical Society
A
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Scheme 1. Cp*RhIII-Catalyzed Cyclization of N-Methoxy-/
N-(Pivaloyloxy)benzamides and Alkynes
On the other hand, we envisioned that the intermediate T1
could undergo Ⓒ-Michael addition to furnish the fused bicyclic
product hydrobenzofurans due to the presence of the highly
reactive Michael acceptor: i.e., cyclohexadienone (Scheme 2).
However, to the best of our knowledge, the straightforward
Ⓒ-Michael addition has difficulty taking place, due to the steric
congestion imposed by the cyclic vinyl Cp*RhIII intermediate
T1. We supposed that the opened vinyl-Rh(III) intermediate
T2 could be generated in protic media and the subsequent
Ⓒ-Michael addition could occur with ease.10 Thus, no C−N
bond reductive elimination process is involved in this sequence,
which provides a new catalytic pattern.
RESULTS AND DISCUSSION
■
The findings by Fagnou and co-workers8 showed that the O-
pivaloyl group in N-hydroxybenzamides can potentially chelate
Rh(III) and promote C−N bond reductive elimination. Thus,
we commenced to examine the Cp*RhIII-catalyzed cyclization
of N-(pivaloyloxy)benzamide (1a) and 1,6-enyne 2a (Table 1).
Table 1. Reaction Optimization toward Cp*RhIII-Catalyzed
Cyclization of N-(Pivaloyloxy)benzamide (1a) and 1,6-
a
Enyne 2a
pathway, and the process without C−N bond reductive
elimination has never been uncovered.10 Considering this
concern, we reasoned that Cp*RhIII-catalyzed cyclization of O-
substituted N-hydroxybenzamides and alkyne-tethered cyclo-
hexadienone15 could provide another reaction pattern, possibly
in a different cascade process. In this case, regioselective
insertion of the carbon−carbon triple bond of cyclohexadie-
none-containing 1,6-enynes into the Rh−Ar bond, derived from
Rh(III)-catalyzed C−H activation of O-substituted N-hydrox-
ybenzamides, could give the seven-membered rhodacycle
intermediate T1 (Scheme 2). The subsequent C−N bond
reductive elimination, N−O bond oxidative addition, and
protonolysis of the Rh−N bond could afford the neutral NH
functional group, which then undergoes an Ⓝ-Michael addition
reaction, leading to the formation of N-substituted isoquino-
lones.
b
entry
solvent
additive
T (°C) t (h) yield (%)
1
2
3
4
5
6
7
8
MeOH
MeOH
i-PrOH
i-PrOH
t-BuOH
THF
25
60
40
60
60
40
60
25
50
25
12
16
30
10
10
10
10
40
12
16
5
eg
,
30
e
42
e
e
54
35
0
e
MeCN
DMF
17
e
f
55
c
9
acetone
DMF
MS (4 Å, 100 mg)
85
91
d
f
10
Cu(OAc)2 (0.4 equiv)
a
Reaction conditions: 1a (0.2 mmol), 2a (1.1 equiv), [Cp*RhCl2]2
(0.005 mmol, 5 mol % Rh), CsOAc (2.0 equiv), solvent (1 mL), under
N2. Piv = pivaolyl. Isolated yield. 1a (1.5 equiv) and 2a (0.2 mmol).
1a (2.0 equiv) and 2a (0.2 mmol). Based on 1a. Based on 2a. 3aa
b
c
d
e
f
g
Scheme 2. Strategic Design for Rh(III)-Catalyzed
Cyclization of Benzamides and 1,6-Enynes
(30% yield) and 7aa (10% yield).
