A flexible synthesis of indoline, indolizidine, and pyrrolizidine derivatives

Article abstract of DOI:10.1002/ejoc.200300123

New and flexible procedures for the synthesis of indoline, indolizidine, and pyrrolizidine derivatives are described. By these new procedures, the target compounds can be synthesized with high diversity from three building blocks (ortho-bromo- or ortho-ch

Full text of DOI:10.1002/ejoc.200300123

FULL PAPER
A Flexible Synthesis of Indoline, Indolizidine, and Pyrrolizidine Derivatives
Igor Bytschkov,[a] Holger Siebeneicher,[a] and Sven Doye*[a]
Keywords: Alkynes / Aminations / Homogeneous catalysis / Palladium / Titanium
New and flexible procedures for the synthesis of indoline,
indolizidine, and pyrrolizidine derivatives are described. By
these new procedures, the target compounds can be synthe-
are commercially available or easily accessible, a huge num-
ber of indoline, indolizidine, and pyrrolizidine derivatives is
theoretically obtainable by the standard reaction sequences
sized with high diversity from three building blocks (ortho- developed. Since the experimental procedures are simple
bromo- or ortho-chloro-iodobenzenes, terminal alkynes, and
primary amines). The synthetic strategies presented include
Sonogashira couplings, Cp2TiMe2-catalyzed hydroamina-
tions of alkynes, and Pd-catalyzed aminations of aryl halides
as key steps. Since many of the employed starting materials
and mostly catalytic, applications of the described methods
for automated synthesis are also imaginable.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
During the last few years, catalytic hydroamination reac-
tions of alkenes and alkynes have been investigated exten-
sively.[1] While the hydroamination of alkenes is still limited
to more or less activated alkenes, great progress has been
achieved in the case of alkynes over the last four years.[2]
Among the various catalysts identified for hydroamination
reactions of alkynes, group-IV metal complexes play an
outstanding role because they offer the possibility to con-
vert both terminal and internal alkynes into the corre-
sponding imines.[3] Furthermore, good regioselectivities of
amine additions are observed in reactions of unsymmetri-
cally substituted 2-alkyl-1-arylalkynes in the presence of ti-
tanium complexes such as [Cp2TiMe2],[4] giving access to
the corresponding anti-Markovnikov products.[5] These ad-
vantages, combined with the fact that 2-alkyl-1-arylalkynes
can easily be obtained by Sonogashira coupling reactions,[6]
have already been utilized for a flexible, three-step synthesis
of biologically interesting 2-arylethylamine derivatives em-
ploying aryl halides, terminal alkynes, and primary amines
as building blocks.[7] A representative example of the strat-
egy, including a final reduction of the initially formed hy-
droamination product (imine), is given in Scheme 1. In this
Scheme 1. Representative example for the flexible synthesis of 2-
arylethylamine derivatives from aryl halides, terminal alkynes, and
primary amines
context, it is worth to mention that the hydroamination step zation and subsequent reduction with NaBH3CN in the
and the final reduction are performed as a one-pot oper- presence of ZnCl2·Et2O.[8d] Interestingly, aminoalkynes
ation.
with a phenyl substituent directly bound to the alkyne sp
Furthermore, it has been shown that titanium complexes center give access to products also possessing the biologi-
also catalyze intramolecular hydroamination reactions.[8] By cally attractive 2-arylethylamine substructure (Scheme 2).
a corresponding approach, γ- and δ-aminoalkynes can be
Being aware of the importance of indoline, indolizidine,
converted into cyclic amines by [Cp2TiMe2]-catalyzed cycli- and pyrrolizidine derivatives with regard to biological ac-
tivity and organic synthesis,[9] we recently decided to com-
bine and extend both strategies to develop a new and
flexible synthetic pathway to molecules containing the
corresponding substructures as well as a 2-phenylethyl-
[a]
Institut für Organische Chemie der Universität Hannover
Schneiderberg 1B, 30167 Hannover, Germany
Fax: (internat.) ϩ49-(0)511/762-3011
E-mail: sven.doye@oci.uni-hannover.de
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DOI: 10.1002/ejoc.200300123
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A Flexible Synthesis of Indoline, Indolizidine, and Pyrrolizidine Derivatives
FULL PAPER
Table 1. Synthesis of ortho-bromo- and ortho-chloro-substituted 2-
alkyl-1-phenylalkynes by Sonogashira coupling
Scheme 2. Representative examples of the synthesis of 2-phenyl-
ethylamine derivatives from aminoalkyl(phenyl)alkynes
amine moiety (Scheme 3). For that purpose, we planned to
use ortho-bromo- or ortho-chloro-functionalized 2-alkyl-1-
phenylalkynes and aminoalkyl(phenyl)alkynes in place of
simple 2-alkyl-1-phenylalkynes and aminoalkyl(phenyl)-
alkynes as starting materials for the one-pot hydro-
amination reduction sequence. In this case, the reduced hy-
droamination products should be suitable substrates for a
final palladium-catalyzed intramolecular amination reac-
tion (BuchwaldϪHartwig reaction),[10] giving access to the
desired target molecules. Since the slightly modified starting
materials should still be obtainable in a straightforward
manner from simple, and in most cases commercially avail-
able, building blocks (e.g., 1-bromo- or 1-chloro-2-iodo-
benzenes and terminal alkynes) the desired strategy should
offer high synthetic flexibility. For that reason, a corre-
sponding approach (Scheme 3) should be suitable for the
fast generation of many indoline, indolizidine, and pyrroliz-
[a]
Reaction conditions: aryl halide (10.0 mmol), alkyne
Scheme 3. A flexible approach towards the synthesis of indoline,
indolizidine, and pyrrolizidine derivatives containing a 2-phenyl-
ethylamine substructure from 1-bromo- or 1-chloro-2-iodo-
benzenes, terminal alkynes, and primary amines
(10.0 mmol), [PdCl2(PPh3)2] (0.2 mmol, 2.0 mol %), CuI
(0.4 mmol, 4.0 mol %), PPh3 (0.4 mmol, 4.0 mol %), HN(iPr)2, 84
°C, 6 h; yields represent isolated yields of pure compounds.
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I. Bytschkov, H. Siebeneicher, S. Doye
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idine derivatives containing a 2-phenylethylamine substruc- tho-bromo- and ortho-chloro-substituted 2-alkyl-1-phe-
ture (a library), that could be used for further applications nylalkynes by Sonogashira coupling reactions. The reac-
in organic synthesis as well as for biological tests.
tions were usually performed under standard Sonogashira
conditions, giving access to the corresponding alkynes
6؊14 in high yields (Table 1). As expected, reactions took
place exclusively at the more reactive iodo-substituted car-
bon centers of the aromatic bis- or tris-halides.
Results and Discussion
Starting from readily available and more or less highly
functionalized 1-bromo- or 1-chloro-2-iodobenzenes 1؊5
and terminal alkynes we first synthesized a number of or-
Since the side chain-functionalized compound 10 pos-
sesses a hydroxy group, which is not tolerated under the
Table 2. Synthesis of ortho-bromo- and ortho-chloro-substituted 2-phenylethylamine derivatives by regioselective hydroamination and
subsequent in situ reduction
[a]
Reaction conditions: a) alkyne (4.0 mmol), amine (4.0 mmol), [Cp2TiMe2] (c ϭ 0.48 mol/L in toluene, 0.2 mmol, 5.0 mol %), 110 °C,
24 h; b) NaBH3CN (8.0 mmol), ZnCl2·Et2O (c ϭ 1.0 mol/L in Et2O, 4.0 mmol), MeOH, 25 °C, 12 h. Yields represent isolated yields of
pure compounds. [b] 10.0 mol % [Cp2TiMe2] was used for the hydroamination step. [c] [Cp*2TiMe2] (c ϭ 0.50 mol/L in toluene, 0.4 mmol,
[d]
[e]
10.0 mol %) was used as catalyst for the hydroamination step.
Markovnikov regioisomer was obtained. 39% of the Markovnikov regioisomer was obtained.
30% of the Markovnikov regioisomer was obtained.
29% of the
[f]
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A Flexible Synthesis of Indoline, Indolizidine, and Pyrrolizidine Derivatives
FULL PAPER
conditions of [Cp2TiMe2]-catalyzed hydroamination reac- amounts (5.0 mol %) of [Cp2TiMe2] at 110 °C in the pres-
tions, this substrate was converted into the corresponding ence of various amines. The initially formed imine products
benzyl ether 15 under standard conditions prior to further were not isolated but were directly reduced to yield the
transformations (Scheme 4).
stable ortho-bromo- and ortho-chloro-functionalized 2-
phenylethylamine derivatives 16؊26 (Table 2). Particularly
interesting are reactions employing para-methoxyaniline
(PMP-NH2, Entries 1, 6, 10) and para-methoxybenzylamine
(PMB-NH2, Entries 3, 11) because these amines represent
potential ammonia equivalents. However, for reactions in-
volving sterically less demanding amines such as para-meth-
oxybenzylamine (Entries 3, 11) and n-hexylamine (Entry 5)
it was necessary to use [Cp*2TiMe2] as catalyst for a suc-
cessful hydroamination step.[11] As observed before, the ob-
tained regioselectivities of the hydroamination reactions are
poor in these cases. In all corresponding reactions, large
amounts (29Ϫ39%) of the corresponding Markovnikov re-
Scheme 4. Protection of the hydroxy group of 10 as a benzyl ether
Subsequently, the obtained alkynes 6؊9 and 11؊15 were
regioselectively hydroaminated in the presence of catalytic
Table 3. Palladium-catalyzed cyclization to indoline derivatives
[a]
Reaction conditions: amine (2.0 mmol), [Pd2(dba)3] (0.1 mmol, 5.0 mol %), ligand precursor (0.2 mmol, 10.0 mol %), KOtBu
[b]
(3.0 mmol), 1,4-dioxane, 110 °C, 12 h. Yields represent isolated yields of pure compounds.
[Pd(PPh3)4] (0.1 mmol, 5.0 mol %), K2CO3 (4.0 mmol), NaOtBu (4.0 mmol), toluene, 110 °C, 5 h.
Reaction conditions: amine (2.0 mmol),
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I. Bytschkov, H. Siebeneicher, S. Doye
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gioisomers were isolated along with the desired products (Scheme 5).[12] The obtained imine products 36 and 37
(48Ϫ58%). could then be converted into nitrogen-functionalized indo-
Finally, the ortho-bromo- and ortho-chloro-substituted 2- line derivatives 38 and 39 by a second Pd-catalyzed intra-
phenylethylamines 16؊23 and 26 were converted into indo- molecular amination reaction. A final cleavage of the CϪN
line derivatives 27؊35 in the presence of a palladium cata- double bonds gave access to the corresponding derivatives
lyst. Depending on the nature of the halide (Br or Cl), dif- 40 and 41 containing unprotected NH2 groups (Scheme 5).
ferent catalyst systems were used. The bromo derivative 16
Indolizidine and pyrrolizidine derivatives were found to
was treated with NaOtBu and [Pd(PPh3)4], while the chloro be accessible in a related manner from ortho-bromo-
derivatives required the presence of KOtBu, [Pd2(dba)3], and ortho-chloro-functionalized aminoalkyl(phenyl)alkynes
and a carbene ligand (Table 3). Product 35 is especially 42؊47, which could be synthesized in a flexible manner
interesting, because the protected oxygen functionality in from 1-bromo- or 1-chloro-2-iodobenzenes by literature
the side chain offers the possibility for further transform- procedures, with a Sonogashira reaction as the key
ations (e.g. cyclizations). Furthermore, the N-protected in- step.[8d,13] Again, a one-pot hydroamination reduction se-
dolines 27, 29, 32, and 35 can be seen as precursors for the
corresponding unprotected derivatives.
This flexible synthetic strategy is characterized by the fact
Table 4. Synthesis of pyrrolidine and piperidine derivatives from
ortho-bromo- and ortho-chloro-substituted aminoalkyl(phenyl)al-
that the indoline target compounds can be synthesized from
three building blocks in only four steps. Since many of these
building blocks are commercially available, a huge number
of indoline derivatives is theoretically accessible by follow-
ing the developed standard reaction sequence. Since the ex-
perimental procedures are simple and mostly catalytic, ap-
plication of the method to automated synthesis is also im-
aginable.
kynes by hydroamination and subsequent in situ reduction
As can be seen from Table 1 and 2, it was also possible
to perform the first three steps of the reaction sequence
starting from 1-bromo-3-chloro-4-iodobenzene (5). In this
case, the presence of the additional bromo substituent in
the 2-phenylethylamine products 24 and 25 (Table 2) offers
the possibility to introduce further functionalities. For that
purpose, we chose a Pd-catalyzed intermolecular amination
reaction employing benzophenone imine which took place
at the bromo-substituted centers in 24 and 25 and estab-
lished a nitrogen functionality at the aromatic systems
[a]
Reaction conditions: a) aminoalkyne (4.0 mmol), [Cp2TiMe2]
(c ϭ 0.48 mol/L in toluene, 0.2 mmol, 5.0 mol %), 110 °C, 4Ϫ6 h;
b) NaBH3CN (8.0 mmol), ZnCl2·Et2O (c ϭ 1.0 mol/L in Et2O,
4.0 mmol), MeOH, 25 °C, 12 h. Yields represent isolated yields of
pure compounds.
Scheme 5. Synthesis of NH2-substituted indoline derivatives
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A Flexible Synthesis of Indoline, Indolizidine, and Pyrrolizidine Derivatives
FULL PAPER
did undergo successful cyclization. Interestingly, under opti-
mized conditions, better yields were obtained from chloro-
benzenes (Table 5, Entries 2, 5, 6) than from bromoben-
zenes (Table 5, Entries 1, 4).
Table 5. Palladium-catalyzed cyclization to indolizidine and pyrrol-
izidine derivatives
Conclusion
In summary, the procedures developed for the synthesis
of indoline, indolizidine, and pyrrolizidine derivatives again
show that clever combinations of recently developed, mod-
ern catalytic organic transformations offer flexible and ef-
ficient synthetic pathways to biologically interesting classes
of molecules. The major advantage of the described (and
related) synthetic strategies is the fact that thousands of
products are theoretically accessible from a relative small
number of readily available building blocks by a standard
procedure. Interestingly, the [Cp2TiMe2]-catalyzed hydroa-
mination of alkynes demonstrates once more that it does
not represent just another curiosity from organometallic
laboratories but should be regarded as a new and powerful
tool for organic synthesis. In our opinion, this judgment is
underlined by the fact that all yields reported in this publi-
cation are isolated yields.
Experimental Section
General Remarks: All reactions were performed under argon in
flame-dried Duran glassware (e.g., Schlenk tubes fitted with Teflon
stopcocks). Toluene was distilled from molten sodium under argon.
