Highly regioselective three-component domino heck-negishi coupling reaction for the functionalization of purines at C6

Article abstract of DOI:10.1021/ol4032683

A highly regioselective three-component domino Heck-Negishi coupling reaction has been developed. Organozinc reagents are used to trap an alkylpalladium intermediate of olefins for a first example in the domino Heck reaction. This reaction is applicable t

Full text of DOI:10.1021/ol4032683

Letter
pubs.acs.org/OrgLett
Highly Regioselective Three-Component Domino Heck−Negishi
Coupling Reaction for the Functionalization of Purines at C6
Dong-Chao Wang,† Hong-Ying Niu,‡ Ming-Sheng Xie,† Gui-Rong Qu,*,† Hui-Xuan Wang,†
and Hai-Ming Guo*,†
†Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, P. R. China
‡School of Chemistry and Chemical Engineering, Henan Institute of Science and Technology, Xinxiang 453003, China
S
* Supporting Information
ABSTRACT: A highly regioselective three-component dom-
ino Heck−Negishi coupling reaction has been developed.
Organozinc reagents are used to trap an alkylpalladium
intermediate of olefins for a first example in the domino
Heck reaction. This reaction is applicable to acrylates (or
acrylamides) and purine compounds, producing a series of
novel purine compounds with carbon substituents at the C6
position in moderate to good yields.
Scheme 1. (a) Intramolecular Carbopalladation Followed by
Trapping with Organoborane. (b) Intermolecular
carbopalladation Followed by Reductive Elimination. (c)
Intermolecular Carbopalladation Followed by Trapping with
Organozinc Bromide
s a powerful method for constructing complex organic
Amolecules, domino reactions with the formation of two or
more bonds under identical reaction conditions in one efficient
step have been extensively studied by synthetic chemists.1 The
well-known Heck coupling reaction, one of the most direct
methods to form carbon−carbon bonds in organic synthesis, is
also used as an initiation reaction for many domino reactions.2
Recently, domino Heck reactions, such as Heck−C−H
activation,3 Heck−cyanation,4 Heck−carbohalogenation2b and
Heck−aza-Michael5 et al. are becoming focuses for researchers.
Although a variety of organometals, such as organoborane,
organoaluminum, organotin and organozinc compounds have
widely been employed in domino carbopalladation−cross-
coupling of alkynes, there are few successful examples of the
carbopalladation−cross-coupling of olefins.6 In 1997, the Grigg
group reported Heck−Suzuki coupling reactions with alkylpal-
ladation followed by trapping with organoborane reagents
(Scheme 1a).7a Subsequently, great endeavors have been
devoted to the one or two-component intramolecular Heck−
Suzuki coupling reactions with a carbopalladium intermediate
(Scheme 1a).2a,7 However, the multicomponent domino Heck
reaction has scarcely been reported up to now. Multi-
component domino reactions are more desirable and play an
extremely important role in organic and medicinal chemistry,
which can create structurally diverse or complex products from
relatively simple starting materials.8
antiviral, and antimicrobial activities10 or receptor modula-
tion.11 The most direct and effective methods for the synthesis
of purines bearing carbon substituent at C6 were transition-
metal-catalyzed cross-coupling reactions such as Suzuki,12
Negishi,13,14 Stille,15 and Sonogashira16 cross-coupling reac-
tions using 6-halopurines as starting material. Somewhat
Purine bases and nucleosides, as the universal units in DNA
and RNA, have found broad applications in biological and
pharmaceutical chemistry. In particular, C6-alkylated purine
analogues exhibit unique biological activities such as cytostatic,9
Received: November 12, 2013
Published: December 12, 2013
© 2013 American Chemical Society
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Organic Letters
Letter
surprisingly, it is difficult to apply the Heck reaction in
modifying purine derivatives.17 Perhaps in this sequence the
typical termination event of the Heck reaction, β-hydride
elimination, is precluded because of the form of extremely
stable alkylpalladium intermediate (Scheme 1b).
catalysts were examined, and no better results were observed,
while the side product 5a was exclusively formed with Ni
catalyst (entries 1−5). Interestingly, the reaction was influenced
greatly by the amount of THF, and the higher yield of 4a was
obtained with 1.0 mL of THF (entries 1 vs 6−8). Importantly,
the yield of 4a was highly dependent on the ratio of reactants
(entries 9−15). When a small amount of benzylzinc bromide
(3a) was employed, such as 1.5 equiv or 2.0 equiv, a trace
amount of product 4a was obtained (entries 12 and 13).
