Palladium-Catalyzed Norbornene-Mediated Tandem Amination/Cyanation Reaction: A Method for the Synthesis of ortho-Aminated Benzonitriles

Article abstract of DOI:10.1021/acs.orglett.6b02249

A palladium-catalyzed, norbornene-mediated tandem amination/cyanation reaction via Catellani-type C-H functionalization was developed using N-benzoyloxyamines as the amination reagent and Zn(CN)₂ as the terminating agent. This transformation, in which one C-N bond and one C-C bond are formed, provides an efficient approach for the synthesis of ortho-aminated benzonitriles in one pot from easily accessible starting materials.

Full text of DOI:10.1021/acs.orglett.6b02249

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Norbornene-Mediated Tandem Amination/
Cyanation Reaction: A Method for the Synthesis of ortho-Aminated
Benzonitriles
Bo Luo,†,‡ Jin-Ming Gao,*,† and Mark Lautens*,‡
†Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Science, Northwest A&F University, Yangling, Shaanxi
712100, China
‡Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada
S
* Supporting Information
ABSTRACT: A palladium-catalyzed, norbornene-mediated tandem
amination/cyanation reaction via Catellani-type C−H functionalization
was developed using N-benzoyloxyamines as the amination reagent and
Zn(CN)2 as the terminating agent. This transformation, in which one
C−N bond and one C−C bond are formed, provides an efficient
approach for the synthesis of ortho-aminated benzonitriles in one pot
from easily accessible starting materials.
Scheme 1. Previous Work and This Work
ransition-metal-catalyzed C−C and C−heteroatom bond
forming reactions are among the most widely used catalytic
T
reactions in synthetic organic chemistry.1 Among them, special
attention has been paid to palladium-catalyzed reactions due to
their broad functional group tolerance and diverse reaction
pathways. The Catellani reaction, which was first discovered by
Catellani2 and further developed by us and others,3,4 is a powerful
method for the synthesis of highly substituted aromatic
compounds and fused aromatic rings due to the capability of
functionalizing both the ortho- and ispo-position of aryl iodides in
a single transformation. Although the scope of terminating
reagents for ispo-C−I functionalization has been broadened
considerably since its discovery, ortho-C−H functionalization is
largely limited to alkylation and arylation. Recently, the
palladium-catalyzed, norbornene-mediated ortho-C−H amina-
tion of aryl iodides was reported by Dong,5 who used iPrOH as
the hydride source to terminate the reaction. This synthetic
strategy has been extended to a wide variety of terminating
reagents, such as terminal olefins,6a aromatic pinacol borona-
tes,6b N-tosylhydrazone,6c bis(pinacolato) diboron,6d alkynyl
carboxylic acids,6e and alkynols6f (Scheme 1a), for the synthesis
of polysubstituted aniline derivatives. However, it was not known
if this type of ortho-amination reaction could tolerate cyanide as
the nucleophile. Herein, we report such a palladium-catalyzed,
norbornene-mediated amination/cyanation reaction using cya-
nide as the terminating reagent to afford ortho-aminated
benzonitriles, which are of great significance as starting materials
for the synthesis of many biologically active agents, such as
quinazolines, 1H-indazoles, quinazolinamines, etc.7 Moreover,
the nitrile group can be transformed into a variety of functional
groups, such as carboxyl, carbonyl, carbamoyl, aminomethyl, and
heterocycles.8
tion reaction (Scheme 1b).9 We found intermolecular
alkylation/cyanation could also occur between aryl iodides and
alkyl halides using [K4Fe(CN)6·3H2O] as the terminating
reagent.10 Most recently, Chen reported the synthesis of 2-
cyanoarylketones through palladium-catalyzed, norbornene-
mediated tandem C−H amination and C−I cyanation, employ-
ing CuCN as the terminating reagent.11
Based on these previous reports, we envisioned that the
protocol could also work for the synthesis of ortho-aminated
benzonitriles through a palladium-catalyzed tandem C−N bond
and C−CN bond formation process, provided that suitable
conditions could be identified (Scheme 1c). Gratifyingly, after
The first example of terminating the Catellani reaction with
Zn(CN)2 was reported by our group in 2006, affording polycyclic
benzonitriles via tandem intramolecular ortho-alkylation/cyana-
Received: July 29, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02249
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
some optimization, we found that when the reaction was carried
out with Pd(OAc)2 (10 mol %), PPh3 (25 mol %), and Zn(CN)2
(2 equiv) in toluene at 100 °C for 24 h, the desired product 3a
could be isolated in 82% yield (Table 1, entry 1). The yield
Scheme 2. Scope of ortho-Substituted Aryl Iodides
Table 1. Optimization of the Reaction Conditions
a
entry
variation from “standard” condition
yield (%)
1
2
none
83(82)
15
[K4Fe(CN)6·3H2O] instead of Zn(CN)2
CH3CN instead of toluene
3
5
4
DME instead of toluene
58
5
DCE instead of toluene
68
6
dioxane instead of toluene
80(76)
72
7
(2-furyl)3P instead of PPh3
8
(3-tolyl)3P instead of PPh3
83(79)
60
9
3.0 equiv of norbornene instead of 10.0 equiv
10
120 °C instead of 100 °C
92(89)
a
1
Determined by H NMR spectroscopy using 1,3,5-trimethoxyben-
zene as an internal standard. Isolated yield after column chromatog-
raphy are given in parentheses.
