Ionic diamine rhodium complex catalyzed hydroaminomethylation of 2-allylanilines

Article abstract of DOI:10.1016/j.tetlet.2010.07.048

Ionic diamine rhodium complexes catalyze the hydroaminomethylation of 2-allylanilines. The reaction involves initial hydroformylation followed by reductive amination, which provides direct access to 1,2,3,4- tetrahydroquinolines and 2,3,4,5-1H-1-benzazepi

Full text of DOI:10.1016/j.tetlet.2010.07.048

Tetrahedron Letters 51 (2010) 4959–4961
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ionic diamine rhodium complex catalyzed hydroaminomethylation
of 2-allylanilines
*
Kazumi Okuro, Howard Alper
Centre for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Canada K1N 6N5
a r t i c l e i n f o
a b s t r a c t
Article history:
Ionic diamine rhodium complexes catalyze the hydroaminomethylation of 2-allylanilines. The reaction
involves initial hydroformylation followed by reductive amination, which provides direct access to
1,2,3,4-tetrahydroquinolines and 2,3,4,5-1H-1-benzazepines.
Received 24 June 2010
Revised 4 July 2010
Accepted 8 July 2010
Available online 14 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Rhodium
Hydroaminomethylation
Tetrahydroquinoline
Benzazepine
+
+
_
_
Five- to seven-membered N-heterocycles, including fused ones,
represent an important class of cyclic compounds since not only do
many derivatives possess biological and pharmacological activities
themselves but they also serve as versatile scaffolds for synthetic
drug discovery.1 For example, a series of 1,2,3,4-tetrahydroquino-
line derivatives are useful synthetic intermediates for selective
thrombin inhibitors.2 Another example includes 2,3,4,5-tetrahy-
dro-1H-1-benzazepine derivatives, several of which function as
non-peptic vasopressin V2 receptor agonists.3
Ph
Ph
Ph
CO
N
CO
CO
CO
CO
N
CO
CO
Cl
Cl
Cl
Cl
Rh
Rh
Rh
Rh
N
II
CO
Ph
N
I
The hydroaminomethylation of 2-allylaniline (1a) was first
examined to determine what conditions gave good results (Table
1). When 1a was treated with 5 mol % of complex I in toluene at
100 °C for 24 h under CO/H2 (700/100 psi), a mixture of six- and se-
ven-membered ring hydroaminomethylation products 2a and 3a,
and the six-membered ring cyclocarbonylation product 4a was ob-
tained in a ratio of 49:8:24 in yield (Table 1, entry 1). The corre-
sponding seven-membered cyclocarbonylation product was not
formed. Decreased partial pressure of CO reduced the extent of for-
mation of 4a; however, the selectivity for 2a compared to 3a also
decreased (entries 2 and 3). In case of the reactions in THF, a higher
partial pressure of H2 was found preferable for the reaction (entries
4 vs 6), and no hydroaminomethylation took place under CO/H2 of
700/100 (psi) though the starting material 1a was completely con-
sumed. It is conceivable that although initial hydroformylation fol-
lowed by cyclic imine formation could occur at CO/H2 = 700/
100 (psi), the resulting imine may not undergo hydrogenation
effectively at lower pressures of H2. The reactions in CH2Cl2 or
CH3CN were inferior to those in toluene or THF in terms of both
Hydroaminomethylation of olefin substrates having an amino
groupareconsideredtoinvolveinitialhydroformylationoftheolefin
unit, followed by intramolecular reductive amination. Such a reac-
tion provides direct access to N-containing heterocycles, whose syn-
thesis usually requires several steps to construct the heterocyclic
ring when traditional methods are used.4 We previously reported
thesynthesisand catalyticactivityof a novel, air stableionicdiamine
rhodium complex (I).5 This unique rhodium complex can catalyze
the hydroaminomethylation of 2-vinylanilines and (2-vinyla-
ryl)methyl amines to form 1,2,3,4-tetrahydroquinolines and
2,3,4,5-tetrahydro-1H-2-benzazepines, respectively.6,7 Pursuing
our general interest in the hydroaminomethylation reaction due to
the importance of the N-containing heterocyclic compounds, we
launched a study of the hydroaminomethylation of allylaniline
derivatives using the ionic diamine rhodium complex.
the yield and the selectivity.
