Nickel-Catalyzed Reaction of C-H Bonds in Amides with I2: Ortho-Iodination via the Cleavage of C(sp2)-H Bonds and Oxidative Cyclization to β-Lactams via the Cleavage of C(sp3)-H Bonds

Article abstract of DOI:10.1021/acscatal.6b00964

The first example of the nickel(II)-catalyzed reaction of amides using inexpensive and milder molecular iodine (I₂) as an iodinating reagent is reported. The reaction of aromatic amides having an 8-amino-5-choloroquinoline as a directing group

Full text of DOI:10.1021/acscatal.6b00964

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Article
2
The Nickel-Catalyzed Reaction of C-H Bonds in Amides with I:
ortho-Iodination via the Cleavage of C(sp2)-H Bonds and Oxidative
Cyclization to #-Lactams via the Cleavage of C(sp3)-H Bonds
Yoshinori Aihara, and Naoto Chatani
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00964 • Publication Date (Web): 24 May 2016
Downloaded from http://pubs.acs.org on May 25, 2016
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The Nickel-Catalyzed Reaction of C-H Bonds in
Amides with I2: ortho-Iodination via the Cleavage of
C(sp2)-H Bonds and Oxidative Cyclization to β-
Lactams via the Cleavage of C(sp3)-H Bonds
Yoshinori Aihara and Naoto Chatani*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-
0871, Japan
C-H activation, bidentate directing group, iodination, nickel, oxidative cyclization
ABSTRACT. The first example of the nickel(II)-catalyzed reaction of amides using inexpensive
and milder molecular iodine (I2) as an iodinating reagent is reported. The reaction of aromatic
amides having an 8-amino-5-choloroquinoline as a directing group with I2 resulted in the
production of ortho-iodination products. Deuterium labeling experiments indicate that the
cleavage of C-H bonds is irreversible and is likely the rate-determining step, which is in sharp
contrast to the previously reported transformation using the same Ni(II) catalyst/8-
aminoquinoline chelation system. The reaction is applicable to the synthesis of β-lactams from
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aliphatic amides as the substrate, in which C(sp3)-H bonds are activated. The results of deuterium
labeling experiments indicate that the cleavage of C(sp3)-H bonds is also irreversible.
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1. INTRODUCTION
Aryl halides are extensively utilized as important starting materials in organic synthesis for
constructing a variety of useful compounds in the fields of material science and medicinal
chemistry.1 An electrophilic aromatic substitution reaction, the Sandmeyer reaction or directed
lithiation are widely used in the synthesis of aryl halides. However, all of these strategies have
some limitations including (i) a low functional group tolerance, (ii) a low regioselectivity, and
(iii) the use of tedious and/or hazardous reagents.2 To address these limitations, the direct,
transition metal-catalyzed halogenation of C-H bonds is a particularly valuable transformation.3
The direct, palladium-catalyzed halogenation of C-H bonds has been extensively studied as an
alternate method for the preparation of aryl halides.4,5 Rh(III),6 Ru(II),7 Cu(I),8 and Co(III)9
complexes have been shown to have a high catalytic activity for the direct halogenation of arenes.
In cases of the iodination of C-H bonds reported so thus, various iodinating reagents, including
NIS,5c,m,p, 6a,c, 7a, 8d, 9 IOAc, generated by the reaction of I2 with PhI(OAc),5b,f,g KIO3/K2S2O8,5n
cyclic iodine(III),5o or NaI/PhI(OAc)26e have been used as an iodinating reagent. Yu recently
reported on the direct, Pd-catalyzed iodination of C-H bonds using the inexpensive and milder
molecular I2 as an iodinating reagent.10 Prompted by this finding, we envisioned the development
of an iodination methodology in which earth-abundant metals, such as nickel and inexpensive I2
could be used as an iodinating reagent.
