Development of new P-chiral phosphorodiamidite ligands having a pyrrolo[1,2-c]diazaphosphol-1-one unit and their application to regio- and enantioselective iridium-catalyzed allylic etherification

Article abstract of DOI:10.1021/jo0615403

(Chemical Equation Presented) Ten types of new P-chiral phosphorodiamidite ligands having pyrrolo[1,2-c][1,3,2]diazaphosphol-1-one backbone were designed and prepared. They were preliminarily utilized for iridium-catalyzed asymmetric allylic etherificatio

Full text of DOI:10.1021/jo0615403

Development of New P-Chiral Phosphorodiamidite Ligands Having
a Pyrrolo[1,2-c]diazaphosphol-1-one Unit and Their Application to
Regio- and Enantioselective Iridium-Catalyzed Allylic Etherification
Masahiro Kimura and Yasuhiro Uozumi*
Institute for Molecular Science (IMS), CREST, and The Graduate UniVersity for AdVanced Studies,
Higashiyama 5-1, Myodaiji, Okazaki 444-8787, Japan
uo@ims.ac.jp
ReceiVed July 25, 2006
Ten types of new P-chiral phosphorodiamidite ligands having pyrrolo[1,2-c][1,3,2]diazaphosphol-1-one
backbone were designed and prepared. They were preliminarily utilized for iridium-catalyzed asymmetric
allylic etherification of cinnamyl carbonate with phenol, where both R- and S-products were obtained
with good enantioselectivity (up to 74% ee) by changing the N- and P-substituents of the ligands. The
opposite enantioselectivity in iridium-catalyzed allylic substitution was explained by DFT calculations
of the energy difference of the π-allyliridium-phosphorodiamidite intermediates.
Introduction
only scant attention has been paid to chiral phosphorodiamidite
ligands (P(OR)(amino)(amino′)). Thus, to the best of our
Asymmetric reactions catalyzed by transition metal complexes
containing optically active phosphorus ligands have attracted
increasing interest for their synthetic utility. One of the most
exciting and challenging aspects of catalytic asymmetric syn-
thesis is the development of chiral ligands which realize high
enantioselectivity in a given reaction. Though chiral phosphine
ligands having alkyl P-substituents, particularly those bearing
P-P or P-N chelating functionalities, occupy a prominent
position in transition metal-catalyzed asymmetric reactions,
chiral phosphoramidite ligands having alkoxy and alkylamino
P-substituents have recently been gaining in popularity due to
their unique catalytic activity and enantiocontrolling potency.
The binaphthol-based phosphoramidites L1 (Figure 1),1 origi-
nally developed by Feringa and co-workers, are representative
of these compounds which have shown excellent enantioselec-
tivity in a variety of transition metal-catalyzed asymmetric
processes.2-4 However, compared to the rapid and successful
growth of chiral phosphoramidite ligands (P(OR)(OR′)(amino)),
(2) For examples of Rh-catalyzed hydrogenation, see: (a) Pen˜a, D.;
Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2002,
124, 14552. (b) van den Berg, M.; Minnaard, A. J.; Haak, R. M.; Leeman,
M.; Schudde, E. P.; Meetsma, A.; Feringa, B. L.; de Vries, A. H. M.;
Maljaars, C. E. P.; Willans, C. E.; Hyett, D.; Boogers, J. A. F.; Henderickx,
H. J. W.; de Vries, J. G. AdV. Synth. Catal. 2003, 345, 308. (c) Jerphagnon,
T.; Renaud, J.-L.; Bruneau, C. Tetrahedron: Asymmetry 2004, 15, 2101.
(3) For examples of Cu-catalyzed conjugate additions: (a) Feringa, B.
L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries, A. H. M. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2620. (b) Feringa, B. L. Acc. Chem. Res.
2000, 33, 346. (c) Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Arnold,
A.; Feringa, B. L. Org. Lett. 2000, 2, 933. (d) Alexakis, A.; Trevitt, G. P.;
Bernardinelli, G. J. Am. Chem. Soc. 2001, 123, 4358. (e) Alexakis, A.;
Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem. Soc. 2002, 124, 5262.
(f) Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem.
2002, 67, 7244. (g) Watanabe, T.; Kno¨pfel, T. F.; Carreira, E. M. Org.
