Enantioselective syntheses of tetrahydroquinolines based on iridium-catalyzed allylic substitutions: Total syntheses of (+)-angustureine and (-)-cuspareine

Article abstract of DOI:10.1002/ejoc.201100981

A protecting-group-free two-step approach for the preparation of tetrahydroquinolines has been developed. The procedure involves a highly regio-and enantioselective intermolecular iridium-catalyzed allylic amination followed by one-pot hydroboration and i

Full text of DOI:10.1002/ejoc.201100981

FULL PAPER
DOI: 10.1002/ejoc.201100981
Enantioselective Syntheses of Tetrahydroquinolines Based on Iridium-Catalyzed
Allylic Substitutions: Total Syntheses of (+)-Angustureine and (–)-Cuspareine
Gedu Satyanarayana,*[a] Daniel Pflästerer,[b] and Günter Helmchen*[b]
Keywords: Alkaloids / Total synthesis / Nitrogen heterocycles / Allylic amination / Asymmetric catalysis / Iridium
A protecting-group-free two-step approach for the prepara-
tion of tetrahydroquinolines has been developed. The pro-
cedure involves a highly regio- and enantioselective intermo-
lecular iridium-catalyzed allylic amination followed by one-
pot hydroboration and intramolecular Suzuki–Miyaura cross-
coupling. This method was applied in total syntheses of the
alkaloids (+)-angustureine and (–)-cuspareine.
These interesting biological properties have motivated
chemists to develop methods for the stereoselective synthe-
sis of tetrahydroquinolines. Although a variety of reactions
have been used as key steps,[4] most syntheses are based on
asymmetric catalytic hydrogenation of quinolines.[5] Our
own approach was stimulated by our interest in Ir-catalyzed
enantioselective allylic substitutions. We envisioned
(Scheme 1) that Ir-catalyzed regio- and stereoselective all-
ylic amination of allylic carbonates with commercially avail-
able 2-haloanilines would furnish allylic secondary amines,
which could be transformed into boranes; subsequent
Suzuki–Miyaura coupling was expected to furnish tetra-
hydroquinolines. The boranes can be used in situ, so this
route involves essentially two steps.[6]
Introduction
Tetrahydroquinoline alkaloids are occurring widely in
plants.[1] Many of them exhibit interesting biological ac-
tivity.[2] Examples include (–)-angustureine, (–)-cuspareine
and (–)-galipinine (Figure 1). These compounds were iso-
lated by Jacquemont-Collet and co-workers from the bark
of Galipea officinalis Hancock,[1b] which comprises ca. 20
species found in northern South America. Extracts from
Galipea officinalis have been used in folk medicine for the
treatment of dysentery and fever.[3a] Recently, ethanolic ex-
tracts of the trunk bark of Galipea officinalis have been
shown to possess antiplasmodial and cytotoxic activities.[3b]
Scheme 1. Strategy for the enantioselective synthesis of chiral tetra-
hydroquinolines.
Figure 1. Examples of naturally occurring tetrahydroquinoline
alkaloids.
Results and Discussion
Ir-catalyzed allylic substitution, first introduced in
1997,[7] has emerged as a versatile tool in enantioselective
catalysis.[8] High degrees of regio- and enantioselectivity in
favor of branched substitution products can be obtained.
Of particular interest are reactions with N-nucleophiles (i.e.,
aliphatic amines,[9] amides[10] and anilines[11]) to give
branched allylic amines, which are often well suited as start-
ing materials for alkaloid syntheses.[12] In the currently
[a] Indian Institute of Technology (IIT) Hyderabad, Ordnance
Factory Estate (ODF),
Yeddumailaram 502205, Medak District, Andhra Pradesh,
India
Fax: +91-40-2301-6032
[b] Organisch-Chemisches Institut der Universität Heidelberg,
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax: +49-6221-544205
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100981.
Eur. J. Org. Chem. 2011, 6877–6886
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. Satyanarayana, D. Pflästerer, G. Helmchen
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most commonly used variant of allylic amination, the cata- nished the branched amine 3aa in about the same yield
lyst is prepared from [Ir(COD)Cl]2 (COD = cycloocta-1,5- (68%), but with high regioselectivity (99:1) and good
diene) and a chiral phosphoramidite L* (Figure 2) by acti- enantioselectivity (94% ee).
vation with a strong base. The commercially available li-
gand L1, introduced by Feringa,[13] has been examined oc-
casionally, but superior results were obtained with the li-
gands L2 and L3, developed by Alexakis.[14]
Further screening of carbonates with systematically
larger substituents R, with either 2-iodo- (2a) or 2-bromo-
aniline (2b) as nucleophiles, showed remarkable invariance
of enantioselectivity (ee = 94Ϯ1%), whereas regioselectivi-
ties and yields decreased with increasing size of R (cf.
Table 1). With substrate 1d conversion ceased after ca.
30 min; with double catalyst loading employed in two por-
tions improved yields of the branched amination products
3da and 3db (54% and 55%, respectively) were obtained
(Table 1, Entries 9 and 10).
Next the intramolecular Suzuki–Miyaura cross-coupling
was addressed, with use of the amines 3ba and 3bb as start-
ing materials for optimization (Table 2).[15] Hydroboration
with 9-BBN at 60 °C for 1–2 h followed by Suzuki–Miyaura
coupling at 80 °C for Ͼ20 h failed to furnish the tetra-
hydroquinolines 5 (Entries 1 and 2). In order to counteract
Figure 2. Ligands used for allylic amination.
Reactions with anilines have been studied thoroughly by side reactions, the reaction time of the hydroboration reac-
Hartwig and co-workers.[11] In a set of 18 examples, the tion was reduced.[16] Hence, treatment of 3ba with 9-BBN
reaction between methyl cinnamyl carbonate and 2-bromo- in THF at 70 °C for only 10 min followed by treatment with
aniline gave the lowest yield (66%).[11a] In our hands, the the Pd catalyst at 80 °C for 71 h furnished the product 5b
reaction between the carbonate 1a and 2-iodoaniline (2a) in 59% yield (Table 2, Entry 3). Finally, it was found that
under standard conditions {[Ir(COD)Cl]2 (2 mol-%)/L* reaction times of 10 min for the hydroboration and 20–48 h
(4 mol-%), TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene, 8 mol- for the Suzuki–Miyaura coupling were optimal (Table 2).
%), dry THF} for 6 h at 50 °C (Table 1, Entries 1–3) fur- With the iodide 3ba the Suzuki–Miyaura coupling pro-
Table 1. Iridium-catalyzed allylic substitutions with the carbonates 1 to give the branched allylamines 3.
Entry
Carbonate
X
L*
Time [h]
3/4[c]
Yield [%][d]
ee [%][f]
1[a]
1a
1a
1a
1b
1b
1c
1c
1c
1d
1d
1d
1d
1d
I
I
I
Br
I
I
I
I
I
I
L2
ent-L2
L3
6
6
3
5
3
4.5
5
3.5
2.75
4
4
4
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
94:6
93:7
94:6
n. d.
91:9
91:9
64
68
68
60
57
57
51
54
45
53[e]
54
55
52
94 (S)
94 (R)
94 (S)
93 (S)
94 (S)
96 (S)
93 (R)
95 (S)
95 (S)
96 (S)
95 (S)
95 (S)
94 (S)
2[a]
3[a]
4[a]
L2
5[a]
L2
L2
6[b]
7[b]
ent-L2
L3
8[b]
9[b]
L2
10[b]
11[b]
12[b]
13[b]
L2
I
Br
I
L2
L2
91:9
93:7
L3
3.5
[a] Reactions were carried out by GP1 (Method A: Ir/L*/TBD 2:4:8 mol-%; see Exp. Sect). [b] Reactions were carried out by GP1
(Method B: Ir/L*/TBD 4:8:16 mol-%). [c] Regioselectivity was determined either by 1H NMR examination of the crude product or by
isolation of the regioisomers. [d] Isolated yields of branched amination products 3. [e] Triethylamine (1 equiv.) was used as an additional
base. [f] Enantiomeric excesses were determined by chiral HPLC. Absolute configurations are assigned according to a general rule,[8a]
which has so far always been found to be valid. Corroboration was obtained for 3da, 3db and 3ea by transformation into the alkaloids
angustureine and cuspareine.
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Enantioselective Syntheses of Tetrahydroquinolines
ceeded smoothly even at room temperature (42 h, 70% yield
of 5b, Entry 4). The Suzuki–Miyaura reaction of the borane
derived from the bromo derivative 3bb was slow at room
temperature, but at 80 °C the reaction gave an excellent re-
sult (82%) after a reaction time of 48 h (Entries 6 and 7).
Table 2. Hydroboration/Suzuki–Miyaura cross-coupling with the
allylamines 3b to give the tetrahydroquinoline 5b.
Scheme 2. Optimal results of transformations of the allylamines 3
into the tetrahydroquinolines 5 by hydroboration/intramolecular
Suzuki–Miyaura reaction and N-methylation of 5d.
also isolated. The pure branched product 3ea was subjected
to the hydroboration/Suzuki–Miyaura cross-coupling pro-
cedure to yield the tetrahydroquinoline 5e in 64% yield. A
final reductive N-methylation[5a] reaction furnished (–)-cus-
pareine in 89% yield.
Entry
X
Hydroboration
T [°C] / time [min]
Suzuki–Miyaura
reaction
T [°C] / time [h]
Yield
[%][a]
1
2
3
4
5
6
7
8
9
10
I
Br
I
I
I
Br
Br
I
I
I
60 / 120
60 / 60
70 / 20
70 / 10
70 / 10
70 / 10
70 / 10
70 / 10
70 / 10
70 / 10
80 / 23
80 / 28
80 / 71
r.t. / 42
r.t. / 25
r.t. / 168
80 / 48
0
0
59
70
48
15
82
75
68
76
80 / 24
100 / 1[b]
120 / 0.5[b]
[a] Isolated yield of pure 5b. [b] Microwave irradiation.
In the hope of shortening reaction times, the microwave
variant of the Suzuki–Miyaura cross-coupling was investi-
gated. The reaction of the borane prepared from 3ba under
microwave irradiation conditions at 100–120 °C furnished
the product 5b after less than 1 h in yields comparable to
those obtained under the thermal conditions (Table 2, En-
tries 9 and 10).
The optimized reaction conditions of the hydroboration/
Suzuki–Miyaura coupling were applied to the other
branched allylamines. The results, including those for 5b,
are shown in Scheme 2. Yields were generally satisfactory.