[Rh(COD)Cl]2 clearly indicates that diamine rhodium complex I is
A control experiment with
* Corresponding author. Tel.: +1 613 562 5189; fax: +1 613 562 5871.
E-mail address: halper@uottawa.ca (H. Alper).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.048

4960
K. Okuro, H. Alper / Tetrahedron Letters 51 (2010) 4959–4961
Table 1
Table 2
Hydroaminomethylation of 2-allylaniline
Effect of the diamine ligand on the hydroaminomethylation of 2-allylanilinea
+
_
Entry
Catalyst
Solvent
CO/H2 (psi)
Yieldb (%)
N
CO
CO
CO
Cl
Rh
Rh
2a
3a
4a
N
Cl
CO
I
1
2
3
II
Tol
THF
THF
700/100
100/700
100/700
25
46
31
10
12
4
12
Trace
8
5 mol%
100 °C
[Rh(COD)Cl]2
+tipeda
NH
1a
N
H
2a
2
4
[Rh(COD)Cl]2
+tmbeda
THF
100/700
23
5
Trace
a
Reaction conditions; 1a (1.0 mmol), complex II (0.05 mmol), or [Rh(COD)Cl]2
+
+
(0.05 mmol) + diamine (0.06 mmol), solvent (2 mL), 100 °C, 24 h.
b
N
H
O
N
H
Isolated yield after column chromatography.
3a
4a
a more effective catalyst for the hydroaminomethylation reaction
than [Rh(COD)Cl]2 (entries 6 vs 7).
Entry
Solvent
CO/H2 (psi)
Yielda (%)
2a
3a
4a
Since complex I showed reasonable selectivity for 2a in toluene,
and a good total yield of 2a and 3a with no selectivity in THF, we
then tried a more sterically demanding diamine complex in order
to try to improve the selectivity for 2a or 3a (Table 2). Complex
II5 could catalyze hydroaminomethylation, and 2a was obtained
in THF in 46% yield (Table 2, entry 2). Because the corresponding
diamine rhodium complexes with N,N,N0,N0-tetra(isopropyl)ethy-
lenediamine(tipeda)8 or with N,N,N0,N0-tetra(o-methylbenzyl)ethy-
lenediamine(tmbeda)9 could not be isolated in pure form using
similar conditions to those for preparing I,5 a combined catalyst
system of [Rh(COD)Cl]2 with these diamines was employed.
Although both catalyst systems induced hydroaminomethylation,
the results were not comparable to those using complex II (Table
2, entries 3 and 4).
1
2
3
4
5
6
Toluene
Toluene
Toluene
THF
THF
THF
THF
THF
CH2Cl2
CH2Cl2
CH3CN
CH3CN
700/100
400/400
100/700
700/100
400/400
100/700
100/700
100/700
700/100
100/700
700/100
100/700
49
22
30
0
29
31
20
28
8
24
18
Trace
3
20
2
5
11
0
13
22
0
10
36
8
17
Trace
18
Trace
11
7b
8c
9
10
11
12
Trace
22
11
0
16
16
21
a
b
c
Isolated yield after column chromatography.
Performed using 5 mol % of [Rh(COD)Cl]2 instead of complex I.
Performed at 80 °C.