Lett. 2003, 5, 4557. (h) Pineschi, M.; Del, Moro, F.; Crotti, P.; Di, Bussolo,
V.; Macchia, F. J. Org. Chem. 2004, 69, 2099. (i) Duursma, A.; Boiteau,
J.-G.; Lefort, L.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G.;
Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2004, 69, 8045. (j) Sua´rez,
R. M.; Pe˜na, D.; Minnaard, A. J.; Feringa, B. L. Org. Biomol. Chem. 2005,
3, 729. (k) Sebesta, R.; Pizzuti, M. G.; Boersma, A. J.; Minnaard, A. J.;
Feringa, B. L. Chem. Commun. 2005, 1711. (l) d’Augustin, M.; Palais, L.;
Alexakis, A. Angew. Chem., Int. Ed. 2005, 44, 1376. (m) Alexakis, A.;
Albrow, V.; Biswas, K.; d’Augustin, M.; Prieto, O.; Woodward, S. Chem.
Commun. 2005, 2843.
(1) (a) Hulst, R.; de Vries, N. K.; Feringa, B. L. Tetrahedron: Asymmetry
1994, 5, 699. (b) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2374.
10.1021/jo0615403 CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/29/2006
J. Org. Chem. 2007, 72, 707-714
707

Kimura and Uozumi
SCHEME 1
FIGURE 1. Chiral phosphoramidite and phosphorodiamidite ligands.
knowledge, only three types of chiral diamine-based phospho-
rodiamidite ligands exhibiting good to excellent enantioselec-
tivity have been developed so far, L2, L3, and L4 (Figure 1).5-7
During our studies on the development of powerful chiral
agents, a hexahydro-1H-pyrrolo[1,2-c]imidazolone framework
bearing a bicyclic [3.3.0] backbone with an N-chiral bridgehead
nitrogen atom was identified as a highly stereoselective chiral
unit. Readily prepared from proline anilides,8 it was used to
prepare the imidazoindolephosphine ligand9 and the NCN pincer
palladium complex.10 As part of our ongoing effort to develop
wide utility for this chiral unit, we decided to replace the skeletal
carbon atom with a coordinating phosphorus atom to construct
chiral phosphorodiamidite ligands bearing the hexahydro-1H-
pyrrolo[1,2-c][1,3,2]diazaphosphole backbone (Scheme 1). Herein
we describe the design and preparation of the chiral phospho-
rodiamidite ligands and their preliminary use in Ir-catalyzed
asymmetric allylic etherification.
(4) For example of Ni-catalyzed hydrovinylation: Francio, G.; Faraone,
F.; Leitner, W. J. Am. Chem. Soc. 2002, 124, 736.
Results and Discussion
(5) (a) Hilgraf, R.; Pfaltz, A. Synlett 1999, 1814. (b) Hilgraf, R.; Pfaltz,
A. AdV. Synth. Catal. 2005, 347, 61.
Preparation of Phosphorodiamidite Ligands. Phospho-
rodiamidite ligands having the N-phenyl-P-phenoxy substituents
(3R,7aS)-1a, (3R,7aS)-1b, and (3R,7aS)-1c were readily prepared
by the reaction of phenylphosphorodichloridite with anilides of
(S)-proline (2), (S)-pyroglutamic acid (3), and (S)-indoline
carboxylic acid (7) in 65%, 76%, and 94% yield, respectively
(Scheme 2 and Figure 2). Phosphorus NMR studies revealed
that the phosphorodiamidites 1a-c were obtained with almost
perfect diastereoselectivities (1a: (3R,7aS)/(3S,7aS) ) 100/0,
1b: (3R,7aS)/(3S,7aS) ) 100/0, 1c: (3R,7aS)/(3S,7aS) ) 98/
2). The phosphorodiamidite ligands (3R,7aS)-1d, (3R,7aS)-1e,
(3R,7aS)-1f, and (3R,9aS)-1g bearing substituted N-aryl groups
were prepared from the corresponding substituted anilides 4,
5, 6, and 8 in 82% (diastereomeric ratio (dr) ) 95/5), 63% (dr
) 99/1), 76% (dr ) 100/0), and quantitative yield (dr ) 100/
0), respectively. 2,6-Disubstituted aryloxy groups were intro-
duced onto the phosphorus atom via the triaminophosphine
intermediates 9 or 10 (Scheme 3). Thus, the pyroglutamic anilide
3 and the indoline carboxylic anilide 7 reacted with tris-
(dimethylamino)phosphine in refluxing toluene for 12 h to give
the triaminophosphines 9 and 10, respectively. The triamino-
phosphines were subsequently treated with 2,6-dimethyl- or 2,6-
bis(isopropyl)phenol to afford single diastereomers of (3R,7aS)-
1h, (3R,7aS)-1i, and (3R,9aS)-1j in 53%, 31%, and 43% yield.