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Our efforts have recently focused on the direct, Ni-catalyzed functionalization of C-H bonds
utilizing a 2-pyridinylmethyl moiety or an 8-aminoquinoline moiety as a directing group.11,12 The
8-aminoquinoline directing group was first used by Daugulis in the Pd-catalyzed
functionalization of C-H bonds.13,14 Since we reported on the first example of the Ni-catalyzed
functionalization of C-H bonds using 8-aminiquinoline chelation assistance in 2013,12b many
groups have followed this approach for the Ni(II)-catalyzed functionalization of C-H bonds,11,15
because this represents the first general system for the Ni-catalyzed chelation-assisted
functionalization of C-H bonds. Herein, to expand the utility of this chelation system we report
on the Ni-catalyzed direct iodination of aromatic C-H bonds using molecular I2 as the iodinating
reagent (Scheme 1). This reaction represents the first example of the Ni-catalyzed iodination of
arenes. The reaction is also applicable to the synthesis of β-lactams from aliphatic amides, which
involves the activation of C(sp3)-H bonds.
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Scheme 1. Reactions of C-H Bonds with I2
2. RESULTS AND DISCUSSION
2.1. ortho-Iodination of C(sp2)-H Bonds. The reaction of the aromatic amide 1a (0.15 mmol)
possessing an 8-amino-5-chloroquinoline moiety12d,g, 16 and I2 (0.3 mmol) in the presence of
Ni(OTf)2 (0.015 mmol) as the catalyst in 1,2-dichloroethane (0.7 mL) at 120 °C for 24 h gave a
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trace amount of ortho-iodination product 2a along with the recovery of the unreacted amide 1a in
99% yield (entry 1, Table 1). The addition of Na2CO3 (0.3 mmol) as a base dramatically
increased the yield of 2a to 74% NMR yield (entry 2). The reaction was found to be significantly
affected by the nature of the base used. The results indicate that Na2CO3 is the choice of base
(entries 2-5). The efficiency of the reaction was also affected by the solvent used (entries 2 and
6-8). Toluene was found to be the optimal solvent for this reaction, with 2a being produced in
76% isolated yield (entry 6). The yield of the product was decreased when the reaction was run
at 100 °C (entry 9). The use of N-iodosuccinimide (NIS) or iodosobenzene diacetate (PIDA)/NaI
as an iodinating reagent resulted in negligible product yields (entries 10 and 11). Other Ni(II)
complexes, such as Ni(OAc)2, NiI2, NiBr2, and NiCl2, also gave the iodination product, but the
yields were lower than when Ni(OTf)2 was used as the catalyst. No iodination product was
produced in reaction of the aromatic amide 1b having an 8-aminoqunoline directing group
instead of 1a, and a side product, which involved iodination at the 5-position on the quinoline
ring was produced (entry 12). The reaction using the aromatic amide 1c containing a methoxy
group instead of chloro group gave a decreased yield of iodination product, indicating that the
chloro group at the 5 position, not only prevents the substitution reaction at the 5-position on the
quinoline ring but also facilitates the reaction (entry 13).
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Table 1. Optimaization of the Direct, Nickel-Catalyzed Iodination of the Aromatic Amide
1a with Iodine
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a
Reaction conditions: amide 1a (0.15 mmol), iodine source (0.3 mmol), Ni(OTf)2 (0.015
b
mmol), base (0.3 mmol) in solvent (0.7 mL) at 120 °C for 24 h. NMR yields. The number in
parenthesis denotes the isolated yield. c The reaction was run at 100 °C for 24 h.
Table 2 provides information concerning the scope of aromatic amides under the standard
reaction conditions. The use of ortho-substituted amides gave good yields of iodination products
(2a, 2d, 2e and 2f). Although the reaction of meta-methyl and meta-trifluoromethyl aromatic
amides resulted in selective iodination at the less hindered C-H bonds (2h and 2j), the reaction of
meta-methoxy aromatic amides gave a mixture of mono-iodination products 2g and di-iodination
products 3g. In the case of a meta-fluoro aromatic amide, the di-iodination product 3i was
selectively formed when 2.5 equivalents of iodine were used at a reaction temperature of 140 °C.
