Zirconium-Mediated Coupling Reactions of Amines and Enol or Allyl Ethers: Synthesis of Allyl- and Homoallylamines

Article abstract of DOI:10.1002/chem.200305374

An easy and efficient zirconium-mediated synthesis of allylamines from simple amines and enol ethers is described. This strategy also allows the synthesis of amino alcohol derivatives containing a Z double bond in their structure when 2,3-dihydrofuran is used. Simple conventional modification of these amino alcohols leads to 2-substituted piperidine derivatives. By applying this approach, a formal total synthesis of the alkaloid coniine is easily achieved from a protected butylamine. Finally, the zirconium-mediated reaction of amines and allyl phenyl ether furnishes homoallylamines or amino ethers depending on the structure of the starting amine.

Full text of DOI:10.1002/chem.200305374

FULL PAPER
Zirconium-Mediated Coupling Reactions of Amines and Enol or Allyl
Ethers: Synthesis of Allyl- and Homoallylamines
Josÿ Barluenga,* Fÿlix RodrÌguez, LucÌa çlvarez-Rodrigo, Josÿ M. Zapico, and
Francisco J. FaÊanµs[a]
Abstract: An easy and efficient zirconi-
um-mediated synthesis of allylamines
from simple amines and enol ethers is
described. This strategy also allows the
synthesis of amino alcohol derivatives
containing a Z double bond in their
structure when 2,3-dihydrofuran is
used. Simple conventional modification
of these amino alcohols leads to 2-sub-
stituted piperidine derivatives. By ap-
plying this approach,a formal total
synthesis of the alkaloid coniine is
easily achieved from a protected butyl-
amine. Finally,the zirconium-mediated
reaction of amines and allyl phenyl
ether furnishes homoallylamines or
amino ethers depending on the struc-
ture of the starting amine.
Keywords: allylamines
¥
CꢀC
coupling ¥ coniine ¥ zirconium
Introduction
Nitrogen-containing organic molecules are without any
doubt among the most important compounds in organic
chemistry. Proof of this can be found in the fundamental bi-
ological activity of compounds such as amino acids[1] or al-
kaloids.[2] For the synthesis of these kinds of molecules,allyl-
amines are considered ideal building blocks,and thus,in
recent years many methods for the racemic and asymmetric
synthesis of allylamines have appeared.[3] These compounds
are also used as starting materials in important industrial
processes.[4] In this context,Buchwald et al. described some
years ago an elegant method to prepare allylamine deriva-
tives from simple amines.[5] As shown in Scheme 1,this proc-
ess relies on the formation of a h2-imine zirconocene com-
plex from a methylzirconocene amide and its entrapment
with an alkyne to give an azazirconacyclopentene derivative,
which affords the desired allylamine on protic work-up.[6]
This sequence constitutes a powerful synthetic transfor-
mation since it accomplishes both a CꢀH activation and a
carbometalation process,reactions which are difficult to ach-
ieve with conventional reagents. However,the method has
some limitations. For example,simple allylamines,unsubsti-
tuted at the 2- and 3-positions are not experimentally easy
Scheme 1. Zirconium-mediated coupling of amines and alkynes. Cp=
cyclopentadiene.
(or are impossible) to obtain since it would require the use
of acetylene as the alkyne counterpart. Also,the use of un-
symmetrical alkynes generally leads to mixtures of re-
gioisomers. Finally,the method always affords geometrically
pure E allylamines but Z allylamines cannot be obtained.
As part of a program concerned with the development of
new reactions involving zirconocene complexes,[7] we wish to
report herein our findings on the reaction of enol ethers
with h2-imine zirconocene complexes. This unprecedented
reaction allowed us to overcome some of the limitations
mentioned above to obtain unsubstituted allylamines and Z
allylamines. Moreover,an extensive study on the reaction of
the zirconocene complexes with allyl ethers is presented.
[a] Prof. Dr. J. Barluenga,Dr. F. RodrÌguez,L. çlvarez-Rodrigo,
J. M. Zapico,Dr. F. J. FaÊanµs
Results and Discussion
Instituto Universitario de QuÌmica Organometµlica ™Enrique Moles∫
Unidad Asociada al CSIC,Universidad de Oviedo
Juliµn ClaverÌa 8,33006 Oviedo (Spain)
Fax : (+34)985-103450
E-mail: barluenga@sauron.quimica.uniovi.es
Insertion reactions of enol ethers and imine zirconocene
complexes: Successive treatment of amines 1 with one
equivalent of butyllithium at ꢀ408C and zirconocene methyl
109
Chem. Eur. J. 2004, 10,109 116
DOI: 10.1002/chem.200305374
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FULL PAPER
chloride at temperatures ranging between ꢀ50 and 208C,
followed by addition of the appropriate enol ether 2 and fur-
ther heating to 808C in a sealed tube,led after 18 h to allyl
amines 3 with high yields in most cases (Scheme 2 and
Table 1).
Thus,the reaction with 23,-dihydrofuran ( 2c) led to amino
alcohols 3i n (Table 1,entries 9 14). It is important to note
that in all cases we observed the exclusive formation of the
allylamine with Z stereochemistry in the double bond. This
stereochemistry is opposite to that obtained from the previ-
ously reported coupling of alkynes and h2-imine zircono-
cene complexes,where the exclusive formation of E olefins
was observed.[5] Next,we tried to extend this reaction to
other cyclic enol ethers such as 3,4-dihydro-2H-pyran. How-
ever,the reaction did not produce the expected coupling
products and unreacted starting amines 1 were recovered in
all cases.[8]
Scheme 2. Zirconium-mediated coupling of amines 1 and enol ethers 2.
Synthesis of allylamines 3. THF=tetrahydrofuran.
Synthesis of 2-substituted piperidines: Formal total synthesis
of coniine: Taking into account the results described above
about the zirconium-mediated
coupling reactions of amines
Table 1. Zirconium-mediated synthesis of allylamines 3 from amines 1 and enol ethers 2.
and 2,3-dihydrofuran (2c) to
give compounds 3i n contain-
ing a Z double bond in their
structures,we devised a simple
method to easily transform
these products into 2-substitut-
ed piperidines (Scheme 3).[9]
Thus,for example,the reaction
between amino alcohols 3k,l,n,
obtained from the zirconium-
mediated reaction described
above,and tosyl chloride in di-
chloromethane led to piperi-
dine derivatives 4a c in a single
step and high yield,as shown in
Scheme 4.
Entry
Starting
amine
R1
R2
Enol
ether
R3
R4
R5
Product
R6
Yield
[%][a]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1b
1c
1d
1e
1f
1g
1a
1a
1b
1d
1e
1f
Ph
Ph
Ph
Ph
Bn[b]
Ph
Ph
Ph
Ph
Ph
Ph
Bn
Ph
Ph
H
Me
Pr
2a
2a
2a
2a
2a
2a
2a
2b
2c
2c
2c
2c
2c
2c
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Me
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
H
H
H
H
H
H
H
H
83
68
70
96
85
87
84
61
68
60
62
64
75
70
Ph
Ph
Ar[c]
Ar[d]
H
H
Me
Ph
(CH2)2
(CH2)2OH
(CH2)2OH
(CH2)2OH
(CH2)2OH
(CH2)2OH
(CH2)2OH
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
Ph
Ar[c]
Ar[d]
1g
[a] Yield based on starting amine 1. [b] Bn=benzyl. [c] Ar=4-MeOC6H4. [d] Ar=4-BrC6H4.
The first examples were performed with butyl vinyl ether
(2a) and the results were satisfactory in all the cases at-
tempted (Table 1,entries 1 7). When the reaction was car-
ried out with an a-substituted enol ether,2-methoxypropene
(2b),the reaction only proceeded with N-methylaniline (1a;
Table 1,entry 8). With all the other amines tried the reac-
tion did not produce the expected allyl amines analogous to
Scheme 3. Strategy devised for the synthesis of 2-substituted piperidines.
3h and unreacted starting amine was recovered. Interesting
results were obtained when cyclic enol ethers were used.