Luckily, when the ratio of 1a:2a:3a was 1:3:4, the highest yield
of 4a was obtained (77% yield), while the side-product 5a
could be avoided totally (entry 14). Thus, the optimized
reaction conditions were as follows: 0.1 mmol of 9-benzyl-6-
chloropurine (1a), 3.0 equiv of tert-butyl acrylate (2a), and 4.0
equiv of benzylzinc bromide (3a) were employed in 1.0 mL of
THF (entry 14).
̌ ́
In 2004, the Dvorak group developed an intermolecular
carbopalladation between 9-benzyl-6-iodopurine and butyl
acrylate (Scheme 1b).17 When phenylboronic acid or phenyl-
tributyltin was used to trap the alkylpalladium intermediate, no
reactions occurred. In this case, a formate anion was used to
trap the alkylpalladium intermediate, and the reductive Heck
reaction occurred, affording a mixture of both α- and β-
products with low regioselectivity (Scheme 1b). In the context
of ongoing projects in modifying of purine derivatives,18 we
encountered a requirement to trap the alkylpalladium
intermediate by other organometal reagents. In the newly
formed purine derivatives, the regioselectivity of α- and β-
products was still a challenging problem (scheme 1c). Herein,
we report the three-component domino Heck−Negishi
reactions of 6-chloropurine derivatives, olefins, and organozinc
bromides, affording the targeted purine derivatives with high
regioselectivity.
Subsequently, different leaving groups at the C6 position of
the purine component were examined (Table 2). When 6-
Table 2. Effect of Different Leaving Groups at C6 Position of
a
Purine Derivatives
Initially, 9-benzyl-6-chloropurine (1a), tert-butyl acrylate
(2a), and benzylzinc bromide (3a) were selected as model
substrates to optimize the reaction conditions (Table 1). When
Table 1. Optimization of the Cross-Coupling Reaction
Conditions
LG
Cl (1a)
Br (1b)
I (1c)
OTs (1d)
OBt (1e)
a
b
yield (%)
77
92
80
0
0
a
Reaction conditions: 1 (0.1 mmol), 2a (3.0 equiv), 3a (4.0 equiv, 0.5
mL of solution in THF), THF (1.0 mL), 70 °C, N2, stirring overnight.
b
Isolated yield based on 1.
bromo- (1b) or 6-iodopurine (1c) were used as purine
components, the target products 4a were obtained in 92% and
80% yields, respectively. However, no reactions occurred when
OTs or OBt connected at C6 position of purine derivatives.
Considering the low cost of purine component, 6-chloropurine
derivatives (1a) was selected as the purine component for the
following investigation.
c
yield (%)
b
catalyst (10
mol %)
2a
3a
THF
(mL)
entry
(equiv)
(equiv)
4a
58
5a
18
1
Pd(PPh3)4
PdCl2(dppf)
PdCl2(PPh3)2
NiCl2 dppp
Ni(acac)2
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
2.0
3.0
7.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
1.5
2.0
4.0
5.0
1.0
1.0
1.0
1.0
1.0
0.5
1.5
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2
26
25
0
40
42
3
Next, to evaluate the generality of the reaction, a series of
α,β-unsaturated carboxylic acid esters and carboxamide
derivatives were subjected to the optimized reaction conditions
(Scheme 2). The domino reactions occurred smoothly when
tert-butyl acrylate, n-butyl acrylate, ethyl acrylate, and methyl
acrylate were tested, giving the 6-alkylpurine compounds in
moderate to good yields (Scheme 2, 4a−d). When α,β-
unsaturated carboxamide derivatives were examined, the
corresponding Heck−Negishi reactions proceeded well, afford-
ing 4e−h with good yields (Scheme 2, 4e−h). Moreover, when
a methyl group was introduced at the β-position of α,β-
unsaturated carboxamide (2i), the desired coupling product 4i
was obtained with excellent yield (Scheme 2, 4i, 96% yield). In
addition, when the reactions were performed on 2.0 mmol
scale, good results could still be obtained (4a: 65% yield; 4i:
87% yield, 0.984 g). In all cases, the Heck−Negishi reactions
exhibited excellent levels of regioselectivity, and only α-position
products were found.
