Stereoselective Synthesis of Tetrahydroisoquinolines from Chiral 4-Azaocta-1,7-diynes and 4-Azaocta-1,7-enynes

Article abstract of DOI:10.1002/ejoc.201901590

The N-propargylation of enantioenriched homopropargylic amine derivatives 3 proceeds in high yields under basic conditions. The resulting 4-azaocta-1,7-dynes 5 were transformed into 1,2,3,4-tetrahydrosioquinolines 7 bearing substituents at 3-, 6- and 7-positions, upon reaction with symmetrical alkynes, through a [2+2+2] cyclotrimerization promoted by Wilkinson catalyst. Ruthenium-catalyzed ring closing metathesis of azaocta-1,7-enynes 9a and 15a gave 1,3-dienes 10a and 16a, respectively, in high yields. Tetrahydroisoquinolines 12a and 18a, with a substitution pattern in the aromatic ring different to that of compounds 7, were prepared by a [4+2] cycloaddition of dimethyl acetylenedicarboxylate with dienes 10a and 16a, respectively.

Full text of DOI:10.1002/ejoc.201901590

A Journal of
Accepted Article
Title: Stereoselective Synthesis of Tetrahydroisoquinolines from Chiral
4-Azaocta-1,7-diynes and 4-Azaocta-1,7-enynes
Authors: Ana Sirvent, M. Jesús García-Muñoz, Miguel Yus, and
Francisco Foubelo
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901590
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10.1002/ejoc.201901590
European Journal of Organic Chemistry
1
Stereoselective Synthesis of Tetrahydroisoquinolines from Chiral 4-Azaocta-1,7-
diynes and 4-Azaocta-1,7-enynes
Ana Sirvent,[a,b,c] M. Jesús García-Muñoz,[a,b,c] Miguel Yus[c] and Francisco Foubelo*[a,b,c]
Keywords: Chiral sulfinyl imines · Diastereoselective propargylation · Diastereoselective allylation · Tetrahydroisoquinolines ·
Cyclotrimerization of alkynes · Ring-closing enyne metathesis
The N-propargylation of enantioenriched homopropargylic amine derivatives 3 proceeds in high yields under
basic conditions. The resulting 4-azaocta-1,7-dynes 5 were transformed into 1,2,3,4-tetrahydrosioquinolines 7
bearing substituents at 3-, 6- and 7-positions, upon reaction with symmetrical alkynes, through a [2+2+2]
cyclotrimerization promoted by Wilkinson catalyst. Ruthenium-catalyzed ring closing metathesis of azaocta-1,7-
enynes 9a and 15a gave 1,3-dienes 10a and 16a, respectively, in high yields. Tetrahydroisoquinolines 12a and
18a, with a substitution pattern in the aromatic ring different to that of compounds 7, were prepared by a [4+2]
cycloaddition of dimethyl acetylenedicarboxylate with dienes 10a and 16a, respectively.
Introduction
Benzo-fused nitrogen-containing heterocycles have attracted much attention to synthetic organic chemists,
especially, 1,2,3,4-tetrahydroisoquinolines. Many compounds with this structural motif bearing substituents at 1-
position display a wide range of biological activities.[1] Some of them are available from natural sources, such as,
for instance, alkaloids (−)-salsolidine,[2] first isolated from a subshrub of Salsola genus, tetracyclic (−)-
xylopinine, a member of protoberberines isolated from Xylopia discrete,[3] (+)-reticuline, a dopamine receptor
antagonist,[4] which is also a biosynthetic precursor of many isoquinoline alkaloids, and (+)-crispine A,
a
pyrroloisoquinoline tricyclic derivative isolated from Carduus crispus, which has been proved to show significant
cytotoxic activity against different cancer cell lines (Scheme 1).[5] Aminoacids phenylalanine and tyrosine were
found to be the biosynthetic precursors of this type of alkaloids.[6] Another numerous group of pharmacologically
active 1,2,3,4-tetrahydroisoquinolines are synthetic analogs of these natural products, which have been prepared
in many cases from 2-arylethylamine derivatives, following a biomimetic approach, involving intramolecular
cyclizations. Among these methodologies to access to both natural and synthetic 1-substituted heterocycles,
Pictet-Spengler[7] and Bichler-Napieralsky[8] reactions are the most commonly used (Scheme 1). Recently, there
has been increasing interest in performing the benzylic C-H bond functionalization in 1,2,3,4-tetrahydro-
__________________
[a]
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99
03080 Alicante, Spain
E-mail: foubelo@ua.es
[b] Instituto de Síntesis Orgánica, Universidad de Alicante, Apdo. 99
03080 Alicante, Spain
[c]
Centro de Innovación en Química Avanzada (ORFEO-CINQA), Universidad de Alicante, Apdo. 99
03080 Alicante, Spain
https://cvnet.cpd.ua.es/curriculum-breve/en/foubelo-garcia-francisco/10428
Supporting information for this article is available on the WWW under http://www.eurjoc.org/ or from the author.
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10.1002/ejoc.201901590
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isoquinolines by oxidative or photoredox activation.[9] Compounds bearing substituents at 3-position are less
represented in nature, and 3-carboxylic acid derivatives, which are constrained analogs of phenylalanine, were
used in peptide synthesis replacing the aminoacid, promoting changes in the activity and selectivity of the
peptide.[10] Interestingly, cyclotrimerization of alkynes under ruthenium, cobalt or rhodium catalysis allowed the
formation of these bicyclic heterocyclic scaffolds with substituents at 3-position in a single step (Scheme 1).[11]
Scheme 1. Selected substituted tetrahydroisoquinoline alkaloids and general strategies to synthesized 1- and 3-
substituted derivatives.
Continuing our interest in the development of new methodologies involving chiral N-tert-butanesulfinyl imines
for the stereoselective synthesis of nitrogen containing heterocyclic systems,[12] we decided to explore new
synthetic pathways to access to 3-substituted 1,2,3,4-tetrahydroisoquinoline derivatives in an enantioenriched
form. These chiral imines have found great applicability in synthesis due to the easy accessibility of both
enantiomers from commercially available (R) and (S)-tert-butanesulfinamide.[13] In addition, the tert-
butanesulfinyl group can be removed easily under mild reaction conditions to produce free amines, and different
synthetic procedures have also been reported to perform the recycling of the chiral auxiliary.[14] Regarding our
research in this area, we have reported the stereoselective synthesis of homoallyl and homopropargyl amine
derivatives, through an indium promoted coupling of N-tert-butanesulfinyl imines with allylic bromides or
alcohols,[15] and also with trimethylsilyl propargyl bromide,[16] respectively. Diastereoselective allylation and
propargylation of chiral N-tert-butanesulfinyl imine, ruthenium-catalyzed ring-closing enyne metathesis
(RCEYM), and rhodium-catalyzed cyclotrimerization are key steps in the synthetic strategy we have envisioned
for the synthesis of these heterocycles (Scheme 2).
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European Journal of Organic Chemistry
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Scheme 2. Retrosynthetic analysis for 3-substituted 1,2,3,4-tetrahydroisoquinoline derivatives.
Results and Discussion
Our synthesis of the 3-substituted 1,2,3,4-tetrahydroisoquinolines started with homopropargyl amine derivatives
3. We had already reported the diastereoselective propargylation of chiral N-tert-butanesulfinyl aldimines 1 using
trimethylsilylpropargyl bromide in the presence of indium metal, and under sonication.[12g,16] The corresponding
silylated homopropargyl amine derivatives 2 were obtained in good yields and excellent diastereomeric ratios,
being isolated in an almost enantiopure form after column chromatography purification (>95:5 dr). The
configuration of the stereogenic centre in compounds 2 was established at this point, and we observed that the
nucleophilic attack took always place in a larger extension to the Si-face of imines 1 with RS configuration.
Further removal of the silicon unit in compounds 2 under mild basic conditions led to the expected terminal
alkynes 3 (Scheme 3).
Br
O
S
O
S
O
S
Me3Si
(2 equiv)
K2CO3 (10 mol%)/MeOH
THF, 23 ºC
N
t-Bu
t-Bu
NH
t-Bu
NH
SiMe3
In (2 equiv), THF, )))
R1
R1
R1
H
1
1a
1b
2a
3a
(93%)
: R = Ph(CH2)2
(80%)
1
2b (73%)
3b (76%)
: R = Ph
1c: R1 = (CH3)2CHCH2
(87%)
(81%)
2c
3c
1d: R1 = CH3(CH2)8
2d
2e
3d
3e
(85%)
(88%)
(80%)
(80%)
1
1e
: R = THPO(CH2)4
Scheme 3. Diastereoselective synthesis of homopropargyl amine derivatives 3.
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Selective N-propargylation of compounds 3 was achieved by performing first deprotonation with n-BuLi in THF,
followed by reaction with an excess of propargyl bromide in the presence of 3 equivalents of HMPA.[17] The
corresponding N-propargylated compounds 4 were obtained in fair to good yields. Final oxidation of the sulfinyl
group led to sulfonamides 5 (Scheme 4). The sulfonyl group usually performs better than the sulfinyl in most of
transition metal-catalyzed reactions.
Scheme 4. Synthesis of 4-azaocta-1,7-diyne derivatives 5.
All the attempts to carry out a cyclotrimerization involving diyne derivative 5a and 3-hexyne (6a) with
[18]
CpCo(CO)2 failed. Better results were obtained working with Wilkinson catalyst. The reaction of a 0.1 M
solution of diyne 5a in toluene, with 2 equivalents of 3-hexyne (6a), in the presence of 5 mol% of Rh(PPh3)3Cl, at
100 ºC for 15 h, produced tetrahydroisoquinoline 7a in only 14% yield (Table 1, entry 1). Fortunately, there was
a greatly increased yield (54%) when the reaction was performed in a ten-times less concentrated solution, and
with a larger excess of symmetrical alkyne 6a (10 equivalents), maintaining the same solvent, temperature and
reaction time (Table 1, entry 2). Cyclotrimerization occurred also under the same reaction conditions in polar
protic solvents, such as ethanol, although the yield was in this case a little bit lower (Table 1, entry 3). When 2-
butyne-1,4-diol (6b) was taken as a model compound for the cyclotrimerization with diyne 5a, the expected
product 7b was not produced in any extension, under the optimal reaction conditions found for 3-hexyne (6a) in
toluene, and also the same happened working in dichloromethane as solvent (Table 1, entries 4 and 5).
Fortunately, we were please to find that switching from apolar solvents to ethanol, the cyclotrimerization with the
rhodium catalyst occurred even in higher yield (68%) than for 6a in toluene (Table 1, entry 6). Concerning the
mechanism,[11] the process begins with the coordination of the triple bonds of diyne 5 to Rh(I) to give
complex A, followed by reductive coupling of the acetylenic units with concomitant oxidation of the
metal, leading to rhodiacyclopentadiene B. Coordination of an external alkyne 6 gives complex C, and
subsequent insertion produces rhodiacyclohepatriene D. The final reductive elimination provides the
expected tetrahydroisoquinoline 7 and regenerates the Rh (I) catalyst (Table 1). Since the stereogenic
center is not involved in the catalytic cycle, we assume that the enantiomeric purity of the starting
diynes 5 (>95:5) is maintained throughout the process and is reflected in the reaction products 7.
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Table 1. Optimization of the rhodium-catalyzed cyclotrimerization of diyne 5a and symmetrical alkynes 6a and
6ba
Alkyne
R2 (equiv)
Reaction conditions
Temperature
Entry
Nº.
6a
6a
6a
6b
6b
6b
Solvent
Time
15 h
15 h
15 h
15 h
15 h
15 h
Yield (%)b
1
2
3
4
5
6
Et (2 equiv)
Et (10 equiv)
PhMe (0.1 M)
PhMe (0.01 M)
EtOH (0.01 M)
PhMe (0.01 M)
CH2Cl2 (0.01 M)
EtOH (0.01 M)
100 ºC
100 ºC
75 ºC
14
54
45
0
Et (10 equiv)
CH2OH (10 equiv)
CH2OH (10 equiv)
CH2OH (10 equiv)
100 ºC
40 ºC
0
75 ºC
68
a
b
All the reactions were carried out with 0.1 mmol of 5a. Isolated yield after column chromatography
purification.