(6) (a) Nemoto, T.; Matsumoto, T.; Masuda, T.; Hitomi, T.; Hatano, K.;
Hamada, Y. J. Am. Chem. Soc. 2004, 126, 3690. (b) Nemoto, T.; Masuda,
T.; Matsumoto, T.; Hamada, Y. J. Org. Chem. 2005, 70, 7172.
(7) For asymmetric reactions by use of ligand L4, see: (a) Brunel, J.
M.; Constantieux, T.; Labande, A.; Lubatti, F.; Buono, G. Tetrahedron Lett.
1997, 38, 5971. (b) Muchow, G.; Burnel, J. M.; Maffei, M.; Pardigon, O.;
Buono, G. Tetrahedron 1998, 54, 10435. (c) Burnel, J. M.; Campo, B. D.;
Buono, G. Tetrahedron Lett. 1998, 39, 9663. (d) Constantieux, T.; Burnel,
J. M.; Labande, A.; Buono, G. Synlett 1998, 49. (e) Delapierre, G.;
Constantieux, T.; Burnel, J. M.; Buono, G. Eur. J. Org. Chem. 2000, 2507.
(f) Burnel, J. M.; Tenaglia, A.; Buono, G. Terahedron: Asymmetry 2000,
11, 3585. (g) Ansell, J.; Wills, M. Chem. Soc. ReV. 2002, 31, 259. (h)
Gavrilov, K. N.; Tsarev, V. N.; Shiryaev, A. A.; Bondarev, O. G.; Lyubimov,
S. E.; Benetsky, E. B.; Korlyukov, A. A.; Antipin, M. Y.; Davankov, V.
A.; Gais, H.-J. Eur. J. Org. Chem. 2004, 629. (j) Tsarev, V. N.; Lyubimov,
S. E.; Shiryaev, A. A.; Zheglov, S. V.; Bondarev, O. G.; Davankov, V. A.;
Kabro, A. A.; Moiseev, S. K.; Kalinin, V. N.; Gavrilov, K. N. Eur. J. Inorg.
Chem. 2004, 2214.
(8) (a) Uozumi, Y.; Mizutani, K.; Nagai, S.-I. Tetrahedron Lett. 2001,
42, 407. (b) Uozumi, Y.; Yasoshima, K.; Miyachi, T.; Nagai, S.-I.
Tetrahedron Lett. 2001, 42, 411.
(9) (a) Uozumi, Y.; Shibatomi, K. J. Am. Chem. Soc. 2001, 123, 2919.
(b) Shibatomi, K.; Uozumi, Y. Tetrahedron: Asymmetry 2002, 13, 1769.
(c) Uozumi, Y.; Tanaka, H.; Shibatomi, K. Org. Lett. 2004, 6, 281. (d)
Nakai, Y.; Uozumi, Y. Org. Lett. 2005, 7, 291. (e) Uozumi, Y.; Kimura,
M. Tetrahedron: Asymmetry 2006, 17, 161.
(10) (a) Takenaka, K.; Uozumi, Y. Org. Lett. 2004, 6, 1833. (b) Takenaka,
K.; Uozumi, Y. AdV. Synth. Catal. 2004, 346, 1693. (c) Takenaka, K.;
Minakawa, M.; Uozumi, Y. J. Am. Chem. Soc. 2005, 127, 12273.
708 J. Org. Chem., Vol. 72, No. 3, 2007

P-Chiral Phosphorodiamidite Ligands
FIGURE 2. Chiral phosphorodiamidite ligands 1a-j.
SCHEME 2
SCHEME 3
All phosphorodiamidites 1a-j were isolated by chromatography
on silica gel and the diastereomeric ratios were determined by
31P{1H} NMR and GC experiments.
