Intramolecular hydroamination of functionalized alkenes and alkynes with a homogenous zinc catalyst

Article abstract of DOI:10.1002/anie.200502006

(Chemical Equation Presented) Simple and versatile: A new zinc complex catalyzes the intramolecular hydroamination of nonactivated alkynes and alkenes (see example in scheme; {(iPr)₂ATI} = N-isopropyl-2-(isopropylamino) troponiminato). The catalyst is relatively robust, exhibits excellent activities, and tolerates various functional groups such as ethers, thioethers, and amides.

Full text of DOI:10.1002/anie.200502006

Communications
Cyclizations
DOI: 10.1002/anie.200502006
Intramolecular Hydroamination of Functionalized
Alkenes and Alkynes with a Homogenous Zinc
Catalyst**
Agustino Zulys, Maximilian Dochnahl, Dirk Hollmann,
Karolin Löhnwitz, Jost-Steffen Herrmann,
Peter W. Roesky,* and Siegfried Blechert*
Dedicated to Professor Dr. Herbert W. Roesky
on the occasion ofhis 70th birthday
Scheme 1. Intramolecular hydroamination of alkenes and alkynes.
À
The catalytic addition of an organic amine N H bond to
rates in their reactions with non-activated substrates. The
scope of catalytic hydroamination was reviewed recently.[1]
Herein we report a new zinc-based catalyst, [N-isopropyl-
2-(isopropylamino)troponiminato]methylzinc [{(iPr)2ATI}-
ZnMe] (I), for the hydroamination of non-activated double
and triple bonds. Catalyst I is compatible with various polar
functional groups such as ethers, amides and hydroxylamines.
Furthermore, the complex is relatively robust in air and shows
excellent catalytic activity. To the best of our knowledge, the
only previously investigated molecular zinc compound used in
catalytic hydroamination is zinc triflate, which in the presence
of amines is only sparingly soluble in toluene.[6,7] Moreover,
the intermolecular hydroamination of activated acetylenes by
zinc-exchanged montmorillonite clay was reported recently.[8]
Compared to other late-transition-metal catalysts, zinc com-
pounds are relatively cheap and nontoxic. Furthermore ZnII is
stable against deactivation as it cannot be reduced to the
metal under the reaction conditions.[6b]
alkenes or alkynes (hydroamination) to give nitrogen-con-
taining molecules is of great interest to both academic and
industrial researchers.[1] At present, most amines are made in
multistepsyntheses, and as such hydroamination offers an
attractive alternative to give nitrogen-containing molecules
that are important for fine chemicals, pharmaceuticals, and as
useful chiral building blocks. Hydroamination can be cata-
lyzed by d- and f-block transition metals, alkali metals,[2] as
well as by calcium compounds, as shown very recently.[3] Early
transition metals (Group4 [1d] and especially the lanthani-
des[1b]) are highly efficient catalysts for the hydroamination
À
reaction of various C C multiple bonds (Scheme 1), but the
high sensitivity of these catalysts towards moisture and air
limits their application. Furthermore, they show a very
limited tolerance to polar functional groups. On the other
hand, late-transition-metal catalysts offer the advantage of
greater polar-functional-group compatibility; however, most
of these catalysts are based on relatively expensive platinum[4]
or on nickel,[5] which has only limited use in the synthesis of
pharmaceuticals. Moreover, most of the late-transition-metal
catalysts show limited scope, modest selectivity, and sluggish
Compound I, which is easily available from {(iPr)2ATI}H
and ZnMe2 (Scheme 2), was reported previously by us as an
intermediate in the synthesis of aminotroponiminate zinc
[*] M.Sc. A. Zulys, Dipl.-Chem. K. Löhnwitz, Dipl.-Chem. J.-S. Herrmann,
Prof. Dr. P. W. Roesky
Institut für Chemie und Biochemie
Freie Universität Berlin
Fabeckstrasse 34–36, 14195 Berlin (Germany)
Fax: (+49)30-8385-2440
E-mail: roesky@chemie.fu-berlin.de
Scheme 2. Synthesis of [{(iPr)2ATI}ZnMe] (I).