decreased significantly to 15% when 2.0 equiv of [K4Fe(CN)6·
3H2O] was used as the CN source (entry 2). Further
investigation of various solvents revealed that toluene was the
best (entries 3−6). The effect of the monodentate phosphine
ligand was also examined. While (2-furyl)3P and (3-tolyl)3P were
effective for the reaction, the yields are slightly lower (entries 7
and 8). The yield decreased to 60% when 3.0 equiv of
norbornene was used (entry 9), which indicates the amount of
norbornene affects this reaction significantly. The isolated yield
of 3a could be further increased to 89% when the reaction was
conducted at 120 °C in a sealed tube (entry 10), which was
defined as the optimal conditions for further study.
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2a (2.0 equiv),
Zn(CN)2 (2.0 equiv), Pd(OAc)2 (10 mol %), PPh3 (25 mol %),
norbornene (10.0 equiv), Cs2CO3 (3.0 equiv), toluene (3.0 mL), 120
°C, 24 h, argon.
Under the optimized reaction conditions, a range of aryl
iodides were examined. Generally, aryl iodides containing
electron-donating and electron-withdrawing groups were well-
tolerated, providing the corresponding ortho-aminated benzoni-
triles 3a−3p in moderate to excellent yields (Scheme 2). More
specifically, ortho-methyl-substituted aryl iodides with a variety of
functional groups (i.e., nitro, ester, fluoro, chloro, amine) at the
meta- or para-position all reacted smoothly with 2a and
Zn(CN)2, affording 3b−j in good to excellent yields (73−
93%). The structure of 3a was confirmed by X-ray analysis (see
Supporting Information). 1-Iodonaphthalene was also em-
ployed, providing the product 3k in good yield (76%). Other
ortho-substituted aryl iodides were also competent in the
reaction, delivering 3l−p in moderate to good yields (63−90%).
To demonstrate the practical utility of the protocol, we scaled
up the reaction with 1.0 mmol 1a, 2.0 mmol 2a, and 2.0 mmol
Zn(CN)2. No significant changes were noted, and the desired
product 3a was obtained in 82% yield (eq 1).
X-ray analysis (see Supporting Information). It is noteworthy
that chloro, cyano, aldehyde, trifluoromethyl, and ester groups
were all compatible with the reaction, suggesting that the
protocol might be useful for the synthesis of more complex
molecules.
To further explore the generality of this reaction, different
substituted N-benzoyloxyamines were tested (Scheme 4). It was
found that the reaction proceeds smoothly for secondary, cyclic
N-benzoyloxyamines, giving the corresponding amination
products 3q−s in good to excellent yields (79−90%). However,
pyrrolidine gave the desired product 3t in low yield (38%). An
acyclic N-benzoyloxyamine was equally compatible with this
multicomponent reaction, giving product 3u in good yield
(66%). Removal of the benzyl group would lead to the secondary
arylamine product.12 Unfortunately, only a trace amount of
product 3v was isolated when the dibenzyl-protected N-
benzoyloxyamine was employed. However, O-benzoyl-N,N-
diethyloxylamine could react with 1a and Zn(CN)2 to afford
product 3w, albeit in low yield (29%).
