Development of biisoquinoline-based chiral diaminocarbene ligands: Enantioselective SN2′ allylic alkylation catalyzed by copper-carbene complexes

Article abstract of DOI:10.1021/jo702512z

Chiral biisoquinoline-based diaminocarbene ligands (BIQ) were designed to create a chiral environment extended toward the metal center, which was confirmed by an X-ray structure. The concise ligand synthesis is highlighted by a modified Bischler-Napieralski cyclization of bisamides prepared from readily available chiral phenethylamines, and allows easy variation of the stereodifferentiating groups. The cyclohexyl-BIQ-copper complex is an efficient catalyst for enantioselective S_N2′ allylic alkylation with Grignard reagents showing S_N2′ regioselectivity higher than 5:1 and enantioselectivity in the range of 68-77% ee.

Full text of DOI:10.1021/jo702512z

metal center, and therefore less discriminating for less sterically
demanding substrates. In addition, the X-ray crystal structure
shows that the aryl groups on the nitrogens are pointing
orthogonal to the plane of NHC-Ru.3b Therefore, it would be
interesting to extend and reposition the stereodifferentiating
groups more toward the metal center. We envisioned that this
possibility could be explored through the tricyclic biisoquinoline-
based chiral carbene 2 featuring stereogenic centers at the
positions R to the nitrogen atoms (Figure 1). Related tricyclic
carbene structures have been reported.4 During the course of
our study, Herrmann reported a phenyl-substituted biisoquino-
line-based carbene ligand and its Rh and Ir complexes.4a,5 Herein
we report a concise synthesis of chiral biisoquinoline-based
carbene ligands (BIQ) and our results on enantioselective allylic
alkylation catalyzed by Cu-carbene complexes.
Development of Biisoquinoline-Based Chiral
Diaminocarbene Ligands: Enantioselective SN2′
Allylic Alkylation Catalyzed by Copper-Carbene
Complexes
Hwimin Seo, Dimitri Hirsch-Weil, Khalil A. Abboud, and
Sukwon Hong*
Department of Chemistry, UniVersity of Florida, P.O. Box
117200, GainesVille, Florida 32611-7200
shong@chem.ufl.edu
ReceiVed NoVember 21, 2007
Chiral biisoquinoline-based diaminocarbene ligands (BIQ)
were designed to create a chiral environment extended toward
the metal center, which was confirmed by an X-ray structure.
The concise ligand synthesis is highlighted by a modified
Bischler-Napieralski cyclization of bisamides prepared from
readily available chiral phenethylamines, and allows easy
variation of the stereodifferentiating groups. The cyclohexyl-
BIQ-copper complex is an efficient catalyst for enantiose-
lective SN2′ allylic alkylation with Grignard reagents showing
SN2′ regioselectivity higher than 5:1 and enantioselectivity
in the range of 68-77% ee.
FIGURE 1. Design of tricyclic carbene ligands featuring an extended
chiral pocket around the metal center.
Tricyclic biisoquinoline-based carbene ligands (BIQ) were
synthesized from chiral phenethylamines (3) which were readily
prepared by modifications of reported procedures6,7 (Scheme
1). Chiral phenethylamines were converted to bisamides (4)
which then were subjected to modified Bischler-Napieralski
cyclization conditions (PCl5 and Zn(OTf)2) to afford 3,3′-
disubstituted tetrahydrobiisoquinolines (5) in good yield. It is
noteworthy that the biisoquinoline compounds (5) are also
Since the discovery and isolation of several types of stable
singlet carbenes, tremendous research efforts have been made
to develop N-heterocyclic carbene (NHC) ancillary ligands.1
NHCs are powerful σ-donating and weak π-accepting ligands,
and their metal complexes generally show better air and
thermal stability than phosphine complexes. Nevertheless, the
development of chiral carbene ligands is still in its early stages.2
Structural diversity in the chiral carbene ligands has not been
fully explored. The chiral Ru complex (1) developed by Grubbs
and co-workers represents one of the best “monodentate”
designs, accounting for over 90% ee in asymmetric ring closing
metathesis reactions (Figure 1).3 However, a substrate depen-
dence on enantioselectivity in these reactions3b might suggest
that the chiral space created by the ligand is remote from the
(3) (a) Funk, T. W.; Berlin, J. M.; Grubbs, R. H. J. Am. Chem. Soc.
