Catalytic asymmetric intramolecular hydroamination of alkynes in the presence of a catalyst system consisting of Pd(0)-methyl Norphos (or tolyl Renorphos)-benzoic acid

Article abstract of DOI:10.1021/jo801785r

(Chemical Equation Presented) Enantiomerically pure methyl Norphos (A), tolyl Norphos (B), CF₃ Norphos (C), methyl Renorphos (D), and tolyl Renorphos (E) were synthesized and used as chiral bisphosphine ligands for the catalyst system, Pd₂(dba)₃·CHCl₃/PhCOOH, in an intramolecular hydroamination of aminoalkynes 15. Among the Norphos series, methyl Norphos (A) was the best ligand for the hydroamination, and the corresponding five- and six-membered nitrogen heterocycles 16 were obtained in high yields with high enantioselectivities. Among the Renorphos series, tolyl Renorphos (E) gave the best result; both methyl Norphos (A) and tolyl Renorphos (E) afforded high yields and high enantioselectivities. NMR investigation using Me-Norphos revealed that this ligand was oxidized gradually in the presence of Pd₂(dba)₃·CHCl₃ in C₆D ₆ even under the conditions using Ar atmosphere to give Me-Norphos oxide, which prevented the intramolecular hydroamination. On the other hand, Me-Norphos was rather stable in C₆D₆ in the absence of the palladium catalyst under Ar atmosphere and was not converted to its oxide even after 3 days. The gradual oxidation of ligands (A and E) in the presence of the Pd catalyst is perhaps a reason why 20 mol % of A or E was needed to obtain high yields and high ee's of 16.

Full text of DOI:10.1021/jo801785r

Catalytic Asymmetric Intramolecular Hydroamination of Alkynes in
the Presence of a Catalyst System Consisting of Pd(0)-Methyl
Norphos (or Tolyl Renorphos)-Benzoic Acid
Meda Narsireddy and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
yoshi@mail.tains.tohoku.ac.jp
ReceiVed August 17, 2008
Enantiomerically pure methyl Norphos (A), tolyl Norphos (B), CF3 Norphos (C), methyl Renorphos
(D), and tolyl Renorphos (E) were synthesized and used as chiral bisphosphine ligands for the catalyst
system, Pd2(dba)3 · CHCl3/PhCOOH, in an intramolecular hydroamination of aminoalkynes 15. Among
the Norphos series, methyl Norphos (A) was the best ligand for the hydroamination, and the corresponding
five- and six-membered nitrogen heterocycles 16 were obtained in high yields with high enantioselectivities.
Among the Renorphos series, tolyl Renorphos (E) gave the best result; both methyl Norphos (A) and
tolyl Renorphos (E) afforded high yields and high enantioselectivities. NMR investigation using Me-
Norphos revealed that this ligand was oxidized gradually in the presence of Pd2(dba)3 · CHCl3 in C6D6
even under the conditions using Ar atmosphere to give Me-Norphos oxide, which prevented the
intramolecular hydroamination. On the other hand, Me-Norphos was rather stable in C6D6 in the absence
of the palladium catalyst under Ar atmosphere and was not converted to its oxide even after 3 days. The
gradual oxidation of ligands (A and E) in the presence of the Pd catalyst is perhaps a reason why 20 mol
% of A or E was needed to obtain high yields and high ee’s of 16.
Introduction
catalysts for the hydroamination/cyclization of primary amino
olefins, allenes, and alkynes.5Besides the well-established
metallocenes, today a number of noncyclopentadienyl lan-
thanide complexes, which are based on amido and alkoxide
ligands, are known to be efficient in hydroamination/
cyclization catalysis.6,7 Although catalytic hydroamination
has been well-established, only few reports are available on
the enantioselective version of this process.8 Among these,
rare earth metal catalysts have been proven to be competent
catalysts for enantioselective hydroamination reactions. How-
ever, the catalysts based on chiral cyclopentadienyl ligands
The catalytic addition of the N-H bond of amines to alkenes
or alkynes (hydroamination) to give nitrogen-containing mol-
ecules is of immense interest to both academic research and
industrial products since most amines are made today in
multistep syntheses.1 It has been shown that hydroamination
can be catalyzed by d- and f-block transition metals,2 by alkali
metals,3 and, very recently, by calcium.4 Early transition metals
(group 4 and especially the lanthanides) are highly efficient
catalysts for the hydroamination reaction of various compounds
containing C-C multiple bonds.2 In the lanthanide chemistry,
amido and alkyl metallocene complexes have proven to be active
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10.1021/jo801785r CCC: $40.75 2008 American Chemical Society
Published on Web 10/15/2008

