Palladium catalyzed intermolecular hydroamination of 1-substituted allenes: An atom-economical method for the synthesis of N-allylamines

Article abstract of DOI:10.1039/c3ra43870h

The palladium complex [(3IP^tBu)Pd(allyl)]OTf previously displayed excellent catalytic activity for the hydroamination of 1,1-dimethylallene with anilines, selectively producing the branched substituted allylamine product (kinetic product) in high conversion. In the current report, the scope of this hydroamination reaction has been expanded to include both alkyl amines and anilines in combination with an array of seven alkyl and aryl allenes. For the majority of amines investigated, the hydroamination of 1,1-dimethylallene, cyclohexylallene, benzylallene, and select aryl allenes with alkyl amines gave the branched substituted allylamine product in nearly quantitative conversion at ambient temperature in less than 1 hour. In contrast, anilines displayed a more limited reaction scope and yielded the linear hydroamination product (thermodynamic product) with all allenes other than 1,1-dimethylallene. Both branched and linear products could be formed selectively in the hydroamination of p-fluorophenylallene with alkyl amines through careful control of [(3IP^tBu)Pd(allyl)]OTf catalyst loading and reaction duration. Overall, the branched allylamines produced are useful synthetic intermediates due to their available unsaturated vinyl group, while the linear allylamine products are chemically similar to a class of known pharmaceuticals. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra43870h

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Palladium catalyzed intermolecular hydroamination of
1-substituted allenes: an atom-economical method for
the synthesis of N-allylamines
Cite this: RSC Adv., 2013, 3, 20708
*
John F. Beck, Danielle C. Samblanet and Joseph A. R. Schmidt
The palladium complex [(3IPtBu)Pd(allyl)]OTf previously displayed excellent catalytic activity for the
hydroamination of 1,1-dimethylallene with anilines, selectively producing the branched substituted
allylamine product (kinetic product) in high conversion. In the current report, the scope of this
hydroamination reaction has been expanded to include both alkyl amines and anilines in combination
with an array of seven alkyl and aryl allenes. For the majority of amines investigated, the
hydroamination of 1,1-dimethylallene, cyclohexylallene, benzylallene, and select aryl allenes with alkyl
amines gave the branched substituted allylamine product in nearly quantitative conversion at ambient
temperature in less than 1 hour. In contrast, anilines displayed a more limited reaction scope and
yielded the linear hydroamination product (thermodynamic product) with all allenes other than 1,1-
dimethylallene. Both branched and linear products could be formed selectively in the hydroamination of
p-fluorophenylallene with alkyl amines through careful control of [(3IPtBu)Pd(allyl)]OTf catalyst loading
and reaction duration. Overall, the branched allylamines produced are useful synthetic intermediates
due to their available unsaturated vinyl group, while the linear allylamine products are chemically similar
to a class of known pharmaceuticals.
Received 24th July 2013
Accepted 28th August 2013
DOI: 10.1039/c3ra43870h
www.rsc.org/advances
methods for the synthesis of allylamines; however, even in the
best cases, a coproduct such as water is formed.28–30 For
Introduction
Functionalized allylamines are a class of molecules that
constitute a useful synthetic target due to their importance as
intermediates in the synthesis of indoles1–5 and heterocycles,6–15
as well as their prevalence in pharmaceuticals, including drugs
such as cinnarizine,16 unarizine,17 naine,18 terbinane,19,20
and zimelidine (Fig. 1).21 These compounds play important and
diverse biological roles. For example, cinnarizine acts as a
calcium channel blocker in the treatment of vertigo22 and
nausea associated with motion sickness.23 Likewise, unarizine
acts as a calcium channel blocker in the relief of chronic
migraines.24 Naine and terbinane are antifungal drugs for
the treatment of athlete's foot (tinea pedis), jock itch (tinea
cruris), and ringworm (tinea corporis), whose modes of action
involve inhibition of squalene epoxidase, an enzyme involved in
the growth of fungal cell walls.25 Zimelidine inhibits serotonin
reuptake acting as an anti-depressant, although it is been
subsequently replaced by more effective remedies.26 The tradi-
tional stepwise synthesis of substituted allylamines is both time
and material intensive, commonly requiring the use of both
protecting groups and multiple purications.2,3,27 Recent
advances in catalytic allylic amination have provided far greener
example, both unarizine and naine were synthesized by
Ohshima et al. via direct catalytic substitution of allylic alco-
hols, each forming water as the sole byproduct.31 Although
allylic amination presents a distinct improvement over the
traditional methods for synthesis of these compounds,17,32
production of allylamines via hydroamination offers an even
greener synthetic alternative because all the atoms present in
the starting materials are incorporated into a single product.
Hydroamination is the direct addition of a nitrogen–hydrogen
bond across a carbon–carbon unsaturated bond, allowing for
the formation of complex molecular frameworks from inex-
pensive precursors.33 Hydroamination is also the only 100%
atom economical method available to prepare allylamines.34
Intermolecular hydroamination of allenes can produce several
different regio- and stereoisomers depending primarily on the
functionality present on the substrate allene and the catalyst
employed to effect the addition reaction. In general, early tran-
sition metal catalysts yield hydroamination products where the
amino group is added to the central carbon of the allene,35,36 while
late transition metal catalysts install the amine functionality at a
terminal carbon atom.37 For asymmetrically substituted allenes
(such as monosubstituted allenes), the terminal carbons are
inequivalent, allowing the possibility of regioselective hydro-
amination to give either branched or linear products. In fact,
Department of Chemistry, School of Green Chemistry and Engineering, College of
Natural Sciences & Mathematics, The University of Toledo, 2801 W. Bancro St. MS
602, Toledo, OH 43606-3390, USA. E-mail: Joseph.Schmidt@utoledo.edu
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Fig. 1 Pharmacologically active allylamine or allylamine derived compounds.
regioselective addition to the substituted carbon atom of a anilines.49 Isomerization to the linear product was minimal and
monosubstituted allene also creates a new stereocenter; chiral in most cases the reaction operated well at room temperature. It
rhodium catalysts for asymmetric hydroamination of allenes have was further shown that the branched isomer could be used in an
recently been disclosed in an elegant study by Breit and aryl amino Claisen rearrangement, producing 2-allyl anilines in
coworkers.38 In the past several years, the intermolecular hydro- good yield via a one-pot two-step synthesis.49 Herein, we report a
amination of allenes has come under great scrutiny, and it has broadly expanded catalytic scope for the 3-iminophosphine pre-
become clear that many late metal systems are capable of selec- catalyst [3IPtBuPd(allyl)]OTf, which has been utilized in the
tively producing the linear (thermodynamic) product,39–42 while hydroamination of a diverse series of mono- and 1,1-disubsti-
selectivity for the branched (kinetic) product remains difficult.38 tuted allenes with both alkyl amines and anilines. These reac-
The relatively low cost of palladium compared to rhodium or gold tions have resulted in the successful synthesis and isolation of a
makes the continued development of palladium based hydro- wide range of new allylamines, demonstrating the broad utility of
amination catalysts an attractive pursuit. A new system capable of this new catalytic system.