The reaction was first performed in MeOH at room
temperature; most of the starting materials were recovered,
and only trace cyclization product was observed (Table 1, entry
1). To our delight, the desired tetracyclic product 3aa was
obtained in 30% yield, accompanied by a 10% yield of
dimerization side product 7aa,17 when the reaction temperature
was raised to 60 °C (Table 1, entry 2). Next, a set of
representative protic solvents (i-PrOH, t-BuOH) and polar
solvents (THF, MeCN, DMF) were screened; the reactions still
afforded low to moderate yields, and their main side products
were the removal of the pivaloyl group in 1a to the formation of
N-hydroxybenzamide (Table 1, entries 3−8). Therefore, an
B
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excess amount of benzamide 1a was used in the next reaction
testing. As a result, the yield was greatly increased to 85% when
the reaction was conducted in acetone at 50 °C with molecular
sieves as an additive (Table 1, entry 9). According to a recent
report by Glorius and co-workers, the addition of a
substoichiometric amount of Cu(OAc)2 facilitated the C−H
bond functionalizations of N-(pivaloyloxy)benzamides and
significantly improved the reaction yields.12 In our case, the
yield dramatically rose to 91% in the presence of Cu(OAc)2 (40
mol %) (Table 1, entry 10). We therefore proposed that copper
could promote the regeneration of the active Rh(III) catalyst
from deactivated Rh(I) species.
With the optimal reaction conditions identified, the scope of
various 1,6-enynes 2 was investigated. With the R2 substituent
as alkyl, benzyl, and phenyl groups in the terminal alkyne
substrates, the reactions proceeded smoothly with moderate to
excellent yields (Table 2, entries 1−5). With a heteroatom (N
for the internal alkyne substrate 2l, due to a lack of obvious
steric or electronic differences at both ends of alkyne, the
cyclization product 3al was obtained in 52% yield, accompanied
by the regioisomer 3al′ (38% yield; see the Supporting
Information), which cannot undergo a further Ⓝ-Michael
reaction (Table 2, entry 12). For the C- and N-linked 1,6-enyne
substrates 2m,n, the desired cyclization products were also
obtained in slightly lower yields (Table 2, entries 13 and 14).
Various N-(pivaloyloxy)benzamides 1 were also examined.
All 4-substituted N-(pivaloyloxy)benzamides, regardless of the
electron-donating or electron-withdrawing properties of the
substitutent at the phenyl ring, afforded the cyclization
products (Table 2, entries 15−19). For 3-methyl-N-
(pivaloyloxy)benzamide (1g), the C−H activation could take
place at either the 6- or 2-position, giving the two inseparable
cyclization products 3ga (43% yield) and 3ga′ (8% yield; Table
2, entry 20). Interestingly, 2-methyl-N-(pivaloyloxy)benzamide
(1h) failed to give the cyclization product, probably due to the
large steric hindrance of the neighboring substituent.16a In most
cases in Table 2, the low yields were mainly attributed to the
decomposition of 1a to form N-hydroxybenzamide.
Table 2. Cp*RhIII-Catalyzed Cyclization of N-
(Pivaloyloxy)benzamides 1 and 1,6-Enynes 2
The recent findings revealed that selecting N-methoxybenza-
mide as a coupling partner with the reaction of terminal alkene
gave the olefinated benzamide, the noncyclized product without
the formation of a C−N bond.10 Thus, we chose N-
methoxybenzamide (4a) as a coupling partner to explore the
Ⓒ-Michael addition cyclization potential with 1,6-enyne 2a.