We studied next the scope of the reaction under the optimized conditions shown in entry 2 of Table 1 for 3-
hexyne (6a), dimethyl acetylenedicarboxylate (6c) and 1-henxyne (6d). Meanwhile, for 2-butyne-1,4-diol (6b),
the reaction conditions were those shown in entry 6 of Table 1. The expected tetrahydroisoquinolines 7 were
obtained in variable yields, these yields depending mainly on the alkyne 6 used. Yields were higher for
compounds 7b, 7e, 7h and 7k, all of them derived from 2-butyne-1,4-diol (6b) (Table 2). Slightly lower yields
were obtained for tetrahydroisoquinolines derived from 3-hexyne (6a), with values ranging between 36% (7j) and
57% (7g) (Table 2). It is worth mentioning that compound 7m (43%) with an alcohol function protected as a
tetrahydropyranyl ether, could be transformed into a tricyclic compound through known reactions, such as the
removal of the sulfinyl group, the transformation of the alcohol functionality in a leaving group, and a final
intramolecular N-alkylation. Unfortunately, tetrahydroisoquinolines 7c, 7f, 7i and 7l, derived from dimethyl
acetylenedicarboxylate (6c), were obtained in low yields in a range of about 20-30% (Table 2). On the
other hand, the reaction of diyne 5a with unsymmetrical alkyne 1-hexyne (6d) took place with lack of
regioselectivity, leading to a mixture of regioisomers 7n and 7o, in a 1:1 ratio, in a fairly good yield (72%) (Table
2). Through this methodology it is also possible to access to the corresponding enantiomers ent-7 starting from
the (SS)-N-tert-butanesulfinyl imine ent-1 (Scheme 3). This was exemplified in the synthesis of compound ent-
7d, and the stereochemical integrity of compounds 7d and its enantiomer ent-7d was determined by HPLC with
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10.1002/ejoc.201901590
European Journal of Organic Chemistry
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columns with chiral stationary phases, exhibiting high enantiomeric ratios (>95:5 er). The rest of compounds 7
should be of similar enantiomeric purity, since all of them were prepared following the same synthetic strategy.
Table 2. Scope of the rhodium-catalyzed cyclotrimerization involving diynes 5 and alkynes 6a
Et
Et
CO2Me
CO2Me
t-BuSO2N
Ph
t-BuSO2N
Ph
t-BuSO2N
Ph
OH
OH
7a (54%)
7b (68%)
7c (22%)
Et
Et
CO2Me
CO2Me
t-BuSO2N
t-BuSO2N
t-BuSO2N
OH
OH
Ph
Ph
Ph
7d (44%, >95:5 er)
7e (80%)
7h (60%)
7k (68%)
7n
7f (18%)
[ent-7d (32%, >95:5 er)]b
Et
CO2Me
CO2Me
t-BuSO2N
t-BuSO2N
i-Pr
t-BuSO2N
i-Pr
OH
OH
i-Pr
Et
7g (57%)
7i (20%)
7l (27%)
7o
Et
CO2Me
CO2Me
t-BuSO2N
t-BuSO2N
t-BuSO2N
OH
OH
Me
Me
( )8
Me
( )8
( )8
Et
7j (36%)
( )
Et
Et
3
t-BuSO2N
THPO
t-BuSO2N
t-BuSO2N
Me
Me
( )3
Ph
Ph
(72%, 1:1)
( )4
7m (43%)
a
All the reactions were carried out with 0.1 mmol of 5. Isolated yield after column chromatography
purification is given in parenthesis. b Diyne ent-5b was used as starting material.
It was also possible to achieve the synthesis of chiral tetrahydroisoquinolines with a different substitution pattern
at the aromatic ring to that of compounds 7, starting from the same precursors 3, but following a different
strategy, being a [4+2] cycloaddion the key step in the formation of the aromatic ring of the
tetrahydroisoquinolinic system. For instance, N-allylation of 3a under the same reaction conditions led to 8a in
46% yield. Further oxidation produced the more robust sulfonamide derivative 9a (Scheme 5).
Scheme 5. Synthesis of 4-azaoct-1-en-7-yne derivative 9a from N-tert-butanesulfinylhomopropargyl amine 3a.
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Intramolecular ruthenium-catalyzed ring-closing enyne metathesis of compound 9a was explored next with the
aim of synthesizing diene 10a.[11b] Total consumption of the starting material was observed using Grubbs second
generation catalyst in toluene at 120 ºC for 1 h. However, along with the expected diene 10a, a significant
amount of triene 11a, resulting from 10a through a homo cross metathesis, was also formed (Table 3, entry 1).
Working with Grubbs first generation catalyst under milder reaction conditions did not give better results. In this
case, both diene 10a and triene 11a were also formed, although most of the starting material remained unaltered
(Table 3, entry 2). Similar results were also obtained performing the ring-closing metathesis with the same
catalyst in the presence of four equivalents of 1,7-octadiene,[19] which has been found to be a useful ethylene
surrogate in ring-closing metathesis, facilitating the regeneration of the ruthenium catalyst species (Table 3, entry
3). Fortunately, Hoveyda-Grubbs second generation catalyst produced total conversion of enyne 9a into cyclic
diene 10a in a highly selective manner (Table 3, entry 4). It has been proposed that a ruthenacyclobutane E
is formed in the initial step of enyne metathesis, followed by elimination of a styrene, giving a new
carbene complex F. Intramolecular cycloaddition involving the triple bond leads to a
ruthenacyclobutene G, which undergoes an electrocyclic opening to give a new carbene H. The reaction
of this carbene with starting enyne 9 leads to expected 1,3-diene 10 and carbene F, which makes it
possible to continue the catalytic cycle (Table 3).[20] In the same way, enantiopurity of diene 10a must
be similar to that of starting enyne 9a (>95:5 er), since the stereogenic center was not involved in these
reactions.
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Table 3. Optimization of the ruthenium-catalyzed intramolecular enyne metathesis of compound 9aa
Entry
Reaction conditions
Grubbs II (10 mol%), PhCH3 (0.01 M), 120 ºC, 1 h
Grubbs I (20 mol%), CH2Cl2 (0.005 M), 40 ºC, 17 h
9a:10a:11ab
--:80:20
64:32:4
45:55:--
1
2
3
4
Grubbs I (10 mol%), 1,7-octadiene (4 equiv), CH2Cl2 (0.005 M), 40 ºC, 17 h
Hoveyda-Grubbs II (10 mol%), 1,7-octadiene (4 equiv), CH2Cl2 (0.01 M), 40 ºC, 12 h
--:98:2
a All the reactions were carried out with 0.2 mmol of 9a. Reaction products ratio was determined by H-
b
1
NMR analysis of the crude reaction mixtures.
Cyclic diene 10a was obtained from 9a in 95% isolated yield. The reaction of 10a with dimethyl
acetylenedicarboxylate (6c), followed by oxidation of the resulting cycloadduct with DDQ gave
tetrahydroisoquinoline derivative 12a with substituents at 7 and 8 positions of the aromatic ring in low yield,
although the yield of this two-step process could be improved after appropriate optimization (Scheme 6).
Scheme 6. Synthesis of tetrahydroisoquinoline 12a from 4-azaoct-1-en-7-yne derivative 9a.
On the other hand, starting from N-tert-butanesulfinylhomoallyl amine 13a, which was easily prepared by an
indium promoted diastereoselective allylation of chiral imine 1a,[15a] 5-azaoct-1-en-7-yne derivative 15a was
prepared by N-propargylation, leading to 14a first, followed by oxidation of the sulfinyl group (Scheme 7).
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Scheme 7. Synthesis of 5-azaoct-1-en-7-yne derivatives 15a and ent-15a from N-tert-butanesulfinylhomoallyl
amines 13.
Similarly to enyne 9a, the intramolecular ruthenium-catalyzed ring-closing metathesis of compound 15a showed
to be strongly catalyst-dependent. For instance, a 1:1 mixture of cyclic diene 16a and triene 17a was obtained
with Grubbs second generation catalyst in toluene at temperatures ranging from 40 to 80 ºC, and different
reaction times (Table 4, entries 1 to 4). It was not possible to transform selectively enyne 15a into cyclic diene
16a, because triene 17a was always formed, even working under high dilution conditions at room temperature,
and short reaction times, in order to avoid cross metathesis of diene 16a leading to 17a (Table 4, entry 5). Grubbs
first generation catalyst showed to be more selective in this transformation, always giving rise to desired product
16a and in a lesser extension of triene 17a, although total conversion was not achieved in dichloromethane at 40
ºC (Table 4, entries 6 and 7). However, this ruthenium catalyst led exclusively to cyclic diene 16 when the ring-
closing metathesis was carried out in the presence of four equivalents of 1,7-octadiene, performing the reaction
under high dilution conditions or at higher concentrations (Table 4, entries 8 and 10, respectively). On the other
hand, Hoveyda-Grubbs second generation catalyst, the most efficient catalyst in the ring closing metathesis of
enyne 9a, was less efficient for the selective transformation of enyne 15a (Table 4, entry 9).
Table 4. Optimization of the intramolecular ruthenium-catalyzed enyne metathesis of compound 15aa
Entry
1
2
3
4
Reaction conditions
Grubbs II (10 mol%), PhCH3 (0.01 M), 80 ºC, 17 h
Grubbs II (10 mol%), PhCH3 (0.01 M), 80 ºC, 3 h
15a:16a:17ab
--:50:50
--:50:50
--:50:50
--:50:50
70:20:10
71:28:1
Grubbs II (10 mol%), PhCH3 (0.005 M), 60 ºC, 2 h
Grubbs II (10 mol%), PhCH3 (0.004 M), 40 ºC, 0.5 h
Grubbs II (10 mol%), PhCH3 (0.00025 M), 25 ºC, 1 h
Grubbs I (10 mol%), CH2Cl2 (0.005 M), 40 ºC, 2.5 h
5
6
7
Grubbs I (10 mol%), CH2Cl2 (0.005 M), 40 ºC, 18 h
40:54:6
8
9
Grubbs I (20 mol%), 1,7-octadiene (4 equiv), CH2Cl2 (0.005 M), 40 ºC, 17 h
Hoveyda-Grubbs II (10 mol%), 1,7-octadiene (4 equiv), CH2Cl2 (0.005 M), 40 ºC, 17 h
--:100:--
--:90:10
10
Grubbs I (20 mol%), 1,7-octadiene (4 equiv), CH2Cl2 (0.01 M), 40 ºC, 20 h
--:100:--
b
1
a All the reactions were carried out with 0.2 mmol of 15a. Reaction products ratio was determined by H-
NMR analysis of the crude reaction mixtures.
The intramolecular ring-closing enyne metathesis of compound 15a under the reaction conditions shown in entry
10 of Table 4 led to cyclic dine 16a in 98% isolated yield. Finally, tetrahydroisoquinoline derivative 18a with
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substituents at 5 and 6 positions of the aromatic ring was obtained from 16a and dimethyl acetylenedicarboxylate
(6c) in 21% overall yield, considering the [4+2] cyclization and the oxidation steps. The synthesis of ent-18a was
also carried out from ent-16a, with the aim of proving that stereochemical integrity of compound 15a (>95:5 er)
was maintained after the intramolecular ruthenium-catalyzed enyne metathesis process. Enantiomeric ratios in
compounds 18a and ent-18a were determined by HPLC with chiral columns, and values were 96:4 and >98:2,
respectively (Scheme 8).
Scheme 8. Synthesis of tetrahydroisoquinolines 18a and ent-18a from 5-azaoct-1-en-7-yne derivatives 15.
Conclusions
In summary, 1,2,3,4-tetrahydrosioquinolines bearing substituents at 3-, 6- and 7-positions were prepared in a
highly enantioselective fashion starting from chiral N-tert-butanesulfinyl imines. Diastereoselective indium-
promoted propargylation of the sulfinyl imine, selective N-propargylation of the resulting homopropargylamine
derivative, and [2+2+2] cyclotrimerization involving the azadiyne system and a symmetrical alkyne, are key
steps of the here presented methodology. Sulfinyl imines could be also precursors of tetrahydroisoquinolines with
substituents at different positions of the aromatic ring, by combining allylation and propargylation processes as
the first steps of this new strategy. The resulting azaenynes were efficiently transformed by a ruthenium-
catalyzed ring-closing metathesis into cyclic 1,3-dienes. A subsequent [4+2] cycloaddition with dimethyl
acetylenedicarboxylate, and final oxidation, led to 5,6- or 7,8-bis(methoxycarbonyl)substituted 1,2,3,4-
tetrahydrosioquinolines.
Experimental Section
General: (RS)-tert-Butanesulfinamide was a gift of MEDALCHEMY SL (> 99% ee by chiral HPLC on a
Chiracel AS column, 90:10 n-hexane/i-PrOH, 1.2 mL/min, λ=222 nm). TLC was performed on silica gel 60 F254,
using aluminium plates and visualized with phosphomolybdic acid (PMA) stain. Flash chromatography was
carried out on hand packed columns of silica gel 60 (230- 400 mesh). Gas chromatographic analyses (GC) were
carried out in a Agilent Technologies 6890N instrument equipped with a flame ionization detector and a 30.0 m
capillary column (0.25 mm diam, 0.25 μm film thickness), using nitrogen (1.4 ml/min) as carrier gas, Tinjector
=
275°C, Tcolumn = 60 °C (3 min) and 60-270 °C (15 °C/min). Melting points are uncorrected. Optical rotations were
measured using a polarimeter with a thermally jacketed 5 cm cell at approximately 23 ºC and concentrations (c)
are given in g/100 mL. Infrared analyses were performed with a spectrophotometer equipped with an ATR
component; wave numbers are given in cm-1. Low-resolution mass spectra (EI) were obtained at 70 eV; and
fragment ions in m/z with relative intensities (%) in parentheses. High-resolution mass spectra (HRMS) were also
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10.1002/ejoc.201901590
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carried out in the electron impact mode (EI) at 70 eV and on an apparatus equipped with a time of flight (TOF)
analyzer and the samples were ionized by ESI techniques and introduced through an ultra-high pressure liquid
chromatography (UPLC) model. 1H NMR spectra were recorded at 300 or 400 MHz for 1H NMR and 75 or 100
MHz for 13C NMR, using CDCl3 as the solvent and TMS as internal standard (0.00 ppm). The data is being
reported as: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, br s = broad signal,
1
coupling constant(s) in Hz, integration. 13C NMR spectra were recorded with H-decoupling at 100 MHz and
referenced to CDCl3 at 77.16 ppm. DEPT-135 experiments were performed to assign CH, CH2 and CH3.