Dipl.-Chem. M. Dochnahl, Dipl.-Chem. D. Hollmann,
Prof. Dr. S. Blechert
Institut für Chemie
Technische Universität Berlin
Strasse des 17. Juni 135, 10623 Berlin (Germany)
Fax: (+49)30-3142-3619
E-mail: blechert@chem.tu-berlin.de
alkoxides.[9] Besides the catalytic properties, we now report
the solid-state structure of I, which was established by single-
crystal X-ray diffraction.[10] Compound I is a monomer in the
solid state, and therefore the zinc atom has a trigonal-planar
coordination sphere (Figure 1). The bond lengths and angles
around the zinc center are in the expected range. In contrast
to early-transition-metal–alkyl complexes, compound I is
relatively robust towards moisture and air and thus no special
experimental techniques are required for its use. This
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(Graduiertenkolleg: “Synthetische, mechanistische und reaktion-
stechnische Aspekte von Metallkatalysatoren”). M.D. thanks the
Fonds der Chemischen Industrie for a fellowship (K174/11).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
amides underwent cyclization to the corresponding lactams
(Table 1, entries 7 and 8). Depending on the reaction
conditions, two different products were observed. When the
reaction was performed in the absence of the cocatalyst, the
cyclized product 7b with an exocyclic double bond was
detected. On the other hand, a 6:1 mixture of the isomerized
dihydropyridone 8b and d-valerolactam 7b was observed
when an equal amount of the cocatalyst was added.
We were also able to cyclize methionine derivative 9a to
the dihydropyrazinone 9b. This substrate is of particular
interest as it contains both an amide functionality and a
thioether group. To the best of our knowledge, this constitutes
the first hydroamination of a compound bearing a thioether
moiety, which is most likely incompatible with most well-
known catalysts for hydroamination. The cyclization of
phenylalanine propargylamide (10a) revealed an influence
of the catalyst concentration on the structure of the product
(Table 1, entries 10 and 11): When 10 mol% of the catalyst
was used complete conversion into the resulting dihydropyr-
azinone 11b was observed. In contrast, when only 5 mol% of
the catalyst was added, only the methylene piperazinone 10b
was formed. Moreover we were able to apply our catalytic
system to alkynes that bear an hydroxylamine functionality to
afford cyclic nitrones (Entry 12).[13] Carbonic acid hydrazide
13a was also cyclized to the resulting N-aminopiperidinone
13b. Interestingly, the more-electron-poor nitrogen atom
added preferentially to the triple bond, thus indicating that
ring size has a larger influence than electronic effects on the
outcome of the reaction. We were pleased to find that our
system catalyzes the formation of seven-membered rings
(Table 1, entry 14). It can be concluded that the rate of
cyclization for aminoalkynes follows the order five-mem-
bered > six-membered @ seven-membered ring, consistent
with classical, stereoelectronically controlled, cyclization
processes.[1b]
With these results in hands, we also investigated the
intramolecular hydroamination of non-activated alkenes
(Table 2). However, it is well known that the hydroamination
of alkenes is significantly slower than that of alkynes.[1g,3,4]
Substrates that bear bulky geminal substituents b to the
amino group(Thorpe–Ingold effect) [14] could be cyclized with
reasonable catalyst/activator loadings of 5 mol% with mod-
erate reaction times (Table 2, entries 1–3). Substrate 16a was
the most reactive and gave the corresponding pyrrolidine
within 5 h. Compound 18a, which is known to be a difficult
substrate for this reaction, was converted into 2,5-dimethyl-
pyrrolidine (18b) in modest yield.
Figure 1. Solid-state structure of I. Hydrogen atoms have been omit-
À
À
ted. Selected distances [pm] and angles [8]: Zn1 C14 194.1(5), Zn1
À
N1 198.0(4), Zn1 N2 195.5(4); C14-Zn1-N1 138.5(2), C14-Zn1-N2
139.6(2), N1-Zn1-N2 81.94(14).
behavior is very different to that of the starting material
ZnMe2, which is pyrophoric (see Supporting Information).
The stability of compounds of the general formula [LZnMe]
(L = ligand) has been described before.[11]
The goal of the current study was to explore the scope,
selectivity, and functional-grouptolerance of the intramolec-
ular hydroamination reaction catalyzed by I. For this reason,
several substrates bearing different functional groups and
leading to different ring sizes were synthesized. The results
are given in Table 1 and demonstrate that I exhibited good
activity in this reaction. The best conditions were found to be
when the reaction was carried out in benzene as the solvent at
a temperature of 1208C; under these conditions, total
conversion occurred within reasonable reaction times in
most cases. In the majority of cases it was possible to lower the
catalyst loading from 10 to 1 mol%, and it was also found that
the reaction rate could be accelerated by the addition of an
equimolar amount (based on I) of [PhNMe2H][B(C6F5)4] as a
cocatalyst.