Unfortunately, only the dimerization products of 2a were
observed under the aforementioned conditions (Table 3,
c
entry
1 (R1)
1a (H)
2 (R2 or R3)
t (h) 3 (yield (%))
b
1
2a (R2 = Me)
15
12
36
24
36
48
24
24
20
12
12
12
12
8
3aa (91)
3ab (75)
3ac (65)
3ad (85)
3ae (66)
3af (40)
3ag (40)
3ah (40)
3ai (47)
3aj (62)
3ak (46)
3al (52)
3am (72)
3an (44)
3ba (49)
3ca (78)
3da (52)
3ea (68)
3fa (50)
a
2
1a (H)
2b (R2 = Et)
Table 3. Reaction Optimization toward Cp*RhIII-Catalyzed
a
3
1a (H)
2c (R2 = i-Pr)
a
Cyclization of N-Methoxybenzamide (4a) and 1,6-Enyne 2a
a
4
1a (H)
2d (R2 = PhCH2)
2e (R2 = Ph)
a
5
1a (H)
a
e
6
1a (H)
2f (R2 = BocNH(CH2)2)
2g (R2 = AcO(CH2)2)
2h (R2 = TBSO(CH2)3)
2i (R2 = MeO)
2j (R3 = Me)
2k (R3 = HOCH2)
2l (R3 = BnOCH2)
2m (R2 = MeO)
2n (R2 = Me)
2a (R2 = Me)
2a (R2 = Me)
2a (R2 = Me)
2a (R2 = Me)
2a (R2 = Me)
2a (R2 = Me)
a
7
1a (H)
a
f
8
1a (H)
a
9
1a (H)
b
10
1a (H)
a
11
1a (H)
yield
b
a
entry
1
solvent
MeOH
additive
T (°C) t (h)
(%)
12
1a (H)
a
c
13
1a (H)
Cu(OAc)2
(0.4 equiv)
50
3
0
a
14
1a (H)
d
a
2
3
4
5
DMF
60
25
25
60
12
48
48
24
0
15
1b (4-MeO)
1c (4-F)
1d (4-Br)
1e (4-CF3)
1f (4-Me)
1g (3-Me)
20
12
24
12
36
40
a
n-BuOH
CF3CH2OH
THF
9
19
24
16
b
17
a
CF3CH2OH
(2.0 equiv)
18
a
19
6
1,4-dioxane
1,4-dioxane
PivOH (2.0 equiv)
PivOH (2.0 equiv)
80
80
60
60
60
24
24
12
12
12
39
0
a
d
20
3ga (43)
e
7
a
Conditions A: 1 (1.5 equiv), 2 (0.2 mmol), [Cp*RhCl2]2 (0.005
mmol, 5 mol % Rh), CsOAc (2.0 equiv), acetone (1 mL), 50 °C,
under N2. Conditions B: 1 (2.0 equiv), 2 (0.2 mmol), [Cp*RhCl2]2
(0.005 mmol, 5 mol % Rh), CsOAc (2.0 equiv), DMF (1 mL), room
temperature, under N2. Isolated yield, based on 2. An inseparable
f
8
fg
ClCH2CH2Cl PivOH (2.0 equiv)
ClCH2CH2Cl PivOH (2.0 equiv)
ClCH2CH2Cl PivOH (2.0 equiv)
62
63
9 ,
b
fh
i
10 ,
31
c
d
a
e
Reaction conditions: 4a (0.4 mmol), 2a (0.2 mmol), [Cp*RhCl2]2
(0.005 mmol, 5 mol % Rh), CsOAc (2.0 equiv), solvent (2 mL), under
regioisomer, 3ga′ (8% yield), was obtained. Boc = tert-butoxycar-
f
bonyl. TBS = tert-butyldimethylsilyl.
b
c
d
e
N2. Isolated yield. 6aa (66% yield). 7aa (79% yield). With no
f
g
CsOAc. Using CsOPiv instead of CsOAc. 4a (0.3 mmol) was used.
h
i
and O) as part of R2 in substrates 2, the cyclization reaction
performed equally well, albeit in around 40% yields (Table 2,
entries 6−9). For the internal alkyne substrates 2j,k
regioselective insertion of the internal alkyne bond into the
Rh−Ar bond readily occurred, leading to the formation of
isoquinolone products (Table 2, entries 10 and 11). However,
4a (0.2 mmol) and 2a (0.6 mmol) were used. Based on 4a.
C
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entries 1 and 2).17 When n-BuOH was used as solvent and the
reaction temperature was lowered, we were delighted to get the
desired bicyclic product 5aa in 9% yield (Table 3, entry 3).
Slightly higher yields were obtained with trifluoroethanol as
solvent or additive (Table 3, entries 4 and 5). The yield was
further increased to 39% with pivalic acid as additive (Table 3,
entry 6).10 However, no cyclization product was observed in
the absence of base (Table 3, entry 7). Fortunately, when the
solvent was changed to 1,2-dichloroethane, the yield was greatly
raised to 62%. Lowering the loading of N-methoxybenzamide
(4a) had no impact on the yield (Table 3, entries 8 and 9).