Microwave-assisted synthesis was performed using microwave oven CEM Discover Intellivent Explorer in sealed
reaction vessels, and the temperature was monitored using a vertically focused IR temperature sensor. All
reactions requiring anhydrous conditions were performed in oven dried glassware under argon. Otherwise
indicated, all commercially available chemicals were purchased from Acros or Sigma-Aldrich and used without
purification. Compounds 1a,[21] 1b,[22] 1c,[23] 1d[24] and 1e[25] were prepared from the corresponding aldehyde and
(RS)-tert-butanesulfinamide in THF in the presence of two equivalents of titanium tetraethoxide.
General Procedure for the Propargylation of N-tert-Butanesulfinylimines 1. Synthesis of
Homopropargylamine Derivatives 2: A mixture of N-tert-butanesulfinyl imine 1 (1.5 mmol), 3-bromo-1-
trimethylsilyl-1-propyne (600 mg, 0.51 mL, 3.0 mmol), and indium (360 mg, 3.0 mmol) was sonicated in dry
THF (6.0 mL) for 3 h. Then the resulting mixture was hydrolyzed with H2O (5 mL) and extracted with EtOAc (3
× 15 mL). The organic phase was washed with brine (3 × 10 mL), dried with anhydrous MgSO4, and the solvent
evaporated (15 Torr). The residue was purified by column chromatography (silica gel, hexane/EtOAc) to yield
products 2. Yields are given in Scheme 3. Compounds 2a,[16] 2b[16] and 2c[12g] were characterized by
comparison of their physical and spectroscopic data with those reported in the literature. The
corresponding physical, spectroscopic, and analytical data for new compounds 2d and 2e follow.
(4R,RS)-N-(tert-Butanesulfinyl)-1-(trimethylsilyl)tridec-1-yn-4-amine (2d): Yellow oil; RF 0.26
(hexane/EtOAc 4:1); [α]20 –6.2 (c 1.10, CH2Cl2); IR (film) ν 3212, 2953, 2924, 2855, 2175, 1248, 1027, 839,
D
758 cm–1; 1H NMR (400 MHz, CDCl3) δ = 0.15 [9H, s, Si(CH3)3], 0.85-0.90 (3H, m, CH3), 1.23 [9H, s, C(CH3)3],
1.26 (14H, s, 7 x CH2), 1.56-1.62 (2H, m, CH2), 2.48 (1H, dd, J = 16.8, 5.0 Hz, CHH), 2.65 (1H, dd, J = 16.8, 5.4
Hz, CHH), 3.30-3.38 (1H, m, NCH), 3.61 (1H, d, J = 7.7 Hz, NH); 13C NMR (100 MHz, CDCl3) δ = 0.16 (CH3),
14.2 (CH3), 22.7 (CH2), 22.8 (CH3), 25.7 (CH2), 28.0 (CH2), 29.4 (2 CH2), 29.6 (2 CH2), 32.0 (CH2), 34.9 (CH2),
54.6 (CH), 56.0 (C), 88.3 (C), 102.9 (C); LRMS (EI) m/z 371 (M+, 0.09%), 315 (25), 299 (17), 268 (16), 267
(72), 260 (19), 204 (29), 203 (53), 188 (12), 157 (11), 156 (100), 154 (16), 140 (31), 83 (17), 75 (19), 73 (81), 70
(21), 57 (75), 43 (21), 41 (24); HRMS (ESI-TOF) Calcd for C16H33NOSSi [M+ − C4H8] 315.2052, found
315.2052.
(4R,RS)-N-(tert-Butanesulfinyl)-8-[(tetrahydro-2H-pyran-2-yl)oxy]-1-(trimethylsilyl)oct-1-yn-4-amine (2e):
Yellow oil (1:1 mixture of diastereoisomers); RF 0.43 (hexane/EtOAc 1:1); IR (film) ν 2942, 2868, 2174, 1248,
1024, 840 cm–1; 1H NMR (300 MHz, CDCl3) δ = 0.15 [9H, s, Si(CH3)3], 1.23 [9H, s, C(CH3)3], 1.41-1.85 (12H,
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m, 6 x CH2), 2.49 (1H, ddd, J = 16.8, 4.9, 0.8 Hz, CHH), 2.68 (1H, dd, J = 16.8, 5.7 Hz, CHH), 3.33-3.44 (2H,
m, NCH + CHH), 3.44-3.58 (1H, m, CHH), 3.62 (1H, d, J = 7.9 Hz, NH), 3.67-3.80 (1H, m, CHH), 3.82-3.89
(1H, m, CHH), 4.53-4.60 (1H, m, CH); 13C NMR (75 MHz, CDCl3) δ = 0.17 (CH3), 19.7 (CH2), 19.8 (CH2), 22.6
(2 CH2), 22.8 (CH3), 25.6 (CH2), 28.1 (CH2), 29.6 (CH2), 30.9 (CH2), 34.7, 34.8 (CH2), 54.6 (CH), 56.1 (C), 62.4,
62.5 (CH2), 67.4 (CH2), 88.4 (C), 98.9 (CH), 99.0 (CH), 102.8 (CH); LRMS (EI) m/z 401 (M+, 0.02%), 261 (18),
213 (13), 85 (100), 73 (15), 57 (18); HRMS (ESI-TOF) Calcd for C16H31NO3SSi [M+ − C4H8] 345.1794, found
345.1795.
General Procedure for the Desilylation of Compounds 2. Synthesis of Terminal Alkynes 3: A suspension of
K2CO3 (40 mg, 0.24 mmol) in methanol (15.0 mL) was added dropwise to a solution of the corresponding
silylated homopropargyl amine derivative 2 (0.5 mmol) in THF (15.0 mL). The reaction mixture was stirred for
15 h at 23 ºC, and then it was hydrolyzed with a 1 N NH4Cl aqueous solution (5.0 mL), and extracted with methyl
tert-butyl ether (3 × 15 mL). The organic phase was dried with anhydrous MgSO4 and the solvent evaporated (15
Torr). The residue was purified by column chromatography (silica gel, hexane/EtOAc, 2:1) to yield products 3.
Yields are given in Scheme 3. Compounds 3a,[16] 3b[12g] and 3c[12g] were characterized by comparison of their
physical and spectroscopic data with those reported in the literature. The corresponding physical,
spectroscopic, and analytical data for new compounds 3d and 3e follow.
(4R,RS)-N-(tert-Butanesulfinyl)tridec-1-yn-4-amine (3d): Yellow oil; RF 0.14 (hexane/EtOAc 4:1); [α]20D –17.5
1
(c 0.99, CH2Cl2); IR (film) ν 3316, 3212, 2238, 2117, 1465, 1363, 1055, 909, 731 cm–1; H NMR (300 MHz,
CDCl3) δ = 0.84-0.91 (3H, m, CH3), 1.23 [9H, s, C(CH3)3], 1.26 (14H, s, 7 x CH2), 1.54-1.65 (2H, m, CH2), 2.06
(1H, t, J = 2.6 Hz, CCH), 2.48 (1H, ddd, J = 16.6, 4.5, 2.6 Hz, CHH), 2.65 (1H, ddd, J = 16.7, 5.6, 2.6 Hz, CHH),
3.28-3.40 (1H, m, NCH), 3.49 (1H, d, J = 8.4 Hz, NH); 13C NMR (75 MHz, CDCl3) δ = 14.2 (CH3), 22.7 (CH2),
22.8 (CH3), 25.8 (CH2), 26.8 (CH2), 29.4 (2 CH2), 29.6 (2 CH2), 32.0 (CH2), 34.9 (CH2), 54.9 (CH), 56.1 (C),
71.6 (CH), 80.3 (C); LRMS (EI) m/z 299 (M+, 0.29%), 243 (10), 204 (31), 203 (100), 188 (11), 156 (52), 154
(12), 116 (39), 70 (18), 57 (74), 43 (19), 41 (27); HRMS (ESI-TOF) Calcd for C13H25NOS [M+ − C4H8]
243.1657, found 243.1661.
(4R,RS)-N-(tert-Butanesulfinyl)-8-[(tetrahydro-2H-pyran-2-yl)oxy]oct-1-yn-4-amine (3e): Yellow oil (1:1
mixture of diastereoisomers); RF 0.27 (hexane/EtOAc 1:1); IR (film) ν 2940, 2867, 1363, 1058, 1030, 730 cm–1;
1H NMR (400 MHz, CDCl3) δ = 1.23 [9H, s, C(CH3)3], 1.36-1.85 (12H, m, 6 x CH2), 2.06 (1H, t, J = 2.6 Hz,
CCH), 2.50 (1H, ddd, J = 16.7, 4.4, 2.6 Hz, CHH), 2.67 (1H, dd, J = 16.7, 5.7, 2.7 Hz, CHH), 3.34-3.41 (2H, m,
NCH + CHH), 3.47-3.53 (2H, m, NH + CHH), 3.71-3.87 (1H, m, CHH), 3.83-3.88 (1H, m, CHH), 4.55-4.59 (1H,
m, CH); 13C NMR (100 MHz, CDCl3) δ = 19.7 (CH2), 19.8 (CH2), 22.6 (CH2), 22.7 (CH2), 22.8 (CH3), 25.6
(CH2), 26.8 (CH2), 29.5 (2 CH2,), 30.8 (CH2), 34.7 (CH2), 34.8 (CH2), 54.9 (CH), 56.1 (C), 62.4 (2 CH2), 67.4
(CH2), 71.7 (CH), 80.2 (C), 98.9 (CH), 99.0 (CH); LRMS (EI) m/z 329 (M+, 0.01%), 189 (26), 85 (100), 84 (12),
57 (21); HRMS (ESI-TOF) Calcd for C13H23NO3S [M+ − C4H8] 273.1399, found 273.1393.
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General Procedure for the N-Propargylation of Compounds 3 and 13a. Synthesis of Diynes 4 and Enyne
14a: To a solution of the corresponding homopropargylamine derivative 3 or the homoallylamine derivatives 13a
or ent-13a (1.1 mmol) in dry THF (10.0 mL) was added dropwise n-BuLi (2.5 M in hexane, 1.4 mL, 3.3 mmol)
at –78 ºC. After 20 min, HMPA (0.60 g, 0.42 mL, 3.3 mmol) was also added, and the resulting solution was
stirred for 10 min, followed by addition of propargyl bromide (80 wt% in PhCH3, 0.84 g, 0.57 mL, 5.5 mmol).
The reaction mixture was stirred at –78 oC for 1 h, and then was allowed to reach room temperature for 15 h. The
reaction mixture was hydrolyzed with saturated aq. NH4Cl (5 mL) and extracted with EtOAc (3 x 15 mL). The
organic phase was dried with anhydrous MgSO4 and the solvent was evaporated (15 Torr). The residue was
purified by column chromatography (silica gel, hexane/EtOAc) to yield products 4, 14a and ent-14a. Yields are
given in Schemes 4 and 7. Physical, spectroscopic, and analytical data follow.
(3R,RS)-N-(tert-Butanesulfinyl)-N-(2-propyl)-1-phenylhex-5-yn-3-amine (4a): Brown oil; RF 0.32
(hexane/EtOAc 4:1); [α]20D +97.1 (c 0.90, CH2Cl2); IR (film) ν 3297, 3225, 3025, 2952, 2916, 2861, 2117, 1600,
1
1454, 1066, 843, 699 cm–1; H NMR (300 MHz, CDCl3) δ = 1.28 [9H, s, C(CH3)3], 2.07 (1H, t, J = 2.7 Hz,
CCH), 2.14-2.23 (2H, m, CH2), 2.26 (1H, t, J = 2.5 Hz, CCH), 2.49-2.55 (2H, m, CH2), 2.62-2.72 (1H, m, CHH),
2.93-3.06 (1H, m, CHH), 3.34 (1H, dd, J = 19.0, 2.4 Hz, CHH), 3.43-3.55 (1H, m, NCH), 4.18 (1H, dd, J = 19.0,
2.6 Hz, CHH), 7.19-7.32 (5H, m, ArH); 13C NMR (100 MHz, CDCl3) δ = 23.5 (CH3), 24.1 (CH2), 28.9 (CH2),
33.3 (CH2), 34.3 (CH2), 58.9 (C), 63.4 (CH), 71.4 (CH), 71.9 (CH), 80.9 (C), 81.6 (C), 126.1 (CH), 128.4 (CH),
128.5 (CH), 141.6 (C); LRMS (EI) m/z 315 (M+, 0.08%), 259 (30), 220 (22), 219 (51), 172 (28), 154 (35), 129
(13), 118 (11), 117 (82), 115 (10), 91 (100), 57 (37), 41 (14); HRMS (ESI-TOF) Calcd for C15H17NOS [M+ - C4-
H8] 259.1031, found 259.1045.