Abstract in Spanish: Se describe una sÌntesis fµcil y eficiente
de alilaminas a partir de aminas sencillas y enol ÿteres pro-
movida por zirconio. Esta estrategia tambiÿn permite la sÌnte-
sis de derivados de aminoalcoholes que contienen en su es-
tructura un doble enlace con estereoquÌmica Z cuando se usa
2,3-dihidrofurano. Una modificaciÛn simple y convencional
de estos aminoalcoholes da lugar a derivados de piperidina
sustituidas en posiciÛn 2. Aplicando esta aproximaciÛn, se ha
logrado la sÌntesis formal del alcaloide coniÌna a partir de
una butilamina protegida. Finalmente, la reacciÛn de aminas
y alil fenil ÿter promovida por zirconio genera homoalilami-
nas o aminoÿteres dependiendo de la estructura de la amina
de partida.
Scheme 4. Synthesis of 2-substituted piperidines 4. Ts=toluene-4-sulfo-
nyl=tosyl,DMAP =4-dimethylaminopyridine,DCM =dichloromethane.
Next,we decided to apply this strategy to the synthesis of
the alkaloid coniine.[10] Thus,starting from PMP-protected
butylamine 1h,we carried out the coupling reaction with
2,3-dihydrofuran (2c) to obtain allylamine 3o in 76% yield
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Zirconium-Mediated Coupling Reactions
109 116
(Scheme 5). Tosylation of the hydroxy group and subsequent
cyclization led,in a single step,to unsaturated piperidine 4d
in 79% yield. Further hydrogenation of the double bond
quantitatively gave the N-protected piperidine 5 (PMP-pro-
tected coniine).
gioselectively on the zirconium carbon bond of 7. More-
over,the insertion of enol ether 2a occurs with the appro-
priate orientation to furnish the zirconaazacyclopentane de-
rivative 8. Both electronic and steric effects favor this orien-
tation of the enol ether as depicted in I (bottom of
Scheme 6).[11] The intermediate 8 can undergo b elimination
of the alkoxy group to give zirconocene derivative 9,which
after hydrolysis gives rise to allylamine 3.
The mechanism for the reaction of amines 1 with 2,3-dihy-
drofuran (2c) is analogous to that described above. Howev-
er,the exclusive formation of Z amino alcohols 3i o,could
be justified by the formation of bicyclic intermediate 10,
which after the b elimination process leads to the Z-oxaaza-
zirconacyclooctene 11 and finally to amino alcohols 3i o
with Z configuration in the double bond (Scheme 7).
Scheme 5. Formal total synthesis of coniine. PMP=para-methoxyphenyl.
Thus,this sequence describes the formal synthesis of the
alkaloid coniine from protected butylamine 1h in only three
steps (Scheme 4; note that the zirconium-mediated coupling
is a one-pot process and can be considered as a single step).
Following this strategy,many other biologically active com-
pounds and natural products with structures related to 4 or
5 can be easily prepared.
Scheme 7. Prposed mechanism for the formation of Z alkene derivatives
3i o.
Insertion reactions of allyl ethers and imine zirconocene
complexes: After our study on the coupling reactions of
enol ethers and h2-imine zirconocene complexes we turned
our attention to the behavior of allyl ethers with this kind of
complexes. In a paper that appeared in 1990,[12] Whitby and
co-workers described a single example of the reaction of the
h2-imine complex derived from tetrahydroquinoline and an
allyl ethyl ether to give a mixture of two products (a homo-
allylamine and an amino ether). As far as we know this is
the only example of this reaction reported in the literature.
We decided to initiate a study into the zirconium-mediated
coupling reaction of different amines 1 and allyl phenyl
ether (12). Thus,successive treatment of amines 1 with one
equivalent of butyllithium and zirconocene methyl chloride
in the conditions described above,followed by addition of
excess allyl phenyl ether (12) and further heating to 808C in
a sealed tube,led to mixtures of homoallylamines 13 and
amino ethers 14 in different ratios depending on the struc-
ture of the initial amine 1 (Scheme 8 and Table 2).
Mechanism of the insertion reaction of enol ethers and
imine zirconocene complexes: The zirconium-mediated for-
mation of allylamines 3 from amines 1 can be explained by
the mechanism depicted in Scheme 6. Treatment of amine 1
with butyllithium generates the corresponding lithium
amide,which reacts with zirconocene methyl chloride to
give zirconocene complex 6. A cyclometalation with subse-
quent elimination of methane leads to h2-imine complex 7.
Insertion of the double bond of enol ether 2a takes place re-
Scheme 8. Zirconium-mediated coupling of amines 1 and allyl phenyl
ether 12.
Analysis of Table 2 showed us several interesting features.
For example,the use of N-methylaniline (1a) as starting ma-
terial basically led to amino ether 14a in 70% yield (ratio
Scheme 6. Top: Proposed mechanism for the formation of allylamines 3.
Bottom: Orientation of the allyl ether during the insertion process.
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FULL PAPER
Table 2. Zirconium-mediated synthesis of homoallylamines 13 and amino
ethers 14 from amines 1 and allyl phenyl ether 12.
Entry
Starting
amine
R1
R2
R3
Product
Yield
[%][a]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1i
Ph
Ph
Ph
Ph
Ph
Ph
Bn
Ph
Ph
H
Me
Pr
iPr
Me
Ph
Ph
H
H
H
H
Me
H
H
H
H
14a
70[b]
18/52
26/52
81
73
96
86
95
84
13b/14b
13c/14c
13d
13e
13f
13g
13h
13i
1j
1d
1e
1f
4-MeOC6H4
4-BrC6H4
1g
[a] Yield based on starting amine 1. [b] The crude mixture of the reac-
tion showed a 14:1 mixture of 14a/13a by 1H NMR spectroscopy. The
major diastereisomer 14a was easily separated.
Scheme 10. Proposed mechanism for the formation of homoallylamines
13 and amino ethers 14.
14a:13a,14:1; Table 2,entry 1). It has to be noted that the
starting amine 1a is unsubstituted in the a position (R2 =
R3 =H). Moreover,−more substituted× amines 1b (R2 =Me)
and 1c (R2 =Pr) led to mixtures of homoallylamines 13b,c
and amino ethers 14b,c,respectively (Table 2,entries 23, ).
Finally,the sterically more demanding amines 1i (R2 =iPr)
and 1j (R2 =R3 =Me),and aryl-substituted amines 1d g ex-
clusively led to homoallylamines 13d i (Table 2,entries 4
9). From these results,it seems that the bulkiness of groups
R2 and R3 in amines 1 is directly related with the formation
of homoallylamines 13 or amino ethers 14. Thus,formation
of 14 is favored when the starting amine 1 contains small R2
Thus,when R 2 =R3 =H,approach of the allyl ether to
7
takes place with the alkoxy group oriented far from the zir-
conocene moiety to avoid steric interactions with the Cp
groups; this gives intermediate 17A as the main product.
2
On the other hand,when the bulkiness of R increases or R2
and R3 ¼
6
H,intermediate 17B is formed as the major or ex-
clusive regioisomer. Presumably,in these cases the steric in-
teractions between the alkoxy and R2/R3 groups are more
important than the interaction between the alkoxy and the
Cp groups. Intermediate 17A is stable and its hydrolysis
generates amino ether 14. On the other hand,intermediate
17B can evolve through a process of b elimination of the
alkoxy group to give zirconocene derivative 18,which after
hydrolysis gives homoallylamine 13 (Scheme 10).
2
and R3 groups and,on the contrary,bigger R and R3 groups
favor the formation of 13.
Finally,in Scheme 9 two examples are depicted that are
intended to show that this zirconium-mediated coupling re-
action might be useful to access more elaborate frameworks
Formation of compounds 16 from amines 1a,d and 15 fol-
lows the same mechanism. As indicated before,this reaction
gives a single product when 1a is used as the starting materi-
al,but a mixture of two diastereiosomers is observed from
amine 1d. This fact can be explained as depicted in
Scheme 11. Thus,we propose that the insertion reaction of
Scheme 9. Synthesis of amino alcohols 16 from amines 1a,d and ether
15.
from simple starting materials.[13] Thus,the reaction of
amines 1a,d with the−symmetric allyl ether× 1,4-dihydro-1,4-
epoxynaphthalene (15) led to amino alcohols 16a,b,respec-
tively,in high yield. Interestingly,compound 16a was ob-
tained as a single diastereoisomer while 16b was isolated as
a 1.6:1 mixture of two diastereiosomers.
