Enantioselective synthesis of tetrahydroisoquinolines via iridium-catalyzed intramolecular Friedel-Crafts-type allylic alkylation of phenols

Article abstract of DOI:10.1021/ol3008793

An efficient iridium-catalyzed intramolecular Friedel-Crafts-type allylic alkylation reaction of phenols was developed, affording tetrahydroisoquinolines with moderate to excellent yields, enantioselectivity, and good regioselectivity.

Full text of DOI:10.1021/ol3008793

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2579–2581
Enantioselective Synthesis of
Tetrahydroisoquinolines via Iridium-
Catalyzed Intramolecular FriedelÀCrafts-
Type Allylic Alkylation of Phenols
Qing-Long Xu, Li-Xin Dai, and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
slyou@sioc.ac.cn
Received April 5, 2012
ABSTRACT
An efficient iridium-catalyzed intramolecular FriedelÀCrafts-type allylic alkylation reaction of phenols was developed, affording tetrahydro-
isoquinolines with moderate to excellent yields, enantioselectivity, and good regioselectivity.
Phenols are cheap and abundant chemical feedstock widely
used in chemical industry and academic laboratories.1
They also serve as nucleophiles in transition-metal-cata-
lyzed allylic substitution reactions.2 Transition-metal-cat-
alyzed allylic substitution reactions with phenols generally
proceed as O-allylation.3À6 There are only limited exam-
ples of C-allylation where phenols proceed as FriedelÀ
Crafts-type alkylation reactions. To date, Pd-,7 Mo-,8 Ru-,9
Rh-,10 and Au-type11 catalysts have been reported to catalyze
the FriedelÀCrafts-type allylic alkylation of phenols.12
(1) Weber, M.; Weber, M.; Kleine-Boymann, M. “Phenol” in Ull-
Figure 1. Intramolecular allylic dearomatization and FriedelÀ
mann’s Encyclopedia of Industrial Chemistry; Wiley-VCH: New York, 2004.
Crafts alkylation of phenols.
(2) (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395. (b)
Trost, B. M. Acc. Chem. Res. 2002, 35, 695. (c) Trost, B. M.; Crawley,
M. L. Chem. Rev. 2003, 103, 2921. (d) Lu, Z.; Ma, S. Angew. Chem., Int.
Ed. 2008, 47, 258.
(3) For Pd: (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120,
However, all these known procedures are limited with
racemic synthesis,13 even with poor regioselectivity on
815. (b) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545. (c)
Trost, B. M.; Shen, H. C.; Dong, L.; Surivet, J.-P. J. Am. Chem. Soc.
2003, 125, 9276. (d) Trost, B. M.; Shen, H. C.; Dong, L.; Surivet, J.-P.;
Sylvain, C. J. Am. Chem. Soc. 2004, 126, 11966. (e) Uozumi, Y.; Kimura,
M. Tetrahedron: Asymmetry 2006, 17, 161. (f) Kirsch, S. F.; Overman,
L. E.; White, N. S. Org. Lett. 2007, 9, 911.
phenol rings in many cases. As part of our ongoing efforts
toward iridium-catalyzed allylic substitution reactions,14
we recently realized the Ir-catalyzed intramolecular asym-
metric allylic dearomatization reaction of phenols by
tethering allylic carbonate at the para-position (Figure 1).15
In this paper, we report an iridium-catalyzed asymmetric
(4) For Rh: (a) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2000, 122,
5012. (b) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2002, 124, 7882.
r
10.1021/ol3008793
2012 American Chemical Society
Published on Web 04/27/2012

intramolecular FriedelÀCrafts-type allylic alkylation reac-
tion of phenols by tethering the allylic carbonate at the
meta-position. This reaction provides a facile access to
enantioenriched tetrahydroisoquinoline derivatives.
isolated yield and selectivities (2a/3a: 4.7/1, yield of 2a:
68%, ee of 2a: 91%, entry 16, Table 1).
Table 1. Screening Different Bases and Solventsa
In our initial investigation, allyl carbonate tethered phenol
1a was chosen as a model substrate. In the presence of 2 mol %
of [Ir(COD)Cl]2, 4 mol % of phosphoramidite ligand L1, and
200 mol % of Cs2CO3, reaction of 1a in THF for 10 h gave
FriedelÀCrafts-type allylic alkylation product 2a in 68%
yield and 90% ee (entry 1, Table 1). Encouraged by this
result, we screened readily available bases and solvents.