˚
Methanol was dried with molecular sieves (3 A). [Cp2TiMe2] was
synthesized according to ref.[4a] 1,3-bis(2,4,6-trimethylphenyl)imid-
azolium chloride according to ref.[14] aminoalkynes 42؊47 accord-
ing to ref.[8d,13] and compound 4 according to ref.[15] All other re-
agents were purchased from commercial sources and were used
without further purification. Unless otherwise noted, yields refer
to isolated yields of pure compounds as gauged by TLC and 1H
and 13C NMR spectroscopy. All products were characterized by
1H NMR, 13C NMR, and infrared (IR) spectroscopy, and mass
spectrometry (MS). New compounds were further characterized by
high-resolution mass spectrometry (HRMS) or CHN elemental
analysis. NMR spectra were recorded with a Bruker Avance
400 MHz spectrometer. All 1H NMR spectra are reported in δ
units ppm downfield from tetramethylsilane internal standard. All
13C NMR spectra are reported in δ units ppm relative to the central
line of the triplet for CDCl3 at δ ϭ 77.0 ppm. Infrared spectra were
recorded with a Bruker Vector 22 spectrometer by an attenuated
total reflection (ATR) method. Mass spectra were recorded with a
Finnigan MAT 312 or a VG Autospec (EI) with an ionization po-
tential of 70 eV or a Micromass LCT (ESI). Elemental analysis
were carried out on an Elementar Vario EL machine. PE: light
petroleum ether, b.p. 40Ϫ60 °C.
[a]
Reaction conditions: amine (1.0 mmol), [Pd2(dba)3] (0.05 mmol,
5.0 mol %), ligand precursor (0.1 mmol, 10.0 mol %), KOtBu
(1.5 mmol), 1,4-dioxane, 110 °C, 3Ϫ12 h. Yields represent isolated
yields of pure compounds.
(1.0 mmol), [Pd(PPh3)4] (0.05 mmol, 5.0 mol %), K2CO3
(2.0 mmol), NaOtBu (2.0 mmol), toluene, 110 °C, 6 h.
[b]
Reaction conditions: amine
quence was used to produce the corresponding ortho-
bromo- and ortho-chloro-substituted 2-phenylethylamine
derivatives containing pyrrolidine and piperidine substruc-
tures (48؊53) in good yields (Table 4).
Palladium-catalyzed cyclization reactions employing the
piperidine derivatives 51؊53 smoothly gave the desired in-
dolizidines 57؊59 in good yields, while the pyrrolidine de-
rivative 50 did not react successfully (Table 5). An expla-
nation for this lack of reactivity may be seen in the combi-
nation of two factors: (i) the presence of an electron-rich
and therefore less reactive aromatic system, and (ii) the
greater ring strain in this substrate than in the correspond-
ing piperidine derivative 53. However, the other molecules
Sonogashira Coupling. General Procedure A: CuI (77 mg, 0.4 mmol,
4.0 mol %), [(PPh3)2PdCl2] (141 mg, 0.2 mmol, 2.0 mol %), PPh3
(105 mg, 0.4 mmol, 4.0 mol %), and HN(iPr)2 (30 mL) were placed
in a round-bottomed flask containing a magnetic stirring bar. After
addition of the aryl halide (10.0 mmol), the mixture was stirred for
30 min at 25 °C, and the alkyne (10.0 mmol) was then added. After
this had been stirred at 84 °C for a further 6 h, saturated NH4Cl
solution was added. The mixture was extracted with tert-butyl
containing a five-membered cyclic amine structure (48, 49) methyl ether (3 ϫ). The combined organic layers were dried with
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I. Bytschkov, H. Siebeneicher, S. Doye
FULL PAPER
MgSO4 and concentrated under vacuum. The residue was purified
by flash chromatography (SiO2).
(400 MHz, CDCl3): δ ϭ 1.67Ϫ1.82 (m, 4 H), 2.51 (t, J ϭ 6.7 Hz,
2 H), 3.70 (t, J ϭ 6.0 Hz, 2 H), 7.14Ϫ7.21 (m, 2 H), 7.35Ϫ7.37 (m,
1 H), 7.41Ϫ7.43 (m, 1 H) ppm. 13C NMR (100.6 MHz, DEPT,
CDCl3): δ ϭ 19.3 (CH2), 24.8 (CH2), 31.7 (CH2), 62.3 (CH2), 77.8
(C), 95.6 (C), 123.6 (C), 126.3 (CH), 128.5 (CH), 129.0 (CH), 133.2
(CH), 135.6 (C) ppm. IR: ν˜ ϭ 3307, 2937, 2935, 2233, 1561, 1473,
1429, 1062, 1032, 750 cmϪ1. MS (60 °C): m/z (%) ϭ 210 (27)
[Mϩ(37Cl)], 208 (26) [Mϩ(35Cl)], 190 (10), 173 (72), 164 (78), 149
(80), 141 (47), 129 (100), 114 (59), 99 (17), 91 (15), 75 (21). HRMS:
calcd. (C12H13ClO) 208.0655; found 208.0653.
Alkyne 6: General Procedure A was used to synthesize alkyne 6
from 1-bromo-2-iodobenzene (1) and 1-hexyne. After purification
by flash chromatography (PE), compound 6 (1.85 g, 7.80 mmol,
1
78%) was isolated as a colorless oil. H NMR (400 MHz, CDCl3):
δ ϭ 0.95 (t, J ϭ 7.3 Hz, 3 H), 1.48Ϫ1.67 (m, 4 H), 2.47 (t, J ϭ
7.0 Hz, 2 H), 7.10 (td, J ϭ 7.7, 1.7 Hz, 1 H), 7.21 (td, J ϭ 7.6,
1.6 Hz, 1 H), 7.42 (dd, J ϭ 7.7, 1.6 Hz, 1 H), 7.55 (dd, J ϭ 8.0,
1.0 Hz, 1 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ
13.6 (CH3), 19.2 (CH2), 22.0 (CH2), 30.6 (CH2), 79.3 (C), 95.6 (C),
125.4 (C), 126.1 (C), 126.8 (CH), 128.6 (CH), 132.2 (CH), 133.3
(CH) ppm. IR: ν˜ ϭ 3061, 2957, 2931, 2871, 2234, 1588, 1558, 1468,
1433, 1026, 749 cmϪ1. MS (25 °C): m/z (%) ϭ 238 (74) [Mϩ(81Br)],
236, (77) [Mϩ(79Br)], 223 (36), 221 (39), 195 (50), 193 (51), 182
(26), 180 (23), 142 (100), 128 (71), 115 (65), 91 (24). HRMS: calcd.
(C12H13Br) 236.0201; found 236.0195.
Alkyne 11: General Procedure A was used to synthesize alkyne 11
from 1-chloro-2-iodo-4-trifluoromethylbenzene (3) and cyclopro-
pylacetylene (c ϭ 70% in toluene). After purification by flash chro-
matography (PE), compound 11 (2.37 g, 9.69 mmol, 97%) was iso-
lated as a colorless oil. 1H NMR (400 MHz, CDCl3): δ ϭ
0.86Ϫ0.97 (m, 4 H), 1.48Ϫ1.55 (m, 1 H), 7.40 (dd, J ϭ 8.4, 1.8 Hz,
1 H), 7.47 (d, J ϭ 8.4 Hz, 1 H), 7.66 (d, J ϭ 2.0 Hz, 1 H) ppm.
13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 0.3 (CH), 9.0 (CH2),
71.6 (C), 101.3 (C), 123.4 (CF3, q, J ϭ 272 Hz), 124.7 (C), 124.8
(CH, q, J ϭ 3 Hz), 129.1 (C, q, J ϭ 33 Hz), 129.6 (CH), 130.1
(CH, q, J ϭ 4 Hz), 139.4 (C, q, J ϭ 1 Hz) ppm. IR: ν˜ ϭ 3098,
3016, 2235, 1607, 1327, 1126, 1078, 825 cmϪ1. MS (25 °C): m/z
(%) ϭ 244 (100) [Mϩ], 209 (93) [Mϩ Ϫ Cl], 175 (57) [Mϩ Ϫ CF3],
139 (50), 99 (13), 87 (12), 74 (11). HRMS: calcd. (C12H8ClF3)
244.0267; found 244.0268.
Alkyne 7: General Procedure A was used to synthesize alkyne 7
from 1-chloro-2-iodobenzene (2) and 1-pentyne. After purification
by flash chromatography (PE), compound 7 (1.76 g, 9.85 mmol,
1
99%) was isolated as a colorless oil. H NMR (400 MHz, CDCl3):
δ ϭ 1.08 (t, J ϭ 7.3 Hz, 3 H), 1.66 (sept, J ϭ 7.2 Hz, 2 H), 2.45
(t, J ϭ 7.0 Hz, 2 H), 7.14Ϫ7.20 (m, 2 H), 7.34Ϫ7.38 (m, 1 H),
7.40Ϫ7.45 (m, 1 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3):
δ ϭ 13.5 (CH3), 21.8 (CH2), 22.1 (CH2), 77.7 (C), 96.0 (C), 126.3
(CH), 128.4 (CH), 129.1 (CH), 133.3 (CH), 135.7 (C), 140.2 (C)
Alkyne 12: General Procedure A was used to synthesize alkyne 12
from 1-chloro-2-iodo-4-methoxybenzene (4) and 1-hexyne. After
purification by flash chromatography (PE/EtOAc, 20:1), compound
12 (2.11 g, 9.47 mmol, 95%) was isolated as a colorless oil. 1H
NMR (400 MHz, CDCl3): δ ϭ 0.95 (t, J ϭ 7.3 Hz, 3 H), 1.46Ϫ1.56
(m, 2 H), 1.58Ϫ1.65 (m, 2 H), 2.46 (t, J ϭ 6.9 Hz, 2 H), 3.76 (s, 3
H), 6.75 (dd, J ϭ 8.9, 3.1 Hz, 1 H), 6.95 (d, J ϭ 3.0 Hz, 1 H), 7.24
(d, J ϭ 8.8 Hz, 1 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3):
δ ϭ 13.6 (CH3), 19.2 (CH2), 21.9 (CH2), 30.6 (CH2), 55.5 (CH3),
77.6 (C), 95.9 (C), 115.3 (CH), 117.6 (CH), 124.3 (C), 127.3 (C),
129.7 (CH), 157.7 (C) ppm. IR: ν˜ ϭ 2957, 2933, 2872, 2232, 1593,
1567, 1468, 1398, 1290, 1209, 1172, 1028, 804 cmϪ1. MS (60 °C):
m/z (%) ϭ 223 (100), 207 (47), 194 (18), 187 (42), 179 (99), 172
(92), 166 (20), 158 (50), 145 (29), 128 (25), 115 (41), 101 (19).
HRMS: calcd. (C13H15ClO) 222.0811; found 222.0811. C13H15ClO
(222.7): calcd. C 70.11, H 6.79; found C 70.17, H 6.62.
ppm. IR: ν˜ ϭ 3069, 2963, 2933, 2233, 1473, 1065, 1033, 749 cmϪ1
.
MS (25 °C): m/z (%) ϭ 180 (77) [Mϩ(37Cl)], 178 (97) [Mϩ(35Cl)],
163 (52), 149 (100) [Mϩ Ϫ C2H5], 143 (79) [Mϩ Ϫ Cl], 136 (60),
128 (80), 115 (57), 111 (23), 101 (18), 87 (17), 75 (30). HRMS:
calcd. (C11H11Cl) 178.0549; found 178.0555.
Alkyne 8: General Procedure A was used to synthesize alkyne 8
from 1-chloro-2-iodobenzene (2) and 1-hexyne. After purification
by flash chromatography (PE), compound 8 (1.89 g, 9.82 mmol,
1
98%) was isolated as a colorless oil. H NMR (400 MHz, CDCl3):
δ ϭ 0.95 (t, J ϭ 7.3 Hz, 3 H), 1.47Ϫ1.66 (m, 4 H), 2.47 (t, J ϭ
7.0 Hz, 2 H), 7.15Ϫ7.20 (m, 2 H), 7.35Ϫ7.37 (m, 1 H), 7.43Ϫ7.44
(m, 1 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 13.6
(CH3), 19.3 (CH2), 21.9 (CH2), 30.7 (CH2), 77.5 (C), 96.1 (C), 123.9
(C), 126.3 (CH), 128.4 (CH), 129.1 (CH), 133.3 (CH), 135.7 (C)
ppm. IR: ν˜ ϭ 3068, 2958, 2931, 2872, 2234, 1591, 1562, 1473, 1428,
1065, 1033, 750 cmϪ1. MS (25 °C): m/z (%) ϭ 192 (58) [Mϩ], 177
(65), 163 (35), 149 (100), 142 (53), 129 (67), 115 (56), 91 (16), 77
(14). HRMS: calcd. (C12H13Cl) 192.0697; found 192.0706.
Alkyne 13: General Procedure A was used to synthesize alkyne 13
from 1-bromo-3-chloro-4-iodobenzene (5) and 1-hexyne. After
purification by flash chromatography (PE), compound 13 (2.55 g,
9.39 mmol, 94%) was isolated as a colorless oil. 1H NMR
(400 MHz, CDCl3): δ ϭ 0.95 (t, J ϭ 7.3 Hz, 3 H), 1.45Ϫ1.55 (m,
2 H), 1.58Ϫ1.65 (m, 2 H), 2.45 (t, J ϭ 7.0 Hz, 2 H), 7.27 (d, J ϭ
8.5 Hz, 1 H), 7.30 (dd, J ϭ 8.3, 1.8 Hz, 1 H), 7.54 (d, J ϭ 1.8 Hz,
1 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 13.6 (CH3),
19.3 (CH2), 21.9 (CH2), 30.5 (CH2), 76.7 (C), 97.4 (C), 121.3 (C),
123.0 (C), 129.6 (CH), 131.8 (CH), 134.0 (CH), 136.6 (C) ppm. IR:
ν˜ ϭ 2957, 2951, 2234, 1579, 1542, 1420, 1082, 1065, 816 cmϪ1. MS
(25 °C): m/z (%) ϭ 272 (100) [Mϩ(81Br)], 270 (99) [Mϩ(79Br)], 257
(99), 255 (83), 229 (99), 227 (93), 216 (63), 214 (43), 193 (20), 191
(19), 176 (99), 162 (88), 156 (92), 150 (60), 141 (58), 131 (68), 87
(21), 75 (23). HRMS: calcd. (C12H12BrCl) 269.9811; found
269.9812. C12H12BrCl (271.6): calcd. C 53.07, H 4.45; found C
52.70, H 4.45.
Alkyne 9: General Procedure A was used to synthesize alkyne 9
from 1-chloro-2-iodobenzene (2) and cyclopropylacetylene (c ϭ
70% in toluene). After purification by flash chromatography (PE),
compound 9 (1.75 g, 9.91 mmol, 99%) was isolated as a colorless
oil. 1H NMR (400 MHz, CDCl3): δ ϭ 0.83Ϫ0.93 (m, 4 H),
1.47Ϫ1.55 (m, 1 H), 7.12Ϫ7.19 (m, 2 H), 7.77Ϫ7.36 (m, 1 H),
7.38Ϫ7.41 (m, 1 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3):
δ ϭ 0.4 (CH), 8.9 (CH2), 72.6 (C), 99.2 (C), 123.7 (C), 126.2 (CH),
128.3 (CH), 129.0 (CH), 133.2 (CH), 135.7 (C) ppm. IR: ν˜ ϭ 3013,
2230, 1474, 1436, 1055, 749 cmϪ1. MS (25 °C): m/z (%) ϭ 176 (92)
[Mϩ], 141 (100) [Mϩ Ϫ Cl], 139 (67), 115 (67), 87 (22), 79 (19).