2006, 128, 1840-1846. (b) Seiders, T. J.; Ward, D. W.; Grubbs, R. H.
Org. Lett. 2001, 3, 3225-3228.
(4) (a) Baskakov, D.; Herrmann, W. A.; Herdtweck, E.; Hoffmann, S.
D. Organometallics 2007, 26, 626-632. (b) Herrmann, W. A.; Baskakov,
D.; Herdtweck, E.; Hoffmann, S. D.; Bunlaksananusorn, T.; Rampf, F.;
Rodefeld, L. Organometallics 2006, 25, 2449-2456. (c) Cavell, K. J.;
Elliott, M. C.; Nielsen, D. J.; Paine, J. S. Dalton Trans. 2006, 4922-4925.
(d) Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C. Chem. Commun.
2002, 2704-2705.
(5) Herrmann reported that during the preparation of the saturated NHC-
Rh or -Ir complexes via transmetalation, the unsaturated NHC-metal
complexes were unexpectedly formed in moderate yields when bromide
was counterion in the imidazolium salt.4a
(1) Recent reviews on NHC-metal complexes: (a) N-heterocyclic
Carbenes in Transition Metal Catalysis; Glorius, F., Ed.; Topics in
Organometallic Chemistry, Vol. 21; Springer-Verlag: New York, 2007.
(b) N-heterocyclic Carbenes in Synthesis; Nolan, S. P., Ed.; Wiley-VCH:
Weinheim, Germany 2006. (c) Kantchev, E. A. B.; O’Brien, C. J.; Organ,
M. G. Angew. Chem., Int. Ed. 2007, 46, 2768-2813.
(2) Reviews on chiral NHC ligands: (a) Gade, L. H.; Bellemin-Laponnaz,
S. Top. Organomet. Chem. 2007, 21, 117-157. (b) Perry, M. C.; Burgess,
K. Tetrahedron: Asymmetry 2003, 14, 951-961.
(6) Nenajdenko, V. G.; Karpov, A. S.; Balenkova, E. S. Tetrahedron:
Asymmetry 2001, 12, 2517-2527.
(7) Takahashi, H.; Chida, Y.; Yoshi, T.; Suzuki, T.; Yanaura, S. Chem.
Pharm. Bull. 1986, 34, 2071-2077.
10.1021/jo702512z CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/12/2008
J. Org. Chem. 2008, 73, 1983-1986
1983

SCHEME 1. Synthesis of Chiral Imidazoliums
a Opposite enantiomer shown for compounds 3c, 4c, 5c, and 6c.
SCHEME 2. Synthesis of Metal-Carbene Complexes
FIGURE 2. X-ray structure of Pd-carbene complex 7a-Pd. Thermal
ellipsoids are drawn at the 50% probability level. The inserted structure
(PdClC9H9 omitted) shows the front view of the tricyclic carbene ligand.
catalyzed asymmetric allylic alkylations12 allow the use of hard
nucleophiles such as Grignard reagents13,14 ,15 or dialkyl zinc16,17
and usually proceed with high SN2′-selectivity, creating new
tertiary or quaternary stereogenic centers from simple linear
allylic substrates. The new BIQ carbene-copper catalysts favor
the γ-alkylation product (SN2′),18 which has been observed with
(12) Reviews: (a) Alexakis, A.; Malan, C.; Louise, L.; Tissot-Croset,
K.; Polet, D.; Falciola, C. Chimia 2006, 60, 124-130. (b) Yorimitsu, H.;
Oshima, K. Angew. Chem., Int. Ed. 2005, 44, 4435-4439. (c) Hoveyda,
A. H.; Hird, A. W.; Kacprzynski, M. A. Chem. Commun. 2004, 1779-
1785.