The results are summarized in Table 1. Various solvents
such as THF, CH2Cl2, toluene, CH3CN, ether, DME,
dioxane, and DCE were examined. All of the solvents
could be tolerated in the reaction, and ether-type solvents
such as THF, dioxane, ether, and DME gave the product
with high enantioselectivity (entries 1, 3, 6, and 8, Table 1).
With THF as the solvent, various bases including inor-
ganic and organic ones could be tolerated to afford
product 2a with excellent enantioselectivity (90À93% ee),
except for BSA (entry 15, Table 1). Notably, the reaction
with DMAP as a base gave overall the best combination of
time convb 2a/
yield
3ab (%) (2a)c (%)
eed
entry
base
solvent
(h)
(%)
1
2
Cs2CO3 THF
Cs2CO3 DCM
Cs2CO3 dioxane
Cs2CO3 MeCN
Cs2CO3 DCE
Cs2CO3 Et2O
Cs2CO3 toluene
Cs2CO3 DME
10
5
100 4.8/1
100 1.8/1
100 7.3/1
100 1.0/1
100 1.5/1
100 9.0/1
100 9.2/1
100 4.8/1
100 3.5/1
58 2.5/1
68
47
65
40
50
67
62
67
47
34
55
64
51
49
NR
68
90
25
90
62
30
84
58
89
91
92
92
91
91
93
3
5
4
5
5
5
6
6
7
6
8
6
9
K3PO4
THF
10
20
10
10
10
10
10
10
10
11
12
13
14
15
16
Li2CO3 THF
(5) For Ru: (a) Trost, B. M.; Fraisse, P. L.; Ball, Z. T. Angew. Chem.,
Int. Ed. 2002, 41, 1059. (b) Mbaye, M. D.; Renaud, J. L.; Demerseman,
B.; Bruneau, C. Chem. Commun. 2004, 1870. (c) Mbaye, M. D.;
Demerseman, B.; Renaud, J.-L.; Toupet, L.; Bruneau, C. Adv. Synth.
Catal. 2004, 346, 835. (d) Bruneau, C.; Renaud, J.-L.; Demerseman, B.
Chem.;Eur. J. 2006, 12, 5178. (e) Onitsuka, K.; Okuda, H.; Sasai, H.
Angew. Chem., Int. Ed. 2008, 47, 1454. (f) van Rijn, J. A.; Lutz, M.;
von Chrzanowski, L. S.; Spek, A. L.; Bouwman, E.; Drent, E. Adv.
Synth. Catal. 2009, 351, 1637. (g) van Rijn, J. A.; Siegler, M. A.; Spek,
A. L.; Bouwman, E.; Drent, E. Organometallics 2009, 28, 7006. (h)
van Rijn, J. A.; van Stapele, E.; Bouwman, E.; Drent, E. J. Catal. 2010,
272, 220. (i) van Rijn, J. A.; den Dunnen, A.; Bouwman, E.; Drent, E.
J. Mol. Catal. A Chem. 2010, 329, 96. (j) van Rijn, J. A.; Bouwman, E.;
Drent, E. J. Mol. Catal. A Chem. 2010, 330, 26. (k) Austeri, M.; Linder,
D.; Lacour, J. Adv. Synth. Catal. 2010, 352, 3339. (l) van Rijn, J. A.;
Guijt, M. C.; Bouwman, E.; Drent, E. Appl. Organometal. Chem. 2011,
25, 207. (m) Sahli, Z.; Derrien, N.; Pascal, S.; Demerseman, B.; Roisnel,
KOAc
K2CO3
Et3N
THF
THF
THF
THF
THF
THF
100 3.5/1
100 4.0/1
80 5.0/1
DBU
100 5.3/1
BSA
DMAP
100 4.7/1
91
a Reaction conditions: 2 mol % of [Ir(COD)Cl]2,4mol%ofL1,0.2mmol
of 1a, and 200 mol % base in solvent (2 mL). b Determined by 1HNMRofthe
crude reaction mixture. c Isolated yield of 2a. d Determined by HPLC analysis.
ꢀ
T.; Barriere, F.; Achard, M.; Bruneau, C. Dalton Trans. 2011, 40, 5625.
(6) For Ir: (a) Lopez, F.; Ohmura, T.; Hartwig, J. F. J. Am. Chem.
Soc. 2003, 125, 3426. (b) Welter, C.; Dahnz, A.; Brunner, B.; Streiff, S.;
€
Doubon, P.; Helmchen, G. Org. Lett. 2005, 7, 1239. (c) Kimura, M.;
Uozumi, Y. J. Org. Chem. 2007, 72, 707.