Interestingly, cyclization of propargyl ethers that bear a
secondary amine moiety opened a new route to the corre-
sponding 1,4-oxazines, as the double bond migrates to give the
thermodynamically more stable vinyl ether. [12] A comparison
of the reaction times of the a-branched amino ether 2a and
the corresponding primary amine 3a demonstrates the
greater propensity of secondary amines to react: even
though the catalyst loading for substrate 3a was 20 times
higher, the reaction time was nearly double that for substrate
2a. On the other hand, bulkier substituents, such as an
isopropyl group a to the amine moiety, caused a significant
decrease in the reaction rate. Nevertheless, valine derivative
4a could be completely converted into the oxazine 4b by the
addition of 10 mol% of the catalyst/activator system.
To our surprise, the incorporation of large substituents in
the b position had no beneficial effect on the cyclization.
Therefore, amino benzyl ether 5a was cyclized within the
same time as substrate 3a. Cyclic secondary amines, such as
proline derivative 6a, exhibited very high reactivity under
these reaction conditions (Table 1, entry 6). Substituted
In conclusion, compound I has proved to be an efficient
catalyst for homogenous intramolecular hydroamination
reactions and has a number of practical advantages, such as
particularly high functional-group tolerance, good activity in
À
the catalytic conversion of non-activated C C multiple bonds,
and a relatively high stability towards moisture and air. The
reaction conditions allowed the manipulation of a multitude
of polar functional groups, including ethers, thioethers, and
amides. It is also notable that seven-membered heterocycles
can be accessed. These advantages lead us to hope that I,
which is an easily accessible reagent, will find further
application as a hydroamination catalyst.
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Table 1: Intramolecular hydroamination of functionalized alkynes.[a]
Entry
Substrate
Product
cat. I
[mol%]
Activ.[b]
[mol%]
t [h]
Conv. [%][c]
1
1
–
1
144
39
>99[d]
>99[d]
1
1a
1b
1
0.1
1
–
0.1
1
72
8
45
>99
>99, (91)[e]
>99[d]
2
3
4
2a
3a
4a
2b
3b
4b
10
2
–
2
144
14
>99
>99, (70)[e]
1
10
1
–
10
1
96
1.5
144
19
>99
94
10
2
–
2
6
14
>99
>99
5
6
7
8
5a
6a
7a
7a
5b
6b
7b
8b
1
0.1
–
0.1
4
8
95
>99
10
10
–
60
60
25
10
>99[f]
9
9a
9b
10
5
–
–
–
15
72
15
92
51
10
11
10a
10a
10b
11b
10
>99
1
0.5
–
0.5
5
4
98[d]
>99[d]
12
13
12a
13a
12b
13b
10
–
14
>99
14
14a
14b
5
–
312
>99
[a] Reaction conditions: amine (430 mmol), catalyst I, benzene (0.5 mL), 1208C. [b] Activator: [PhNMe2H][B(C6F5)4]. [c] Determined by 1H NMR
spectroscopy. [d] The reaction was carried out at 608C. [e] Yield of isolated product; the reaction was performed on a 2-mmol scale. [f] 8b/7b=6:1.
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Table 2: Intramolecular hydroamination of alkenes.[a]
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344, 795 – 813; g) J.-J. Brunet, D.
Neibecker in Catalytic Heterofunc-
tionalization (Eds.: A. Togni, H.
Grützmacher), VCH, Weinheim,
2001, pp. 91 – 141; h) M. Nobis, B.
Drießen-Hölscher, Angew. Chem.
2001, 113, 4105 – 4108; Angew.
Chem. Int. Ed. 2001, 40, 3983 –
3985; i) M. Johannsen, K. A. Jør-
gensen, Chem. Rev. 1998, 98, 1689 –
1708; j) T. E. Müller, M. Beller,
Chem. Rev. 1998, 98, 675 – 704;
k) D. M. Roundhill, Chem. Rev.
1992, 92, 1 – 27.
Entry
Substrate
Product
cat. I
[mol%]
Activ.[b]
[mol%]
t [h]
Conv. [%][c]
10
5
5
–
–
5
30
28
8
87[d]
>99
80
1
15a
16a
15b
16b
10
10
5
–
–
5
12
24
5
>99
69[d]
>99
2
13.3
5
–
5
72
52
>99
46
3
4
17a
18a
17b
18b
10
10
36
19
[a] Reaction conditions: amine (430 mmol), catalyst I, benzene (0.5 mL), 1208C. [b] Activator:
[PhNMe2H][B(C6F5)4]. [c] Determined by 1H NMR spectroscopy. [d] Yield of isolated product; the
reaction was carried out at 1008C in toluene.
[2] A. Ates, C. Quinet, Eur. J. Org.