Table 3
Results of the Rh-catalyzed hydroaminomethylation of a variety of 2-allylaniline derivativesa
Entry Starting material
R1
Condition
Product and yieldb (%)
R1
R1
R1
R
R
1
1
NH2
NH
2
N
H
O
N
H
N
H
1
2
3
1b
1c
Br
A
B
C
2b
2c
21 3b
38
21
9 4b
25
15
18 5b
8
18
0
16
12
4
5
6
OCH3
A
B
C
19 3c
27
37
13 4c
11
15
15 5c
11
7
0
5
17
NH
NH
2
2
N
H
N
N
H
O
H
7
8
9
1d
A
B
C
2d
0 3d
0
0
16 4d
27
14
0 5d
2
7
2
20
50
N
H
NH 2
NH
2
N
H
O
N
H
10
11
1e
A
B
2e
2f
26 3e
26
17 4e
9
21 5e
8
0
0
1
1
1
R1
R
R
R1
R
NH
N
O
N
NH2
2
N
H
H
H
12
13
14
1f
H
A
B
C
26 3f
50
48
46 4f
14
6
10 5f
3
11
0
0
5

K. Okuro, H. Alper / Tetrahedron Letters 51 (2010) 4959–4961
4961
Table 3 (continued)
Entry Starting material
R1
Condition
Product and yieldb (%)
14 4g
15
16
17
1g
CH3
A
B
C
2g
2h
27 3g
27
28
7 5g
2
13
0
12
11
21
8
Ph
Ph
Ph
Ph
Ph
1
N
1
NH2
N
O
NH
R1
1
R
R1
2
N
R
R
H
H
H
18
19
20
21
1h
H
A
B
C
D
27 3h
60
54
0 4h
8 5h
Trace
11
0
28
37
0
0
0
0
69
0
22
23
1i
1j
5-CH3
D
D
2i
2j
60 3i
63 3j
0 4i
0 4j
0 5i
0 5j
0
0
6-
OCH3
a
Reaction conditions; A: anilines (1.0 mmol), I (0.05 mmol), toluene, CO/H2 = 700/100 (psi); B: anilines (1.0 mmol), I (0.05 mmol), THF, CO/H2 = 100/700 (psi); C: anilines
(1.0 mmol), II (0.05 mmol), THF, CO/H2 = 100/700 (psi); D: anilines (1.0 mmol), I (0.05 mmol), THF, CO/H2 = 300/700 (psi).
b
Isolated yield after column chromatography.
The reactions of a variety of 2-allylaniline derivatives were then
examined under typical conditions utilized for 1a, and the results
are summarized in Table 3. The reactions of 1b10 and 1c10 gave
lower yields compared to the reaction of 1a, implying that the
reaction is sensitive to the electronic nature of the substituents
at the para-position of the amino group. The reactions of 2-(meth-
allyl)aniline (1d)11 gave a different product distribution from those
of 2-allylanilines (1a–c). A rhodium hydride intermediate formed
in the initial catalytic step (i.e., hydroformylation), could add to
the double bond in such a way that the Rh atom binds selectively
to the less hindered terminal carbon atom, resulting in the exclu-
sive formation of seven-membered compounds regardless of
hydroaminomethylation or cyclocarbonylation. The reaction of
1f11 in toluene showed interesting selectivity in that the seven-
membered hydroaminomethylation product 3f was the major
product. In contrast, the substrate 1g having a methyl group para
to the amine, was hydroaminomethylated less selectively. It should
be noted that 2-(3-phenyl-2-butenyl)aniline (1h)11 underwent
hydroaminomethylation upon treatment with complex I in THF
to furnish 3-benzyl-1,2,3,4-tetrahydroquinoline 2h in upto 60%
yields with no seven membered product being formed (entry 19).
The reaction of 1h using complex II also gave 2h in moderate selec-
tivity (entry 20). Substrate 1h also provided a significant amount of
hydrogenation product 5h as a side product. The hydrogenation
might compete with hydroaminomethylation under high partial
pressure of H2 due to steric hinderance of the double bond. When
the reaction was repeated with complex I under increased relative
CO pressure to H2, the yield of 2h improved substantially up to 69%
and 5h was no longer detected (entry 21). Other substrates (1i, 1j)
having the same substitution pattern on the allyl group with 1h,
also afforded the corresponding 3-benzyl-1,2,3,4-tetrahydroquino-
line derivatives (2i, 2j) as a single product in 60–63% yields (entries
22 and 23).
Acknowledgment
We are grateful to the Natural Sciences and Engineering Council
of Canada (NSERC) for support of this research.