utilizing the less expensive palladium center while still allowing
for the facile isolation of the kinetic product with broad substrate
scope would represent a signicant advancement in palladium
Results and discussion
catalyzed amination. Unfortunately, there are exceptionally few In our previous communication,49 we used [3IPtBuPd(allyl)]OTf in
palladium complexes that will perform hydroamination43,44 or the hydroamination of 1,1-dimethylallene with various anilines;
allylic amination45–48 in a manner that allows for the isolation of some of these results are reproduced herein (Table 1; entries
the branched product, mostly due to limitations in turnover 1.6–1.9). In order to expand the scope of 1,1-dimethylallene
frequency and necessary reaction temperatures.
reactivity, primary and secondary alkyl amines were subsequently
We have previously established alicyclic 3-iminophosphines as investigated with this catalyst. Primary amines, cyclohexylamine
effective supporting ligands for use in palladium-catalyzed and 2-octylamine, proceeded slowly (Table 1; entries 1.10 and
hydroamination of allenes,49–51 1,3-dienes50 and alkynes.52 Our 1.11), although they did react faster than even the most compe-
initial allene hydroamination study focused on [3IPArPd(allyl)]- tent anilines.49 The hydroamination of 1,1-dimethylallene with
OTf, which performed well in the hydroamination of allenes with secondary alkyl amines proceeded much more rapidly, yielding
secondary amines.50 Regrettably, in this initial study, the hydro- exclusively the branched isomer in as little as 30 minutes
amination of 1,1-dimethylallene with secondary alkyl amines (Table 1; entries 1.1–1.5). There seems to be a relationship
yielded only the linear allylamines (thermodynamic products).50 between the pKa of the amine's conjugate acid and the rate of
The ability to isolate the branched allylamines (kinetic products), hydroamination. For example, the pKa of the conjugate acid of
where the double bond is terminal (vinylic), is highly desirable morpholine is 8.50 while that for para-toluidene is 5.08.55 Given
due to the ease in which these compounds can be further deriv- the increased rate of hydroamination of morpholine compared to
atized via reactions such as hydroformylation53 and alkene para-toluidene, it is clear that basic, electron-rich amines make
metathesis.54 In order to obtain these more valuable and ther- better substrates for allene hydroamination (Table 1). Generally,
modynamically less favorable products, modications to the anilines are much less basic than alkyl amines due to delocal-
substituents on the ligand were investigated, ultimately resulting ization of the nitrogen lone pair into the p system of the aromatic
in the development of [3IPtBuPd(allyl)]OTf.49 This complex was ring. Amine basicity is not the only factor affecting the rate of the
found to effectively produce the branched isomer in good to reaction; steric factors also play a role. We have previous noted
excellent yield when used for the hydroamination of allenes with that 2-substituted anilines are ineffective substrates for the
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Table 1 The hydroamination of 1,1-dimethylallene with primary and secondary amines
Entry
Amine
Time (h)
Conversion (A : B)
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8
1.9
1.10
1.11
Morpholine
Piperidine
1-Methylpiperazine
Pyrrolidine
1,2,3,4-Tetrahydroisoquinoline
3-Methylaniline
4-Methylaniline
3-Methoxyaniline
4-Methoxyaniline
Cyclohexylamine
2-Octylamine
0.5
0.5
0.5
0.5
0.5
20
20
20
20
3
95 (100 : 0)
95 (100 : 0)
95 (100 : 0)
95 (100 : 0)
95 (100 : 0)
62 (100 : 0)a
95 (100 : 0)a
73 (100 : 0)a
95 (100 : 0)a
95 (100 : 0)
95 (100 : 0)
3
a
Ref. 49.
hydroamination of 1,1-dimethylallene.49 With a conjugate acid
The main focus of the study reported herein was to investi-
pKa of 4.45,55 ortho-toluidene is more basic than many of the gate the hydroamination of other allenes. We were especially
halogenated anilines that act as competent coupling partners interested in mono-substituted allenes since formation of the
with 1,1-dimethylallene, but ortho-toluidene was found to be branched isomer in these cases would create a new chiral
unreactive even at elevated temperature.49 This is likely due to center. Though a racemic mixture would result with the current
steric congestion around the palladium center caused by the catalyst, the successful creation of new chiral centers would
ortho substituent during catalysis. Neither steric nor electronic inspire development of chiral versions of this catalyst system.
arguments alone can adequately explain why primary alkyl The hydroamination of cyclohexylallene with secondary alkyl
amines react slowly. For example, cyclohexylamine is reasonably amines proceeded readily at room temperature to yield the
basic (conjugate acid pKa of 10.64),55 but reacts slowly compared branched products as racemic mixtures in 30 to 60 minutes
to secondary alkyl amines. It may be that different steps in the (Table 2). Unfortunately, anilines were unreactive with cyclo-
catalytic mechanism are rate-limiting depending on the type of hexylallene in the presence of [3IPtBuPd(allyl)]OTf. 1,2,3,4-Tet-
amine used. A full kinetic and mechanistic evaluation of this rahydroquinoline was also found to be completely unreactive,
system remains a subject of future work in our group.
similar to the ortho-substituted anilines tested with this catalyst
Table 2 The hydroamination of cyclohexylallene with secondary amines
Entry
Amine
Time (h)
Conversion (A : B)
2.1
2.2
2.3
2.4
2.5
Morpholine
Piperidine
1-Methylpiperazine
Pyrrolidine
1,2,3,4-Tetrahydroisoquinoline
0.5
0.5
0.5
0.5
1
95 (100 : 0)
91 (100 : 0)
85 (100 : 0)
56 (100 : 0)
95 (100 : 0)
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Table 3 The hydroamination of benzylallene with secondary amines
Entry
Amine
Time (h)
Conversion (A : B)
3.1
3.2
3.3.1
3.3.2
3.3.3
3.4
Morpholine
Piperidine
1-Methylpiperazine
1-Methylpiperazine
1-Methylpiperazine
Pyrrolidine
1.0
1.0
0.75
1.0
2.0
1.0
1.0
95 (100 : 0)
95 (100 : 0)
95 (100 : 0)
95 (87 : 13)
95 (100 : 0)a
95 (100 : 0)
95 (100 : 0)a
3.5
1,2,3,4-Tetrahydroisoquinoline
a
Conversion reported at a catalyst loading of 1 mol%.
system. Its isomer, 1,2,3,4-tetrahydroisoquinoline, although isomerized to linear allylamines using Lewis acid catalysts in
slower than the other secondary alkyl amines, readily hydro- the presence of a Brønsted acid.47,48,56 The palladium complexes
aminated cyclohexylallene. The inclusion of a methylene group utilized in this study are no exception and generally, all of the
between the aromatic ring and the amine was enough to allow branched allylamine products slowly convert to the linear
hydroamination to proceed. The reactivity difference between isomer in a matter of hours in the presence of the catalyst;
these two isomers ts well within both the electronic and steric however, the branched benzylallene hydroamination products
considerations discussed above, allowing 1,2,3,4-tetrahy- undergo this isomerization somewhat faster than many of the
droisoquinoline to react, while 1,2,3,4-tetrahydroquinoline other products reported herein. Thus, the longer reaction times
does not. Overall, cyclohexylallene underwent hydroamination necessary for hydroamination of benzylallene led to some cases
effectively in the presence of [3IPtBuPd(allyl)]OTf and secondary where the branched product had partially isomerized. For
amines.