Asymmetric Intramolecular Hydroamination of Alkynes
were prone to undergo facile epimerization, hampering wide
use of those catalysts.9 Recently, new chiral rare earth metal
catalysts based on noncyclopentadienyl ligands such as chiral
bis(oxazolinates),10 bis(phenolates),11 bis(naphtholates),12 and
bis(naphtholamides)13,14 were developed. However, the enan-
tioselectivities of the hydroamination through those newly
developed ligands have not been improved markedly com-
pared to those through the previously known lanthanocene
ligands. Furthermore, these rare earth metal catalysts are
highly moisture-sensitive and also show a very limited
tolerance to polar functional groups when compared to late
transition metal catalysts. Hence, development of a new
catalytic asymmetric hydroamination using robust late transi-
tion metals, which can be handed more easily, is highly
desired.
nation of aminoalkynes using Pd2(dba)3 ·CHCl3 and PhCOOH
catalytic system in the presence of (R,R)-Renorphos as a chiral
ligand, which produced five- and six-membered nitrogen
heterocycles in good yields with good to high ee’s (eq 2). The
use of the ordinary conditions A, 5 mol % of Pd2(dba)3 ·CHCl3,
10 mol % of PhCOOH, and 25 mol % of (R,R)-Renorphos, gave
good to fair enantioselectivities. To obtain higher enantiose-
lectivities (81-91% ee), we had to use the conditions B, 20
mol % of Pd2(dba)3 ·CHCl3, 40 mol % of PhCOOH, and 100
mol % of (R,R)-Renorphos.18
Previously, we reported an entirely new method for the
addition of carbon pronucleophiles15 to alkynes in the presence
of a Pd(0)/carboxylic acid combined catalyst, and it was
extended to the addition of nitrogen16 and oxygen17 nucleophiles
to alkynes (eq 1). These results encouraged us to develop a
catalytic asymmetric hydroamination method.18 Accordingly,
we developed a catalytic asymmetric intramolecular hydroami-
The use of a stoichiometric amount of the expensive chiral
ligand for obtaining a better yield and enantioselectivity was a
drawback for this reaction. During this investigation, we
examined various commercially available bisphosphine ligands19
and realized that only Renorphos was effective. In the hy-
droamination of aminoalkynes using Norphos ligand, the product
was obtained in a very low yield, but with a better enantiose-
lectivity, compared to Renorphos. From these results, it is clear
that a small change in the norbornane framework of the
bisphosphine ligands gave a drastic change both in the rate of
reaction and in the enantioselectivity of the hydroamination of
aminoalkynes. Therefore, we prepared various Norphos and
Renorphos derivatives (Figure 1) and investigated the effective-
ness and usefulness of these ligands in the catalytic asymmetric
intramolecular hydroamination of aminoalkynes.
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in the previous communication are following. A NH-Nf group is much less
common than NH-Tf or NH-Ts, but NH-Nf gave better ee’s and chemical yields
than the other protective groups. The reaction without a protective group, that
is, the reaction using-NH2 itself, gave lower ee’s. The hydroamination of 15a
did not proceed at all in the absence of PhCOOH, and the starting material was
recovered. A reviewer asked what would happen in the presence of 10 mol %
of a base under the standard conditions (Table 2, entry 5). The reaction of 15a
in the presence of Cs2CO3 or tricyclohexylamine gave lower ee’s and lower
yields. The reaction in the presence of tricyclohexylphosphine gave 16a with
87% ee and 93% yield.
(19) Patil, N. T.; Lutete, L. M.; Wu, H.; Pahadi, N. K.; Gridnev, I. D.;
Yamamoto, Y. J. Org. Chem. 2006, 71, 4270–4279. We have tested various
bisphosphine ligands such as QUINAP, BINAP, MOP, Trost ligand, Me-BPE,
Me-DUPHOS, Me-FerroTane, PHANEPHOS, CHIRAPHOS, NORPHOS, BDPP,
PROPHOS, DIOP, BPPM, JOSIPHOS, and BPPFOAc in the hydroamination
of alkynes. However, unsatisfactory results were obtained.
J. Org. Chem. Vol. 73, No. 24, 2008 9699

Narsireddy and Yamamoto
FIGURE 1. Norphos and Renorphos derivatives.
Results and Discussion
mercially available C-2 symmetric bisphosphine ligands together
with monodentate ligands gave unsatisfactory results. Therefore,
efforts were undertaken to prepare Norphos and Renorphos
derivatives by slightly modifying the original procedure,21 in
order to find a better phosphine ligand. Treatment of chlo-
rodiphenylphosphine 1 with Li wire in THF at room temperature
followed by addition of trans-1,2-dichloroethylene gave trans-
1,2-ethenediylbis(diphenylphosphine) 2, which upon air oxida-
tion using 30% H2O2 led to formation of the corresponding oxide
3. The Diels-Alder reaction of 3 with an excess amount of
methylcyclopentadiene in an autoclave reactor at 170 °C gave
the racemic 5-methyl Norphos oxide 4 in 80% yield (Scheme
1). All the spectral data of 4 were identical with the reported
data.21 Then, according to the literature procedure,21 we carried
out the resolution of 4 using dibenzoyl-L-(-)-tartaric acid
monohydride as a chiral resolving agent. In the literature
procedure, the authors mentioned that, after three successive
operations, the R,R-enantiomer of 4 could be obtained in a pure
Synthesis of Bisphosphine Ligands. In 1979, Brunner et al.
reported the synthesis of chiral Norphos ligand, which gave
excellent results in Rh-catalyzed asymmetric hydrogenation of
(Z)-R-(N-acetamido)cinnamic acid.20 Later, Brunner reported the
Rh-catalyzed asymmetric hydrogenation of (Z)-R-(N-acetami-
do)cinnamic acid and itaconic acid using Me-Norphos (A) as a
ligand,21 and the hydrogenated products were obtained with 92
and 60% ee.21 Since then, Me-Norphos ligand (A) was never
applied as a bisphosphine ligand for asymmetric catalysts. Chiral
Norphos, Renorphos, and their derivatives were used by
Brunner’s group themselves22 and by other researchers,23 but
mostly unsatisfactory results were obtained,23 except for Rh-
catalyzed hydrogenation,20-22 Co-catalyzed Diels-Alder reac-
tion,24 and hydrogenation of R-keto acids.25 It seems that this
type of bisphosphine ligands derived from norbornene frame-
work have been underestimated in spite of Brunner’s success a
long time ago;20 instead, nowadays other C-2 symmetric
bisphosphine ligands have been used frequently, and successful
results have been obtained with those ligands. As mentioned
above, in our hydroamination of aminoalkynes, only Renorphos
gave satisfactory to allowable results, and all the other com-
form (100% ee) with [R]20 ) -64 (c 1, CHCl3).
D
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9700 J. Org. Chem. Vol. 73, No. 24, 2008