(1S,RS)-N-(tert-Butanesulfinyl)-N-(2-propyl)-1-phenylbut-3-yn-1-amine (4b): Brown wax; RF 0.35
(hexane/EtOAc 4:1); [α]20D +14.6 (c 1.02, CH2Cl2); IR (film) ν 3297, 3231, 2952, 2922, 2861, 2117, 1455, 1068,
725 cm–1; 1H NMR (400 MHz, CDCl3) δ = 1.29 [9H, s, C(CH3)3], 1.96 (1H, t, J = 2.6 Hz, CCH), 2.21 (1H, t, J =
2.5 Hz, CCH), 2.88-3.06 (2H, m, CH2), 3.16 (1H, dd, J = 18.7, 2.4 Hz, CHH), 4.00 (1H, dd, J = 18.7, 2.6 Hz,
CHH), 4.62 (1H, dd, J = 9.3, 6.1 Hz, NCH), 7.32-7.48 (5H, m, ArH); 13C NMR (100 MHz, CDCl3) δ = 23.7
(CH3), 24.8 (CH2), 32.3 (CH2), 59.1 (C), 64.1 (CH), 71.2 (CH), 72.4 (CH), 80.4 (C), 80.8 (C), 128.4 (CH), 128.5
(CH), 128.7 (CH), 137.8 (C); LRMS (EI) m/z 287 (M+, 0.37%), 231 (16), 192 (23), 191 (50), 152 (16), 149 (13),
144 (27), 130 (13), 129 (100), 128 (62), 127 (26), 115 (17), 104 (14), 91 (12), 77 (16), 57 (44), 55 (10), 43 (38),
41 (18); HRMS (ESI-TOF) Calcd for C13H13NOS [M+ − C4H8] 231.0718, found 231.0723.
(1R,SS)-N-(tert-Butanesulfinyl)-N-(2-propyl)-1-phenylbut-3-yn-1-amine (ent-4b): Physical and spectroscopic
data were found to be same than for 4b. [α]D20 = −17.8 (c = 1.01, CH2Cl2).
(4R,RS)-N-(tert-Butanesulfinyl)-N-(2-propyl)-2-methylhept-6-yn-4-amine (4c): Brown oil; RF 0.46
(hexane/EtOAc 4:1); [α]20D +102.2 (c 1.05, CH2Cl2); IR (film) ν 3310, 3225, 2956, 2864, 2117, 1363, 1070, 897,
1
828, 729 cm–1; H NMR (300 MHz, CDCl3) δ = 0.93 (3H, d, J = 6.6 Hz, CH3), 0.94 (3H, d, J = 6.6 Hz, CH3),
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1.27 [9H, s, C(CH3)3], 1.72-1.85 (2H, m, CH2), 1.87-1.98 (1H, m, CH), 2.07 (1H, t, J = 2.7 Hz, CCH), 2.22 (1H,
t, J = 2.5 Hz, CCH), 2.44-2.50 (2H, m, CH2), 3.28 (1H, dd, J = 19.0, 2.4 Hz, CHH), 3.45-3.59 (1H, m, NCH),
4.12 (1H, dd, J = 19.0, 2.5 Hz, CHH); 13C NMR (75 MHz, CDCl3) δ = 22.1 (CH3), 22.8 (CH3), 23.4 (CH3), 24.0
(CH2), 24.6 (CH), 28.4 (CH2), 41.6 (CH2), 58.7 (C), 61.5 (CH), 71.2 (CH), 71.6 (CH), 81.2 (C), 81.6 (C); LRMS
(EI) m/z 267 (M+, 0.74%), 211 (14), 172 (56), 171 (82), 154 (24), 149 (14), 129 (17), 128 (10), 124 (30), 73 (16),
69 (18), 57 (47), 43 (100), 41 (28); HRMS (ESI-TOF) Calcd for C15H25NOS [M+] 267.1657, found 267.1653.
(4R,RS)-N-(tert-Butanesulfinyl)-N-(2-propyl)tridec-1-yn-4-amine (4d): Brown oil; RF 0.53 (hexane/EtOAc
4:1); [α]20D +90.8 (c 1.05, CH2Cl2); IR (film) ν 3310, 3231, 2923, 2855, 2117, 1457, 1362, 1072, 871, 731 cm–1;
1H NMR (400 MHz, CDCl3) δ = 0.85-0.91 (3H, m, CH3), 1.26 [25H, s, 7 x CH2 + C(CH3)3], 1.79-1.87 (2H, m,
CH2), 2.06 (1H, t, J = 2.7 Hz, CCH), 2.21 (1H, t, J = 2.5 Hz, CCH), 2.46-2.49 (2H, m, CH2), 3.31 (1H, dd, J =
18.9, 2.4 Hz, CHH), 3.37-3.44 (1H, m, NCH), 4.13 (1H, dd, J = 18.9, 2.6 Hz, CHH); 13C NMR (100 MHz,
CDCl3) δ = 14.2 (CH3), 22.8 (CH2), 23.5 (CH3), 24.0 (CH2), 27.0 (CH2), 29.1 (CH2), 29.4 (CH2), 29.5 (CH2), 29.6
(CH2), 29.7 (CH2), 32.0 (CH2), 32.6 (CH2), 58.8 (C), 63.5 (CH), 71.1 (CH), 71.6 (CH), 81.3 (C), 81.6 (C); LRMS
(EI) m/z 337 (M+, 0.07%), 281 (7), 243 (13), 242 (63), 241 (100), 154 (35), 57 (22), 41 (13); HRMS (ESI-TOF)
Calcd for C11H16NOS [M+ − C9H19] 210.0953, found 210.0947.
(4R)-N-(tert-Butanesulfinyl)-N-(2-propyl)-8-[(tetrahydro-2H-pyran-2-yl)oxy]oct-1-yn-4-amine (4e): Brown
oil (1:1 mixture of diastereoisomers); RF 0.20 (hexane/EtOAc 4:1); IR (film) ν 3303, 2943, 2866, 1266, 1120,
1073, 1030, 734 cm–1; 1H NMR (400 MHz, CDCl3) δ = 1.26 [9H, s, C(CH3)3], 1.45-1.64 (10H, m, 5 x CH2), 1.81-
1.91 (2H, m, CH2), 2.06 (1H, t, J = 2.7 Hz, CCH), 2.22 (1H, t, J = 2.5 Hz, CCH), 2.47-2.50 (2H, m, CH2), 3.31
(1H, dd, J = 18.9, 2.4 Hz, CHH), 3.35-3.46 (2H, m, NCH + CHH), 3.46-3.54 (1H, m, CHH), 3.71-3.79 (1H, m,
CHH), 3.81-3.89 (1H, m, CHH), 4.13 (1H, dd, J = 18.9, 2.6 Hz, CHH), 4.57-4.59 (1H, m, CH); 13C NMR (100
MHz, CDCl3) δ = 19.7 (CH2), 23.5 (CH3), 23.8 (2 CH2), 24.0 (2 CH2), 25.6 (CH2), 28.9 (CH2), 29.7 (CH2), 30.9
(CH2), 32.4 (CH2), 58.9 (C), 62.4 (CH2), 63.5 (C), 67.4 (CH2), 67.5 (CH2), 71.2 (CH), 71.7 (CH), 81.1 (C), 81.4
(C), 98.9 (CH), 99.0 (CH); LRMS (EI) m/z 367 (M+, 0.01%), 227 (41), 122 (10), 85 (100), 57 (19); HRMS (ESI-
TOF) Calcd for C11H16NOS [M+ − C9H17O2] 210.0953, found 210.0962.
(3R,RS)-N-(tert-Butanesulfinyl)-N-(2-propyl)-1-phenylhex-5-en-3-amine (14a): C19H27NOS; Orange wax; RF
0.47 (hexane/EtOAc 4:1); [α]20D +104.9 (c 1.08, CH2Cl2); IR (film) ν 3304, 3219, 3025, 2928, 2861, 1639, 1454,
1
1361, 1068, 915, 699 cm–1; H NMR (400 MHz, CDCl3) δ = 1.28 [9H, s, C(CH3)3], 1.88-1.97 (1H, m, CHH),
2.05-2.14 (1H, m, CHH), 2.26 (1H, t, J = 2.5 Hz, CCH), 2.29-2.35 (1H, m, CHH), 2.40-2.47 (1H, m, CHH), 2.60
(1H, ddd, J = 13.6, 10.7, 5.4 Hz, CHH), 3.03 (1H, ddd, J = 13.6, 10.9, 5.5 Hz, CHH), 3.23 (1H, dd, J = 19.0, 2.4
Hz, CHH), 3.30-3.36 (1H, m, NCH), 4.18 (1H, dd, J = 19.0, 2.6 Hz, CHH), 5.04-5.14 (2H, m, CH2), 5.72-5.86
(1H, m, CH), 7.14-7.28 (3H, m, ArH), 7.23-7.32 (2H, m, ArH); 13C NMR (100 MHz, CDCl3) δ = 23.6 (CH3),
28.2 (CH2), 33.6 (CH2), 34.9 (CH2), 38.2 (CH2), 58.9 (C), 65.3 (CH), 71.6 (CH), 82.1 (C), 117.8 (CH2), 126.0
(CH), 128.4 (CH), 128.5 (CH), 134.9 (CH), 142.0 (C); LRMS (EI) m/z 317 (M+, 0.33%), 261 (32), 220 (58), 219
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(26), 172 (10), 117 (92), 91 (100), 57 (27), 41 (14); HRMS (ESI-TOF) Calcd for C15H19NOS [M+ − C4H8]
261.1187, found 261.1191.
(3S,SS)-N-(tert-Butanesulfinyl)-N-(2-propyl)-1-phenylhex-5-en-3-amine (ent-14a): Physical and spectroscopic
data were found to be same than for 14a. [α]D20 = −70.0 (c = 1.18, CH2Cl2).
Synthesis of Enamine Derivative 8a by N-Allylation of 3a: To a solution of homopropargylamine derivative 3a
(304,7 mg, 1.1 mmol) in dry THF (10.0 mL) was added dropwise n-BuLi (2.5 M in hexane, 1.4 mL, 3.3 mmol) at
–78 ºC. After 20 min, HMPA (0.60 g, 0.42 mL, 3.3 mmol) was also added, and the resulting solution was stirred
for 10 min, followed by addition of allyl bromide (0.66 g, 0.48 mL, 5.5 mmol). The reaction mixture was stirred
o
at –78 C for 1 h, and then was allowed to reach room temperature for 15 h. The reaction mixture was
hydrolyzed with saturated aq. solution of NH4Cl (5 mL) and extracted with EtOAc (3 x 15 mL). The organic
phase was dried with anhydrous MgSO4 and the solvent was evaporated (15 Torr). Purification by column
chromatography (silica gel, hexane/EtOAc) yielded 8a (160.4 mg, 0.50 mmol, 46%). Physical, spectroscopic,
and analytical data follow.
(3R,RS)-N-(tert-Butanesulfinyl)-N-(2-propenyl)-1-phenylhex-5-yn-3-amine (8a): Orange wax; RF 0.40
(hexane/EtOAc 4:1); [α]20 +40.6 (c 1.05, CH2Cl2); IR (film) ν 3297, 3219, 3025, 2916, 2117, 1455, 1066, 920,
D
1
699 cm–1; H NMR (300 MHz, CDCl3) δ = 1.23 [9H, s, C(CH3)3], 1.83-1.98 (1H, m, CHH), 2.03 (1H, t, J = 2.7
Hz, CCH), 2.09-2.23 (1H, m, CHH), 2.45-2.86 (4H, m, 2 x CH2), 3.16-3.33 (2H, m, CHH + NCH), 3.98-4.09
(1H, m, CHH), 5.08-5.27 (2H, m, CH2), 5.77-5.93 (1H, m, CH), 7.18-7.21 (3H, m, ArH), 7.27-7.33 (2H, m,
ArH); 13C NMR (100 MHz, CDCl3) δ = 23.6 (CH2), 23.8 (CH3), 32.9 (CH2), 34.9 (CH2), 45.4 (CH2), 58.3 (C),
61.1 (CH), 70.6 (CH), 81.9 (C), 118.0 (CH2), 126.1 (CH), 128.4 (CH), 128.5 (CH), 135.7 (CH), 141.4 (C);
LRMS (EI) m/z 317 (M+, 0.07%), 261 (32), 222 (47), 221 (66), 174 (23), 157 (11), 156 (36), 117 (80), 91 (100),
57 (30), 41 (26); HRMS (ESI-TOF) Calcd for C15H19NOS [M+ − C4H8] 261.1187, found 261.1191.