example, hydroamination of benzylallene with 1-methylpiper-
Benzylallene was found to have a very similar reactivity azine in the presence of [3IPtBuPd(allyl)]OTf (5 mol%) resulted
prole to that of cyclohexylallene, although slightly longer in partial isomerization aer one hour. This isomerization was
reaction times were necessary, occasionally leading to small avoided by limiting the reaction time to 45 minutes or reducing
amounts of product isomerization (Table 3). Previous reports the catalyst loading to 1 mol% with a reaction time of 2 hours.
have shown that branched allylamines can be readily Either approach gave complete product formation with no
Table 4 The hydroamination of 1,1-diphenylallene with secondary amines
Entry
Amine
Time (h)
Conversion (A : B)
4.1
4.2
4.3
4.4
4.5
Morpholine
Piperidine
1-Methylpiperazine
Pyrrolidine
1,2,3,4-Tetrahydroisoquinoline
20
20
20
20
20
95 (0 : 100)
95 (0 : 100)
95 (0 : 100)
95 (0 : 100)
95 (0 : 100)
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isomerization (Table 3; entries 3.3.1 to 3.3.3). Similarly, lower entry 5.1.2). In an effort to isolate the branched product, catalyst
catalyst loading was necessary in the hydroamination using loading was reduced to 1 mol%, slowing both hydroamination
1,2,3,4-tetrahydroisoquinoline (Table 3; entry 3.5). para-Tolui- and product isomerization. Aer 10 minutes, the reaction was
dene was also found to hydroaminate benzylallene (with heat- complete with only 22% of the product isomerized to the linear
ꢀ
ing to 70 C), but multiple inseparable isomers were observed. isomer (Table 5; entry 5.1.4). Hydroamination of phenylallene
Overall, benzylallene proved to be a good substrate for hydro- with 1,2,3,4-tetrahydroisoquinoline reached completion in 90
amination, with only minor procedural modications necessary minutes, while the other secondary alkyl amines were done in
to achieve high yields of branched allylamine products.
30 minutes or less (Table 5; entries 5.2 to 5.5). Anilines required
1,1-Diphenylallene proved to be the least reactive of the longer reaction times with conversions recorded at 20 hours
allenes studied. It was completely inert towards anilines and and isomerization to the linear product complete by this time
hydroaminated slowly with all secondary alkyl amines studied, (Table 5; entries 5.6 to 5.9). Cinnamyl amines (trans-3-phenyl-
leading to isolation of linear isomers exclusively (Table 4). NMR allylamines) are found in N-cinnamyl-piperazines such as cin-
spectroscopy was used to follow the progress of these reactions narizine and unarizine, both of which are medicinally active
and small amounts of the branched isomers were observed in compounds, as discussed in the Introduction. Hydroamination
each reaction mixture throughout the course of the experi- of phenylallene with commercially available 1-(diphenylmethyl)
ments; however, the rates of conversion from the branched to piperazine yielded quantitative conversion to cinnarizine
linear isomers appeared to be similar in magnitude to the rates (Scheme 1) with 100% atom efficiency in only three hours (Table
of the hydroamination reactions, such that the branched 5; entry 5.12), showing the utility of these catalysts in real world
isomers could not be isolated. The reactions were found to be applications. Although it was difficult to isolate branched
complete at 20 hours for all secondary amines studied, leading allylamine products, the hydroamination of phenylallene
to high yields of the linear hydroamination products for each proved to be an exceptionally efficient method for installation of
secondary alkyl amine.
new nitrogen–carbon bonds, producing the particularly inter-
The hydroamination of phenylallene was incredibly facile for esting cinnamyl moiety with 100% atom economy at room
all alkyl amines studied. Unfortunately, the isomerization from temperature.
branched to linear allylamine products was also very rapid with
In order to investigate the role of electronics within the
this system. Hydroamination using morpholine was complete allene without varying the steric component, para-substituted
in less than one minute with 28% of the material already iso- phenylallene derivatives p-methoxyphenylallene and p-uo-
merized to the linear product (Table 5; entry 5.1.1). This isom- rophenylallene were tested in hydroamination. The reactions of
erization was nearly complete only 3 minutes later (Table 5; p-methoxyphenylallene with morpholine and 4-methylaniline
Table 5 The hydroamination of phenylallene with anilines and secondary amines
Entry
Amine
Time
Conversion (A : B)
5.1.1
5.1.2
5.1.3
5.1.4
5.2
5.3
5.4
5.5
5.6
5.7
5.8
5.9
5.12
Morpholine
Morpholine
Morpholine
Morpholine
Piperidine
1-Methylpiperazine
Pyrrolidine
1,2,3,4-Tetrahydroisoquinoline
3-Methylaniline
4-Methylaniline
3-Methoxyaniline
4-Methoxyaniline
1-(Diphenylmethyl)piperazine
1 min
4 min
10 min
10 min
30 min
30 min
30 min
1.5 h
20 h
20 h
20 h
20 h
95 (72 : 28)
95 (5 : 95)
95 (0 : 100)
99 (78 : 22)a
95 (0 : 100)
95 (0 : 100)
95 (0 : 100)
95 (0 : 100)
95 (0 : 100)
95 (0 : 100)
95 (0 : 100)
95 (0 : 100)
95 (0 : 100)
3 h
a
Conversion reported at a catalyst loading of 1 mol%.
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Scheme 1 Hydroamination of phenylallene with 1-(diphenylmethyl)piperazine yields the pharmaceutical cinnarizine (5.12B).