Asymmetric Intramolecular Hydroamination of Alkynes
SCHEME 1. Synthesis of Methyl Norphos Ligand (A)
However, we obtained an [R]20 value higher than the
phine oxides 526 and 1026 were prepared through the reaction
of the corresponding para-substituted arylmagnesium bromides
with Cl2PNEt2. In the case of tolyl Norphos ligand, the chloro
derivative 6 was prepared from 5 using PCl3 in benzene. Then
the reaction of this chloro compound 6 with lithium wire
followed by addition of trans-1,2-dichloroethylene gave the
trans-1,2-alkenylbis(ditolylphosphine) 7, which upon air oxida-
tion with 30% H2O2 gave the corresponding oxide 8. In the
case of CF3 Norphos ligand, we tried to prepare the correspond-
ing CF3-based alkenylphosphine oxide 13 in a similar way.
However, we were unable to obtain 13 through a procedure
similar to that mentioned in Scheme 2. The reason was not yet
clear. The bisphosphine oxide 10 was reduced to the bisphos-
phine 11 using DIBAL-H in THF at -78 °C for 3 h according
to a reported procedure,26 and the cross-coupling between this
bisphosphine and trans-1,2-dichloroethylene in the presence of
Ni catalyst in DMF gave 12 in 52% yield, which upon air
oxidation with H2O2 gave the Diels-Alder precursor 13 in 90%
yield.
Racemic tolyl Norphos oxide 9 and CF3 Norphos oxide 14
were prepared by the Diels-Alder reaction of 8 and 13,
respectively, with excess amounts of cyclopentadiene in an
autoclave reactor. The separation of these racemic Norphos
oxides into pure enantiomers was carried out using quantitative
chiral HPLC in a manner similar to that mentioned in Scheme
1. In the case of tolyl Norphos oxide 9, hexane/ethanol (80:20)
as a mobile phase with 8 mL/min flow rate was used. Similarly,
in the case of CF3 Norphos oxide 14, hexane/ethanol (50:50)
as a mobile phase with 4 mL/min flow rate was used. Then,
D
reported one after three successive operations. We doubted that
an enantiomer (R,R)-4 having [R]20D ) -64 (c 1, CHCl3) would
not be 100% pure. To obtain a really 100% pure (R,R)-4, we
carried out the separation of racemic methyl Norphos oxide 4
into pure enantiomers using quantitative chiral HPLC with
hexane/ethanol (60:40) as a mobile phase, and the flow rate
was 4 mL/min. Then, the [R]20D value of each enantiomer was
recorded to be -115. Accordingly, it is now clear that (R,R)-4,
which Brunner et al. thought to be enantiomerically pure, was
not pure, but perhaps contaminated with enantiomer or byprod-
uct. Then, we carried out the reduction of chiral methyl Norphos
oxide using trichlorosilane and tributylamine in xylene at 120
°C, giving (R,R)-methyl Norphos A in 78% yield; [R]20
)
D
-39.2 (c 1, CHCl3). The previously reported data for A were
[R]20D ) -32 (c 1, CHCl3).21 The difference between the [R]20
D
value of our (R,R)-4 and that of Brunner’s (R,R)-4, -115 versus
-64, was far greater than the difference between the [R]20D value
of our (R,R)-A and that of Brunner’s (R,R)-A, -39.2 versus
-32. Although there is no strict relation between the difference
of the [R]20D values of the enantiomers and their enantiopurities,
we guess that Brunner’s (R,R)-4 was contaminated with
significant amounts of byproduct rather than with its enantiomer.
Hydrogenation of (R,R)-A using 10% Pd/C with hydrogen
balloon gave the corresponding (R,R)-methyl Renorphos D in
85% yield; [R]20D ) -38.2 (c 1, CHCl3). The stereochemistry
of a methyl group was determined unambiguously by NOE
experiments (see Supporting Information).
In a similar way, we carried out the synthesis of tolyl Norphos
(Scheme 2) and CF3 Norphos ligands (Scheme 3). In the
preparation of these new phosphine ligands, initially bisphos-
(26) Busacca, C. A.; Lorenz, J. C.; Grinberg, N.; Haddad, N.; Hrapchak,
M.; Latli, B.; Lee, H.; Sabila, P.; Saha, A.; Sarvestani, M.; Shen, S.; Varsolona,
R.; Wei, X.; Senanayake, C. H. Org. Lett. 2005, 7, 4277–4280.
J. Org. Chem. Vol. 73, No. 24, 2008 9701

Narsireddy and Yamamoto
SCHEME 2. Synthesis of Tolyl Norphos Ligand
these pure Norphos oxides (R,R)-9 and (R,R)-14 were reduced
to the corresponding Norphos derivatives (R,R)-B and (R,R)-C
using HSiCl3 and tributylamine in xylene.
Comparison of these results indicates that Me-Norphos (A)
is the best one among the ligands tested for the hydroamination,
and the corresponding product 16a was obtained in a high yield
with a high enantioselectivity (95% yield, 95% ee). It should
be noted that tolyl Renorphos (E) gave an excellent result
comparable to A. Then we monitored the reaction progress of
the hydroamination of 15a using 25 mol % of A, 5 mol % of
Pd2(dba)3 ·CHCl3, and 10 mol % of PhCOOH in benzene at
100 °C. Also, we measured the ee of 16a at the same point as
the reaction progress was monitored. The results are shown in
Figure 2. It is clear that the product yield increased smoothly
as reaction time increased up to 48 h, and beyond this, the yield
of the product did not increase at all. The enantioselectivity of
the product was always the same throughout the reaction (95%
ee). We also examined the chloroform-free Pd(0) catalysts, such
as Pd2(dba)3, Pd(dba)2, and Pd(PPh3)4, under the conditions
similar as above; 16a was obtained in high chemical yields as
well, but enantioselectivities were very low.
Newly synthesized tolyl Norphos (B), tolyl Renorphos (E),
and CF3 Norphos (C) were prone to be oxidized very gradually
by air, leading to the corresponding oxides (vide infra, the NMR
study section). More or less, this trend was observed also for
the known Norphos, Renorphos, Me-Norphos (A), and Me-
Renorphos (D). Especially, C was rather easily oxidized among
Norphos and Renorphos series. Furthermore, as mentioned later,
the outcome on the enantioselectivity in the hydroamination of
15a in the presence of CF3 Norphos (C) was the worst among
the ligands tested (Table 1). Accordingly, we did not synthesize
CF3 Renorphos (F) since we could not expect that a better result
would be obtained using F.
Intramolecular Hydroamination of Aminoalkynes Using Nor-
phos and Renorphos Series. To know the effectiveness of newly
synthesized ligands in the hydroamination of alkynes, the
reaction of substrate 15a under the previous optimized condi-
tions18 was carried out for comparison, and the results are
summarized in Table 1.
We also studied the effect of the amount of methyl Norphos
A, Pd catalyst, and PhCOOH on the product yield and
enantioselectivity, and the results are shown in Table 2.
9702 J. Org. Chem. Vol. 73, No. 24, 2008