Scheme 3. Reagents and conditions: a) i) 9-BBN, THF, 70 °C,
10 min; ii) Pd(dppf)Cl2, AsPh3, Cs2CO3, DMF/H2O 15:1, (E)-
ICH=CH(COOMe), room temp., 16 h, 84%; b) DIBAL-H, THF,
–78 °C, 3 h, 86%; c) Py, ClCOOMe, CH2Cl2, 0 °C to r.t., 30 min,
(+)-Angustureine was prepared from the tetrahydro- 93%; d) 2a, [Ir(COD)Cl]2 (6 mol-%)/(R,R,R)-L2 (12 mol-%)/TBD
quinoline 5d in 94% yield by reductive N-methylation[5a]
(24 mol-%), THF, 50 °C, 6 h, 46% (94% ee); e) i) 9-BBN, THF,
70 °C, 10 min, ii) then Pd(dppf)Cl2, AsPh3, Cs2CO3, DMF/H2O
(15:1), 80 °C, 24 h, 59% or microwave irradiation, 120 °C, closed
vessel, 300 W, 30 min, 64%; f) (CH2O)n, AcOH, Na(CN)BH3,
(Scheme 2).
As further test of our synthesis route, a total synthesis of
(–)-cuspareine was carried out (Scheme 3). Firstly, the al-
lylic carbonate 1e was prepared in 67% yield from the com-
mercially available olefin 7a by a hydroboration/Suzuki–
Miyaura sequence yielding ester 7b, reduction of this with
DIBAL-H to give the allylic alcohol 7c and treatment of
this with methyl chloroformate. The Ir-catalyzed allylic am-
CH3CN, r.t.,16 h, 89%.
Conclusions
In conclusion, we have developed an enantioselective,
ination of 1e proceeded with a regioselectivity of 3ea/4ea = protecting-group-free method for the synthesis of tetra-
88:12 and gave 3ea with 94% ee in 46% yield; a small hydroquinolines. The key steps are a regio- and enantiose-
amount of the corresponding methyl ether 8[17] (2%) was lective Ir-catalyzed allylic amination and a hydroboration/
Eur. J. Org. Chem. 2011, 6877–6886
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G. Satyanarayana, D. Pflästerer, G. Helmchen
FULL PAPER
product by 1H NMR or by isolation of the regioisomers. Pure am-
ination products were obtained after purification by flash
chromatography on silica or, if necessary, preparative HPLC.
intramolecular Suzuki–Miyaura cross-coupling sequence.
Total syntheses of the alkaloids (+)-angustureine and (–)-
cuspareine were carried out as applications.
Method B: As in Method A, except that a second portion of freshly
prepared catalyst (2 mol-% of Ir) was added after 30 min. The cata-
lyst solution was transferred with a syringe under argon.
Experimental Section
1
General: H NMR spectra were recorded with Bruker Avance 300
Method C: As in Method A, except that initially 3 mol-% of the
catalyst were used, and a second and a third portion of catalyst
(3 mol-% of Ir) were added after 30 and 60 min, respectively.
(300 MHz) or Bruker Avance 500 (500 MHz) spectrometers at
room temp. in CDCl3; chemical shifts are reported in δ units rela-
tive to CHCl3 (δH = 7.26 ppm) or TMS (δH = 0.00 ppm). For atom
numbering see the Supporting Information. 13C NMR spectra were
recorded with Bruker Avance 300 (75 MHz) or Bruker Avance 500
(125 MHz) spectrometers at room temp. in CDCl3; chemical shifts
are reported in δ units relative to CDCl3 [δC = 77.16 ppm (central
line of the triplet)]. The following abbreviations are used through-
out: s = singlet, d = doublet, t = triplet, q = quartet, quint =
quintet, m = multiplet, br. = broad. The assignment of signals was
confirmed by 1H,1H-COSY, 1H,13C-COSY and DEPT spectra. Op-
tical rotations were measured with a Perkin–Elmer 341 polarimeter
in a 1 dm thermostatted cuvette and with a mercury lamp. HRMS
were recorded with a JEOL JMS-700 instrument (EI and FAB) or
a Bruker ApexQe instrument (ESI). HRMS data refer to the iso-
tope 79Br. Elemental analyses were carried out at the Organisch-
Chemisches Institut, Universität Heidelberg. Enantiomeric excesses
were determined by HPLC with a HP 1090 or HP 1100 instrument
or by GC with a HP 5890 instrument. For HPLC the following
columns from Daicel were used: Chiralpak AD-H (250ϫ4.6 mm,
5 μm) with guard cartridge AD-H (10ϫ 4 mm, 5 μm), Chi-
ralpak AS-H (250ϫ 4.6 mm, 5 μm) with guard cartridge AS-H
(10ϫ 4 mm, 5 μm), Chiralcel OD-H (250ϫ 4.6 mm, 5 μm) with
guard cartridge OD-H (10ϫ 4 mm, 5 μm) and Chiralcel OJ-H
(250ϫ 4.6 mm, 5 μm) with guard cartridge OJ-H (10ϫ 4 mm,
5 μm). For GC a permethyl-β-cyclodextrin column from Chrom-
pack (WCOT fused silica, Cp-cyclodextrin-B-236-M-19,
25 mϫ0.25 mm) was used. For preparative HPLC a Gilson-305
pump coupled with a Knauer UV detector 2600 and a silica gel
column (Latek, 5 μ, 21ϫ250 mm) were used. Microwave experi-
ments were carried out with a CEM Discover LabmateTM instru-
ment (method: Chem. DriverTM Software, 10 mL microwave vials,
closed vessel, Power: 300 W, temperature: 100 (60 min) or 120 °C
(30 min).
(+)-(2-Iodophenyl)[(1S)-1-methylprop-2-en-1-yl]amine [(+)-(S)-3aa]:
GP1 (Method A) was carried out with [Ir(COD)Cl]2 (26.8 mg,
40 μmol), (R,R,aR)-L3 (45.6 mg, 80 μmol), anhydrous TBD
(22.3 mg, 160 μmol), the carbonate 1a (260 mg, 2 mmol) and 2-
iodoaniline (2a, 525.65 mg, 2.4 mmol) in dry THF (2 mL). The re-
action mixture was stirred for 3 h at 50 °C, after which TLC moni-
toring [petroleum ether/ethyl acetate 9:1, Rf (2a) = 0.40, Rf (1a) =
0.50, Rf (3aa) = 0.80, KMnO4] showed no further conversion. The
reaction mixture was then concentrated in vacuo. Purification by
flash chromatography on silica (40 g, petroleum ether to petroleum
ether/ethyl acetate 99:1) gave (+)-(S)-3aa (370 mg, 68%) as a yellow
oil. [α]2D0 = +41.6 (c = 1.06, CHCl3, 94% ee by HPLC). HPLC
{Chiralcel OD-H (250ϫ 4.6 mm, 5 μm), n-hexane/2-propanol 99:1
(0.5 mLmin–1), tR for [(+)-(S)-3aa] = 10.24 min, tR for [(–)-(R)-3aa]
1
= 13.43 min}. H NMR (300 MHz, CDCl3): δ = 7.66 (dd, J = 7.9,
1.6 Hz, 1 H, 3ЈЈ-H), 7.17 (ddd, J = 8.1, 7.2, 1.1 Hz, 1 H. 5ЈЈ-H),
6.57 (dd, J = 8.2, 1.3 Hz, 1 H, 6ЈЈ-H), 6.43 (ddd, J = 7.5, 7.5,
1.3 Hz, 1 H, 4ЈЈ-H), 5.80 (ddd, J = 17.2, 10.6, 5.5 Hz, 1 H, 2-H),
5.20 (ddd, J = 17.2, 1.28, 1.3 Hz, 1 H, 3-HZ), 5.10 (ddd, J = 10.2,
1.3, 1.3 Hz, 1 H, 3-HE), 4.17 (br. s, 1 H, NH), 4.12–3.88 (m, 1 H,
1-H), 1.39 (d, J = 6.6 Hz, 3 H, 1Ј-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 146.57 (s, C-1ЈЈ), 140.67 (d, C-2), 139.13 (d, C-3ЈЈ),
129.36 (d, C-5ЈЈ), 118.66 (d, C-4ЈЈ), 114.54 (t, C-3), 111.89 (d, C-
6ЈЈ), 85.77 (s, C-2ЈЈ), 51.65 (d, C-1), 21.83 (q, C-1Ј) ppm. HRMS
(ESI+): calcd. for C10H13IN+ [M + H]+: 274.0087; found 274.0088.
C10H12IN (273.11): calcd. C 43.98, H 4.43, N 5.13, I 46.47; found
C 44.26, H 4.48, N 5.08, I 46.43.
(+)-N-[(1S)-1-Ethylprop-2-en-1-yl]-2-iodoaniline [(+)-(S)-3ba]: GP1
(Method A) was carried out with [Ir(COD)Cl]2 (53.7 mg, 80 μmol),
(R,R,aR)-L2 (95.9 mg, 160 μmol), anhydrous TBD (44.5 mg,
320 μmol), 1b (576 mg, 4 mmol) and 2-iodoaniline (2a, 1.05 g,
4.8 mmol) in dry THF (2 mL). The reaction mixture was stirred
for 3 h at 50 °C, after which TLC monitoring [petroleum ether/ethyl
acetate 9:1, Rf (2a) = 0.40, Rf (1b) = 0.50, Rf (3ba) = 0.80, KMnO4]
showed no further conversion. The mixture was then concentrated
in vacuo. Purification by flash chromatography on silica (45 g, pe-
troleum ether to petroleum ether/ethyl acetate 99:1) gave (+)-(S)-
3ba (654 mg, 57%) as a yellow oil. [α]2D0 = +20.1 (c = 1.20, CHCl3,
94% ee by HPLC). HPLC {Chiralcel OD-H (250ϫ4.6 mm, 5 μm),
n-hexane/2-propanol 99:1 (0.5 mLmin–1), tR for [(+)-(S)-3ba] =
Methyl (2E)-oct-2-en-1-yl carbonate[9b] [(2E)-1d] and 1,2-dimeth-
oxy-4-vinylbenzene[18] (7) were prepared as reported in the litera-
ture.
General Procedure (GP1) for Iridium-Catalyzed Allylic Substitu-
tions: Success with any of the following procedures for iridium-
catalyzed allylic substitutions requires dry THF (H2O content less
than 30 mgL–1, Karl-Fischer titration). Anhydrous TBD (1,5,7-tri-
azabicyclo[4.4.0]dec-5-ene) was stored in a desiccator over KOH;
alternatively, small amounts were stored under argon in a Schlenk
tube.