General Procedure for the Selective S-Oxydation of Compounds 4, 8a and 14. Synthesis of Sulfonamides 5,
9a and 15a: To a solution of the corresponding sulfinyl imine 4, 8a or 14a (0.5 mmol) in CH2Cl2 (7 mL) was
o
added at 0 ºC mCPBA (0.14 g, 0.75 mmol) in portions every 5 min. The reaction was stirred at 0 C for 20
additional min, and after that, was allowed to warm to 23 oC for 1 h. A diluted aq. solution of Na2S2O3 (3.0 mL)
was added, followed by the addition of a saturated aq. solution of NaHCO3 (3.0 mL). The mixture was stirred at
o
23 C for 1 h, and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried with
anhydrous MgSO4 and the solvent was evaporated (15 Torr). The residue was purified by column
chromatography (silica gel, hexane/EtOAc) to yield products 5, 9a and 15a. Yields are given in Schemes 4, 5 and
7. Physical, spectroscopic, and analytical data follow.
o
(3R)-N-(tert-Butanesulfonyl)-N-(2-propyl)-1-phenylhex-5-yn-3-amine (5a): Orange solid; mp 102-103 C
(hexane/ CH2Cl2); RF 0.51 (hexane/EtOAc 5:1); [α]20D –0.8 (c 1.03, CH2Cl2); IR (film) ν 3291, 3267, 2983, 2916,
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10.1002/ejoc.201901590
European Journal of Organic Chemistry
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1
2124, 1361, 1312, 1127, 996, 889, 684 cm–1; H NMR (300 MHz, CDCl3) δ = 1.43 [9H, s, C(CH3)3], 2.10-2.20
(2H, m, CCH + CHH), 2.24-2.35 (2H, m, CCH + CHH), 2.71-2.78 (4H, m, 2 x CH2), 3.99-4.04 (1H, m, NCH),
13
4.20-4.32 (2H, m, CH2), 7.17-7.32 (5H, m, ArH); C NMR (75 MHz, CDCl3) δ = 24.6 (CH2), 24.7 (CH3), 33.3
(CH2), 33.6 (CH2), 34.7 (CH2), 58.5 (C), 62.0 (CH), 71.9 (CH), 72.9 (CH), 81.0 (C), 81.2 (C), 126.2 (CH), 128.4
(CH), 128.6 (CH), 141.3 (C); LRMS (EI) m/z 331 (M+, 0.03%), 292 (13), 173 (13), 172 (100), 106 (11), 91 (24),
57 (23); HRMS (ESI-TOF) Calcd for C19H25NO2S [M+] 331.1606, found 331.1614.
(1S)-N-(tert-Butanesulfonyl)-N-(2-propyl)-1-phenylbut-3-yn-1-amine (5b): Yellow solid; mp 72-74 oC
(hexane/ CH2Cl2); RF 0.54 (hexane/EtOAc 5:1); [α]20 +14.2 (c 0.96, CH2Cl2); IR (film) ν 3304, 3279, 2987,
D
1978, 1478, 1300, 1132, 1016, 774, 702 cm–1; 1H NMR (400 MHz, CDCl3) δ = 1.49 (9H, s, C(CH3)3), 1.98 (1H, t,
J = 2.7 Hz, CCH), 2.29 (1H, t, J = 2.5 Hz, CCH), 3.04-3.12 (1H, m, CHH), 3.46 (1H, ddd, J = 17.0, 10.7, 2.6 Hz,
CHH), 3.57 (1H, d, J = 19.0 Hz, CHH), 4.17 (1H, d, J = 18.3 Hz, CHH), 5.34 (1H, dd, J = 10.7, 4.8 Hz, NCH),
7.32-7.34 (1H, m, ArH), 7.38-7.43 (2H, m, ArH), 7.55-7.60 (2H, m, ArH); 13C NMR (100 MHz, CDCl3) δ = 23.3
(CH2), 24.9 (CH3), 34.4 (CH2), 61.4 (CH), 62.2 (C), 71.6 (CH), 73.1 (CH), 81.0 (C), 81.1 (C), 128.5 (CH), 128.8
(2 CH), 136.6 (C); LRMS (EI) m/z 303 (M+, 0.04%), 264 (15), 145 (12), 144 (100), 57 (27), 43 (28); HRMS
(ESI-TOF) Calcd for C17H21NO2S [M+] 303.1293, found 303.1288.
(1R)-N-(tert-Butanesulfonyl)-N-(2-propyl)-1-phenylbut-3-yn-1-amine (ent-5b): Physical and spectroscopic
data were found to be same than for 5b. [α]D20 = −17.9 (c = 0.97, CH2Cl2).
(4R)-N-(tert-Butanesulfonyl)-N-(2-propyl)-2-methylhept-6-yn-4-amine (5c): Yellow oil; RF 0.58
(hexane/EtOAc 5:1); [α]20 +3.8 (c 0.96, CH2Cl2); IR (film) ν 3289, 2956, 2932, 2871, 2117, 1715, 1315, 1158,
D
1
1053, 847 cm–1; H NMR (300 MHz, CDCl3) δ = 0.95 (3H, d, J = 6.2 Hz, CH3), 0.97 (3H, d, J = 6.2 Hz, CH3),
1.45 [9H, s, C(CH3)3], 1.70-1.75 (2H, m, CH2), 1.77-1.83 (1H, m, CH), 2.09 (1H, t, J = 2.7 Hz, CCH), 2.29 (1H,
t, J = 2.5 Hz, CCH), 2.59-2.71 (2H, m, CH2), 3.99-4.07 (1H, m, NCH), 4.13-4.26 (2H, m, CH2); 13C NMR (75
MHz, CDCl3) δ = 22.4 (CH3), 22.9 (CH3), 24.7 (CH2), 24.8 (CH3), 24.9 (CH), 33.7 (CH2), 41.9 (CH2), 56.7 (CH),
61.9 (C), 71.6 (CH), 72.6 (CH), 81.3 (2 C); LRMS (EI) m/z 283 (M+, 0.15%), 244 (10), 144 (19), 125 (10), 124
(100), 106 (12), 70 (13), 61 (13), 57 (42), 45 (12), 43 (82), 41 (16); HRMS (ESI-TOF) Calcd for C15H25NO2S
[M+] 283.1606, found 283.1602.
(4R)-N-(tert-Butanesulfonyl)-N-(2-propyl)tridec-1-yn-4-amine (5d): Yellow oil; RF 0.67 (hexane/EtOAc 5:1);
[α]20D +6.1 (c 1.02, CH2Cl2); IR (film) ν 3307, 2925, 2853, 2120, 1457, 1317, 1140, 880, 732 cm–1; 1H NMR (400
MHz, CDCl3) δ = 0.83-0.92 (3H, m, CH3), 1.26 (14H, s, 7 x CH2), 1.44 [9H, s, C(CH3)3], 1.72-2.01 (2H, m, CH2),
2.08 (1H, t, J = 2.7 Hz, CCH), 2.28 (1H, t, J = 2.5 Hz, CCH), 2.62-2.74 (2H, m, CH2), 3.89-3.60 (1H, m, NCH),
4.09 (1H, d, J = 19.2 Hz, CHH), 4.23 (1H, dd, J = 18.9, 2.5 Hz, CHH); 13C NMR (100 MHz, CDCl3) δ = 14.2
(CH3), 22.8 (CH2), 24.7 (CH2), 24.8 (CH3), 27.0 (CH2), 29.4 (CH2), 29.6 (2 CH2), 29.7 (CH2), 32.0 (CH2), 32.9
(CH2), 33.5 (CH2), 58.9 (CH), 62.0 (C), 71.5 (CH), 72.6 (CH), 81.2 (C), 81.4 (C); LRMS (EI) m/z 353 (M+,
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10.1002/ejoc.201901590
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0.01%), 258 (15), 195 (35), 194 (100), 106 (21), 57 (37); HRMS (ESI-TOF) Calcd for C20H35NO2S [M+]
353.2389, found 353.2372.
(4R)-N-(tert-Butanesulfonyl)-N-(2-propyl)-8-[(tetrahydro-2H-pyran-2-yl)oxy]oct-1-yn-4-amine (5e): Brown
oil (1:1 mixture of diastereoisomers); RF 0.31 (hexane/EtOAc 5:1); IR (film) ν 3269, 2940, 2869, 1316, 1122,
1031, 881 cm–1; 1H NMR (400 MHz, CDCl3) δ = 1.44 [9H, s, C(CH3)3], 1.50-1.90 (12H, m, 6 x CH2), 2.08 (1H, t,
J = 2.7 Hz, CCH), 2.29 (1H, t, J = 2.5 Hz, CCH), 2.61-2.79 (2H, m, CH2), 3.37-3.43 (1H, m, NCH), 3.46-3.55
(1H, m, CHH), 3.70-3.82 (1H, m, CHH), 3.84-3.88 (1H, m, CHH), 3.89-3.96 (1H, m, CHH), 4.08-4.13 (1H, m,
13
CHH), 4.23 (1H, dd, J = 19.0, 2.5 Hz, CHH), 4.55-4.58 (1H, m, CH); C NMR (100 MHz, CDCl3) δ = 19.8 (2
CH2), 24.7 (CH2), 24.8 (CH3), 29.6 (2 CH2), 30.9 (CH2), 32.6 (CH2), 33.5 (CH2), 58.9 (CH), 62.0 (C), 62.4 (2
CH2), 67.3 (CH2), 71.4 (CH), 72.6 (CH), 81.2 (C), 81.3 (C), 98.9 (CH), 99.0 (CH); LRMS (EI) m/z 383 (M+,
0.01%), 260 (41), 224 (11), 178 (11), 140 (100), 122 (22), 106 (26), 85 (94), 57 (51), 56 (11), 43 (11), 41 (17);
HRMS (ESI-TOF) Calcd for C16H24NO4S [M+ − C4H9] 326.1426, found 326.1422.
(3R)-N-(tert-Butanesulfonyl)-N-(2-propenyl)-1-phenylhex-5-yn-3-amine (9a): White solid; mp 63-64 oC
(hexane/ CH2Cl2); RF 0.54 (hexane/EtOAc 5:1); [α]20D –3.1 (c 0.40, CH2Cl2); IR (film) ν 3265, 2975, 2861, 2117,
1
1602, 1452, 1310, 1125, 989, 891, 737, 699 cm–1; H NMR (300 MHz, CDCl3) δ = 1.41 (9H, s, C(CH3)3), 2.02-
2.10 (2H, m, CH2), 2.10 (1H, t, J = 2.7 Hz, CCH), 2.60-2.64 (2H, m, CH2), 2.68-2.74 (2H, m, CH2), 3.90-4.00
(3H, m, CH2 + NCH), 5.08-5.25 (2H, m, CH2), 5.93-6.10 (1H, m, CH), 7.15-7.23 (3H, m, ArH), 7.25-7.33 (2H,
m, ArH); 13C NMR (75 MHz, CDCl3) δ = 24.7 (CH2), 25.0 (CH3), 33.5 (CH2), 36.6 (CH2), 48.7 (CH2), 58.7 (CH),
62.2 (CH), 71.6 (CH), 81.4 (C), 117.4 (CH2), 126.2 (CH), 128.4 (CH), 128.6 (CH), 137.8 (CH), 141.4 (C);
LRMS (EI) m/z 333 (M+, 0.01%), 294 (17), 238 (19), 175 (13), 174 (100), 108 (12), 91 (21), 57 (27); HRMS
(ESI-TOF) Calcd for C16H24NO2S [M+ – C3H3] 294.1528, found 294.1537.
(3R)-N-(tert-Butanesulfonyl)-N-(2-propyl)-1-phenylhex-5-en-3-amine (15a): Orange solid; mp 61-63 oC
(hexane/ CH2Cl2); RF 0.62 (hexane/EtOAc 5:1); [α]20D –4.5 (c 1.05, CH2Cl2); IR (film) ν 3262, 2987, 2930, 2117,
1
1639, 1312, 1124, 1051, 884, 700 cm–1; H NMR (400 MHz, CDCl3) δ = 1.43 [9H, s, C(CH3)3], 1.98-2.05 (2H,
m, CH2), 2.29 (1H, t, J = 2.5 Hz, CCH), 2.45-2.62 (2H, m, CH2), 2.62-2.73 (1H, m, CHH), 2.75-2.85 (1H, m,
CHH), 3.86-3.96 (1H, m, NCH), 4.05-4.20 (2H, m, CH2), 5.06-5.15 (2H, m, CH2), 5.77-5.90 (1H, m, CH), 7.16-
7.21 (3H, m, ArH), 7.26-7.30 (2H, m, ArH); 13C NMR (100 MHz, CDCl3) δ = 24.8 (CH3), 33.2 (CH2), 33.6
(CH2), 35.2 (CH2), 39.3 (CH2), 60.0 (CH), 61.8 (C), 72.6 (CH), 81.4 (C), 117.8 (CH2), 126.1 (CH), 128.4 (CH),
128.5 (CH), 135.1 (CH), 141.8 (C); LRMS (EI) m/z 333 (M+, 0.01%), 292 (11), 173 (13), 172 (100), 108 (11), 91
(23), 57 (21); HRMS (ESI-TOF) Calcd for C19H27NO2S [M+] 333.1762, found 333.1765.
(3S)-N-(tert-Butanesulfonyl)-N-(2-propyl)-1-phenylhex-5-en-3-amine (ent-15a): Physical and spectroscopic
data were found to be same than for 15a. [α]D20 = +3.1 (c = 1.12, CH2Cl2).