Mechanism of the insertion reaction of allyl ethers and
imine zirconocene complexes: In the first place,we must
consider the h2-imine complex 7 as described before (see
Scheme 6). Insertion of the double bond of allyl ether 12
leads to the two regioisomers 17A and 17B depending on
the orientation of 12 during the insertion step (Scheme 10).
Scheme 11. Proposed mechanism for the formation of amino alcohols 16.
the double bond of 15 into 7 takes place from the less-hin-
dered face of 15. Moreover,an initial coordination of the
oxygen atom of 15 to the zirconium atom can also be in-
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Zirconium-Mediated Coupling Reactions
109 116
ture and an excess of the appropriate enol ether 2 (10 mmol) was added.
The sealed tube containing the reaction mixture was heated to 808C for
18 h. The reaction was cooled to room temperature,worked up by addi-
tion of water (20 mL) and then extracted with diethyl ether (3î10 mL).
The combined organic layers were dried over anhydrous sodium sulphate
and concentrated,and the residue was purified by column chromatogra-
phy to give compounds 3. Compound 3a is commercially available and
its analytical data were compared with those of an authentic sample. An-
alytical data for compounds 3b,[14] 3d,[15] 3e,[16] and 3h[17] were in com-
plete accordance with literature values.
voked to justify the coordination of the double bond of 15
from the face where the oxygen atom is placed. However,
two different orientations of 7 are possible and two inter-
mediates 19A and 19B can be formed. Each of these inter-
mediates undergoes b elimination of the alkoxy group to fi-
nally generate a mixture of compounds 16 and diast-16. For
1a, R2 is H,in which case 16 and diast-16 are the same prod-
uct. Only if R2 ¼
6
H,can the two diastereiosomers be ob-
served (for example,with 1d).
N-(1-Propyl-2-propenyl)aniline (3c): Amine 1c (0.15 g,1 mmol) was
treated with BuLi (0.75 mL,1.2 mmol) and [Cp 2Zr(Me)Cl] (0.34 g,
1.2 mmol). This was followed by addition of butyl vinyl ether (2a;
0.76 mL,10 mmol). After the extractive work-up,the resulting crude
product was purified by silica gel column chromatography (hexane/ethyl
Conclusions
acetate (10:1)) to give 3c as a pale yellow oil. Rf =0.57 (hexane/ethyl ace-
We have described a new,easy,and efficient strategy to gen-
erate allylamines from simple amines and enol ethers
through the formation of a h2-imine zirconocene complex.
The use of 2,3-dihydrofuran as the enol ether counterpart al-
lowed access to new amino alcohol derivatives containing a
Z double bond in their structure. Further conventional mod-
ification of these amino alcohols permitted the synthesis of
piperidine derivatives closely related with the structure of
many alkaloids and other biologically active products. As an
example,a three-step formal total synthesis of coniine from
PMP-protected butylamine was achieved. Moreover,a study
of the zirconium-mediated coupling reactions of amines and
allyl ethers was carried out. Thus,it was observed that this
reaction could generate homoallylamines or amino ethers
depending on the structure of the starting amine. The zirco-
nium-promoted reactions of amines with both enol and allyl
ethers can be formally considered as a sequential CaꢀH acti-
vation of the amine followed by a nucleophilic substitution
of the alkoxy group. Moreover,all the products obtained
following the strategies described here are of high interest
in organic chemistry. Investigations directed toward the de-
velopment of asymmetric,and also catalytic,versions of
these processes are in progress.
1
tate (5:1)); H NMR (300 MHz,CDCl ): d=7.38 7.20,6.88 6.62 (2îm,5
3
H; ArH),5.87 (ddd, J=16.4,10.8,6.5 Hz,1H; C H=CH2),5.34 (d, J=
16.4 Hz,1H; CH =CHH),5.24 (d, J=10.1 Hz,1H; CH =CHH),3.95 (q,
J=6.2 Hz,1H; NHC H),3.72 (brs,1H; NH),1.80 1.45 (m,4H;
(CH2)2CH3),1.08 (t, J=7.0 Hz,3H; CH 3) ppm; 13C NMR (100 MHz,
CDCl3): d=147.4,140.0,128.9,116.8,114.7,113.1,55.4,37.8,18.9,
13.8 ppm; HRMS (EI): calcd for C12H17N: 175.1361; found: 175.1364; ele-
mental analysis: calcd (%) for C12H17N: C 82.23,H 9.78,N 7.99; found:
C 82.34,H 9.69,N 7.96.
N-[1-(4-Methoxyphenyl)-2-propenyl]aniline (3f): Amine 1f (0.23 g,
1 mmol) was treated with BuLi (0.75 mL,1.2 mmol) and [Cp 2Zr(Me)Cl]
(0.34 g,1.2 mmol). This was followed by addition of butyl vinyl ether ( 2
a; 0.76 mL,10 mmol). After the extractive work-up,the resulting crude
product was purified by silica gel column chromatography (hexane/ethyl
acetate (7:1)) to give 3f as a pale yellow oil. Rf =0.32 (hexane/ethyl ace-
tate (10:1)); 1H NMR (300 MHz,CDCl 3): d=7.40 6.60 (m,9H; ArH),
6.08 (ddd, J=16.2,10.2,5.8 Hz,1H; C H=CH2),5.33 (d, J=16.2 Hz,1H;
CH=CHH),5.27 (d, J=10.2 Hz,1H; CH =CHH),4.95 (d, J=5.8 Hz,1H;
NHCH),4.05 (brs,1H; NH),3.84 (s,3H; OCH
3) ppm; 13C NMR
(100 MHz,CDCl 3): d=158.7,147.1,139.0,133.8,128.9,128.1,117.3,
115.6,113.9,113.4,60.0,55.1 ppm; HRMS (EI): calcd for C
16H17NO:
239.1310; found: 239.1310; elemental analysis: calcd (%) for C16H17NO:
C 80.30,H 7.16,N 5.85; found: C 80.41,H 7.07,N 5.93.
N-[1-(4-Bromophenyl)-2-propenyl]aniline (3g): Amine 1g (0.28 g,
1 mmol) was treated with BuLi (0.75 mL,1.2 mmol) and [Cp 2Zr(Me)Cl]
(0.34 g,1.2 mmol). This was followed by addition of butyl vinyl ether ( 2
a; 0.76 mL,10 mmol). After the extractive work-up,the resulting crude
product was purified by silica gel column chromatography (hexane/ethyl
acetate (7:1)) to give 3g as a pale yellow oil. Rf =0.37 (hexane/ethyl ace-
tate (10:1)); 1H NMR (300 MHz,CDCl 3): d=7.60 6.50 (m,9H; ArH),
6.06 (ddd, J=16.4,10.6,6.0 Hz,1H; C H=CH2),5.29 (d, J=16.4 Hz,1H;
CH=CHH),5.28 (d, J=10.6 Hz,1H; CH =CHH),4.95 (d, J=6.0 Hz,1H;
Experimental Section
NHCH),4.08 (brs,1H; NH) ppm;
13C NMR (100 MHz,CDCl 3): d=
General: All reactions involving organometallic species were carried out
under an atmosphere of dry N2 with oven-dried glassware and syringes.
THF,hexane and Et 2O were distilled over sodium benzophenone ketyl
under N2 immediately prior to use,and CH 2Cl2 was distilled over P2O5.
The solvents used in column chromatography,hexane and EtOAc,were
distilled before use. TLC was performed on aluminum-backed plates
coated with silica gel 60 with F254 indicator (Scharlau). Flash column
chromatography was carried out on silica gel 60,230 240 mesh. 1H NMR
(200,300,400 MHz) and 13C NMR (50.5,75.5,100 MHz) spectra were
measured at room temperature on Bruker AC-200,AC-300 and AMX-
400 instruments,respectively,with tetramethylsilane ( d=0.0, 1H NMR)
or CDCl3 (d=77.00, 13C NMR) as the internal standard. Carbon multi-
plicities were assigned by DEPT techniques. High-resolution mass spec-
tra (HRMS) were determined on a Finnigan MAT 95 spectrometer. Ele-
mental analyses were carried out on a Perkin Elmer 2400 microanalyzer.