HRMS: calcd. (C11H9Cl) 176.0393; found 176.0383. C11H9Cl
(176.6): calcd. C 74.79, H 5.14; found C 74.50, H 5.09.
Alkyne 10: General Procedure A was used to synthesize alkyne 10
from 1-chloro-2-iodobenzene (2) and 5-hexynol. After purification
by flash chromatography (PE/EtOAc, 10:1), compound 10 (2.08 g,
Alkyne 14: General Procedure A was used to synthesize alkyne 14
from 1-bromo-3-chloro-4-iodobenzene (5) and cyclopropylacety-
9.97 mmol, 99%) was isolated as a colorless oil. 1H NMR lene (c ϭ 70% in toluene). After purification by flash chromatogra-
2894
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2888Ϫ2902

A Flexible Synthesis of Indoline, Indolizidine, and Pyrrolizidine Derivatives
phy (PE), compound 14 (2.48 g, 9.70 mmol, 97%) was isolated as (CH2), 54.4 (CH), 55.8 (CH3), 114.5 (CH), 114.9 (CH), 124.9 (C),
FULL PAPER
1
a colorless oil. H NMR (400 MHz, CDCl3): δ ϭ 0.83Ϫ0.94 (m, 4
H), 1.45Ϫ1.52 (m, 1 H), 7.24 (d, J ϭ 8.4 Hz, 1 H), 7.29 (dd, J ϭ
127.2 (CH), 127.8 (CH), 131.5 (CH), 132.8 (CH), 138.9 (C), 142.0
(C), 151.8 (C) ppm. MS (70 °C): m/z (%) ϭ 363 (22) [Mϩ(81Br)],
8.3, 1.9 Hz, 1 H), 7.51 (d, J ϭ 1.9 Hz, 1 H) ppm. 13C NMR 361 (23) [Mϩ(79Br)], 306 (8), 304 (7), 272 (32), 192 (100), 175 (20),
(100.6 MHz, DEPT, CDCl3): δ ϭ 0.4 (CH), 8.9 (CH2), 71.8 (C), 171 (14), 169 (14), 149 (23), 136 (17), 134 (18), 85 (50). HRMS:
100.5 (C), 121.2 (C), 122.8 (C), 129.6 (CH), 131.8 (CH), 134.0 calcd. (C19H24BrNO) 361.1041; found 361.1042.
(CH), 136.6 (C) ppm. IR: ν˜ ϭ 3091, 3011, 2236, 1578, 1540, 1471,
Amine 17: General Procedure B was used to synthesize amine 17
1082, 1054, 1028, 814 cmϪ1. MS (25 °C): m/z (%) ϭ 256 (100)
from 4-methylaniline and alkyne 7. After purification by flash chro-
[Mϩ(81Br)], 254 (93) [Mϩ(79Br)], 221 (69), 219 (72), 175 (79), 139
matography (PE/EtOAc, 10:1), compound 17 (955 mg, 3.32 mmol,
(86), 118 (76). HRMS: calcd. (C11H8BrCl) 253.9498; found
253.9499. C11H8BrCl (255.5): calcd. C 51.70, H 3.16; found C
83%) was isolated as a bright yellow oil. 1H NMR (400 MHz,
CDCl3): δ ϭ 0.88 (t, J ϭ 6.9 Hz, 3 H), 1.33Ϫ1.57 (m, 4 H), 2.21
(s, 3 H), 2.86 (dd, J ϭ 13.7, 6.6 Hz, 1 H), 3.00 (dd, J ϭ 13.7, 6.7 Hz,
51.57, H 3.18.
Alkyne 15: Sodium hydride (288 mg, c ϭ 60% in oil, 7.8 mmol) and
THF (5.0 mL) were placed in a round-bottomed flask containing
a magnetic stirring bar. After addition of a solution of alkyne 10
1 H), 3.38 (br. s, 1 H), 3.70 (m, 1 H), 6.51 (d, J ϭ 8.0 Hz, 2 H),
6.94 (d, J ϭ 8.0 Hz, 2 H), 7.09Ϫ7.16 (m, 2 H), 7.19Ϫ7.23 (m, 1
H), 7.32Ϫ7.34 (m, 1 H) ppm. 13C NMR (100.6 MHz, DEPT,
(1.25 g, 6.0 mmol) in THF (5.0 mL), the mixture was stirred at 25 CDCl3): δ ϭ 14.1 (CH3), 19.2 (CH2), 20.3 (CH3), 37.0 (CH2), 38.9
°C for 30 min, and benzyl bromide (927 µL, 7.2 mmol) and a cata-
lytic amount of potassium iodide were then added. After this had
been stirred at 25 °C for 12 h, water was added. The mixture was
extracted with tert-butyl methyl ether (3 ϫ). The combined organic
layers were dried with MgSO4 and concentrated under vacuum.
After purification by flash chromatography (PE/EtOAc, 20:1) on
(CH2), 53.3 (CH), 113.1 (CH), 126.0 (C), 126.6 (CH), 127.5 (CH),
129.5 (CH), 129.7 (CH), 131.5 (CH), 134.3 (C), 137.1 (C), 145.4
(C) ppm. IR: ν˜ ϭ 3407, 3016, 2956, 2929, 2869, 1617, 1517, 1474,
1442, 1036, 805, 748 cmϪ1. MS (70 °C): m/z (%) ϭ 287 (30) [Mϩ],
244 (30) [Mϩ Ϫ C3H7], 209 (19), 162 (100), 132 (19), 125 (19), 120
(24), 106 (13), 91 (24). HRMS: calcd. (C18H22ClN) 287.1441; found
287.1441. C18H22ClN (287.8): calcd. C 75.11, H 7.70, N 4.87; found
SiO2, compound 15 (1.60 g, 5.35 mmol, 89%) was isolated as a col-
1
orless oil. H NMR (400 MHz, CDCl3): δ ϭ 1.70Ϫ1.87 (m, 4 H), C 75.00, H 7.71, N 5.02.
2.49 (t, J ϭ 6.8 Hz, 2 H), 3.53 (t, J ϭ 6.2 Hz, 2 H), 4.51 (s, 2 H),
Amine 18: General Procedure B was used to synthesize amine 18
7.12Ϫ7.19 (m, 2 H), 7.23Ϫ7.36 (m, 6 H), 7.40Ϫ7.42 (m, 1 H) ppm.
13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 19.4 (CH2), 25.3
(CH2), 28.8 (CH2), 69.8 (CH2), 72.8 (CH2), 77.8 (C), 95.7 (C), 123.8
(C), 126.3 (CH), 127.5 (CH), 127.6 (CH), 128.3 (CH), 128.5 (CH),
129.1 (CH), 133.2 (CH), 135.7 (C), 138.6 (C) ppm. IR: ν˜ ϭ 3063,
3030, 2936, 2859, 2234, 1495, 1473, 1453, 1429, 1104, 1065, 751,
734, 696 cmϪ1. MS (70 °C): m/z (%) ϭ 298 (11) [Mϩ], 207 (21),
191 (11), 163 (4), 149 (27), 139 (17), 125 (60), 115 (18), 105 (19),
91 (100), 77 (8). HRMS: calcd. (C19H19ClO) 298.1124; found
298.1126.
from 4-methoxybenzylamine and alkyne 8. [Cp*2TiMe2] (c ϭ 0.50
mol/L in toluene, 0.4 mmol, 10.0 mol %) was used as catalyst for
the hydroamination step. After purification by flash chromatogra-
phy (PE/EtOAc, 3:1), compound 18 (770 mg, 2.32 mmol, 58%) and
its Markovnikov regioisomer (396 mg, 1.19 mmol, 30%) were iso-
lated as colorless oils. 1H NMR (400 MHz, CDCl3): δ ϭ 0.88 (t,
J ϭ 6.9 Hz, 3 H), 1.23Ϫ1.47 (m, 6 H), 2.78Ϫ2.91 (m, 3 H), 3.66
(d, J ϭ 12.8 Hz, 1 H), 3.72 (d, J ϭ 12.9 Hz, 1 H), 3.77 (s, 3 H),
6.80 (d, J ϭ 8.5 Hz, 2 H), 7.12 (d, J ϭ 8.7 Hz, 2 H), 7.12Ϫ7.21 (m,
3 H), 7.33 (dd, J ϭ 7.0, 2.1 Hz, 1 H) ppm. 13C NMR (100.6 MHz,
DEPT, CDCl3): δ ϭ 14.0 (CH3), 22.9 (CH2), 27.9 (CH2), 33.9
(CH2), 39.0 (CH2), 50.7 (CH2), 55.2 (CH3), 56.7 (CH), 113.7 (CH),
126.5 (CH), 127.5 (CH), 129.1 (CH), 129.5 (CH), 131.6 (CH), 133.0
(C), 134.3 (C), 137.7 (C), 158.4 (C) ppm. IR: ν˜ ϭ 3338, 2953, 2928,
2857, 2834, 1611, 1585, 1510, 1464, 1243, 1172, 1035, 822, 748
cmϪ1. HRMS (ESI, CH3CN): calcd. (C20H26ClNOϩH) 332.1781;
Hydroamination/Reduction. General Procedure B: A Schlenk tube
fitted with a Teflon stopcock and containing a magnetic stirring
bar was charged with amine (4.0 mmol), alkyne (4.0 mmol), and a
solution of [Cp2TiMe2] (0.41 mL, c ϭ 0.48 mol/L in toluene,
0.2 mmol, 5.0 mol %). The mixture was heated to 110 °C for 24 h
(TLC monitoring). Then, a mixture of NaBH3CN (503 mg,
8.0 mmol) and ZnCl2·Et2O (4.0 mL, c ϭ 1.0 mol/L in Et2O, found 332.1796. C20H26ClNO (331.9): calcd. C 72.38, H 7.90, N
4.0 mmol) in MeOH (10 mL) was added. After this had been stirred 4.22; found C 72.39, H 7.79, N 4.16. Characterization of the Mar-
at 25 °C for 12 h, HCl (2 ) and CH2Cl2 were added. The organic kovnikov regioisomer: 1H NMR (400 MHz, CDCl3): δ ϭ 0.84 (t,
layer was separated and the aqueous layer was extracted with
CH2Cl2 (2 ϫ). KOH (2 ) was added to the aqueous layer until
pH ϭ 12 was reached. The basic aqueous layer was extracted with
CH2Cl2 (2 ϫ). The combined organic layers were extracted with
KOH (2 ) and brine. After drying with Na2SO4 and concentration
under vacuum, the residue was purified by flash chromatography
(SiO2).
J ϭ 6.8 Hz, 3 H), 1.22Ϫ1.36 (m, 6 H), 1.65 (q, J ϭ 7.5 Hz, 2 H),
3.47 (d, J ϭ 12.7 Hz, 1 H), 3.54 (d, J ϭ 12.8 Hz, 1 H), 3.79 (s, 3
H), 4.20 (t, J ϭ 6.6 Hz, 1 H), 6.84 (d, J ϭ 8.7 Hz, 2 H), 7.17 (td,
J ϭ 7.6, 1.5 Hz, 1 H), 7.19 (d, J ϭ 8.5 Hz, 2 H), 7.28 (td, J ϭ 7.5,
1.2 Hz, 1 H) 7.34 (dd, J ϭ 8.0, 1.2 Hz, 1 H), 7.54 (dd, J ϭ 7.8,
1.5 Hz, 1 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ
14.0 (CH3), 22.5 (CH2), 25.7 (CH2), 31.8 (CH2), 37.1 (CH2), 51.0
(CH2), 55.2 (CH3), 58.3 (CH), 113.7 (CH), 127.0 (CH), 127.7 (CH),
128.1 (CH), 129.3 (CH), 129.5 (CH), 132.8 (C), 133.9 (C), 141.8
(C), 158.6 (C) ppm. IR: ν˜ ϭ 3338, 2953, 2929, 2856, 1611, 1585,
1510, 1463, 1440, 1244, 1173, 1034, 821, 752 cmϪ1. HRMS (ESI,
CH3CN): calcd. (C20H26ClNOϩH) 332.1781; found 332.1780.
C20H26ClNO (331.9): calcd. C 72.38, H 7.90, N 4.22; found C
72.71, H 7.58, N 4.89.
Amine 16: General Procedure B was used to synthesize amine 16
from 4-methoxyaniline and alkyne 6. [Cp2TiMe2] (10.0 mol %) was
used for the hydroamination step. After purification by flash chro-
matography (PE/EtOAc, 10:1), compound 16 (1.07 g, 2.95 mmol,
1
74%) was isolated as a colorless oil. H NMR (400 MHz, CDCl3):
δ ϭ 0.86 (t, J ϭ 7.2 Hz, 3 H), 1.24Ϫ1.57 (m, 6 H), 2.88 (dd, J ϭ
13.8, 6.4 Hz, 1 H), 2.97 (dd, J ϭ 13.7, 7.1 Hz, 1 H), 3.25 (br. s, 1
H), 3.63Ϫ3.67 (m, 1 H), 3.72 (s, 3 H), 6.53 (d, J ϭ 9.0 Hz, 2 H),
Amine 19: General Procedure B was used to synthesize amine 19
6.73 (d, J ϭ 8.9 Hz, 2 H), 7.01Ϫ7.05 (m, 1 H), 7.16Ϫ7.21 (m, 2 from tert-butylamine and alkyne 9. After purification by flash chro-
H), 7.51 (d, J ϭ 7.8 Hz, 1 H) ppm. 13C NMR (100.6 MHz, DEPT, matography (PE/EtOAc, 1:1), compound 19 (635 mg, 2.52 mmol,
1
CDCl3): δ ϭ 14.1 (CH3), 22.8 (CH2), 28.2 (CH2), 34.6 (CH2), 41.6 63%) was isolated as a colorless oil. H NMR (400 MHz, CDCl3):
Eur. J. Org. Chem. 2003, 2888Ϫ2902
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2895

I. Bytschkov, H. Siebeneicher, S. Doye
FULL PAPER
δ ϭ Ϫ0.15 to Ϫ0.09 (m, 1 H), 0.06Ϫ0.12 (m, 1 H), 0.25Ϫ0.31 (m,
(d, J ϭ 3.0 Hz, 1 H), 6.94 (d, J ϭ 8.2 Hz, 2 H), 7.22 (d, J ϭ 8.8 Hz,
1 H), 0.34Ϫ0.41 (m, 1 H), 0.71Ϫ0.81 (m, 1 H), 1.05 (s, 9 H), 2.35 1 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 14.0 (CH3),
(q, J ϭ 8.2 Hz, 1 H), 2.89 (dd, J ϭ 13.0, 7.8 Hz, 1 H), 3.04 (dd, 20.3 (CH3), 22.7 (CH2), 28.2 (CH2), 34.5 (CH2), 39.0 (CH2), 53.5
J ϭ 13.2, 6.2 Hz, 1 H), 7.10Ϫ7.17 (m, 2 H), 7.24Ϫ7.27 (m, 1 H),
(CH), 55.4 (CH3), 113.0 (CH), 113.2 (CH), 117.1 (CH), 125.8 (C),
7.30Ϫ7.32 (m, 1 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): 126.0 (C), 129.7 (CH), 130.0 (CH), 138.0 (C), 145.4 (C), 158.1 (C)
δ ϭ 3.6 (CH2), 4.8 (CH2), 18.4 (CH), 30.2 (CH3), 43.0 (CH2), 50.3 ppm. IR: ν˜ ϭ 3401, 2954, 2930, 2858, 1617, 1518, 1476, 1298, 1240,
(C), 56.2 (CH), 126.2 (CH), 127.3 (CH), 129.2 (CH), 132.3 (CH), 1063, 1026, 803 cmϪ1. MS (70 °C): m/z (%) ϭ 333 (7) [Mϩ(37Cl)],
134.2 (C), 137.9 (C) ppm. IR: ν˜ ϭ 3074, 2963, 1474, 1441, 1388,
1361, 1051, 747 cmϪ1. MS (25 °C): m/z (%) ϭ 237 (14) [Mϩ ϩ H 155 (10), 134 (27), 120 (32), 86 (10). HRMS (ESI, CH3CN): calcd.