References and notes
1. Kouznetsov, V.; Palma, A.; Ewert, C. Curr. Org. Chem. 2001, 5, 519.
2. Derek, B.; Alice, B.; Vera, D.; Joseph, D. F.; Sheila, M. G.; Judy, F. H.; Diana, J.;
Peter, D. K.; Mark, M.; Garrik, O. S.; Robert, W.; Clive, V. W.; Graham, H.;
William, H.; Mark, C. A.; John, A.; Keith, B.; Mark, D. T. J. Med. Chem. 1999, 42,
4584.
3. Christopher, M. Y.; Christine, E. A.; Doreen, M. A.; James, B.; Andy, J. B.; Janice,
D. B.; Richard, J. F.; Sally, L. H.; Peter, H.; John, A. H.; Paul, D. J.; Andy, M. P.;
Gary, R. W. P.; Pierre, R.; Peter, A. R.; David, P. R.; Graeme, S.; Andy, S.; Robert,
M. H.; Michael, B. R. J. Med. Chem. 2008, 51, 8124.
4. Gilchrist, T. L. In Heterocyclic Chemistry, 3rd ed.; Addison Wesley: Essex,
England, 1997; p 414.
5. Kim, J. J.; Alper, H. Chem. Commun. 2005, 3059.
6. Vieira, T. O.; Alper, H. Chem. Commun. 2007, 2710.
7. Vieira, T. O.; Alper, H. Org. Lett. 2008, 10, 485.
8. William, J. M.; Vladimir, V. G. Can. J. Chem. 2005, 83, 640.
9. A mixture of ethylenediamine (10 mmol, 600 mg), o-methylbenzyl bromide
(60 mmol, 11.1 g), K2CO3 (60 mmol, 8.28 g) in NMP (70 mL) was heated at
100 °C for 20 h. After being cooled to room temperature, water was added
(140 mL) and the precipitated N,N,N0,N0-tetra(o-methylbenzyl)ethylenediamine
was filtered off.
10. Nicolaou, K. C.; Roecker, A. J.; Pfefferkorn, J. A.; Cao, G.-Q. J. Am. Chem. Soc. 2000,
122, 2966.
11. To a THF solution of 2-iodo(phenylmethylidene)aminobenzene, which was
prepared from 2-iodoaniline (56 mmol, 12.0 g) and benzaldehyde (56 mmol,
5.9 g) with a catalytic amount of concd H2SO4 (a few drops) in toluene, was
added i-PrMgCl (2.0 M THF, 64 mmol, 32 mL) at ꢀ20 °C. On completion of the
addition, the reaction mixture was stirred for 30 min at ꢀ10 °C. The reaction
mixture was cooled to ꢀ50 °C, after which CuI (8 mmol, 1.52 g) and then 3-
chloro-1-butene (80 mmol, 7.24 g) was slowly added while keeping the
temperature below ꢀ40 °C. Thereafter, the reaction mixture was further
stirred for 5 h at ꢀ40 °C, and then warmed to room temperature. The reaction
was quenched using saturated NH4Cl (aq). After the usual work-up, crude 2-(2-
buten-1-yl)phenylmethylideneaminobenzene was obtained with
a small
amount of 2-(3-buten-2-yl)phenylmethylidenaminobenzene, and the ratio
was 94:6 as determined by an 1H NMR. The crude product was treated with 1 N
HCl (30 mL) at room temperature for 5 h to give 2-(2-buten-1-yl)aniline (1f),
which was carefully purified by column chromatography on silica gel (5.70 g,
In conclusion, we have demonstrated that the hydroaminome-
thylation of allylanilines, catalyzed by ionic diamine rhodium com-
plexes, can afford 6-membered ring heterocycles sometimes in
reasonable yields. This methodology can also be applied to the syn-
thesis of fused N-containing heterocyclic compounds.
74%). In
a similar manner, 1d, 1g, 1h–j were prepared with 1-chloro-2-
methylpropene, 3-chloro-1-butene, cinnamyl bromide, respectively, as an
electrophile.