4
81
5
0
83
6
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
30
19
18
57
66
58
trace
trace
77
72
50
7
58
8
60
9
14
10
11
12
13
14
15
trace
19
72
73
0
trace
a
Reaction conditions: 1a (0.1 mmol), 70 °C, N2, stirring overnight.
PhCH2ZnBr·LiCl in THF (0.805 M). Isolated yield based on 1a.
b
c
Pd(PPh3)4 was used as catalyst, the reaction proceeded well
(entry 1). To our delight, the α-position product 4a was
detected as the major form (58% yield), along with the side
product 5a (18% yield) of Negishi coupling between 1a and 3a.
It is worth mentioning that the Heck−Negishi reaction had
high regioselectivity19 and the β-position product 4a′ was not
detected (entry 1). Subsequently, several kinds of Pd or Ni
Then, a number of 6-chloropurine derivatives with various
substituents at the N9 position, including alkyl and sugar
carbon substituents, were investigated (Scheme 3). It was found
that alkyl substituents at N9 position of purine had little effect
on the yields of the target products, and N9-alkyl substituted
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Organic Letters
Letter
4p in 61% yield (Scheme 3, 4p), which provided a useful access
for the preparation of purine nucleoside analogues. Indeed, it is
the first time that purine nucleoside was modified via this
domino Heck−Negishi strategy. Other heterocyclic compounds
have also been investigated, including 2-chloropyridine, 2-
chloropyrimidine, 2-chloropyrazine, and 8-bromoquinoline.
Unfortunately, the competitive Negishi reactions worked well,
and the domino Heck−Negishi reactions did not occur. Finally,
a variety of organozinc halides were also subjected to the
optimized conditions. When primary benzylzinc bromides
including p-methylbenzylzinc bromide, p-fluorobenzylzinc bro-
mide, p-chlorobenzylzinc bromide, m-chlorobenzylzinc bro-
mide, or p-trifluoromethylbenzylzinc bromide were used as
starting material, the corresponding products 4q−u were
obtained in good yields (Scheme 3, 4q−u). The use of primary
benzyl zinc bromide was necessary to ensure the occurrence of
the domino Heck−Negishi reaction. When other alkyl- or
arylzinc halides, such as methylzinc iodide, n-butylzinc iodide,
isopropylzinc bromide, cyclopentylzinc bromide, (1-phenyl-
ethyl)zinc bromide as well as phenylzinc iodide were used, the
side reactions of Negishi coupling proceeded well, while the
Heck−Negishi coupling products could not be formed.
Scheme 2. Reaction of Various α,β-Unsaturated Carboxylic
Acid Esters and Carboxamide Derivatives
a,b
In summary, we have developed the first example of a three-
component domino Heck−Negishi coupling reaction for the
synthesis of novel purine compounds with carbon substituents
at C6. It is the first time that organozinc reagents are used to
trap an alkylpalladium intermediate of olefins in the domino
Heck reaction. This three-component domino process can be
applicable for a variety of olefins, purine compounds and
organozinc halides. In all cases, this three-component domino
Heck−Negishi reactions exhibited excellent levels of regiose-
lectivity, and only α-position products were found.
a
Unless otherwise noted, all reactions were carried out with 1a (0.1
mmol), 2 (3.0 equiv), 3a (4.0 equiv, 0.5 mL of solution in THF), THF
b
(1.0 mL), 70 °C, N2, stirring overnight. Isolated yield based on 1a.
c
The reactions were performed on 2.0 mmol scale.
Scheme 3. Reaction of Various 6-Chloropurines and
Benzylzinc Bromides
a,b
ASSOCIATED CONTENT
* Supporting Information
Experimental procedure, characterization data, and copies of 1H
and 13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: quguir@sina.com.
*E-mail: guohm518@hotmail.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 21072047, 21172059,
21272059, 21202039, and 21372066), Excellent Youth
Foundation of Henan Scientific Committee (No.
114100510012), the Program for Innovative Research Team
from the University of Henan Province (2012IRTSTHN006),
the Program for Changjiang Scholars and Innovative Research
Team in the University (IRT1061), and the Program for
Science & Technology Innovation Talents in Universities of
Henan Province (No.13HASTIT013).
a
Reaction conditions: 1 (0.1 mmol), 2d (3.0 equiv), 3 (4.0 equiv), 70
b
°C, N2, stirring overnight. Isolated yield based on 1.
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