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10.1002/ejoc.201901590
European Journal of Organic Chemistry
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General Procedure for the Cyclotrimerization of Diynes 5 and Alkynes 6a, 6c and 6d. Synthesis of
Tetrahydroisoquinolines 7: To a solution of the corresponding diyne 5 (0.1 mmol) in degasified and dry toluene
(10.0 mL) was added Wilkinson’s catalyst (4.6 mg, 0.005 mmol) and the corresponding alkyne 6a, 6c or 6d (1.0
o
mmol). The reaction mixture was stirred at 100 C for 17 h. Then the solvent was evaporated (15 Torr). The
residue was purified by column chromatography (silica gel, hexane/EtOAc) to yield products 7. Yields are given
in Table 2. Physical, spectroscopic, and analytical data follow.
(3R)-2-(tert-Butanesulfonyl)-6,7-diethyl-3-phenethyl-1,2,3,4-tetrahydroisoquinoline (7a): Yellow wax; RF
0.55 (hexane/EtOAc 6:1); [α]20 +0.7 (c 0.58, CH2Cl2); IR (film) ν 3055, 2970, 2874, 2856, 1452, 1311, 1265,
D
1
1128, 734, 701 cm–1; H NMR (300 MHz, CDCl3) δ = 1.20 (3H, t, J = 7.5 Hz, CH3), 1.21 (3H, t, J = 7.5 Hz,
CH3), 1.35 [9H, s, C(CH3)3], 1.67-2.15 (2H, m, CH2), 2.60 (4H, q, J = 7.6 Hz, 2 x CH2), 2.65-2.76 (3H, m, CHH
+ CH2), 3.23 (1H, dd, J = 16.9, 6.0 Hz, CHH), 4.16-4.22 (1H, m, NCH), 4.35 (1H, d, J = 16.9 Hz, CHH), 4.61
(1H, d, J = 16.9 Hz, CHH), 6.83 (1H, s, ArH), 6.90 (1H, s, ArH), 7.14-7.17 (3H, m, ArH), 7.21-7.25 (2H, m,
ArH); 13C NMR (75 MHz, CDCl3) δ = 15.3 (2 CH3), 24.6 (CH3), 25.2 (2 CH2), 29.8 (CH2), 33.2 (CH2), 33.6
(CH2), 44.4 (CH2), 53.2 (CH), 61.4 (C), 125.6 (CH), 126.0 (CH), 128.5 (2 CH), 129.2 (C), 129.3 (C), 129.6 (CH),
139.9 (C), 140.6 (C), 141.7 (C); LRMS (EI) m/z 413 (M+, 1.71%), 356 (11), 292 (39), 252 (12), 189 (14), 188
(100), 187 (14), 186 (18), 160 (19), 57 (17); HRMS (ESI-TOF) Calcd for C25H35NO2S [M+] 413.2389, found
413.2409.
Dimethyl (3R)-2-(tert-butanesulfonyl)-3-phenethyl-1,2,3,4-tetrahydroisoquinoline-6,7-dicarboxylate (7c):
o
Yellow solid; mp 38-39 C (hexane/ CH2Cl2); RF 0.33 (hexane/EtOAc 3:1); [α]20 +11.4 (c 0.90, CH2Cl2); IR
D
1
(film) ν 3061, 2922, 2850, 1725, 1310, 1266, 1126, 1058, 734, 700 cm–1; H NMR (300 MHz, CDCl3) δ = 1.35
[9H, s, C(CH3)3], 1.66-2.00 (2H, m, CH2), 2.63-2.76 (2H, m, CH2), 2.81 (1H, d, J = 17.2 Hz, CHH), 3.30 (1H, dd,
J = 17.0, 6.1 Hz, CHH), 3.90 (3H, s, CH3), 3.90 (3H, s, CH3), 4.20-4.27 (1H, m, NCH), 4.38 (1H, d, J = 17.8 Hz,
CHH), 4.74 (1H, d, J = 17.9 Hz, CHH), 7.09-7.21 (3H, m, ArH), 7.23-7.26 (2H, m, ArH), 7.46 (1H, s, ArH), 7.50
(1H, s, ArH); 13C NMR (100 MHz, CDCl3) δ = 24.6 (CH3), 29.8 (CH2), 32.8 (CH2), 33.1 (CH2), 33.7 (CH2), 44.3
(CH2), 52.6 (CH), 52.8 (CH3), 61.7 (C), 126.3 (CH), 126.9 (CH), 128.4 (2 CH), 128.7 (2 CH), 130.0 (C), 130.8
(CH), 130.9 (C), 135.5 (C), 136.1 (C), 141.0 (C), 167.7 (C), 167.9 (C); LRMS (EI) m/z 473 (M+, 0.12%), 353
(15), 352 (52), 321 (12), 249 (15), 248 (100), 246 (11), 235 (11), 217 (10), 216 (46), 189 (22), 91 (10), 57 (32);
HRMS (ESI-TOF) Calcd for C21H22NO6S [M+ − C4H9] 416.1168, found 416.1172.
(3S)-2-(tert-Butanesulfonyl)-6,7-diethyl-3-phenyl-1,2,3,4-tetrahydroisoquinoline (7d): Yellow wax; RF 0.53
(hexane/EtOAc 6:1); 95.5:4.5 er [HPLC (Chiralpak AD-H column, hexane/i-PrOH = 98/2, 1.0 mL/min, 210 nm):
tmajor = 9.09 min, tminor = 16.53 min]; [α]20 +34.6 (c 0.81, CH2Cl2); IR (film) ν 3061, 2965, 2927, 2856, 1724,
D
1452, 1312, 1265, 1128, 948, 735, 700 cm–1; 1H NMR (300 MHz, CDCl3) δ = 1.18-1.25 (6H, m, 2 x CH3), 1.39
[9H, s, C(CH3)3], 2.54-2.68 (4H, m, 2 x CH2), 3.25 (1H, d, J = 16.8 Hz, CHH), 3.51 (1H, dd, J = 16.8, 6.7 Hz,
CHH), 4.06 (1H, d, J = 16.7 Hz, CHH), 4.51 (1H, d, J = 16.7 Hz, CHH), 5.36 (1H, d, J = 6.4 Hz, NCH), 6.76
(1H, s, ArH), 7.02 (1H, s, ArH), 7.21-7.29 (3H, m, ArH), 7.36-7.41 (2H, m, ArH); 13C NMR (100 MHz, CDCl3)
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δ = 15.1 (CH3), 15.2 (CH3), 24.8 (CH3), 25.2 (CH2), 25.3 (CH2), 29.9 (CH2), 32.1 (CH2), 55.4 (CH), 61.7 (C),
125.5 (CH), 127.6 (CH), 127.9 (CH), 128.6 (CH), 129.9 (C), 130.1 (C), 132.4 (CH), 139.5 (C), 140.0 (C), 140.7
(C); LRMS (EI) m/z 385 (M+, 0.92%), 328 (10), 265 (20), 264 (96), 263 (33), 161 (17), 160 (100), 57 (20);
HRMS (ESI-TOF) Calcd for C23H31NO2S [M+] 385.2075, found 385.2083.
(3R)-2-(tert-Butanesulfonyl)-6,7-diethyl-3-phenyl-1,2,3,4-tetrahydroisoquinoline (ent-7d): Physical and
spectroscopic data were found to be same than for 7d. 4.6:95.4 er [HPLC (Chiralpak AD-H column, hexane/i-
PrOH = 98/2, 1.0 mL/min, 210 nm): tminor = 9.24 min, tmajor = 17.05 min]; [α]D20 = −52.0 (c = 0.70, CH2Cl2).
Dimethyl
(3S)-2-(tert-butanesulfonyl)-3-phenyl-1,2,3,4-tetrahydroisoquinoline-6,7-dicarboxylate
(7f):
o
Yellow solid; mp 37-38 C (hexane/ CH2Cl2); RF 0.31 (hexane/EtOAc 3:1); [α]20 +62.2 (c 0.51, CH2Cl2); IR
D
1
(film) ν 3061, 2983, 2952, 2922, 1726, 1433, 1265, 1127, 732, 700 cm–1; H NMR (400 MHz, CDCl3) δ = 1.41
(9H, s, C(CH3)3), 3.40 (1H, d, J = 17.4 Hz, CHH), 3.60 (1H, dd, J = 17.4, 6.7 Hz, CHH), 3.88 (3H, s, CH3), 3.92
(3H, s, CH3), 4.08 (1H, d, J = 17.7 Hz, CHH), 4.62 (1H, d, J = 17.6 Hz, CHH), 5.43 (1H, d, J = 6.4 Hz, NCH),
7.22-7.34 (5H, m, ArH), 7.39 (1H, s, ArH), 7.64 (1H, s, ArH); 13C NMR (100 MHz, CDCl3) δ = 24.8 (CH3), 29.8
(CH2), 45.0 (CH2), 52.8 (CH3), 52.9 (CH3), 55.0 (CH), 62.0 (C), 126.9 (CH), 127.7 (CH), 128.1 (CH), 128.9
(CH), 129.9 (CH), 130.0 (C), 131.0 (C), 136.3 (C), 136.8 (C), 138.2 (C), 167.7 (C), 168.0 (C); LRMS (EI) m/z
445 (M+, 1.54%), 414 (11), 325 (39), 324 (100), 310 (15), 293 (17), 292 (13), 278 (21), 248 (15), 220 (31), 208
(11), 207 (62), 190 (10), 189 (40), 91 (11), 57 (42); HRMS (ESI-TOF) Calcd for C23H27NO6S [M+] 445.1559,
found 445.1571.
(3R)-2-(tert-Butanesulfonyl)-6,7-diethyl-3-(sec-butyl)-1,2,3,4-tetrahydroisoquinoline (7g): Yellow oil; RF
0.63 (hexane/EtOAc 6:1); [α]20 +4.9 (c 0.60, CH2Cl2); IR (film) ν 2960, 2926, 2871, 1730, 1464, 1365, 1315,
D
1129, 1052, 939, 709 cm–1; 1H NMR (400 MHz, CDCl3) δ = 0.92 (3H, d, J = 6.5 Hz, CH3), 0.95 (3H, d, J = 6.6
Hz, CH3), 1.21 (3H, t, J = 7.6 Hz, CH3), 1.22 (3H, t, J = 7.6 Hz, CH3), 1.36 [9H, s, C(CH3)3], 1.42-1.50 (2H, m,
CH2), 1.62-1.68 (1H, m, CH), 2.58-2.64 (5H, m, CHH + 2 x CH2), 3.19 (1H, dd, J = 16.4, 6.1 Hz, CHH), 4.16-
4.21 (1H, m, NCH), 4.30 (1H, d, J = 16.8 Hz, CHH), 4.57 (1H, d, J = 16.8 Hz, CHH), 6.83 (1H, s, ArH), 6.90
(1H, s, ArH); 13C NMR (100 MHz, CDCl3) δ = 15.2 (2 CH3), 22.4 (CH3), 23.4 (CH3), 24.7 (CH3), 25.2 (CH2),
25.2 (CH), 25.25 (CH2), 29.9 (CH2), 40.7 (CH2), 44.3 (CH2), 51.4 (CH), 61.3 (C), 125.5 (CH), 129.4 (C), 129.5
(C), 129.6 (CH), 139.8 (C), 140.5 (C); LRMS (EI) m/z 365 (M+, 0.51%), 308 (18), 252 (15), 244 (29), 189 (15),
188 (100), 186 (31), 160 (24), 57 (23); HRMS (ESI-TOF) Calcd for C17H26NO2S [M+ - C4H9] 308.1684, found
308.1685.
Dimethyl (3R)-2-(tert-butanesulfonyl)-3-(sec-butyl)-1,2,3,4-tetrahydroisoquinoline-6,7-dicarboxylate (7i):
Yellow wax; RF 0.38 (hexane/EtOAc 3:1); [α]20 +17.0 (c 0.90, CH2Cl2); IR (film) ν 3049, 2959, 2928, 2874,
D
1
1728, 1265, 1129, 733, 701 cm–1; H NMR (300 MHz, CDCl3) δ = 0.90-0.96 (6H, m, 2 x CH3), 1.37 (9H, s,
C(CH3)3), 1.54-1.65 (3H, m, CH2 + CH), 2.74 (1H, d, J = 17.0 Hz, CHH), 3.26 (1H, dd, J = 16.9, 6.1 Hz, CHH),
3.90 (3H, s, CH3), 3.90 (3H, s, CH3), 4.20-4.27 (1H, m, NCH), 4.34 (1H, d, J = 17.9 Hz, CHH), 4.72 (1H, d, J =
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17.8 Hz, CHH), 7.45 (1H, s, ArH), 7.50 (1H, s, ArH); 13C NMR (100 MHz, CDCl3) δ = 23.4 (CH3), 24.6 (CH3),
25.1 (CH), 32.7 (CH2), 40.7 (CH2), 44.3 (CH2), 50.9 (CH), 52.9 (2 CH3), 61.6 (C), 126.8 (CH), 129.8 (C), 130.7
(C), 130.8 (CH), 135.8 (C), 136.4 (C), 167.8 (C), 168.1 (C); LRMS (EI) m/z 425 (M+, 0.35%), 368 (19), 304
(15), 262 (20), 249 (15), 248 (100), 246 (11), 216 (46), 189 (17), 187 (10), 57 (34); HRMS (ESI-TOF) Calcd for
C21H31NO6S [M+] 425.1872, found 425.1845.