TABLE 1. Yield, Diastereomeric Ratio, and Calculated Relative
Energy of Ligand 1a-j
entry
ligand
yield (%)a
drb
∆E (â-R) (kcal/ mol)c
Structural Studies. Since the stereochemical structures of
the major diastereomers of 1a-j could not be determined by
X-ray diffraction because of the difficulty in obtaining an
adequate single-crystal suitable for X-ray diffraction studies,
or spectroscopic studies (e.g., NOE experiments), we therefore
examined DFT calculations of the relative energies of each set
of â- and R-isomers of 1a-j (Table 1). The geometry optimiza-
tions of all â- and R-isomers were carried out at the B3LYP/
6-31G(d) level. The relative energies of all â-isomers (R-
configuration) were ascertained to be 2.15-3.83 kcal/mol lower
than the corresponding R-isomers, as shown in Table 1. The
DFT calculated NMR simulations of the 31P resonance were
also examined for compound (3R*,7aS*)-1d and its R-isomer
(3S*,7aS)-1d by the Gauge-Independent Atomic Orbital method11
(GIAO-B3LYP) with basis sets 6-311G(3d) for the phosphorus
atom and 6-311G(d) for the other atoms in their optimized
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
65
76
94
82
63
76
quant.
53
31
100/0
100/0
98/2
95/5
99/1
100/0
100/0
100/0
100/0
100/0
-2.88
-2.58
-2.64
-2.45
-2.47
-2.58
-2.22
-2.15
-2.30
-3.83
10
1j
43
a Isolated yield. b Determined by 31P NMR. c Relative energy of â-form
to R-form calculated at the B3LYP/6-31G(d) level.
structure, obtained using the above-mentioned DFT calculations
(Figure 3). The calculated phosphorus resonances (δ values) of
the â- and R-isomers were +128.0 and +147.6 ppm, respec-
tively, where the 31P NMR signal of the â-isomer is expected
J. Org. Chem, Vol. 72, No. 3, 2007 709

Kimura and Uozumi
TABLE 2. Iridium-Catalyzed Asymmetric Allylic Etherification
with Ligands 1a-ja
entry
ligand
yield (%)b
13/14c
ee (%)d
config
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
8
63
50
22
54
58
30
76
71
7
92/8
91/9
87/13
97/3
96/4
96/4
94/6
73/27
31/69
90/10
18
11
70
70
40
62
16
74
5
R
S
R
S
S
S
S
R
S
R
10
1j
60
a All reactions were carried out at 50 °C for 20 h. The ratio of cinnamyl
carbonate (mol)/ phenol (mol)/triethylamine (mol)/iridium (mol)/ligand
(mol)/THF (L) ) 1.0/2.0/2.0/ 0.02/0.02/1.0. b Isolated yields of 13 and 14.
c Determined by 1H NMR of crude reaction mixtures. d Determined by
HPLC analysis with a chiral stationary phase column (CHIRALCEL OJ-
H).
CHART 1
FIGURE 3. Optimized structures and calculated chemical shifts of
(3R,7aS)- and (3S,7aS)-1d. Geometry optimization was carried out at
the B3LYP/6-31G(d) level. Magnetic shieldings of phosphorus were
calculated by the GIAO-B3LYP method with 6-311G(3d) for P and
6-311G(d) for others on the optimized structures, which were trans-
formed to NMR chemical shifts by the equation, shift(X) - shift(ref)
) -shield(X) + shield(ref). (shield(ref ) P(OMe)3) ) 149.86 ppm,
shift(ref ) P(OMe)3) ) 140 ppm).
chiral phosphoramidite ligand to iridium catalysis with aryl-
oxides to achieve up to 97% stereoselectivity.14 Our continuing
interest in asymmetric allylic etherification9e led us to examine
the Ir-catalyzed reaction of cinnamyl carbonate with phenol in
the presence of the chiral phosphorodiamidite ligands 1. The
reaction of cinnamyl methyl carbonate (11) with 2 equiv of
phenol (12) was carried out in THF at 50 °C for 20 h in the
presence of 2 equiv of triethylamine and with an iridium
complex generated in situ by mixing 1 mol % of bis[(1,5-
cyclooctadiene)iridium(I) chloride] ([IrCl(cod)]2) and 2 mol %
of the ligand to give 1-phenyl-1-phenoxy-2-propene (13) and
1-phenoxy-3-phenyl-2-propene (14). 1H NMR of a crude
reaction mixture revealed a ratio of regioisomers (13/14).