146.7,140.7,138.5,131.7,129.0,128.7,121.0,117.8,116.5,113.4,
60.1 ppm; HRMS (EI): calcd for C15H14BrN: 287.0304; found: 287.0301;
elemental analysis: calcd (%) for C15H14BrN: C 62.52,H 4.90,N 4.86;
found: C 62.62,H 4.80,N 4.79.
(Z)-5-Phenylamino-3-penten-1-ol (3i): Amine 1a (0.11 g,1 mmol) was
treated with BuLi (0.75 mL,1.2 mmol) and [Cp 2Zr(Me)Cl] (0.34 g,
1.2 mmol). This was followed by addition of enol ether 2c (0.76 mL,
10 mmol). After the extractive work-up,the resulting crude product was
purified by silica gel column chromatography (hexane/ethyl acetate
(2:1)) to give 3i as a pale yellow oil. Rf =0.19 (hexane/ethyl acetate
(2:1)); 1H NMR (300 MHz,CDCl 3): d=7.40 7.20,6.90 6.55 (2îm,5H;
ArH),5.76 (dt, J=10.8,6.5 Hz,1H; NHCHC H=CH),5.65 (dt, J=10.8,
6.7 Hz,1H; NHCHCH =CH),3.79 (d, J=6.5 Hz,2H; NHC H2),3.67 (t,
J=6.7 Hz,2H; C H2OH),3.40 (brs,1H; OH),2.41 (q,
J=6.7 Hz,2H;
CH=CHCH2) ppm; 13C NMR (100 MHz,CDCl 3): d=147.9,129.0,128.9,
128.8,117.5,113.0,61.4,40.8,30.7 ppm; HRMS (EI): calcd for
C11H15NO: 177.1154; found: 177.1150; elemental analysis: calcd (%) for
C11H15NO: C 74.54,H 8.53,N 7.90; found: C 74.66,H 8.46,N 7.96.
General procedure for the preparation of compounds 3: Butyllithium
(1.2 mmol) was added to a stirred solution of the required amine 1
(1 mmol) in dry THF (10 mL) at ꢀ408C. After stirring at this tempera-
ture for 30 min,the solution was added dropwise through a cannula to a
stirred solution of bis(cyclopentadienyl)zirconium methyl chloride
(1.2 mmol) in dry THF (10 mL) in a sealed tube at ꢀ508C. After 30 min
at this temperature the mixture was allowed to warm to room tempera-
(Z)-5-Phenylamino-3-hexen-1-ol (3j): Amine 1b (0.12 g,1 mmol) was
treated with BuLi (0.75 mL,1.2 mmol) and [Cp 2Zr(Me)Cl] (0.34 g,
1.2 mmol). This was followed by addition of enol ether 2c (0.76 mL,
113
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim

J. Barluenga et al.
FULL PAPER
10 mmol). After the extractive work-up,the resulting crude product was
purified by silica gel column chromatography (hexane/ethyl acetate
(2:1)) to give 3j as a yellow oil. Rf =0.25 (hexane/ethyl acetate (2:1));
1H NMR (300 MHz,CDCl 3): d=7.30 7.18,6.82 6.59 (2îm,5H; ArH),
5.59 5.39 (m,2H; C H=CH),4.29 (quintet, J=6.6 Hz,1H; NHC H),3.68
(t, J=6.4 Hz,2H; C H2OH),2.95 (brs,2H; OH and NH),2.55 2.35 (m,2
(Z)-5-(4-Methoxyphenylamino)-3-octen-1-ol (3o): Amine 1h (0.18 g,
1 mmol) was treated with BuLi (0.75 mL,1.2 mmol) and [Cp 2Zr(Me)Cl]
(0.34 g,1.2 mmol). This was followed by addition of enol ether 2c
(0.76 mL,10 mmol). After the extractive work-up,the resulting crude
product was purified by silica gel column chromatography (hexane/ethyl
acetate (2:1)) to give 3o as a pale yellow oil. Rf =0.30 (hexane/ethyl ace-
tate (2:1)); 1H NMR (300 MHz,CDCl 3): d=6.75 (d, J=9.0 Hz,2H;
H; CH=CHCH2),1.31 (d,
(100 MHz,CDCl 3): d=147.1,136.6,129.0,126.5,117.5,113.6,61.8,46.4,
31.1,21.8 ppm; HRMS (EI): calcd for 12H17NO: 191.1310; found:
J=6.6 Hz,3H; CH 3) ppm; 13C NMR
ArH),6.58 (d, J=9.0 Hz,2H; ArH),5.47 (dt,
J=10.4,7.2 Hz,1H;
NHCHCH=CH),5.29 (t, J=10.4 Hz,1H; NHCHC H=CH),4.05 3.85 (m,
1H; NHCH),3.71 (s,3H; OCH 3),3.70 3.50 (m,2H; C H2OH),3.05 (brs,
2H; OH and NH),2.50 2.20 (m,2H; CH =CHCH2),1.70 1.20 (m,4H;
(CH2)2CH3),0.91 (t, J=6.7 Hz,3H; CH 3) ppm; 13C NMR (100 MHz,
CDCl3): d=152.0,141.2,135.1,127.2,115.3,114.4,61.6,55.3,51.6,37.7,
31.2,18.8,13.8 ppm; HRMS (EI): calcd for C 15H23NO2: 249.1729; found:
249.1733; elemental analysis: calcd (%) for C15H23NO2: C 72.25,H 9.30,
N 5.62; found: C 72.33,H 9.19,N 5.53.
C
191.1307; elemental analysis: calcd (%) for C12H17NO: C 75.35,H 8.96,N
7.32; found: C 75.41,H 8.88,N 7.41.
(Z)-5-Phenyl-5-phenylamino-3-penten-1-ol (3k): Amine 1d (0.18 g,
1 mmol) was treated with BuLi (0.75 mL,1.2 mmol) and [Cp 2Zr(Me)Cl]
(0.34 g,1.2 mmol). This was followed by addition of enol ether 2c
(0.76 mL,10 mmol). After the extractive work-up,the resulting crude
product was purified by silica gel column chromatography (hexane/ethyl
acetate (2:1)) to give 3k as a pale yellow oil. Rf =0.25 (hexane/ethyl ace-
tate (2:1)); 1H NMR (300 MHz,CDCl 3): d=7.50 6.55 (m,10H; ArH),
5.73 (dd, J=10.7,8.6 Hz,1H; NHCHC H=CH),5.60 (dt, J=10.7,7.6 Hz,
1H; NHCHCH=CH),5.21 (d, J=8.6 Hz,1H; NHC H),3.71 (t, J=
6.4 Hz,2H; C H2OH),2.80 (brs,2H; OH and NH),2.60 2.40 (m,2H;
CH=CHCH2) ppm; 13C NMR (100 MHz,CDCl 3): d=147.1,142.9,134.3,
129.0,128.6,127.7,127.0,126.4,117.6,113.6,61.6,55.5,31.3 ppm; HRMS
(EI): calcd for C17H19NO: 253.1467; found: 253.1466; elemental analysis:
calcd (%) for C17H19NO: C 80.60,H 7.56,N 5.53; found: C 80.74,H 7.47,
N 5.60.
General procedure for the preparation of compounds 4: Tosyl chloride
(1.2 mmol),Et 3N (1.5 mmol),and a catalytic amount of DMAP were
added to a solution of the appropriate amino alcohol 3 (1 mmol) in di-
chloromethane (10 mL). After stirring for 6 h the reaction was quenched
by addition of water (10 mL). The aqueous layer was separated and ex-
tracted with CH2Cl2 (3î5 mL). The combined organic layers were dried
over anhydrous sodium sulphate and concentrated,and the residue was
purified by column chromatography to give compounds 4.