Asymmetric Intramolecular Hydroamination of Alkynes
SCHEME 3. Synthesis of CF3 Norphos Ligand
TABLE 1. Intramolecular Hydroamination of 15a using
(R,R)-Norphos and (R,R)-Renorphos Derivatives
TABLE 2. Effect of the Amount of the Methyl Norphos A, Pd,
and PhCO2H on Yields and Enantiomeric Excess in the
Intramolecular Asymmetric Hydroamination of Aminoalkyne 15aa
Pd2(dba)3 ·CHCl3
A
PhCO2H yield of 16a ee of 16a
entry
(mol %)
(mol %) (mol %)
(%)b
(%)c
1
2
3
4
5
2.5
3
5
5
5
10
15
15
25
20
5
6
10
10
10
95
85
95
95
93
11
10
7
95
92
ligand
Norphos18
methyl Norphos (A)
yolyl Norphos (B)
CF3 Norphos (C)
Renorphos18
yield (%)a
ee (%)b
5
95
15
75
65
90
98
92
95
68
36
83
60
92
a All the reactions were carried out in benzene solvent at 100 °C for
48 h. b Yields are of isolated products. c All the ee’s were confirmed by
chiral HPLC.
methyl Renorphos (D)
tolyl Renorphos (E)
low (Table 2, entry 1). The reaction without palladium catalyst,
that is, the reaction in the presence of Me-Norphos and
PhCOOH in benzene at 100 °C, did not proceed at all, and the
starting material 15a was recovered. Nowadays, the use of
benzene as a solvent is not desirable, and therefore, we examined
the reaction in toluene. The reaction of 15a in toluene under
the standard conditions (entry 5) at 100 °C gave 16a in similar
yield and ee as that in benzene. From these results, it is clear
that at least 20 mol % of the ligand and 5 mol % of
Pd2(dba)3 ·CHCl3 are required to obtain a high yield and high
enantioselectivity; in this case, the ratio of Pd and P is 1:4,
a Yields are of isolated products. b All the ee’s were confirmed by
chiral HPLC.
When we used 5 mol % of Pd2(dba)3 ·CHCl3, 20 or 25 mol
% of methyl Norphos, and 10 mol % of PhCOOH in benzene,
the product was obtained in high yields with high ee’s (Table
2, entries 4 and 5). However, when the reaction was carried
out with 2.5 mol % of Pd2(dba)3 ·CHCl3, 10 mol % of methyl
Norphos, and 5 mol % of PhCOOH in benzene, the product
was obtained in high yield but the enantioselectivity was very
J. Org. Chem. Vol. 73, No. 24, 2008 9703

Narsireddy and Yamamoto
(entries 1-4). In the case of naphthyl derivative, rather low ee
was obtained. The six-membered nitrogen heterocycles were
obtained in high chemical yields with high enantioselectivities
(entries 7 and 8). We tested the present optimized conditions
to the intramolecular hydroamination of aniline derivatives,16f
but the ee’s of the products were not improved so much.
NMR Studies of the Hydroamination of Alkynes. In the
Table 2, when the amount of A decreased from 20-25 to 10-15
mol % (entries 4 and 5 vs entries 1-3), dramatic decrease of
ee’s of 16a was observed. In order to help clarify this remarkable
change, mechanistic investigation using NMR was carried out.
We examined the reaction of 15a using 5 mol % of Pd2-
(dba)3 ·CHCl3, 10 mol % of PhCOOH, and 25 mol % of methyl
Norphos oxide 4 in benzene at 100 °C. Even after 3 days, no
cyclization product 16a was formed at all, and the starting
material 15a was recovered. This clearly shows that intramo-
lecular hydroamination does not proceed in the presence of
methyl Norphos oxide 4 as a ligand. Methyl Norphos A was air
sensitive and very slowly converted to its oxide if it was exposed
to air for many days. Similar observation was made also for
the other Norphos and Renorphos series. It was necessary to
store A under Ar and to be used under the conditions of inert
atmosphere. Hence we carried out all the reactions under Ar
atmosphere. As mentioned above, methyl Norphos A was very
effective in the cyclization of 15a, and the product 16a was
obtained in an excellent yield with very high enantioselectivity
(Scheme 4). After completing the reaction, we were unable to
recover A. Accordingly, we assumed that the ligand A was
oxidized after the completion of reaction or during the reaction
progress, and it was converted to the corresponding stable oxide.
FIGURE 2. Reaction profile of 15a using A as a ligand.
corresponding a palladium complex coordinated by four phos-
phine atoms. Such a fully coordinated complex is inactive as a
catalyst. As mentioned later, gradual oxidation of the ligand
might make a hemilabile ligand. We also examined the
concentration effect of substrate on the enantioselectivity and
chemical yield. A higher concentration (1 mol) of substrate
decreased the ee and chemical yield, and the present diluted
condition (0.08 mol) gave the best result (entries 4 and 5). The
substrate concentration was kept at 0.08 mol at the early stage
of the reaction, and then 15a was added portion-wise along the
reaction progress, but this attempt gave a lower ee. The effect
of an electron-donating group (EDG) and electron-withdrawing
group (EWG) at the para-position of benzoic acid upon the
chemical yield and enantioselectivity was examined. The
reaction of 15a using p-MeO- or p-NO2-substituted benzoic acid,
instead of benzoic acid, under the standard conditions (entry 5)
afforded similarly high chemical yield (∼95%), but the ee in
the former case was 2% and that in the latter case was 30%.
The reason for this dramatic change of enantioselectivity is not
clear. Since the optimized conditions on the reaction time and
on the catalyst composition were obtained, we carried out the
hydroamination of various aminoalkynes, and the results are
summarized in Table 3.
In the case of a catalyst system, Pd(0)/A/PhCO2H, the five-
membered nitrogen heterocycles 16a-e were obtained from the
aminoalkynes 15a-e in high yields with high to good enanti-
oselectivities (entries 1-5). It is clear that the ligand is effective
for hydroamination of the aromatic alkynes (entries 1-5 and
7-8) compared to the aliphatic alkyne 15f (entry 6) as for the
completion of reaction. The reaction of the aliphatic alkyne
needs long reaction time (5 days) as observed previously in the
case of the reaction using Renorphos,18 and also the product is
obtained as a 1:1 mixture of cis- and trans-isomers. The
substrates 15c and 15d having electron-donating and -withdraw-
ing groups gave the corresponding products 16c and 16d in good
yields and with high enantioselectivities. The cyclization of 15g
having one carbon longer on the tether afforded the six-
membered piperidine 16g in 92% yield and 79% ee (entry 7).
The reaction of 15h with a benzene ring linker on the tether
gave the tetrahydroisoquinoline derivative 16h in a high yield
and with an excellent ee (entry 8). The reaction using tolyl
Renorphos E was carried out similarly. Again, very high to good
chemical yield and enantioselectivities were obtained for the
aminoalkynes bearing phenyl groups at the alkyne terminus
We carried out NMR experiments using Me-Norphos because
we have carried out the hydroamination of alkynes 15, and the
corresponding products 16 were obtained in very high ee using
20 mol % of Me-Norphos (Table 3). Initially, an NMR sample
of Me-Norphos was prepared under Ar atmosphere, and its 1H
and 31P NMR spectra in C6D6 were recorded (Figures 3 and 4).
1
After 3 days, again its H and 31P NMR were recorded, and it
was confirmed that there was no change in the spectra (Figure
3a and 4a). This clearly indicates that Me-Norphos is not
oxidized even after 3 days under this condition.
Next, a 4:1 mixture of Me-Norphos and Pd2(dba)3 ·CHCl3 in
C6D6 was prepared under Ar atmosphere, and immediately, its
1H NMR spectra were recorded (Figure 3c). We have also taken
the spectra of dba in C6D6 alone. In this, the olefinic peaks
appeared in the aromatic region. 1H NMR spectra of
Pd2(dba)3 ·CHCl3 in C6D6 are shown in Figure 3b. An ethyl
signal appeared in the spectra of Pd2(dba)3 ·CHCl3, which was
obtained commercially.27 We repeatedly measured the 1H NMR
spectra of Pd2(dba)3 ·CHCl3 obtained through different sources,
but always an ethyl signal appeared. Perhaps, an unidentified
impurity is contaminated in commercially available Pd2(dba)3 ·
(27) We used other Pd(0) reagents, such as Pd2(dba)3, Pd(dba)2, Pd(PPh3)4,
and Pd(OAc)2/excess diphosphine, instead of Pd2(dba)3 · CHCl3. The reaction of
15a proceeded smoothly, and the product 16a was obtained in high chemical
yields, but the enantioselectivities in these cases were significantly lower than
the reaction with Pd2(dba)3 · CHCl3. We also took NMR spectra of
Pd2(dba)3 ·CHCl3, purchased from several different sources. However, all of those
samples exhibited small peaks, resembling Et of ethyl ether, around 1 and 3
ppm region, as observed in Figure 3! We could identify this Et is due to ethyl
ether. Furthermore, we found that the reaction of 15a with a catalyst system, 5
mol % of Pd2(dba)3 plus 1 equiv CHCl3, under the conditions similar as those
of entry 4, Table 2, gave 16a in 94% ee and 95% yield. This result clearly
indicates that the presence of CHCl3 is essential to obtain high enantioselectivity.
The effect of ethyl ether contaminated in commercially available Pd2(dba)3CHCl3
upon enantioselectivity is not so important.
9704 J. Org. Chem. Vol. 73, No. 24, 2008