Ϫ CH3], 154 (15), 126 (84), 91 (11), 77 (4), 70 (100). HRMS: calcd. (C20H26ClNOϩH) 332.1781; found 332.1765. C20H26ClNO (331.9):
331 (6) [Mϩ(35Cl)], 274 (5), 223 (47), 207 (14), 176 (100), 172 (17),
(C14H20ClN) 237.1284; found 237.1236. C15H22ClN (251.8): calcd. calcd. C 72.38, H 7.90, N 4.22; found C 72.49, H 7.74, N 4.14.
C 71.55, H 8.81, N 5.56; found C 71.10, H 8.79, N 5.35.
Amine 23: General Procedure B was used to synthesize amine 23
Amine 20: General Procedure B was used to synthesize amine 20
from 1-hexylamine and alkyne 9. [Cp*2TiMe2] (c ϭ 0.50 mol/L in
from tert-butylamine and alkyne 12. After purification by flash
chromatography (PE/EtOAc, 1:1), compound 23 (843 mg,
toluene, 0.4 mmol, 10.0 mol %) was used as catalyst for the hydroa- 2.83 mmol, 71%) was isolated as a colorless oil. 1H NMR
mination step. After purification by flash chromatography (PE/
EtOAc, 7:1 Ǟ 1:1), compound 20 (738 mg, 2.64 mmol, 66%) and 1.29Ϫ1.39 (m, 6 H), 2.60 (dd, J ϭ 13.2, 7.7 Hz, 1 H), 2.85 (dd, J ϭ
its Markovnikov regioisomer (323 mg, 1.15 mmol, 29%) were iso- 13.2, 6.0 Hz, 1 H), 2.89Ϫ2.94 (m, 1 H), 3.78 (s, 3 H), 6.69 (dd, J ϭ
lated as bright yellow oils. 1H NMR (400 MHz, CDCl3): δ ϭ Ϫ0.15 8.7, 3.1 Hz, 1 H), 6.76 (d, J ϭ 3.0 Hz, 1 H), 7.23 (d, J ϭ 8.8 Hz, 1
to Ϫ0.10 (m, 1 H), 0.13Ϫ0.19 (m, 1 H), 0.30Ϫ0.36 (m, 1 H),
H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 14.1 (CH3),
(400 MHz, CDCl3): δ ϭ 0.88 (t, J ϭ 7.0 Hz, 3 H), 0.95 (s, 9 H),
0.46Ϫ0.53 (m, 1 H), 0.73Ϫ0.81 (m, 1 H), 0.87 (t, J ϭ 6.7 Hz, 3 H), 22.9 (CH2), 28.4 (CH2), 29.9 (CH3), 37.6 (CH2), 41.6 (CH2), 50.7
1.24Ϫ1.45 (m, 8 H), 2.05 (td, J ϭ 9.1, 6.7 Hz, 1 H), 2.53Ϫ2.60 (m, (C), 51.8 (CH), 55.4 (CH3), 112.8 (CH), 117.5 (CH), 125.7 (C),
1 H), 2.73Ϫ2.80 (m, 1 H), 2.98 (d, J ϭ 6.8 Hz, 2 H), 7.12Ϫ7.19
(m, 2 H), 7.25Ϫ7.27 (m, 1 H), 7.33Ϫ7.34 (m, 1 H) ppm. 13C NMR 1597, 1574, 1476, 1465, 1387, 1361, 1240, 1161, 1027, 800 cmϪ1
(100.6 MHz, DEPT, CDCl3): δ ϭ 2.4 (CH2), 4.0 (CH2), 14.0 (CH3),
MS (60 °C): m/z (%) ϭ 297 (1) [Mϩ], 282 (16), 241 (21), 184 (32),
130.0 (CH), 139.1 (C), 157.9 (C) ppm. IR: ν˜ ϭ 2955, 2932, 2859,
.
16.3 (CH), 22.6 (CH2), 26.9 (CH2), 30.2 (CH2), 31.7 (CH2), 40.0 155 (22), 142 (61), 86 (100). HRMS (ESI, CH3CN): calcd.
(CH2), 47.8 (CH2), 63.1 (CH), 126.4 (CH), 127.5 (CH), 129.4 (CH), (C17H28ClNOϩH) 298.1938; found 298.1936. C17H28ClNO (297.9):
131.9 (CH), 134.2 (C), 137.5 (C) ppm. IR: ν˜ ϭ 3668, 3074, 3000, calcd. C 68.55, H 9.47, N 4.70; found C 68.58, H 9.34, N 4.50.
2924, 2854, 1571, 1473, 1442, 1121, 1051, 1019, 747, 681 cmϪ1. MS
Amine 24: General Procedure B was used to synthesize amine 24
(25 °C): m/z (%) ϭ 279 (3) [Mϩ], 238 (7), 208 (6), 154 (100), 125
from 4-methylaniline and alkyne 13. After purification by flash
(32), 91 (16), 70 (32). HRMS (ESI, CH3CN): calcd.
(C17H26ClNϩH) 280.1832; found 280.1824. C17H26ClN (279.9):
calcd. C 72.96, H 9.36, N 5.01; found C 72.60, H 9.00, N 4.69.
Because of the presence of impurities in the obtained Markovnikov
chromatography (PE/EtOAc, 20:1), compound 24 (1.11 g,
2.92 mmol, 73%) was isolated as a bright yellow oil. 1H NMR
(400 MHz, CDCl3): δ ϭ 0.85 (t, J ϭ 7.2 Hz, 3 H), 1.25Ϫ1.58 (m,
6 H), 2.21 (s, 3 H), 2.82 (dd, J ϭ 13.7, 6.2 Hz, 1 H), 2.92 (dd, J ϭ
13.8, 6.8 Hz, 1 H), 3.32 (br. s, 1 H), 3.64 (m, 1 H), 6.48 (d, J ϭ
regioisomer, this product was not fully characterized.
Amine 21: General Procedure B was used to synthesize amine 21
from 4-methoxyaniline and alkyne 11. After purification by flash
chromatography (PE/EtOAc, 10:1), compound 21 (1.08 g,
8.5 Hz, 2 H), 6.94 (d, J ϭ 8.2 Hz, 2 H), 7.06 (d, J ϭ 8.3 Hz, 1 H),
7.26 (dd, J ϭ 8.2, 2.0 Hz, 1 H), 7.49 (d, J ϭ 2.0 Hz, 1 H) ppm. 13
NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 14.0 (CH3), 20.3 (CH3),
C
2.92 mmol, 73%) was isolated as a colorless oil. 1H NMR 22.7 (CH2), 28.2 (CH2), 34.5 (CH2), 38.4 (CH2), 53.4 (CH), 113.2
(400 MHz, CDCl3): δ ϭ 0.78Ϫ0.87 (m, 1 H), 2.97 (dd, J ϭ 12.9,
7.0 Hz, 1 H), 3.01Ϫ3.07 (m, 1 H), 3.25 (dd, J ϭ 12.7, 5.6 Hz, 1 H), 135.2 (C), 136.2 (C), 145.2 (C) ppm. MS (60 °C): m/z (%) ϭ 381
3.42 (br. s, 1 H), 3.72 (s, 3 H), 6.56 (d, J ϭ 8.9 Hz, 2 H), 6.74 (d,
(24) [Mϩ(81Br)], 379 (19) [Mϩ(79Br)], 324 (10), 322 (8), 269 (29),
J ϭ 8.9 Hz, 2 H), 7.37 (dd, J ϭ 8.4, 1.9 Hz, 1 H), 7.43 (d, J ϭ 226 (40), 205 (13), 203 (10), 176 (100), 120 (32), 91 (28), 77 (9).
8.4 Hz, 1 H), 7.50 (d, J ϭ 1.6 Hz, 1 H) ppm. 13C NMR
HRMS: calcd. (C19H23BrClN) 379.0702; found 379.0703.
(CH), 120.1 (C), 126.2 (C), 129.8 (CH), 131.9 (CH), 132.6 (CH),
(100.6 MHz, DEPT, CDCl3): δ ϭ 2.7 (CH2), 4.0 (CH2), 16.4 (CH), C19H23BrClN (380.8): calcd. C 59.94, H 6.09, N 3.68; found C
36.6 (CH2), 55.7 (CH3), 58.5 (CH), 114.9 (CH), 115.0 (CH), 123.8 59.97, H 5.72, N 3.66.
(CF3, q, J ϭ 272 Hz), 124.3 (CH, q, J ϭ 4 Hz), 128.9 (CH, q, J ϭ
Amine 25: General Procedure B was used to synthesize amine 25
4 Hz), 128.9 (C, q, J ϭ 33 Hz), 129.8 (CH), 138.0 (C), 138.0 (C),
from 4-methoxyaniline and alkyne 14. After purification by flash
141.6 (C), 152.2 (C) ppm. IR: ν˜ ϭ 3401, 3081, 3000, 2932, 2832,
chromatography (PE/EtOAc, 10:1), compound 25 (1.20 g,
1611, 1582, 1509, 1328, 1275, 1232, 1167, 1122, 818 cmϪ1. MS (70
3.15 mmol, 79%) was isolated as a bright yellow oil. 1H NMR
°C): m/z (%) ϭ 369 (59) [Mϩ], 328 (4), 193 (13), 176 (100), 158 (60),
(400 MHz, CDCl3): δ ϭ 0.02Ϫ0.06 (m, 1 H), 0.20Ϫ0.26 (m, 1 H),
0.36Ϫ0.46 (m, 2 H), 2.90 (dd, J ϭ 13.1, 6.6 Hz, 1 H), 3.01 (dd, J ϭ
13.7, 6.7 Hz, 1 H), 3.12 (dd, J ϭ 13.1, 5.9 Hz, 1 H), 3.73 (s, 3 H),
6.55 (d, J ϭ 8.9 Hz, 2 H), 6.74 (d, J ϭ 8.9 Hz, 2 H), 7.11 (d, J ϭ
143 (82), 115 (12), 81 (15), 77 (9). HRMS: calcd. (C19H19ClF3NO)
369.1107; found 369.1107. C19H19ClF3NO (369.8): calcd. C 61.71,
H 5.18, N 3.79; found C 61.66, H 5.29, N 4.09.
Amine 22: General Procedure B was used to synthesize amine 22
from 4-methylaniline and alkyne 12. After purification by flash
chromatography (PE/EtOAc, 10:1), compound 22 (1.25 g,
3.77 mmol, 94%) was isolated as a bright yellow oil. 1H NMR
8.2 Hz, 1 H), 7.26 (dd, J ϭ 8.2, 2.0 Hz, 1 H), 7.50 (d, J ϭ 2.0 Hz,
1 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 2.6 (CH2),
4.0 (CH2), 16.3 (CH), 38.9 (CH2), 55.7 (CH3), 58.5 (CH), 114.8
(CH), 120.1 (C), 129.6 (CH), 131.8 (CH), 133.0 (CH), 135.2 (C),
(400 MHz, CDCl3): δ ϭ 0.86 (t, J ϭ 7.1 Hz, 3 H), 1.26Ϫ1.60 (m, 136.0 (C), 141.7 (C), 152.0 (C) ppm. IR: ν˜ ϭ 3394, 2998, 2930,
6 H), 2.21 (s, 3 H), 2.82 (dd, J ϭ 13.7, 6.5 Hz, 1 H), 2.96 (dd, J ϭ
2830, 1583, 1508, 1469, 1231, 1036, 815 cmϪ1. MS (100 °C): m/z
13.7, 6.5 Hz, 1 H), 3.39 (br. s, 1 H), 3.66Ϫ3.69 (m, 1 H), 3.71 (s, 3 (%) ϭ 382 (11) [Mϩ(81Br)], 379 (17) [Mϩ(79Br)], 205 (10), 203 (12),
H), 6.51 (d, J ϭ 8.4 Hz, 2 H), 6.66 (dd, J ϭ 8.7, 3.0 Hz, 1 H), 6.73 176 (100), 160 (23), 146 (10), 144 (10), 134 (17), 130 (10), 86 (13).
2896
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2888Ϫ2902

A Flexible Synthesis of Indoline, Indolizidine, and Pyrrolizidine Derivatives
FULL PAPER
HRMS (ESI, CH3CN): calcd. (C18H19BrClNOϩH) 380.0417;
found 380.0431. C18H19BrClNO (380.7): calcd. C 56.79, H 5.03, N
3.68; found C 57.23, H 4.71, N 3.59.
Synthesis of Indolines. General Procedure C: A Schlenk tube fitted
with a Teflon stopcock and containing a magnetic stirring bar was
charged with amine (2.0 mmol), [Pd2(dba)3] (92 mg, 0.1 mmol, 5.0
mol %),
1,3-bis(2,4,6-trimethylphenyl)imidazolium
chloride
Amine 26: General Procedure B was used to synthesize amine 26
from 4-methoxybenzylamine and alkyne 15. [Cp*2TiMe2] (c ϭ 0.50
mol/L in toluene, 0.4 mmol, 10.0 mol %) was used as catalyst for
the hydroamination step. After purification by flash chromatogra-
phy (PE/EtOAc, 1:1), compound 26 (845 mg, 1.93 mmol, 48%) and
its Markovnikov regioisomer (682 mg, 1.56 mmol, 39%) were ob-
tained as colorless oils. 1H NMR (400 MHz, CDCl3): δ ϭ 1.31 (br.
s, 1 H), 1.38Ϫ1.60 (m, 6 H), 2.77Ϫ2.91 (m, 3 H), 3.44 (t, J ϭ
6.4 Hz, 2 H), 3.66 (d, J ϭ 12.9 Hz, 1 H), 3.71 (d, J ϭ 12.9 Hz, 1
H), 3.77 (s, 3 H), 4.48 (s, 2 H), 6.79 (d, J ϭ 8.7 Hz, 2 H), 7.11 (d,
J ϭ 8.7 Hz, 2 H), 7.13Ϫ7.20 (m, 3 H), 7.24Ϫ7.34 (m, 6 H) ppm.