(7) Kimura, M.; Fukasaka, M.; Tamaru, Y. Synthesis 2006, 21, 3611.
(8) (a) Malkov, A. V.; Davis, S. L.; Baxendale, I. R.; Mitchell, W. L.;
ꢁ
ꢂ
Kocovsky, P. J. Org. Chem. 1999, 64, 2751. (b) Malkov, A. V.; Spoor, P.;
ꢁ
ꢂ
Vinader, V.; Kocovsky, P. J. Org. Chem. 1999, 64, 5308. (c) Yamamoto,
Y.; Itonaga, K. Org. Lett. 2009, 11, 717.
ꢂ
(9) (a) Fernandez, I.; Hermatschweiler, R.; Breher, F.; Pregosin,
Figure 2. Ligands used in the present work.
P. S.; Veiros, L. F.; Calhorda, M. J. Angew. Chem., Int. Ed. 2006, 45,
ꢂ
6386. (b) Fernandez, I.; Schott, D.; Gruber, S.; Pregosin, P. S. Helv.
Chim. Acta 2007, 90, 271.
Under the above conditions (entry 16, Table 1), several
ligands were further evaluated (Figure 2). The results are
summarized in Table 2. The results suggested that ligands
L1ÀL3 could be employed for the reaction, giving similar
results (entries 1À3, Table 2). The catalyst derived from L4, a
diastereoisomer of L1, could catalyze the reaction in a lower
yield and enantioselectivity (36% yield, 88% ee, entry 4,
Table 2). Ligand L5 was tested but afforded only a trace
amount of product (entry 5, Table 2). When the reaction was
run at room temperature with ligand L1, the product was
obtained with slightly higher enantioselectivity (92% ee, entry
6, Table 2).
(10) Tsukada, N.; Yagura, Y.; Sato, T.; Inoue, Y. Synlett 2003, 1431.
(11) Rao, W.; Chan, P. W. H. Org. Biomol. Chem. 2008, 6, 2426.
(12) For a recent example on Lewis acid catalyzed FriedelÀCrafts allylic
alkylation of phenols, see: Vece, V.; Ricci, J.; Poulain-Martini, S.; Nava, P.;
~
Carissan, Y.; Humbel, S.; Dunach, E. Eur. J. Org. Chem. 2010, 6239.
(13) After the submission of this manuscript, Hamada and co-workers
reported an elegant Pd-catalyzed asymmetric intramolecular FriedelÀCrafts
allylic alkylation of phenols: Suzuki, Y.; Nemoto, T.; Kakugawa, K.;
Hamajima, A.; Hamada, Y. Org. Lett. 2012, DOI: 10.1021/ol300700w.
(14) For reviews, see: (a) Takeuchi, R.; Kezuka, S. Synthesis 2006,
€
3349. (b) Helmchen, G.; Dahnz, A.; Dubon, P.; Schelwise, M.; Weihofen,
R. Chem. Commun. 2007, 675. (c) Hartwig, J. F.; Stanley, L. M. Acc.
Chem. Rev. 2010, 43, 1461. (d) Hartwig, J. F.; Pouy, M. J. Top
Organomet. Chem. 2011, 34, 169. (e) Liu, W.-B.; Xia, J.-B.; You, S.-L.
Top Organomet. Chem. 2012, 38, 155.
(15) Wu,Q.-F.;Liu,W.-B.;Zhuo,C.-X.;Rong,Z.-Q.;Ye,K.-Y.;You,S.-
L. Angew. Chem., Int. Ed. 2011, 50, 4455. For an allylic dearomatization of
phenols by palladium catalyst, see: Nemoto, T.; Ishige, Y.; Yoshida, M.;
Kohno, Y.; Kanematsu, M.; Hamada, Y. Org. Lett. 2010, 12, 5020.
Under the optimized reaction conditions [2 mol % of
[Ir(COD)Cl]2, 4 mol % of L1, 200 mol % of DMAP,
2580
Org. Lett., Vol. 14, No. 10, 2012

Table 2. Screening Different Ligands and Temperaturea
entry ligands convb (%) 2a/3ab yield (%) (2a)c eed (%)
1
L1
L2
L3
L4
L5
L1
100
100
100
32
4.7/1
2.0/1
4.6/1
4.0/1
68
91
92
2
55
3
73
89
4
26
88
5
6e
trace
68
ND
92
100
4.8/1
a Reactions wereconductedunder the conditionsof entry 16, Table 1.
b Determined by 1H NMR of the crude reaction mixture. c Isolated yield
of 2a. d Determined by HPLC analysis. e Room temperature.