Asymmetric Intramolecular Hydroamination of Alkynes
TABLE 3. Intramolecular Asymmetric Hydroamination of Aminoalkynes Using Pd(0)/Methyl Norphos A/PhCO2H or Pd(0)/Tolyl Renorphos
E/PhCO2Ha
a All the reactions were carried out using aminoalkyne (0.125 mmol), 5 mol % of Pd2(dba)3 ·CHCl3, 10 mol % of PhCOOH, and 20 mol % of methyl
Norphos in benzene (1.5 mL) at 100 °C for 48 and 72 h in the case of tolyl Renorphos ligand (20 mol %). b Yields are of isolated products. c All the
ee’s were confirmed by chiral HPLC. d No satisfactory separation of enantiomers could be obtained.18
SCHEME 4. Hydroamination in the Presence of A or in the Presence of Its Oxide
CHCl3, but as mentioned later, this ethyl signal works as an
internal standard in the NMR experiments and the impurity due
to this ethyl signal does not exert any significant influence on
the reaction progress. Comparison of the spectra of Figure 3c
J. Org. Chem. Vol. 73, No. 24, 2008 9705

Narsireddy and Yamamoto
FIGURE 3. 1H NMR spectra of Me-Norphos and its oxide in C6D6. The spectra of the aromatic region were omitted.
with those of Figure 3a,b clearly indicates that new spectra
appear immediately after mixing Me-Norphos and Pd2(dba)3 ·
CHCl3. The new spectra consist of the peaks of Me-Norphos,
Me-Norphos oxide, unidentified peaks, and the ethyl signal. We
expanded this spectra in order to see the olefinic peaks of dba,
but those peaks could not be found; perhaps they were shifted
to some other region by coordination of palladium to Me-
Norphos. It was thought that unidentified peaks correspond to
Me-Norphos monoxides (a mixture of exo- and endo-monox-
ides) and/or palladium-phosphine complexes. After 6 h, the
spectra 3c changed gradually, as shown in Figure 3d. After 24 h,
completely different spectra were obtained (Figure 3e), which
matched the spectra of Me-Norphos oxide. It should be noted
that an internal standard, ethyl signal, remains unchanged. More
detailed spectral changes depending on time are shown in the
Supporting Information.
Accordingly, it is now clear that, in presence of Pd2(dba)3 ·
CHCl3, Me-Norphos was converted to Me-Norphos oxide even
under the conditions using Ar atmosphere. Oxygen dissolved
in C6D6 for the NMR experiments was not removed, but we
handled C6D6, Me-Norphos, Pd2(dba)3 ·CHCl3, and NMR tube
under Ar atmosphere. Therefore, it was thought that oxygen
dissolved in the solvent worked as an oxidant in the presence
of palladium catalyst.28 Formation of the phosphine oxide
9706 J. Org. Chem. Vol. 73, No. 24, 2008

