Microwave-assisted synthesis of allylic amines: Considerable rate acceleration in the hydrozirconation-transmetalation-aldimine addition sequence

Article abstract of DOI:10.1039/b316741k

The hydrozirconation of alkynes with zirconocene hydro-chloride and the dimethylzinc-mediated addition of alkenylzirconocenes to diphenylphosphinoyl imines can be greatly accelerated with microwave irradiation, resulting in a convenient and rapid one-pot

Full text of DOI:10.1039/b316741k

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Microwave-assisted synthesis of allylic amines: considerable rate
acceleration in the hydrozirconation–transmetalation–aldimine
addition sequence†
Peter Wipf,a,c Jelena Janjicb,c and Corey R. J. Stephensona,c
a Department of Chemistry, University of Pittsburgh, Pittsburgh Pennsylvania, 15260, USA.
E-mail: pwipf@pitt.edu; Fax: ϩ1-412-624-0787; Tel: ϩ1-412-624-8606
b Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261,
USA
c Center for Chemical Methodologies & Library Development, University of Pittsburgh,
Pittsburgh, PA 15260, USA
Received 23rd December 2003, Accepted 19th January 2004
First published as an Advance Article on the web 28th January 2004
The hydrozirconation of alkynes with zirconocene hydro-
chloride and the dimethylzinc-mediated addition of
alkenylzirconocenes to diphenylphosphinoyl imines can be
greatly accelerated with microwave irradiation, resulting in
a convenient and rapid one-pot process for the preparation
of synthetically useful allylic amines.
Our preliminary studies immediately revealed a large rate
acceleration for the Zr Zn methodology in the preparation of
allylic amines using microwave irradiation. Under our original
conditions,1 the hydrozirconation of 1 was performed in
CH2Cl2; however, this proved to be a poor solvent for the
alkenylzirconocene addition and led to considerable concomi-
tant C-cyclopropylalkylamine formation. While toluene was
the preferred solvent for the nucleophilic imine addition, hydro-
zirconation in toluene was prohibitively slow: hydrozirconation
of 4-octyne at room temperature in toluene did not reach com-
pletion even after 48 h. Fortunately, microwave irradiation
greatly accelerated this process, and for all alkynes tested thus
far, including functionalized, non-functionalized, internal and
terminal substrates, hydrozirconation was complete in toluene
within 5 min at ca. 100 ЊC with a power setting of 100–150 W.
Conventional heating at 100 ЊC in toluene also accelerated the
reaction but was accompanied by significant (∼25–30%) side
product formation and discoloring of the reaction mixture.
Since toluene is a rather transparent solvent for microwave
radiation, we hypothesize that dipolar zirconocene and zinc
complexes are predominantly responsible for absorption of
microwave energy, and that a dielectric heating mechanism is
operative. Rate acceleration is particularly effective when the
polarity is enhanced from ground to transition state.7
In a typical protocol, Schwartz reagent was suspended in dry
toluene and treated with terminal or internal alkyne. The reac-
tion mixture was heated in a single-mode microwave reactor,8
providing a clear yellow to orange solution of alkenyl–
zirconium complex. Upon optimization of the conditions with
1-hexyne and 4-octyne, we found that the conversion was com-
plete in 45 s based on GC analysis. Unsymmetrical internal
alkynes produced a mixture of regioisomeric alkenes after
hydrozirconation with Cp2ZrHCl and quenching; the kinetic-
ally controlled reaction only slightly favoured the isomer
derived from addition of the zirconium atom at the carbon
bearing the sterically least demanding substituent. In order
to improve this ratio, an excess of Cp2ZrHCl and elevated
temperatures were used to reach thermodynamic equilibrium,
which generally provides a much greater preference for the
least substituted zirconium complex.2,9 The regioselectivity of
hydrozirconation in toluene under microwave conditions was
studied in more detail for the cyclohexyl/alkyl-substituted
alkynes 5 and 6 (Table 1). Despite the notable difference in the
steric bulk of the two triple bond substituents, the observed
regioselectivity was poor in the presence of 1 equivalent
of Cp2ZrHCl (Entry 1, 2). While these alkynes were rapidly
hydrozirconated in toluene at 100 ЊC, and favorable ratios were
achieved in the presence of a slight excess of reagent (Entry 3),
this temperature led to a discoloring of the solution and a
Allylic amines are valuable building blocks for organic and
medicinal chemists and can be easily transformed into 1,2-
amino alcohols and α-amino acids. We have recently reported
the preparation of functionalized allylic and C-cyclopropyl
amines via addition of alkenylzirconocenes to diphenyl-
phosphinoyl imines in the presence of dimethylzinc. The allylic
amide 3 is formed in an in situ protocol from alkyne 1 and imine
2 in toluene, whereas C-cyclopropylalkylamide 4 is the major
product in CH2Cl2 (Scheme 1).1 Hydrozirconation2 is a mild
method for the selective preparation of functionalized organo-
metallics and its compatibility with a wide variety of common
protecting groups represents a considerable advantage of these
species over traditional organometallic reagents. The inter-
mediate alkenylzirconocenes have been used in Pd(0)-mediated
coupling reactions3 and in nucleophilic additions to a number
of common electrophiles.4 A drawback of the method shown in
Scheme 1 is that overall reaction times can easily exceed 12 h,
