Efficient cyclization of tertiary amines and alkenes promoted by KOt-Bu-DMF

Article abstract of DOI:10.1039/c3cc46340k

Nitrogen heterocycles could be prepared in good yields via intramolecular cyclization of tertiary amines and alkenes promoted by KOt-Bu-DMF. This journal is The Royal Society of Chemistry 2013.

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Efficient cyclization of tertiary amines and alkenes promoted by KOt-
Bu/DMF
Yan-yan Chen, Xue-jing Zhang, Hui-min Yuan, Wen-tao Wei, and Ming Yan*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Nitrogen heterocycles could be prepared in good yields via
Table 1 Intramolecular cyclization of 1aa
intramolecular cyclization of tertiary amines and alkenes
promoted by KOt-Bu/DMF.
Nitrogen heterocycles are most privileged structures in natural
50
10 products and synthetic drugs. Their synthetic methods have been
receiving great attention.1 In recent years, there have been
Entry
Solvent
Base
Yield (%)b
1
2
3
4
DMF
DMSO
DMA
DMF
DMF
DMF
THF
DMF
DMF
DMF
DMF
DMF
DMF
KOt-Bu
KOt-Bu
KOt-Bu
NaOt-Bu
NaOMe
KHMDS
n-BuLi
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
67 (64)
62
11
63
10
56
0
82 (76)
78 (65)
82 (69)
0
5
31
increasing interests in the direct functionalization of
α C−H
bonds of amines.2 The strategy provides superior advantages over
the traditional methods in terms of synthetic efficiency, atom
15 economy and green chemistry. Typical activation modes of α
C−H bonds of amines include α-amino anion pathway, α-amino
cation (iminium) pathway, α-amino radical pathway, and
transition metal mediated C−H activation pathway.2 The
generation of reactive α-amino radicals and consequent addition
5
6
7c
8d
9e
10f
11 d,g
12 d,h
20 to alkenes are highly efficient for the synthesis of α-alkyl amines
13 d,i
4
and nitrogen heterocycles.3,
So far the generation of α-
a
Reaction conditions: 1a (0.1 mmol), base (0.3 mmol), solvent (1.2 mL), 90
b
aminoalkyl radicals has been reported via the homolysis of α
C−X bonds, radical translocation, photoinduced single electron
transfer, and SmI2-promoted reduction of imines or iminium
25 cations.5 However these methods still suffer from the limited
substrate scope, toxic reagents, or the requirement of special
°C, 4 h. Yields were determined by GC with n-dodecane as the internal
standard. The values in the parenthesis are the isolated yields after the
column chromatograph. c 1a (0.1 mmol), n-BuLi (0.3 mmol), THF (1.2 mL),
-30 °C, 4 h. d KOt-Bu (0.15 mmol) was used. e 1a (0.3 mmol), KOt-Bu (0.15
mmol). KOt-Bu (>99.99% purity, 0.15 mmol) was used. Benzoquinone
(0.15 mmol) was used. h TEMPO (0.15 mmol) was added. i The reaction was
carried out with an oxygen balloon.
f
g
precursors (such as
light irradiation.
α-sulfanyl amines or α-TMS amines) and
Knochel, Pines and their co-workers found that KOt-Bu could
30 catalyze the addition of carbonyl derivatives (lactams, ketones,
nitriles and imines) to styrene.6 The carbanion reaction pathway
was proposed by Pines et al.6a In 2008, Itami et al. reported the
KOt-Bu promoted biaryl coupling of electron-deficient nitrogen
heterocycles with aryl iodides.7 Shi and other researchers found
35 that the coupling reactions of aryl halides and arenes could be
promoted by KOt-Bu in combination with 1, 10-phenanthroline
or DMF.8 Recently Hayashi, Rueping and their co-workers
reported Mizoroki-Heck reaction promoted by KOt-Bu/DMF.9 In
these reactions, the generation of aryl radical via the single
40 electron transfer from t-butoxy anion to aryl halides and the
consequent elimination of halogen anion was suggested. In this
paper, we report a new strategy for the generation of α-
aminoalkyl radicals via the direct reaction of tertiary amines with
KOt-Bu/DMF. The resulted α-aminoalkyl radicals readily
45 undergo intramolecular cyclization with alkenes.