However, an attempt to increase 1,6-enyne 2a loading also
resulted in a decreased yield (Table 3, entry 10).
at the phenyl ring, delivered the cyclization products (Table 4,
entries 11−18). For 3-methyl-N-methoxybenzamide (4i), the
C−H activation selectively occurred at the 6-position, only
giving cyclization product 5ia (Table 4, entry 19). Intriguingly,
2-methyl-N-methoxybenzamide (4j) also gave the cyclization
product (Table 4, entry 20).
The structure and relative configuration of product 5do were
determined by an X-ray diffraction analysis (Figure 1).18
With the satisfactory conditions in hand, various 1,6-enynes 2
were then examined. With the R5 substituent as alkyl, benzyl,
and phenyl groups in the terminal alkyne substrates, the
Ⓒ-Michael addition cyclization occurred readily with good
yields (Table 4, entries 1−5). With a heteroatom (N, O, and
Table 4. Cp*RhIII-Catalyzed Cyclization of N-
a
Methoxybenzamides 4 and 1,6-Enynes 2
Figure 1. X-ray structure of 5do.
To get further insight into the mechanism of these cascade
reactions, deuterium-labeling experiments were designed to
determine the values of the kinetic isotope effects (KIEs).16 For
the Ⓝ-Michael addition process, two parallel reactions, one with
the hydrogenated substrate 1a (1.5 equiv) and the other with
the deuterated substrate d5-1a (1.5 equiv), were conducted
separately within 5 min under standard conditions A, which
only afforded the intermediates 3aa′ and d4-3aa′,19 respectively
(Exp. I, Scheme 3). Their relative ratio gave a sketchy KIE value
of kH/kD = 6.1, indicating that the C−H bond cleavage process
should be the turnover-limiting step.20 The intermolecular KIE
experiment was then performed by treating 1.5 equiv of 1a, 1.5
equiv of d5-1a, and 1.0 equiv of 2a within 5 min to give a KIE
value of kH/kD = 6.7 (Exp. II, Scheme 3). The intramolecular
KIE was also determined to be kH/kD = 5.7 by treatment of d-
1a with 2a (Exp. III, Scheme 3). Thus, the intermolecular and
intramolecular KIEs provided additional evidence regarding the
turnover-limiting step. The KIEs of experiments IV (H/D-
alkynes) and V (H/D-cyclohexadienones) were also deter-
mined to be 1.2 and 1.0, respectively, demonstrating that the
insertion of the carbon−carbon triple bond and Ⓝ-Michael
addition steps are not involved in the turnover-limiting step.16a
For the Ⓒ-Michael addition process, similar outcomes were
observed. The KIEs of experiments VI−VIII were determined
to be 2.0, 6.1, and 4.3, respectively.16a These results clearly
suggest that the C−H bond cleavage process is equally involved
in the turnover-limiting step.