(13) (P,N) or (S,N) ligands: (a) Carosi, L.; Hall, D. G. Angew. Chem.,
Int. Ed. 2007, 46, 5913-5915. (b) Falciola, C. A.; Alexakis, A. Angew.
Chem., Int. Ed. 2007, 46, 2619-2622. (c) Geurts, K.; Fletcher, S. P.; Feringa,
B. L. J. Am. Chem. Soc. 2006, 128, 15572-15573. (d) Lo´pez, F.; van Zijl,
A. W.; Minnaard, A. J.; Feringa, B. L. Chem. Commun. 2006, 409-411.
(e) Falciola, C. A.; Tissot-Croset, K.; Alexakis, A. Angew. Chem., Int. Ed.
2006, 45, 5995-5998. (f) Tissot-Croset, K.; Polet, D.; Alexakis, A. Angew.
Chem., Int. Ed. 2004, 43, 2426-2428. (g) Alexakis, A.; Croset, K. Org.
Lett. 2002, 4, 4147-4149. (h) Meuzelaar, G. J.; Karlstro¨m, A. S. E.; van
Klaveren, M.; Persson, E. S. M.; del Villar, A.; van Koten, G.; Ba¨ckvall,
J-E. Tetrahedron 2000, 56, 2895-2903.
(14) NHC ligands: (a) Okamoto, S.; Tominaga, S.; Saino, N.; Kase, K.;
Shimoda, K. J. Organomet. Chem. 2005, 690, 6001-6007. (b) Tominaga,
S.; Oi, Y.; Kato, T.; An, D. K.; Okamoto, S. Tetrahedron Lett. 2004, 45,
5585-5588.
(15) Lewis base activation of Grignard reagents with NHC (Cu-free
AAA): Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 15604-
15605.
(16) NHC ligands: (a) Kacprzynski, M. A.; May, T. L.; Kazane, S. A.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46, 4554-4558. (b)
Gillingham, D. G.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46, 3860-
3864. (c) Van Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda,
A. H. J. Am. Chem. Soc. 2005, 127, 6877-6882. (d) Larsen, A. O.; Leu,
W.; Oberhuber, C. N.; Campbell, J. E.; Hoveyda, A. H. J. Am. Chem. Soc.
2004, 126, 11130-11131.
(17) Other nitrogen or phosphine based ligands: (a) Kacprzynski, M.
A.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 10676-10681. (b) Piarulli,
U.; Daubos, P.; Claverie, C.; Roux, M.; Gennari, C. Angew. Chem., Int.
Ed. 2003, 42, 234-236. (c) Luchaco-Cullis, C. A.; Mizutani, H.; Murphy,
K. E.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2001, 40, 1456-1460. (d)
Malda, H.; van Zijl, A. W.; Arnold, L. A.; Feringa, B. L. Org. Lett. 2001,
3, 1169-1171. (e) Du¨bner, F.; Knochel, P. Angew. Chem., Int. Ed. 1999,
38, 379-381.
a Opposite enantiomer shown for compounds 6c and 8c.
potentially interesting C2-symmetric chiral bisimine ligands.
Standard reaction of the bisimines (5) with chloromethyl ethyl
ether smoothly produced the C2-symmetric imidazolium salts
(6) in excellent yield.8
Palladium(II) and copper(I) complexes were successfully
synthesized from the chiral imidazoliums (6) via a transmeta-
lation route9 (Scheme 2) and single crystals of carbene-Pd(II)
complex (7a-Pd) suitable for X-ray diffraction were easily
obtained.10 The X-ray structure of 7a-Pd confirmed our design
hypothesis showing that the stereodifferentiating groups (i-Bu)
are projected toward the Pd metal center in this C2-symmetric
ligand structure (Figure 2).