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Experimental Section
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I: A solution of ZnMe2 (2.0m in toluene; 0.64 mL, 1.28 mmol,
1.05 equiv) was diluted in toluene (25 mL) and cooled to À788C. A
solution of {(iPr)2ATI}H (250 mg, 1.22 mmol) in toluene (25 mL) was
added. The reaction mixture was slowly warmed upto room
temperature, and gas was evolved for about 3 h. The solution was
then filtered off, the solvent was evaporated under reduced pressure.
The resulting yellow solid was washed with n-pentane (3 ” 10 mL) and
dried under vacuum. Yield: 287 mg (83%). 1H NMR (C6D6,
400 MHz, 258C): d = 0.00 (s, 3H; ZnCH3), 1.14 (d, J = 6.1 Hz, 12H;
NCH(CH3)2), 3.76 (sept, J = 6.2 Hz, 2H; NCH(CH3)2), 6.35 (d, J =
9.4 Hz, 1H; HAr), 6.57 (d, J = 10.2 Hz, 2H; HAr), 6.95 ppm (dd, J =
9.4 Hz, 10.2 Hz, 2H; HAr); 13C{1H} NMR (C6D6, 100.4 MHz, 258C):
d = À9.9 (ZnCH3), 24.5 (NCH(CH3)2), 48.3 (NCH(CH3)2), 111.6
(CAr), 117.7 (CAr), 134.5 (CAr), 160.2 ppm (CAr); MS (EI): m/z (%):
282 (33) [M]+, 267 (51) [MÀCH3]+, 204 (24) [MÀZnCH3]+.
NMR-tube-scale intramolecular hydroamination: All NMR-
tube-scale reactions were prepared in an N2-filled glovebox. The
aminoalkynes (430 mmol) were dissolved in [D6]benzene (0.5 mL) and
then added to the catalyst (e.g. 4.30 mmol for 1 mol%). The mixture
was injected into an NMR tube, which was removed from the
glovebox and flame-sealed under vacuum. The reaction mixture was
then heated to the appropriate temperature for the stated duration of
[10] Single-crystal X-ray diffraction data for 1: C14H22N2Zn (Mr =
283.71): Bruker Smart 1000 CCD, space group P21/c (No. 14);
a = 1579(3), b = 906(2), c = 2176(4) pm, b = 109.40(4)8; T=
time. All products were analyzed by H, 13C, 13C DEPT, COSY, and
173 K, Z = 8, V= 2935(10) ” 106 pm3, 1 = 1.284 gcmÀ3, 2qmax
558, 16208 reflections collected, 6333 unique reflections (Rint
=
1
HMQC NMR spectroscopy and by IR, MS, and HRMS when
possible. The ratio between the reactant and the product was
calculated by comparison of the integrations of the corresponding
signals in the 1H NMR spectra. The concentration of the catalyst was
controlled by comparing the integration of a well-resolved signal for
the heterocyclic product with that for a signal for a catalyst ligand.
=
0.0593). The structure was solved by Patterson methods
(SHELXS-97 and SHELXL-97)[15] and refined by full-matrix
least-square techniques with I > 2s(I) to R1 = 0.0412 and wR2 =
0.1097. CCDC-274802 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Received: June 10, 2005
[11] M. P. Coles, P. B. Hitchcock, Eur. J. Inorg. Chem. 2004, 13, 2662 –
2672.
Revised: August 17, 2005
Published online: November 4, 2005
[12] Recently
a copper mediated approach to 3,4-dihydro-2H-
benzoxazines was published. However the products were
obtained in moderate yields only: Y.-G. Zhou, P.-Y. Yang, X.-
W. Han, J. Org. Chem. 2005, 70, 1679 – 1683.
Keywords: cyclization · heterocycles · homogenous catalysis ·
hydroamination · zinc
.
[13] Activated olefins: A. Padwa, G. S. K. Wong, J. Org. Chem. 1986,
51, 3125 – 3133; non-activated olefins: E. C. Davison, I. T.
Forbes, A. B. Holmes, J. A. Warner, Tetrahedron 1996, 52,
11601 – 11624.
[14] a) R. M. Beesley, C. K. Ingold, J. F. Thorpe, J. Chem. Soc. 1915,
107, 1080 – 1106; b) C. K. Ingold, J. Chem. Soc. 1921, 119, 305 –
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329; c) A. J. Kirby, Adv. Phys. Org. Chem. 1980, 17, 183 – 278;
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[15] a) G. M. Sheldrick, SHELXS-97, Program for Crystal Structure
Solution, University of Göttingen, Germany, 1997; b) G. M.
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