b
Entry
4 (R4)
4a (H)
2 (R5)
2a (Me)
5 (yield (%))
1
5aa (63)
5ab (68)
5ac (61)
5ad (61)
5ae (67)
5ao (63)
5af (43)
5ag (51)
5ap (61)
5aq (62)
5ba (55)
5ca (57)
5da (66)
5do (54)
5ea (63)
5fa (60)
5ga (63)
5ha (59)
5ia (62)
5ja (61)
2
4a (H)
2b (Et)
3
4a (H)
2c (i-Pr)
4
4a (H)
2d (PhCH2)
2e (Ph)
5
4a (H)
6
4a (H)
2o (4-Br-C6H4)
2f (BocNH(CH2)2)
2g (AcO(CH2)2)
2p (n-PrO)
2q (Br(CH2)3)
2a (Me)
7
4a (H)
8
4a (H)
9
4a (H)
10
11
12
13
14
15
16
17
18
19
20
4a (H)
4b (4-MeO)
4c (4-F)
4d (4-Br)
4d (4-Br)
4e (4-CF3)
4f (4-NO2)
4g (4-MeCO2)
4h (4-Me)
4i (3-Me)
4j (2-Me)
2a (Me)
2a (Me)
2o (4-BrC6H4)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
2a (Me)
a
Reaction conditions: 4 (0.3 mmol), 2 (0.2 mmol), [Cp*RhCl2]2
(0.005 mmol, 5 mol % Rh), CsOPiv (2.0 equiv), PivOH (2.0 equiv),
1,2-dichloroethane (2 mL), under N2, at 60 °C for 12 h. Isolated
b
Piecing together these above details, we proposed that their
mechanisms differ regarding such O substitution in N-
hydroxybenzamides (Figure 2). Initially, a highly reactive
rhodium(III) species A/F is generated from the Rh precatalyst
[Cp*RhCl2]2 in the presence of CsOAc/CsOPiv. Subsequently
the chelation-assisted C−H activation occurs at the ortho
position via a base-assisted concerted metalation/deprotonation
(CMD) pathway,21 which is the turnover-limiting step in the
entire tandem reaction. The five-membered rhodacycle B/G
undergoes regioselective syn addition to the carbon−carbon
triple bond in 2 to afford the seven-membered rhodium
intermediate C/H. For N-(pivaloyloxy)benzamides, the O-
yield, based on 2.
Br) as part of R5 in substrates 2, the cyclization reaction
proceeded equally well (Table 4, entries 6−10). For the
internal alkyne 2j and the C- and N-linked 1,6-enynes 2m,n
(for the structures of substrates 2j,m,n, see Table 2), no desired
cyclization products were observed under the standard reaction
conditions.16a
Next, various N-methoxybenzamides 4 were also inves-
tigated. All 4-substituted substrates, regardless of the electron-
donating or electron-withdrawing properties of the substituent
D
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Scheme 3. Deuterium-Labeling Experiments and Study of the Kinetic Isotope Effects
Figure 2. Postulated mechanisms for the two different arylative cyclization reactions.
pivaloyl group can potentially chelate Rh(III) and promote C−
N bond reductive elimination, thus allowing the facile
formation of intermediate D and the Rh(I) species (Cp*Rh).
Then, a fast oxidative addition occurs to provide the
intermediate E, which is readily protonated by acetic/pivalic
acid to regenerate the reactive species A and liberate the
cyclohexadienone-containing isoquinolone intermediate 3′.
Finally, an intramolecular Ⓝ-Michael addition reaction under
CsOAc/CsOPiv19 leads to the formation of the tetracyclic
product 3. On the other hand, for N-methoxybenzamides, there
is no additional chelating functionality that promotes C−N
bond reductive elimination; thus, the seven-membered rhoda-
cycle H is rapidly protonated by pivalic acid to give the opened
vinyl−Rh(III) intermediate J. Next, the favorable six-membered
chairlike form of J enables syn-migratory insertion in the
Ⓒ-Michael addition, providing the oxa-π-allylrhodium inter-
mediate K, which is readily protonated by pivalic acid to
regenerate F and release the product 5. It should be noted that
E
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rhodium stayed in a constant oxidation state of +3 throughout
this catalytic cycle.
versions are in progress in our laboratories and will be reported
in due course.
To further demonstrate the synthetic utility of this
methodology, the cyclization products were converted into
pharmaceutically interesting isoquinolone derivatives and the
useful core structures were related to natural products (Scheme
4). When compound 3aa was treated with NBS, selective
EXPERIMENTAL SECTION
■
General Information. All solvents were dried before use following
the standard procedures. Unless otherwise indicated, all starting
materials purchased from commercial suppliers were used without
further purification. The 1H and 13C NMR spectra were recorded on a
Bruker AV-400 MHz instrument in the indicated solvents. Chemical
shifts are reported in δ (ppm) referenced to an internal TMS standard
Scheme 4. Transformations of the Cyclization Products
1
for H NMR and CDCl3 (δ 77.10 ppm) for 13C NMR. Coupling
constants (J) are quoted in Hz. IR spectra were recorded on a Nicolet
iN 10 MX instrument. ESI mass spectra were recorded on an
Agilent1200/G6100A instrument.