13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 22.3 (CH2), 29.8
(CH2), 33.9 (CH2), 39.0 (CH2), 50.6 (CH2), 55.2 (CH3), 56.6 (CH),
70.2 (CH2), 72.8 (CH2), 113.7 (CH), 126.5 (CH), 127.4 (CH), 127.5
(CH), 127.6 (CH), 128.3 (CH), 129.1 (CH), 129.5 (CH), 131.6
(CH), 132.9 (C), 134.3 (C), 137.6 (C), 138.6 (C), 158.5 (C) ppm.
IR: ν˜ ϭ 3338, 3062, 3029, 2932, 2855, 1611, 1585, 1530, 1454, 1441,
1244, 1101, 1034, 802, 748, 734, 696 cmϪ1. HRMS (ESI, CH3CN):
calcd. (C27H32ClNO2ϩH) 438.2200; found 438.2205. C27H32ClNO2
(438.0): calcd. C 74.04, H 7.36, N 3.20; found C 74.12, H 7.37, N
(68 mg, 0.2 mmol, 10.0 mol %), KOtBu (337 mg, 3.0 mmol), and
1,4-dioxane (5.0 mL). The mixture was heated to 110 °C for 12 h
(TLC monitoring). The reaction mixture was filtered through SiO2.
After the SiO2 had been washed with CH2Cl2, the organic layer
was concentrated under vacuum. The residue was purified by flash
chromatography (SiO2).
Indoline 28: General Procedure C was used to synthesize indoline
28 from amine 17. After purification by flash chromatography (PE/
EtOAc, 20:1), compound 28 (501 mg, 1.99 mmol, 99%) was isolated
1
as a bright yellow oil. H NMR (400 MHz, CDCl3): δ ϭ 0.89 (t,
J ϭ 7.3 Hz, 3 H), 1.25Ϫ1.56 (m, 3 H), 1.71Ϫ1.78 (m, 1 H), 2.34
(s, 3 H), 2.81 (dd, J ϭ 15.4, 8.5 Hz, 1 H), 3.24 (dd, J ϭ 15.5, 9.0 Hz,
1 H), 4.19 (ddd, J ϭ 17.8, 8.9, 3.1 Hz, 1 H), 6.63Ϫ6.69 (m, 2 H),
6.97 (m, 1 H), 7.08Ϫ7.18 (m, 5 H) ppm. 13C NMR (100.6 MHz,
DEPT, CDCl3): δ ϭ 14.2 (CH3), 18.7 (CH2), 20.9 (CH3), 34.8
(CH2), 36.0 (CH2), 64.6 (CH), 107.7 (CH), 118.1 (CH), 123.0 (CH),
124.6 (CH), 127.1 (CH), 129.3 (C), 129.8 (CH), 133.0 (C), 141.2
(C), 150.7 (C) ppm. IR: ν˜ ϭ 3026, 2955, 2927, 2862, 1601, 1511,
1479, 1459, 1291, 812, 740 cmϪ1. MS (25 °C): m/z (%) ϭ 251 (60)
[Mϩ], 208 (100), 193 (26), 116 (11), 91 (33), 77 (5). HRMS: calcd.
(C18H21N) 251.1674; found 251.1673. C18H21N (251.4): calcd. C
86.01, H 8.42, N 5.57; found C 85.73, H 8.31, N 5.71.
1
3.59. Characterization of the Markovnikov regioisomer: H NMR
(400 MHz, CDCl3): δ ϭ 1.22Ϫ1.40 (m, 4 H), 1.53Ϫ1.69 (m, 4 H),
3.41 (t, J ϭ 6.6 Hz, 2 H), 3.46 (d, J ϭ 12.8 Hz, 1 H), 3.53 (d, J ϭ
12.8 Hz, 1 H), 3.78 (s, 3 H), 4.19 (t, J ϭ 6.7 Hz, 1 H), 4.46 (s, 2
H), 6.83 (d, J ϭ 8.7 Hz, 2 H), 7.18 (d, J ϭ 8.5 Hz, 2 H), 7.14Ϫ7.19
(m, 1 H), 7.24Ϫ7.35 (m, 7 H), 7.52 (dd, J ϭ 7.7, 1.4 Hz, 1 H)
ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 25.9 (CH2), 26.1
(CH2), 29.6 (CH2), 37.0 (CH2), 51.0 (CH2), 55.2 (CH3), 58.2 (CH),
70.3 (CH2), 72.8 (CH2), 113.7 (CH), 127.0 (CH), 127.4 (CH), 127.5
(CH), 127.7 (CH), 128.1 (CH), 128.3 (CH), 129.3 (CH), 129.5
(CH), 132.8 (C), 133.8 (C), 138.7 (C), 141.6 (C), 158.6 (C) ppm.
IR: ν˜ ϭ 3062, 3030, 2932, 2855, 1611, 1585, 1510, 1454, 1244, 1100,
1032, 821, 752, 734, 696 cmϪ1. HRMS (ESI, CH3CN): calcd.
(C27H32ClNO2ϩH) 438.2200; found 438.2216. C27H32ClNO2
(438.0): calcd. C 74.04, H 7.36, N 3.20; found C 74.06, H 7.31,
N 3.64.
Indoline 29: General Procedure C was used to synthesize indoline
29 from amine 18. After purification by flash chromatography (PE/
EtOAc, 20:1), compound 29 (580 mg, 1.96 mmol, 98%) was isolated
1
as a colorless oil. H NMR (400 MHz, CDCl3): δ ϭ 0.89 (t, J ϭ
7.0 Hz, 3 H), 1.20Ϫ1.37 (m, 4 H), 1.46Ϫ1.56 (m, 1 H), 1.77Ϫ1.83
(m, 1 H), 2.70 (dd, J ϭ 15.6, 9.9 Hz, 1 H), 3.12 (dd, J ϭ 15.5,
9.9 Hz, 1 H), 3.57 (qd, J ϭ 9.5, 3.1 Hz, 1 H), 3.78 (s, 3 H), 4.11
(d, J ϭ 15.9 Hz, 1 H), 4.32 (d, J ϭ 15.9 Hz, 1 H), 6.32 (d, J ϭ
7.8 Hz, 1 H), 6.61 (td, J ϭ 7.3, 0.6 Hz, 1 H), 6.84 (d, J ϭ 8.7 Hz,
2 H), 6.97 (t, J ϭ 7.7 Hz, 1 H), 7.03 (d, J ϭ 7.2 Hz, 1 H), 7.25 (d,
J ϭ 8.7 Hz, 2 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3):
δ ϭ 14.1 (CH3), 22.9 (CH2), 27.8 (CH2), 33.7 (CH2), 35.1 (CH2),
50.8 (CH2), 55.2 (CH3), 65.0 (CH), 106.8 (CH), 113.8 (CH), 117.2
(CH), 124.1 (CH), 127.3 (CH), 128.4 (CH), 128.8 (C), 131.2 (C),
152.9 (C), 158.5 (C) ppm. IR: ν˜ ϭ 3026, 2953, 2927, 2856, 1606,
1510, 1483, 1461, 1241, 1171, 1035, 820, 741 cmϪ1. HRMS (ESI,
CH3CN): calcd. (C20H25NOϩH) 296.2014; found 296.2010.
C20H25NO (295.4): calcd. C 81.31, H 8.53, N 4.74; found C 81.39,
H 8.50, N 5.31.
Indoline 27: A Schlenk tube fitted with a Teflon stopcock and con-
taining a magnetic stirring bar was charged with amine 16 (725 mg,
2.0 mmol), [Pd(PPh3)4] (116 mg, 0.1 mmol, 5.0 mol %), K2CO3
(553 mg, 4.0 mmol), NaOtBu (384 mg, 4.0 mmol), and toluene
(5.0 mL). The mixture was heated to 110 °C for 5 h (TLC monitor-
ing). The reaction mixture was filtered through SiO2. After the SiO2
had been washed with CH2Cl2, the organic layer was concentrated
under vacuum. Purification by flash chromatography on SiO2 (PE/
EtOAc, 5:1) gave compound 27 (546 mg, 1.94 mmol, 97%) as a col-
Indoline 30: General Procedure C was used to synthesize indoline
orless oil. 1H NMR (400 MHz, CDCl3): δ ϭ 0.86 (t, J ϭ 6.9 Hz, 3 30 from amine 19. After purification by flash chromatography (PE/
H), 1.20Ϫ1.38 (m, 4 H), 1.47Ϫ1.55 (m, 1 H), 1.69Ϫ1.76 (m, 1 H),
2.81 (dd, J ϭ 15.4, 9.4 Hz, 1 H), 3.22 (dd, J ϭ 15.4, 8.8 Hz, 1 H), as a bright yellow oil. 1H NMR (400 MHz, CDCl3): δ ϭ 0.13Ϫ0.19
3.81 (s, 3 H), 4.08 (qd, J ϭ 9.2, 3.2 Hz, 1 H), 6.46 (d, J ϭ 7.9 Hz, (m, 1 H), 0.31Ϫ0.42 (m, 2 H), 0.50Ϫ0.57 (m, 1 H), 0.91Ϫ0.99 (m,
1 H), 6.66 (td, J ϭ 7.3, 0.8 Hz, 1 H), 6.92 (d, J ϭ 8.9 Hz, 2 H), 1 H), 1.37 (s, 9 H), 2.65 (d, J ϭ 14.6 Hz, 1 H), 3.11Ϫ3.22 (m, 2
EtOAc, 10:1), compound 30 (425 mg, 1.97 mmol, 99%) was isolated
6.96 (t, J ϭ 7.7 Hz, 1 H), 7.09 (d, J ϭ 7.2 Hz, 1 H), 7.16 (d, J ϭ
H), 6.67 (td, J ϭ 7.3, 0.6 Hz, 1 H), 6.82 (d, J ϭ 7.8 Hz, 1 H), 7.00
8.9 Hz, 2 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ (t, J ϭ 7.7 Hz, 1 H), 7.07 (d, J ϭ 7.2 Hz, 1 H) ppm. 13C NMR
14.1 (CH3), 22.8 (CH2), 27.7 (CH2), 34.9 (CH2), 55.4 (CH2), 65.7 (100.6 MHz, DEPT, CDCl3): δ ϭ 2.4 (CH2), 6.1 (CH2), 17.3 (CH),
(CH), 107.3 (CH), 114.6 (CH), 117.9 (CH), 124.5 (CH), 125.9
(CH), 127.1 (CH), 129.0 (C), 137.0 (C), 151.3 (C), 156.5 (C) ppm. (CH), 124.3 (CH), 126.3 (CH), 132.5 (C), 149.2 (C) ppm. IR: ν˜ ϭ
IR: ν˜ ϭ 3098, 3046, 2929, 2857, 1602, 1507, 1480, 1458, 1439, 1241,
3072, 2972, 1606, 1475, 1392, 1362, 1019, 736 cmϪ1. MS (25 °C):
1036, 831, 742 cmϪ1. MS (25 °C): m/z (%) ϭ 281 (59) [Mϩ], 224 m/z (%) ϭ 215 (72) [Mϩ], 200 (79), 174 (19), 159 (66), 118 (100),
28.8 (CH3), 36.4 (CH2), 54.3 (C), 64.3 (CH), 113.7 (CH), 117.9
(100), 131 (10), 91 (8). HRMS: calcd. (C19H23NO) 281.1780; found
281.1779. C19H23NO (281.4): calcd. C 81.10, H 8.24, N 4.98; found
C 80.80, H 8.30, N 4.81.
77 (9), 91 (26). HRMS: calcd. (C15H21N) 215.1674; found 215.1663.
C15H21N (215.3): calcd. C 83.67, H 9.83, N 6.50; found C 83.32,
H 9.17, N 6.13.
Eur. J. Org. Chem. 2003, 2888Ϫ2902
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2897

I. Bytschkov, H. Siebeneicher, S. Doye
FULL PAPER
Indoline 31: General Procedure C was used to synthesize indoline (100.6 MHz, DEPT, CDCl3): δ ϭ 14.1 (CH3), 22.8 (CH2), 28.0
31 from amine 20. After purification by flash chromatography (CH3), 28.8 (CH3), 35.5 (CH2), 36.7 (CH2), 55.6 (CH3), 55.7 (C),
(PE), compound 31 (471 mg, 1.94 mmol, 97%) was isolated as a 60.3 (CH), 111.0 (CH), 111.1 (CH), 116.8 (CH), 135.4 (C), 143.4
colorless oil. 1H NMR (400 MHz, CDCl3): δ ϭ 0.08Ϫ0.14 (m, 1 (C), 153.8 (C) ppm. IR: ν˜ ϭ 2955, 2932, 2871, 1577, 1522, 1483,
H), 0.32Ϫ0.38 (m, 1 H), 0.45Ϫ0.52 (m, 1 H), 0.63Ϫ0.69 (m, 1 H), 1466, 1390, 1362, 1257, 1213, 1190, 1179, 1038, 802 cmϪ1. MS (25
0.89 (t, J ϭ 6.7 Hz, 1 H), 0.93Ϫ0.98 (m, 1 H), 1.26Ϫ1.38 (m, 6 H), °C): m/z (%) ϭ 261 (78) [Mϩ], 246 (76), 206 (85), 190 (13), 174
2.79Ϫ2.88 (m, 2 H), 3.03Ϫ3.30 (m, 3 H), 6.36 (d, J ϭ 7.8 Hz, 1 (13), 160 (32), 148 (100), 133 (47), 117 (26). HRMS (ESI, CH3CN):
H), 6.57 (td, J ϭ 7.3, 0.7 Hz, 1 H), 7.00 (d, J ϭ 7.3 Hz, 1 H), 7.03 calcd. (C17H27NOϩH) 262.2171; found 262.2182. C17H27NO
(t, J ϭ 7.7 Hz, 1 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): (261.4): calcd. C 78.11, H 10.41, N 5.36; found C 77.83, H 10.14,
δ ϭ 0.2 (CH2), 5.1 (CH2), 14.0 (CH3), 14.8 (CH), 22.7 (CH2), 26.5 N 4.97.
(CH2), 27.1 (CH2), 31.7 (CH2), 35.7 (CH2), 46.4 (CH2), 69.7 (CH),
105.6 (CH), 116.4 (CH), 124.0 (CH), 127.3 (CH), 128.5 (C), 152.4
Indoline 35: General Procedure C was used to synthesize indoline
35 from amine 26. After purification by flash chromatography (PE/
(C) ppm. IR: ν˜ ϭ 3076, 3001, 2926, 2854, 1606, 1483, 1461, 1260,
EtOAc, 10:1), compound 35 (742 mg, 1.84 mmol, 92%) was isolated
1020, 740, 714 cmϪ1. MS (25 °C): m/z (%) ϭ 243 (60) [Mϩ], 202
as a colorless oil. 1H NMR (400 MHz, CDCl3): δ ϭ 1.31Ϫ1.66 (m,
(46), 172 (71), 130 (50), 118 (40), 91 (28). HRMS (ESI, CH3CN):
5 H), 1.76Ϫ1.85 (m, 1 H), 2.70 (dd, J ϭ 15.6, 9.8 Hz, 1 H), 3.12
calcd. (C17H25NϩH) 244.2065; found 244.2061. C17H25N (243.4):
(dd, J ϭ 15.6, 8.7 Hz, 1 H), 3.44 (t, J ϭ 6.5 Hz, 2 H), 3.57 (qd,
calcd. C 83.39, H 10.35, N 5.75; found C 83.42, H 10.53, N 5.50.
