Rhenium-Catalyzed Phthalide Synthesis from Benzamides and Aldehydes via C-H Bond Activation

Article abstract of DOI:10.1021/acs.orglett.9b02142

The [4 + 1] annulation of benzamides and aldehydes for phthalide synthesis was achieved via rhenium-catalyzed C-H activation, which demonstrates an unprecedented reaction pattern distinct from those of other transition-metal catalyses. The reaction also features readily available starting materials, a wide scope for both electro-rich and electro-deficient substrates, and the elimination of homoannulation byproducts.

Full text of DOI:10.1021/acs.orglett.9b02142

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rhenium-Catalyzed Phthalide Synthesis from Benzamides and
Aldehydes via C−H Bond Activation
Bing Jia,†,‡ Yunhui Yang,†,∥ Xiqing Jin,† Guoliang Mao,*,‡ and Congyang Wang*,†,§,∥
†Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, CAS
Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China
‡Provincial Key Laboratory of Oil & Gas Chemical Technology, College of Chemistry and Chemical Engineering, Northeast
Petroleum University, Daqing 163318, China
§University of Chinese Academy of Sciences, Beijing 100049, China
∥Physical Science Laboratory, Huairou National Comprehensive Science Center, Beijing 101400, China
S
* Supporting Information
ABSTRACT: The [4 + 1] annulation of benzamides and
aldehydes for phthalide synthesis was achieved via rhenium-
catalyzed C−H activation, which demonstrates an unprece-
dented reaction pattern distinct from those of other transition-
metal catalyses. The reaction also features readily available
starting materials, a wide scope for both electro-rich and
electro-deficient substrates, and the elimination of homo-
annulation byproducts.
n the past few decades, the strategic use of C−H bond
Scheme 1. Transition-Metal-Catalyzed C−H Bond
I
activation for new chemical bond formation and the
Activation Reactions of Benzamides with Aldehydes
expedient buildup of molecular complexity from hydrocarbon
feedstock has attracted tremendous attention.1 In comparison
with the widely studied C−H activation reactions with alkynes
and alkenes, the direct C−H addition to polar unsaturated C−
X (X = heteroatom) bonds, such as the CO bond of
aldehydes, has met limited success until recently.2 Although
benzamides are easily available and commonly used substrates
for ortho-C−H bond transformations, only a few C−H
activation reactions between benzamides and aldehydes have
been reported so far.3,4 Kim et al. described a Rh-catalyzed
oxidative ortho-C−H acylation of tertiary benzamides with
aldehydes (Scheme 1a).3a Shortly afterward, the same group
developed a tandem Rh-catalyzed ortho-C−H acylation/
intramolecular cyclization reaction of secondary benzamides
and aldehydes to access 3-hydroxyisoindolin-1-ones under
slightly modified conditions.3b Later on, Huang and Zhao et al.
provided an alternative approach to 3-hydroxyisoindolin-1-
ones from benzamides and aldehydes by using a Pd-based
catalytic system (Scheme 1b).4a With the aid of a Lewis acid
and modified conditions, they further demonstrated the
efficient synthesis of biaryl imino-carboxylic acids through
the ring-opening process of 3-hydroxyisoindolin-1-one inter-
mediates.4b
pattern of benzamides and aldehydes from those previously
achieved by using Rh and Pd catalysis.3,4 This Re-catalyzed
reaction is compatible with a wide range of electronically and
sterically varied benzamides and aldehydes, thus providing a
complementary protocol to previous methods.7,8
At the outset, we selected benzamide 1a and p-
methylbenzaldehyde 2b as model substrates to optimize the
reaction conditions.9 After an extensive survey of various
Recently, we have reported a Re/Mg-cocatalyzed [4 + 2]
annulation of benzamides and alkynes to furnish varied 3,4-
dihydroisoquinolinones.5a With our continuous interest in Re-
catalysis,5,6 we herein disclose a Re-catalyzed [4 + 1]
annulation of benzamides and aldehydes to afford phthalide
derivatives (Scheme 1c), which showcases a distinct reaction
Received: June 20, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02142
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
a b
,
reaction parameters, phthalide 3ab was obtained in 79% H
NMR yield and 71% isolated yield under the catalysis of
ReBr(CO)5 with the aid of Me2Zn and ZnBr2 (Table 1, entry
Scheme 2. Scope of Aldehydes
a
Table 1. Screening of Reaction Parameters
yield of
b
entry
variations of standard conditions
3ab (%)
c
1
2
3
4
none
79 (71)
THF instead of DME
1,4-dioxane instead of DME
MeCN, t-BuOMe, PhOMe, (i-Pr)2O, DMSO, c-
hexane, DCE instead of DME
60
32
0
5
without ReBr(CO)5
0
6
7
8
9
Re2(CO)10 instead of ReBr(CO)5
ReCl(CO)5 instead of ReBr(CO)5
MnBr(CO)5 instead of ReBr(CO)5
without Me2Zn and ZnBr2
without Me2Zn or without ZnBr2
Et2Zn, AlMe3, or PhMgBr instead of Me2Zn
FeBr2 instead of ZnBr2
FeCl3 instead of ZnBr2
MgBr2 instead of ZnBr2
CuBr2 instead of ZnBr2
R = OMe, R′ = H
R = NMe2, R′ = H
R = Et, R′ = H
R = R′ = Me
37
61
15
trace
trace
0
32
24
15
39
0
a
Reaction conditions: 1a (0.75 mmol), 2 (0.5 mmol), ReBr(CO)5 (5
mol %), Me2Zn (0.85 mmol), ZnBr2 (0.75 mmol), DME (3.75 mL),
130 °C, 24 h, then quenched with 2 M HCl (5 mL), 80 °C, 3 h.
