KI-catalyzed imidation of sp3 C-H bond adjacent to amide nitrogen atom

Article abstract of DOI:10.1039/c2ob26430g

We have developed a new KI-catalyzed method for the imidation of an sp ³ C-H bond adjacent to an amide nitrogen atom by using TBHP (tert-butyl hydroperoxide, 70% aqueous solution) as the oxidant. This novel procedure tolerated air and moisture and provided a series of novel products in moderate to excellent yields under mild conditions.

Full text of DOI:10.1039/c2ob26430g

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KI-catalyzed imidation of sp3 C–H bond adjacent to amide nitrogen atom†
Zhi-Qi Lao, Wen-He Zhong, Qing-Hua Lou, Zhong-Jun Li* and Xiang-Bao Meng*
Received 21st July 2012, Accepted 24th August 2012
DOI: 10.1039/c2ob26430g
reactions, nitrene derivatives were used as the primary nitrogen
sources and transition-metal catalysts were used. Recently, Fu
and co-workers reported copper-catalyzed amidation of the sp3
C–H bond adjacent to a nitrogen atom in N,N-dimethylaniline
via a CDC process.10 However, there is still no published report
on the amidation of the sp3 C–H bond adjacent to an amide
nitrogen atom. Herein, we developed a transition-metal-free
method for the amidation of the sp3 C–H bond in amides
through a CDC process. This novel reaction is catalyzed by KI
in the presence of TBHP under mild conditions and provides
products containing potential bioactivity11 in moderate to excel-
lent yields without the need to exclude air and moisture.
Table 1 shows the optimization of reaction conditions. By
using phthalimide as the nitrogen source and N,N-dimethylacet-
amide as the substrate in the presence of tert-butyl hydroperoxide
(TBHP), no product was observed (entry 1). However, when NaI
was added to the reaction, 81% yield of 3a was obtained. Further
We have developed a new KI-catalyzed method for the imi-
dation of an sp3 C–H bond adjacent to an amide nitrogen
atom by using TBHP (tert-butyl hydroperoxide, 70%
aqueous solution) as the oxidant. This novel procedure toler-
ated air and moisture and provided a series of novel products
in moderate to excellent yields under mild conditions.
Direct C–H bond activation and subsequent coupling with other
reagents to form new C–C and C–heteroatom bonds provide
important alternative methods for the synthesis of novel com-
pounds.1 Recently, the transition-metal-catalyzed cross-dehydro-
genative-coupling (CDC) reaction in C–H bond activation and
subsequent formation of new C–C and C–heteroatom bonds has
attracted much attention.2 The applications of this novel metho-
dology allow the functionalization of sp, sp2 and sp3 C–H bonds,
and it was found that the presence of an adjacent heteroatom was
essential for the functionalization of sp3 C–H bonds.3,4 Most of
the past works focused on aryl substituted substrates, such as the
functionalization of the sp3 C–H bond adjacent to the nitrogen of
N,N-dimethylaniline and 1,2,3,4-tetrahydroisoquinoline and the
sp3 C–H bond adjacent to the oxygen of isochroman.3,4 Similar
reactions of non-aryl substituted substrates have rarely been
reported. Xu et al. reported an alkynylation reaction of the C–H
in the methylamino group of an aliphatic amine mediated by
copper–diethyl azodicarboxylate.5 Very recently, Li and co-
workers developed a thiolation reaction of the sp3 C–H bond
adjacent to an amide nitrogen atom mediated by TBHP, without
the use of metal catalyst.6 However, examples of direct C–H
bond oxidative activation adjacent to an amide nitrogen are still
limited.
Table 1 Condition optimization studiesa
Entry
Catalyst (equiv)
Yieldb (%)
1
2
3
4
—
NaI (0.2)
KI (0.2)
Bu4NI (0.2)
I2 (0.2)
0
81
95
93
0
5
In addition, C–N bond formation has also attracted broad
attention because of its prevalence in therapeutic drugs and
natural products.7 Traditional C–N bond formation that is based
on functional group interconversion cannot satisfy the present-
day need of atom economy and green chemistry.8 In the past
decade, much progress in intramolecular and intermolecular ami-
dation of the C–H bond has been made.9 In many of these
6
7
8
9
10
11
12
13
14
15
16
17
18
KCl (0.2)
KBr (0.2)
FeCl3 (0.2)
FeSO4 (0.2)
CuI (0.2)
CuCl (0.2)
SnCl2 (0.2)
KI (0.2)
KI (0.2)
KI (0.1)
KI (0.2)
KI (0.2)
0
0
0
0
37
<10
0
93c
88d
88
76e
93f
94g
State Key Laboratory of Natural and Biomimetic Drugs, Department of
Chemical Biology, School of Pharmaceutical Sciences, Peking
University Health Science Center, Beijing 100191, PR China.
E-mail: xbmeng@bjmu.edu.cn, zjli@bjmu.edu.cn;
Fax: +86 10 82805496; Tel: +86 10 82801714
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob26430g
KI (0.2)
a Reaction conditions: phthalimide (1 mmol), N,N-dimethylacetamide
(1 mL, 9 mmol). b Isolated yield. c 2 equiv TBHP. d 3 h. e At 80 °C.
f In dark. g N2 protection.
This journal is © The Royal Society of Chemistry 2012
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Table 2 KI-catalyzed imidation of amidea
investigation of other iodides showed that KI provided the most
efficient catalysis (entries 2–5).12 Employing KBr and KCl as
catalysts yielded no product in this reaction (entries 6 and 7).
Considering the beneficial effects of transition-metals in C–H
bond activation, several metal salts, such as FeCl3, FeSO4 and
SnCl2, were added to the reaction but no product was obtained
(entries 8–12). When CuCl was added, a small amount of
product was obtained; however, CuI catalyzed the reaction to
furnish 3a in moderate yield (entries 10 and 11), further indicat-
ing that iodide was essential for this transformation. Subsequent
exploration in reactant ratios showed that 0.2 equiv of KI and 4
equiv of TBHP to the imide provided the highest yield (entries