1
10.77 min, tR for [(–)-(R)-3ba] = 17.93 min}. H NMR (300 MHz,
CDCl3): δ = 7.65 (dd, J = 7.7, 1.5 Hz, 1 H, 3-H), 7.16 (ddd, J =
8.0, 7.3, 1.1 Hz, 1 H, 5-H), 6.55 (dd, J = 8.2, 1.3 Hz, 1 H, 6-H),
6.42 (ddd, J = 7.8, 7.2, 1.0 Hz, 1 H, 4-H), 5.76 (ddd, J = 17.2, 10.2,
5.8 Hz, 1 H, 2Ј-H), 5.21 (ddd, J = 17.0, 1.3, 1.3 Hz, 1 H, 3Ј-HZ),
5.16 (ddd, J = 10.4, 1.1, 1.1 Hz, 1 H, 3Ј-HE), 4.22 (d, J = 5.5 Hz,
1 H, NH), 3.79 (dddd, J = 6.2, 6.1, 6.1, 6.0 Hz, 1 H, 1Ј-H), 1.75–
1.58 (m, 2 H, 1ЈЈ-H), 1.03 (t, J = 7.5 Hz, 3 H, 2ЈЈ-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 146.73 (s, C-1), 139.30 (d, C-2Ј),
139.06 (d, C-3), 129.34 (d, C-5), 118.51 (d, C-4), 115.53 (t, C-3Ј),
111.82 (d, C-6), 85.82 (s, C-2), 57.88 (d, C-1Ј), 28.69 (t, C-1ЈЈ),
10.43 (q, C-2ЈЈ) ppm. HRMS (ESI+): calcd. for C11H15IN+ [M +
Method A: A Schlenk tube was dried under argon with a heat-gun.
The catalyst was prepared by addition of a solution of [Ir(COD)-
Cl]2 (13.4 mg, 0.02 mmol) and the chiral ligand L* (0.04 mmol) in
dry THF (1.0 mL). Anhydrous TBD (11.1 mg, 0.08 mmol) was
added, and the mixture was stirred for 5 min (L2) or 30 min (L3).
The carbonate (1 mmol) and the aniline 2a or 2b (1.1–1.2 mmol)
were then added and the mixture was stirred either until complete
conversion or until no further conversion was detected by TLC or
GC–MS monitoring. For workup the mixture was concentrated in
vacuo. Regioselectivity was determined by analysis of the crude
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Enantioselective Syntheses of Tetrahydroquinolines
H]+: 288.0244; found 288.0245. C11H14IN (287.14): calcd. C 46.01,
H 4.91, N 4.88, I 44.20; found C 46.13, H 4.91, N 4.87, I 44.16.
47.86, H 5.35, N 4.65, I 42.14; found C 47.71, H 5.34, N 4.79, I
41.91.
1
Compound (2E)-4ca: H NMR (300 MHz, CDCl3): δ = 7.66 (dd, J
(+)-(2-Bromophenyl)[(1S)-1-ethylprop-2-en-1-yl]amine [(+)-(S)-3bb]:
GP1 (Method A) was carried out with [Ir(COD)Cl]2 (26.8 mg,
40 μmol), (R,R,aR)-L2 (47.9 mg, 80 μmol), anhydrous TBD
(22.3 mg, 160 μmol), the carbonate 1b (288 mg, 2 mmol), 2-bromo-
aniline (2b, 378.5 mg, 2.2 mmol) and dry THF (2 mL). The reaction
mixture was stirred for 5 h at 50 °C, after which TLC monitoring
[petroleum ether/ethyl acetate 9:1, Rf (2b) = 0.40, Rf (1b) = 0.50,
Rf (3bb) = 0.80, KMnO4] showed no further conversion. The mix-
ture was then concentrated in vacuo. Purification by flash
chromatography on silica (30 g, petroleum ether to petroleum
ether/ethyl acetate 99:1) gave (+)-(S)-3bb (288 mg, 60%) as a yellow
oil. [α]2D0 = +10.6 (c = 1.17, CHCl3, 93% ee by HPLC). HPLC [Chi-
ralcel OD-H (250ϫ 4.6 mm, 5 μm), n-hexane/2-propanol 95:5
(0.5 mLmin–1), tR for [(+)-(S)-3bb] = 9.29 min, tR for [(–)-(R)-3bb]
= 7.8, 1.5 Hz, 1 H, 3Ј-H), 7.20 (ddd, J = 8.6, 7.4, 1.5 Hz, 1 H, 5Ј-
H), 6.58 (dd, J = 8.2, 1.3 Hz, 1 H, 6Ј-H), 6.44 (ddd, J = 7.7, 7.6,
1.4 Hz, 1 H, 4Ј-H), 5.72 (dt, J = 14.7, 7.1 Hz, 1 H, 3-H), 5.57 (dt,
J = 15.3, 5.6 Hz, 1 H, 2-H), 4.23 (br. s, 1 H, NH), 3.75 (dd, J =
5.5, 0.8 Hz, 2 H, 1-H), 2.04 (dtd, J = 6.9, 6.9, 0.4 Hz, 2 H, 4-H),
1.41 (tq, J = 7.4, 7.4 Hz, 2 H, 5-H), 0.91 (t, J = 7.4 Hz, 3 H, 6-
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 147.29 (s, C-1Ј), 139.07
(d, C-3Ј), 133.66 (d, C-3), 129.46 (d, C-5Ј), 126.23 (d, C-2), 118.69
(d, C-4Ј), 111.08 (d, C-6Ј), 85.53 (s, C-2Ј), 46.31 (t, C-1), 34.52 (t,
C-4), 22.47 (t, C-5), 13.79 (q, C-6) ppm. HRMS (ESI+): calcd. for
C12H17IN+ [M + H]+: 302.0400; found 302.0401. C12H16IN
(301.17): calcd. C 47.86, H 5.35, N 4.65, I 42.14; found C 48.16, H
5.48, N 4.69, I 42.42.
1
= 11.38 min]. H NMR (300 MHz, CDCl3): δ = 7.41 (dd, J = 7.9,
(+)-(2-Iodophenyl)[(1S)-1-pentylprop-2-en-1-yl]amine [(+)-(S)-3da]
and (2-Iodophenyl)[(2E)-oct-2-en-1-yl]amine [(2E)-4da]: GP1
(Method B) was applied with [Ir(COD)Cl]2 (26.8 mg, 0.04 mmol),
(R,R,aR)-L2 (47.9 mg, 0.08 mmol), TBD (22.3 mg, 0.16 mmol), the
carbonate 1d (376.00 mg, 2.0 mmol), 2-iodoaniline (2a, 525.7 mg,
2.4 mmol) and dry THF (2.0 mL). The mixture was allowed to stir
at 50 °C. After 30 min an additional quantity of catalyst {[Ir-
(COD)Cl]2 (0.04 mmol)/L* (0.08 mmol)/TBD (0.16 mmol) and dry
THF (1 mL)} in a separate Schlenk tube was added by syringe. The
mixture was stirred for 5 h and 45 min at 50 °C, after which TLC
monitoring [petroleum ether/ethyl acetate 9:1, Rf (3da) = 0.82, Rf
(4da) = 0.80, Rf (1d) = 0.65, Rf (2a) = 0.58, KMnO4] showed no
further conversion. The mixture was then concentrated in vacuo.
Purification by flash chromatography on silica [50 g, petroleum
ether to petroleum ether/ethyl acetate 99:1] furnished (+)-(S)-3da
(360.3 mg, 54%) and (2E)-4d (38.0 mg, 6%) as yellow oils.
1.5 Hz, 1 H, 3ЈЈ-H), 7.13 (ddd, J = 8.3, 7.2, 1.3 Hz, 1 H, 5ЈЈ-H),
6.62 (dd, J = 8.2, 1.4 Hz, 1 H, 6ЈЈ-H), 6.54 (ddd, J = 7.6, 7.6,
1.4 Hz, 1 H, 4ЈЈ-H), 5.75 (ddd, J = 17.2, 10.3, 5.9 Hz, 1 H, 2-H),
5.20 (ddd, J = 17.2, 1.4, 1.4 Hz, 1 H, 3-HZ), 5.15 (ddd, J = 10.4,
1.3, 1.3 Hz, 1 H, 3-HE), 4.35 (d, J = 5.6 Hz, 1 H, NH), 3.78 (dddd,
J = 6.4, 6.4, 6.4, 6.4 Hz, 1 H, 1-H), 1.82–1.55 [m, 2 H, 1Ј-(Ha,Hb)],
1.02 (t, J = 7.4 Hz, 3 H, 2Ј-H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 144.53 (s, C-1ЈЈ), 139.38 (d, C-3ЈЈ), 132.46 (d, C-2), 128.40 (d,
C-5ЈЈ), 117.63 (d, C-4ЈЈ), 115.49 (t, C-3), 112.51 (d, C-6ЈЈ), 109.93
(s, C-2ЈЈ), 57.57 (d, C-1), 28.72 (t, C-1Ј), 10.42 (q, C-2Ј) ppm.
HRMS (ESI+): calcd. for C11H15BrN+ [M + H]+: 240.0382; found
240.0385. C11H14BrN (239.03): calcd. C 55.02, H 5.88, N 5.83, Br
33.27; found C 55.28, H 5.97, N 5.77, Br 33.32.
(2-Iodophenyl)[(1S)-1-propylprop-2-en-1-yl]amine [(+)-(S)-3ca] and
N-[(2E)-Hex-2-en-1-yl]-2-iodoaniline [(2E)-4ca]: GP1 (Method B)
was carried out with [Ir(COD)Cl]2 (53.68 mg, 0.08 mmol),
(R,R,aR)-L2 (95.94 mg, 0.16 mmol), TBD (44.54 mg, 0.32 mmol),
(2E)-hex-2-en-1-yl-methyl carbonate (1c, 632.78 mg, 4.00 mmol), 2-
iodoaniline (2a, 1.051 g, 4.8 mmol) and dry THF (2 mL). After
30 min an additional quantity of freshly prepared catalyst
{[Ir(COD)Cl]2 (0.04 mmol)/L* (0.08 mmol)/TBD (0.16 mmol) in
dry THF (1 mL)} in a separate Schlenk tube was added by syringe
and the reaction mixture was stirred for 4.5 h at 50 °C. TLC moni-
toring then showed no further conversion [petroleum ether/ethyl
acetate 9:1, Rf (3ca) = 0.75, Rf (4ca) = 0.73, Rf (1c) = 0.46, Rf (2a)
= 0.30, KMnO4]. The crude product was subjected to flash column
chromatography on silica (50 g, petroleum ether/ethyl acetate 99:1),
which furnished (+)-(S)-3ca (702.5 mg, 58%) and then (2E)-4ca
(42.5 mg, 4%) as yellowish oils.