10
11
12
13
14
15
16
17
18
19
b
c
Isolated yields of product 3 are shown. p-Toluenesulfonic acid (2
M, 5 mL) instead of HCl, 80 °C, 4 h.
series of electronically varied aromatic aldehydes were
amenable to this reaction, giving the corresponding phthalides
3aa−g in good yield. When electron-rich p-methoxylbenzalde-
hyde 2h was employed as the substrate, phthalide 3ah was
obtained as the major product with the contaminant formation
of lactam 4ah. Interestingly, lactam 4ai became the sole
product from the reaction of p-(N,N-dimethyl)benzaldehyde
2i and benzamide 1a. The benzylic cation intermediates
stabilized by electron-donating groups might account for the
formation of lactam products (vide infra). Meta- and ortho-
substituted aromatic aldehydes were also compatible with the
reaction conditions, leading to phthalides 3aj−m in moderate
to good yield. Also, 1- and 2-naphthaldehydes and indolyl
aldehyde gave the expected products 3an−p with ease.
Unfortunately, the use of aliphatic aldehydes such as
cyclohexanecarbaldehyde 2q resulted in the formation of
phthalide 3aq in relatively low yield.
Next, the scope of benzamides was examined (Scheme 3).
Benzamides bearing both electron-donating and electron-
withdrawing substituents were compatible in the reaction,
and a wide range of functional groups including OMe, OCF3,
CF3, CO2Me, F, Cl, Br, and I remained intact after the reaction
(3bk−kk), which allowed for further synthetic transformations
of the reaction products. Ortho-substituted benzamide showed
a slightly lower reactivity, giving phthalide 3lk in a synthetically
useful yield. When two C−H bonds were available in the
starting material, the sterically less congested one was
preferably functionalized (3mk and 3mk′). Naphthamides
were also suitable substrates for this reaction, with 2-
naphthamide affording two regioisomeric products (3nk,
3ok, and 3ok′).
16
66
0
a
Reaction conditions: 1a (0.3 mmol), 2b (0.2 mmol), cat. (5 mol %),
Me2Zn (0.34 mmol), ZnBr2 (0.3 mmol), DME (1.5 mL), 130 °C, 24
b
h, then quenched with 2 M HCl (2 mL), 80 °C, 3 h. Determined by
c
1H NMR. Isolated yield on 0.5 mmol scale.
1). 1,2-Dimethoxyethane (DME) proved to be the best
solvent, with others resulting only in a decreased yield of
3ab, if any at all (entries 2−4). No reaction occurred in the
absence of ReBr(CO)5, and other rhenium and manganese
carbonyl catalysts gave inferior results (entries 5−8). The
presence of Me2Zn and ZnBr2 was shown to be essential for
achieving the catalytic turnovers (entries 9 and 10). Surrogates
of Me2Zn such as Et2Zn, AlMe3, and PhMgBr demonstrated no
reactivity at all (entry 11). Variations of other Lewis acid
additives instead of ZnBr2 gave much lower yields of 3ab under
otherwise identical conditions (entries 12−15). Of particular
note, no formation of lactam 4ab or homoannulation phthalide
3aa or 3bb was detected during the screening process, which
underlined the high chemoselectivity of this reaction. In
addition, N-methoxybenzamide displayed no reactivity at all in
the reaction, and N′,N′-dimethylbenzohydrazide gave 3ab in
very low yield (entries 16 and 17). N-Ethylbenzamide was
shown to be less reactive than 1a, whereas no reaction
occurred with N,N-dimethylbenzamide (entries 18 and 19).