Table 3. Substrate Scopea
Figure 3. ORTEP representation of enantiopure (R)-3h (thermal
ellipsoids are set at 30% probability).
78% yield, 89% ee, entry 7; 4-Br, 6-MeO, 80% yield, 92%
ee, entry 9; 5-OH, 90% yield, 86% ee, entry 10; 5-OH,
6-MeO, 86% yield, 88% ee, entry 11). Notably, two
hydroxyl groups were well tolerated. With a strong elec-
tron-withdrawing group (6-NO2) on the phenol scaffold,
the product was obtained with only 25% yield, but ex-
cellent enantioselectivity (93% ee) (entry 6, Table 3). The
carbon-tethered phenol 1l was also a suitable substrate,
affording the product in 87% yield with 4.0/1 regioselec-
tivity and 91% ee, under the conditions of 200 mol %
Cs2CO3, and dioxane (2 mL), 50 °C (entry 12, Table 3).
To determine the absolute configuration of the product,
an X-ray crystallographic analysis of enantiopure bro-
mine-containing compound 3h disclosed the configuration
as R (Figure 3).
entry
1, R
yieldb (%) 2/3c eed (%)
1
1a, X = NBn, R = H
84
88
72
80
82
25
78
50
80
90
86
87
4.8/1
6.0/1
3cg
92
92
93
94
95
93
89
96
92
86
88
91
2
1b, X = N-allyl, R = H
3
1c, X = NBn, R = 2-MeO
1d, X = NBn, R = 2-Cl
4
3dg
4.0/1
2fh
5
1e, X = NBn, R = 6-MeO
1f, X = NBn, R = 6-NO2
1g, X = NBn, R = 4-Br
6e
7e
8e
9e
10
11
2gg
1h, X = NBn, R = 2-Br, 6-MeO
1i, X = NBn, R = 4-Br, 6-MeO
1j, X = NBn, R = 5-OH
1k, X = NBn, R = 5-OH, 6-MeO
3hg
2ig
2jg
2kg
4.0/1
12f 1l, X = C(COOMe)2, R = H
In summary, we have developed an efficient iridium-
catalyzed intramolecular FriedelÀCrafts-type allylic alkyla-
tion reaction of phenols, affording tetrahydroisoquinolines
with moderate to excellent yields, enantioselectivity and
regioselectivity.
a Reactions were conducted under the conditions of entry 6, Table 2.
b Isolated yield of 2 and 3. c Determined by 1H NMR of the crude
reaction mixture. d Determined by HPLC analysis. e 50 °C. f Using
200 mol % of Cs2CO3, and dioxane (2 mL), at 50 °C. g Isolated as a
single isomer. h Ratio of 2/3 was not determined by 1H NMR.
Acknowledgment. We thank the National Basic Re-
search Program of China (973 Program 2009CB825300)
and the National Natural Science Foundation of China
(21025209, 20923005, 20932008, 21121062) for generous
financial support.
THF, rt], various substrates were tested to examine the scope
of the reaction. The results are summarized in Table 3. Both
benzyl and allyl groups on the linked nitrogen atom could
be well tolerated to deliver alkylated products in excellent
enantioselectivity (92% ee) (entries 1 and 2, Table 3).
Substrates bearing either electron-withdrawing or elec-
tron-donating groups at the 2-, 4-, or 6-position of phenol
were tested in the reaction. When a substituent was
introduced at the 2-position of the phenol, the allylic
alkylation reaction proceeded smoothly to afford a single
regioisomer by reacting at the para-position of the phenols.
In all cases, excellent enantioselectivity was obtained (2-
MeO, 93% ee, entry 3; 2-Cl, 94% ee, entry 4; 2-Br, 6-MeO,
96% ee, entry 8). When a substituent was introduced at the
4 or 5 position of the phenol ring, a single isomer of 2 was
obtained with good to excellent yields and ee values (4-Br,
Note Added after ASAP Publication. Compound 2h was
changed to 3h in the Figure 3 caption, the last line of the
second to last paragraph of the main text on p 3, and the
second to last line of the right column on p 3, the correct
version reposted May 1, 2012.
Supporting Information Available. Detailed experimen-
tal procedures and spectroscopic data for all new compounds
and X-ray crystal data of (R)-3h. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 10, 2012
2581