Compound (+)-(S)-3da: [α]2D0 = +12.6 (c = 1.04, CHCl3, 94% ee by
HPLC). HPLC {Chiralcel OD-H (250ϫ 4.6 mm, 5 μm), n-hexane/
2-propanol 99:1 (0.5 mLmin–1), tR for [(+)-(S)-3da] = 9.12 min, tR
1
for [(–)-(R)-3da] = 12.56 min}. H NMR (CDCl3, 300 MHz): δ =
7.65 (dd, J = 7.8, 1.5 Hz, 1 H, 3ЈЈ-H), 7.16 (ddd, J = 7.7, 7.7,
1.4 Hz, 1 H, 5ЈЈ-H), 6.54 (dd, J = 8.2, 1.3 Hz, 1 H, 6ЈЈ-H), 6.42
(ddd, J = 7.6, 7.6, 1.4 Hz, 1 H, 4ЈЈ-H), 5.76 (ddd, J = 17.2, 10.3,
5.9 Hz, 1 H, 2-H), 5.19 (ddd, J = 17.2, 1.4, 1.4 Hz, 1 H, 3-HZ),
5.14 (ddd, J = 10.3, 1.3, 1.3 Hz, 1 H, 3-HE), 4.20 (br. s, 1 H, NH),
3.84 (ddd, J = 12.8, 6.4, 6.4 Hz, 1 H, 1-H), 1.76–1.58 (m, 2 H, 1Ј-
H), 1.60–1.16 (m, 6 H, 2Ј-H, 3Ј-H, 4Ј-H), 0.91 (t, J = 6.9 Hz, 3 H,
5Ј-H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 146.77 (s, C-1ЈЈ),
139.68 (d, C-2), 139.06 (d, C-3ЈЈ), 129.33 (d, C-5ЈЈ), 118.50 (d, C-
4ЈЈ), 115.27 (t, C-3), 111.82 (d, C-6ЈЈ), 85.80 (s, C-2ЈЈ), 56.57 (d, C-
1), 35.90 (t, C-1Ј), 31.82 (t, C-3Ј), 25.66 (t, C-2Ј), 22.69 (t, C-4Ј),
14.16 (q, C-5Ј) ppm. HRMS (ESI+): calcd. for C14H21IN+
[M + H]+: 330.0713; found 330.0723. HRMS (FAB+): calcd. for
C14H20IN+ [M]+: 329.0640; found 329.0650. C14H20IN (329.22):
calcd. C 51.08, H 6.12, N 4.25, I 38.55; found C 51.07, H 6.11, N
4.20, I 38.63.
Compound (+)-(S)-3ca: [α]2D0 = +18.5 (c = 0.99, CHCl3, 96% ee by
HPLC). HPLC [Chiralcel OD-H (250ϫ 4.6 mm, 5 μm), n-hexane/
2-propanol 99:1 (0.5 mLmin–1), tR for [(+)-(S)-3ca] = 9.12 min, tR
for [(–)-(R)-3ca] = 12.56 min]. 1H NMR (CDCl3, 300 MHz): δ =
7.65 (dd, J = 7.8, 1.5 Hz, 1 H, 3ЈЈ-H), 7.16 (ddd, J = 7.9, 7.6,
1.5 Hz, 1 H, 5ЈЈ-H), 6.55 (dd, J = 8.2, 1.1 Hz, 1 H, 6ЈЈ-H), 6.42
1
(ddd, J = 7.8, 7.8, 1.4 Hz, 1 H, 4ЈЈ-H), 5.76 (ddd, J = 17.1, 10.3, Compound (2E)-4da: H NMR (CDCl3, 300 MHz): δ = 7.66 (dd, J
5.9 Hz, 1 H, 2-H), 5.20 (ddd, J = 17.2, 1.3, 1.3 Hz, 1 H, 3-HZ),
= 7.8, 1.5 Hz, 1 H, 3Ј-H), 7.20 (ddd, J = 8.6, 7.4, 1.5 Hz, 1 H, 5Ј-
5.14 (ddd, J = 10.3, 1.3, 1.3 Hz, 1 H, 3-HE), 4.21 (br. s, 1 H, NH), H), 6.57 (dd, J = 8.2, 1.3 Hz, 1 H, 6Ј-H), 6.44 (ddd, J = 7.7, 7.7,
3.98–3.75 (m, 1 H, 1-H), 1.77–1.53 (m, 2 H, 1Ј-H), 1.65–1.32 (m,
2 H, 2Ј-H), 0.98 (t, J = 7.2 Hz, 3 H, 3Ј-H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 146.71 (s, C-1ЈЈ), 139.61 (d, C-2), 139.04 (d, C-3ЈЈ),
1.4 Hz, 1 H, 4Ј-H), 5.72 (dt, J = 14.7, 7.2 Hz, 1 H, 3-H), 5.56 (dt,
J = 15.4, 5.6 Hz, 1 H, 2-H), 4.22 (br. s, 1 H, NH), 3.75 (d, J =
5.5 Hz, 2 H, 1-H), 2.05 (dt, J = 6.8, 6.7 Hz, 2 H, 4-H), 1.55–1.11
129.33 (d, C-5ЈЈ), 118.48 (d, C-4ЈЈ), 115.27 (t, C-3), 111.77 (d, C- (m, 6 H, 7-H, 6-H, 5-H), 0.89 (t, J = 6.7 Hz, 3 H, 8-H) ppm. 13C
6ЈЈ), 85.76 (s, C-2ЈЈ), 56.25 (d, C-1), 38.05 (t, C-1Ј), 19.23 (t, C-2Ј),
14.14 (q, C-3Ј) ppm. HRMS (ESI+): calcd. for C12H17IN+
[M + H]+: 302.0400; found 302.0401. C12H16IN (301.17): calcd. C
NMR (CDCl3, 75 MHz): δ = 147.31 (s, C-1Ј), 139.07 (d, C-3Ј),
133.93 (d, C-3), 129.46 (d, C-5Ј), 126.02 (d, C-2), 118.67 (d, C-4Ј),
111.06 (d, C-6Ј), 85.52 (s, C-2Ј), 46.31 (t, C-1), 32.42 (t, C-4), 31.50
Eur. J. Org. Chem. 2011, 6877–6886
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6881

G. Satyanarayana, D. Pflästerer, G. Helmchen
FULL PAPER
(t, C-6), 28.98 (t, C-5), 22.66 (t, C-7), 14.23 (q, C-8) ppm. HRMS 50 °C, after which TLC monitoring [petroleum ether/ethyl acetate
(ESI+): calcd. for C14H21IN+ [M + H]+: 330.0713; found 330.0714.
4:1, Rf (8) = 0.45, Rf (3ea+4ea) = 0.50, Rf (2a) = 0.55, KMnO4]
showed no further conversion and the mixture was concentrated in
vacuo. Purification by flash chromatography on silica (50 g, petro-
leum ether/ethyl acetate 97:3 to 90:10) first furnished a 88:12 mix-
ture of (–)-(S)-3ea and 4ea (52% together) followed by 8 (30 mg,
2%), as a yellow oil. Separation of (–)-(S)-3ea and (2E)-4ea was
accomplished by preparative HPLC (petroleum ether/ethyl acetate
90:10) to give first (–)-(S)-3ea (690 mg, 46%) followed by (2E)-4ea
(90 mg, 6%), as yellow oils.
(+)-(2-Bromophenyl)[(1S)-1-pentylprop-2-en-1-yl]amine [(+)-(S)-
3db] and (2-Bromophenyl)[(2E)-oct-2-en-1-yl]amine [(2E)-4db]: GP1
(Method B) was carried out with [Ir(COD)Cl]2 (26.8 mg,
0.04 mmol), (R,R,aR)-L2 (47.9 mg, 0.08 mmol), the carbonate 1d
(376.0 mg, 2.0 mmol), TBD (22.3 mg, 0.16 mmol), 2-bromoaniline
(2b, 412.8 mg, 2.4 mmol) and dry THF (2 mL). After 30 min an-
other portion of freshly prepared catalyst {[Ir(COD)Cl]2 (26.8 mg,
0.04 mmol), (R,R,aR)-L2 (47.9 mg, 0.08 mmol), TBD (22.3 mg,
0.16 mmol), dry THF (1 mL)} was added. The mixture was stirred
for 6 h at 50 °C, after which TLC monitoring [petroleum ether/ethyl
acetate 9:1, Rf (3db) = 0.82, Rf (4db) = 0.80, Rf (1d) = 0.65, Rf (2b)
= 0.58, KMnO4] showed no further conversion. The mixture was
concentrated in vacuo and the residue was subjected to flash
chromatography on silica [45 g, petroleum ether to petroleum ether/
Compound (–)-(S)-3ea: [α]2D0 = –22.9 (c = 0.96, CHCl3, 94% ee by
HPLC). HPLC {Chiralcel OD-H (250ϫ 4.6 mm, 5 μm), n-hexane/
2-propanol 95:5 (0.5 mLmin–1), tR for [(–)-(S)-3ea] = 23.19 min, tR
for [(+)-(S)-3ea] = 32.33 min}. 1H NMR (300 MHz, CDCl3): δ =
7.66 (dd, J = 7.8, 1.4 Hz, 1 H, 3-H), 7.14 (ddd, J = 8.3, 7.2, 1.4 Hz,
1 H, 5-H), 6.80 (d, J = 8.1 Hz, 1 H, 5ЈЈЈ-H), 6.73 (dd, J = 8.2,
ethyl acetate 99:1] to give (+)-(S)-3db (303.3 mg, 55%) and (2E)- 1.9 Hz, 1 H, 6ЈЈЈ-H), 6.67 (d, J = 1.9 Hz, 1 H, 2ЈЈЈ-H), 6.47 (dd, J
4db (34.3 mg, 6%) as yellowish liquids.