1,2,3,6-Tetrahydro-1,6-diphenylpyridine (4a): Amino alcohol 3k (0.25 g,
1 mmol) was treated with TsCl (0.23 g,1.2 mmol),Et 3N (0.21 mL,
1.5 mmol),and a catalytic amount of DMAP. After the extractive work-
up,the resulting crude product was purified by silica gel column chroma-
tography (hexane/ethyl acetate (5:1)) to give 4a as a pale yellow oil. Rf =
0.55 (hexane/ethyl acetate (2:1)); 1H NMR (300 MHz,CDCl 3): d=7.42
7.18,6.97 6.75 (2îm,10H; ArH),6.11 5.95 (m,2H; C H=CH),5.19 (s,1
H; PhCH),3.69 (dt, J=12.9,5.0,1H; NC HH),3.46 (ddd, J=12.9,9.2,
(Z)-5-Benzylamino-5-phenyl-3-penten-1-ol (3l): Amine 1e (0.20 g,
1 mmol) was treated with BuLi (0.75 mL,1.2 mmol) and [Cp 2Zr(Me)Cl]
(0.34 g,1.2 mmol). This was followed by addition of enol ether 2c
(0.76 mL,10 mmol). After the extractive work-up,the resulting crude
product was purified by silica gel column chromatography (hexane/ethyl
acetate (2:1)) to give 3l as a pale yellow oil. Rf =0.35 (hexane/ethyl ace-
tate (1:2)); 1H NMR (300 MHz,CDCl 3): d=7.35 6.25 (m,10H; ArH),
5.79 (dd, J=10.7,8.7 Hz,1H; NHCHC H=CH),5.62 (dt, J=10.7,7.4 Hz,
1H; NHCHCH=CH),4.61 (d, J=8.7 Hz,1H; NHC H),3.75 (s,2H;
CH2Ph),3.75 3.55 (m,2H; C H2OH),2.78 (brs,2H; OH and NH),2.52
(dq, J=14.4,7.4 Hz,1H; CH =CHCHH),2.38 (dq, J=14.4,7.4 Hz,1H;
4.2 Hz,1H; NCH H),2.46 (ddd, J=14.5,9.2,5.0,1H; C
HHCH=CH),
2.29 2.15 (m,1H; CH HCH=CH) ppm; 13C NMR (100 MHz,CDCl ): d=
3
149.9,141.8,129.2,128.9,128.3,126.9,126.7,125.6,117.9,115.4,59.8,
42.0,24.3 ppm; HRMS (EI): calcd for
C 17H17N: 235.1355; found:
235.1351; elemental analysis: calcd (%) for C17H17N: C 86.77,H 7.28,N
5.95; found: C 86.84,H 7.21,N 5.90.
CH=CHCHH) ppm; 13C NMR (100 MHz,CDCl ): d=142.4,139.1,134.1,
3
128.3,128.1,127.6,126.9,126.8,126.7,60.8,58.1,50.5,31.3 ppm; HRMS
(EI): calcd for C18H21NO: 267.1618; found: 267.1608; elemental analysis:
calcd (%) for C18H21NO: C 80.86,H 7.92,N 5.24; found: C 80.93,H 7.82,
N 5.17.
1-Benzyl-1,2,3,6-tetrahydro-6-phenylpyridine (4b): Amino alcohol 3l
(0.30 g,1 mmol) was treated with TsCl (0.23 g,1.2 mmol),Et 3N (0.21 mL,
1.5 mmol),and a catalytic amount of DMAP. After the extractive work-
up,the resulting crude product was purified by silica gel column chroma-
tography (hexane/ethyl acetate (5:1)) to give 4b as a pale yellow oil. Rf =
0.50 (hexane/ethyl acetate (2:1)); 1H NMR (300 MHz,CDCl 3): d=7.70
7.10 (m,10H; ArH),5.92 5.80 (m,1H; CH 2CH=CH),5.67 (dd, J=9.8,
1.2 Hz,1H; CH 2CH=CH),4.05 (s,1H; PhC H),3.88 (d, J=13.6 Hz,1H;
(Z)-5-(4-Methoxyphenyl)-5-phenylamino-3-penten-1-ol (3m): Amine 1f
(0.23 g,1 mmol) was treated with BuLi (0.75 mL,1.2 mmol) and
[Cp2Zr(Me)Cl] (0.34 g,1.2 mmol). This was followed by addition of enol
ether 2c (0.76 mL,10 mmol). After the extractive work-up,the resulting
crude product was purified by silica gel column chromatography (hexane/
ethyl acetate (2:1)) to give 3m as a pale yellow oil. Rf =0.65 (hexane/
ethyl acetate (1:2)); 1H NMR (300 MHz,CDCl 3): d=7.40 6.55 (m,9H;
ArH),5.74 (dd, J=10.9,8.3 Hz,1H; NHCHC H=CH),5.59 (dt, J=10.9,
7.1 Hz,1H; NHCHCH =CH),5.18 (d, J=8.3 Hz,1H; NHC H),3.95 3.60
PhCHH),3.21 (d,
J=13.6 Hz,1H; PhCH H),3.09 2.93 (m,1H;
CHHCH=CH),2.51 2.34 (m,2H; NCH 2),2.17 2.01 (m,1H; CH HCH=
CH) ppm; 13C NMR (100 MHz,CDCl 3): d=143.5,139.4,130.4,128.5,
128.3,127.9,127.0,126.6,124.2,66.2,58.8,47.2,25.8 ppm; HRMS (EI):
calcd for C18H19N: 249.1517; found: 249.1522; elemental analysis: calcd
(%) for C18H19N: C 86.70,H 7.68,N 5.62; found: C 86.84,H 7.58,N 5.56.
(m with s at 3.82,5H; C H2OH and OCH3),2.58 2.48 (m,2H; CH
CHCH2) ppm; 13C NMR (100 MHz,CDCl 3): d=158.6,147.1,134.8,128.9,
127.5,127.3,117.6,114.0,113.6,61.8,55.1,54.9,31.3 ppm; HRMS (EI):
=
6-(4-Bromophenyl)-1,2,3,6-tetrahydro-1-phenylpyridine (4c): Amino al-
cohol 3n (0.33 g,1 mmol) was treated with TsCl (0.23 g,1.2 mmol),Et 3N
(0.21 mL,1.5 mmol),and a catalytic amount of DMAP. After the extrac-
tive work-up,the resulting crude product was purified by silica gel
column chromatography (hexane/ethyl acetate (5:1)) to give 4c as a pale
yellow oil. Rf =0.58 (hexane/ethyl acetate (2:1)); 1H NMR (300 MHz,
CDCl3): d=7.50 7.15,6.98 6.75 (2îm,9H; ArH),6.12 5.92 (m,2H;
calcd for C18H21NO2: 283.1572; found: 283.1569; elemental analysis: calcd
(%) for C18H21NO2: C 76.29,H 7.47,N 4.94; found: C 76.41,H 7.41,N
5.01.
(Z)-5-(4-Bromophenyl)-5-phenylamino-3-penten-1-ol (3n): Amine 1g
(0.28 g,1 mmol) was treated with BuLi (0.75 mL,1.2 mmol) and
[Cp2Zr(Me)Cl] (0.34 g,1.2 mmol). This was followed by addition of enol
ether 2c (0.76 mL,10 mmol). After the extractive work-up,the resulting
crude product was purified by silica gel column chromatography (hexane/
ethyl acetate (2:1)) to give 3n as a pale yellow oil. Rf =0.70 (hexane/
ethyl acetate (1:2)); 1H NMR (300 MHz,CDCl 3): d=7.60 6.50 (m,9H;
ArH),5.85 5.55 (m,2H; C H=CH),5.21 (d, J=7.6 Hz,1H; NHC H),3.70
CH=CH),5.13 (s,1H,BrC
NCHH),3.42 (ddd, J=12.5,8.9,4.5 Hz,1H; NCH H),2.55 2.38 (m,1H;
CHHCH=CH),2.31 2.17 (m,1H; CH
HCH=CH) ppm; 13C NMR
6H4CH),3.65 (dt, J=12.5,4.5 Hz,1H;
(100 MHz,CDCl 3): d=149.8,141.0,131.3,129.0,128.8,128.6,126.1,
120.5,118.5,115.9,59.4,42.3,24.4 ppm; HRMS (EI): calcd for
C17H16BrN: 313.0466; found: 313.0471; elemental analysis: calcd (%) for
C17H16BrN: C 64.98,H 5.13,N 4.46; found: C 65.06,H 5.08,N 4.40.