(Table 1, entry 1). DMSO is also suitable solvent and a slightly
lower yield was obtained (Table 1, entry 2). The reaction in N, N-
dimethylacetamide (DMA) led to poor yield (Table 1, entry 3).
55 The combination of NaOt-Bu/DMF provided slightly lower yield
(Table 1, entry 4). Sodium methoxide also provided poor yield
(Table 1, entry 5). Potassium hexamethyldisilazide (KHMDS)
could promote the reaction and 2a was obtained in 56% yield
(Table 1, entry 6), however the use of butyl lithium in THF did
60 not give the product 2a (Table 1, entry 7). Other solvents and
bases were also examined, but no substantial amount of 2a could
be obtained.10 The decrease of the loading of KOt-Bu (1.5 equiv)
led to better yield (Table 1, entry 8). The use of substoichiometric
amount of KOt-Bu (0.5 equiv) still gave good yield (Table 1,
65 entry 9). The sublimed grade of KOt-Bu (>99.99% purity) was
also examined and the similar yield was obtained (Table 1, entry
10). The fact supported that the reaction is promoted by KOt-Bu
itself, rather than contaminated transition metals in KOt-Bu. The
radical scavenger such as benzoquinone and TEMPO (2, 2, 6, 6-
70 tetramethylpiperidinooxy)
Initially we examined the reaction of N-2-ethenyl-phenyl
tetrahydroisoquinoline 1a in the presence of KOt-Bu (3 equiv) in
DMF. The reaction gave 64% yield of cyclization product 2a
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Table 2 Intramolecular cyclization of tetrahedroisoquinoline derivatives
1a-1j promoted by KOt-Bu/DMFa
The reaction was further extended to arylmethylamine derivatives
30 3a−3g and the results are summarized in Table 3. The reaction of
N-benzyl-N-methyl-2-vinylaniline 3a gave a mixture of 6-endo
cyclization product 4a and 5-exo cyclization product 5a
(4a/5a=29/71) in good yield (Table 3, entry 1). The introduction
of
β
35 product (Table 3, entry 2). On the other hand,
-phenyl group significantly increased the selectivity for 5-exo
-phenyl
α
Entry
1
2
1
R1
H
H
H
H
H
H
H
R2
H
R3
H
H
H
H
H
H
H
2
Yield (%)b
substituted substrate 3c provided 6-endo product exclusively
(Table 3, entry 3). 2-Naphthylmethylamine, 2-quinolylamine and
2-benzofuranylamine derivatives 3d−3f provided 6-endo products
(Table 3, entries 4−6). For these substrates, big steric hindrance
40 strongly favors 6-endo-trig cyclization pathway.11 N, N-
Dimethylamine derivatives 3g was also examined and found to be
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2b
2c
2d
2e
2f
2g
2h
2i
76
68
75
57
52
0
3-Br
3-Cl
3-Me
3-MeO
3-CF3
4-NO2
H
3
4
5c
6
7
0
unreactive (Table 3, entry 7). The activation of α C−H bond by
the neighboring aryl group seems to be necessary for this
8c
9
6,7-(MeO)2
H
Me
di-Me
72
85d
84
H
H
H
H
transformation.
10
1j
2j
a
45
β-Vinyl substituted substrate 3h and 3i were also examined.
Reaction conditions: 1a-1j (0.1 mmol), KOt-Bu (0.15 mmol), DMF (1.2
mL), 90 °C, 4 h. b Isolated yields after the column chromatograph. c KOt-
Bu (0.3 mmol) and DMF (2 mL) were used. d The product was obtained as
a mixture of cis- and trans-isomers (cis/trans=3:2).