since both hydrozirconation and imine addition of the inter-
mediate vinyl zinc reagent are often slow even at room temper-
ature. In recent years microwaves have found an increasing
number of applications in organometallic chemistry and drug
discovery.5,6 We have now found that alkenylzirconocene and
-zinc species are surprisingly stable in the microwave environ-
ment under elevated temperature and pressure and thus offer
another opportunity for a synthetically advantageous use of
this technology.
Scheme 1 One-pot synthesis of allylic and C-cyclopropylalkylamines.
† Electronic supplementary information (ESI) available: experimental
1
procedures and H and 13C NMR spectra for all new compounds. See
http://www.rsc.org/suppdata/ob/b3/b316741k/
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 4 4 3 – 4 4 5
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Table 1 Regioselective hydrozirconation in toluene
Entry
R
Eq. Cp2ZrHCl
Time (min)
Temp (ЊC)a
7a, 7b or 8a, 8bb
1
2
3
4
5
6
7
Et
Et
Et
Et
Et
Et
Me
1.0
1.0
1.25
1.5
1.5
2.0
2.0
30
30
30
30
60
30
30
60
100
100
60
60
60
2.0 : 1
2.2 : 1
14 : 1
3.0 : 1
3.5 : 1
>20 : 1
>20 : 1
60
a Microwave power set at 150 W. b Ratio determined by 1H NMR integration of the crude reaction mixture; yields for entries 6 and 7 were essentially
quantitative.
Table 2 Microwave-accelerated condensation of alkynes and imines to give allylic amides
Entry
1
Alkyne
Imine
Allylic amide
Methoda
A
Yield (%)b
73
2
3
2
A
B
62
80
4
1
12
B
95
5
6
2
C
C
77
74
12
7
8
5
6
12
2
D
D
60
63
a Method A: i) Cp2ZrHCl (1.5 eq.), alkyne (1.6 eq.), µW 60 ЊC (150 W), 5 min, ii) Me2Zn (1.5 eq.), Ϫ78 ЊC to 0 ЊC, iii) imine, µW 100 ЊC (150 W), 5
min; Method B: i) Cp2ZrHCl (1.7 eq.), alkyne (1.5 eq.), µW 80 ЊC (75 W), flash heating, ii) Me2Zn (1.5 eq.), Ϫ78 ЊC to 0 ЊC, iii) imine, µW 100 ЊC (150
W), flash heating; Method C: i) Cp2ZrHCl (1.7 eq.), alkyne (1.5 eq.), µW 100 ЊC (100 W), flash heating, ii) Me2Zn (1.5 eq.), Ϫ78 ЊC to 0 ЊC, iii) imine,
µW 100 ЊC (150 W), flash heating; Method D: i) Cp2ZrHCl (2 eq.), 5 or 6 (1 eq.), µW 60 ЊC (150 W), 30 min, ii) 5 or 6 (1 eq.), µW 60 ЊC (150 W), 15
min, iii) Me2Zn (1 eq.), Ϫ78 ЊC to 0 ЊC, iv) imine, µW 100 ЊC (150 W), 15 min; b Yield of isolated products based on imines.
poor yield in the subsequent imine addition reaction. Under
optimum conditions, hydrozirconation of unsymmetrical
internal alkynes was accomplished with 2.0 eq. of Cp2ZrHCl at
60 ЊC in 30 min (Table 1, Entries 6, 7). Accordingly, slightly
longer reaction times in the microwave are necessary for achiev-
ing thermodynamic equilibrium and high regioselectivity for
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 4 4 3 – 4 4 5
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unsymmetrical internal alkynes, compared to terminal and
symmetrical internal alkynes.
Acknowledgements
Support for this research by the NIGMS CMLD program
(P50-GM067082) is gratefully acknowledged.
A series of alkynes and imines were subjected to the
optimized accelerated reaction conditions in the microwave
(Table 2). The hydrozirconation products of terminal (Entries
1–4) and symmetrical internal alkynes (Entries 5–6) under-
went rapid addition (1–5 min) to imines in the presence
of dimethylzinc. Under conventional conditions,1 terminal
alkenylzirconocenes were more reactive than complexes derived
from internal alkynes. Under microwave conditions, the
reaction rates for both species were comparable. The highest
rate increase in the imine addition was observed for Entries
3–6. These examples were performed using the flash heat-
ing mode, which led to complete conversion in <1 min.10
Perhaps due to the short reaction times, the elevated temper-
atures used in these experiments did not cause the same level
of decomposition products compared to the conventional
approach, and purification by chromatography on SiO2 was
simplified. All allylic amides were isolated in good to excellent
yields. Not unexpectedly, unsymmetrical internal alkynes were
found to be the least reactive toward imine addition and
required up to 15 min reaction time at 100 ЊC; however, with
these substrates complete conversion was not accomplished
even after 24 h under conventional conditions. The advantages
of the microwave methodology lie both in the significant time
savings of the domino process as well as the increased conveni-
ence of carrying out both hydrozirconation and imine addition
in a single reaction environment using a non-chlorinated
solvent.
References
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8 A CEM Discover single mode microwave reactor with controlled
temperature, power, pressure and time settings was used for all
reactions.
9 J. S. Panek and T. Hu., J. Org. Chem., 1997, 62, 4912.
10 Flash heating is accomplished by continuous irradiation at high
(100–150) wattage until the target temperature is reached in the
reaction vessel. On the CEM Discover reactor, this is accomplished
using the “powertime” setting.
In summary, we have developed an expedient new protocol
for allylic amine formation using a microwave-based strategy.
Hydrozirconation as well as transmetalation to zinc and imine
addition steps are greatly accelerated and toluene can now serve
as a reaction solvent throughout the entire process. Studies
directed towards the application of this technology to the
generation of libraries of allylic and C-cyclopropylalkylamides
are currently under way in our laboratories and will be reported
in due course.
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445