With the optimized conditions in hand, the scope of
aldehydes was first explored (Scheme 2). It turned out that a
B
DOI: 10.1021/acs.orglett.9b02142
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a b
,
4ah was subjected to the standard reaction conditions. These
results supported the intermediacy of alcohol 5ah for the
phthalide formation under the acidic conditions.10 In addition,
the competition experiments with benzamides bearing
electronically varied substituents were conducted (Scheme
4b). The formation of product 3fk derived from electron-
deficient benzamide 1f was slightly more favored than that of
electron-rich benzamide 1d. Not surprisingly, almost no
difference was detected in the competition reaction between
1i and 1f. In contrast, the reaction had an obvious preference
for the formation of product 3af originating from electron-
deficient aldehyde 2f in comparison with phthalide 3ab derived
from aldehyde 2b (Scheme 4b), which might be ascribed to
the higher affinity of 2f to nucleophilic attack.
Scheme 3. Scope of Benzamides
To examine the reversibility of the C−H activation step,
pentadeuterated benzamide 1a-d5 was first tested under the
standard reaction conditions, and only a slight deuterium loss
was found at the ortho positions of 1a-d5 (Scheme 5a). When
Scheme 5. Deuterium Labeling Experiments
a
Reaction conditions: 1 (0.75 mmol), 2k (0.5 mmol), ReBr(CO)5 (5
mol %), Me2Zn (0.85 mmol), ZnBr2 (0.75 mmol), DME (3.75 mL),
130 °C, 24 h, then quenched with 2 M HCl (5 mL), 80 °C, 3 h.
b
c
d
Isolated yields of product 3 are shown. 150 °C. Determined by 1H
NMR.
To probe the possible reaction intermediates, the reaction of
benzamide 1a and p-methoxylbenzaldehyde 2h was selected as
a model reaction (Scheme 4a). Gratifyingly, alcohol 5ah was
obtained in 51% isolated yield, with the formation of phthalide
3ah and lactam 4ah in low yield when the reaction was directly
quenched with water. In contrast, the treatment of the reaction
with tosyl acid at 80 °C for 4 h resulted in the clearly increased
yield of 3ah and 4ah with no detection of 5ah. Furthermore,
no formation of phthalide 3ah was observed when pure lactam
Scheme 4. Mechanistic Experiments
aldehyde 2k was subjected to the reaction of 1a-d5 under the
same conditions, tetradeuterated phthalide 3ak-d4 was
obtained in 83% isolated yield. Importantly, no D/H
scrambling was detected at the remaining ortho position of
3ak-d4, which indicated that the C−H activation step was
irreversible in the reaction. Furthermore, kinetic isotope effect
(KIE) competition experiments were conducted with varied
reaction times, and the KIE value was determined to be 2.7
(Scheme 5b).
On the basis of the above results, a tentative reaction
mechanism is depicted in Scheme 6. Deprotonative coordina-
tion of benzamide 1a with the rhenium catalyst gives
intermediate A, which undergoes C−H bond cleavage with
the aid of Me2Zn, affording a five-membered rhenacycle B. The
insertion of benzaldehyde 2 into the C−Re bond of B leads to
the formation of a seven-membered rhenacycle D through the
aldehyde-coordinated intermediate C. Ligand exchange of D
with 1a forms zinc species E and regenerates A, thus closing
the catalytic cycle. Quenching of E with acid gives alcohol 5,
which undergoes intramolecular N- or O-attacked cyclization,
affording lactam 4 or iminoether F, respectively.10 The O-
attacked cyclization is preferred in the reactions of electron-
deficient and electron-neutral aldehydes, possibly through a
SN2 pathway. When electron-rich aldehydes are used, the N-
C
DOI: 10.1021/acs.orglett.9b02142
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Letter
Notes
Scheme 6. Plausible Reaction Mechanism
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21772202, 21831008, 51534004, and
U1362110), Beijing Municipal Science & Technology
Commission (project no. Z181100004218004), and Beijing
National Laboratory for Molecular Sciences (BNLMS-CXXM-
201901) is gratefully acknowledged.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02142.
Experimental details, characterization data, and NMR
spectra for all new compounds (PDF)
Accession Codes
CCDC 1935437 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: maoguoliang@nepu.edu.cn (G.M.).
*E-mail: wangcy@iccas.ac.cn (C.W.).
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