Table 6 The hydroamination of para-substituted phenylallenes with anilines and secondary amines
Entry
Amine
Time (h)
Conversion (A : B)
6.1
6.7
Morpholine
4-Methylaniline
Morpholine
Morpholine
Piperidine
1
95 (0 : 100)
95 (0 : 100)
95 (100 : 0)a
95 (0 : 100)
84 (70 : 30)b
95 (0 : 100)
95 (40 : 60)
95 (0 : 100)
80 (80 : 20)b
95 (0 : 100)
70 (100 : 0)a
95 (0 : 100)
95 (0 : 100)
95 (0 : 100)
20
0.5
1.5
10
1.5
1.5
2
10
1.5
0.6
1.5
20
3
7.1.1
7.1.2
7.2.1
7.2.2
7.3.1
7.3.2
7.4.1
7.4.2
7.5.1
7.5.2
7.7
Piperidine
1-Methylpiperazine
1-Methylpiperazine
Pyrrolidine
Pyrrolidine
1,2,3,4-Tetrahydroisoquinoline
1,2,3,4-Tetrahydroisoquinoline
4-Methylaniline
1-(Diphenylmethyl)piperazine
7.12
a
b
Conversion reported at a catalyst loading of 1 mol%. Conversion reported at a catalyst loading of 2 mol%.
proceeded similarly to those of the unsubstituted phenylallene was that virtually no hydroamination activity was observed at
(Table 6; entries 6.1 and 6.7), and so this allene was not further 1 mol% and 2 mol% catalyst loading. This may be caused by the
tested. p-Fluorophenylallene underwent hydroamination at a presence of the extra lone pair on 1-methylpiperazine, which
slower rate than phenylallene for all amines investigated, could bind to the palladium center, thus inhibiting catalysis. As
yielding the linear allylamine as the only isolable product at 5 with all other substrates, 4-methylaniline again reacted slowly
mol% catalyst loading (Table 6). Initial formation of the compared to the secondary amines. Thus, because of the
branched allylamine in the hydroamination of p-uo- extremely slow rate of hydroamination when anilines are used,
rophenylallene with morpholine followed by its subsequent only the linear isomer was isolated from the hydroamination of
conversion to the linear product was readily observed via NMR p-uorophenylallene with 4-methylaniline (Table 6; entry 7.7).
spectroscopy (Fig. 2). Isolation of signicant yields of the Finally, we also used 1-(diphenylmethyl)piperazine in the
branched isomer was achieved for morpholine, piperidine, hydroamination of p-uorophenylallene, which produced the
pyrrolidine, and 1,2,3,4-tetrahydroisoquinoline (Table 6; entries monouorinated derivative of cinnarizine in nearly quantitative
7.1.1–7.5.1) through careful control of catalyst loading and conversion (Table 6; entry 7.12). Given the simplicity of the
reaction time. Despite many attempts, isolation of the branched synthesis of this pharmaceutical derivative, it is easy to envision
isomer in the hydroamination of p-uorophenylallene with 1- the utility of allene hydroamination in the synthesis of
methylpiperazine proved to be ineffective. The main problem compounds for structure–activity relationship studies.
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Fig. 2 Hydroamination yields N-(1-(4-fluorophenyl)-2-propenyl)-morpholine (7.1A), which subsequently isomerizes to N-(3-(4-fluorophenyl)-2-propenyl)-morpholine
(7.1B) at low catalyst loading.
Ultimately, hydroamination of p-uorophenylallene was very [3IPtBuPd(allyl)]OTf is a remarkably effective catalyst for the
successful with selective isolation of either branched or linear selective hydroamination of allenes, providing a high yielding
allylamine products controlled merely by catalyst loading and route to many new allylamine products.
reaction time.
General methods and instrumentation
Conclusion
All manipulations involving [(3IPtBu)Pd(allyl)]OTf were per-
The palladium complex [3IPtBuPd(allyl)]OTf efficiently catalyzed formed under an inert N2 atmosphere using standard glove box
the room-temperature hydroamination of a diverse range of and Schlenk techniques. Benzene-d6 was dried over sodium
˚
allenes with alkyl amines. This catalytic process is an effective metal, freeze–pump–thawed three times, and stored over 4 A
˚
means for the synthesis of branched allylamines in near quanti- molecular sieves. Chloroform-d was dried and stored over 4 A
tative conversion for many of the allenes investigated. The molecular sieves. Styrene, allylbenzene, 1,1-diphenylethylene,
branched N-allylamines are the kinetic products of these hydro- 4-methoxystyrene, bromoform, cyclohexylallene and 1,1-dime-
amination reactions and possess terminal vinylic moieties, thylallene were purchased from Sigma-Aldrich and each was
making them especially useful species for further derivatization. used as received. 4-Fluorostyrene was purchased from P212121,
Mono- and 1,1-diphenylallene gave the linear (thermodynamic) LLC and used as received. Amines were purchased from
products in most cases. Utilizing this selectivity for the linear commercial sources and dried over calcium hydride, either neat
product, we successfully synthesized the medicinally active (liquids) or as solutions in methylene chloride (solid amines).
compound cinnarizine (Scheme 1), as well as its monouorinated Liquid amines were freeze–pump–thawed three times, and
derivative N-(diphenylmethyl)-N0-(3-(4-uorophenyl)-2-propenyl)- vacuum distilled. Solutions of solid amines in methylene
piperazine (Table 6; entry 7.12). A number of other piperazine chloride were freeze–pump–thawed three times, ltered and the
based allylamines were also isolated. Hydroamination alone or methylene chloride removed via reduced pressure. Non-
coupled with hydrogenation could prove to be atom economical commercially available allenes were dried as a solution in
ways of building complex piperazine based therapeutics. The use pentane using CaH2, ltered and the pentane removed via
˚
of p-uorophenylallene was especially interesting since catalyst reduced pressure. Silica gel (porosity: 60 A, particle size: 40–63
loading and reaction time could be adjusted to allow for the mm) was purchased from Sorbent Technologies and used as
1
selective isolation of either the branched or linear hydro- received. H and 13C NMR data were obtained on a 600 MHz
amination product in high yield. Both branched and linear Inova NMR or a 400 MHz VXRS NMR spectrometer at ambient
1
allylamines are desirable compounds due to their applicability as temperature at 599.9 MHz for H NMR and 150.8 MHz for 13C
building blocks in the synthesis of heterocycles, natural products, NMR and 399.95 MHz for 1H NMR and 100.56 MHz for 13C
and pharmaceuticals. In conclusion, we have shown that NMR, respectively. All spectra were taken using C6D6 or CDCl3
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as the NMR solvent. 1H NMR shis are given relative to the 4.7 Hz, 4H), 2.27 (t, 4.7 Hz, 4H), 0.90 (s, 6H); 13C{1H} NMR
residual solvent resonances at 7.16 ppm and 7.26 ppm, (C6D6): d 146.2, 112.2, 67.8, 57.8, 46.8, 22.2; HRMScalc: 156.1388
respectively, and 13C NMR shis are given relative to C6D6 for C9H18NO [M + H]+; HRMSmeas: 156.1391.
(128.1 ppm) and CDCl3 (77.16 ppm). Unless otherwise noted, all
N-(1,1-Dimethyl-2-propenyl)-N0-methylpiperazine (1.3A). 1H
3
coupling constants are JHH. High resolution mass spectrom- NMR (CDCl3): d 5.83 (dd, 16.7 Hz, 9.9 Hz, 1H), 5.02 (d, 9.9 Hz,
etry, using electrospray ionization, was performed at the 1H), 5.01 (d, 16.7 Hz, 1H), 2.57 (br. s, 4H), 2.41 (br. s, 4H), 2.25
University of Illinois Mass Spectrometry Laboratory, Urbana, IL. (s, 3H), 1.11 (s, 6H); 13C{1H} NMR (CDCl3): d 146.2, 117.7, 58.2,
56.1, 46.2, 46.1, 22.6; HRMScalc: 169.1705 for C10H21N2 [M + H]+;
Catalyst and allene synthesis
HRMSmeas: 169.1705.