In the case of aryl iodides 4 lacking an ortho-substituent, 2,6-
diaminated benzonitriles 5 can be obtained (Scheme 3).
Moderate to excellent yields of products 5a−i (54−88%) were
observed when 2.5 equiv of 2a and 5.0 equiv of Cs2CO3 were
employed in the reaction. The structure of 5b was confirmed by
Based on the above experimental results and previous
reports,5,6 a plausible mechanism is proposed in Scheme 5.
The first step involves oxidative addition of iodoarene 1 or 4 with
B
DOI: 10.1021/acs.orglett.6b02249
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Scheme 3. Scope of Aryl Iodides without an ortho-
Substituent
Scheme 5. Possible Catalytic Cycle
a
a
blocked substrates (R1 ≠ H), retro-carbopalladation with
concomitant expulsion of norbornene gives an aminated ArPd-
OBz intermediate D, which reacts with Zn(CN)2 to give the final
product 3, along with the regeneration of Pd(0) to complete the
catalytic cycle. With species C, without ortho-substituent (R1 =
H), the C−H activation process can be repeated at the second
ortho-position, leading to a new five-membered palladacycle E
and the amination complex F, which following a similar pathway
would afford the diaminated product 5.
Reaction conditions: 4 (0.2 mmol, 1.0 equiv), 2a (2.5 equiv),
Zn(CN)2 (2.0 equiv), Pd(OAc)2 (10 mol %), PPh3 (25 mol %),
norbornene (10.0 equiv), Cs2CO3 (5.0 equiv), toluene (3.0 mL), 120
°C, 24 h, argon.
a
Scheme 4. Scope of N-Benzoyloxyamines
In conclusion, we have developed a palladium-catalyzed,
norbornene-mediated tandem amination/cyanation reaction to
synthesize ortho-aminated benzonitriles in moderate to excellent
yields and with good functional group tolerance. This approach
involves the formation of a C−N bond and a C−CN bond by
using electron-deficient N-benzoyloxyamines as the electrophilic
nitrogen source and Zn(CN)2 as the nucleophilic coupling
partner. This method is complementary to the reported
protocols for the Catellani-type reaction and demonstrates that
cyanide can act as a terminating reagent in the ortho-C−H
amination reactions of aryl iodides. Moreover, it should stimulate
the design of new synthetic methods to access valuable arylamine
and benzonitrile derivatives.
ASSOCIATED CONTENT
* Supporting Information
■
S
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2 (2.0 equiv),
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02249.
Zn(CN)2 (2.0 equiv), Pd(OAc)2 (10 mol %), PPh3 (25 mol %),
norbornene (10.0 equiv), Cs2CO3 (3.0 equiv), toluene (3.0 mL), 120
°C, 24 h, argon.
All characterization data; 1H and 13C spectra (PDF)
Crystallographic data for 3a (CIF)
Crystallographic data for 5b (CIF)
Pd(0), followed by carbopalladation of norbornene, forming
species A. Subsequent ortho-C−H activation and elimination of
HI with the aid of base gives a five-membered palladacycle B. The
oxidative addition of N-benzoyloxyamines (R3R4N-OBz) to
palladacyale B is proposed to form a Pd(IV) species, which
undergoes reductive elimination, leading to the ortho-aminated
arene C. Alternatively, the direct electrophilic amination of
R3R4N-OBz with palladacycle B followed by N−O bond cleavage
may also form amination complex C.5,6 Next, in the case of ortho-
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jinminggao@nwsuaf.edu.cn.
*E-mail: mlautens@chem.utoronto.ca.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b02249
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2016, 18, 1690. (f) Sutherell, C.; Tallant, C.; Monteiro, O.; Yapp, C.;
ACKNOWLEDGMENTS
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Fuchs, J.; Fedorov, O.; Siejka, P.; Muller, S.; Knapp, S.; Brenton, J.;
̈
This work was supported financially by the Natural Sciences and
Engineering Research Council of Canada (NSERC), the
University of Toronto and Alphora Research Inc. B.L. thanks
NSERC and the China Scholarship Council for supporting his
stay at the University of Toronto in the course of his doctoral
studies. Dr. Alan Lough (University of Toronto) is thanked for
single-crystal X-ray structural analysis of 3a and 5b. Juntao Ye
and Thomas Johnson are thanked for proofreading the text.
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