General Method A for Cp*RhIII-Catalyzed Cyclization of N-
(Pivaloyloxy)benzamides 1 and 1,6-Enynes 2. A dried Schlenk
flask was charged with cyclohexadienone-containing 1,6-enyne
substrate 2 (0.2 mmol), N-(pivaloyloxy)benzamide 1 (0.3 mmol, 1.5
equiv), [Cp*RhCl2]2 (3.1 mg, 0.005 mmol, 5 mol % as Rh), MS 4 Å
(100 mg), CsOAc (76.8 mg, 0.4 mmol, 2.0 equiv), and acetone (dry, 1
mL) under a nitrogen atmosphere. Then the reaction mixture was
stirred at 50 °C until the substrate was completely consumed. The
resulting mixture was cooled to room temperature, quenched with
saturated aqueous NaHCO3 (5 mL), and extracted with DCM (15 mL
× 3). The combined organic phases were dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The residue was purified
by silica gel (300−400 mesh) column chromatography to afford the
desired product 3.
cis-4a-Ethyl-1,13a-dihydrobenzo[5,6][1,4]oxazino[4,3-b]-
isoquinoline-2,12(4aH,6H)-dione (3ab, Table 2, entry 2): colorless
1
oil, 44.2 mg, 75% yield; H NMR (400 MHz, CDCl3) δ (ppm) 8.41
bromination occurred to afford bromide 8aa in high yield,
which could undergo further transformations to furnish
diversely useful molecules. For example, the pentacyclic
structure 9aa was accomplished through Suzuki−Miyaura
coupling with phenylboronic acid. The relative configuration
of 8aa was unequivocally determined as the cis form on the
basis of an X-ray diffraction analysis.18 Additionally, the existing
nitrogen atom in 3af provided another handle to construct the
consecutively pentacyclic skeleton 8af through aza-Michael
addition with excellent yield. Very similarly, removal of the
acetyl group in 5ag and simultaneous in situ oxa-Michael
addition under basic conditions led to the formation of product
10ag. A subsequent ozonolysis produced the tricyclic skeleton
11ag, serving as the architecture unit of incarviditone.22
(d, J = 8.0 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.51−7.44 (m, 2H), 6.80
(d, J = 10.4 Hz, 1H) 6.38 (s, 1H), 6.23 (d, J = 10.4 Hz, 1H), 5.28 (dd,
J = 11.6, 5.2 Hz, 1H), 4.92, 4.81 (AB, JAB = 16.0 Hz, 2H), 3.02 (dd, J =
16.4, 5.2 Hz, 1H), 2.66 (dd, J = 16.4, 11.6 Hz, 1H), 1.90−1.70 (m,
2H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm)
196.39, 161.78, 146.85, 136.11, 134.31, 132.91, 131.35, 128.04, 126.72,
125.65, 124.64, 72.68, 61.67, 48.57, 39.57, 27.91, 7.56; ESI-MS [M +
+
H]+ 296.2; HRMS (FTMS-ESI) [M + H]+ calcd for C18H18NO3
296.1287, found 296.1281; IR (KBr) ν (cm−1) 2970, 2937, 1690,
1655, 1622, 1598, 1429, 1338, 1294, 1169, 1064, 924, 824, 759, 734,
697.
General Method B for Cp*RhIII-Catalyzed Cyclization of N-
(Pivaloyloxy)benzamides 1 and 1,6-Enynes 2. A dried Schlenk
flask was charged with cyclohexadienone-containing 1,6-enyne
substrate 2 (0.2 mmol), N-(pivaloyloxy)benzamide 1 (0.4 mmol, 2.0
equiv), Cu(OAc)2 (14.5 mg, 0.08 mmol, 0.4 equiv), [Cp*RhCl2]2 (3.1
mg, 0.005 mmol, 5 mol % as Rh), CsOAc (76.8 mg, 0.4 mmol, 2.0
equiv), and DMF (dry, 1 mL) under a nitrogen atmosphere. Then the
mixture was stirred at room temperature until the substrate was
completely consumed. The resulting mixture was quenched with
saturated aqueous NaHCO3 (5 mL) and extracted with DCM (15 mL
× 3). The combined organic phases were dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The residue was purified
by silica gel (300−400 mesh) column chromatography to afford the
desired product 3.