Some functional groups, such as esters, fluorides, chlorides and bromides survived under the
reaction conditions employed. Polyhalo-substituted aromatic amides also reacted with I2 to give
the corresponding ortho-iodination products, as in 2n and 2p.
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To examine the electronic effect of substituents, we performed a competition experiment using
a 1:1 mixture of 1h and 1j in a reaction with I2 (Scheme 2). The reaction gave nearly a 1:1
mixture of the products 2h and 2j, indicating that the electronic nature of substituents had no
significant effect on the efficiency of the reaction. This is in sharp contrast to the our previous
results showing that the presence of an electron withdrawing group on an aromatic amide
dramatically facilitated the nickel-catalyzed arylation and alkylation of aromatic amides, in
which reductive elimination was proposed to be the rate-determining step.12b,e,h,i The difference
between the results shown in Scheme 2 and our previous results indicates that reductive
elimination is not a rate-determining step in the present iodination reaction.
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Table 2. The Direct, Nickel-Catalyzed Iodination of Aromatic Amides with Iodine
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a Reaction conditions: amide (0.15 mmol), iodide (0.3 mmol), Ni(OTf)2 (0.015 mmol), Na2CO3
(0.3 mmol) in toluene (0.7 mL) at 120 °C for 24 h. The number is isolated yields. The number in
parenthesis is the yields of recovered starting amide. b The reaction was run at 140 °C for 24 h. c
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d
2.5 Equivalents of iodide were used. Ni(OTf)2 (20 mol%) and 4 equivalents of Na2CO3 were
used.
Scheme 2. Competition Experiment: Electronic Effect
We next performed deuterium labeling experiments to gain more information on the rate-
determining step. The deuterated amide 1a-d7 was reacted with I2 at 120 °C for 3 h (Scheme 3).
No H/D exchange was observed in the ortho position on the recovered amide 1a. In addition, no
H/D exchange was observed in the absence of I2 when the reaction was carried out at 120 °C,
although there was a significant amount of H/D exchange in our previously reported reaction at
the ortho position, when the reaction temperature was 140 or 160 °C.12b,d,e,h To determine
whether or not H/D exchange occurs at 140 °C, the deuterated amide 1a-d7 was reacted with I2 at
140 °C (Scheme 4). No H/D exchange was detected in the recovered starting amide, although
H/D exchange occurred in the absence of I2. These results indicate that (i) the cleavage of C-H
bonds takes place, even at 120 °C, (ii) the cleavage of C-H bond is irreversible at 120 °C, (iii)
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the cleavage of C-H bond is reversible at 140 °C in the absence of I2, (iv) the cleavage of C-H
bonds is irreversible, even at 140 °C in the presence of I2. In other words, the cleavage of C-H
bonds occurs prior to the reaction with I2 and the reaction of the metallacycle, which is formed
by the cleavage of C-H bonds, with I2 proceeds much faster than the protonation of the
metallacycle, thus leading to H/D exchange.
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Scheme 3. Deuterium Labeling Experiments at 120 °C
Scheme 4. Deuterium Labeling Experiments at 140 °C
We next conducted parallel experiments using amide 1a and deuterated amide 1a-d7 (Scheme
5). The results showed that the rate of consumption of deuterated amide 1a-d7 was slower than
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that for amide 1a. A kinetic isotope effect (KIE) of 1.82 was observed at 120 °C. These results
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suggest that the cleavage of C-H bonds is the rate-determining step in the catalytic cycle.
