Catalytic addition of alkenylzirconocene chloride to 3,4-dihydroisoquinoline and its enantioselective reaction

Article abstract of DOI:10.1016/j.tetlet.2008.11.078

The addition of alkenylzirconocene chloride to 3,4-dihydroisoquinoline in the presence of a stoichiometric amount of acylating agent such as (Boc)₂O or ClCOOC₂H₅ was carried out in the presence of a catalytic amount of Cu(

Full text of DOI:10.1016/j.tetlet.2008.11.078

Tetrahedron Letters 50 (2009) 587–589
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalytic addition of alkenylzirconocene chloride
to 3,4-dihydroisoquinoline and its enantioselective reaction
*
Akio Saito, Koichi Iimura, Miki Hayashi, Yuji Hanzawa
Laboratory of Organic Reaction Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen Machida, Tokyo 194-8543, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The addition of alkenylzirconocene chloride to 3,4-dihydroisoquinoline in the presence of a stoichiome-
tric amount of acylating agent such as (Boc)2O or ClCOOC2H5 was carried out in the presence of a catalytic
amount of Cu(I) (10 mol %) to give an alkenylation–carbamation product. The enantioselective addition
(56–75%ee) of the alkenylzirconocene chloride was also achieved under Cu(I)/chiral amine (10 mol %)
conditions.
Received 14 October 2008
Revised 18 November 2008
Accepted 20 November 2008
Available online 24 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Cl
ZrCp2
Ph
Organozirconocene chloride complexes are readily accessible
by the hydrozirconation of unsaturated compounds with Schwartz
reagent [Cp2Zr(H)Cl] or by the treatment of alkenyl halide with
Negishi reagent [Cp2Zr-nBu2].1 The poor nucleophilic reactivity of
organozirconocene chloride complexes to aldehydes, ketones, and
imines, however, has kept them from being used in organic synthe-
ses. Thus, the search for new reactions of organozirconocene com-
plexes for the formation of carbon–carbon bond is significant in
terms of chemoselective reactions. Recently, several procedures
to attain the nucleophilic reactivity of alkenylzirconocene chloride
toward electrophiles have been reported.2 Among the procedures,
transmetallation of the alkenylzirconocene species have been
proven to be an useful procedure for the nucleophilic addition of
the alkenyl group of the alkenylzirconocene species.3 The trans-
metallation of the alkenylzirconocene chloride, however, requires
the stoichiometric use of metal salts or organometallics,3,4 and
therefore we seek a catalytic process for the reaction of the
alkenylzirconocene chloride. Previously, we reported that rho-
dium(I)-catalyzed additions of alkenylzirconocene chloride to
N-p-toluenesulfonyl aldimines proceeded in good yields to give
alkenylation products, and the transient generation of an alkenyl-
rhodium species as a reactive intermediate through transmetalla-
tion was suggested.5 Herein, we report the copper(I)-catalyzed
addition of alkenylzirconocene chloride to 3,4-dihydroisoquinoline
(1) in the presence of a stoichiometric amount of acylating agent
and the enantioselective formation of 1-alkenyltetrahydroisoquin-
oline,6which has received considerable attention due to intriguing
biological activities (see Scheme 1).7
2
10 mol% Cu(I)
ClCOOEt
CH2Cl2, rt
N
N
COOEt
1
3
Ph
Scheme 1.
stereoselective manner would be considered a simple procedure
for the preparation of 1-substituted tetrahydroisoquinoline
derivatives, and thus, a variety of metallic reagents has been
employed for that purpose.7a Typical organometallics such as
Grignard or organolithium reagent are often problematic in the
tolerability of the functional group due to their high reactivity
and strong basicity. To the best of our knowledge, the catalytic
enantioselective alkenylation of imine C@N double bond by using
alkenylzirconocene chloride has not been reported.8 The aforemen-
tioned rhodium(I) catalyst did not catalyze the addition of alkenyl-
zirconocene chloride to the aldimines derived from aliphatic
amine.5
2. Results and discussion
At the outset, we examined the reaction of 1 with (E)-styrylzirc-
onocene chloride (2) in CH2Cl2 at an ambient temperature, and we
confirmed that the reaction did not take place. However, premixing
a stoichiometric amount of ethyl chlorocarbonate (ClCOOEt) with 1
in CH2Cl2 at an ambient temperature for 0.5 h followed by the
addition of 2 to the reaction mixture afforded an alkenylation–
carbamation product 3 in 36% yield after being stirred at an ambi-
ent temperature for 16 h (Table 1, entry 1).
Nucleophilic additions of organometallics to the imine C@N
double bond of 3,4-dihydroisoquinoline (1) in an enantio- or dia-
* Corresponding author. Tel./fax: +81 (0) 42 721 1569.