= 8.5, 1.3 Hz, 1 H, 6-H), 6.42 (ddd, J = 7.5, 7.5, 1.3 Hz, 1 H, 4-
H), 5.79 (ddd, J = 17.2, 10.3, 5.8 Hz, 1 H, 2Ј-H), 5.22 (ddd, J =
17.3, 1.3, 1.3 Hz, 1 H, 3Ј-HZ), 5.16 (ddd, J = 10.4, 1.1, 1.1 Hz, 1
H, 3Ј-HE), 4.25 (br. s, 1 H, NH), 3.95–3.70 (m, 1 H, 1Ј-H), 3.86 (s)
and 3.77 (s) (2ϫ ArOCH3), 2.76 (dd, J = 7.6, 7.6 Hz, 2 H, 2ЈЈ-H),
2.10–1.80 (m, 2-H, 1ЈЈ-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
148.86 (s) and 147.32 (s) (2 C, 2ϫ COCH3], 146.51 (s, C-1), 139.22
(d, C-2Ј), 139.00 (d, C-3), 133.87 (s, C-1ЈЈЈ), 129.35 (d, C-5), 120.31
(d, ArCH), 118.65 (d, C-4), 115.51 (t, C-3Ј), 111.89 (d, ArCH),
111.82 (d, ArCH), 111.34 (d, C-6), 85.76 (s, C-2), 55.98 (q, OCH3),
55.73 (q, OCH3), 55.43 (d, C-1Ј), 37.50 (t, C-1ЈЈ), 31.76 (t, C-
Compound (+)-(S)-3db: [α]2D0 = +8.0 (c = 1.00, CHCl3, 95% ee, by
HPLC). HPLC {Chiralcel OD-H (250ϫ4.6 mm, 5 μm), n-hexane/
2-propanol 99:1 (0.5 mLmin–1), tR for [(+)-(S)-3db] = 8.32 min, tR
1
for [(–)-(R)-3db] = 12.64 min}. H NMR (CDCl3, 300 MHz): δ =
7.41 (dd, J = 7.9, 1.5 Hz, 1 H, 3ЈЈ-H), 7.13 (ddd, J = 7.7, 7.7,
1.5 Hz, 1 H, 5ЈЈ-H), 6.62 (dd, J = 8.2, 1.2 Hz, 1 H, 6ЈЈ-H), 6.53
(ddd, J = 7.6, 7.6, 1.5 Hz, 1 H, 4ЈЈ-H), 5.76 (ddd, J = 17.1, 10.3,
6.0 Hz, 1 H, 2-H), 5.20 (ddd, J = 17.2, 1.3, 1.3 Hz, 1 H, 3-HZ),
5.13 (ddd, J = 10.3, 1.3, 1.3 Hz, 1 H, 3-HE), 4.33 (s, 1 H, NH),
3.95–3.73 (m, 1 H, 1-H), 1.77–1.56 (m, 2 H, 1Ј-H), 1.65–1.18 (m,
6 H, 2Ј-H, 3Ј-H, 4Ј-H), 0.90 (t, J = 6.7 Hz, 3 H, 5Ј-H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 144.52 (s, C-1ЈЈ), 139.73 (d, C-2),
132.44 (d, C-3ЈЈ), 128.40 (d, C-5ЈЈ), 117.60 (d, C-4ЈЈ), 115.24 (t, C-
3), 112.49 (d, C-6ЈЈ), 109.90 (s, C-2ЈЈ), 56.22 (d, C-1), 35.91 (t, C-
+
2ЈЈ) ppm. HRMS (ESI+): calcd. for C19H23INO2 [M + H]+:
424.0768; found 424.0776. C19H22INO2 (423.29): calcd. C 53.91, H
5.24, N 3.31, I 29.98; found C 54.10, H 5.42, N 3.06, I 29.91.
1
Compound (2E)-4ea: H NMR (300 MHz, CDCl3): δ = 7.66 (dd, J
1Ј), 31.83 (t, C-3Ј), 25.67 (t, C-2Ј), 22.69 (t, C-4Ј), 14.16 (q, C- = 7.8, 1.4 Hz, 1 H, 3-H), 7.19 (ddd, J = 8.3, 7.1, 1.3 Hz, 1 H, 5-
5Ј) ppm. HRMS (ESI+): calcd. for C14H21BrN+ [M + H]+:
H), 6.79 (d, J = 8.6 Hz, 1 H, 5ЈЈ-H), 6.78–6.64 (m, 2 H, 2ЈЈ-H, 6ЈЈ-
282.0852; found 282.0852. C14H20BrN (282.22): calcd. C 59.58, H H), 6.54 (dd, J = 8.2, 1.3 Hz, 1 H, 6-H), 6.44 (ddd, J = 7.6, 7.6,
7.14, N 4.96, Br 28.31; found C 59.71, H 7.17, N 5.02, Br 28.05.
1.3 Hz, 1 H, 4-H), 5.74 (dt, J = 15.4, 6.5 Hz, 1 H, 3Ј-H), 5.56 (dt,
J = 15.5, 5.5 Hz, 1 H, 2Ј-H), 4.23 (br. s, 1 H, NH), 3.87 (s) and
3.86 (s, 2ϫ ArOCH3), 3.75 (br. s, 2 H, 1Ј-H), 2.66 (t, J = 6.9 Hz,
2 H, 5Ј-H), 2.36 (td, J = 7.3, 7.3 Hz, 2 H, 4Ј-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 148.87 (s) and 147.28 (s, 2 C, 2ϫ COCH3],
147.23 (s, C-1), 139.08 (d, C-3), 134.42 (s, C-1ЈЈ), 132.57 (d, C-3Ј),
129.46 (d, C-5), 126.87 (d, C-2Ј), 120.37 (d, ArCH), 118.73 (d, C-
4), 111.84 (d, ArCH), 111.27 (d, ArCH), 111.02 (d, C-6), 85.50 (s,
C-2), 56.04 (q, OCH3), 55.95 (q, OCH3), 46.15 (t, C-1Ј), 35.32 (t,
1
Compound (2E)-4db: H NMR (CDCl3, 300 MHz): δ = 7.42 (dd, J
= 7.9, 1.5 Hz, 1 H, 3Ј-H), 7.17 (ddd, J = 8.7, 7.4, 1.5 Hz, 1 H, 5Ј-
H), 6.64 (dd, J = 8.2, 1.4 Hz, 1 H, 6Ј-H), 6.56 (ddd, J = 7.7, 7.7,
1.5 Hz, 1 H, 4Ј-H), 5.72 (dt, J = 15.1, 7.1 Hz, 1 H, 3-H), 5.56 (dt,
J = 15.3, 5.6 Hz, 1 H, 2-H), 4.38 (br. s, 1 H, NH), 3.75 (dd, J =
5.6, 0.8 Hz, 2 H, 1-H), 2.05 (dt, J = 6.8, 6.8 Hz, 2 H, 4-H), 1.56–
1.15 (m, 6 H, 7-H, 6-H, 5-H), 0.90 (t, J = 6.8 Hz, 3 H, 8-H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 145.06 (s, C-1Ј), 133.93 (d, C-3Ј),
132.45 (d, C-3), 128.52 (d, C-5Ј), 126.11 (d, C-2), 117.79 (d, C-4Ј),
111.76 (d, C-6Ј), 109.84 (s, C-2Ј), 45.98 (t, C-1), 32.42 (t, C-4),
+
C-5Ј), 34.41 (t, C-4Ј) ppm. HRMS (ESI+): calcd. for C19H23INO2
[M + H]+: 424.0768; found 424.0769.
1
31.51 (t, C-6), 28.99 (t, C-5), 22.65 (t, C-7), 14.20 (q, C-8) ppm. Compound (2E)-8: H NMR (300 MHz, CDCl3): δ = 6.79 (d, J =
HRMS (ESI+): calcd. for C14H21BrN+ [M + H]+: 282.0852; found
282.0853. C14H20BrN (282.22): calcd. C 59.58, H 7.14, N 4.96, Br 10.5, 7.7 Hz, 1 H, 4Ј-H), 5.23 (ddd, J = 10.5, 1.8, 0.7 Hz, 1 H, 5Ј-
8.6 Hz, 1 H, 3-H), 6.77–6.68 [m, 2 H, (5,6)-H], 5.69 (ddd, J = 17.0,
28.31; found C 59.59, H 7.23, N 5.06, Br 28.17.
HE), 5.19 (ddd, J = 17.2, 1.5, 0.8 Hz, 1 H, 5Ј-HZ), 3.86 (s) and 3.85
(s) (2ϫ ArOCH3), 3.51 (ddd, J = 7.3, 7.3, 6.0 Hz, 1 H, 3Ј-H), 3.28
(s, OCH3), 2.80–2.45 (m, 2 H, 1Ј-H), 1.90 (dddd, J = 13.9, 8.9, 6.9,
6.8 Hz, 1 H, 2Ј-Ha), 1.75 (dddd, J = 13.4, 9.4, 7.0, 6.0 Hz, 1 H, 2Ј-
Hb) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.91 (s) and 147.23
(s) (2 C, 2ϫ COCH3), 138.72 (d, C-4Ј), 134.79 (s, C-4), 120.34 (d,
ArCH), 117.46 (t, C-5Ј), 111.93 (d, ArCH), 111.35 (d, ArCH),
82.17 (d, C-3Ј), 56.29 (q, ArOCH3), 56.03 (q, ArOCH3), 55.90 (q,
OCH3), 37.37 (t, C-2Ј), 31.23 (t, C-1Ј) ppm. HRMS (ESI): calcd.
for C14H20O3Na+ [M + Na]+: 259.1305; found 259.1306.
(–)-N-{(1S)-1-[2-(3,4-Dimethoxyphenyl)ethyl]prop-2-en-1-yl}-2-iodo-
aniline [(–)-(S)-3ea], N-[(2E)-5-(3,4-Dimethoxyphenyl)pent-2-en-1-
yl]-2-iodoaniline [(2E)-4ea] and 1,2-Dimethoxy-4-[(3S)-3-meth-
oxypent-4-en-1-yl]benzene [(S)-8]: GP1 (Method C) was carried out
with [Ir(COD)Cl]2 (71.9 mg, 107 μmol), (R,R,aR)-L2 (128.5 mg,
214 μmol), TBD (59.7 mg, 428 μmol), the carbonate (2E)-1e
(1.00 g, 3.57 mmol), 2-iodoaniline (2a, 938.6 mg, 4.3 mmol) and
dry THF (4 mL). The reaction mixture was stirred for 30 min at
50 °C. An additional quantity of freshly prepared catalyst
{[Ir(COD)Cl]2 (71.9 mg, 107 μmol)/(R,R,aR)-L2 (128.5 mg,
214 μmol)/TBD (59.7 mg, 428 μmol) in dry THF (2 mL)} was then
added to the reaction mixture. Stirring was continued for 5.5 h at
General Procedure (GP2) for Hydroboration/Intramolecular Suzuki–
Miyaura Cross-Coupling. Method A: Pd(dppf)Cl2 (5 mol-%), AsPh3
(10 mol-%) and Cs2CO3 (2 mmol) were added to DMF/water (15:1,
6882
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Eur. J. Org. Chem. 2011, 6877–6886

Enantioselective Syntheses of Tetrahydroquinolines
2.5 mL) under argon in a Schlenk tube. The resulting red to orange
mixture was stirred vigorously for 5 min at room temperature. In a
separate round-bottomed flask, 9-BBN (2.5 mmol) was added un-
der argon to a solution of the pure branched amination product 3
(1 mmol) in dry THF (1.25 mL). This mixture was allowed to stir
for 10 min at 70 °C and was then transferred to the catalyst suspen-
sion; the flask was rinsed with THF (1.25 mL). The resultant yel-
low suspension was stirred at 80 °C for 20–40 h. When TLC moni-
toring showed complete conversion, the mixture was washed with
saturated NH4Cl solution (5 mL) and the aqueous layer was ex-
tracted with diethyl ether (3ϫ 5 mL). The combined organic layers
were dried with Na2SO4 and concentrated in vacuo. The crude
product was purified by flash column chromatography on silica
with pentane/ethyl acetate as eluent.