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Scheme 5. Competition Experiment for Kinetic Isotope Effect: Parallel Reaction
I2
0.3 mmol
Ni(OTf)2 10 mol%
Na2CO3 2 equiv
1a
toluene 0.7 mL
120 °C, 1.5 h
KIE = 1.82
1a-d7
In order to obtain mechanistic information regarding a radical species, reactions were carried
out in the presence of radical scavengers (Scheme 6). The addition of TEMPO (2 equivalents)
dramatically decreased the yield of the product to 9% yield. In the use of BHT and 1,4-
cyclohexadiene, no reactions were detected. These results suggest that a radical species
participates in this reaction. However, the involvement of background reaction that radical
scavengers were reacted with I2 cannot be excluded, this background reaction would be expected
to consume most of the I2.17
Scheme 6. Reactions with Radical Scavengers
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A proposed mechanism for the reaction is shown in Scheme 7. Amide 1a coordinates to NiX2
followed by a ligand exchange with the generation of HX, this step is accelerated by Na2CO3, to
give the nickel complex A. Complex A undergoes cyclometalation to give complex B via a
concerted metalation deprotonation (CMD) mechanism, which is also accelerated by the
presence of Na2CO3. Based on the deuterium labeling experiments shown in Schemes 3 and 4,
this step is an irreversible and a rate-determining step. There are three possible pathways for the
reaction of cyclometalated complex B and I2. The first pathway (i) proceeds via an iodine atom
transfer18 to give the Ni(III) species C (left cycle in Scheme 7).19 The complex C undergoes
reductive elimination and protonation to give the iodination product 2a with the generation of the
Ni(I) complex. The Ni(II) catalyst is regenerated by the reaction of Ni(I) and an iodine radical or
I2. The second pathway (ii) involves the oxidative addition of I2 to complex B to give Ni(IV)
species D (right cycle in Scheme 7).20,21 This oxidative addition may take place via SET and a
recombination pathway (or the homolysis and recombination of a two iodine radical pathway).
The reductive elimination from D for the formation of a C-I bond and successive protonation
gives the iodination product 2a and with the regeneration of the Ni(II) species. Finally, a third
pathway (iii) involves the direct electrophilic cleavage of the Ni-Ar bond (bottom scheme in
Scheme 7).22 The reaction of the Ni(II) complex B and I2 directly gives the Ni(II) intermediate E
through the transition state F without increasing the oxidation state of the Ni center. Sanford
reported on a study of the formation of an Ar-X bond at a nickel center by using a stoichiometric
amount of a nickel complex, and an electrophilic pathway is unlikely based on the experimental
results reported in this paper.19b On the basis of these results and seminal work, we propose that
an electrophilic cleavage pathway is not likely, but the reaction would likely proceed through a
Ni(I)/Ni(III) catalytic cycle, such as pathway (i).23
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Scheme 7. Proposed Mechanism
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2.2. Intramolecular Oxidative Cyclization of C(sp3)-H Bonds. We next examined the
reaction of aliphatic amides with I2 in an attempt to extend the utility of this new iodination
reaction. However, the reaction of aliphatic amides and I2 did not give the expected -iodinated
products, but instead -lactams were formed via the cleavage of C(sp3)-H bonds (Scheme 8).
This type of transformation was achieved by utilizing a bidentate chelation system and various
strong oxidants in conjunction with palladium,24 copper25 or cobalt26 catalysts. Ge recently
reported on the Ni-catalyzed amidation of C(sp3)-H bonds using TEMPO as an oxidant.27 In all
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of these reports, the formation of -lactams was proposed to proceed via C-N bond forming
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reductive elimination.
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Scheme 8. Oxidative Cyclization of C(sp3)-H Bonds
Table 3. Optimization of the Nickel-Catalyzed Formation of β-lactam via cleavage of
C(sp3)-H Bondsa
a
Reaction conditions: amide 1a (0.15 mmol), iodine (0.3 mmol), Ni(OTf)2 (0.015 mmol),
additive (0.0375 mmol), base (0.3 mmol) and solvent (0.3 mL) were added in the sealed tube,
b
and heated at 140 °C for 24 h. NMR yields. The number in parenthesis represents the isolated
c
yield. Reaction conditions: amide 1a (0.15 mmol), iodine (0.3 mmol), Ni(OTf)2 (0.015 mmol),
additive (0.0375 mmol), base (0.3 mmol) and solvent (0.5 mL) were added in the two-necked
flask equipped with a condenser, and heated at 140 °C for 24 h.