(t, J=6.4 Hz,2H;
C H2OH),2.62 2.36 (m,2H; CH =CHCH2) ppm;
13C NMR (100 MHz,CDCl 3): d=146.7,141.9,133.4,131.5,128.9,128.0,
120.5,117.7,113.5,61.3,54.8,31.1 ppm; HRMS (EI): calcd for
C17H18BrNO: 331.0566; found: 331.0559; elemental analysis: calcd (%)
for C17H18BrNO: C 61.46,H 5.46,N 4.22; found: C 61.56,H 5.37,N 4.30.
1,2,3,6-Tetrahydro-1-(4-methoxyphenyl)-6-propylpyridine (4d): Amino al-
cohol 3o (0.23 g,1 mmol) was treated with TsCl (0.23 g,1.2 mmol),Et 3N
(0.21 mL,1.5 mmol),and a catalytic amount of DMAP. After the extrac-
tive work-up,the resulting crude product was purified by silica gel
114
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
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Zirconium-Mediated Coupling Reactions
109 116
column chromatography (hexane/ethyl acetate (7:1)) to give 4d as a pale
yellow oil. Rf =0.75 (hexane/ethyl acetate (2:1)); 1H NMR (300 MHz,
CDCl3): d=6.93 (d, J=9.0 Hz,2H; ArH),6.85 (d, J=9.0 Hz,2H; ArH),
6.95 6.78 (m,2H; C H=CH),3.98 3.85 (m,1H; CH 3(CH2)2CH),3.78 (s,3
H; OCH3),3.39 (ddd, J=12.6,5.5,3.5 Hz,1H; NC HH),3.21 (ddd, J=
12.6,8.9,4.3 Hz,1H; NCH H),2.39 2.19 (m,1H; C HHCH=CH),2.14
1.97 (m,1H; CH HCH=CH),1.50 1.20 (m,4H; CH 3(CH2)2),0.91 (t, J=
6.7 Hz,3H; CH 3) ppm; 13C NMR (100 MHz,CDCl 3): d=152.9,144.9,
129.8,125.1,118.9,114.3,56.8,55.4,43.1,34.7,24.4,19.3,14.1 ppm;
129.1,116.9,116.5,113.0,57.7,35.5,30.7,18.5,18.3 ppm; HRMS (EI):
calcd for C13H19N: 189.1517; found: 189.1519; elemental analysis: calcd
(%) for C13H19N: C 82.48,H 10.12,N 7.40; found: C 82.55,H 10.01,N
7.36.
N-[1-(4-Bromophenyl)-3-butenyl]aniline (13i): Amine 1g (0.28 g,
1 mmol) was treated with BuLi (0.75 mL,1.2 mmol) and [Cp 2Zr(Me)Cl]
(0.34 g,1.2 mmol). This was followed by addition of allyl phenyl ether
(12; 0.27 mL,2 mmol). After the extractive work-up,the resulting crude
product was purified by silica gel column chromatography (hexane/ethyl
acetate (7:1)) to give 13i as a pale yellow oil. Rf =0.40 (hexane/ethyl ace-
tate (10:1)); 1H NMR (200 MHz,CDCl 3): d=7.57 (d,J =8.4 Hz,2H; 4-
BrC6H4),7.35 (d,J =8.4 Hz,2H; 4-BrC 6H4),7.29 6.55 (m,5H; ArH),
5.86 (ddt, J=17.0,10.0,6.7 Hz,1H; C H=CH2),5.30 (d, J=17.0 Hz,1H;
CH=CHH),5.28 (d, J=10.0 Hz,1H; CH =CHH),4.46 (dd, J=7.7,
5.2 Hz,1H; NHC H),4.28 (brs,1H; NH),2.80 2.45 (m,2H;
NHCHCH2) ppm; 13C NMR (100 MHz,CDCl 3): d=146.6,142.3,133.8,
131.3,128.8,127.8,120.3,118.3,117.3,113.2,56.2,42.7 ppm; HRMS (EI):
calcd for C16H16BrN: 301.0461; found: 301.0456; elemental analysis: calcd
(%) for C16H16BrN: C 63.59,H 5.34,N 4.63; found: C 63.63,H 5.28,N
4.68.
HRMS (EI): calcd for C15H21NO: 231.1618; found: 231.1610; elemental
analysis: calcd (%) for C15H21NO: C 77.88,H 9.15,N 6.05; found: C
78.00,H 9.09,N 5.97.
1-(4-Methoxyphenyl)-2-propylpiperidine (5): Amine 4d (0.23 g,1 mmol)
was added to a suspension of palladium (10 wt% on carbon,0.70 g) in
ethyl acetate (10 mL). The suspension was stirred under hydrogen
(1 atm) for 1 h and then filtered through a plug of silica gel to give,after
removal of the solvents,pure compound 5 as a colorless oil. Rf =0.75
(hexane/ethyl acetate (2:1)); 1H NMR (300 MHz,CDCl 3): d=6.94 (d,
J=9.0 Hz,2H; ArH),6.85 (d, J=9.0 Hz,2H; ArH),3.79 (s,3H; OCH 3),
3.47 3.31 (m,1H; CH 3(CH2)2CH),3.12 2.90 (m,2H; NCH 2),1.90 0.90
N-(2-Methyl-3-phenoxypropyl)aniline (14a): Amine 1a (0.11 g,1 mmol)
was treated with BuLi (0.75 mL,1.2 mmol) and [Cp 2Zr(Me)Cl] (0.34 g,
1.2 mmol). This was followed by addition of allyl phenyl ether (12;
0.27 mL,2 mmol). After the extractive work-up,the resulting crude prod-
uct was purified by silica gel column chromatography (hexane/ethyl ace-
tate (7:1)) to give 14a as a yellow oil. Rf =0.40 (hexane/ethyl acetate
(10:1)); 1H NMR (300 MHz,CDCl 3): d=7.55 6.66 (m,10H; ArH),4.06
(dd, J=9.0,5.2 Hz,1H; PhOC HH),4.00 (dd, J=9.0,6.3 Hz,1H;
PhOCHH),3.41 (dd, J=12.5,7.0 Hz,1H; PhNHC HH),3.25 (dd, J=
12.5,6.3 Hz,1H; PhNHCH H),2.90 (brs,1H; NH),2.55 2.30 (m,1H;
(m,10H; CH 3(CH2)2 and aliphatic ring),0.88 (t,
J=6.7 Hz,3H;
CH3) ppm; 13C NMR (100 MHz,CDCl 3): d=153.4,145.7,120.3,114.1,
57.7,55.3,47.9,30.4,28.7,25.9,20.5,19.7,14.1 ppm; HRMS (EI): calcd
for C15H23NO: 233.1780; found: 233.1781; elemental analysis: calcd (%)
for C15H23NO: C 77.21,H 9.93,N 6.00; found: C 77.26,H 9.88,N 5.97.
General procedure for the preparation of compounds 13 and 14: The
procedure is analogous to that described before for the synthesis of com-
pounds 3. Instead of addition of the appropriate enol ether,in these
cases allyl phenyl ether (12; 2 mmol) was used. Analytical data for com-
pounds 13e,[18] 13f,[19] 13 g,[20] and 13h[21] were in complete accordance
with literature values.