Asymmetric Intramolecular Hydroamination of Alkynes
FIGURE 4. 31P NMR spectra of Me-Norphos and its oxide in C6D6.
prevents the hydroamination of alkyne (Scheme 4). To overcome
this problem, we weighed all the materials under a glovebox
and used C6D6 bubbled by passing Ar and carried out the NMR
experiments. However, the same results were obtained. If we
use a vacuum line to completely deoxygenate C6D6, oxidation
of Me-Norphos must be prevented. We were unable to minimize
or halt completely oxidation of Me-Norphos in the presence of
Pd2(dba)3 ·CHCl3. It should be noted that oxidation of Me-
Norphos to Me-Norphos oxide is facilitated remarkably by the
palladium catalyst; as mentioned above, Me-Norphos is not
oxidized in the absence of palladium catalyst even after 3 days.
From the NMR experiments, it is now clear why initially the
rate of reaction using A as a ligand is very fast; there is no
formation of methyl Norphos oxide at an early stage of the
reaction (Figure 2). As time goes on, the rate of reaction
becomes slow due to the gradual conversion of methyl Norphos
A to its oxide 4 form. After 12 h, the product was obtained in
58% yield, after 24 h 70% yield, and after 2 days 95% yield
(Figure 2).29 As shown in Table 2, 20 mol % of A was required
to obtain high ee and high yield of 16a, and use of a less amount
(28) The use of a vacuum line and vacuum technique, as physical chemists
often use it to make a completely degassed solvent, must give a really oxygen-
free C6D6. We did (or do) not have such equipment. We are not able to completely
remove solvated oxygen merely by bubbling a solvent with Ar. Similar oxidation
of DuPhos has been observed by Charette and co-workers: Charette, A. B.; Cote,
A.; Desrosiers, J.-N.; Bonnaventure, I.; Lindsay, V. N. G.; Lauzon, C.; Tannous,
J.; Boezio, A. A. Pure Appl. Chem. 2008, 80, 881–890. They reported that
DuPhos monoxide produces high enantioselectivities.
J. Org. Chem. Vol. 73, No. 24, 2008 9707