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The aliphatic amide 4a was reacted under the standard reaction conditions used for the
iodination of aromatic C-H bonds to give the -lactam 5a in 8% (Table 3, entry 1). The choice of
solvent had a significant effect on the yield of the -lactam 5a (entries 1-4). The reaction of the
aliphatic amide 4a and I2 in the presence of Ni(OTf)2, Na2CO3 with DMF as the solvent in a
sealed tube gave the -lactam 5a in 53% yield, along with 38% of unreacted 4a being recovered
(entry 4). This reaction was also dependent on the choice of base (entries 4-7). The addition of a
catalytic amount of Ag2CO3 improved the yield of -lactam 5a to 63% yield. The yield of -
lactam 5a was increased to 82% yield, when the reaction was conducted in an open system
instead of a closed system. Finally, the combined use of Ag2CO3 and an open system gave the -
lactam 5a in 91% isolated yield (entry 10).
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Table 4. The Nickel-Catalyzed Formation of Lactams with Iodine a
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Cl
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Ni(OTf)2 10 mol%
Ag2CO3 25 mol%
Na2CO3 2 equiv
O
H
R
O
R
R
R
N
+
I2
N
H
N
DMF 0.5 mL
140 C, 24 h
ClQ
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5
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substrate
O
product [%]b
O
N
91
NHClQ
ClQ
4a
5a
5b
5c
H
O
Pr
Et
O
Pr
74c
NHClQ
N
N
ClQ
O
4b
H
O
Et
Et
Et
79 (16)c
NHClQ
ClQ
O
4c
H
O
Ph
75
Ph
NHClQ
N
N
4d
5d
5e
H
O
ClQ
O
Ar
MeO
64 (24)
NHClQ
ClQ
O
H
O
4e
Ph
Ph
74 (7)c
50 (22)
27 (46)
47 (30)c
NHClQ
N
N
N
4f
5f
H
O
ClQ
O
AcO
AcO
NHClQ
4g
ClQ 5g
H
O
O
NHClQ
ClQ
H
O
4h
5h
O
NHClQ
N
H
4i
5i
ClQ
a
Reaction conditions: amide 1a (0.15 mmol), iodine (0.3 mmol), Ni(OTf)2 (0.015 mmol),
Ag2CO3 (0.0375 mmol), Na2CO3 (0.3 mmol) and DMF (0.5 mL) were added in a two-necked
flask equipped with a condenser, and heated at 140 °C for 24 h. b Isolated yields. The number in
parenthesis is the yield of the recovered starting amide. c Reaction run at 160 °C for 24 h.
With the optimized reaction conditions in hand, we examined the scope of the substrate (Table
4). αααTrisubstituted amides gave the corresponding -lactams in good yields. In all cases, the
reactions proceeded exclusively at the methyl group in a highly regioselective manner, and -
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methylene C-H bonds in 4b and 4c, cyclic -methylene C-H bonds in 4h and 4i and -aromatic
C-H bonds in 4d and 4e did not react with I2. In contrast to Ge’s finding that the reaction of
amide 4d in the presence of a Ni(II) catalyst and TEMPO as an oxidant gave a mixture of the -
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lactam 5d and another -lactam which was obtained via the cleavage of benzylic C-H bonds,27
aliphatic amides containing a benzylic C-H bonds, as in 4d and 4e gave only the product, in
which methyl C-H bonds reacted. The reaction was applicable to the synthesis of -lactams
having a spiro motif, as in 5h and 5i.
Deuterium labeling experiments using 4a-d9 at 140 °C were carried out (Scheme 9). Similar to
the case of an aromatic system, the cleavage of C-H bonds was found to be irreversible in the
presence of I2. Next, deuterium labeling experiments using 4c-d3 were carried out (Scheme 10).
No H/D exchange was observed in the presence of I2. In addition, the activation of a methylene
C-H bond in 4c-d3 was observed, as in 5c-d3, although methylene C-H bonds in 4c did not react,
as shown in Table 4. These results suggest that the cleavage of C-H bonds is the rate-determining
step in this reaction.
Scheme 9. Deuterium Experiments at 140 °C
Scheme 10. Deuterium Experiments at 160 °C
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The addition of radical scavengers, such as TEMPO and BHT resulted in no reaction (Scheme
11), similar to aromatic iodination reactions, as shown in Scheme 6. These results indicate that a
radical is involved in the reaction.