J ϭ 9.2, 3.1 Hz, 1 H), 3.77 (s, 3 H), 4.10 (d, J ϭ 15.9 Hz, 1 H),
Indoline 32: General Procedure C was used to synthesize indoline 4.30 (d, J ϭ 15.9 Hz, 1 H), 4.48 (s, 2 H), 6.32 (d, J ϭ 7.8 Hz, 1 H),
32 from amine 21. After purification by flash chromatography 6.61 (td, J ϭ 7.4, 0.5 Hz, 1 H), 6.83 (d, J ϭ 8.7 Hz, 2 H), 6.97 (t,
(PE), compound 32 (634 mg, 1.90 mmol, 95%) was isolated as a J ϭ 8.7 Hz, 1 H), 7.03 (d, J ϭ 7.2 Hz, 1 H), 7.23 (d, J ϭ 8.7 Hz,
white solid. 1H NMR (400 MHz, CDCl3): δ ϭ Ϫ0.12 to Ϫ0.06 (m, 2 H), 7.24Ϫ7.35 (m, 5 H) ppm. 13C NMR (100.6 MHz, DEPT,
1 H), 0.07Ϫ0.13 (m, 1 H), 0.45Ϫ0.46 (m, 2 H), 0.98Ϫ1.07 (m, 1 CDCl3): δ ϭ 22.3 (CH2), 29.9 (CH2), 33.7 (CH2), 35.0 (CH2), 50.8
H), 2.98 (dd, J ϭ 15.9, 8.4 Hz, 1 H), 3.28 (dd, J ϭ 15.9, 9.1 Hz, 1 (CH2), 55.2 (CH3), 64.9 (CH), 70.2 (CH2), 72.9 (CH2), 106.8 (CH),
H), 3.43 (q, J ϭ 8.7 Hz, 1 H), 3.83 (s, 3 H), 6.32 (d, J ϭ 8.3 Hz, 1 113.8 (CH), 117.2 (CH), 124.1 (CH), 127.3 (CH), 127.5 (CH), 127.6
H), 6.93 (d, J ϭ 8.9 Hz, 2 H), 7.20 (d, J ϭ 8.9 Hz, 3 H), 7.28 (br. (CH), 128.3 (CH), 128.4 (CH), 128.7 (C), 131.1 (C), 138.6 (C),
s, 1 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 0.6 152.9 (C), 158.5 (C) ppm. IR: ν˜ ϭ 3029, 3002, 2923, 2839, 1608,
(CH2), 5.2 (CH2), 15.3 (CH), 34.9 (CH2), 55.4 (CH3), 72.1 (CH), 1512, 1488, 1453, 1350, 1247, 1107, 1035, 827, 811, 747, 736, 716,
106.2 (CH), 114.7 (CH), 119.2 (C, q, J ϭ 32 Hz), 121.4 (CH, q, 696 cmϪ1
. HRMS (ESI, CH3CN): calcd. (C27H31NO2ϩH)
J ϭ 4 Hz), 125.2 (CF3, q, J ϭ 270 Hz), 125.3 (CH, q, J ϭ 4 Hz), 402.2433; found 402.2424. C27H31NO2 (401.54): calcd. C 80.76, H
127.8 (CH), 129.0 (C), 136.0 (C), 154.2 (C), 157.7 (C) ppm. IR: 7.78, N 3.49; found C 80.41, H 7.47, N 3.35.
ν˜ ϭ 3079, 3013, 2960, 2902, 1621, 1513, 1456, 1328, 1276, 1247,
Synthesis of Benzophenone Imine Compounds. General Procedure D:
A Schlenk tube fitted with a Teflon stopcock and containing a
1217, 1091, 1028, 820, 816 cmϪ1. MS (80 °C): m/z (%) ϭ 333 (100)
[Mϩ], 318 (27), 314 (28), 305 (29), 292 (81), 278 (25), 261 (25), 248
magnetic stirring bar was charged with amine (2.5 mmol), benzo-
(28), 235 (20), 224 (21), 198 (28), 159 (25), 146 (18). HRMS: calcd.
phenone imine (544 mg, 3.0 mmol), [Pd2(dba)3] (27 mg, 0.03 mmol,
(C19H18F3NO) 333.1340; found 333.1341. C19H18F3NO (333.4):
calcd. C 68.46, H 5.44, N 4.20; found C 68.66, H 5.40, N 4.06.
1.0 mol %), 1,1Ј-bis(diphenylphosphanyl)ferrocene (DPPF, 44 mg,
0.08 mmol, 3.0 mol %), NaOtBu (336 mg, 3.5 mmol), and toluene
Indoline 33: General Procedure C was used to synthesize indoline (5.0 mL). The mixture was heated to 100 °C for 24 h (TLC moni-
33 from amine 22. After purification by flash chromatography toring). The reaction mixture was filtered through SiO2. After the
(PE), compound 33 (528 mg, 1.79 mmol, 89%) was isolated as a SiO2 had been washed with CH2Cl2, the organic layer was concen-
colorless oil. 1H NMR (400 MHz, CDCl3): δ ϭ 0.87 (t, J ϭ 6.8 Hz, trated under vacuum. The residue was purified by flash chromatog-
3 H), 1.26Ϫ1.31 (m, 4 H), 1.49Ϫ1.57 (m, 1 H), 1.74Ϫ1.80 (m, 1 raphy (SiO2).
H), 2.32 (s, 3 H), 2.76 (dd, J ϭ 15.6, 8.0 Hz, 1 H), 3.21 (dd, J ϭ
Amine 36: General Procedure D was used to synthesize amine 36
15.6, 8.7 Hz, 1 H), 3.74 (s, 3 H), 4.11 (qd, J ϭ 8.7, 3.1 Hz, 1 H),
from amine 24. After purification by flash chromatography (PE/
6.55 (dd, J ϭ 8.5, 2.5 Hz, 1 H), 6.62 (d, J ϭ 8.5 Hz, 1 H), 6.75 (d,
EtOAc, 20:1), compound 36 (1.18 g, 2.45 mmol, 98%) was isolated
J ϭ 2.5 Hz, 1 H), 7.10 (d, J ϭ 8.5 Hz, 2 H), 7.15 (d, J ϭ 8.4 Hz,
as a bright yellow oil, contaminated with benzophenone imine im-
purities. H NMR (400 MHz, CDCl3): δ ϭ 0.84 (t, J ϭ 6.9 Hz, 3
H), 1.25Ϫ1.48 (m, 6 H), 2.21 (s, 3 H), 2.69 (dd, J ϭ 13.7, 7.0 Hz,
1 H), 2.91 (dd, J ϭ 13.7, 6.3 Hz, 1 H), 3.32 (br. s, 1 H), 3.56Ϫ3.59
2 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 14.1 (CH3),
20.8 (CH3), 22.8 (CH2), 27.6 (CH2), 33.5 (CH2), 35.1 (CH2), 56.0
(CH3), 65.2 (CH), 108.5 (CH), 111.5 (CH), 112.0 (CH), 121.8 (CH),
129.8 (CH), 131.0 (C), 132.1 (C), 142.2 (C), 144.0 (C), 153.1 (C)
1
(m, 1 H), 6.47 (dd, J ϭ 8.1, 2.1 Hz, 1 H), 6.49 (d, J ϭ 8.4 Hz, 2
ppm. IR: ν˜ ϭ 2928, 2859, 1614, 1596, 1512, 1484, 1373, 1246, 1035,
H), 6.78 (d, J ϭ 2.1 Hz, 1 H), 6.93 (dd, J ϭ 8.2, 3.1 Hz, 3 H), 7.07
797 cmϪ1. MS (90 °C): m/z (%) ϭ 295 (77) [Mϩ], 238 (100), 207
(dd, J ϭ 8.0, 1.4 Hz, 2 H), 7.19Ϫ7.28 (m, 3 H), 7.37Ϫ7.40 (m,
(11). HRMS (ESI, CH3CN): calcd. (C20H25NOϩH) 296.2014;
2 H), 7.44Ϫ7.49 (m, 1 H), 7.71Ϫ7.73 (m, 2 H) ppm. 13C NMR
found 296.2003. C20H25NO (295.4): calcd. C 81.31, H 8.53, N 4.74;
found C 81.14, H 8.17, N 4.53.
(100.6 MHz, DEPT, CDCl3): δ ϭ 14.0 (CH3), 20.3 (CH3), 22.6
(CH2), 28.1 (CH2), 34.2 (CH2), 38.2 (CH2), 53.6 (CH), 113.1 (CH),
Indoline 34: General Procedure C was used to synthesize indoline 119.4 (CH), 122.0 (CH), 125.9 (C), 127.9 (CH), 128.2 (CH), 128.7
34 from amine 23. After purification by flash chromatography (PE/ (CH), 129.3 (CH), 129.7 (CH), 130.9 (CH), 131.2 (CH), 131.5 (C),
EtOAc, 20:1), compound 34 (451 mg, 1.72 mmol, 86%) was isolated 134.0 (C), 135.8 (C), 139.3 (C), 145.5 (C), 150.5 (C), 169.0 (C) ppm.
1
as a colorless oil. H NMR (400 MHz, CDCl3): δ ϭ 0.88 (t, J ϭ IR: ν˜ ϭ 3402, 3022, 2924, 2852, 1660, 1616, 1594, 1518, 1482, 1445,
6.9 Hz, 3 H), 1.26 (s, 9 H), 1.27Ϫ1.45 (m, 6 H), 2.43 (d, J ϭ 1317, 1291, 960, 805, 693 cmϪ1. MS (150 °C): m/z (%) ϭ 480 (7)
15.7 Hz, 1 H), 3.14 (dd, J ϭ 15.7, 8.7 Hz, 1 H), 3.62Ϫ3.67 (m, 1 [Mϩ], 444 (4), 305 (83), 182 (27), 176 (100), 120 (23), 105 (49),
H), 3.73 (s, 3 H), 6.56 (dd, J ϭ 8.6, 2.6 Hz, 1 H), 6.69 (d, J ϭ 84 (43), 77 (53). HRMS (ESI, CH3CN): calcd. (C32H33ClN2ϩH)
2.6 Hz, 1 H), 6.78 (d, J ϭ 8.5 Hz, 1 H) ppm. 13C NMR 481.2411; found 481.2402.
2898
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 2888Ϫ2902

A Flexible Synthesis of Indoline, Indolizidine, and Pyrrolizidine Derivatives
FULL PAPER
Amine 37: General Procedure D was used to synthesize amine 37
from amine 25. After purification by flash chromatography (PE/
Cleavage of the Benzophenone Imine. General Procedure E: A
round-bottomed flask containing a magnetic stirring bar was
EtOAc, 5:1), compound 37 (1.18 g, 2.45 mmol, 98%) was isolated charged with indoline (1.5 mmol), THF (5.0 mL), and HCl (2 ,
as a bright yellow oil, contaminated with benzophenone imine im-
purities. H NMR (400 MHz, CDCl3): δ ϭ Ϫ0.31 to Ϫ0.15 (m, 1
0.5 mL). After this had been stirred at 25 °C for 30 min (TLC
monitoring), KOH (2 ) and tert-butyl methyl ether were added.
1
H), 0.11Ϫ0.17 (m, 1 H), 0.20Ϫ0.26 (m, 1 H), 0.32Ϫ0.40 (m, 1 H), The organic layer was separated and the aqueous layer was ex-
0.73Ϫ0.81 (m, 1 H), 2.74 (dd, J ϭ 13.3, 7.8 Hz, 1 H), 2.85Ϫ2.91 tracted with CH2Cl2 (3 ϫ). The combined organic layers were dried
(m, 1 H), 3.13 (dd, J ϭ 13.3, 5.5 Hz, 1 H), 3.73 (s, 3 H), 6.49 (dd, with Na2SO4 and concentrated under vacuum. The residue was
J ϭ 8.0, 2.1 Hz, 1 H), 6.57 (d, J ϭ 8.9 Hz, 2 H), 6.74 (d, J ϭ purified by flash chromatography (SiO2).
9.0 Hz, 2 H), 6.78 (d, J ϭ 2.0 Hz, 1 H), 6.99 (d, J ϭ 8.2 Hz, 1
Indoline 40: General Procedure E was used to synthesize indoline
H), 7.08Ϫ7.11 (m, 2 H), 7.22Ϫ7.29 (m, 3 H), 7.38Ϫ7.41 (m, 2 H),
40 from indoline 38. After purification by flash chromatography
7.45Ϫ7.49 (m, 1 H), 7.72Ϫ7.74 (m, 2 H) ppm. 13C NMR
(PE/EtOAc, 10:1), compound 40 (388 mg, 1.38 mmol, 92%) was
(100.6 MHz, DEPT, CDCl3): δ ϭ 2.4 (CH2), 4.1 (CH2), 16.3 (CH),
1
isolated as a colorless oil. H NMR (400 MHz, CDCl3): δ ϭ 0.85
39.0 (CH2), 55.8 (CH3), 59.0 (CH), 114.8 (CH), 114.9 (CH), 119.2
(t, J ϭ 6.8 Hz, 3 H), 1.25Ϫ1.33 (m, 4 H), 1.45Ϫ1.51 (m, 1 H),
(CH), 121.8 (CH), 128.0 (CH), 128.2 (CH), 128.7 (CH), 129.3
1.70Ϫ1.76 (m, 1 H), 2.33 (s, 3 H), 2.70 (dd, J ϭ 14.9, 8.5 Hz, 1 H),
(CH), 129.3 (CH), 130.9 (CH), 131.4 (CH), 131.6 (CH), 133.9 (C),
3.12 (dd, J ϭ 15.0, 8.6 Hz, 1 H), 3.26 (br. s, 2 H), 4.15 (qd, J ϭ
135.8 (C), 139.2 (C), 142.0 (C), 150.6 (C), 152.0 (C), 169.1 (C) ppm.
8.9, 3.1 Hz, 1 H), 6.00Ϫ6.02 (m, 2 H), 6.86 (d, J ϭ 8.0 Hz, 1 H),
IR: ν˜ ϭ 3075, 3000, 2925, 2854, 1571, 1473, 1442, 1121, 1051, 1019,
7.11 (d, J ϭ 8.5 Hz, 2 H), 7.16 (d, J ϭ 8.3 Hz, 2 H) ppm. 13C
823, 747, 681 cmϪ1. MS (160 °C): m/z (%) ϭ 480 (4) [Mϩ], 307
NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 14.0 (CH3), 20.8 (CH3),
(41), 305 (100), 176 (74), 160 (11), 134 (6), 105 (7). HRMS (ESI,
22.7 (CH2), 27.6 (CH2), 33.4 (CH2), 34.1 (CH2), 65.2 (CH), 95.8
CH3CN): calcd. (C31H29ClN2OϩH) 481.2047; found 481.2037.
(CH), 104.8 (CH), 119.5 (C), 123.4 (CH), 124.9 (CH), 129.8 (CH),
133.0 (C), 141.1 (C), 146.0 (C), 151.2 (C) ppm. IR: ν˜ ϭ 3444, 3361,
Indoline 38: General Procedure C was used to synthesize indoline
3024, 2926, 2857, 1607, 1510, 1496, 1378, 1304, 1200, 813 cmϪ1
.