E-mail address: hanzaway@ac.shoyaku.ac.jp (Y. Hanzawa).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.078

588
A. Saito et al. / Tetrahedron Letters 50 (2009) 587–589
Table 1
Ph
Cu(I)-catalyzed addition of 2 to 1a
2
2
ClCOOEt
+
Ph
10 mol% Cu(I)
ClCOOEt
CH2Cl2, rt
N
N
N
1
Cl
COOEt
3
N
CH2Cl2,
rt, 0.5 h
rt, Time (h)
COOEt
COOEt
No Cu(I) catalyst!
95% (1,2-/1,4 = 4/1)
Entry
Catalystb
Time (h)
Yieldc (%)
1
2
3
4
5
6
7
None
16
2
2
2
2
36
68
51
81
87
48
80
N
N
CuBr
COOEt
CuCNd
CuOTf
[Cu(CH3CN)4]PF6
[RhCl(cod)]2
(CH3)2Zne
82%
Ph
4
2
Scheme 3.
a
Ratio of reagents: 1:[ClCOOEt]:2 = 1:1:2.
10 mol %.
Isolated yield.
50 mol %.
150 mol %.
b
c
Table 2
d
e
CuI-catalyzed addition of 2 to 1
A catalytic amount of CuBr (10 mol %) accelerated the reaction,
N
Cl
ZrCp2
and 3 was obtained in 68% yield in less than 2 h (TLC monitoring)
(entry 2).9 It turned out that (Boc)2O, instead of ClCOOEt, was also
an efficient additive for the reaction. It should be mentioned that
the CuBr-catalyzed addition of 2 to 1 did not occur in the absence
of ClCOOEt or (Boc)2O. These observations suggest that the activa-
tion of the imine portion by the formation of N-acyl iminium ion is
essential for the present Cu(I)-catalyzed reaction.10 Among the
examined copper(I) catalysts (entries 2–5), [Cu(CH3CN)4]PF6 indi-
cated notable catalytic efficiency (entry 5). Although the sole use
of Rh(I) catalyst did not give a product, the presence of ClCOOEt
showed the formation of 3 (48%) as well (entry 6). The use of a
stoichiometric amount of dimethylzinc, transmetallation from Zr
to Zn,2,3 under otherwise identical conditions gave 3 in 80% yield
(entry 7). The Cu(I)-catalyzed addition of alkenylzirconocene
chloride to 1 was confirmed to be quite general (Scheme 2). How-
ever, the reaction of 1 with 3-phenylpropylzirconocene chloride,
which is generated by the hydrozirconation of 3-phenylpropene,
did not give an alkylation–acylation product.11
(Boc)2O
N
COOtBu
Ph
10 mol% Cu(I)
chiralamine
*
56~75%ee
CH2Cl2 (-23 ºC
6 h
rt)
Ph
Entry
Catalyst
Liganda
Yieldb (%)
eec (%)
1
2
3
4
5
6
CuBr
(ꢀ)-SP
63
86
78
74
90
65
18d
63d
56d
44
50
75
[Cu(CH3CN)4]PF6
CuOTf
(ꢀ)-SP
(ꢀ)-SP
CuOTf
(S,S)-Box-tBu
(S,S)-Box-tBu
5e
[Cu(CH3CN)4]PF6
[Cu(CH3CN)4]PF6
a
O
R
R
O
R
N
N
N
N
R
tBu
tBu
(-)-Sparteine [(-)SP]
It is worth commenting that the reaction of 2 with heteroaro-
matic compounds such as quinoline or isoquinoline proceeded
efficiently without the use of a Cu(I) catalyst to give alkenyla-
tion–acylation products at an ambient temperature (Scheme 3).
In these reactions, the presence of an acylating agent was also cru-
cial as in the case of the reaction of 1 with 2, since the absence of
ethyl chlorocarbonate did not afford any products.
R = H; (S,S)-Box-tBu
R = CH3; 5
b
Isolated yield.
c
d
e
Determined by chiral HPLC (DAISEL chiralpak AD, 2-propanol/hexane = 1:19)
(R)-4 was obtained as a major enantiomer.
0 °C, 24 h.
Based on the described results, we examined the enantioselec-
tive alkenylation of 1 using 2, since highly enantioselective addi-
tions of organometallics to 1 or related heterocycles have been
reported.7,12 Results of the examination of chiral amine ligands
(10 mol %) under the present Cu(I)-catalyzed conditions are shown
in Table 2.13 It is important to note that the Cu(I) catalyst affects
the yields and optical purity of 4. Thus, [Cu(CH3CN)4]PF6 catalyst
was preferable to CuX (X = halogen) or CuOTf catalyst in terms of
both chemical and optical yields (Table 2, entry 2). Most of the
Cu(I)-catalyzed reactions of 2 using various chiral amine ligands
proceeded to give 4 in good yields (63–90%), albeit disappointingly
low enantioselectivity (18–56%ee) (entries 1–5). Among the exam-
t
ined Box ligand derivatives, the use of butyl-substituted (S,S)-Box
ClCOOEt
ligand 514 showed somewhat improved results (65% yield, 75%ee)
(entry 6). The use of (ꢀ)-sparteine (10 mol %)15 as a chiral ligand
(entries 1–3) showed moderate enantiomeric inductions in a
reversed enantioselectivity (86% yield, 63%ee).