Interestingly 3-propyl indole derivatives 6h and 6i were obtained
in good yields (Scheme 1). In these cases, 5-exo-trig cyclization
occurred exclusively. The indole derivatives were generated after
the rearrangement of the double bond.12
5
significantly inhibited the reaction (Table 1, entries 11−12). The
reaction was also inhibited in the presence of oxygen (Table 1,
entry 13). The results undoubtedly implicated a free radical
reaction pathway.
The reaction was also applied to other tetrahydroisoquinoline
50
10 derivatives 1a−1j and the results are summarized in Table 2. The
reaction of 1b−1c bearing with 3-halide styrene moiety gave the
products 2b−2c in good yields (Table 2, entries 2-3). The
substitution with electron-donating groups such as methyl and
methoxyl slightly decreased the yields (Table 2, entries 4-5). The
15 reactions of substates 1f−1g with trifluoromethyl and nitro groups
did not provide the expected cyclization products (Table 2,
entries 6-7), instead polmerized products were probably
generated. The electron-deficient olefins may be prone to the
polymerization under the reaction conditions. The substitution
20 with methoxyl groups at the tetrahydroisoquinoline moiety was
also tolerable. The product 2h was obtained in good yield (Table
Scheme 1. Reaction of β-vinyl substituted substrates 3h and 3i.
When the reaction of 1a was carried out in DMF-d1, extensive
deuterium incorporations at the benzyl positions were observed
(Scheme 2). On the other hand, no deuteration was found if the
55 reaction was carried out in non-deuterated DMF combined with 5
equivalents of t-BuOD. The results indicated that the reaction
intermediate abstracts a hydrogen from DMF, but not from t-
BuOH. If the reaction proceeds via an α-amino anion
intermediate, the abstraction of a proton from more acidic t-
60 BuOH should be favorable. The present evidence strongly
supports a radical reaction pathway. Because t-butoxy radical is a
possible intermediate in the reaction, we examined the general
initiators of t-butoxy radical including t-BuOOBu-t and
PhCOOOBu-t for the reaction of 1a, however no 2a was obtained.
2, entry 8). The substitution of styrene moiety with
-dimethyl were also examined. The products 2i and 2j were
obtained in good yields (Table 2, entries 9-10).
β-methyl or β,
β
25 Table 3. Intramolecular cyclization of arylmethylamine derivatives 3a-
3g promoted by KOt-Bu/DMF. a
Me
N
Me
N
Me
N
R1
R2
R1
R2
R1
R3
R2
KOt-Bu (1.5 equiv)
DMF, 90 o
+
C
R3
R3
3a-3g
4a-4f
5a-5f
Entry
3
R1
Ph
Ph
Ph
R2
H
Ph
H
H
H
R3
H
H
Ph
H
H
H
H
4/5
Yield (%)b
84c
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
29/71
0/100
100/0
100/0
100/0
100/0
--
82d
80e
70
2-Naphthyl
2-Quinolyl
2-Benzofuranyl
H
77
H
H
41
65
3g
nrf
a Reaction conditions: 3a−3g (0.1 mmol) and KOt-Bu (0.15 mmol) in DMF (1.2
mL) at 90 °C for 4 h.. b Combined isolated yields of 4 and 5. c 5a (cis/trans=1:5). d
Isomers (cis/trans=1:10). e Isomers (cis/trans=1:3.3). f No reaction.
Scheme 2. Study of reaction mechanism.