38 from amine 36. The mixture was heated to 100 °C for 16 h.
After purification by flash chromatography (PE/EtOAc, 50:1),
compound 38 (782 mg, 1.76 mmol, 88%) was isolated as a bright
HRMS (ESI, CH3CN): calcd. (C19H24N2ϩH) 281.2018; found
281.2020. C19H24N2 (280.4): calcd. C 81.33, H 8.63, N 9.99; found
C 80.87, H 8.26, N 9.54.
1
yellow oil. H NMR (400 MHz, CDCl3): δ ϭ 0.85 (t, J ϭ 6.7 Hz,
3 H), 1.24Ϫ1.26 (m, 4 H), 1.42Ϫ1.51 (m, 1 H), 1.68Ϫ1.72 (m, 1
Indoline 41: General Procedure E was used to synthesize indoline
H), 2.29 (s, 3 H), 2.68 (dd, J ϭ 15.4, 7.6 Hz, 1 H), 3.13 (dd, J ϭ 41 from indoline 39. After purification by flash chromatography
15.4, 8.9 Hz, 1 H), 4.08 (qd, J ϭ 8.9, 3.0 Hz, 1 H), 6.04 (d, J ϭ (PE/EtOAc, 10:1), compound 41 (381 mg, 1.36 mmol, 91%) was
1.6 Hz, 1 H), 6.18 (dd, J ϭ 7.7, 1.8 Hz, 1 H), 6.78 (d, J ϭ 8.3 Hz, isolated as a colorless oil. 1H NMR (400 MHz, CDCl3): δ ϭ Ϫ0.14
2 H), 6.89 (d, J ϭ 7.7 Hz, 1 H), 7.03 (d, J ϭ 8.2 Hz, 2 H),
7.13Ϫ7.15 (m, 2 H), 7.27Ϫ7.48 (m, 6 H), 7.79 (dd, J ϭ 7.0, 1.4 Hz, 0.97Ϫ1.06 (m, 1 H), 2.84 (dd, J ϭ 14.7, 8.4 Hz, 1 H), 3.13 (dd, J ϭ
2 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 14.1 (CH3),
15.1, 8.8 Hz, 1 H), 3.32 (q, J ϭ 8.7 Hz, 1 H), 3.82 (s, 3 H), 5.76 (d,
to Ϫ0.09 (m, 1 H), 0.05Ϫ0.11 (m, 1 H), 0.31Ϫ0.42 (m, 2 H),
20.8 (CH3), 22.7 (CH2), 27.4 (CH2), 33.4 (CH2), 34.3 (CH2), 65.0 J ϭ 2.0 Hz, 1 H), 6.01 (dd, J ϭ 7.7, 2.1 Hz, 1 H), 6.85 (d, J ϭ
(CH), 101.9 (CH), 111.7 (CH), 122.1 (CH), 124.2 (CH), 124.6 (C), 7.7 Hz, 1 H), 6.90 (d, J ϭ 8.9 Hz, 2 H), 7.22 (d, J ϭ 8.9 Hz, 2 H)
127.8 (CH), 128.0 (CH), 128.3 (CH), 129.2 (CH), 129.5 (CH), 129.6 ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 0.6 (CH2), 5.0
(CH), 130.3 (CH), 132.2 (C), 136.7 (C), 140.1 (C), 141.0 (C), 149.7 (CH2), 15.2 (CH), 34.7 (CH2), 55.4 (CH3), 72.4 (CH), 95.9 (CH),
(C), 150.4 (C), 167.4 (C) ppm. IR: ν˜ ϭ 3058, 3025, 2954, 2928, 104.5 (CH), 114.4 (CH), 119.1 (C), 124.7 (CH), 127.7 (CH), 137.7
2858, 1661, 1597, 1511, 1480, 1276, 809, 695 cmϪ1. MS (80 °C):
(C), 146.1 (C), 152.8 (C), 157.0 (C) ppm. IR: ν˜ ϭ 3444, 3361, 3000,
m/z (%) ϭ 445 (2) [Mϩ ϩ H], 388 (2), 280 (6), 182 (100), 131 (24), 2933, 2835, 1615, 1497, 1456, 1286, 1239, 1031, 826 cmϪ1. HRMS
105 (97), 77 (77). HRMS (ESI, CH3CN): calcd. (C32H32N2ϩH)
(ESI, CH3CN): calcd. (C18H20N2OϩH) 281.1654; found 281.1660.
445.2644; found 445.2652.
Amine 48: General Procedure B was used to synthesize amine 48
from aminoalkyne 42. The reaction time for the hydroamination
step was 4 h. After purification by flash chromatography (MeOH/
EtOAc, 1:1), compound 48 (845 mg, 3.52 mmol, 88%) was isolated
as a colorless oil. 1H NMR (400 MHz, CDCl3): δ ϭ 1.65Ϫ1.74 (m,
1 H), 1.84Ϫ1.95 (m, 3 H), 2.86 (dd, J ϭ 13.3, 10.0 Hz, 1 H),
2.92Ϫ3.03 (m, 1 H), 3.30Ϫ3.45 (m, 1 H), 3.45Ϫ3.60 (m, 2 H), 5.15
(br. s, 1 H), 7.09Ϫ7.15 (m, 1 H), 7.24Ϫ7.28 (m, 2 H), 7.56 (d, J ϭ
7.6 Hz, 1 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ
22.9 (CH2), 30.2 (CH2), 38.2 (CH2), 53.7 (CH2), 65.4 (CH), 124.6
(C), 127.8 (CH), 128.8 (CH), 131.3 (CH), 133.2 (CH), 136.6 (C)
ppm. IR: ν˜ ϭ 3102, 2982, 2961, 2858, 2422, 2405, 2200, 1657, 1470,
1435, 1375, 1360, 1275, 1220, 1166, 1133, 1118, 1077, 1045, 1023,
969, 943, 907, 864, 745, 697, 659, 598 cmϪ1. MS (25 °C): m/z (%) ϭ
241 (1) [Mϩ(81Br)], 239 (1) [Mϩ(79Br)], 238 (4), 199 (39), 197 (31),
172 (52), 170 (38), 157 (27), 155 (26), 145 (12), 143 (13), 130 (18),
128 (23), 121 (32), 116 (27), 115 (32), 114 (43), 107 (27), 103 (13),
95 (25), 91 (53), 82 (100), 77 (21), 70 (52), 65 (25). HRMS: calcd.
(C11H14BrN) 239.0309; found 239.0192.
Indoline 39: General Procedure C was used to synthesize indoline
39 from amine 37. The mixture was heated to 100 °C for 16 h.
After purification by flash chromatography (PE/EtOAc, 20:1),
compound 39 (819 mg, 1.84 mmol, 92%) was isolated as a bright
1
yellow oil. H NMR (400 MHz, CDCl3): δ ϭ Ϫ0.17 to Ϫ0.11 (m,
1 H), 0.02Ϫ0.08 (m, 1 H), 0.30Ϫ0.41 (m, 2 H), 0.94Ϫ1.03 (m, 1
H), 2.83 (dd, J ϭ 15.3, 8.2 Hz, 1 H), 3.12 (dd, J ϭ 15.4, 8.8 Hz, 1
H), 3.23 (q, J ϭ 8.5 Hz, 1 H), 3.79 (s, 3 H), 5.78 (d, J ϭ 1.8 Hz, 1
H), 6.17 (dd, J ϭ 7.7, 1.8 Hz, 1 H), 6.78 (d, J ϭ 9.0 Hz, 2 H), 6.90
(d, J ϭ 8.9 Hz, 1 H), 6.88Ϫ6.92 (m, 1 H), 7.10Ϫ7.13 (m, 2 H),
7.27Ϫ7.42 (m, 6 H), 7.64Ϫ7.66 (m, 2 H) ppm. 13C NMR
(100.6 MHz, DEPT, CDCl3): δ ϭ 0.7 (CH2), 5.1 (CH2), 15.2 (CH),
35.1 (CH2), 55.4 (CH3), 72.4 (CH), 102.0 (CH), 111.3 (CH), 114.2
(CH), 124.1 (CH), 124.1 (C), 126.6 (CH), 127.8 (CH), 128.0 (CH),
128.2 (CH), 129.2 (CH), 129.5 (CH), 130.3 (CH), 136.7 (C), 137.8
(C), 140.1 (C), 150.6 (C), 151.4 (C), 156.6 (C), 167.4 (C) ppm. IR:
ν˜ ϭ 2999, 2931, 2834, 1595, 1506, 1484, 1441, 1287, 1240, 1031,
832, 693 cmϪ1. MS (150 °C): m/z (%) ϭ 444 (100) [Mϩ], 403 (28),
222 (6). HRMS (ESI, CH3CN): calcd. (C31H28N2OϩH) 445.2280;
found 445.2302.
Amine 49: General Procedure B was used to synthesize amine 49
from aminoalkyne 43. The reaction time for the hydroamination
Eur. J. Org. Chem. 2003, 2888Ϫ2902
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2899

I. Bytschkov, H. Siebeneicher, S. Doye
step was 4 h. After purification by flash chromatography (PE/ 3117, 3044, 2955, 2929, 2817, 2791, 2762, 2714, 2678, 2559, 2500,
FULL PAPER
EtOAc, 1:1), compound 49 (523 mg, 2.49 mmol, 62%) was isolated
as a colorless oil. 1H NMR (400 MHz, CDCl3): δ ϭ 0.20Ϫ0.80 (br.
s, 1 H), 1.47 (d, J ϭ 6.5 Hz, 2 H), 1.57 (d, J ϭ 6.5 Hz, 2 H),
2449, 2360, 2323, 2051, 1983, 1712, 1613, 1587, 1468, 1443, 1415,
1385, 1332, 1275, 1200, 1176, 1122, 1078, 1030, 990, 959, 933, 895,
828, 752, 729, 656, 600, 566, 533, 517 cmϪ1. MS (60 °C): m/z (%) ϭ
1.85Ϫ2.05 (m, 2 H), 2.43 (s, 3 H), 3.27Ϫ3.45 (m, 2 H), 3.75Ϫ3.95 277 (1) [Mϩ], 240 (3), 222 (12), 193 (11), 159 (6), 158 (4), 145 (2), 98
(m, 1 H), 7.10Ϫ7.14 (m, 2 H), 7.20Ϫ7.24 (m, 1 H) ppm. 13C NMR (2), 85 (17), 84 (100), 70 (2), 67 (3). HRMS: calcd. (C13H15ClF3N)
(100.6 MHz, DEPT, CDCl3): δ ϭ 15.9 (CH2), 18.9 (CH2), 21.1 277.0845; found 277.0794.
(CH3), 29.2 (CH2), 31.2 (CH2), 54.8 (CH), 127.7 (CH), 128.5 (CH),
Amine 53: General Procedure B was used to synthesize amine 53
129.8 (CH), 132.0 (C), 134.4 (C), 139.4 (C) ppm. IR: ν˜ ϭ 3513,
from aminoalkyne 47. The reaction time for the hydroamination
step was 6 h. After purification by flash chromatography (MeOH/
3455, 3079, 2983, 1612, 1567, 1454, 1400, 1287, 1117, 1015, 959,
863, 784, 723 cmϪ1. MS (180 °C): m/z (%) ϭ 209 (3) [Mϩ], 174 (5),
EtOAc, 1:8), compound 53 (929 mg, 3.88 mmol, 97%) was isolated
139 (17), 126 (29), 115 (5), 113 (13), 105 (6), 91 (10), 70 (34), 65
(3). HRMS: calcd. (C12H16ClN) 209.0971; found 209.0928.
as a bright yellow oil. 1H NMR (400 MHz, CDCl3): δ ϭ 1.32Ϫ1.42
(m, 1 H), 1.70Ϫ1.88 (m, 4 H), 1.90Ϫ2.05 (m, 1 H), 3.03 (t, J ϭ
Amine 50: General Procedure B was used to synthesize amine 50
from aminoalkyne 44. The reaction time for the hydroamination
step was 4 h. After purification by flash chromatography (EtOAc),
compound 50 (878 mg, 3.89 mmol, 97%) was isolated as a bright
10.2 Hz, 1 H), 3.18Ϫ3.25 (m, 1 H), 3.44 (d, J ϭ 9.6 Hz, 2 H), 3.76
(s, 3 H), 3.74Ϫ3.78 (m, 1 H), 6.71 (dd, J ϭ 8.8, 3.0 Hz, 1 H), 7.00
(d, J ϭ 2.9 Hz, 1 H), 7.18 (d, J ϭ 8.8 Hz, 1 H), 8.00Ϫ8.70 (br. s,
1 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 22.1 (CH2),
22.2 (CH2), 27.5 (CH2), 37.3 (CH2), 45.8 (CH2), 55.8 (CH3), 57.7
(CH), 115.0 (CH), 117.0 (CH), 125.4 (C), 130.2 (CH), 134.3 (C),
158.5 (C) ppm. IR: ν˜ ϭ 2944, 2837, 1596, 1480, 1283, 1242, 1211,
1
yellow oil. H NMR (400 MHz, CDCl3): δ ϭ 1.65Ϫ1.81 (m, 1 H),
1.82Ϫ1.96 (m, 1 H), 1.97Ϫ2.12 (m, 2 H), 3.04Ϫ3.15 (m, 3 H),
3.25Ϫ3.40 (m, 1 H), 3.60Ϫ3.70 (m, 1 H), 3.79 (s, 3 H), 6.10 (br. s,
1 H), 6.75 (dd, J ϭ 8.8, 2.9 Hz, 1 H), 6.91 (d, J ϭ 3.0 Hz, 1 H),
7.24 (d, J ϭ 8.8 Hz, 1 H) ppm. 13C NMR (100.6 MHz, DEPT,
CDCl3): δ ϭ 23.6 (CH2), 30.2 (CH2), 36.6 (CH2), 45.4 (CH2), 55.7
(CH3), 60.1 (CH), 114.6 (CH), 116.4 (CH), 125.1 (C), 130.5 (CH),
135.5 (C), 158.6 (C) ppm. IR: ν˜ ϭ 2962, 2836, 1596, 1575, 1477,
1417, 1382, 1293, 1241, 1211, 1191, 1163, 1123, 1062, 1024, 929,
872, 809 cmϪ1. MS (80 °C): m/z (%) ϭ 226 (3) [Mϩ], 190 (3), 174
(3), 155 (11), 125 (6), 112 (100), 91 (4), 84 (7), 70 (92). HRMS:
calcd. (C12H16ClNO) 225.0920; found 225.0880.
1191, 1165, 1123, 1063, 1022, 981, 924, 873, 810, 734, 700 cmϪ1
.
MS (100 °C): m/z (%) ϭ 239 (1) [Mϩ], 202 (2), 155 (10), 148 (7),
128 (9), 115 (8), 105 (4), 98 (6), 92 (32), 91 (50), 85 (28), 84 (100),
77 (4), 65 (3). HRMS: calcd. (C13H18ClNO) 239.1076; found
239.1078.