Narsireddy and Yamamoto
0 °C, and concentrated aqueous hydrogen chloride (8.0 mL, 100
mmol) was added slowly, and the resulting mixture was stirred at
rt for 4 h. The reaction was quenched by adding water (100 mL).
Ethyl acetate (200 mL) was added, and the organic layer was
separated. The aqueous layer was further extracted with ethyl acetate
(50 mL) two times. The combined organic layers were washed with
brine (20 mL) and dried over magnesium sulfate. After evaporation
of the solvents under vacuum, the residue was purified by column
chromatography on silica gel (hexane/EtOAc ) 1:1) to give the
product 5 (14.1 g, 65% yield) as a white solid. All the spectral
data were identical with the reported data.26
Synthesis of Bis(4-methylpheny)chlorophosphine 6: To a stirred
solution of PCl3 (6.00 g, 45 mmol) in benzene (20 mL) was added
dropwise bis(4-methylphenyl)phosphine oxide 5 (10.0 g, 46 mmol)
in 25 mL of toluene at 0-10 °C. The reaction mixture was stirred
for 30 min at 0-10 °C. Distillation of the solvent under vacuum
gave the crude product, which was further purified by high vacuum
distillation: bp 145-150 °C/mmHg. Pure 6 (7.0 g) was obtained
in 65% yield as a yellowish liquid. All the spectral data were
identical with the reported data.
Synthesis of trans-1,2-Ethenediylbis[di(4-methylphenyl)phos-
phineoxide] 8: To a stirred solution of Li wire (0.5 g, 72 mmol) in
THF (100 mL) was added bis(4-methylpheny)chlorophosphine 6
(6.0 g, 24 mmol) at room temperature. The reaction mixture was
stirred at the same temperature for 4 h and then refluxed for 1 h.
The organic layer was transferred to another reaction flask via a
cannula to remove an excess amount of unreacted Li wire and
cooled to 0 °C. To this cooled solution was added trans-1,2-
dichloroethylene (1.9 g, 12 mmol), and the reaction mixture was
allowed to stir at room temperature for 3 h. Removal of the solvent
under vacuum, addition of water, filtration of solid, followed by
washing with water, methanol, and acetone gave trans-1,2-
ethenediylbis[di(4-methylphenyl)phosphine] 7 (7.2 g, 66% yield).
This compound was dissolved in acetone (500 mL) and treated with
aqueous hydrogen peroxide (3.5 mL). The reaction mixture was
stirred at room temperature for 1 h. Removal of the solvent under
vacuum, addition of water, filtration of solid, followed by washing
with water, methanol, and acetone gave trans-1,2-ethenediylbis[di(4-
methylphenyl)phosphineoxide] 8, which was purified by column
chromatography on silica gel using CHCl3/MeOH (95:5) as an
eluent, giving the product 8 as a white solid (5.1 g, 70% yield from
7): mp 315-316 °C; IR (neat) 3017, 2987, 1600, 1184, 1166, 709
cm-1; 1H NMR (300 MHz, CDCl3) δ 2.31 (s, 12H), 7.18 (m, 8H),
7.49 (m, 8H), 7.61 (d, J ) 24 Hz, 2H); 13C NMR (75 MHz, CDCl3)
δ 21.9, 128.5 (4 lines), 129.8 (m), 131.6 (m,), 141.6 (5 lines), 143.1;
HRMS (ESI) calcd for C30H30O2P2Na [M + Na] m/z 507.1619,
found 507.1613.
Synthesis of Tolyl Norphos Oxide 9: trans-1,2-Ethenediyl-
bis[di(4-methylphenyl)phosphineoxide] 8 (2.4 g, 5 mmol) and
freshly cracked cyclopentadiene (9 mL, 100 mmol) were heated in
a sealed metal reactor at 170 °C for 4 h. Then the reactor was cooled
to rt. The product was taken out of the reactor by dissolving in
dichloromethane. The solvent was evaporated under vacuum to
obtain the crude product, which was further purified by silica gel
column chromatography using CHCl3/EtOAc (1:1) as an eluent,
giving tolyl Norphos oxide 9 as a white solid (1.9 g, 71% yield):
mp 158-160 °C; IR (neat) 3027, 2980, 1603, 1501, 1394, 1171,
1107, 767 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.23 (m, 1H), 2.14
(s, 3H), 2.17 (br s, 1H), 2.22 (s, 3H), 2.33 (s, 3H), 2.34 (s, 3H),
2.89 (br s, 1H), 3.16 (dd, J ) 4.5, 15.6 Hz, 1H), 3.68 (dm, J ) 15
Hz, 1H), 5.83 (dd, J ) 2.7, 5.1 Hz, 1H), 6.29 (dd, J ) 2.7, 5.7 Hz,
1H), 6.77 (d, J ) 6 Hz, 2H), 6.85 (d, J ) 6.3 Hz, 2H), 7.21 (t, J
of A was not suitable because of gradual oxidation of A to
methyl Norphos monoxides and the methyl Norphos oxide.
More remarkable change with the use of less amounts of A was
the enantioselectivities (Table 2, entries 1-3 vs 4-5). Perhaps,
only A could produce high ee and methyl Norphos monoxides
formed before conversion to A (dioxide) would produce very
low ee, although the hydroamination proceeded in the presence
of the monoxides. In the previous communication,18 a stoichio-
metric amount (100 mol %) of Renorphos was needed to obtain
high ee and high yield of the hydroamination products. A reason
for this is also now clear; oxidation of Renorphos in the presence
of palladium catalyst would compete with the intramolecular
hydroamination process. In Table 1 and in the previous
communication,18 we reported that the use of Norphos gave a
high ee (92% ee) but the yield was very low (5%). We observed
that the rate of reaction is very slow with Norphos ligand
compared to other Norphos and Renorphos derivatives (Table
1), and from the NMR experiments, it was clear that oxidation
of Norphos to Norphos oxide occurring in the presence of
Pd2(dba)3 ·CHCl3 in C6D6 was quick when compared to the rate
of the hydroamination reaction (more details about the NMR
experiments using Norphos ligand are shown in the Supporting
Information). Accordingly, the hydroamination using Norphos
would be halted by conversion of the ligand to its oxide. Now
all of these previous observations are understandable.
1
Since the difference between the H NMR spectra of the
intermediate stages (Figure 3c,d) is not necessarily clear, 31P
NMR spectra were measured. Two singlet peaks of Me-Norphos
appeared at -1.247 and -0.970 ppm (Figure 4a). Immediately
after mixing Me-Norphos and Pd2(dba)3 ·CHCl3, Me-Norphos
and a small amount of Me-Norphos oxide were observed
together with unidentified signals, perhaps due to intermediates
of palladium-methyl Norphos complex or due to Me-Norphos
monoxides (Figure 4b). After 6 h, the signals of Me-Norphos
oxide and of unidentified intermediates increased, whereas those
of Me-Norphos decreased (Figure 4c). After 24 h, two doublet
signals of Me-Norphos oxide appeared at 28.367 and 30.522
ppm (Figure 4d).
Conclusion
We have developed a convenient method for the synthesis
of chiral Norphos derivatives and used diphosphine ligands for
the hydroamination of alkynes with a Pd catalyst. Among
Norphos derivatives, methyl Norphos A was found to be the
best ligand for the hydroamination of alkynes, and the corre-
sponding five- and six-membered nitrogen heterocyclic com-
pounds were obtained in high yields with high enantioselectiv-
ities. Tolyl Renorphos E gave also excellent results. NMR
experiments revealed that these Norphos and Renorphos ligands
underwent slow oxidation in the presence of Pd2(dba)3 ·CHCl3
catalyst in C6D6 even under Ar atmosphere.
Experimental Section
Synthesis of Tolyl Norphos (B) and Tolyl Renorphos (E).
Synthesis of Bis(4-methylphenyl)phosphineoxide 5: A 1.0 M
solution of 4-methylphenylmagnesium bromide was prepared by
slow addition of 4-methylbromobenzene (12.3 mL, 100 mmol) in
30 mL of THF to a slurry of 2.6 g (110 mmol) of Mg turnings in
60 mL of dry THF. After stirring this mixture at rt for 2 h, this
solution was added slowly to a solution of 8.3 g (50 mmol) of
(Et2N)PCl2 in 50 mL of THF at 0 °C. The resulting mixture was
further stirred at rt overnight. This reaction mixture was cooled to
(29) A reviewer pointed out that the following observations seemed to be
contradictory; the diphosphine has been oxidized after 24 h as shown in Figures
3 and 4, while the catalytic cycle is still active after 36 h, as shown in Figure 2.
We think that the former case consists of a two-component system (phosphine
and palladium), whereas the latter case consists of a three-component system
(phosphine, palladium, and substrate), and this difference may lead to seemingly
contradictory observations.
9708 J. Org. Chem. Vol. 73, No. 24, 2008

