Homoallylic amines by reductive inter- and intramolecular coupling of allenes and nitriles

Article abstract of DOI:10.3762/bjoc.7.94

The one-pot hydrozirconation of allenes and nitriles followed by an in situ transmetalation of the allylzirconocene with dimethylzinc or zinc chloride provides functionalized homoallylic amines. An intramolecular version of this process leads to 3-aminote

Full text of DOI:10.3762/bjoc.7.94

Homoallylic amines by reductive inter- and
intramolecular coupling of allenes and nitriles
Peter Wipf* and Marija D. Manojlovic
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 824–830.
Department of Chemistry, University of Pittsburgh, 219 Parkman
Avenue, Pittsburgh, PA 15260, USA
doi:10.3762/bjoc.7.94
Received: 08 March 2011
Accepted: 30 May 2011
Published: 17 June 2011
Email:
Peter Wipf* - pwipf@pitt.edu
* Corresponding author
This article is part of the Thematic Series "Allene chemistry".
Guest Editor: K. M. Brummond
Keywords:
allene; 3-aminotetrahydrofurans; 3- and 4-aminotetrahydropyrans;
hydrozirconation; nitrile; transmetalation
© 2011 Wipf and Manojlovic; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The one-pot hydrozirconation of allenes and nitriles followed by an in situ transmetalation of the allylzirconocene with
dimethylzinc or zinc chloride provides functionalized homoallylic amines. An intramolecular version of this process leads to
3-aminotetrahydrofurans and 3-aminotetrahydropyrans.
Introduction
The reversible addition of zirconocene hydrochloride order to achieve the carbalumination of 1-alkynes [10], internal
(Cp2Zr(H)Cl, Schwartz’s reagent) to π-bonds usually leads alkynes [11], conjugated enynes [12], and 1-iodoalkynes [13].
predominantly to σ-complexes, and the resulting organozir- Huang and Pi found that allylzirconocenes underwent conju-
conocene complexes are valuable reactive intermediates for the gated addition to enones in the presence of CuBr·SMe2 [14].
formation of carbon–halogen and carbon–carbon bonds [1-6]. Wipf and Pierce demonstrated that, upon the addition of a zinc
The reaction of Schwartz’s reagent with allenes occurs at low reagent to allylzirconocenes, transient allylzinc intermediates
temperature and provides a ready access to σ-bound allylzir- can be successfully added to phosphoryl- and sulfonylimines to
conocenes [7]. These species can be added diastereoselectively provide homoallylic amines in good yields and diastereoselec-
to aldehydes and ketones to yield homoallylic alcohols, but they tivities [15]. Of particular interest was the reaction of tin- or
are generally not sufficiently reactive towards many other elec- silicon-substituted allenes that furnish bis-metallic reagents that
trophiles [8,9]. Similar to the related alkyl- and alkenyl- could potentially serve as dianion equivalents and provide (E)-
zirconocenes [1-3,6], this limitation of sterically hindered vinylsilanes and (E)-vinylstannanes in good yields [15].
allylzirconocene complexes can be overcome by selective trans-
metalation of zirconium to other metals. Suzuki and co-workers N-Metalloimines are reactive intermediates that represent
treated allylzirconocenes with methylaluminoxane (MAO) in masked imine derivatives of ammonia, which are often unstable
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and difficult to prepare. A common method for the preparation pot hydrozirconation of allenes and nitriles that facilitates the
of these species is the addition of various metal hydrides to reductive coupling to yield N-unprotected homoallylic amines.
nitriles [16-20], including aluminium [21-24], niobium [25],
samarium [26] and iron hydrides [27]. Zirconocene hydrochlo- Results and Discussion
ride can also be added to nitriles to provide N-zirconoimines, We first investigated the addition of allylzirconocenes to
which can be trapped with a range of electrophiles to form N-aluminoimines. N-aluminoisobutyroimine 1 was prepared in
imine derivatives [28-30]. Floreancig and co-workers devel- situ by the reduction of nitrile 3 with DIBAL (1 equiv) in
oped a method for the preparation of α-functionalized amides toluene. The resulting mixture was cannulated at −78 °C into a
by trapping N-zirconoimines with acyl chlorides, followed by solution of allylzirconocene (1.4 equiv), prepared by the
the addition of nucleophiles to the intermediate acyl imines [31- hydrozirconation of 3-methyl-1,2-butadiene (2). After stirring
33]. Furthermore, the utility of the hydrozirconation of nitriles for 30 min, the desired product 4 was isolated in 76% yield as a
can be enhanced by using Lewis acids to engage nitrile-derived single regioisomer. Other aliphatic nitriles were also good
acylimines in Friedel–Crafts reactions, generating indanyl or substrates for this reaction; however, N-aluminoimines obtained
tetrahydronaphthyl derivatives [34,35].
from aromatic nitriles were unreactive towards allylzir-
conocenes, and the desired product was not detected from these
Previous work in our group had concentrated on the transmeta- substrates (Table 1).