CONCLUSIONS
■
In summary, the Cp*RhIII-catalyzed C−H activation of N-
hydroxybenzamides could undergo tunable arylative cyclization
with cyclohexadienone-containing 1,6-enynes on the basis of
the selection of different O substitutions. For N-(pivaloyloxy)-
benzamides, tetracyclic products bearing isoquinolone and
cyclohexenone substructures are offered in moderate to
excellent yields via an Ⓝ-Michael addition process. However,
for N-methoxybenzamides, cis-hydrobenzofuran frameworks are
achieved in moderate yields via a Ⓒ-Michael addition process
with a perfect atom economy. We believe that this research
could allow researchers to fine tune the reaction selectivity by
simply changing substituents on the directing group. Mecha-
nistic investigations of these two cascade reactions clearly
indicated that the C−H bond cleavage process was involved in
the turnover-limiting step. Furthermore, the cyclization
products could be subjected to various transformations for
elaborating the pharmaceutical potential. The present results
extend the application realm of Cp*RhIII-catalyzed C−H
activation cascade reactions. Further studies on asymmetric
cis-4a-Methyl-1,13a-dihydrobenzo[5,6][1,4]oxazino[4,3-b]-
isoquinoline-2,12(4aH,6H)-dione (3aa, Table 2, entry 1): pale yellow
semisolid, 51.0 mg, 91% yield; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.41 (d, J = 8.0 Hz, 1H), 7.68−7.66 (m, 1H), 7.50−7.46 (m, 2H), 6.75
(d, J = 10.0 Hz, 1H), 6.37 (s, 1H), 6.18 (d, J = 10.0 Hz, 1H), 5.09 (dd,
J = 11.6, 6.8 Hz, 1H), 4.94, 4.89 (AB, JAB = 16.0 Hz, 2H), 3.02 (dd, J =
16.0, 4.8 Hz, 1H), 2.65 (dd, J = 16.0, 12.0 Hz, 1H), 1.51 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 196.46, 161.96, 148.19, 136.11,
133.89, 132.95, 130.54, 128.04, 126.74, 125.63, 124.70, 102.06, 69.91,
61.48, 51.36, 39.34, 22.46; ESI-MS [M + Na]+ 304.0; HRMS (FTMS-
+
ESI) [M + H]+ calcd for C17H16NO3 282.1130, found 282.1125; IR
(KBr) ν (cm−1) 3307, 2977, 2925, 2855, 1689, 1655, 1622, 1429,
1336, 1280, 1183, 1102, 1063, 898, 822, 758, 696.
F
dx.doi.org/10.1021/ja5072702 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
General Procedure for Cp*RhIII-Catalyzed Cyclization of N-
Methoxybenzamides 4 and 1,6-Enynes 2. A dried Schlenk flask
was charged with cyclohexadienone-containing 1,6-enyne substrate 2
(0.2 mmol), N-methoxybenzamide 4 (0.3 mmol, 1.5 equiv),
[Cp*RhCl2]2 (3.1 mg, 0.005 mmol, 5 mol % as Rh), PivOCs (93.6
mg, 0.4 mmol, 2.0 equiv), PivOH (40.9 mg, 0.4 mmol, 2.0 equiv), and
DCE (dry, 2 mL) under a nitrogen atmosphere. Then the mixture was
stirred at 60 °C for 12 h. The resulting mixture was cooled to room
temperature, diluted with DCM, and filtered through Celite. The
filtrate was concentrated under reduced pressure. The residue was
purified by silica gel (300−400 mesh) column chromatography with
hexane/ethyl acetate (2/3) eluent (for 5ae,ao,do, with CHCl3/MeOH
(100/1) eluent) to afford the desired product 5.