The carbene-copper(I) complexes (8a-c) were tested in
asymmetric allylic alkylation (AAA) reactions11 (Table 1). Cu-
(8) Arduengo, A. J., III; Krafczyk, R.; Schmutzler, R. Tetrahedron 1999,
55, 14523-14534.
(9) Wang, H. M. J.; Lin, I. J. B. Organometallics 1998, 17, 972-975.
(10) Attempts to grow single crystals of BIQ-copper(I) complexes (8a-
c) for X-ray diffraction were unsuccessful.
(11) Pfaltz, A.; Lautens, M. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin,
Germany, 1999; Vol. II, pp 833-884.
1984 J. Org. Chem., Vol. 73, No. 5, 2008

TABLE 1. Optimization of Reaction Conditions
TABLE 2. Reaction Scope
a Isolated yield. b Determined by 1H NMR. c Determined by chiral HPLC
(see the Supporting Information for details).
survey where changing the solvent to THF or CH2Cl2 signifi-
cantly lowered regioselectivity and enantioselectivity (entries
1, 11, and 13). The enantioselectivity was rather insensitive to
temperature; however, lower yields were obtained at -78 °C
(entries 9 and 10). When the ligand structure is varied, the
cyclohexyl complex (8c) gives the best regioselectivity (88:12)
and enantioselectivity (72% ee).
The reaction scope was studied under the optimized condi-
tions (Table 2). Other alkyl Grignard reagents can be used
without significantly decreasing reaction yield, regioselectivity,
or enantioselectivity (entries 1-3). However, use of phenyl
Grignard reagent affords the SN2 product exclusively, implying
a possible change in mechanism. The reaction was also effective
for the formation of a quaternary chiral center (entry 5). The
aryl substrates also tolerate electron-donating (entry 6) and
electron-withdrawing substituents (entry 7), as well as ortho-
substituents (entry 8).
In summary, we have synthesized chiral biisoquinoline-based
tricyclic chiral diaminocarbene ligands (BIQ) and their Pd and
Cu complexes. The chiral environment is created in close
proximity to the metal center, which is confirmed by an X-ray
crystal structure. The concise ligand synthesis allows easy
variation of stereodifferentiating groups from readily accessible
starting materials. The cyclohexyl-BIQ-copper complex is an
efficient catalyst for enantioselective SN2′ allylic alkylation with
Grignard reagents and the BIQ carbene ligands can be applied
to other asymmetric catalyses. Application of BIQ carbene and
imine ligands in other asymmetric transformations is currently
in progress in our laboratory.
a Isolated yield. b Determined by 1H NMR. c Determined by chiral HPLC.
Absolute configuration is determined by the optical rotation value (see the
Supporting Information for details).
other reported copper catalysts.12 The initial optimization of the
reaction conditions was mostly performed with 3 mol % [(S)-
i-Bu-BIQ]CuCl catalyst (8a) on naphthyl substrates (9). Interest-
ingly, the BIQ-CuCl catalysts show better regioselectivity and
enantioselectivity with ester leaving groups such as acetate
(OAc) or pivaloate (OPiv) (entries 6, 14, and 15 vs entries 1-5).
This is in contrast to the phosphoramidite ligands which typically
use allylic halide substrates for Grignard reagent alkylations.13
Diethyl ether was selected as the optimum solvent after a brief
(18) When a secondary alcohol pivaloate substrate was used, the linear
substitution product was obtained as a major product. This result excludes
the possible formation of an η3-allyl Cu intermediate and implies that a
SN2′-type substitution mechanism is operative.
Experimental Section
N1,N2-Bis((S)-1-cyclohexyl-2-phenylethyl)oxalamide, 4c-(S,S).