lation of alkenyl- and allylzirconium species to give zinc
organometallics, which were added to phosphoryl- and We also investigated the one-pot hydrozirconation of allenes
sulfonylimines to obtain homoallylic amines [15,36]. The and nitriles, aiming to explore the in situ formation-addition of
preparation of phosphoryl- and sulfonylimines as well as the allylzirconocenes to N-zirconoimines (Scheme 1). Exposure of
subsequent removal of these activating groups was often low- benzonitrile (7) and 3-methyl-1,2-butadiene (2) to an excess of
yielding. Because of that, as well as limited functional group Schwartz’s reagent in CH2Cl2 at −78 °C led to the formation of
compatibility in this methodology, we sought to develop a new a bright red solution after gradual warming to room tempera-
approach for the protective group-free synthesis of homoallylic ture. However, upon aqueous work-up, none of the desired
amines. The ease of synthesis of N-metalloimines by hydromet- amine was obtained, even when the more Lewis acidic
alation of nitriles could potentially provide suitable intermedi- Cp2Zr(H)Cl prepared in situ by the Negishi protocol [37] was
ates for this synthetic strategy. In this article, we report a one- used. In contrast, adding 1.4 equiv of ZnCl2 to the hydrozir-
Table 1: Reaction of N-aluminoimines with allylzirconocene derived from allene 2.
Entry
1
Nitrile
Product
Yield (%)
76
2
3
69
—a
aNone of the desired product was detected in this reaction; instead, a mixture of high molecular weight byproducts was observed.
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Beilstein J. Org. Chem. 2011, 7, 824–830.
Scheme 1: One-pot hydrozirconation-reductive coupling of allene 2 and nitrile 7.
conation reaction mixture, according to Suzuki’s protocol for duct 15 in good yield as a single diastereoisomer. In all of these
the reductive coupling of allenes and alkynes [38], led to the examples, the γ-adduct was isolated as the sole regioisomer, and
formation of homoallylic amine 8 in 75% yield after stirring at no internal alkene was detected. This regioselectivity is consis-
room temperature for 3 h.
tent with the allylzincation of imines [15] and opposite to that
of the zinca-Claisen reaction observed by Suzuki and
co-workers [38]. Analogous to the previous work in our group
[15], the silyl-substituted allene 16 produced the (E)-vinylsi-
lane 17 as the sole product in this reaction.
Under the optimized conditions for the reaction of benzonitrile
(7), we further explored the scope of the reaction of nitriles with
2 (Table 2). Both aromatic (Table 2, entries 1 and 2) and ali-
phatic (Table 2, entries 3 and 4) N-zirconoimines derived from
the corresponding nitriles reacted smoothly with allylzir- Given the success of the one-pot intermolecular reductive
conocene in the presence of a slight excess of ZnCl2 (1.4 equiv) coupling of allenes and nitriles, we sought to expand our
to give homoallylic amines in moderate to good yields. The methodology to an intramolecular variant. For this purpose, we
phenylallene 13 yielded exclusively the terminal alkene pro- synthesized substrate 18 by O-alkylation of allenylmethanol
Table 2: Reductive coupling of allenes and nitriles in the presence of Cp2Zr(H)Cl and ZnCl2.a
Entry
Allene
Nitrile
Product
Yield (%)
75 (78)b
1
2
3
55 (67)b
80 (81)b
4
5
65 (71)b,c
67 (70)b,d
aAll reactions were carried out by hydrozirconation of a mixture of allene (1.4 equiv) and nitrile (1 equiv) in CH2Cl2 at −78 °C, followed by the addition
of a 1 M solution of ZnCl2 in ether (1.4 equiv) at 0 °C. bYields in parentheses correspond to the reaction in which transmetalation was performed using
Me2Zn (1.4 equiv) in toluene. cOnly one diastereoisomer was observed by 1H NMR analysis of the crude reaction mixture. dAlkene geometry was
assigned by coupling constant analysis.
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Beilstein J. Org. Chem. 2011, 7, 824–830.
[39] with bromoacetonitrile (Supporting Information File 1). good yield and provided a single diastereoisomer. This observa-
We were pleased to see that treatment of substrate 18 with 3.6 tion is in agreement with previous work in our group that
equiv of Schwartz’s reagent in CH2Cl2 followed by the addi- showed the transmetalation from zirconium to zinc to occur
tion of 1.4 equiv of ZnCl2 led to the formation of the desired faster in toluene than in CH2Cl2 [15]. Furthermore, we also
tetrahydrofuran product 19 as a single diastereoisomer in 60% repeated some earlier examples of the intermolecular reaction
yield (Scheme 2). Surprisingly, however, we found that using dimethylzinc in toluene for the transmetalation step.
repeating this reaction gave variable yields. Because the reac- These new experiments produced results similar to the reac-
tion mixture was heterogeneous after the addition of the zinc tions in the presence of zinc chloride (Table 2).
salt, we argued that decreasing the amount of Cp2Zr(H)Cl or a
lower substrate concentration might help to address this Next, we investigated the scope of the intramolecular reaction
problem. Unfortunately, these studies were inconclusive, and (Table 4). Both tetrahydrofuran and tetrahydropyran products
3.6 equiv of Schwartz’s reagent were generally needed for a were obtained in moderate to good yields as single diastereo-
satisfactory reaction progress.
mers, as determined by 1H NMR analysis. The conversion of
substrate 22 was good, but met with difficulties in isolating the
free amine product. Accordingly, treatment of the crude reac-
tion mixture with Boc2O and Et3N for 2 h at room temperature
improved the reaction workup and provided compound 23 in
60% yield.