(3R)-2-(tert-Butanesulfonyl)-6,7-diethyl-3-nonanyl-1,2,3,4-tetrahydroisoquinoline (7j): Colorless oil; RF 0.68
(hexane/EtOAc 6:1); [α]20 –6.1 (c 0.62, CH2Cl2); IR (film) ν 2961, 2924, 2854, 1733, 1462, 1316, 1130, 1013,
D
735 cm–1; 1H NMR (400 MHz, CDCl3) δ = 0.83-0.89 (3H, m, CH3), 1.19-1.27 (20H, m, 2 x CH3 + 7 x CH2), 1.36
(9H, s, C(CH3)3), 1.55-1.68 (2H, m, CH2), 2.58-2.66 (5H, m, CHH + 2 x CH2), 3.18 (1H, dd, J = 16.4, 6.0 Hz,
CHH), 4.05-4.10 (1H, m, NCH), 4.30 (1H, d, J = 16.8 Hz, CHH), 4.56 (1H, d, J = 16.8 Hz, CHH), 6.83 (1H, s,
ArH), 6.91 (1H, s, ArH); 13C NMR (100 MHz, CDCl3) δ = 14.2 (CH3), 15.2 (2 CH3), 22.8 (CH2), 24.6 (CH3),
25.2 (2 CH2), 26.9 (CH2), 29.4 (CH2), 29.7 (2 CH2), 29.8 (CH2), 31.8 (CH2), 32.0 (CH2), 32.3 (CH2), 44.4 (CH2),
53.4 (CH), 61.4 (C), 125.5 (CH), 129.5 (2 C), 129.6 (CH), 139.8 (C), 140.5 (C); LRMS (EI) m/z 435 (M+,
0.15%), 378 (10), 314 (23), 252 (20), 202 (23), 189 (15), 188 (100), 186 (34), 160 (20), 57 (22); HRMS (ESI-
TOF) Calcd for C22H36NO2S [M+ − C4H9] 378.2467, found 378.2464.
Dimethyl (3R)-2-(tert-butanesulfonyl)-3-nonanyl-1,2,3,4-tetrahydroisoquinoline-6,7-dicarboxylate (7l):
Yellow oil; RF 0.49 (hexane/EtOAc 3:1); [α]20D +3.9 (c 1.35, CH2Cl2); IR (film) ν 2952, 2923, 2856, 1728, 1434,
1
1270, 1128, 700 cm–1; H NMR (300 MHz, CDCl3) δ = 0.84-0.92 (3H, m, CH3), 1.22-1.28 (14H, m, 7 x CH2),
1.36 (9H, s, C(CH3)3), 1.50-1.58 (2H, m, CH2), 2.76 (1H, d, J = 17.0 Hz, CHH), 3.26 (1H, dd, J = 17.0, 6.0 Hz,
CHH), 3.90 (3H, s, CH3), 3.90 (3H, s, CH3), 4.10-4.16 (1H, m, NCH), 4.34 (1H, d, J = 17.6 Hz, CHH), 4.70 (1H,
13
d, J = 17.6 Hz, CHH), 7.45 (1H, s, ArH), 7.50 (1H, s, ArH); C NMR (100 MHz, CDCl3) δ = 14.2 (CH3), 22.8
(CH2), 24.6 (CH3), 26.8 (CH2), 29.4 (CH2), 29.6 (2 CH2), 29.8 (CH2), 31.8 (CH2), 32.0 (CH2), 32.8 (CH2), 44.3
(CH2), 52.8 (CH), 52.8 (2 CH3), 61.6 (C), 126.8 (CH), 129.8 (C), 130.7 (C), 130.8 (CH), 135.7 (C), 136.4 (C),
167.8 (C), 168.1 (C); LRMS (EI) m/z 495 (M+, 0.33%), 374 (16), 368 (15), 264 (13), 262 (43), 249 (15), 248
(100), 246 (15), 216 (39), 189 (14), 156 (16), 57 (34); HRMS (ESI-TOF) Calcd for C26H41NO6S [M+] 495.2655,
found 495.2652.
(3R)-2-(tert-Butanesulfonyl)-6,7-diethyl-3-[4-((tetrahydro-2H-pyran-2-yl)oxy)butyl]-1,2,3,4-tetrahydroiso-
quinoline (7m): Colorless wax (1:1 mixture of diastereoisomers); RF 0.31 (hexane/EtOAc 6:1); IR (film) ν 2937,
1
2872, 1456, 1312, 1265, 1129, 1031, 1021, 733, 703 cm–1; H NMR (300 MHz, CDCl3) δ = 1.20 (3H, t, J = 7.5
Hz, CH3), 1.21 (1H, t, J = 7.5 Hz, CH3), 1.36 (9H, s, C(CH3)3), 1.40-1.70 (12H, m, 6 x CH2), 2.56-2.69 (5H, m,
CHH + 2 x CH2), 3.18 (1H, dd, J = 16.3, 6.1 Hz, CHH), 3.31-3.40 (1H, m, NCH), 3.41-3.52 (1H, m, CHH), 3.66-
3.76 (1H, m, CHH), 3.76-3.87 (1H, m, CHH), 4.04-4.13 (1H, m, CHH), 4.31 (1H, d, J = 16.7 Hz, CHH), 4.50-
4.61 (2H, m, CHH + CH), 6.83 (1H, s, ArH), 6.91 (1H, s, ArH); 13C NMR (100 MHz, CDCl3) δ = 15.2 (CH3),
19.7 (CH2), 19.8 (CH2), 23.7 (CH2), 24.5 (CH3), 25.1 (CH2), 25.3 (CH2), 25.6 (CH2), 29.6 (CH2), 30.6 (CH2),
31.6 (CH2), 32.3 (CH2), 44.4 (CH2), 53.2 (CH), 61.4 (C), 62.4 (2 CH2), 67.4 (CH2), 67.5 (CH2), 98.8 (CH), 98.9
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(CH), 125.5 (CH), 129.4 (2 C), 129.6 (CH), 139.8 (C), 140.5 (C); LRMS (EI) m/z 465 (M+, 0.03%), 380 (17),
344 (21), 261 (19), 260 (100), 258 (16), 252 (11), 242 (21), 189 (13), 188 (94), 186 (22), 160 (21), 85 (20), 57
(24); HRMS (ESI-TOF) Calcd for C22H34NO2 [M+ − C4H9O2S] 344.2590, found 344.2588.
(3R)-2-(tert-Butanesulfonyl)-6-butyl-3-phenethyl-1,2,3,4-tetrahydroisoquinoline (7n) and (3R)-2-(tert-
Butanesulfonyl)-7-butyl-3-phenethyl-1,2,3,4-tetrahydroisoquinoline (7o): Orange wax (1:1 mixture of
regioisomers); RF 0.55 (hexane/EtOAc 6:1); IR (film) ν 3061, 2959, 2929, 2856, 1455, 1314, 1130, 1045, 938,
735, 700, 675 cm–1; 1H NMR (300 MHz, CDCl3) δ = 0.92 (3H, t, J = 7.3 Hz, CH3), 0.93 (3H, t, J = 7.3 Hz, CH3),
1.35 [18H, s, 2 x C(CH3)3], 1.41-1.63 (8H, m, 4 x CH2), 1.75-2.00 (4H, m, 2 x CH2), 2.51-2.60 (4H, m, 2 x CH2),
2.61-2.81 (6H, m, 2 x CH2 + 2 x CHH), 3.20-3.29 (2H, m, 2 x CHH), 4.16-4.23 (2H, m, 2 x NCH), 4.36 (2H, d, J
= 17.0 Hz, 2 x CHH), 4.62 (2H, d, J = 16.9 Hz, 2 x CHH), 6.85 (1H, s, ArH), 6.93-7.01 (5H, m, ArH), 7.13-7.17
(6H, m, ArH), 7.21-7.25 (4H, m, ArH); 13C NMR (100 MHz, CDCl3) δ = 14.9 (CH3), 22.6 (CH2), 24.6 (CH3),
29.8 (CH2), 33.2 (CH2), 33.6 (CH2), 33.7 (CH2), 33.8 (CH2), 35.4 (CH2), 35.45 (CH2), 44.5 (CH2), 44.6 (CH2),
53.0 (CH), 53.1 (CH), 61.4 (C), 125.8 (CH), 125.9 (CH), 126.1 (CH), 126.6 (CH), 127.3 (CH), 128.4 (CH), 128.5
(CH), 129.1 (C), 129.15 (C), 129.8 (CH), 129.85 (CH), 131.7 (C), 141.1 (C), 141.6 (C), 141.7 (C); LRMS (EI)
m/z 413 (M+, 0.62%), 356 (9), 292 (36), 252 (11), 189 (15), 188 (100), 186 (13), 57 (20); HRMS (ESI-TOF)
Calcd for C25H35NO2S [M+] 413.2389, found 413.2391.
General Procedure for the Cyclotrimerization of Diynes 5 and 2-Butyne-1,4-diol (6b). Synthesis of
Tetrahydroisoquinolines 7: To a solution of the corresponding diyne 5 (0.1 mmol) in degasified and HPLC
quality ethanol (10.0 mL) was added Wilkinson’s catalyst (4.6 mg, 0.005 mmol) and alkyne 6b (86.0 mg,77.5
μL, 1.0 mmol). The reaction mixture was stirred at 75 oC for 17 h. Then the solvent was evaporated (15 Torr) and
CH2Cl2 (5.0 mL) was added to the crude of the reaction and washed with H2O (3 x 10 mL) in order to remove the
excess of 2-butyne-1,4-diol (6b). The organic phase was dried with anhydrous MgSO4 and the solvent was
evaporated (15 Torr). The residue was purified by column chromatography (silica gel, hexane/EtOAc) to yield
products 7. Yields are given in Table 2. Physical, spectroscopic, and analytical data follow.
(3R)-2-(tert-Butanesulfonyl)-6,7-di(hydroxymethyl)-3-phenethyl-1,2,3,4-tetrahydroisoquinoline
(7b):
o
Orange solid; mp 56-58 C (hexane/ CH2Cl2); RF 0.30 (hexane/EtOAc 1:2); [α]20 +10.7 (c 0.75, CH2Cl2); IR
D
1
(film) ν 3376, 2922, 2856, 1457, 1433, 1308, 1124, 1013, 722, 698 cm–1; H NMR (300 MHz, CDCl3) δ = 1.36
[9H, s, C(CH3)3], 1.72-2.07 (2H, m, CH2), 2.71-2.77 (3H, m, CHH + CH2), 2.84 (2H, s, 2 x OH), 3.26 (1H, dd, J
= 16.7, 6.0 Hz, CHH), 4.19-4.27 (1H, m, NCH), 4.36 (1H, d, J = 17.3 Hz, CHH), 4.64-4.70 (5H, m, 2 x CH2 +
CHH), 7.05 (1H, s, ArH), 7.14-7.28 (7H, m, ArH); 13C NMR (100 MHz, CDCl3) δ = 24.6 (CH3), 29.8 (CH2), 33.1
(CH2), 33.6 (CH2), 44.3 (CH2), 52.9 (CH), 61.5 (C), 63.9 (2 CH2), 126.1 (CH), 127.3 (CH), 128.4 (CH), 128.5
(CH), 128.7 (CH), 128.8 (CH), 131.4 (CH), 132.1 (C), 132.7 (C), 137.6 (C), 138.3 (C), 141.3 (C); LRMS (EI)
m/z 417 (M+, 0.55%), 360 (11), 296 (42), 294 (13), 278 (10), 193 (12), 192 (100), 190 (32), 188 (20), 175 (14),
174 (41), 172 (16), 144 (12), 91 (18), 57 (48), 41 (11); HRMS (ESI-TOF) Calcd for C19H22NO4S [M+ − C4H9]
360.1270, found 360.1259.
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(3S)-2-(tert-Butanesulfonyl)-6,7-di(hydroxymethyl)-3-phenyl-1,2,3,4-tetrahydroisoquinoline (7e): Yellow
o
solid; mp 63-64 C (hexane/ CH2Cl2); RF 0.28 (hexane/EtOAc 1:2); [α]20 +61.9 (c 0.63, CH2Cl2); IR (film) ν
D
3352, 2952, 2922, 2861, 1308, 1124, 947, 697 cm–1; 1H NMR (400 MHz, CDCl3) δ = 1.39 [9H, s, C(CH3)3], 2.77
(2H, s, 2 x OH), 3.30 (1H, d, J = 17.0 Hz, CHH), 3.54 (1H, dd, J = 17.1, 6.7 Hz, CHH), 4.05 (1H, d, J = 17.1 Hz,
CHH), 4.55 (1H, d, J = 17.0 Hz, CHH), 4.66 (2H, s, CH2), 4.71 (2H, s, CH2), 5.38 (1H, d, J = 6.1 Hz, NCH), 6.96
(1H, s, ArH), 7.20-7.27 (4H, m, ArH), 7.30-7.37 (2H, m, ArH); 13C NMR (100 MHz, CDCl3) δ = 24.7 (CH3),
29.8 (CH2), 45.0 (CH2), 55.2 (CH), 61.8 (C), 63.9 (CH2), 64.0 (CH2), 127.3 (CH), 127.8 (CH), 128.7 (CH), 128.9
(CH), 130.5 (CH), 132.3 (CH), 132.5 (CH), 132.9 (C), 133.0 (C), 137.6 (C), 138.4 (C), 138.9 (C); LRMS (EI)
m/z 389 (M+, 1.13%), 332 (10), 269 (21), 268 (100), 267 (14), 266 (12), 251 (19), 250 (16), 164 (48), 146 (17),
118 (13), 117 (14), 91 (14), 57 (33); HRMS (ESI-TOF) Calcd for C21H27NO4S [M+] 389.1661, found 389.1651.