Cl
ZrCp2
[Cu(CH3CN)4]PF6
(10 mol%)
CH2Cl2, rt
1
R1
N
+
COOEt
R2
R2
The absolute configuration of (S)-4, 75%ee ½a D
ꢁ
122.6 (c 1.0,
R1
CHCl3), obtained by using tbutyl-(S,S)-Box ligand 5, was deter-
mined by converting it to compound (S)-6 whose absolute config-
uration has been established (Scheme 4).16
R1= nBu,
R1= tBu,
R1= Et,
R2= H
R2= H
R2= Et
78%
72%
80%
In summary, we indicated that the Cu(I)-catalyzed addition of
an alkenylzirconocene chloride to 3,4-dihydroisoquinoline pro-
Scheme 2.

A. Saito et al. / Tetrahedron Letters 50 (2009) 587–589
589
2. (a) Suzuki, K.; Hintermann, L.; Yamanoi, S. In Titanium and Zirconium in Organic
Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim, 2002; pp 282–318; (b)
Chinkov, N.; Marek, I. In New Aspects of Zirconium Containing Organic
Compounds; Marek, I., Ed.; Springer Verlag: Berlin, Heidelberg, 2005; pp 133–
166.
3. (a) Wipf, P.; Kendall, C. Chem. Eur. J. 2002, 8, 1778; (b) Lipshutz, B. H.; Pfeiffer, S.
S.; Noson, K.; Tomioka, T. In Titanium and Zirconium in Organic Synthesis; Marek,
I., Ed.; Wiley-VCH: Weinheim, 2002; pp 110–148.
4. Wipf, P.; Stephenson, C. R. J. Org. Lett. 2003, 5, 2449–2452. and the references
cited therein.
5. (a) Kakuuchi, A.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 2003, 44, 923; (b)
Hanzawa, Y.; Takebe, Y.; Saito, A.; Kakuuchi, A.; Fukaya, H. Tetrahedron Lett.
2007, 48, 6471.
1) H2 / 10% Pd-C
N
NH
Ph
2) TMSOTf / CH2Cl2
84%
Boc
(S)-4
(S)-6
Ph
[α]D = 122.7º
(75%ee)
[α]D = - 18.9º
[ ] = - 23.5º
lit. ref. 16 α D
Scheme 4.
6. For the enantioselective addition of alkenylzirconocene chloride to imines
through transmetallation: Wipf, P.; Ribe, S. J. Org. Chem. 1998, 63, 6454.
7. For review, see: Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104,
3341; Brossi, A.. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego,
1998; Vol. 50, pp 109–139; (a) Chrzanowska, M.; Sokolowska, J. Tetrahedron:
Asymmetry 2001, 12, 1435; (b) Cabello, N.; KIzirian, J.-C.; Gille, S.; Alexakis, A.;
Bernardinelli, G.; Pinchard, L.; Caille, J.-C. Eur. J. Org. Chem. 2005, 4835; (c)
Alexakis, A.; Amiot, F. Tetrahedron: Asymmetry 2002, 13, 2117; (d) Amiot, F.;
Cointeaux, L.; Silve, E. J.; Alexakis, A. Tetrahedron 2004, 60, 8221; (e) Cointeaux,
L.; Alexakis, A. Tetrahedron: Asymmetry 2005, 16, 925; (f) Wu, T. R.; Chong, J. M.
J. Am. Chem. Soc. 2006, 128, 9646; (g) Sakamoto, N.; Dubs, C.; Hamashima, Y.;
Sodeoka, M. J. Am. Chem. Soc. 2006, 128, 9646.
ceeds efficiently in the presence of a stoichiometric amount of an
acylating agent to give an alkenylation–acylation product. It is also
observed that a moderate induction of enantiomeric excess was
achieved by the Cu(I)/chiral amine-catalyzed addition of the alke-
nylzirconocene chloride to 3,4-dihydroisoquinoline. Although the
mechanism of the addition of alkenyl group to 3,4-dihydroisoquin-
oline under the present conditions is uncertain at present,17 the de-
scribed reaction of the alkenylzirconocene chloride indicates a new
possibility of organozirconocene complexes in organic synthesis.