To a cooled, magnetically stirred solution of 3c (0.458 g, 2.25
mmol) and triethylamine (0.350 mL, 2.53 mmol) in THF (28 mL)
J. Org. Chem, Vol. 73, No. 5, 2008 1985

under argon was added oxalyl chloride (0.096 mL, 1.1 mmol)
dropwise at 0 °C. The reaction mixture was allowed to warm to
room temperature and was then stirred for 12 h. The reaction
mixture was cooled to 0 °C before quenching with water (10 mL).
The mixture was extracted with CHCl3 (3 × 15 mL). The combined
organic extracts were dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 3:1 chloroform/hexane) to afford 4c
(0.349 g, 0.778 mmol, 71% yield). 1H NMR (300 MHz, CDCl3) δ
7.27-7.09 (m, 12H), 3.95 (m, 2H), 2.88 (dd, J ) 5.6, 14 Hz, 2H),
2.66 (dd, J ) 8.3, 14 Hz, 2H), 1.78-1.58 (m, 10H), 1.44 (m, 2H),
1.24-1.02 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 159.5, 138.2,
129.3, 128.6, 126.6, 56.1, 41.0, 38.2, 30.3, 28.3, 26.5, 26.3, 26.2.
HRMS-ESI (m/z) [M + H]+ calcd for C30H40N2O2 461.3163, found
concentrated under reduced pressure to afford the crude silver-
carbene complex, which was used immediately in the next step
without further purification. (b) A solution of the crude silver-
carbene complex and CuCl (64 mg, 0.64 mmol) in CH2Cl2 (5 mL)
was stirred for 2 h at room temperature under argon and then filtered
through a pad of celite. The filtrate was concentrated under reduced
pressure. The residue was purified quickly by flash column
chromatography on silica gel (CH2Cl2) to yield 8c (0.24 g, 0.45
1
mmol, 71% yield). H NMR (300 MHz, CDCl3) δ 7.88 (dd, J )
2.3, 6.2 Hz, 2H), 7.29-7.23 (m, 6H), 4.43 (m, 2H), 3.26 (dd, J )
5.0, 15.8 Hz, 2H), 3.16 (dd, J ) 1.8, 15.6 Hz, 2H), 1.73-0.89 (m,
22H); 13C NMR (75 MHz, CDCl3) δ 133.4, 129.4, 129.1, 127.3,
126.3, 124.1, 124.0, 61.7, 38.2, 32.7, 31.4, 30.0, 26.1, 26.0, 25.9.
Anal. Calcd for C31H36ClCuN2: C, 69.51; H, 6.77; N, 5.23.
Found: C, 69.42; H, 6.75; N, 4.83. [R]23D +173.6 (c 0.78, CHCl3).
461.3164. [R]24 -24.4 (c 4.78, CHCl3).
D
(3S,3′S)-3,3′-Dicyclohexyl-3,3′,4,4′-tetrahydro-1,1′-biisoquino-
line, 5c-(S,S). To a solution of 4c (619 mg, 1.38 mmol) in toluene
(60 mL) under nitrogen was added Zn(OTf)2 (1.51 g, 4.14 mmol)
and PCl5 (1.72 g, 8.28 mmol). The reaction mixture was heated at
85 °C for 12 h and then was cooled to room temperature before
quenching with a 30% aqueous NH4OH solution (20 mL). The
mixture was extracted with EtOAc (3 × 35 mL). The combined
organic extracts were dried over MgSO4, filtered, and concentrated
under reduced pressure. Purification of the crude product by flash
column chromatography (silica gel, 7:1 hexanes/EtOAc) afforded
5c (357 mg, 0.841 mmol, 61% yield). 1H NMR (300 MHz, CDCl3)
δ 7.26-7.05 (m, 8H), 3.40 (m, 2H), 2.69 (m, 4H), 1.93-1.54 (m,
12H), 1.29-1.09 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 163.9,
138.2, 130.9, 128.5, 127.8, 62.0, 42.9, 30.4, 29.2, 27.9, 26.8, 26.7,
26.6. HRMS-ESI (m/z) [M + H]+ calcd for C30H36N2 425.2951,
Typical Procedure for Asymmetric Allylic Alkylation. A
flame-dried Schlenk flask was charged with a substrate (0.5 mmol),
a copper catalyst (0.015 mmol, 3 mol %), and a solvent (3 mL).