Enantiomeric purity of the branched product 13 was determined
by HPLC analysis with a chiral stationary phase column. The
absolute configuration of 13 was determined by comparison of
to appear at higher field with a ∆δ value of 19.6 ppm compared
to that of the R-isomer (∆δcalc(â - R) ) -19.6). The 31P NMR
chemical shifts (δ values) of the major and the minor diaster-
eomers of 1d were observed at +106.6 and +124.2 ppm (∆δobs
(â - R) ) -17.6), respectively, in a ratio of 95/5 to show good
agreement with the results of the DFT-assisted NMR simula-
tions. These results indicate that the major diastereomer of 1d
is the â-form, (3R*,7aS)-1d.
The DFT calculation of the energy profile for the epimer-
ization of P-central chirality was also examined for the ligand
1b (Figure 4). It should be noted that ca. 97 kcal/mol of energy
is required for the epimerization of P-central chirality to
demonstrate the stability of P-chirality during the reaction
conditions (Vide infra).
Phosphorodiamidite Ligands in Asymmetric Catalysis.
The stereocontrolling potentials of the ligands 1a-j were
examined for the iridium-catalyzed asymmetric allylic etheri-
fication of cinnamyl carbonate (11) with phenol (12). Since
Takeuchi’s pioneering findings of Ir-catalyzed branch-selective
allylic substitution of linear allylic esters in 1997,12 chiral-
switching of the catalysis has received much attention.13 Thus,
in 2003, Hartwig and co-workers applied the binaphthyl-based
(13) For asymmetric π-allylic alkylation with high stereoselectivity,
see: (a) Alexakis, A.; Polet, D. Org. Lett. 2004, 6, 3529. (b) Lipowsky,
G.; Miller, N.; Helmchen, G. Angew. Chem., Int. Ed. 2004, 43, 4595. For
amination: (c) Welter, C.; Dahnz, A.; Brunner, B.; Streiff, S.; Du¨bon, P.;
Helmchen, G. Org. Lett. 2005, 7, 1239. (d) Leitner, A.; Shu, C.; Hartwig,
J. F. Org. Lett. 2005, 7, 1093. (e) Leitner, A.; Shekhar, S.; Pouy, M. J.;
Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15506. (d) Kiener, C. A.; Shu,
C.; Incarvito, C.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 14272. (e)
Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164. (f) Shu,
C.; Leitner, A.; Hartwig, J. F. Angew. Chem., Int. Ed. 2004, 43, 4797. (g)
Tissot-Croset, K.; Polet, D.; Alexakis, A. Angew. Chem., Int. Ed. 2004, 43,
2426.
(14) (a) Lo´pez, F.; Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2003,
125, 3426. (b) Kiener, C. A.; Shu, C.; Incarvito, C.; Hartwig, J. F. J. Am.
Chem. Soc. 2003, 125, 14272. (c) Shu, C.; Hartwig, J. F. Angew. Chem.,
Int. Ed. 2004, 43, 4794. (d) Leitner, A.; Shu, C.; Hartwig, J. F. Org. Lett.
2005, 7, 1093.
(11) (a) Ditchfield, R. Mol. Phys. 1974, 27, 789. (b) Wolinski, K.; Hilton,
J. F.; Pulay, P. J. Am. Chem. Soc. 1990, 112, 8251.
(12) (a) Takeuchi, R.; Kashio, M. Angew. Chem., Int. Ed. Engl. 1997,
36, 263. (b) Takeuchi, R.; Kashio, M. J. Am. Chem. Soc. 1998, 120, 8647.
(c) Takeuchi, R.; Ue, N.; Tanabe, K.; Yamashita, K.; Shiga, N. J. Am. Chem.
Soc. 2001, 123, 9525.
710 J. Org. Chem., Vol. 72, No. 3, 2007

P-Chiral Phosphorodiamidite Ligands
FIGURE 4. Energy profile for the epimerization of P-chirality of 1b. Geometry optimization was carried out at the B3LYP/6-31G(d) level.
CHART 2
FIGURE 5. Plausible reaction pathway of the iridium-catalyzed allylic
etherification of cinnamyl carbonate with phenol.