Table 4: Cyclative reductive couplings.a
Scheme 2: Cyclization of allenylnitrile 18.
Entry
1
Substrate
Product
Yield
To address the reproducibility issue, we also investigated
different zinc sources (Table 3). The presence of zinc halides
and triflates (ZnCl2, Zn(OTf)2) in a range of solvents always
resulted in the formation of a precipitate. Therefore, we turned
our attention to dialkylzincs. We were pleased to see that the
addition of a 1 M solution of diethylzinc to the hydrozirconated
18 at −78 °C produced a homogeneous red solution; however,
only traces of the desired product 19 were detected. Switching
the solvent from CH2Cl2 to toluene before the addition of the
dialkylzinc reagent resulted in the desired product formation in
69%b
2
3
53%c
Table 3: Optimization of the intramolecular reductive coupling of allene
and nitrile to give tetrahydrofuran 19.
60%b,d
aAll reactions were carried out by hydrozirconation of a mixture of
allene (1.4 equiv) and nitrile (1 equiv) in CH2Cl2 at −78 °C, followed by
a solvent switch to toluene and addition of 1 M ZnMe2 (entries 1 and 2)
or 1 M ZnEt2 (entry 3) in toluene (1.4 equiv) at −78 °C. bRelative con-
figuration was assigned in analogy to 21. cRelative configuration was
determined by coupling constant analysis (Figure 1). dCompound 23
was isolated as a Boc-protected amine upon treatment of the crude
reaction mixture with Boc2O (1 equiv) and Et3N (6 equiv) in THF/
CH2Cl2.
Entry
Zinc source
Solvent
Yield (%)
1
2
3
4
5
6
7
ZnCl2a
ZnCl2b
CH2Cl2
CH2Cl2
53
50
17
55
<5
68
69
Zn(OTf)2b
ZnCl2a
CH2Cl2
DCE
In order to determine the relative configuration of pyran 21, the
amine was protected as the t-butyl carbamate (Supporting Infor-
mation File 1). Signals for both hydrogen atoms Hb and Hc
were doublets of doublets with one large and one small
coupling constant. The large coupling constant, Jbc = 11.4 Hz,
corresponds to the geminal coupling between Hb and Hc, while
Et2Znc
CH2Cl2
Et2Znd
CH2Cl2/Toluene
CH2Cl2/Toluene
Me2Znd
a1 M solution in Et2O. bNeat salt was added. c1 M solution in CH2Cl2.
d1 M solution in toluene.
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Beilstein J. Org. Chem. 2011, 7, 824–830.
the small coupling constants, Jab = 1.8 Hz and Jac = 2.7 Hz, We propose a chelated transition state for the formation of 19,
correspond to the coupling between Hb/c and Ha. This analysis 21, and 23 (Scheme 3). After the initial hydrozirconation and
implies that hydrogen atom Ha is in the equatorial position, transmetallation with dimethylzinc, both (E)- and (Z)-allylzinc
placing the electronegative carbamate substituent and the C–O species can exist in the solution. The chelation of the
bond in the tetrahydropyran ring into a gauche orientation zirconocene to the ether oxygen and the imine nitrogen leads to
(Figure 1).
a preference for the (Z)-TS species, paving the way for the for-
mation of the observed cis-product.
To further elaborate on the utility of this methodology, we
demonstrated that the homoallylic amine products could be
readily converted to synthetically useful building blocks, such
as β-amino acids (Scheme 4). N-Boc-protection of the primary
amine 12 followed by ozonolysis under Marshall’s conditions
[40] yielded the β-amino acid derivative 24. The cyclic amine
19 was subjected to analogous reaction conditions to form the
tetrahydrofuran β-amino acid derivative 26.
Figure 1: Coupling constant analysis of the Boc-protected aminopyran
ring in 21.
Scheme 3: Proposed chelated transition state model.
Scheme 4: Conversion of homoallylic amines to β-amino acid derivatives.
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Beilstein J. Org. Chem. 2011, 7, 824–830.
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We have developed a method for the one-pot simultaneous
hydrozirconation of allenes and nitriles to yield allylic
zirconocenes and N-zirconoimines, respectively. These inter-
mediates can be transmetalated in situ with dimethylzinc or zinc
chloride, which facilities the cross-coupling process to give
N-unprotected homoallylic amines after aqueous workup. All
products were isolated as single regio- and diastereoisomers,
and the regioselectivity of the allylation step was shown to
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Acknowledgements
This work has been supported by the National Science Founda-
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