Iron-mediated one-pot formal nitrocyclization onto unactivated alkenes

Article abstract of DOI:10.1039/c0ob00905a

One-pot synthesis of heterocycles having a nitromethyl group was achieved by sequential steps that involved chloronitration of alkenes using iron(iii) nitrate nonahydrate followed by elimination and intramolecular Michael addition. This reaction provides

Full text of DOI:10.1039/c0ob00905a

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Iron-mediated one-pot formal nitrocyclization onto unactivated alkenes†
Tsuyoshi Taniguchi,* Tatsuya Fujii and Hiroyuki Ishibashi
Received 20th October 2010, Accepted 4th November 2010
DOI: 10.1039/c0ob00905a
One-pot synthesis of heterocycles having a nitromethyl group
was achieved by sequential steps that involved chloronitra-
tion of alkenes using iron(III) nitrate nonahydrate followed
by elimination and intramolecular Michael addition. This
reaction provides an efficient method for the synthesis of
heterocycles due to the simple experimental procedure and
the use of inexpensive reagents of low toxicity.
Nitro compounds are useful for medicines, industrial materials
and fuels, and their compounds are also valuable synthetic inter-
mediates in organic chemistry.1 For example, they are transformed
Scheme 2 Chloronitration followed by the one-pot construction of
heterocycles.
into various derivatives such as amines and ketones by reduction of
using the nitronium ion (NO2 ) has never been reported.10 It
+
a nitro group and the Nef reaction.2 Moreover, C–C and C–X (X =
+
is presumed that the extreme reactivity of NO2 is the main
N, O) bond formations by nitro-aldol reaction and nitro-Michael
reason for this. Our present reaction can be regarded as a formal
reaction have been extensively investigated.3 To date, a number of
nitroamination (or nitrooxygenation), and, to the best of our
nitration methods have been established.4,5 Recently, we reported
knowledge, this direct transformation from unactivated alkenes
radical halonitration of alkenes by thermal decomposition of
has never been explored.
iron(III) nitrate nonahydrate [Fe(NO3)3·9H2O] (Scheme 1, eq. 1).6
After treatment of compound 1a with Fe(NO3)3·9H2O in the
In this reaction, subsequent treatment of the reaction mixture
presence of FeCl3 in boiling MeCN, addition of K2CO3 and MeOH
with an appropriate base gives corresponding nitroalkenes in one-
to the reaction mixture gave pyrrolidine 2a in 21% yield (Table 1,
pot.7 Herein, we report one-pot synthesis of heterocycles by iron-
entry 1). The use of LiNO3 instead of Fe(NO3)3·9H2O resulted
mediated halonitration of w-alkenylamine (or alcohol) derivatives
in no improvement in yield of the product (Table 1, entry 2),
and subsequent elimination followed by intramolecular nitro-
whereas the use of LiCl instead of FeCl3 afforded compound
Michael addition (Scheme 2). Many useful difunctionalization
2a in improved yield (Table 1, entry 3). When KOAc was used
reactions of unactivated alkenes involving cyclization reactions
such as halolactonization and haloamination have been reported
(Scheme 1, eq. 2).8,9 On the other hand, electrophilic nitrocycliza-
Table 1 Optimizations of the one-pot synthesis heterocycle 2aa
tion of w-alkenylamine or w-alkenylcarboxylic acid derivatives
Entry [NO3]
[Cl]
Base
Time/h Yield (%)b
1
Fe(NO3)3·9H2O FeCl3
LiNO3 FeCl3
K2CO3
K2CO3
K2CO3
KOAc
1
6
8
8
8
8
8
8
21
15
36
55
9
0
63
70
2c
3
Fe(NO3)3·9H2O LiCl
Fe(NO3)3·9H2O LiCl
Fe(NO3)3·9H2O LiCl
Fe(NO3)3·9H2O LiCl
Fe(NO3)3·9H2O LiCl
Fe(NO3)3·9H2O LiCl
4
5
6
LiOH·H2O
Scheme 1 Iron-mediated chloronitration of alkenes and intramolecular
iodoamination.