enantioselectivity (70% ee (S)) were observed with ligand 1d
having the N-(2,6-dimethylphenyl) group. (entry 4). Ligands 1e
and 1f bearing the 2,6-diethylphenyl and the 3,5-di-tert-
the optical rotation with (S)-13 prepared by the reaction of (R)-
1-phenyl-2-propen-1-ol with phenol under Mitsunobu condi-
tions. Representative results are summarized in Table 2. The
catalyst with the L-proline-derived ligand 1a gave the allyl
phenyl ethers 13 and 14 in only 8% yield with 18% ee (R) (entry
1). On the other hand, ligand 1b gave the opposite and poor
enantioselectivity (11% ee (S), entry 2). Ligand 1c, which was
derived from (S)-(-)-indoline-2-carboxylic acid, gave 70% ee
of (R)-13 with nonsubstituted phenyl rings as both N-Ar and
P-OAr groups (entry 3). Although reactivity was low (22%
yield), the highest regioselectivity (13/14 ) 97/3) and good
butylphenyl groups as N-substituents provided lower enantio-
selectivities: 40% ee and 62% ee, respectively (entries 5 and
6). The use of the indolinecarboxylic acid-derived ligand 1g
having the N-(2,6-dimethylphenyl) group gave (S)-13 with only
16% ee (entry 7). The best enantioselectivity was obtained when
ligand 1h, prepared from L-pyroglutamic acid, having methyl
groups at the 2,6-positions of the P-phenoxy group was used
(entry 8). The allyl ethers 13 and 14 were obtained in 76% yield
with 73/27 regioselectivity and 74% ee (R). Ligand 1i having
bulky isopropyl groups at the 2,6-positions remarkably lowered
both the regioselectivity and the enantioselectivity (13/14 ) 31/
J. Org. Chem, Vol. 72, No. 3, 2007 711

Kimura and Uozumi
FIGURE 6. Optimized structures and relative energies of complex 1hE and its isomers (1hE′ and 1hE′′) at the B3LYP/3-21G* (LanL2DZ for Ir)
level.
69, 5% ee; entry 9). Moderate enantioselectivity (60% ee) was
obtained by use of the indolinecarboxylic acid-derived ligand
1j having 2,6-dimethyl groups on the P-phenoxy group (entry
10). It should be noted that the stereochemical outcome of the
Ir-catalyzed allylic etherification is strongly affected by the
substituents of the N-aryl and the P-aryloxy groups. Thus, the
N-(2,6-dimethylphenyl) ligand 1d gave (S)-13 with 70% ee,
whereas the P-(2,6-dimethylphenyloxy) ligand 1h gave 74% ee
of the opposite enantiomer (R)-13, both of which were derived
from the same chiral source, (S)-pyroglutamic acid.
Mechanistic Discussion with DFT Calculation. Considering
the crucial role of the N- and P-substituents of the ligand in the
stereodiscrimination steps, we were prompted to elucidate the
reaction pathway of the present allylic substitution with the
chiral phosphorodiamidite ligands. Takeuchi proposed the
intermediacy of a π-allyliridium complex 15 to elucidate the
high branch selectivity observed in his system.15 Thus, triphenyl
phosphite coordinates with the metal trans to the substituted
allylic terminus to avoid steric repulsion, and nucleophilic
substitution takes place at the relatively cationic allylic terminus
to give the branched product (Chart 1).
According to Takeuchi’s rationale, the reaction pathway of
the present asymmetric iridium-catalyzed allylic etherification
of cinnamyl carbonate with phenol would be as shown in Figure
5. The phosphorodiamidite-IrCl(cod) complex A generated in
situ by mixing [IrCl(cod)]2 and a phosphorodiamidite ligand
reacts with the cinnamyl carbonate 11 to give η3-(1-phenyl)-
propenyl iridium(III) complex B. Nucleophilic attack of the
phenoxy anion at the substituted allylic terminus would give
the desired branched product 13 and the iridium(I) complex C
by releasing an anion X (X ) Cl or OMe). Oxidative addition
of cinnamyl carbonate to the complex C occurs again to give
the η3-(1-phenyl) propenyl iridium(III) complex B. Nucleophilic
attack of phenoxy anion completes the catalytic cycle.
According to the mechanistic insight, the reaction pathways
giving the opposite enantiomers with ligands 1d and 1h (entry
4 vs 8, Table 2) were studied by DFT calculations of the relative
thermodynamic stability of the η3-(1-phenyl)propenyl iridium-
(III) intermediate D [Ir(OMe)2(thf)(ligand 1d or 1h)].16 The
relative energies of the six isomers of the η3-(1-phenyl)propenyl
iridium(III)-phosphorodiamidites E-J (Chart 2) for each ligand
were calculated. The geometry optimization was performed
using the B3LYP method with LanL2DZ for iridium and
3-21G* for others as the basis sets. The phosphorodiamidite
ligand was fixed trans to the substituted allylic terminus. First,
the most stable configuration of the coordinated ligand was
explored (by rotation of the Ir-P bond) using the complex E.