We reason that a radical derived from DMF plays the crucial
role. Sliwka et al. observed the generation of radical
intermediates in the basic DMF and DMSO solution via EPR
2
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†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/.
analysis, however the exact structures of these radical
intermediates are not clear.13 The trapping of the radical
intermediate with 1,1-diphenylethylene was attempted (Scheme
2). To our delight, N,N-dimethyl-3,3-diphenylacrylamide 7 was
obtained in 20% yield. The result together with the above
deuterium-labeling experiment data suggest the generation of a
carbamoyl radical from DMF. Such a carbamoyl radical was
previously suggested in the oxidative reactions with tert-butyl
hydroperoxide or tert-butyl perbenzoate in DMF.14
1
For selected reviews of nitrogen heterocycles in natural products
and drugs, see: (a) J. P. Michael, Nat. Prod. Rep., 2008, 25, 166; (b)
M. Mori, Heterocycles 2009, 78, 281; (c) V. Sridharan, P. A.
Suryavanshi and J. C. Menéndez, Chem. Rev. 2011, 111, 7157.
For the reviews of direct functionalization of tertiary amines, see: (a)
K. R. Campos, Chem. Soc. Rev. 2007, 36, 1069; (b) P. Thansandote
and M. Lautens, Chem.-Eur. J. 2009, 15, 5874; (c) G. E. Dobereiner
and R. H. Crabtree, Chem. Rev. 2010, 110, 681; (d) C. S. Yeung and
V. M. Dong, Chem. Rev. 2011, 111, 1215; (e) C. Liu, H. Zhang, W.
Shi and A.-W. Lei, Chem. Rev. 2011, 111, 1780 .
50
55
60
65
70
75
80
85
90
5
2
10
A tentative reaction mechanism is proposed in Scheme 3. The
formation of the carbamoyl anions via the deprotonation of N,N-
disubstituted formamides with lithium diisopropylamide or other
strong bases had been reported by Reeves, Smith and their
coworkers.15 In the present reaction, DMF is probably
3
For reviews of α-aminoalkyl radicals in organic synthesis, see: (a) J.
Cossy, Radicals in Organic Synthesis, Vol. 1 (Eds: P. Renaud, M. P.
Sibi), Wiley-VCH, Weinheim, 2001, pp 229−249; (b) J. M.
Aurrecoechea and R. Suero, Arkivoc 2004, xiv, 10.
4
5
For the review of radical cyclizations, see: G. J. Rowlands,
Tetrahedron 2010, 66, 1593.
15 deprotonated by KOt-Bu to give the carbamoyl anion with η2
coordination of potassium by the carbonyl group. The anion is
further transformed to the carbamoyl radical A by a single
electron transfer process. The possible single electron acceptor
may be another DMF molecule and a radical anion species such
20 as B is formed. The radical A abstracts C-1 hydrogen atom of
tetrahydroisoquinoline and the consequent radical cyclization
provides the intermediate D. After the abstraction a hydrogen
atom from DMF, the product 2a is formed and the carbamoyl
radical A is regenerated. Because the reaction proceeds via a
25 chain process with the carbamoyl radical A being recycled, only a
trivial amount of the radical anion B is formed depending on the
chain length.
For the selected recent reports of α-aminoalkyl radicals, see: (a) T.
Yoshimitsu, Y. Arano and H. Nagaoka, J. Am. Chem. Soc. 2005,
127, 11610; (b) C. M. R. Volla and P. Vogel, Org. Lett. 2009, 11,
1701; (c) Y. Miyake, K. Nakajima and Y. Nishibayashi, J. Am.
Chem. Soc. 2012, 134, 3338; (e) Z.-Q. Wang, M. Hu, X.-C. Huang,
L.-B. Gong, Y.-X. Xie and J.-H. Li, J. Org. Chem. 2012, 77, 8705;
(d) P. Kohls, D. Jadhav, G. Pandey and O. Reiser, Org. Lett. 2012,
14, 672; (e) S. Zhu, A. Das, L. Bui, H. Zhou, D. P. Curran and M.
Rueping, J. Am. Chem. Soc. 2013, 135, 1823.
6
(a) H. Pines, S. V. Kannan and J. Simonik, J. Org. Chem. 1971, 36,
2311; (b) A. L. Rodriguez, T. Bunlaksananusorn and P. Knochel,
Org. Lett. 2000, 2, 3285.