CHCH3),1.24 (d,
CDCl3): d=158.7,148.2,129.4,129.1,120.7,117.4,114.4,112.6,71.0,47.4,
33.0,15.3 ppm; HRMS (EI): calcd for 16H19NO: 241.1467; found:
J=6.6 Hz,3H; CH 3) ppm; 13C NMR (100 MHz,
N-(1-Methyl-3-butenyl)aniline (13b): Amine 1b (0.12 g,1 mmol) was
treated with BuLi (0.75 mL,1.2 mmol) and [Cp 2Zr(Me)Cl] (0.34 g,
1.2 mmol). This was followed by addition of allyl phenyl ether (12;
0.27 mL,2 mmol). After the extractive work-up,the resulting crude prod-
uct was purified by silica gel column chromatography (hexane/ethyl ace-
tate (10:1)) to give 13b as a pale yellow oil. Rf =0.26 (hexane/ethyl ace-
tate (20:1)); 1H NMR (300 MHz,CDCl 3): d=7.40 7.11,6.85 6.52 (2îm,
5H; ArH),5.85 5.70 (m,1H; C H=CH2),5.14 (d, J=17.0 Hz,1H; CH =
CHH),5.12 (d, J=10.0 Hz,1H; CH =CHH),3.65 3.49 (m,1H; NHC H),
2.48 2.26 (m,2H; NHCHC H2),1.22 (d, J=6.4 Hz,3H; CH 3) ppm;
13C NMR (100 MHz,CDCl 3): 147.2,134.8,129.2,117.4,116.9,113.2,47.8,
C
241.1467; elemental analysis: calcd (%) for C16H19NO: C 79.63,H 7.94,N
5.80; found: C 79.78,H 7.79,N 5.71.
N-(1,2-Dimethyl-3-phenoxypropyl)aniline (14b): Amine 1b (0.12 g,
1 mmol) was treated with BuLi (0.75 mL,1.2 mmol) and [Cp 2Zr(Me)Cl]
(0.34 g,1.2 mmol). This was followed by addition of allyl phenyl ether
(12; 0.27 mL,2 mmol). After the extractive work-up,the resulting crude
product was purified by silica gel column chromatography (hexane/ethyl
acetate (7:1)) to give 14b as a pale yellow oil. Rf =0.18 (hexane/ethyl ace-
tate (20:1)); 1H NMR (300 MHz,CDCl 3): d=7.51 6.65 (m,10H; ArH),
4.10 (dd, J=9.1,7.4 Hz,1H; PhOC HH),3.98 (dd, J=9.1,5.5 Hz,1H;
PhOCHH),3.95 3.85 (m,1H; PhNHC H),3.75 (brs,1H; NH),2.45 2.30
(m,1H; PhOCH 2CH),1.33 (d, J=5.4 Hz,3H; CH 3),1.20 (d, J=7.1 Hz,
3H; CH3) ppm; 13C NMR (100 MHz,CDCl 3): d=158.6,147.6,129.2,
129.1,120.5,116.7,114.3,112.5,69.9,50.1,37.4,17.1,12.7 ppm; HRMS
(EI): calcd for C17H21NO: 255.1623; found: 255.1628; elemental analysis:
calcd (%) for C17H21NO: C 79.96,H 8.29,N 5.49; found: C 80.08,H 8.23,
N 5.39.
40.7,20.2 ppm; HRMS (EI): calcd for
C 11H15N: 161.1204; found:
161.1205; elemental analysis: calcd (%) for C11H15N: C 81.94,H 9.38,N
8.69; found: C 82.05,H 9.28,N 8.63.
N-(1-Propyl-3-butenyl)aniline (13c): Amine 1c (0.15 g,1 mmol) was
treated with BuLi (0.75 mL,1.2 mmol) and [Cp 2Zr(Me)Cl] (0.34 g,
1.2 mmol). This was followed by addition of allyl phenyl ether (12;
0.27 mL,2 mmol). After the extractive work-up,the resulting crude prod-
uct was purified by silica gel column chromatography (hexane/ethyl ace-
tate (10:1)) to give 13c as a pale yellow oil. Rf =0.50 (hexane/ethyl ace-
tate (10:1)); 1H NMR (300 MHz,CDCl 3): d=7.25 7.10,6.73 6.54 (2îm,
5H; ArH),5.88 5.70 (m,1H; C H=CH2),5.18 5.05 (m,2H; CH =CH2),
3.60 3.35 (m,2H; NH and NHC H),2.38 2.25 (m,2H; NHCHC H2),
1.65 1.25 (m,4H; CH 3(CH2)2),0.93 (t,3H; CH
(100 MHz,CDCl 3): 162.2,147.7,134.9,129.1,117.4,116.7,113.0,52.0,
38.4,36.5,19.1,14.0 ppm; HRMS (EI): calcd for C
found: 189.1517; elemental analysis: calcd (%) for C13H19N: C 82.48,H
10.12,N 7.40; found: C 82.53,H 10.02,N 7.41.
N-[1-(1-Methyl-2-phenoxyethyl)butyl]aniline (14c): Amine 1c (0.15 g,
1 mmol) was treated with BuLi (0.75 mL,1.2 mmol) and [Cp 2Zr(Me)Cl]
(0.34 g,1.2 mmol). This was followed by addition of allyl phenyl ether
(12; 0.27 mL,2 mmol). After the extractive work-up,the resulting crude
product was purified by silica gel column chromatography (hexane/ethyl
acetate (7:1)) to give 14c as a pale yellow oil. Rf =0.41 (hexane/ethyl ace-
tate (10:1)); 1H NMR (300 MHz,CDCl 3): d=7.49 6.65 (m,10H; ArH),
3) ppm; 13C NMR
13H19N: 189.1517;
4.02 (t, J=9.0 Hz,1H; PhOC HH),3.88 (dd,
J=9.0,5.6 Hz,1H;
PhOCHH),3.77 (brs,1H; NH),3.68 3.46 (m,1 h; PhNHC H),2.42 2.39
(m,1H; C HCH3),1.70 1.30 (m,4H; (C H2)2CH3),1.10 (d, J=6.5 Hz,3
J=6.9 Hz,3H; (CH 2)2CH3) ppm; 13C NMR
N-(1-Isopropyl-3-butenyl)aniline (13d): Amine 1i (0.15 g,1 mmol) was
treated with BuLi (0.75 mL,1.2 mmol) and [Cp 2Zr(Me)Cl] (0.34 g,
1.2 mmol). This was followed by addition of allyl phenyl ether (12;
0.27 mL,2 mmol). After the extractive work-up,the resulting crude prod-
uct was purified by silica gel column chromatography (hexane/ethyl ace-
tate (10:1)) to give 13d as a pale yellow oil. Rf =0.50 (hexane/ethyl ace-
tate (10:1)); 1H NMR (300 MHz,CDCl 3): d=7.40 7.10,6.80 6.55 (2îm,
5H; ArH),5.96 5.80 (m,1H; C H=CH2),5.21 5.07 (m,2H; CH =CH2),
3.58 (brs,1H; NH),3.33 (dt, J=7.4,5.1 Hz,1H; NHC H),2.46 1.88 (m,
3H; NHCHCH2 and CH(CH3)2),1.03 (d, J=7.4 Hz,3H; CH 3),1.01 (d,
J=7.4 Hz,3H; CH 3) ppm; 13C NMR (100 MHz,CDCl 3): 148.1,135.5,
H; CHCH3),1.00 (t,
(100 MHz,CDCl 3): d=158.7,148.6,129.2,129.1,120.4,116.5,114.4,
112.8,70.2,53.9,36.5,35.2,19.9,14.0,11.7 ppm; HRMS (EI): calcd for
C19H25NO: 283.1936; found: 283.1937; elemental analysis: calcd (%) for
C19H25NO: C 80.52,H 8.89,N 4.94; found: C 80.61,H 8.86,N 5.04.
General procedure for the preparation of compounds 16: The procedure
is analogous to that described before for the synthesis of compounds 3.
Instead of addition of the appropriate enol ether,in these cases 14, -dihy-
dro-1,4-epoxynaphthalene (15; 2 mmol) was used.