N-(1,1-Dimethyl-2-propenyl)-cyclohexylamine (1.10A).70 1H
NMR (CDCl3): d 5.76 (dd, 17.3 Hz, 10.8 Hz, 1H), 4.97 (d, 17.3 Hz,
1H), 4.94 (d, 10.8 Hz, 1H), 2.33–2.29 (m, 1H), 1.73–1.71 (m, 2H),
1.66–1.63 (m, 2H), 1.54–1.52 (m, 1H), 1.26–1.16 (m, 3H), 1.13 (s,
6H), 1.08–1.02 (m, 2H); 13C{1H} NMR (CDCl3): d 147.4, 111.4,
54.9, 51.7, 36.9, 28.0, 25.9, 25.0; HRMScalc: 168.1752 for C11H22N
[M + H]+; HRMSmeas: 168.1753.
The ligand 3IPtBu and catalyst [(3IPtBu)Pd(allyl)]OTf were prepared
according to previously published procedures.49 2-Chlorocy-
clopent-1-enecarbaldehyde, the key precursor to 3IPtBu, was
prepared via a recently published improved procedure.51 All non-
commercially available allenes were synthesized via the ring
opening of the corresponding dibromocyclopropane.57 Formation
of the desired products was established via NMR spectroscopy for
phenylallene,58 diphenylallene,58 benzylallene,58 p-methoxy-
phenylallene58 and p-uorophenylallene.59
N-(1,1-Dimethyl-2-propenyl)-2-octylamine (1.11A).70 1H NMR
(C6D6): d 5.79 (dd, 17.6 Hz, 10.8 Hz, 1H), 4.97 (d, 17.6 Hz, 1H),
4.93 (d, 10.8 Hz, 1H), 2.61–2.56 (m, 1H), 1.40–1.21 (m, 10H), 1.11
(s, 3H), 1.10 (s, 3H), 1.01 (d, 6.4 Hz, 3H), 0.91 (t, 6.4 Hz, 3H); 13
C
General catalytic procedure
{1H} NMR (C6D6): d 148.3, 110.8, 54.6, 47.8, 40.5, 32.4, 30.0, 28.2,
27.9, 26.7, 24.4, 23.1, 14.4; HRMScalc: 198.2222 for C13H28N [M +
H]+; HRMSmeas: 198.2220.
All manipulations were performed in a nitrogen lled glove box.
To a solution of [(3IPtBu)Pd(allyl)]OTf (14.8 mg, 0.025 mol, 5 mol
%) in benzene-d6 (0.8 ml), amine (0.5 mmol) was added.
Subsequently, the allene (0.5 mmol) was added and the reaction
was sealed and allowed to react at 25 ꢀC. Conversion and
product ratios were determined via 1H NMR spectroscopy aer
the time noted. Conversion percentage reects comparison
of peak integrations for unreacted allene and the two
product regioisomers. Ratios given for the two regioisomeric
product allylamines are reported as whole numbers
summing to 100%. Both values are subject to the usual exper-
imental error associated with 1H NMR experiments, perhaps as
high as ꢁ5%. The products were subsequently puried via
column chromatography (silica gel; 5 : 1 pentane–ethyl acetate)
to remove the catalyst and any unreacted starting materials
prior to nal 1H and 13C{1H} NMR spectroscopic analysis of the
products.
N-(1-Cyclohexyl-2-propenyl)-morpholine (2.1A). 1H NMR
(CDCl3): d 5.59 (dt, 3Jtrans ¼ 17.2 Hz, 3Jcis ¼ 3JC–H ¼ 10.0 Hz, 1H),
3
2
3
5.20 (dd, Jcis ¼ 10.0 Hz, JHH ¼ 2.0 Hz, 1H), 4.98 (dd, Jtrans
¼
2
17.2 Hz, JHH ¼ 2.0 Hz, 1H), 3.71–3.62 (m, 4H), 2.54–2.42 (m,
2H), 2.39–2.30 (m, 3H), 1.84–1.74 (m, 1H), 1.73–1.62 (m, 4H),
1.54–1.45 (m, 1H), 1.25–0.77 (m, 5H); 13C{1H} NMR (CDCl3): d
136.0, 118.6, 74.5, 67.6, 50.4, 37.6, 30.8, 29.5, 27.0, 26.6, 26.5;
HRMScalc
210.1853.
: 210.1858 for C13H24NO [M + :
H]+; HRMSmeas
N-(1-Cyclohexyl-2-propenyl)-piperidine (2.2A). 1H NMR
(CDCl3): d 5.60 (dt, 3Jtrans ¼ 17.2 Hz, 3Jcis ¼ 3JC–H ¼ 10.0 Hz, 1H),
3
2
3
5.15 (dd, Jcis ¼ 10.0 Hz, JHH ¼ 2.0 Hz, 1H), 4.93 (dd, Jtrans
¼
2
17.2 Hz, JHH ¼ 2.0 Hz, 1H), 2.50–2.46 (m, 2H), 2.36 (t, 9.2 Hz,
1H), 2.25–2.22 (m, 2H), 1.90 (d, 3JC–H ¼ 10.0 Hz, 1H), 1.77–1.38
(m, 11H), 1.27–1.06 (m, 3H), 0.95–0.74 (m, 2H); 13C{1H} NMR
(CDCl3): d 136.8, 117.6, 74.8, 50.8, 38.2, 30.9, 30.4, 27.1, 26.70,
26.69, 26.65, 25.2; HRMScalc: 208.2065 for C14H26N [M + H]+;
Characterization of hydroamination products
N-(1,1-Dimethyl-2-propenyl)-piperidine (1.2A),47 N-(1,1-dimethyl- HRMSmeas: 208.2060.
2-propenyl)-pyrrolidine (1.4A),60 N-(1,1-dimethyl-2-propenyl)-
N-(1-Cyclohexyl-2-propenyl)-N0-methylpiperazine (2.3A). 1H
1,2,3,4-tetrahydroisoquinoline (1.5A),47 N-(1-phenyl-3-buten-2-yl)- NMR (CDCl3): d 5.58 (dt, 3Jtrans ¼ 17.2 Hz, 3Jcis ¼ 3JC–H ¼ 10.4 Hz,
morpholine (3.1A),61 N-(3,3-diphenylallyl)-piperidine (4.2B),62 N- 1H), 5.15 (dd, 3Jcis ¼ 10.4 Hz, 2JHH ¼ 1.6 Hz, 1H), 4.96 (dd, 3Jtrans
2
(1-phenyl-2-propenyl)-morpholine (5.1A),63 N-(3-phenyl-2-pro- ¼ 17.2 Hz, JHH ¼ 1.6 Hz, 1H), 2.56–2.27 (m, 9H), 2.24 (s, 3H),
penyl)-morpholine (5.1B),64 N-(3-phenyl-2-propenyl)-piperidine 1.79 (d, 3JC–H ¼ 10.4 Hz, 1H), 1.72–0.87 (m, 10H); 13C{1H} NMR
(5.2B),65 N-(3-phenyl-2-propenyl)-N0-methylpiperazine (5.3B),31 N- (CDCl3): d 136.4, 118.3, 74.1, 55.8, 46.3, 38.0, 30.9, 29.9, 29.7,
(3-phenyl-2-propenyl)-pyrrolidine (5.4B),60 N-(3-phenyl-2-pro- 27.1, 26.7, 26.6; HRMScalc: 223.2174 for C14H27N2 [M + H]+;
penyl)-1,2,3,4-tetrahydroisoquinoline (5.5B),66 N-(3-phenyl-2-pro- HRMSmeas: 223.2175.