DBU
7
NaHCO3
NaHCO3
8d
a Reaction conditions: 1a (0.4 mmol), [NO3] (0.48 mmol) and [Cl] (0.60
mmol) in MeCN (2 mL), then base (4.0 mmol) and MeOH (1 mL).
b Isolated yield. c 5.0 equiv. of LiNO3 (2.0 mmol) and 2.0 equiv. of FeCl3
(0.8 mmol) was used. d 1.5 equiv. of Fe(NO3)3·9H2O (0.60 mmol) and 1.9
equiv. of LiCl (0.76 mmol) were used.
School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical
and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-
1192, Japan. E-mail: tsuyoshi@p.kanazawa-u.ac.jp; Fax: +81-76-234-4439;
Tel: +81-76-234-4439
† Electronic supplementary information (ESI) available: Spectroscopic
data for all new products is available. See DOI: 10.1039/c0ob00905a
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Table 2 One-pot synthesis of various heterocycles
instead of K2CO3 as a base, a significantly improved result was
obtained (Table 1, entry 4). LiOH·H2O, which was efficient in
one-pot synthesis of nitroalkenes using this method (Scheme 1,
eq. 1),6b gave the product in very low yield (Table 1, entry 5). The
reaction using an organic base gave no desired product (Table 1,
entry 6). Eventually, we found that the use of NaHCO3 gave the
best result (Table 1, entries 7 and 8).‡
Entry
Substrate
Time/h
Producta,b
Next, the synthesis of various heterocycles using optimized
conditions (Table 1, entry 8) was examined (Table 2). Reactions of
substrates 1b and 1c bearing dimethyl and diphenyl groups on the
tether moiety gave corresponding pyrrolidine derivatives 2b and
2c in good and moderate yields, respectively (Table 2, entries 2 and
3). Substrate 1d bearing a phenyl group on the tether moiety gave
pyrrolidine derivative 2d in good yield, but the diastereomeric
selectivity was low (Table 2, entry 4). Substrate 1e bearing a
cyclohexyl group gave spiro cycles 2e in good yield (Table 2, entry
5). In the case of a-phenylamine derivative 1f, diastereoselective
cyclization proceeded to give cis-2,5-disubstituted pyrrolidine
derivative 2f as a sole product in good yield (Table 2, entry 6).11,12
The reaction of 2,2-disubstituted alkene 1g gave cyclized product
2g in lower yield than that of the reaction of 1b, probably because
of the steric effect in the intramolecular Michael addition (Table
2, entry 7). The use of a Cbz (benzyloxycarbonyl) group as a
protecting group caused a significant decline in the yield of cyclized
product 2h (Table 2, entry 8). This smaller yield might be due to
the lower nucleophilicity of a nitrogen atom of a carbamate than
that of a sulfonamide. When pentenamide derivatives 1i and 1j
were used as substrates, cyclization on the nitrogen atom took
place to give g-lactams 2i and 2j, respectively (Table 2, entries 9
and 10).13,14 This was confirmed by reduction of g-lactams 2i by
borane to give pyrrolidine compound 3, and no O-cyclized product
was detected (Scheme 3). The present reaction could be applied to
the construction of piperidine ring 2k and tetrahydrofuran ring 2l,
respectively (Table 2, entries 11 and 12). Reactions of cis- and trans-
2-allylcyclohexylamine derivatives 1m and 1n resulted in nitrations
and diastereoselective cyclizations to give bicyclic compounds 2m
and 2n, respectively, in good yields (Table 2, entries 13 and 14).
N-Tosyl-2-allylaniline (1o) never gave a cyclized product because
nitration of an electron-rich aromatic ring occurred the as a
significant competitive reaction (Table 2, entry 15). However, we
soon found that use of electron-drawing protecting groups on the
nitrogen atom gave dihydroindole derivatives 2p–r (Table 2, entries
16–18).
1
1a: R = H, R¢ = H
1b: R = Me, R¢ = Me
1c: R = Ph, R¢ = Ph
1d: R = Ph, R¢ = H
5
9
4
5
9
2a: 70%
2
2b: 75%
3c
4
2c: 48%
2d: 75% (57 : 43)
5
6
7
5
2
8
6
9c
1i: R = Ph
1j: R = Ts
12
1
4
2i: 47%
2j: 60%
10c
11
12
13
6
5
Scheme 3 Reduction of 2i.