115
Chem. Eur. J. 2004, 10,109 116
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim

J. Barluenga et al.
FULL PAPER
(1R*,2S*)-1,2-Dihydro-2-phenylaminomethyl-1-naphthol (16a): Amine 1
1999, 121,2933; d) B. M. Trost,R. Radinov, J. Am. Chem. Soc. 1997,
119,5962.
a
(0.11 g,1 mmol) was treated with BuLi (0.75 mL,1.2 mmol) and
[Cp2Zr(Me)Cl] (0.34 g,1.2 mmol). This was followed by addition of 14,-
dihydro-1,4-epoxynaphthalene (15; 0.29 g,2 mmol). After the extractive
work-up,the resulting crude product was purified by silica gel column
chromatography (hexane/ethyl acetate (5:1)) to give 16a as a colorless
oil. Rf =0.55 (hexane/ethyl acetate (2:1)); 1H NMR (300 MHz,CDCl 3):
d=7.50 6.70 (m,9H; ArH),6.65 (d, J=9.5 Hz,1H; ArC H=CH),5.93
(dd, J=9.5,3.2 Hz,1H; ArCH =CH),4.85 (d, J=4.9 Hz,1H; C HOH),
3.58 (dd, J=12.8,8.9 Hz,1H; NHC HH),3.45 (dd, J=12.8,5.8 Hz,1H;
[4] S. Akutagawa,K. Tani,in Catalytic Asymmetric Synthesis (Ed.: I.
Ojima),2nd ed.,Wiley-VCH,Weinheim,Germany,
2000,p. 145.
[5] a) S. L. Buchwald,B. T. Watson,M. W. Wannamaker,J. C. Dewan, J.
Am. Chem. Soc. 1989, 111,4486. For an enantioselective version,
see: b) R. B. Grossman,W. M. Davis,S. L. Buchwald, J. Am. Chem.
Soc. 1991, 113,2321.
[6] For an excellent study on the formation of h2-imine zirconocene
complexes from amines,see: N. Coles,M. C. J. Harris,R. J. Whitby,
J. Blagg, Organometallics 1994, 13,190.
NHCHH),3.22 (brs,2H; OH and NH),2.98 2.84 (m,1H; CH
CHCH) ppm; 13C NMR (100 MHz,CDCl 3): d=147.8,136.0,132.4,129.1,
128.1,128.0,127.4,127.0,126.1,117.6,113.2,69.7,43.7,39.3 ppm; HRMS
=
[7] a) J. Barluenga,R. Sanz,F. J. FaÊanµs, Chem. Eur. J. 1997, 3,1324;
b) J. Barluenga,R. Sanz,F. J. FaÊanµs, J. Org. Chem. 1997, 62,5953;
(EI): calcd for C17H17NO: 251.1309; found: 251.1305; elemental analysis:
calcd (%) for C17H17NO: C 81.24,H 6.82,N 5.57; found: C 81.31,H 6.78,
N 5.49.
(1R*,2S*)-1,2-Dihydro-2-(1-phenyl-1-phenylaminoethyl)-1-naphthol (16
b): Amine 1d (0.18 g,1 mmol) was treated with BuLi (0.75 mL,
1.2 mmol) and [Cp2Zr(Me)Cl] (0.34 g,1.2 mmol). This was followed by
addition of 1,4-dihydro-1,4-epoxynaphthalene (15; 0.29 g,2 mmol). After
the extractive work-up,the resulting crude product was purified by silica
gel column chromatography (hexane/ethyl acetate (5:1)) to give 16b as a
c) J. Barluenga,R. Sanz,F. J. FaÊanµs,
J. Chem. Soc. Chem.
Commun. 1995,1009; d) J. Barluenga,R. Sanz,F. J. FaÊanµs, Z. Na-
turforsch. Teil B 1995, 50,312; e) J. Barluenga,R. Sanz,R. Gon-
zµlez,F. J. FaÊanµs, J. Chem. Soc. Chem. Commun. 1994,989.
[8] The same behavior was observed in the reaction of h2-alkyne zirco-
nocene complexes and enol ethers: T. Takahashi,D. Y. Kondakov,
Z. Xi,N. Suzuki, J. Am. Chem. Soc. 1995, 117,5871.
[9] 2-Substituted piperidine subunits are widely found in biologically
active molecules and natural products: a) A. Numata,T. Ibuka,in
The Alkaloids, Vol. 31 (Ed.: A. Brossi),Academic Press,New York,
1987. For some recent reviews,see: b) S. Laschat,T. Dickner, Syn-
thesis 2000,1781; c) A. Mitchinson,A. Nadin, J. Chem. Soc. Perkin
Trans. 1 2000,2862.
[10] Coniine is a common synthetic target. For some selected examples,
see: a) A. B. Charette,M. Grenon,A. Lemire,M. Pourasraf,J.
Martel, J. Am. Chem. Soc. 2001, 123,11829; b) T. J. Wilkinson,
N. W. Stehle,P. Beak, Org. Lett. 2000, 2,155; c) M. T. Reding,S. L.
Buchwald, J. Org. Chem. 1998, 63,6344; d) A. R. Katritzky,G. Qiu,
B. Yang,P. J. Steel, J. Org. Chem. 1998, 63,6699; e) M. J. Munchhof,
A. I. Meyers, J. Org. Chem. 1995, 60,7084.
[11] The same electronic effects have been invoked to explain the results
of the hydroboration reaction of enol ethers: E. Negishi, Organome-
tallics in Organic Synthesis,John Wiley & Sons,New York, 1980,
p. 297.
colorless oil and as mixture of two diastereiosomers. Rf =0.60 (hexane/
1
ethyl acetate (2:1)); major diastereoisomer: H NMR (300 MHz,CDCl ):
3
d=7.50 6.60 (m,15H; ArH and ArC H=CH),6.15 (dd, J=9.7,2.2 Hz,1
H; ArCH=CH),5.00 4.92 (m,1H; C HOH),4.64 4.51 (m,1H; NHC H),
2.93 2.84 (m,1H; CH =CHCH) ppm; minor diastereiosomer: 1H NMR
(300 MHz,CDCl 3): d=7.50 6.60 (m,15H; ArH and ArC H=CH),5.92
(dd, J=9.6,2.9 Hz,1H; ArCH =CH),4.88 (d, J=7.1 Hz,1H; C HOH),
4.71 (d, J=3.8 Hz,1H; NHC H),3.04 2.95 (m,1H; CH =CHCH) ppm;
13C NMR (100 MHz,CDCl 3): d=147.0 (maj),146.9 (min),141.7 (maj),
141.1 (min),136.2 (maj),136.0 (min),132.6 (min),132.2 (maj),129.3,
128.5,128.4,127.7,127.6,127.4,127.0,126.7,126.5,126.4,117.5 (maj),
117.4 (min),113.9 (min),113.6 (maj),69.6 (maj),59.5 (min),57.5 (maj),
47.4 (maj),45.8 (min) ppm (maj =major diastereoisomer,min =minor di-
astereoisomer); HRMS (EI): calcd for C23H21NO: 327.1633; found:
327.1618; elemental analysis: calcd (%) for C23H21NO: C 84.37,H 6.46,
N 4.28; found: C 84.46,H 6.35,N 4.18.
[12] N. Coles,R. J. Whitby,J. Blagg, Synlett 1990,271.
[13] A large number of bioactive molecules possess a tetrahydronaphtha-
lene core,for example,the antidepressant sertraline (M. Lautens,T.
Rovis, J. Org. Chem. 1997, 62,5246,and references therein) and the
anticancer agent podophyllotoxin (A. Kamal,N. L. Gayatri, Tetrahe-
dron Lett. 1996, 37,3359,and references therein).
Acknowledgement
[14] F. Ozawa,H. Okamoto,S. Kawagishi,S. Yamamoto,T. Minami,M.
Yoshifuji, J. Am. Chem. Soc. 2002, 124,10968.
[15] M. Johannsen,K. A. Joergensen, J. Org. Chem. 1994, 59,214.
Financial support for this work was provided by the DirecciÛn General
de InvestigaciÛn CientÌfica y Tÿcnica (DGICYT) of Spain (BQU-2001
3853) and the Ministerio de EducaciÛn y Cultura of Spain (grant to L.A.-
R.). F.R. thanks the MCYT (Programa RamÛn y Cajal) for funding.
[16] R. Takeuchi,N. Ue,K. Tanabe,K. Yamashita,N. Shiga,
Chem. Soc. 2001, 123,9525.
J. Am.
[17] Y. Yoshida,Y. Tanabe, Synthesis 1997,533.
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Synthesis 2002,
Received: July 24,2003 [F5374]
1999, 121,6761; c) Y. Donde,L. E. Overman,
J. Am. Chem. Soc.
116
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
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