Figures 6 and 7 show the results of the relative energies and
the optimized structures for ligands 1h and 1d, respectively. It
was found that the conformation of 1hE makes a more stable
complex than 1hE′ (1.3 kcal/mol) and 1hE′′(5.9 kcal/mol) for
ligand 1h (Figure 6). On the other hand, in the case of ligand
1d, the conformation of the complex 1dE was stable compared
to those of 1dE′ (3.6 kcal/mol) and 1dE′′ (4.7 kcal/mol), as
shown in Figure 7. These results indicate that both the 2,6-
dimethyl substituents on the phenoxy group in ligand 1h and
the anilino group in 1d are located in the less hindered space
(nonsubstituted allylic terminus) to avoid the steric repulsion
between the bulky 2,6-dimethylphenyl group and the other
ligands (OMe or THF).
The energy calculations of the possible π-allyliridium inter-
mediates 1hF-hJ and 1dF-dJ were carried out using the
configuration of the phosphorodiamidite ligand obtained in the
complexes 1hE or 1dE for the initial structure. Figure 8 shows
the optimized structures and relative energies of the complexes
1hE-hJ, among which complex 1hH was identified as the most
stable. Thus, the π-allyl intermediate 1hH giving (R)-13 (Chart
3) was 3.4 kcal/mol more stable than the intermediate 1hG
resulting in the S-isomer (1hG (-7.6 kcal/mol) vs 1hH (-11.0
kcal/mol)). The DFT-assisted stereochemical prediction showed
good agreement with the enantioselectivity obtained with ligand
1h. Similarly, the most stable π-allyliridium complex of the
ligand 1d was calculated to be 1dG leading to the S-form 13,
the energy of which was 1.8 kcal/mol lower than that of 1dH
(Figure 9).17 The simulation of ligand 1d was also consistent
with the experimental results giving (S)-13 as the major
enantiomer with 1d (Chart 3).
(16) It is yet unclear if the enantioselectivity of this catalysis was
controlled by the thermodynamic stabilities of the π-allyliridium intermedi-
ates via the π-allylic isomerization (B1-B2 equilibrium of Figure 5) or by
the kinetic π-face selective oxidative addition to form π-allyliridium
intermediates (ref 13a). The energy profiles of R- and S-selective kinetic
oxidative addition should be affected by the thermodynamic stability of
the products of this step, i.e. π-allyliridium intermediates.
(15) Takeuchi, R. Polyhedron 2000, 19, 557.
712 J. Org. Chem., Vol. 72, No. 3, 2007

P-Chiral Phosphorodiamidite Ligands
FIGURE 7. Optimized structures and relative energies of complex 1dE and its isomers (1dE′ and 1dE′′) at the B3LYP/3-21G* (LanL2DZ for Ir)
level.
FIGURE 8. Optimized structures and relative energies of complexes 1hE-hJ calculated at the B3LYP/3-21G* (LanL2DZ for Ir) level.
CHART 3
and (S)-1-phenyl-1-phenoxy-2-propenes were obtained by use
of the L-pyroglutamic acid-derived ligands 1h and 1d, which
have P-(2,6-dimethylphenoxy) and N-(2,6-dimethylphenyl) groups,
respectively. The opposite enantioselectivity in iridium-catalyzed
allylic substitution was explained by DFT calculations of the
energy difference of the π-allyliridium-phosphorodiamidite
intermediates. Further fine-tuning of the N- and P-substituents
thus identified effective diversity groups, and applications of
the chiral phosphorodiamidite ligands for various asymmetric
transformations are currently underway.
Experimental Section
General Procedure for the Preparation of the Phosphorodi-
amidite Ligand 1. Procedure A. To a solution of the amide (1.5
mmol) and triethylamine (3.0 mmol) in toluene (15 mL) was added
Conclusions
In summary, we have described the development of new
P-chiral phosphorodiamidite ligands having the pyrrolo[1,2-c]-
[1,3,2]diazaphosphol-1-one unit. The ligands were utilized for
iridium-catalyzed asymmetric allylic etherification of cinnamyl
carbonate with phenol, where both R- and S-products were
obtained with good enantioselectivity (up to 74% ee) by
changing the N- and P-substituents of the ligands. Thus, (R)-
(17) A referee has argued that the relationship between the thermal
stabilities and the DFT-optimized structures of π-allyliridium complexes,
e.g. 1hG, 1hH, 1dG, and 1dH, could be plausible. Thus, in the relatively
stable structures 1hH and 1dG, the bond lengths between iridium and Ph-
substituted allylic carbon were shorter than those of less stable isomeric
structures, i.e. 1hG and 1dH. Ir-C(Ph)H-CHCH2 (nm): 1hH ) 0.238, 1dG
) 0.243, 1hG ) 0.252, 1dH ) 0.259. We deeply appreciate the referee’s
suggestion.