In summary, we have developed a method of one-pot formal
nitrocyclizations for synthesis of heterocycles using a subse-
quent process involving iron-mediated chloronitration followed
by elimination and intramolecular Michael addition under at
basic conditions. Inexpensive reagents of low toxicity are used
in the reaction, and the experimental procedure is very simple.
The present reaction will provide a new practical method for
the synthesis of heterocyclic compounds. Further studies directed
14
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Table 2 (Contd.)
5 Recent examples of nitration reactions, see: (a) L. Grossi, P. C.
Montevecchi and S. Strazzari, Eur. J. Org. Chem., 2001, 741; (b) Y.
Nishiwaki, S. Sakaguchi and Y. Ishii, J. Org. Chem., 2002, 67, 5663;
(c) L. Grossi and P. C. Montevecchi, Chem.–Eur. J., 2002, 8, 380; (d) K.
Jayakanthan, K. P. Madhusudanan and Y. D. Vankar, Tetrahedron,
2004, 60, 397; (e) B. P. Fors and S. L. Buchwald, J. Am. Chem. Soc.,
2009, 131, 12898. See also ref. 7.
6 (a) T. Taniguchi and H. Ishibashi, Org. Lett., 2010, 12, 124;
(b) T. Taniguchi, T. Fujii and H. Ishibashi, J. Org. Chem., 2010,
DOI: 10.1021/jo101769d.
Entry
Substrate
Time/h
Producta,b
7 Examples of synthesis of nitroalkenes, see: (a) F. G. Bordwell and E.
W. Garbisch, Jr., J. Org. Chem., 1962, 27, 2322; (b) E. J. Corey and H.
Estreicher, J. Am. Chem. Soc., 1978, 100, 6294; (c) W. W. Sy and A. W.
By, Tetrahedron Lett., 1985, 26, 1193; (d) E. Hata, T. Yanada and T.
Mukaiyama, Bull. Chem. Soc. Jpn., 1995, 68, 3629; (e) P. J. Campos,
B. Garc´ıa and M. A. Rodr´ıguez, Tetrahedron Lett., 2000, 41, 979; (f) I.
Jovel, S. Prateeptongkum, R. Jackstell, N. Vogl, C. Weckbecker and M.
Beller, Adv. Synth. Catal., 2008, 350, 2493.
8 Reviews, see: (a) M. D. Dowle and D. I. Davies, Chem. Soc. Rev., 1979,
8, 171; (b) G. Cardillo and M. Orena, Tetrahedron, 1990, 46, 3321; (c) J.
Mulzer, In Organic Synthesis Highlights, J. Mulzer, H. J. Altenbach,
M. Braun, K. Krohn and H. U. Reissig, ed., VCH, Weinheim, 1991, pp
158-164; (d) G. Rousseau and S. Robin, Tetrahedron, 1998, 54, 13681;
(e) S. Robin and G Rousseau, Eur. J. Org. Chem., 2002, 3099; (f) K.
H. Jensen and M. S. Sigman, Org. Biomol. Chem., 2008, 6, 4083; (g) S.
Minakata, Acc. Chem. Res., 2009, 42, 1172.
9 Recent examples, see: (a) M. C. Marcotullio, V. Campagna, S.
Sternativo, F. Costantino and M. Curini, Synthesis, 2006, 2760; (b) S.
Minakata, Y. Morino, Y. Oderaotoshi and M Kamatsu, Org. Lett.,
2006, 8, 3335; (c) T. J. Donohoe, P. C. M. Winship and D. S. Walter,
J. Org. Chem., 2009, 74, 6394; (d) T. Wu, G. Yin and G. Liu, J. Am.
Chem. Soc., 2009, 131, 16354; (e) P. A. Sibbald and F. E. Michael, Org.
Lett., 2009, 11, 1147; (f) A. K. Verma, T. Aggarwal, V. Rustagi and R.
C. Larock, Chem. Commun., 2010, 46, 4064; (g) S. Mehta and R. C.
Larock, J. Org. Chem., 2010, 75, 1652.