penyl)-4-methylaniline
(5.7B),67
N-(3-phenyl-2-propenyl)-4-
N-(1-Cyclohexyl-2-propenyl)-pyrrolidine (2.4A). 1H NMR
methoxyaniline (5.9B),31 N-(diphenylmethyl)-N0-(3-phenyl-2-pro- (CDCl3): d 5.68 (dt, 3Jtrans ¼ 16.8 Hz, 3Jcis ¼ 3JC–H ¼ 10.2 Hz, 1H),
3
2
3
penyl)-piperazine (5.12B),68 and N-(1-(4-uorophenyl)-2-propenyl)- 5.05 (dd, Jcis ¼ 10.2 Hz, JHH ¼ 2.4 Hz, 1H), 4.99 (dd, Jtrans
¼
2
piperidine (7.2A)69 were identied by comparison to published 16.8 Hz, JHH ¼ 2.4 Hz, 1H), 2.43–2.42 (br. s, 4H), 2.34 (dd,
NMR data.
3JC–H ¼ 10.2 Hz, 5.7 Hz, 1H), 1.80–1.23 (m, 10H), 1.22–0.89 (m,
N-(1,1-Dimethyl-2-propenyl)-morpholine (1.1A). 1H NMR 5H); 13C{1H} NMR (CDCl3): d 138.0, 117.0, 74.5, 51.8, 40.6, 31.2,
(C6D6): d 5.71 (dd, 17.2 Hz, 10.7 Hz, 1H), 4.90 (dd, 10.7 Hz, 2JHH 27.7, 27.0, 26.9, 26.8, 23.3; HRMScalc: 194.1909 for C13H24N [M +
¼ 2.0 Hz, 1H), 4.85 (dd, 17.2 Hz, JHH ¼ 2.0 Hz, 1H), 3.56 (t, H]+; HRMSmeas: 194.1910.
2
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N-(1-Cyclohexyl-2-propenyl)-1,2,3,4-tetrahydroisoquinoline
N-(3,3-Diphenylallyl)-1,2,3,4-tetrahydroisoquinoline (4.5B).
(2.5A). 1H NMR (CDCl3): d 7.12–7.02 (m, 4H), 5.70 (dt, 3Jtrans ¼ 17.2 1H NMR (CDCl3): d 7.46–7.41 (m, 14H), 6.39 (t, 5.2 Hz, 1H), 3.67
Hz, 3Jcis ¼ 3JC–H ¼ 10.4 Hz, 1H), 5.26 (dd, 3Jcis ¼ 10.4 Hz, 2JHH ¼ 2.4 (s, 2H), 3.30 (d, 5.2 Hz, 2H), 2.96 (t, 5.9 Hz, 2H), 2.77 (t, 5.9 Hz,
Hz, 1H), 5.10 (dd, 3Jtrans ¼ 17.2 Hz, 2JHH ¼ 2.4 Hz, 1H), 3.77 (d, 14.7 2H); 13C{1H} NMR (CDCl3): d 130.0, 128.8, 128.7, 128.3, 128.2,
Hz, 1H), 3.58 (d, 14.7 Hz, 1H), 2.94–2.79 (m, 3H), 2.67–2.54 (m, 127.4, 127.39, 127.30, 126.7, 126.5, 126.2, 125.7, 65.3, 57.3, 50.9,
2H), 1.95 (d, 3JC–H ¼ 10.4 Hz, 1H), 1.78–1.60 (m, 5H), 1.32–0.87 (m, 29.4; HRMScalc: 326.1909 for C24H24N [M + H]+; HRMSmeas
:
5H); 13C{1H} NMR (CDCl3): d 136.2, 136.1, 135.2, 128.9, 126.9, 326.1906.
125.9, 125.6, 118.7, 73.7, 53.3, 46.3, 38.4, 30.9, 30.3, 27.1, 26.7;
HRMScalc: 256.2065 for C18H26N [M + H]+; HRMSmeas: 256.2058.
N-(3-Phenyl-2-propenyl)-3-methylaniline (5.6B). 1H NMR
(CDCl3): d 7.40 (d, 8.8 Hz, 2H), 7.34 (t, 8.8 Hz, 2H), 7.25 (t, 6.8 Hz,
N-(1-Phenyl-3-buten-2-yl)-piperidine (3.2A). 1H NMR (CDCl3): 1H), 7.11 (t, 8.8 Hz, 1H), 6.64 (d, 16.0 Hz, 1H), 6.58 (d, 6.8 Hz,
d 7.27–7.23 (m, 2H), 7.18–7.15 (m, 3H), 5.77–5.68 (m, 1H), 5.04 1H), 6.52 (s, 1H), 6.49 (d, 6.8 Hz, 1H), 6.35 (dt, 16.0 Hz, 5.6 Hz,
(dd, 10.0 Hz, 2JHH ¼ 1.6 Hz, 1H), 4.80 (dd, 17.2 Hz, 2JHH ¼ 1.6 Hz, 1H), 3.94 (dd, 5.6 Hz, 1.7 Hz, 2H), 3.78 (br. s, 1H), 2.32 (s, 3H);
1H), 3.09–3.02 (m, 2H), 2.71–2.59 (m, 3H), 2.55–2.49 (m, 2H), 13C{1H} NMR (CDCl3): d 148.3, 139.3, 137.1, 131.7, 129.4, 128.8,
1.64–1.56 (m, 4H), 1.48–1.43 (m, 2H); 13C{1H} NMR (CDCl3): d 127.7, 127.4, 126.6, 118.8, 114.1, 110.4, 46.5, 21.9; HRMScalc
:
140.2, 136.8, 129.7, 128.2, 126.0, 117.9, 70.9, 50.9, 38.6, 26.6, 25.0; 224.1439 for C16H18N [M + H]+; HRMSmeas: 224.1447.
HRMScalc: 216.1752 for C15H22N [M + H]+; HRMSmeas: 216.1761.