7
8
S. Yanagisawa, K. Ueda, T. Taniguchi and K. Itami, Org. Lett. 2008,
10, 4673.
(a) W. Liu, H. Cao, H. Zhang, H. Zhang, K. H. Chung, C. He, H.
Wang, F. Y. Kwong and A.-W. Lei, J. Am. Chem. Soc. 2010, 132,
16737; (b) C.-L. Sun, H. Li, D.-G. Yu, M. Yu, X. Zhou, X.-Y. Lu, K.
Huang, S.-F. Zheng, B.-J. Li and Z.-J. Shi, Nat. Chem. 2010, 2, 1044;
(c) G.-P. Yong, W.-L. She, Y.-M. Zhang and Y.-Z. Li, Chem.
Commun. 2011, 47, 11766; (d) S. De, S. Ghosh, S. Bhunia, J. A.
Sheikh and A. Bisai, Org. Lett. 2012, 14, 4466; (e) W.-C. Chen, Y.-C.
Hsu, W.-C. Shih, C.-Y. Lee, W.-H. Chuang, Y.-F. Tsai, P. P.-Y. Chen
and T.-G. Ong, Chem. Commun. 2012, 48, 6702; (f) H.-Q. Zhao, J.
Shen, J.-J. Guo, R.-J. Ye and H.-Q. Zeng, Chem. Commun. 2013, 49,
2323.
O
O
K
KO -Bu
t
H
N
N
O K
-BuOH
t
SET
N
H
DMF
B
O
N
N
N
A
1a
9
(a) E. Shirakawa, X.-J. Zhang and T. Hayashi, Angew. Chem. 2011,
123, 4767; Angew. Chem. Int. Ed. 2011, 50, 4671; (b) E. Shirakawa,
K. Itoh, T. Higashino and T. Hayashi, J. Am. Chem. Soc. 2010, 132,
15537; (c) M. Rueping, M. Leiendecker, A. Das, T. Poisson and L.
Bui, Chem. Commun. 2011, 47, 10629.
C
N
N
DMF
95 10 See supporting information for the details of the screen of solvents
and bases.
11 The 5-exo cyclization and the subsequent neophyl rearrangement
could also give the 6-endo cyclization products, but the deuterium-
labeling experiments of 1a (Scheme 2, eq. 1) and 3d (see supporting
D
2a
Scheme 3. Tentative reaction mechanism.
30
In summary, we have developed an efficient intramolecular
cyclization of α-aryl substituted tertiary amines and alkenes
promoted by KOt-Bu/DMF. The reaction provided a number of
nitrogen heterocycles in good yields. The experiment results
100
information) did not support this mechanism.
12 See supporting information for the tentative generation pathway of
products 6h and 6j.
13 C. L. Øpstad, T. B. MelØ, H. R. Sliwka and V. Partali,
Tertrahedron 2009, 65, 7616.
35 support a radical reaction pathway. The carbamoyl radical
derived from DMF is proposed to be the crucial initiator in the
reaction. Such a radical cyclization reaction promoted by the
simple combination of KOt-Bu and DMF is unprecedented. The
new pathway to reactive α-aminoalkyl radical should find wide
40 applications for the direct functionalization of α C−H bonds of
amines.
105 14 (a) Z.-J. Liu, J. Zhang, S.-L. Chen, E.-B. Shi, Y. Xu and X.-B. Wan,
Angew. Chem. 2012, 124, 3285; Angew. Chem. Int. Ed. 2012, 51,
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Chem. Commun. 2011, 47, 8946; (d) W.-P. Mai, H.-H. Wang, Z.-C.
110
Li, J.-W. Yuan, Y.-M. Xiao, L.-R. Yang, P. Mao and L.-B. Qu, Chem.
Commun. 2012, 48, 10117.
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Notes and references
115
Institute of Drug Synthesis and Pharmaceutical Process, School of
Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006,
45 China. E-mail: yanming@mail.sysu.edu.cn.
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