0.70 mmol) under microwave irradiation at 120 °C for 30 min, to
furnish (–)-(S)-5b (43 mg, 76%) as a yellow oil. [α]2D0 = –76.5 (c =
1.07, CHCl3, 94% ee). 1H NMR (300 MHz, CDCl3): δ = 6.98 (t, J
= 7.1 Hz, 1 H, 7-H), 6.97 (d, J = 7.2 Hz, 1 H, 5-H), 6.62 (ddd, J
= 7.4, 7.4, 0.9 Hz, 1 H, 6-H), 6.50 (dd, J = 8.4, 0.8 Hz, 1 H, 8-H),
3.69 (br. s, 1 H, NH), 3.19 (dddd, J = 9.6, 6.4, 6.4, 3.1 Hz, 1 H, 2-
H), 2.84 (ddd, J = 16.1, 10.6, 5.4 Hz, 1 H, 4-Ha), 2.75 (ddd, J =
15.9, 5.0, 4.0 Hz, 1 H, 4-Hb), 1.99 (dddd, J = 12.8, 5.5, 4.0, 3.1 Hz,
1 H, 3-Ha), 1.75–1.42 (m, 3 H, 3-Hb, 1Ј-H), 1.02 (t, J = 7.6 Hz, 3
H, 2ЈЈ-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 144.85 (s, C-8a),
129.35 (d, C-5), 126.82 (d, C-7), 121.52 (s, C-4a), 117.00 (d, C-6),
114.13 (d, C-8), 53.17 (d, C-2), 29.52 (t, C-1Ј), 27.70 (t, C-3), 26.54
(t, C-4), 10.17 (q, C-2Ј) ppm. HRMS (EI+): calcd. for C11H15N+
[M]+: 161.1205; found 161.1221. C11H15N (161.24): calcd. C 81.94,
H 9.38, N 8.69; found C 81.67, H 9.50, N 8.52.
Method B: As Method A, except that the Suzuki–Miyaura coupling
was carried out with microwave irradiation for 30 min (120 °C) or
60 min (100 °C), 300 W, closed vessel.
(2S)-2-Propyl-1,2,3,4-tetrahydroquinoline
[(–)-(S)-5c]:
GP2
(Method A) was followed with (+)-(S)-3ca (301.2 mg, 1.0 mmol),
9-BBN (305.1 mg, 2.5 mmol), dry THF (total 4 mL), Pd(dppf)Cl2
(36.6 mg, 50 μmol), AsPh3 (30.6 mg, 100 μmol), Cs2CO3 (651.6 mg,
2.0 mmol) and DMF/H2O (15:1, 4 mL) at 80 °C for 23 h. TLC
showed complete conversion [petroleum ether/ethyl acetate 9:1, Rf
(5c) = 0.66, Rf (borane residues) = 0.16, KMnO4]. After standard
workup, the crude product was subjected to flash chromatography
on silica (30 g, n-pentane/ethyl acetate 99:1) to give (–)-(S)-5c
(128 mg, 71%) as a yellowish oil.
(–)-(2S)-2-Methyl-1,2,3,4-tetrahydroquinoline [(–)-(S)-5a]: GP2
(Method A) was carried out with (+)-(S)-3aa (207 mg, 0.7 mmol),
9-BBN (148.0 mg, 1.21 mmol), THF (total 4 mL), Pd(dppf)Cl2
(27.8 mg, 38 μmol), AsPh3 (23.2 mg, 76 μmol), Cs2CO3 (494.1 mg,
1.52 mmol) and DMF/water (15:1, 4 mL) at 80 °C for 26 h. Purifi-
cation of the crude product by flash chromatography on silica
(30 g, pentane to pentane/ethyl acetate 99:1) furnished (–)-(S)-5a
(70 mg, 63%) as a yellow oil. Rf (5a) = 0.55 (petroleum ether/ethyl
acetate 9:1, KMnO4).
GP2 (Method B) was employed with (+)-(S)-3ca (98.9 mg,
0.33 mmol), 9-BBN (101.3 mg, 0.83 mmol), Pd(dppf)Cl2 (12.46 mg,
17 μmol), AsPh3 (10.11 mg, 34 μmol), Cs2CO3 (232.86 mg,
0.66 mmol) and dry THF (3 mL) under microwave irradiation at
120 °C for 30 min. The tetrahydroquinoline (–)-(S)-5c (43 mg, 74%)
was obtained as a yellowish oil. [α]2D0 = –81.0 (c = 1.1, CHCl3,
GP2 (Method B) was followed with (+)-(S)-3aa (104 mg,
0.38 mmol), 9-BBN (116 mg, 0.95 mmol), Pd(dppf)Cl2 (14.0 mg
μmol), AsPh3 (11.7 mg, 38 μmol) and Cs2CO3 (248.2 mg,
0.76 mmol) under microwave irradiation for 30 min (120 °C, 300 W,
closed vessel). Workup and purification as described above fur-
nished (–)-(S)-5a (38 mg, 68%) as a yellow oil. [α]2D0 = –78.3 (c =
1.00, CHCl3, 94% ee). 1H NMR (300 MHz, CDCl3): δ = 7.08–6.85
(m, 2 H, 5-H, 7-H), 6.62 (ddd, J = 7.4, 7.4, 1.0 Hz, 1 H, 6-H), 6.49
(dd, J = 8.6, 1.1 Hz, 1 H, 8-H), 3.45 (br. s, 1 H, NH), 3.41 (ddq, J
= 12.9, 9.5, 3.1 Hz, 1 H, 2-H), 2.86 (ddd, J = 16.6, 11.2, 5.4 Hz, 1
H, 4-Ha), 2.74 (ddd, J = 16.3, 5.3, 3.5 Hz, 1 H, 4-Hb), 1.95 (dddd,
J = 12.8, 5.8, 3.0, 3.0 Hz, 1 H, 3-Ha), 1.23 (dddd, J = 12.8, 11.4,
10.0, 5.5 Hz, 1 H, 3-Hb), 1.23 (d, J = 6.2 Hz, 3 H, 1Ј-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 144.78 (s, C-8a), 129.39 (d, C-5),
126.81 (d, C-7), 121.29 (s, C-4a), 117.18 (d, C-6), 114.19 (d, C-8),
47.30 (d, C-2), 30.21 (t, C-3), 26.70 (t, C-4), 22.70 (q, C-1Ј) ppm.
1
96% ee). H NMR (CDCl3, 300 MHz): δ = 6.97 (t, J = 6.8 Hz, 2
H, 7-H), 6.95 (d, J = 7.2 Hz, 1 H, 5-H), 6.60 (ddd, J = 7.4, 7.4,
1.0 Hz, 1 H, 6-H), 6.48 (dd, J = 8.2, 1.2 Hz, 1 H, 8-H), 3.60 (br. s,
1 H, NH), 3.40–3.12 (m, 1 H, 2-H), 2.84 (ddd, J = 10.8, 10.8,
5.5 Hz, 1 H, 4-Ha), 2.74 (ddd, J = 16.2, 10.3, 5.7 Hz, 1 H, 4-Hb),
1.97 (dddd, J = 12.8, 5.5, 4.1, 3.1 Hz, 1 H, 3-Ha), 1.61 (dddd, J =
12.8, 10.6, 9.6, 5.6 Hz, 1 H, 3-Hb), 1.60–1.28 (m, 4 H, 1Ј-H, 2Ј-H),
0.98 (t, J = 7.0 Hz, 3 H, 3Ј-H) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 144.84 (s, C-8a), 129.38 (d, C-5), 126.82 (d, C-7), 121.54 (s, C-
4a), 117.03 (d, C-6), 114.18 (d, C-8), 51.44 (d, C-2), 39.02 (t, C-1Ј),
28.25 (t, C-3), 26.56 (t, C-4), 19.03 (t, C-2Ј), 14.33 (q, C-3Ј) ppm.
HRMS (ESI+): calcd. for C12H18N+ [M + H]+:176.1434; found
176.1434.
+
HRMS (ESI+): calcd. for C20H27N2 = [2M + H]+: 295.2169;
found 295.2170. HRMS (EI+): calcd. for C10H13N+ [M]+: 147.1048;
found 147.1060.
(2S)-2-Pentyl-1,2,3,4-tetrahydroquinoline
[(–)-(S)-5d]:
GP2
(Method A) was carried out with (+)-(S)-3da (626.2 mg,
1.90 mmol), 9-BBN (580.9 mg, 4.76 mmol), THF (total 5 mL),
Pd(dppf)Cl2 (69.61 mg, 95 μmol), AsPh3 (58.2 mg, 190 μmol),
Cs2CO3 (1.341 g, 3.80 mmol) and DMF/H2O (15:1, 5 mL) at 80 °C
for 20 h. Purification of the crude product by flash chromatography
on silica (30 g, pentane to n-pentane/ethyl acetate 99:1) furnished
(–)-(S)-5d (315 mg, 81%) as a yellow oil. Rf (5d) = 0.55 (petroleum
ether/ethyl acetate 9:1, KMnO4).
(–)-(2S)-2-Ethyl-1,2,3,4-tetrahydroquinoline
[(–)-(S)-5b]:
GP2
(Method A) was carried out with the amine (+)-(S)-3bb (87 mg,
0.36 mmol), 9-BBN (111 mg, 0.91 mmol), THF (total 3 mL),
Pd(dppf)Cl2 (13.3 mg, 18 μmol), AsPh3 (11.1 mg, 36 μmol),
Cs2CO3 (237.2 mg, 0.73 mmol) and DMF/water (15:1, 3 mL) at
80 °C for 48 h. Purification of the crude product by flash
chromatography on silica (20 g, pentane to pentane/ethyl acetate
99:1) furnished (–)-(S)-5b (48 mg, 82%) as a yellow oil. Rf (5b) =
0.65 (petroleum ether/ethyl acetate 9:1, KMnO4).