Synthesis of Pyrrolizidines and Indolizidines from Chloro Deriva-
tives. General Procedure F: A Schlenk tube fitted with a Teflon
stopcock and containing a magnetic stirring bar was charged with
amine (1.0 mmol), [Pd2(dba)3] (46 mg, 0.05 mmol, 5.0 mol %), 1,3-
bis(2,4,6-trimethylphenyl)imidazolium chloride (34 mg, 0.1 mmol,
10.0 mol %), KOtBu (168 mg, 1.5 mmol), and 1,4-dioxane
(2.0 mL). After this had been stirred at 110 °C for 3Ϫ12 h (TLC
monitoring), water and tert-butyl methyl ether were added. The
organic layer was separated and the aqueous layer was extracted
with tert-butyl methyl ether (3 ϫ). The combined organic layers
were dried with Na2SO4 and concentrated under vacuum. The resi-
due was purified by flash chromatography (SiO2).
Amine 51: General Procedure B was used to synthesize amine 51
from aminoalkyne 45. The reaction time for the hydroamination
step was 6 h. After purification by flash chromatography (MeOH/
EtOAc, 1:1), compound 51 (682 mg, 2.68 mmol, 67%) was isolated
as a colorless oil. 1H NMR (400 MHz, CDCl3): δ ϭ 1.17Ϫ1.38 (m,
2 H), 1.34Ϫ1.58 (m, 1 H), 1.58 (d, J ϭ 13.2 Hz, 1 H), 1.68 (d, J ϭ
11.2 Hz, 1 H), 1.78 (d, J ϭ 12.2 Hz, 1 H), 2.55 (dt, J ϭ 11.7, 2.8 Hz,
1 H), 2.70 (dd, J ϭ 12.4, 7.3 Hz, 1 H), 2.76Ϫ2.90 (m, 2 H), 3.02
(d, J ϭ 12.3 Hz, 1 H), 7.02Ϫ7.11 (m, 1 H), 7.15Ϫ7.25 (m, 2 H),
7.54 (d, J ϭ 7.8 Hz, 1 H) ppm. 13C NMR (100.6 MHz, DEPT,
CDCl3): δ ϭ 24.8 (CH2), 26.2 (CH2), 32.7 (CH2), 43.9 (CH2), 47.2
(CH2), 56.3 (CH), 124.9 (C), 127.2 (CH), 127.9 (CH), 131.5 (CH),
132.9 (CH), 138.6 (C) ppm. IR: ν˜ ϭ 3055, 2927, 2852, 2798, 2736,
1566, 1470, 1439, 1379, 1331, 1320, 1267, 1150, 1118, 1077, 1051,
1022, 981, 944, 930, 887, 808, 747, 718, 701, 659 cmϪ1. MS (25 °C):
m/z (%) ϭ 254 (14) [Mϩ(81Br)], 252 (15) [Mϩ(79Br)], 224 (3), 198
(3), 196 (2), 171 (28), 169 (28), 144 (10), 130 (21), 128 (11), 118
(27), 115 (27), 103 (13), 98 (8), 91 (32), 90 (28), 84 (100), 82 (27),
77 (16), 70 (7), 68 (12), 65 (17). HRMS: calcd. (C12H16BrN)
253.0466; found 253.0305.
Synthesis of Pyrrolizidines and Indolizidines from Bromo Deriva-
tives. General Procedure G: A Schlenk tube fitted with a Teflon
stopcock and containing a magnetic stirring bar was charged with
amine (1.0 mmol), [Pd(PPh3)4] (58 mg, 0.05 mmol, 5.0 mol %),
K2CO3 (276 mg, 2.0 mmol), NaOtBu (192 mg, 2.0 mmol), and
toluene (2.0 mL). After this had been stirred at 110 °C for 6 h (TLC
monitoring), water and tert-butyl methyl ether were added. The
organic layer was separated and the aqueous layer was extracted
with tert-butyl methyl ether (3 ϫ). The combined organic layers
were dried with Na2SO4 and concentrated under vacuum. The resi-
due was purified by flash chromatography (SiO2).
Amine 52: General Procedure B was used to synthesize amine 52
from aminoalkyne 46. The reaction time for the hydroamination
Pyrrolizidine 54: General Procedure G was used to synthesize pyr-
rolizidine 54 from amine 48. After purification by flash chromatog-
step was 6 h. After purification by flash chromatography (MeOH/ raphy (PE/EtOAc, 5:1), compound 54 (113 mg, 0.71 mmol, 71%)
1
EtOAc, 1:8), compound 52 (1.04 g, 3.74 mmol, 94%) was isolated
as a bright yellow oil. 1H NMR (400 MHz, CDCl3): δ ϭ 1.31Ϫ1.42
(m, 1 H), 1.66 (d, J ϭ 13.7 Hz, 1 H), 1.76Ϫ1.96 (m, 3 H),
was isolated as a bright yellow oil. H NMR (400 MHz, CDCl3):
δ ϭ 1.31Ϫ1.42 (m, 1 H), 1.82Ϫ1.90 (m, 3 H), 2.95 (dd, J ϭ 16.1,
2.6 Hz, 1 H), 3.12Ϫ3.26 (m, 2 H), 3.45Ϫ3.55 (m, 1 H), 3.97Ϫ4.04
1.96Ϫ2.12 (m, 1 H), 2.95 (t, J ϭ 12.8 Hz, 1 H), 3.28Ϫ3.38 (m, 2 (m, 1 H), 6.67 (d, J ϭ 7.8 Hz, 1 H), 6.81 (t, J ϭ 7.2 Hz, 1 H),
H), 3.58 (d, J ϭ 12.9 Hz, 1 H), 3.70 (d, J ϭ 9.2 Hz, 1 H), 7.42Ϫ7.52
7.07Ϫ7.15 (m, 2 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3):
δ ϭ 25.7 (CH2), 31.4 (CH2), 34.0 (CH2), 52.8 (CH2), 65.4 (CH),
(m, 2 H), 7.60 (s, 1 H), 8.90Ϫ10.20 (br. s, 1 H) ppm. 13C NMR
(100.6 MHz, DEPT, CDCl3): δ ϭ 21.9 (CH2), 22.2 (CH2), 27.3 111.8 (CH), 120.3 (CH), 124.9 (CH), 127.7 (CH), 132.3 (C), 153.2
(CH2), 36.9 (CH2), 44.8 (CH2), 56.3 (CH), 123.4 (CF3, q, J ϭ (C) ppm. IR: ν˜ ϭ 3069, 3046, 3022, 2957, 2926, 2872, 1603, 1475,
272 Hz), 125.6 (CH, q, J ϭ 4 Hz), 128.7 (CH, q, J ϭ 4 Hz), 129.5
1456, 1434, 1358, 1313, 1263, 1224, 1180, 1152, 1114, 1089, 1070,
(C, q, J ϭ 33 Hz), 130.3 (CH), 134.8 (C), 138.2 (C) ppm. IR: ν˜ ϭ 1021, 985, 957, 913, 867, 845, 744, 714, 695 cmϪ1. MS (25 °C):
2900
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 2888Ϫ2902

A Flexible Synthesis of Indoline, Indolizidine, and Pyrrolizidine Derivatives
m/z (%) ϭ 159 (100) [Mϩ], 144 (9), 131 (97), 117 (30), 103 (21), 91 (br. d, J ϭ 12.7 Hz, 1 H), 3.73 (s, 3 H), 6.35 (d, J ϭ 8.4 Hz, 1 H),
FULL PAPER
(22), 89 (24), 77 (30), 65 (18).
6.61 (dd, J ϭ 8.4, 2.5 Hz, 1 H), 6.75 (br. s, 1 H) ppm. 13C NMR
(100.6 MHz, DEPT, CDCl3): δ ϭ 24.4 (CH2), 24.6 (CH2), 30.4
(CH2), 35.8 (CH2), 46.0 (CH2), 56.0 (CH3), 66.2 (CH), 106.0 (CH),
111.4 (CH), 112.4 (CH), 131.1 (C), 146.3 (C), 152.8 (C) ppm. IR:
ν˜ ϭ 2932, 2853, 1666, 1595, 1485, 1452, 1382, 1283, 1245, 1206,
1155, 1134, 1061, 1033, 887, 855, 799, 761, 700 cmϪ1. MS (25 °C):
m/z (%) ϭ 203 (97) [Mϩ], 202 (17), 189 (27), 188 (100), 185 (34),
174 (15), 160 (18), 157 (16), 147 (19), 142 (13), 133 (13), 117 (13),
104 (11), 91 (10), 77 (8), 65 (9). HRMS: calcd. (C13H17NO)
203.1310; found 203.1311.
Pyrrolizidine 55: General Procedure F was used to synthesize pyrro-
lizidine 55 from amine 49. The reaction time was 12 h. After purifi-
cation by flash chromatography (PE/EtOAc, 8:1), compound 55
(171 mg, 0.99 mmol, 99%) was isolated as a bright yellow oil. 1H
NMR (400 MHz, CDCl3): δ ϭ 1.31 (quin, J ϭ 9.9 Hz, 1 H),
1.78Ϫ1.94 (m, 3 H), 2.18 (s, 3 H), 2.87 (dd, J ϭ 16.0, 3.2 Hz, 1 H),
3.02Ϫ3.19 (m, 2 H), 3.35Ϫ3.45 (m, 1 H), 3.85Ϫ3.95 (m, 1 H), 6.40
(d, J ϭ 7.8 Hz, 1 H), 6.60 (d, J ϭ 7.6 Hz, 1 H), 7.00 (t, J ϭ 7.7 Hz,
1 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 18.7 (CH3),
25.8 (CH2), 31.7 (CH2), 32.9 (CH2), 52.3 (CH2), 65.0 (CH), 108.4
(CH), 120.4 (CH), 127.6 (CH), 128.6 (C), 134.2 (C), 154.4 (C) ppm.
IR: ν˜ ϭ 3027, 2917, 1774, 1704, 1595, 1453, 1436, 1397, 1371, 1336,
1262, 1233, 1175, 1146, 1115, 1074, 1025, 959, 910, 882, 860, 767,
715 cmϪ1. MS (25 °C): m/z (%) ϭ 173 (100) [Mϩ], 158 (27), 144
(84), 130 (60), 115 (29), 103 (23), 91 (20), 87 (21), 77 (30), 65 (13).
HRMS: calcd. (C12H15N) 173.1205; found 173.1204.
Acknowledgments
Generous support by Professor E. Winterfeldt is most gratefully
acknowledged. We further thank the Deutsche Forschungsgemein-
schaft, the Fonds der Chemischen Industrie, and the Dr. Otto
Röhm Gedächtnisstiftung, Darmstadt for financial support of
our research.
Indolizidine 57: General Procedure G was used to synthesize indoli-
zidine 57 from amine 51. After purification by flash chromatogra-
phy (EtOAc), compound 57 (111 mg, 0.64 mmol, 64%) was isolated
as a bright yellow oil. 1H NMR (400 MHz, CDCl3): δ ϭ 1.33Ϫ1.72
(m, 4 H), 1.76Ϫ1.92 (m, 2 H), 2.52Ϫ2.68 (m, 2 H), 2.94 (dd, J ϭ
14.8, 7.5 Hz, 1 H), 3.15Ϫ3.26 (m, 1 H), 3.63 (dd, J ϭ 12.0, 1.9 Hz,
1 H), 6.44 (d, J ϭ 7.6 Hz, 1 H), 6.63 (t, J ϭ 7.3 Hz, 1 H), 7.01Ϫ7.14
(m, 2 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 24.3
(CH2), 24.6 (CH2), 30.6 (CH2), 35.5 (CH2), 45.2 (CH2), 65.2 (CH),
106.0 (CH), 119.5 (CH), 124.5 (CH), 127.2 (CH), 129.4 (C), 151.5
(C) ppm. IR: ν˜ ϭ 3048, 3025, 2930, 2850, 2789, 1608, 1480, 1456,
1441, 1384, 1360, 1337, 1316, 1299, 1283, 1250, 1210, 1178, 1151,
1134, 1117, 1089, 1056, 1020, 981, 972, 943, 915, 892, 860, 835,
821, 744, 729, 714 cmϪ1. MS (25 °C): m/z (%) ϭ 173 (100) [Mϩ],
158 (11), 144 (53), 132 (33), 130 (74), 117 (75), 103 (9), 91 (17), 89
(16), 77 (11), 65 (8).
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Indolizidine 58: General Procedure F was used to synthesize indoli-
zidine 58 from amine 52. The reaction time was 3 h. After purifi-
cation by flash chromatography (PE/EtOAc, 10:1), compound 58
For a review on group-IV metal complexes as hydroamination
[3a]
catalysts, see:
I. Bytschkov, S. Doye, Eur. J. Org. Chem.
1
(234 mg, 0.97 mmol, 97%) was isolated as a bright yellow oil. H
2003, 935Ϫ946. For early studies on group-IV metal complexes
[3b]
NMR (400 MHz, CDCl3): δ ϭ 1.37Ϫ1.63 (m, 3 H), 1.70 (d, J ϭ
12.8 Hz, 1 H), 1.86 (td, J ϭ 13.4, 2.6 Hz, 2 H), 2.57 (dd, J ϭ 15.2,
9.6 Hz, 1 H), 2.72 (td, J ϭ 12.2, 3.0 Hz, 1 H), 3.01 (dd, J ϭ 15.2,
7.8 Hz, 1 H), 3.37 (qd, J ϭ 9.8, 2.8 Hz, 1 H), 3.63 (dd, J ϭ 14.6,
4.4 Hz, 1 H), 6.35 (d, J ϭ 8.2 Hz, 1 H), 7.23 (s, 1 H), 7.29 (d, J ϭ
8.2 Hz, 1 H) ppm. 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ
24.1 (CH2), 24.5 (CH2), 30.9 (CH2), 35.0 (CH2), 44.5 (CH2), 64.4
(CH), 104.2 (CH), 118.5 (CH, q, J ϭ 33 Hz), 121.3 (CH, q, J ϭ
4 Hz), 125.2 (CF3, q, J ϭ 269 Hz), 125.3 (CH, q, J ϭ 4 Hz), 129.3
(C), 154.0 (C) ppm. IR: ν˜ ϭ 2941, 2919, 2853, 2820, 1708, 1618,
1593, 1497, 1447, 1399, 1322, 1295, 1251, 1209, 1168, 1151, 1135,
1095, 1056, 1026, 975, 927, 890, 872, 853, 812, 758, 737, 699, 643,
626, 609, 580, 562, 530 cmϪ1. MS (25 °C): m/z (%) ϭ 241 (100)
[Mϩ], 240 (100), 222 (13), 212 (19), 200 (12), 185 (22), 166 (5), 135
(3), 97 (4), 91 (3), 81 (4), 67 (3). HRMS: calcd. (C13H14F3N)
241.1078; found 241.1078.
as hydroamination catalysts, see:
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Indolizidine 59: General Procedure F was used to synthesize indoli-
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1
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1.73Ϫ1.45 (m, 3 H), 1.88Ϫ1.80 (m, 2 H), 2.54 (td, J ϭ 12.0, 3.4 Hz,
2 H), 2.88 (dd, J ϭ 14.8, 7.2 Hz, 1 H), 3.15Ϫ3.05 (m, 1 H), 3.57
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www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2901

I. Bytschkov, H. Siebeneicher, S. Doye
FULL PAPER
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Received March 3, 2003
2902
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2888Ϫ2902