N-(3-Phenyl-2-propenyl)-3-methoxyaniline (5.8B). 1H NMR
N-(1-Phenyl-3-buten-2-yl)-N0-methylpiperazine (3.3A). 1H (CDCl3): d 7.37 (d, 6.8 Hz, 2H), 7.35 (s, 1H), 7.31 (t, 7.9 Hz, 2H),
NMR (CDCl3): d 7.32–7.22 (m, 2H), 7.18–7.10 (m, 3H), 5.69 (dt, 7.23 (t, 6.8 Hz, 1H), 7.10 (t, 7.9 Hz, 1H), 6.62 (d, 15.6 Hz, 1H),
3Jtrans ¼ 16.8 Hz, 3Jcis ¼ 3JC–H ¼ 9.9 Hz, 1H), 5.04 (d, 3Jcis ¼ 9.9 Hz, 6.37–6.28 (m, 4H), 3.93 (dd, 6.8 Hz, 1.2 Hz, 2H), 3.77 (s, 3H); 13
C
1H), 4.83 (d, 3Jtrans ¼ 16.8 Hz, 1H), 3.08–3.02 (m, 2H), 2.68–2.45 {1H} NMR (CDCl3): d 160.9, 136.9, 132.3, 130.3, 128.78, 128.77,
(m, 9H), 2.29 (s, 3H); 13C{1H} NMR (CDCl3): d 139.6, 136.5, 127.8, 126.5, 126.4, 106.4, 103.7, 99.8, 55.3, 46.9; HRMScalc
:
129.6, 128.1, 125.9, 118.1, 70.1, 55.5, 49.6, 46.1, 38.3; HRMScalc
231.1861 for C15H23N2 [M + H]+; HRMSmeas: 231.1867.
:
240.1388 for C16H18NO [M + H]+; HRMSmeas: 240.1397.
N-(3-(4-Methoxyphenyl)-2-propenyl)-morpholine (6.1B). 1H
N-(1-Phenyl-3-buten-2-yl)-pyrrolidine (3.4A). 1H NMR (CDCl3): NMR (CDCl3): d 7.30 (d, 8.8 Hz, 2H), 6.84 (d, 8.8 Hz, 2H), 6.46 (d,
d 7.27–7.23 (m, 2H), 7.18–7.12 (m, 3H), 5.73–5.64 (m, 1H), 4.94 (dd, 15.6 Hz, 1H), 6.10 (dt, 15.6 Hz, 7.2 Hz, 1H), 3.79 (s, 3H), 3.74–
10.3 Hz, 2JHH ¼ 1.9 Hz, 1H), 4.77 (dd, 17.2 Hz, 2JHH ¼ 1.9 Hz, 1H), 3.72 (m, 4H), 3.21 (d, 7.2 Hz, 2H), 2.48 (br. s, 4H); 13C{1H} NMR
3.14 (dd, 2JHH ¼ 13.2 Hz, 4.0 Hz, 1H), 2.88 (dt, 9.5 Hz, 4.0 Hz, 1H), (CDCl3): d 128.2, 128.1, 115.8, 115.6, 93.1, 79.2, 68.1, 31.8, 22.8,
2.68–2.59 (m, 5H), 1.84–1.74 (m, 4H); 13C{1H} NMR (CDCl3): d 14.3; HRMScalc: 234.1494 for C14H20NO2 [M + H]+; HRMSmeas
:
139.5, 138.9, 129.9, 128.2, 126.1, 117.2, 70.8, 52.1, 41.1, 23.5; 234.1504.
HRMScalc: 202.1596 for C14H20N [M + H]+; HRMSmeas: 202.1593.
N-(3-(4-Methoxyphenyl)-2-propenyl)-4-methylaniline (6.7B).70
N-(1-Phenyl-3-buten-2-yl)-1,2,3,4-tetrahydroisoquinoline (3.5A). 1H NMR (CDCl3): d 7.28 (d, 6.0 Hz, 2H), 6.98 (d, 6.0 Hz, 2H), 6.82
1H NMR (CDCl3): d 7.30–7.12 (m, 8H), 7.05 (d, 7.4 Hz, 1H), 5.81 (d, 6.0 Hz, 2H), 6.57 (d, 6.0 Hz, 2H), 6.53 (d, 12.0 Hz, 1H), 6.17
(ddd, 17.4 Hz, 12.0 Hz, 10.2 Hz, 1H), 5.15 (dd, 10.2 Hz, 2JHH ¼ 1.7 (dt, 12.0 Hz, 6.0 Hz, 1H), 3.85 (d, 6.0 Hz, 2H), 3.77 (s, 3H), 2.23 (s,
Hz, 1H), 4.96 (dd, 17.4 Hz, 2JHH ¼ 1.7 Hz, 1H), 3.86 (d, 2JHH ¼ 10.2 3H); 13C{1H} NMR (CDCl3): d 130.9, 129.8, 127.8, 127.5, 126.8,
Hz, 1H), 3.80 (d, 2JHH ¼ 10.2 Hz, 1H), 3.33–3.29 (m, 1H), 3.18 (dd, 125.0, 115.3, 114.2, 114.0, 113.3, 55.3, 46.7, 22.5; HRMScalc
:
12.0 Hz, 10.2 Hz, 1H), 3.04–3.00 (m, 1H), 2.94–2.93 (m, 2H), 2.84– 254.1545 for C17H20NO [M + H]+; HRMSmeas: 254.1553.
2.79 (m, 2H); 13C{1H} NMR (CDCl3): d 139.8, 136.4, 135.5, 134.9,
N-(1-(4-Fluorophenyl)-2-propenyl)-morpholine (7.1A). 1H
129.8, 128.9, 128.4, 126.9, 126.24, 126.21, 125.8, 118.6, 69.8, 53.1, NMR (CDCl3): d 7.37–7.33 (m, 2H), 7.05 (t, 3JHH ¼ 3JHF ¼ 8.7 Hz,
46.9, 38.8, 29.9; HRMScalc: 264.1752 for C19H22N [M + H]+; 2H), 5.95–5.86 (m, 1H), 5.26 (dd, 16.7 Hz, JHH ¼ 1.7 Hz, 1H),
2
HRMSmeas: 264.1750.
5.15 (dd, 10.1 Hz, 2JHH ¼ 1.7 Hz, 1H), 3.74–3.72 (m, 4H), 3.65 (d,
1
N-(3,3-Diphenylallyl)-morpholine (4.1B). H NMR (CDCl3): d 9.9 Hz, 1H), 2.51 (br. s, 2H), 2.37–2.33 (m, 2H); 13C{1H} NMR
7.41–7.33 (m, 4H), 7.31–7.25 (m, 4H), 7.17–7.15 (m, 2H), 6.21 (t, (CDCl3): d 162.1 (d, 1JCF ¼ 243.8 Hz), 139.6, 129.5 (d, 3JCF ¼ 7.8
4
2
6.0 Hz, 1H), 3.74–3.72 (m, 4H), 3.08 (d, 6.0 Hz, 2H), 2.45 (br. s, Hz), 128.9 (d, JCF ¼ 7.0 Hz), 116.8, 115.6 (d, JCF ¼ 20.0 Hz),
4H); 13C{1H} NMR (CDCl3): d 130.0, 128.5, 128.4, 127.6, 127.5, 74.7, 67.2, 51.9; HRMScalc: 222.1294 for C13H17FNO [M + H]+;
125.6, 67.2, 57.9, 53.9; HRMScalc: 280.1701 for C19H22NO [M + HRMSmeas: 222.1298.