N-Methoxy-2-((((3a,7a)-cis,E)-7a-methyl-5-oxo-3a,4,5,7a-tetra-
hydrobenzofuran-3(2H)-ylidene)methyl)benzamide (5aa, Table 4,
entry 1): colorless oil, 39.3 mg, 63% yield; 1H NMR (400 MHz,
CDCl3) δ (ppm) 8.76 (s, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.40 (t, J = 7.2
Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 6.65 (s,
1H), 6.50 (d, J = 10.0 Hz, 1H), 5.94 (d, J = 10.0 Hz, 1H), 4.53 (d, J =
13.6 Hz, 1H), 4.25 (d, J = 13.6 Hz, 1H), 3.79 (s, 3H), 3.34 (s, 1H),
2.38 (dd, J = 15.6, 4.8 Hz, 1H), 2.18 (d, J = 15.6 Hz, 1H), 1.55 (s, 3H).
13C NMR (100 MHz, CDCl3) δ (ppm) 199.74, 167.26, 151.53,
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144.14, 134.48, 133.13, 130.36, 129.59, 128.87, 128.11, 127.83, 120.12,
81.33, 70.85, 64.40, 47.17, 37.11, 22.75; ESI-MS: [M + H]⊕ 314.2;
HRMS (FTMS-ESI) [M + Na]+ calcd for C18H19NO4Na+ 336.1206,
found 336.1206; IR (KBr) ν (cm−1) 3235, 3060, 2973, 2934, 2851,
1675, 1596, 1569, 1497, 1462, 1442, 1422, 1375, 1281, 1230, 1162,
1116, 1099, 1082, 1042, 890.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Text, figures, tables, and CIF files giving experimental
procedures, structural proofs, and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(5) For selected works on carboxylic acid directed Cp*RhIII-catalyzed
C−H bond functionalizations, see: (a) Ueura, K.; Satoh, T.; Miura, M.
Org. Lett. 2007, 9, 1407−1409. (b) Mochida, S.; Hirano, K.; Satoh, T.;
Miura, M. J. Org. Chem. 2011, 76, 3024−3033. (c) Shia, X.; Li, C.-J.
Adv. Synth. Catal. 2012, 354, 2933−2938.
AUTHOR INFORMATION
Corresponding Authors
*E-mail for P.T.: tianping@sioc.ac.cn.
*E-mail for G.-Q.L.: lingq@sioc.ac.cn.
■
(6) For selected C−H bond functionalizations of N-benzoylsulfona-
mides, see: (a) Zhu, C.; Xie, W.; Falck, J. R. Chem. Eur. J. 2011, 17,
12591−12595. (b) Zhu, C.; Falck, J. R. Chem. Commun. 2012, 48,
1674−1676.
(7) For selected C−H bond functionalizations of benzamides, see:
(a) Hyster, T. K.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 10565−
10569. (b) Wang, F.; Song, G.; Li, X. Org. Lett. 2010, 12, 5430−5433.
(c) Park, J.; Park, E.; Kim, A.; Lee, Y.; Chi, K.-W.; Kwak, J. H.; Jung, Y.
H.; Kim, I. S. Org. Lett. 2011, 13, 4390−4393. (d) Hesp, K. D.;
Bergman, R. G.; Ellman, J. A. Org. Lett. 2012, 14, 2304−2307.
(e) Wencel-Delord, J.; Nimphius, C.; Patureau, F. W.; Glorius, F.
Angew. Chem., Int. Ed. 2012, 51, 2247−2251. (f) Wencel-Delord, J.;
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Present Address
†Shionogi & Co., Ltd., 1-3 Kuise Terajima 2-chome, Amagasaki,
Hyogo 660-0813, Japan.
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work was generously provided by the
973 Program (2015CB856600), the National Natural Science
Foundation of China (NSFC 21372243, 21232009, 21102161),
the Shanghai Municipal Committee of Science and Technology
(13JC1406900), and the Collaborative Innovation Center of
Chemical Science and Engineering (Tianjin). We thank Prof.
Guosheng Liu (SIOC), Prof. Ran Hong (SIOC), and Dr.
Hanqing Dong (Arvinas Inc.) for helpful discussions.
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