With (+)-(S)-3db (123 mg, 0.44 mmol), 9-BBN (134.2 mg,
1.10 mmol), Pd(dppf)Cl2 (16.1 mg, 20 μmol), AsPh3 (12.2 mg,
40 μmol) and Cs2CO3 (310.5 mg, 0.88 mmol) at 80 °C for 29 h the
reaction produced (–)-(S)-5d (68 mg, 77%).
With (+)-(S)-3ba (102 mg, 0.35 mmol), 9-BBN (108.4 mg,
0.89 mmol), Pd(dppf)Cl2 (13.0 mg, 18 μmol), AsPh3 (10.9 mg,
35 μmol) and Cs2CO3 (231.6 mg, 0.71 mmol) at 80 °C for 24 h the
reaction produced (–)-(S)-5b (43 mg, 75%) as a yellow oil.
GP2 (Method B) was followed with (+)-(S)-3da (100 mg,
GP2 (Method B) was followed with (+)-(S)-3ba (101 mg, 0.30 mmol), 9-BBN (92.74 mg, 0.76 mmol), THF (total 3 mL),
0.35 mmol), 9-BBN (107.4 mg, 0.88 mmol), Pd(dppf)Cl2 (12.9 mg, Pd(dppf)Cl2 (11.15 mg, 15 μmol), AsPh3 (9.31 mg, 30 μmol),
18 μmol), AsPh3 (10.8 mg, 35 μmol) and Cs2CO3 (229.3 mg,
Cs2CO3 (198.1 mg, 0.61 mmol) and DMF/water (15:1, 3 mL) under
Eur. J. Org. Chem. 2011, 6877–6886
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6883

G. Satyanarayana, D. Pflästerer, G. Helmchen
microwave irradiation at 100 °C for 1 h to give (–)-(S)-5d (53 mg, 10 mL) and brine (10 mL). The aqueous layer was extracted with
FULL PAPER
81%).
diethyl ether (3ϫ 10 mL). The combined organic layers were dried
with Na2SO4 and concentrated in vacuo. The crude product was
subjected to flash column chromatography (14 g silica, n-pentane/
ethyl acetate 99:1) to give (+)-angustureine (157.2 mg, 94%) as a
yellowish oil. [α]2D0 = +8.5 (c = 1.12, CHCl3, 94% ee) {lit.[1b] for
(–)-angustureine [α]2D5 = –7.16 (c = 1.00, CHCl3)}. 1H NMR
(CDCl3, 300 MHz): δ = 7.10 (t, J = 7.7 Hz, 1 H, 7-H), 6.99 (d, J
= 7.3 Hz, 1 H, 5-H), 6.60 (t, J = 7.3 Hz, 1 H, 6-H), 6.54 (d, J =
8.2 Hz, 1 H, 8-H), 3.25 (dddd, J = 8.5, 4.2, 4.2, 4.2 Hz, 1 H, 2-H),
2.95 (s, 3 H, NCH3), 2.83 (ddd, J = 16.5, 10.0, 7.6 Hz, 1 H, 4-H),
2.67 (ddd, J = 16.2, 4.2, 4.2 Hz, 1 H, 4-H), 1.98–1.83 (m, 2 H, 3-
Ha, 1Ј-H), 1.71–1.48 (m, 1 H, 3-Hb), 1.52–1.14 (m, 7 H, 1Ј-H, 2Ј-
H, 3Ј-H, 4Ј-H), 0.92 (t, J = 6.7 Hz, 3 H, 5Ј-H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 145.51 (s, C-8a), 128.75 (d, C-5), 127.17 (d,
C-7), 121.97 (s, C-4a), 115.30 (d, C-6), 110.52 (d, C-8), 59.07 (d,
C-2), 38.08 (q, NCH3), 32.17 (t, C-3Ј), 31.32 (t, C-1Ј), 25.89 (t, C-
2Ј), 24.53 (t, C-3), 23.70 (t, C-4), 22.81 (t, C-4Ј), 14.18 (q, C-
5Ј) ppm.[19] HRMS (ESI+): calcd. for C15H24N+ [M + H]+:
218.1903; found 218.1904.
With (+)-(S)-3db (88 mg, 0.31 mmol), 9-BBN (92.74 mg,
0.76 mmol), Pd(dppf)Cl2 (11.1 mg, 15 μmol), AsPh3 (9.3 mg,
30 μmol) and Cs2CO3 (198.0 mg, 0.61 mmol) under microwave irra-
diation at 120 °C for 30 min the reaction furnished (–)-(S)-5d
(45 mg, 71%) as a yellow oil. [α]2D0 = –65.8 (c = 1.00, CHCl3,
1
94% ee). H NMR (CDCl3, 300 MHz): δ = 6.98 (t, J = 7.0 Hz, 2
H, 7-H), 6.96 (d, J = 7.3 Hz, 1 H, 5-H), 6.62 (ddd, J = 7.4, 7.4,
1.1 Hz, 1 H, 6-H), 6.50 (dd, J = 8.4, 1.0 Hz, 1 H, 8-H), 3.58 (br. s,
1 H, NH), 3.25 (dddd, J = 9.5, 6.3, 6.3, 3.2 Hz, 1 H, 2-H), 2.84
(ddd, J = 16.2, 10.7, 5.4 Hz, 1 H, 4-Ha), 2.75 (ddd, J = 15.9, 10.1,
5.5 Hz, 1 H, 4-Hb), 1.98 (dddd, J = 12.9, 4.9, 4.1, 3.8 Hz, 1 H, 3-
Ha), 1.62 (dddd, J = 12.7, 10.3, 10.1, 5.6 Hz, 1 H, 3-Hb), 1.62–1.15
(m, 8 H, 1Ј-H, 2Ј-H, 3Ј-H, 4Ј-H), 0.93 (t, J = 6.8 Hz, 3 H, 5Ј-
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 144.75 (s, C-8a), 129.37
(d, C-5), 126.82 (d, C-7), 121.58 (s, C-4a), 117.08 (d, C-6), 114.22
(d, C-8), 51.75 (d, C-2), 36.77 (t, C-1Ј), 32.08 (t, C-3Ј), 28.22 (t, C-
3), 26.55 (t, C-4), 25.53 (t, C-2Ј), 22.78 (t, C-4Ј), 14.20 (q, C-
5Ј) ppm. HRMS (FAB+): calcd. for C14H21N+ [M]+: 203.1674;
found 203.1676. HRMS (ESI+): calcd. for C14H22N+ [M + H]+:
204.1747; found 204.1749. C14H21N (203.32): calcd. C 82.70, H
10.41, N 6.89; found C 82.53, H 10.52, N 6.74.
(–)-(2S)-2-[2-(3,4-Dimethoxyphenyl)ethyl]-1-methyl-1,2,3,4-tetra-
hydroquinoline [(–)-Cuspareine]: A mixture of (–)-(S)-5e (115.00 mg,
0.39 mmol), acetonitrile (4 mL), paraformaldehyde (174.4 mg,
5.81 mmol), sodium cyanoborohydride (243.3) mg, 3.87 mmol) and
acetic acid (0.22 mL, 3.87 mmol) was stirred for 16 h at room tem-
perature. TLC monitoring showed complete conversion. The mix-
ture was diluted with diethyl ether and washed with KOH solution
(1 m, 10 mL) and brine (10 mL), and the aqueous layer was ex-
tracted with diethyl ether (3ϫ 10 mL). The combined organic lay-
ers were dried with Na2SO4 and concentrated in vacuo. Purification
of the crude product by flash chromatography on silica (20 g, petro-
leum ether/ethyl acetate 95:5 to 9:1) furnished (–)-cuspareine
(107 mg, 89%) as a yellow oil. Rf (cuspareine) = 0.50 (petroleum
ether/ethyl acetate 7:3, KMnO4). [α]2D0 = –25.6 (c = 1.02, CHCl3,
93.5% ee) {lit.[1c] [α]2D5 = –22.8 (c = 1.00, CHCl3)}. 1H NMR
(300 MHz, CDCl3): δ = 7.12 (ddd, J = 8.1, 7.3, 0.9 Hz, 1 H, 7-H),
7.02 (d, J = 7.3 Hz, 1 H, 5-H), 6.82 (d, J = 8.0 Hz, 1 H, 5Ј-H),
6.81–6.71 (m, 2 H, 2ЈЈ-H, 6ЈЈ-H), 6.63 (dd, J = 7.2, 7.2 Hz, 1 H, 6-
H), 6.57 (d, J = 8.3 Hz, 1 H, 8-H), 3.90 (s) and 3.88 (s) (2ϫ Ar-
OCH3), 3.32 (dddd, J = 8.5, 4.2, 4.2, 4.2 Hz, 1 H, 2-H), 2.95 (s,
NCH3), 2.89 (ddd, J = 17.0, 11.2, 6.3 Hz, 1 H, 4-Ha), 2.81–2.62
(m, 2 H, 4-Hb, 2Ј-Ha), 2.57 (ddd, J = 14.0, 10.0, 6.4 Hz, 1 H, 2Ј-
Hb), 2.09–1.84 (m, 3 H, 3-Ha, 1Ј-H), 1.77 (dddd, J = 13.9, 9.8, 8.9,
5.2 Hz, 1 H, 3-Hb) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.96
(s) and 147.28 (s, 2 C, 2ϫ COCH3), 145.36 (s, C-8a), 134.70 (s, C-
1ЈЈ), 128.76 (d, C-5), 127.19 (d, C-7), 121.79 (s, C-4a), 120.13 (d,
ArCH), 115.46 (d, C-6), 111.66 (d, ArCH), 111.36 (d, ArCH),
110.69 (d, C-8), 58.47 (d, C-2), 56.00 (q, OCH3), 55.94 (q, OCH3),
38.16 (q, NCH3), 33.15 (t, C-1Ј), 31.99 (t, C-2Ј), 24.47 (t, C-3),
(–)-(2S)-2-[2-(3,4-Dimethoxyphenyl)ethyl]-1,2,3,4-tetrahydro-
quinoline [(–)-(S)-5e]: GP2 (Method A) was followed with (–)-(S)-3e
(400 mg, 0.95 mmol), 9-BBN (288.46 mg, 2.36 mmol), THF (total
4 mL), Pd(dppf)Cl2 (34.7 mg, 47 μmol), AsPh3 (28.96 mg,
94 μmol), Cs2CO3 (616.2 mg, 1.89 mmol) and DMF/water (15:1,
4 mL) at 80 °C for 24 h. Purification of the crude product by flash
chromatography on silica (40 g, n-pentane/ethyl acetate 95:5 to
90:10) furnished (–)-(S)-5e (165 mg, 59%) as a yellow oil. Rf (5e)
= 0.41 (petroleum ether/ethyl acetate 7:3, KMnO4).