3, 14 and 15). Increasing reaction time to 3 h did not provide sig-
nificant improvement in the product yield (entry 13). Reducing
temperature to 80 °C decreased the yield slightly (entry 16). It is
noteworthy that tolerance of air, moisture and light was also
observed (entries 17 and 18), which greatly simplified the per-
formance of the reactions compared with other catalytic
methods. Finally, the optimal reaction conditions were deter-
mined as the following: 0.2 equiv KI and 4 equiv TBHP relative
to imide at 90 °C for 1 h.
Under the optimized conditions, the scope of this reaction was
then investigated. Table 2 shows that various imides and amides
reacted to generate the desired products in moderate to excellent
yields. The reactions of phthalimides substituted by electron-
withdrawing groups proceeded slowly but gave excellent yields
after 3 h (3b and 3c). A phthalimide derivative bearing an elec-
tron-donating group afforded the product in an excellent yield of
91% (3d). Moreover, although it was reported that benzylic C–H
can be easily oxidized by the KI-TBHP system,13 the benzylic
C–H of 4-methylphthalimide was not affected by this procedure.
1,8-Naphthalimide and its chlorinated derivative reacted
smoothly in 1 h and yielded the respective products in excellent
yields (3e and 3f). Aliphatic imides also reacted smoothly under
the optimized condition, albeit with moderate to good yields
(3g–3i). However, sulfonamide was found to be a poor substrate
and the product was isolated only in 44% yield even the reaction
time was prolonged to 24 h (3j). In addition to N,N-dimethylacet-
amide, various types of amides were also tested. N,N-dimethyl-
formamide (DMF) gave the desired product in 54% yield (3k),
and we found that adding the oxidant in two portions increased
the yield to 73%. Interestingly, when N-methylpyrrolidone
(NMP) was subjected to this procedure, the methylene C–H was
preferentially activated and the reaction proceeded in high
regioselectivity (3m); no methyl-substituted product was
observed. Subsequent exploration of other amides also afforded
the target products in good to excellent yields (3l, 3n and 3o).
When N,N-dimethylaniline was subjected to our procedure,
the desired products were obtained in excellent yields
(Scheme 1, 3p and 3q). Compared with previous copper cata-
lyzed reaction conditions,10 this methodology is not sensitive to
air and moisture and could be performed in an open flask.
a Reaction conditions: amide (1 mL, 9 mmol), imide (except for 3j
which is an amide) (1 mmol), TBHP (4 mmol, 70% aqueous solution),
c
KI (0.2 mmol). Isolated yields are shown. b12 h. 24 h. d2 mmol of
TBHP (70% aqueous solution) was added first and 2 mmol after 0.5 h.
Scheme 1 Imidation of N,N-dimethylaniline.
To investigate a plausible reaction mechanism, a radical-
trapping reagent 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
was added to the reaction mixture. As shown in Scheme 2a, con-
densation product 3x was obtained in 71% yield, indicating that
the reaction likely proceeded through a free radical intermediate.
Previous studies indicated that hypoiodite species could be pro-
duced in the presence of iodide and TBHP.12b,e,14 However,
when the reaction was conducted in the presence of I2 and KOH,
which generated hypoiodite species in situ, no product was
observed (Scheme 2b). Therefore, the hypoiodite intermediate
could not be involved in this procedure.
Based on these results, a plausible reaction mechanism is pro-
posed in Scheme 3. TBHP firstly reacts with iodide anion and
7870 | Org. Biomol. Chem., 2012, 10, 7869–7871
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3 For C–H bond adjacent to an oxygen atom, see: (a) Y.-H. Zhang and
C.-J. Li, Angew. Chem., Int. Ed., 2006, 45, 1949; (b) Y.-H. Zhang
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4 For C–H bond adjacent to a nitrogen atom, see: (a) L. Zhao, O. Basle
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Scheme 2 Investigation of possible reaction mechanism.
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Scheme 3 Plausible reaction mechanism.
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generates three important species: tert-butyl oxide free radical,
iodine and hydroxyl anion.3f The oxide free radical reacts with
amide and produces intermediate A, which is subsequently oxi-
dized by iodine to generate specie B and iodide anion, complet-
ing a catalytic cycle. The deprotonated imide reacts with
intermediate B to furnish the target product C.
In conclusion, we have developed a novel method for the imi-
dation of sp3 C–H bonds adjacent to an amide nitrogen atom by
employing iodide anion as catalyst. Considering the mild con-
ditions and readily available reagents used in the reaction, this
new methodology may represent an efficient method for the
direct construction of C–N bonds by oxidative activation of sp3
C–H bonds adjacent to an amide nitrogen atom.
10 Y.-M. Zhang, H. Fu, Y.-Y. Jiang and Y.-F. Zhao, Org. Lett., 2007, 9,
3813.
11 Selected examples for bioactive analogues of our products, see:
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12 Selected examples for iodide-catalyzed reaction, see: (a) M. Uyanik,
H. Okamoto, T. Yasui and K. Ishihara, Science, 2010, 328, 1376;
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This work was supported by grants from the National Basic
Research Program of China (Grant No. 2012CB822100) and
the National Natural Science Foundation of China (NSFC
No. 21072017, 21072016, 20972012).
Notes and references
1 For selected C–H bond functionalization reviews, see: (a) C.-L. Sun,
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This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7869–7871 | 7871