Scheme 11. Reactions with Radical Scavengers
The most important issue to be addressed is how the -lactam is formed. There are two
possible pathways for the formation of a β-lactam as shown in Scheme 12. One possibility is a
direct pathway, in which the -lactam is directly formed through the C-N bond reductive
elimination from the Ni(III) intermediate H or the Ni(IV) intermediate I, which are generated by
the reaction of the metallacycle G with I2. All of the β-lactam synthesis reactions involving a
cleavage of C(sp3)-H bonds reported so thus are proposed to proceed through this direct path.23-26
The other possibility is a stepwise pathway, involving the direct -iodination of the aliphatic
amide to 6 and a facile intramolecular cyclization of the resulting 6 to form the -lactam.
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Scheme 12. Proposed Mechanism for the Formation of β-Lactams
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Scheme 13. Conversion of 6 to 5a
In order to confirm which of these pathways is operative, the β-iodinated amide 6 was
independently prepared and reacted under the standard reaction conditions in the absence of I2
(Scheme 13). The β-lactam 5a was obtained in 84% yield. In addition, the cyclization took
place even in the absence of Ni(OTf)2 and Ag2CO3. This result suggests that the β-lactam is
formed via a stepwise pathway, and not via a direct pathway.28 However, these results do not
completely exclude the possibility of a direct pathway because 6 was not detected in the catalytic
reaction of 4a.
β-Lactams are an important structure for natural products and pharmaceutical compounds, such
as penicillin and ezetimibe.29 The deprotection of 8-aminoqunoline moieties in the products
increases the potential of this transformation. Treatment of the β-lactam 7 containing an 8-
amino-5-methoxyquinoline with ceric ammonium nitrate (CAN) gave the deprotected β-lactam 8
in 72% yield (Scheme 14).30
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Scheme 14. Deprotection
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3. CONCLUSION
We report on the first example of the Ni(II)-catalyzed direct iodination of aromatic amides
using molecular I2 as an iodinating reagent.31 The reaction does not require strong co-oxidants.
Mechanistic experiments revealed that the cleavage of C-H bonds is irreversible and is the rate-
determining step in the catalytic cycle, in sharp contrast to other Ni(II)-catalyzed
functionalization of C-H bonds in amides.12b,e,i This reaction is applicable to the synthesis of -
lactams by using aliphatic amides and I2, in which C(sp3)-H bonds are activated. The results of
deuterium labeling experiments indicate that the cleavage of C(sp3)-H bonds is also irreversible.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and characterization data of all new
compounds. This material is available free of charge via the Internet at http://pubs.acs.org/
AUTHOR INFORMATION
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Corresponding Author
chatani@chem.eng.osaka-u.ac.jp
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported, in part, by a Grant-in-Aid for Scientific Research on Innovative Areas
"Molecular Activation Directed toward Straightforward Synthesis (22105001)" from Monbusho
(The Ministry of Education, Culture, Sports, Science and Technology), and by JST Strategic
Basic Research Programs “Advanced Catalytic Transformation Program for Carbon Utilization
(ACT-C) (52571)” from Japan Science and Technology Agency. Y.A. expresses his special
thanks for a JSPS Research Fellowship for Young Scientists.
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(30) An 8-amino-5-methoxyquinoline directing group was not a superior directing group, as
shown in Table 1. In fact, the compound 7 was obtained in 17% isolated yield. However, Ge
reported a new and general protocol for the deprotection of an 8-aminoqunoline moiety with
PhI(OAc)2/BF3Et2O and CAN to give β-lactams.
(31) Recently, Wu, Su, and coworkers reported the Cu-catalyzed C-H iodination of aromatic
amides having an-8-aminoquinoline as the directing group with I2, in which iodination took place
at the quinoline ring. Wu, C.; Zhou, H.; Wu, Q.; He, M.; Li, P.; Su, Q.; Mu, Y. Synlett 2016, 27,
868.
Table of Contents Graphic and Synopsis
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