GP2 (Method B) was carried out with (–)-(S)-3e (190 mg,
0.45 mmol), 9-BBN (137.04 mg, 1.12 mmol), THF (total 3 mL),
Pd(dppf)Cl2 (16.5 mg, 22 μmol), AsPh3 (13.76 mg, 45 μmol),
Cs2CO3 (292.7 mg, 0.90 mmol) and DMF/water (15:1, 3 mL) under
microwave irradiation at 120 °C for 30 min to give (–)-(S)-5e
(86 mg, 64%). [α]2D0 = –60.9 (c = 0.82, CHCl3, 93.5% ee). 1H NMR
(300 MHz, CDCl3): δ = 7.05–6.90 (m, 2 H, 5-H, 7-H), 6.82 (d, J =
8.1 Hz, 1 H, 2ЈЈ-H), 6.80–6.70 (m, 2 H, 5ЈЈ-H, 6ЈЈ-H), 6.62 (ddd, J
= 7.6, 7.4, 1.0 Hz, 1 H, 6-H), 6.46 (dd, J = 8.4, 1.1 Hz, 1 H, 4-H),
3.88 (s) and 3.87 (s, 2ϫ ArOCH3), 3.75 (br. s, 1 H, NH), 3.32
(dddd, J = 9.3, 6.3, 6.3, 3.0 Hz, 1 H, 2-H), 2.90–2.60 (m, 4 H, 4-
H, 2Ј-H), 2.01 (dddd, J = 12.8, 5.0, 5.0, 3.2 Hz, 1 H, 3-Ha), 1.83
(ddd, J = 9.3, 6.3, 6.3 Hz, 2 H, 1Ј-H), 1.69 (dddd, J = 12.9, 9.6,
9.6, 5.9 Hz, 1 H, 3-Hb) ppm. 13C NMR (75 MHz, CDCl3): δ =
149.09 (s) and 147.45 (s) (2 C, 2ϫ COCH3), 144.58 (s, C-8a), 134.59
(s, C-1ЈЈ), 129.37 (d, C-5), 126.86 (d, C-7), 121.44 (s, C-4a), 120.26
(d, ArCH), 117.19 (d, C-6), 114.28 (d, C-8), 111.79 (d, ArCH),
111.48 (d, ArCH), 56.08 (q, OCH3), 55.98 (q, OCH3), 51.35 (d, C-
2), 38.52 (t, C-1Ј), 31.95 (t, C-2Ј), 28.13 (t, C-3), 26.31 (t, C-4) ppm.
+
23.65 (t, C-4) ppm. HRMS (ESI+): calcd. for C20H26NO2 [M +
H]+: 312.1958; found 312.1956. C20H25NO2 (311.42): calcd. C
77.14, H 8.09, N 4.50; found C 77.12, H 8.25, N 4.43.
HRMS (ESI+): calcd. for C19H24NO2 [M + H]+: 298.1802; found
298.1803. C19H23NO2 (297.39): calcd. C 76.73, H 7.80, N 4.71;
found C 76.51, H 7.97, N 4.48.
+
Methyl (2E)-5-(3,4-Dimethoxyphenyl)pent-2-enoate [(2E)-7b]:
A
mixture of Pd(dppf)Cl2 (335.5 mg, 0.46 mmol), AsPh3 (280.1 mg,
0.91 mmol), methyl (2E)-3-iodoacrylate (3.86 g, 18.29 mmol),
Cs2CO3 (6.95 g, 21.34 mmol) and DMF/water (15:1, 6 mL) was
(+)-(2S)-1-Methyl-2-pentyl-1,2,3,4-tetrahydroquinoline [(+)-Angus-
tureine]: A mixture of the amine (–)-(S)-5d (157.0 mg, 0.77 mmol), stirred vigorously for 5 min at room temperature under argon in a
acetonitrile (6 mL), paraformaldehyde (333.3 mg, 11.1 mmol), so-
dium cyanoborohydride (465.0 mg, 7.40 mmol) and acetic acid
Schlenk tube. In
18.29 mmol) was added under argon to a solution of the olefin 7a
a round-bottomed flask, 9-BBN (2.23 g,
(444.4 mg, 7.40 mmol) was stirred for 17 h at room temperature. (2.5 g, 15.24 mmol) in dry THF (3 mL) and the resulting reaction
TLC monitoring showed complete conversion {petroleum ether/
ethyl acetate 18:1, Rf [(+)-angustureine] = 0.65, KMnO4}. The mix-
ture was diluted with diethyl ether and washed with KOH (1 m,
mixture was allowed to stir for 10 min at 70 °C. The mixture was
transferred into the catalyst suspension and the flask was rinsed
with additional THF (3 mL). The resulting yellow suspension was
6884
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Eur. J. Org. Chem. 2011, 6877–6886

Enantioselective Syntheses of Tetrahydroquinolines
stirred at room temp. for 16 h. The reaction mixture was diluted
with diethyl ether and washed with saturated NH4Cl solution
(40 mL), and the aqueous layer was extracted with diethyl ether
(3ϫ 30 mL). The combined organic layers were dried with Na2SO4
and concentrated in vacuo. Purification of the crude product by
flash chromatography on silica (50 g, petroleum ether/ethyl acetate
90:10 to 4:1) furnished the ester (2E)-7b (3.206 g, 84%) as a yellow
oil. Rf [(2E)-7b] = 0.35, petroleum ether/ethyl acetate 7:3, KMnO4.
OCOOCH3), 2.65 (t, J = 7.8 Hz, 2 H, 5-H), 2.36 (dt, J = 7.4,
7.3 Hz, 2 H, 4-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.75
(s, OCOOCH3), 148.83 (s) and 147.30 (s) (2 C, 2ϫ COCH3), 136.40
(d, C-3), 134.19 (s, C-1Ј), 123.95 (d, C-2), 120.25 (d, ArCH), 111.77
(d, ArCH), 111.22 (d, ArCH), 68.60 (t, C-1), 55.99 (q, ArOCH3),
55.89 (q, ArOCH3), 54.82 (q, COOCH3), 34.90 (t, C-5), 34.33 (t,
C-4) ppm. HRMS (ESI+): calcd. for C15H20O5Na+ [M + Na]+:
303.1203; found 303.1024. C15H20O5 (280.32): calcd. C 64.27, H
1H NMR (300 MHz, CDCl3): δ = 7.01 (dt, J = 15.7, 6.9 Hz, 1 H, 7.19; found C 64.05, H 7.22.
3-H), 6.79 (d, J = 8.0 Hz, 1 H, 5Ј-H), 6.71 (dd, J = 8.3, 1.8 Hz, 1
Supporting Information (see footnote on the first page of this arti-
H, 6Ј-H), 6.69 (d, J = 1.7 Hz, 1 H, 2Ј-H), 5.84 (dt, J = 15.6, 1.4 Hz,
1 H, 2-H), 3.86 (s) and 3.85 (s) (6 H, 2ϫ ArOCH3), 3.72 (s, 3 H,
COOCH3), 2.72 (t, J = 7.6 Hz, 2 H, 5-H), 2.50 (dt, J = 8.3, 6.8 Hz,
2 H, 4-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.13 (s, O–
C=O), 148.95 (s, COCH3), 148.56 (d, C-3), 147.51 (s, COCH3),
133.45 (s, C-1Ј), 121.54 (d, C-2), 120.27 (d, ArCH), 111.74 (d,
ArCH), 111.36 (d, ArCH), 56.03 (q, ArOCH3), 55.94 (q, ArOCH3),
51.57 (q, COOCH3), 34.25 (t, C-4), 34.08 (t, C-5) ppm. HRMS
cle): Copies of HPLC data for compounds 3aa to 3ea, together
1
with H and 13C NMR spectra of compounds.
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG) (SFB 623) and the Fonds der Chemischen Industrie.
+
(ESI+): calcd. for C14H19O4 [M + H]+: 251.1280; found 251.1278.
HRMS (ESI+): calcd. for C14H18O4K+ [M + K]+: 289.0837; found
289.0840. C14H18O4 (250.29): calcd. C 67.18, H 7.25; found C
66.94, H 7.43.
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(2E)-5-(3,4-Dimethoxyphenyl)pent-2-en-1-ol [(2E)-7c]: DIBAL-H
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oled (–78 °C) solution of the ester (2E)-7b (1.02 g, 4.1 mmol) in dry
THF (16 mL) in a round-bottomed flask and the resulting reaction
mixture was stirred at the same temperature for 2.5 h. The reaction
mixture was treated dropwise with aq. NH4Cl (20 mL) at –78 °C
and then washed with HCl solution (3 n, 20 mL). The aqueous
layer was extracted with diethyl ether (3ϫ 20 mL) and the com-
bined organic layers were dried with Na2SO4 and concentrated in
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on silica (40 g, petroleum ether/ethyl acetate 70:30 to 30:70) fur-
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6.75–6.65 (m, 2 H, 2Ј-H, 6Ј-H), 5.82–5.58 (m, 2 H, 2-H, 3-H), 4.08
(d, J = 4.7 Hz, 2 H, 1-H), 3.86 (s) and 3.85 (s, 6 H, 2ϫ ArOCH3),
2.65 (t, J = 8.2 Hz, 2 H, 5-H), 2.35 (dt, J = 8.9, 6.3 Hz, 2 H, 4-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.86 (s) and 147.29
(s, 2 C, 2ϫ COCH3), 134.45 (s, C-1Ј), 132.35 (d, C-3), 129.66 (d,
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(t, C-1), 56.01 (q, ArOCH3), 55.92 (q, ArOCH3), 35.22 (t, C-5),
34.29 (t, C-4) ppm. HRMS (ESI+): calcd. for C13H18O3Na+ [M +
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(2E)-5-(3,4-Dimethoxyphenyl)pent-2-en-1-yl Methyl Carbonate
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Eur. J. Org. Chem. 2011, 6877–6886
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6885

G. Satyanarayana, D. Pflästerer, G. Helmchen
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but reversed with respect to that of ref.[1b]
,
Received: July 6, 2011
Published Online: September 28, 2011
6886
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6877–6886