To this solution under argon was added a Grignard reagent (0.75
mmol in Et2O) via syringe at a specified temperature and the
resulting reaction mixture was stirred for 1 h at the same
temperature. Then the reaction was quenched with a saturated
aqueous NH4Cl solution (10 mL). The mixture was extracted with
Et2O (3 × 15 mL). The combined organic extracts were dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash column chromatography (silicagel,
1
hexanes). The regioselectivity (SN2′:SN2) was determined by H
NMR. The integration values of the olefinic proton signal of the
two regioisomers were compared. The absolute configuration of
the chiral center of 2-(pent-1-en-3-yl)naphthalene (10) was deter-
mined by comparing the [R]D value of our product with the reported
value.17a The values for enantiomeric excess of the chiral products
were measured by chiral stationary phase HPLC analysis. (HPLC
condition for 10: Whelk-O1 column, 254 nm, 100% pentane, 0.2
mL/min, tS ) 25.5 min, tR ) 26.9 min.)
found 425.2957. [R]24 +6.2 (c 2.64, CHCl3).
D
[6(S),8(S)-Dicyclohexyl-5,6,8,9-tetrahydro-6a,7a-diazadi-
benzo[c,g]fluorenium] Chloride, 6c-(S,S). To a solution of 5c
(0.0822 g, 0.194 mmol) in THF (8 mL) was added chloromethyl
ethyl ether (0.110 mL, 1.18 mmol). The reaction mixture was stirred
for 12 h. Volatiles were removed at reduced pressure and the
resulting sticky residue was purified by flash column chromatog-
raphy (silica gel, 10:1 CH2Cl2/MeOH) to afford 6c (0.0750 g, 0.159
Acknowledgment. We thank the University of Florida and
the Donors of the Petroleum Research Fund, administered by
the American Chemical Society (PRF no. 46157-G1) for
financial support of this research. S.H. thanks Oak Ridge
Associated Universities for the Ralph E. Powe Junior Faculty
Enhancement Award.
1
mmol, 82% yield). H NMR (300 MHz, CDCl3) δ 11.31 (s, 1H),
7.92 (d, J ) 7.2 Hz, 2H), 7.39-7.32 (m, 6H), 7.17 (m, 2H), 3.34
(dd, J ) 5.5, 16.1 Hz, 2H), 3.20 (d, J ) 15.9 Hz, 2H), 1.73-0.82
(m, 20H); 13C NMR (75 MHz, CDCl3) δ 137.2, 132.8, 130.7, 129.9,
127.9, 124.5, 124.1, 124.0, 60.1, 38.3, 31.6, 29.5, 29.4, 25.9, 25.7,
25.6. HRMS-ESI (m/z) [M - Cl]+ calcd for C31H37ClN2 437.2957,
found 437.2971. [R]25 +212.1 (c 2.44, CHCl3).
D
Supporting Information Available: Detailed synthetic proce-
dures and analytical data for new compounds (pdf) and X-ray
crystallographic data for 7a-Pd (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
[6(S),8(S)-Dicyclohexyl-5,6,8,9-tetrahydro-6a,7a-diazadi-
benzo[c,g]fluoren-5-ylidene]chlorocopper(I), 8c. (a) A solution
of 6c (0.30 g, 0.63 mmol) and Ag2O (0.088 g, 0.38 mmol) in CH2-
Cl2 (5 mL) was stirred for 12 h at room temperature under argon
and then filtered through a pad of celite. The filtrate was
JO702512Z
1986 J. Org. Chem., Vol. 73, No. 5, 2008