H]+; HRMSmeas: 280.1705.
N-(3-(4-Fluorophenyl)-2-propenyl)-morpholine (7.1B). 1H
N-(3,3-Diphenylallyl)-N0-methylpiperazine (4.3B). 1H NMR NMR (CDCl3): d 7.31 (dd, 8.8 Hz, JHF ¼ 5.6 Hz, 2H), 6.99
4
(CDCl3): d 7.41–7.16 (m, 10H), 6.28 (t, 6.8 Hz, 1H), 3.05 (d, 6.8 (t, 3JHH ¼ 3JHF ¼ 8.8 Hz, 2H), 6.48 (d, 15.9 Hz, 1H), 6.16 (dt, 15.9
Hz, 2H), 2.38 (br. s, 4H), 1.63–1.57 (m, 4H), 1.42 (br. s, 3H); 13
C
Hz, 6.7 Hz, 1H), 3.74–3.72 (m, 4H), 3.13 (d, 6.7 Hz, 2H), 2.49 (br.
{1H} NMR (CDCl3): d 129.9, 128.2, 127.3, 127.2, 127.1, 126.9, s, 4H); 13C{1H} NMR (CDCl3): d 162.5 (d, 1JCF ¼ 245.5 Hz), 133.4,
3
2
58.3, 54.8, 26.1, 24.4.
133.2, 128.0 (d, JCF ¼ 7.9 Hz), 125.9, 115.7 (d, JCF ¼ 21.9 Hz),
N-(3,3-Diphenylallyl)-pyrrolidine (4.4B). 1H NMR (CDCl3): d 67.2, 61.6, 53.9; HRMScalc: 222.1294 for C13H17FNO [M + H]+;
7.39–7.16 (m, 10H), 6.22 (t, 6.8 Hz, 1H), 3.74–3.72 (m, 4H), 3.08 HRMSmeas: 222.1298.
(d, 6.8 Hz, 2H), 2.45 (br. s, 4H); 13C{1H} NMR (CDCl3): d 129.8,
N-(3-(4-Fluorophenyl)-2-propenyl)-piperidine (7.2B). 1H NMR
4
3
128.3, 128.2, 127.4, 127.3, 125.7, 57.8, 57.1, 53.8; HRMScalc
264.1752 for C19H22N [M + H]+; HRMSmeas: 264.1761.
:
(CDCl3): d 7.31 (dd, 8.4 Hz, JHF ¼ 6.6 Hz, 2H), 6.97 (t, JHH ¼
3JHF ¼ 8.4 Hz, 2H), 6.45 (d, 15.6 Hz, 1H), 6.21 (dt, 15.6 Hz, 6.4
20716 | RSC Adv., 2013, 3, 20708–20718
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N-(Diphenylmethyl)-N0-(3-(4-uorophenyl)-2-propenyl)-pipera-
zine (7.12B). 1H NMR (CDCl3): d 7.40 (d, 7.9 Hz, 4H), 7.32–7.28 (m,
2H), 7.26 (t, 7.9 Hz, 4H), 7.16 (t, 7.9 Hz, 2H), 6.99–6.96 (m, 2H),
6.45 (d, 15.6 Hz, 1H), 6.17 (dt, 15.6 Hz, 6.6 Hz, 1H), 4.24 (s, 1H),
3.14 (d, 6.6 Hz, 2H), 2.52 (br. s, 8H); 13C{1H} NMR (CDCl3): d 162.4
(d, 1JCF ¼ 246.6 Hz), 142.9, 133.3 (d, 4JCF ¼ 3.8 Hz), 132.0, 128.6,
128.2, 128.0 (d, 3JCF ¼ 8.1 Hz), 127.1, 126.5, 115.6 (d, 2JCF ¼ 21.6
Hz), 76.4, 61.2, 53.7, 52.2; HRMScalc: 387.2237 for C26H28FN2 [M +
H]+; HRMSmeas: 387.2232.
Hz, 1H), 3.10 (d, 6.4 Hz, 2H), 2.40 (br. s, 4H), 1.63–1.57 (m, 4H),
1
1.43 (br. s, 2H); 13C{1H} NMR (CDCl3): d 162.4 (d, JCF ¼ 246.1
4
3
Hz), 133.4 (d, JCF ¼ 3.8 Hz), 131.8, 128.0 (d, JCF ¼ 7.9 Hz),
126.9, 115.6 (d, 2JCF ¼ 21.4 Hz), 61.9, 54.8, 26.1, 24.5; HRMScalc
:
220.1502 for C14H19FN [M + H]+; HRMSmeas: 220.1500.
N-(3-(4-Fluorophenyl)-2-propenyl)-N0-methylpiperazine (7.3B).
1H NMR (CDCl3): d 7.32–7.25 (m, 2H), 7.02–6.70 (m, 2H), 6.46 (d,
15.9 Hz, 1H), 6.16 (dt, 15.9 Hz, 6.9 Hz, 1H), 3.12 (d, 6.9 Hz, 2H),
2.49 (br. s, 8H), 2.27 (s, 3H); 13C{1H} NMR (CDCl3): d 162.4 (d,
1JCF ¼ 246.5 Hz), 132.2, 129.5 (d, 4JCF ¼ 7.8 Hz), 128.0 (d, 3JCF ¼ 8.3
Hz), 126.4 (d, 5JCF ¼ 2.5 Hz), 115.6 (d, 2JCF ¼ 21.5 Hz), 61.2, 55.3,
Acknowledgements
53.3, 46.2; HRMScalc: 235.1611 for C14H20FN2 [M + H]+; HRMSmeas
235.1609.
:
This material is based upon work supported by the National
Science Foundation under CHE-0841611. We would like to
acknowledge Dr Glenn Kuchenbeiser for his early contributions
to this project related to catalytic screening.
N-(1-(4-Fluorophenyl)-2-propenyl)-pyrrolidine (7.4A). 1H
NMR (CDCl3): d 7.30 (dd, 8.3 Hz, 4JHF ¼ 5.9 Hz, 2H), 6.98 (t, 3JHF
¼ 3JHH ¼ 8.3 Hz, 2H), 5.97 (ddd, 17.4 Hz, 10.2 Hz, 8.9 Hz, 1H),
5.17 (dd, 17.4 Hz, 2JHH ¼ 2.0 Hz, 1H), 4.99 (dd, 10.2 Hz, 2JHH
¼
2.0 Hz, 1H), 3.56 (d, 8.9 Hz, 1H), 2.48–2.45 (m, 2H), 2.35–2.32
(m, 2H), 1.77–1.72 (m, 4H); 13C{1H} NMR (CDCl3): d 162.2 (d,
1JCF ¼ 244.8 Hz), 141.5, 129.2 (d, 3JCF ¼ 7.5 Hz), 128.3, 115.4 (d,
2JCF ¼ 21.4 Hz), 115.1, 74.5, 53.2, 23.5; HRMScalc: 206.1345 for
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