15c
16c
17c
18c
1o: R = Ts
3
1.5
3
2o: no detected
2p: 69%
1p: R = Ac
1q: R = TFA
1r: R = Cbz
2q: 56%
1
2r: 42%
a Isolated yields. b Diastereomeric ratio was determined by 1H NMR
analysis. c FeCl3 was used instead of LiCl because the reaction did not
complete.
toward the application of this method to the synthesis of bioactive
compounds are currently underway in our laboratory.
This research was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology of Japan.
Notes and references
‡ Typical procedure: To a solution of 1a (95.7 mg, 0.40 mmol) and LiCl
(31.8 mg, 0.76 mmol) in MeCN (2 mL) was added Fe(NO3)3·9H2O (242
mg, 0.60 mmol), and the mixture was heated at reflux for 5 h. To the
reaction mixture was added NaHCO3 (336 mg, 4.00 mmol) and MeOH (1
mL) and the mixture was heated at reflux for 1 h. After cooling to room
temperature, the resultant suspension was diluted with Et2O and filtered.
Solvent of filtrate was removed under reduced pressure and the residue
was purified by silica gel chromatography (hexane–EtOAc, 5 : 1) to give 2a
(80.0 mg, 70%) as a colourless oil.
10 Electrophilic nitration of alkenes using NO2Cl has been reported, see:
H. Shechter, F. Conrad, A. L. Daulton and R. B. Kaplan, J. Am. Chem.
Soc., 1952, 74, 3052.
11 It has been reported that 5-exo-trig intramolecular Michael addi-
tion of a 2-substituted toluenesulfonamide derivative gave a cis-
pyrrolidine compound in good diastereomeric selectivity, see: R.
E. Dolle, C.-S. Li and A. N. Shaw, Tetrahedron Lett., 1989, 30,
4723.
12 A relative configuration of compound 2f was presumed by comparison
with reported spectroscopic data of known similar compounds, cis-
or trans-1-(4-methylphenylsulfonyl)-2-hydroxymethylphenyl-5-phenyl-
pyrrolidine (4). 1H NMR signals of 5-H of these compounds are 4.71
(1H, app. t, J = 6.6 Hz, for 2f), 4.79 (1H, dd, app. t, J = 7.0 Hz, for cis-4)
and 5.06 (1H, d, J = 8.5 Hz, for trans-4), see: P. Evans, T. McCabe, B.
S. Morgan and S. Reau, Org. Lett., 2005, 7, 43.
13 Synthesis of a b-lactam derivative by intramolecular Michael addition
of unsaturated amides has been reported, see: Y.-H. W. J. R. Corrigan
and R. F. Feldkamp, J. Org. Chem., 1961, 26, 1531.
1 H. Feuer and T. Nielsen, Nitro compounds: Recent Advances in Synthesis
and Chemistry, VCH, New York, 1990.
2 N. Ono, The Nitro Group in Organic Synthesis, John Wiley-VCH, New
York, 2001.
3 (a) A. G. M. Barrett and G. G Graboski, Chem. Rev., 1986, 86,
751; (b) R. Ballini, E. Marcantoni and M. Petrini, In Amino Group
Chemistry, A. Ricci, Ed., Wiley-VCH, 2008, pp 93-148; (c) R. Ballini
and M. Petrini, ARKIVOC, 2009, 195.
4 For reviews on nitration reactions, see: (a) G. A. Olah, R. Malhotra
and S. C. Narang, Nitration: Methods and Mechanisms, VCH Publishers
Inc., New York, 1989; (b) T. Mori and H. Suzuki, Synlett, 1995, 383;
(c) T. Suzuki and R. Noyori, Chemtracts, 1997, 10, 813; (d) A. V.
Stepanov and V. V. Veselovsky, Russ. Chem. Rev., 2003, 72, 327.
14 For a recent study of selectivity in O-cyclizations or N-cyclizations of
unsaturated amides using electrophiles, see: T. Hu, K. Liu, M. Shen, X.
Yuan, Y. Tang and C. Li, J. Org. Chem., 2007, 72, 8555 and references
therein.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 653–655 | 655
©