Asymmetric Intramolecular Hydroamination of Alkynes
) 8.1 Hz, 4 H), 7.36 (dd, J ) 8.1, 10.5 Hz, 2H), 7.47 (dd, J ) 7.8,
10.8 Hz, 2H), 7.58 (dd, J ) 8.1, 10.5 Hz, 2H), 7.67 (dd, J ) 8.1,
10.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 21.3 (2C), 21.4 (2C),
Hz), 137.5, 138.1, 138.4, 138.9 (4 lines for 2C); HRMS (ESI) calcd
for C35H37P2 [M + H] m/z 519.2370, found 519.2365.
Synthesis of (R,R)-Tolyl Renorphos: To a solution of (R,R)-tolyl
Norphos B (0.52 g, 1 mmol) in methanol (20 mL) was added 5%
Pd/C (0.187, 10 mol %). Reaction mixture was stirred at rt for 12 h
under hydrogen atmosphere (hydrogen balloon). Reaction mixture
was filtered through Celite to remove the Pd/C and washed with
methanol. Evaporation of the solvent under vacuum yielded (R,R)-
38.4 (d, JCP ) 74.6 Hz), 39.5 (d, JCP ) 66.6 Hz), 47.0 (d, JCP
)
14.1 Hz), 48.0 (d, JCP ) 10.5 Hz), 129.1 (8 lines for 2C), 130.6 (9
lines for 2C), 137.9 (7 lines); HRMS (ESI) calcd for C35H36O2P2Na
[M + Na] m/z 573.2088, found 573.2083.
Resolution of Tolyl Norphos Oxide 9: Racemic tolyl Norphos
oxide 9 was separated using quantitative chiral HPLC CHIRALPAK
IA. The racemic compound 9 (50 mg) dissolved in 5 mL of ethanol
was injected in the column using hexane/EtOH (80:20) as an eluent.
The flow rate was 8 mL/min. First, the enantiomer (R,R)-9 was
collected at 25 min, and then the enantiomer (S,S)-9 was collected
at 37 min. This procedure was repeated several times, and each
enantiomer was collected in separate conical flasks. Evaporation
of the solvents gave the pure enantiomers as a white solid. For
(R,R)-9: [R]20D ) -13.9 (c 1, CHCl3); mp 253-255 °C. For (S,S)-
tolyl Renorphos E as a white solid (0.42 g, 82% yield): [R]20
)
D
-5.1 (c 1, CHCl3); mp 123-125 °C; IR (neat) 3068, 2947, 1599,
1
1885, 1495, 1081, 793 cm-1; H NMR (300 MHz, C6D6) δ 0.63
(d, J ) 11 Hz, 1H), 0.74 (d, J ) 11 Hz, 1H), 0.95 (m, 1H), 1.29
(m, 2H), 1.67 (s, 3H), 1.73 (s, 3H), 1.75 (s, 3H), 2.03 (s, 1H), 2.21
(m, 2H), 2.82 (m, 1H), 6.54 (dd, J ) 8, 12 Hz, 4H), 6.65 (dd, J )
8, 12 Hz, 4H), 7.00 (m, 2H), 7.00 (m, 2H), 7.00 (t, J ) 7 Hz, 2H),
7.39 (m, 2H); 13C NMR (75 MHz, C6D6) δ 21.2, 25.7 (d, J ) 23.4
Hz), 32.2, 32.7, 41.4 (dd, J ) 3, 11 Hz), 41.8 (d, J ) 3 Hz), 44.1
(dd, J ) 20, 22 Hz), 44.3 (dd, J ) 8, 12 Hz), 129.3 (ddd, J ) 7.5,
12.3 Hz), 132.8 (d, J ) 17 Hz), 134.0 (d, J ) 20 Hz), 135.2 (m),
136.0 (d, J ) 11 Hz), 137.1, 138.6 (3 lines); HRMS (ESI) calcd
for C35H39P2 [M + H] m/z 521.2527, found 521.2522.
General Procedure for Asymmetric Intramolecular Hydroami-
nation of Alkynes. To Pd2(dba)3 ·CHCl3 (5 mol %), PhCOOH (10
mol %), and (R,R)-methyl Norphos or (R,R)-tolyl Renorphos
derivatives (20 mol %) was added the substrate 15 (0.125 mmol)
in 1.5 mL of benzene under Ar atmosphere in a screw capped vial.
After heating at 100 °C for 48 h, the reaction mixture was filtered
through a short silica gel column using diethyl ether as an eluent.
After evaporation of the solvents, the residue was purified by silica
gel column chromatography to afford the corresponding cyclization
product 16. All the products were identified by IR, NMR, Mass,
and elemental analysis data, and those data were compared with
the reported data if they were known.18,19 All the ee’s were
confirmed by chiral HPLC using CHIRALCELL OD.
9: [R]20 ) +14.0 (c 1, CHCl3); mp 253-255 °C.
D
Synthesis of (R,R)-Tolyl Norphos (B): To a stirred solution of
tolyl Norphos oxide (R,R)-9 (1.0 g, 2 mmol) in xylene (25 mL)
were added tributylamine (1 mL, 10 mmol) and trichlorosilane (2.38
mL, 10 mmol). The reaction mixture was heated to 120 °C for 6 h
in an autoclave excluding air and moisture. The solvent and excess
of reagents were evaporated. The residue was dissolved in benzene.
After cooling to 0 °C, 25 mol % of NaOH (10 mL) was added
slowly. The water phase was washed with benzene (25 mL). The
combined benzene solution was evaporated under vacuum to obtain
the crude product, which was purified by column chromatography
on silica gel (hexane/EtOAC ) 10:1) to obtain (R,R)-tolyl Norphos
(B) as a white solid (0.77 g, 74% yield): [R]20 ) -10.1 (c 1,
D
CHCl3); mp 129-130 °C; IR (neat) 3065, 2917, 1597, 1495, 1020,
800, 751 cm-1; 1H NMR (300 MHz, C6D6) δ 1.25 (d, J ) 9.9 Hz,
1H), 1.38 (d, J ) 9.9 Hz, 1H), 1.89 (m, 2H), 1.97 (s, 3H), 1.99 (s,
3H), 2.01 (s, 3H), 2.06 (s, 3H), 2.62 (dd, J ) 5.3, 11.1 Hz, 1H),
2.90 (br s, 1H), 3.16 (dm, J ) 17 Hz, 1H), 6.25 (br s, 2H), 6.75 (d,
J ) 7.5 Hz, 2H), 6.80 (d, J ) 7.9 Hz, 2H), 6.92 (d, J ) 8.4 Hz,
2H), 6.96 (d, J ) 7.5 Hz, 2H), 7.32 (dd, J ) 6.6, 7.5 Hz, 2H), 7.65
(m, 6H); 13C NMR (75 MHz, C6D6) δ 21.1, 21.2 (2C), 21.2, 40.9
(dd, J ) 16, 23 Hz), 42.8 (dd, J ) 11, 22 Hz), 47.3 (multiple lines,
2C), 47.7 (dd, J ) 4, 12 Hz), 129.0 (d, JCP ) 6 Hz, 2C), 129.3 (d,
JCP ) 4 Hz), 129.4 (d, JCP ) 4 Hz), 133.1 (d, JCP ) 17 Hz), 134.2
(dd, JCP ) 2, 21 Hz), 134.3 (d, JCP ) 20 Hz), 135.0 (d, JCP ) 20
Hz), 135.1 (m), 136.6 (dd, JCP ) 1, 28 Hz), 136.7 (dd, JCP ) 2, 24
Supporting Information Available: Complete experimental
procedures for the synthesis of methyl Norphos, methyl Renor-
1
phos, and CF3 Norphos ligands, characterization, H and 13C
NMR spectra (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
JO801785R
J. Org. Chem. Vol. 73, No. 24, 2008 9709