8. Rh(I)-catalyzed highly enantioselective 1,4-addition of organozirconocene
chloride to
a,b-enones has been reported: (a) Oi, S.; Sato, T.; Inoue, Y.
Tetrahedron Lett. 2004, 45, 5051; (b) Nikolaou, K. C.; Tang, W.; Dagneau, P.;
Faraoni, R. Angew. Chem., Int. Ed. 2005, 44, 3874.
3. Typical experimental procedure
9. In the copper(I)-catalyzed reaction, the inevitable formation of 1,4-
diphenylbutadiene (<10%) was observed.
made in the reaction of a Cu(I)-catalyzed conjugate addition of 1 to a,b-enones,
see: Ref. 17a.
A similar observation has been
Under an Ar atmosphere, to a solution of alkenylzirconocene
chloride (1.0 mmol) in CH2Cl2 (2 mL) was added successively a pre-
mixed (0.5 h at room temperature) solution of 1 (0.5 equiv) and
ClCOOC2H5 (0.5 equiv) in CH2Cl2 (2 mL), and Cu(I) catalyst
(10 mol % to 1), and the mixture were stirred at room temperature
for 28 h. The reaction was terminated by adding saturated aqueous
solution of NaHCO3, and the resulting mixture was extracted with
CHCl3. The combined organic layer was dried over Na2SO4 and fil-
tered. The filtrate was concentrated to dryness to give a crude
product, which was purified by silica gel column chromatography
(hexane–ethyl acetate = 30:1) to give a pure product. The analyti-
cal sample was obtained by a further MPLC purification (hexane–
ethyl acetate = 30:1).
10. In the Pd-catalyzed nucleophilic addition of soft carbon nucleophiles to 3,4-
dihydroisoquinoline in the presence of [(Boc)2]O, the formation of N-acyl
iminium salt via N,O-actal has been reported. See, Ref. 7g. For the in situ
activation of C@N double bond with acid halide for the addition of alkynilides,
see: (a) Fischer, C.; Carreria, E. M. Org. Lett. 2004, 6, 1497; (b) Black, D. A.;
Arndtsen, B. A. Org. Lett. 2004, 6, 1107.
11. Similar observation has been made in the Rh(I)-catalyzed reactions. See, Ref. 5.
12. (a) Shun, Z.; Yu, S.; Ding, Z.; Ma, D. J. Am. Chem. Soc. 2007, 129, 9300; (b) Taylor,
A. M.; Schreiber, S. L. Org. Lett. 2006, 8, 143; Addition of alkenylzinc to 3,4-
dihydroisoquinoline N-oxide: Wang, S.; Seto, C. T. Org. Lett. 2006, 8, 3979.
13. Examination of phosphine ligands (10 mol %) such as (S)-BINAP or (R)-QUINAP
showed 3% or 10%ee, respectively.
14. Box ligands were purchased. Commercially unavailable Box ligands were
prepared according to the procedure by the following papers: (a) Cornejo, A.;
Fraile, J. M.; Garcia, J. I.; Gil, M. J.; Martinez-Merino, V.; Mayoral, J. A.; Pires, E.;
Villalba, I. Synlett 2005, 2321; (b) Itagaki, M.; Masumoto, K.; Yamamoto, Y. J.
Org. Chem. 2005, 70, 3292; (c) Itagaki, M.; Yamamoto, Y. Tetrahedron Lett. 2006,
47, 523.
Acknowledgment
15. Enantioselective alkylation by the reaction of organolithium and 3,4-
dihydroisoquinoline derivatives using (ꢀ)-sparteine, see: Refs. 7a–c.
16. Meyers, A. I.; Dickman, D. A.; Boes, M. Tetrahedron 1987, 43, 5095.
17. We have no evidence for the generation of alkenyl copper species through
transmetallation. Recently, it has been reported that copper(I)-catalyzed
This work was supported by Grant-in-Aid for Scientific Re-
search (C), Japan Society for the Promotion of Science (No.
19590012).
conjugate additions of alkenylzirconocene chloride to
proceed via a simultaneous three-component mechanism, which is proposed
for the copper(I)-catalyzed addition of alkylzirconocene chloride to ,b-enone
a,b-enone might
References and notes
a
1. (a) Schwartz, J.; Labinger, J. A. Angew. Chem., Int. Ed. Engl. 1976, 15, 333; (b)
Takahashi, T.; Kotora, M.; Fischer, R.; Nishihara, Y.; Nakajima, K. J. Am. Chem.
Soc. 1995, 117, 11039.
by Wipf et al. (a) El-Batta, A.; Hage, T. R.; Plotkin, S.; Bergdahl, M. Org. Lett.
2004, 6, 107; (b) Wipf, P.; Xu, W.; Smitrovich, J. H.; Lehmann, R.; Venanzi, L. M.
Tetrahedron 1944, 50, 1935.