J. Org. Chem, Vol. 72, No. 3, 2007 713

Kimura and Uozumi
FIGURE 9. Optimized structures and relative energies of complexes 1dE-1dJ calculated at the B3LYP/3-21G* (LanL2DZ for Ir) level.
1
phenylphosphorodichloridite (1.5 mmol) at 0 °C. The reaction
mixture was stirred at 80 °C for 12 h, and the generated
triethylammonium chloride was filtered off thorough a dry Celite
pad. The filtrate was concentrated in vacuo, and the crude products
were purified by column chromatography on dry silica gel.
Procedure B. The mixture of the amide (1.5 mmol) and tris-
(dimethylamino)phosphine (1.5 mmol) in toluene (15 mL) was
stirred at 120 °C for 12 h. The substituted phenol (1.5 mmol) then
was added to the mixture and stirred at 120 °C for 5 days. After
concentration in vacuo, the crude products were purified by column
chromatography on dry silica gel.
General Procedure for the Asymmetric Allylic Etherification
of 11 with 12. [IrCl(cod)]2 (6.7 mg, 0.01 mmol) and ligand 1 (0.02
mmol) were dissolved in THF (1.0 mL) in a sealed tube. Cinnamyl
methyl carbonate (11, 192 mg, 1.0 mmol), phenol (12 188 mg, 2.0
mmol), and triethylamine (202 mg, 2.0 mmol) were successively
added, and the resulting reaction mixture was stirred at 50 °C for
20 h. The reaction mixture was poured into brine and extracted
with ethyl acetate. The extract was dried over Na2SO4, filtered,
and concentrated in vacuo. The ratio of regioisomers 13/14 was
determined by H NMR analysis of the crude mixture. The crude
residue was purified by column chromatography on silica gel to
afford the mixture of 13 and 14. The enantiomeric excess of 13
was determined by HPLC analysis using a chiral stationary phase
column (CHIRALCEL OJ-H, eluent; n-hexane/2-propanol ) 300/
1, flow rate; 0.8 mL/min, retention times; major isomer 37.9 min
and minor 34.0 min).
Calculations. All computational calculations were carried out
by using the Gaussian 98 program.18 Geometries were fully
optimized with Beck’s three-parameter hybrid functional method
(B3LYP).19 Basis set LnaL2DZ, which combines Hay-Wadt’s
effective core potential (ECP),20 was used for the iridium atom in
all calculations. The standard 6-31G(d) and 3-21G* basis sets were
employed for the other atoms for geometry optimization of ligands
and π-allyliridium complexes, respectively. Magnetic shieldings
were calculated by the Gauge-Independent Atomic Orbital method11
(GIAO-B3LYP) on the optimized structure.
Acknowledgment. This work was supported by the CREST
program, sponsored by the JST. We also thank the JSPS
(GRANT-in-AID for Scientific Research, No.15205015) and the
MEXT (Scientific Research on Priority Areas) for partial
financial support of this work.
(18) Gaussian 98, Revision A.9, Frisch, M. J.; Trucks, G. W.; Schlegel,
H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.;
Montgomery, J. A.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam,
J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.;
Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.; Replogle,
E. S.; Pople, J. A., Gaussian, Inc.: Pittsburgh, PA, 1998.
Supporting Information Available: Experimental details for
the preparation of the amides 4-6 and 8 and iridium-catalyzed
allylic etherification, characterization data of 1a-j, 4-6, 8, and 13
(14), and H and 13C NMR charts of new compounds. Optimized
1
structures (Cartesian coordinates) and total energies of â- and
R-1a-j (at B3LYP/6-31G(d) level), and iridium complexes 1hE-
hJ and 1dE-dJ (at B3LYP/3-21G* (LanL2DZ for Ir) level). This
material is available free of charge via the Internet at http://
pubs.acs.org.
(19) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785. (b)
Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(20) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299.
JO0615403
714 J. Org. Chem., Vol. 72, No. 3, 2007