(3R)-2-(tert-Butanesulfonyl)-6,7-di(hydroxymethyl)-3-(sec-butyl)-1,2,3,4-tetrahydroisoquinoline
(7h):
o
Orange solid; mp 61-63 C (hexane/ CH2Cl2); RF 0.33 (hexane/EtOAc 1:2); [α]20 +7.1 (c 1.30, CH2Cl2); IR
D
(film) ν 3382, 2952, 2924, 2850, 1433, 1310, 1122, 1014, 734, 695 cm–1; 1H NMR (300 MHz, CDCl3) δ = 0.88-
0.95 (6H, m, 2 x CH3), 1.36 [9H, s, C(CH3)3], 1.54-1.68 (3H, m, CH2 + CH), 2.66 (1H, d, J = 16.7 Hz, CHH),
3.20 (1H, dd, J = 16.7, 5.8 Hz, CHH), 3.22-3.50 (2H, bs, 2 x OH), 4.17-4.24 (1H, m, NCH), 4.30 (1H, d, J = 17.3
Hz, CHH), 4.60-4.68 (5H, m, 2 x CH2 + CHH), 7.03 (1H, s, ArH), 7.12 (1H, s, ArH); 13C NMR (100 MHz,
CDCl3) δ = 14.8 (CH3), 24.5 (CH3), 25.1 (CH), 32.3 (CH2), 40.6 (CH2), 44.2 (CH2), 51.1 (CH), 61.4 (C), 64.0 (2
CH2), 127.3 (CH), 131.5 (CH), 132.3 (C), 132.6 (C), 137.4 (C), 138.1 (C); LRMS (EI) m/z 369 (M+, 0.41%), 312
(24), 277 (13), 248 (22), 206 (14), 202 (10), 193 (12), 192 (100), 190 (38), 188 (34), 175 (10), 174 (42), 172 (12),
144 (11), 57 (58), 43 (25), 41 (16); HRMS (ESI-TOF) Calcd for C15H22NO4S [M+ − C4H9] 312.1270, found
312.1269.
(3R)-2-(tert-Butanesulfonyl)-6,7-di(hydroxymethyl)-3-nonanyl-1,2,3,4-tetrahydroisoquinoline (7k): Yellow
o
solid; mp 39-40 C; RF 0.38 (hexane/EtOAc 1:2); [α]20 –1.2 (c 1.01, CH2Cl2); IR (film) ν 3364, 2959, 2922,
D
1
2856, 1463, 1312, 1128, 1011, 735 cm–1; H NMR (400 MHz, CDCl3) δ = 0.82-0.91 (3H, m, CH3), 1.21-1.28
(14H, m, 7 x CH2), 1.36 [9H, s, C(CH3)3], 1.49-1.64 (2H, m, CH2), 2.69 (1H, d, J = 16.7 Hz, CHH), 3.20 (1H, dd,
J = 16.5, 6.0 Hz, CHH), 4.07-4.13 (1H, m, NCH), 4.30 (1H, d, J = 17.0 Hz, CHH), 4.61 (1H, d, J = 16.6 Hz,
CHH), 4.68 (4H, s, 2 x CH2), 7.03 (1H, s, ArH), 7.12 (1H, s, ArH); 13C NMR (100 MHz, CDCl3) δ = 14.2 (CH3),
22.8 (CH2), 24.6 (CH3), 26.8 (CH2), 29.4 (CH2), 29.6 (CH2), 29.7 (CH2), 29.8 (CH2), 31.8 (CH2), 32.0 (CH2),
32.4 (CH2), 44.2 (CH2), 53.2 (CH), 61.5 (C), 64.0 (2 CH2), 127.3 (CH), 131.5 (CH), 132.3 (C), 132.6 (C), 137.4
(C), 138.1 (C); LRMS (EI) m/z 439 (M+, 0.01%), 330 (12), 316 (13), 314 (14), 206 (31), 204 (49), 203 (17), 202
(100), 192 (35), 190 (52), 188 (74), 186 (31), 174 (28), 172 (17), 158 (16), 156 (26), 57 (63), 43 (30), 41 (29);
HRMS (ESI-TOF) Calcd for C20H32NO4S [M+ − C4H9] 382.2052, found 382.2055.
Ruthenium-Catalyzed Ring Closing Metathesis of Enyne 9a. Synthesis of Cyclic 1,3-Diene 10a: A mixture
of enyne 9a (66.6 g, 0.2 mmol), Hoveyda-Grubbs second generation ruthenium catalyst (12.4 mg, 0.02 mmol),
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and 1,7-octadiene (0.088 g, 0.116 mL, 0.8 mmol) in dry CH2Cl2 (20 mL) was stirred at 40 oC for 12 h. Then the
solvent was evaporated (15 Torr). Purification by column chromatography (silica gel, hexane/EtOAc) yielded
10a (63.3 mg, 0.19 mmol, 95%). Physical, spectroscopic, and analytical data follow.
(2R)-1-(tert-Butanesulfonyl)-2-phenethyl-4-vinyl-1,2,3,6-tetrahydropyridine (10a): Colorless wax; RF 0.54
(hexane/EtOAc 4:1); [α]20D +10.1 (c 0.95, CH2Cl2); IR (film) ν 3061, 2977, 2935, 2904, 2861, 2837, 1713, 1312,
1128, 950, 734 cm–1; 1H NMR (400 MHz, CDCl3) δ = 1.35 [9H, s, C(CH3)3], 1.73-2.00 (2H, m, CH2), 2.27 (1H,
d, J = 16.6 Hz, CHH), 2.51-2.62 (1H, m, CHH), 2.65-2.77 (2H, m, CH2), 3.83 (1H, d, J = 19.5 Hz, CCH), 4.06-
4.18 (2H, m, NCH + CHH), 4.99-5.30 (2H, m, CH2), 5.67-5.73 (1H, m, CH), 6.39 (1H, dd, J = 17.5, 10.7 Hz,
CH), 7.15-7.20 (3H, m, ArH), 7.24-7.30 (2H, m, ArH); 13C NMR (100 MHz, CDCl3) δ = 24.5 (CH3), 29.8 (CH2),
33.3 (CH2), 34.1 (CH2), 42.6 (CH2), 52.2 (CH), 61.5 (C), 112.1 (CH2), 119.9 (CH), 123.9 (CH), 126.1 (CH),
128.4 (CH), 128.5 (CH), 133.0 (C), 136.6 (CH), 138.6 (CH), 141.7 (C); LRMS (EI) m/z 333 (M+, 0.41%), 276
(17), 252 (32), 213 (30), 212 (95), 148 (34), 109 (14), 108 (100), 106 (19), 105 (11), 91 (40), 79 (16), 77 (11), 57
(69), 41 (14); HRMS (ESI-TOF) Calcd for C19H27NO2S [M+] 333.1762, found 333.1776.
Ruthenium-Catalyzed Ring Closing Metathesis of Enynes 15a and ent-15a. Synthesis of Cyclic 1,3-Diene
16a: A mixture of enyne 15a or ent-15a (66.6 g, 0.2 mmol), Grubbs first generation ruthenium catalyst (32.8 mg,
0.04 mmol), and 1,7-octadiene (0.088 g, 0.116 mL, 0.8 mmol) in dry CH2Cl2 (20 mL) was stirred at 40 oC for 20
h. Then the solvent was evaporated (15 Torr). Purification by column chromatography (silica gel, hexane/EtOAc)
yielded 16a (65.3 mg, 0.195 mmol, 98%) or jent-16a (66.0 mg, 0.195 mmol, 98%). Triene 17a was isolated and
characterized as a side reaction product working under different reaction conditions (see table 4). Physical,
spectroscopic, and analytical data follow.
(2R)-1-(tert-Butanesulfonyl)-2-phenethyl-5-vinyl-1,2,3,6-tetrahydropyridine (16a): Colorless wax; RF 0.51
(hexane/EtOAc 4:1); [α]20D –11.0 (c 0.40, CH2Cl2); IR (film) ν 3057, 2975, 2935, 2868, 1603, 1313, 1265, 1129,
733, 700 cm–1; 1H NMR (300 MHz, CDCl3) δ = 1.35 [9H, s, C(CH3)3], 1.69-2.04 (2H, m, CH2), 2.15 (1H, dd, J =
19.0, 5.7 Hz, CHH), 2.62-2.76 (3H, m, CHH + CH2), 3.77 (1H, d, J = 17.8 Hz, CHH), 4.00-4.07 (1H, m, NCH),
4.20 (1H, d, J = 17.4 Hz, CHH), 4.95-5.11 (2H, m, CH2), 5.80 (1H, d, J = 5.7 Hz, CH), 6.29 (1H, dd, J = 17.8,
11.0 Hz, CH), 7.13-7.22 (3H, m, ArH), 7.23-7.32 (2H, m, ArH); 13C NMR (100 MHz, CDCl3) δ = 24.6 (CH3),
29.8 (CH2), 33.2 (CH2), 34.1 (CH2), 41.5 (CH2), 52.1 (CH), 61.4 (C), 111.5 (CH2), 125.4 (CH), 126.1 (CH),
126.4 (CH), 128.4 (CH), 128.5 (CH), 128.8 (CH), 132.7 (C), 136.5 (CH), 141.7 (C); LRMS (EI) m/z 333 (M+,
1.13%), 213 (20), 212 (29), 172 (12), 108 (100), 91 (17), 79 (13), 57 (38); HRMS (ESI-TOF) Calcd for
C19H27NO2S [M+] 333.1762, found 333.1769.
(2S)-1-(tert-Butanesulfonyl)-2-phenethyl-5-vinyl-1,2,3,6-tetrahydropyridine
(ent-16a):
Physical
and
spectroscopic data were found to be same than for 16a. [α]D20 = +8.6 (c = 0.84, CH2Cl2).
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(E)-1,2-bis[(2R)-1-(tert-Butanesulfonyl)-6-phenethyl-1,2,3,6-tetrahydropyridin-3-yl]ethane (17a): Orange
o
solid; mp 72-74 C (hexane/ CH2Cl2); RF 0.39 (hexane/EtOAc 3:1); [α]20 –12.1 (c 0.45, CH2Cl2); IR (film) ν
D
3027, 2933, 1454, 1312, 1266, 1127, 733, 700 cm–1; 1H NMR (300 MHz, CDCl3) δ = 1.35 [18H, s, 2 x C(CH3)3],
1.74-1.98 (4H, m, 2 x CH2), 2.14-2.22 (2H, m, 2 x CCH), 2.67-2.75 (6H, m, 2 x CHH + 2 x CH2), 3.79 (2H, d, J
= 17.5 Hz, 2 x CCH), 4.00-4.07 (2H, m, 2 x NCH), 4.19 (2H, d, J = 17.5 Hz, 2 x CCH), 5.82 (1H, d, J = 4.7 Hz,
CH), 6.01 (1H, s, CH), 7.13-7.30 (10H, m, ArH); 13C NMR (100 MHz, CDCl3) δ = 24.6 (CH3), 29.8 (CH2), 33.2
(CH2), 34.0 (CH2), 41.8 (CH2), 52.2 (CH), 61.5 (C), 125.7 (CH), 125.8 (CH), 126.1 (CH), 128.4 (CH), 128.5
(CH), 132.2 (C), 141.7 (C); LRMS (EI) m/z 638 (M+, 0.84%), 427 (11), 413 (14), 397 (18), 293 (11), 264 (30),
214 (11), 159 (11), 134 (15), 132 (18), 117 (20), 105 (19), 91 (53), 57 (100), 41 (24); HRMS (ESI-TOF) Calcd
for C36H50N2O4S2 [M+] 638.3212, found 638.3217.
General Procedure for the Diels-Alder Reaction of Cyclic Dienes 10a, 16a and ent-16a with Dimethyl
Acetylenedicarboxylate (6c), and Further Oxidation with DDQ. Synthesis of Tetrahydroisoquinolines 12a,
18a and ent-18a: To a solution of the corresponding diene 10a, 16a or ent-16a (0.2 mmol) in dry toluene (3.0
mL) was added freshly distilled dimethyl acetylenedicarboxylate (6c, 0.084 g, 0.072 mL, 0.6 mmol). The reaction
mixture was stirred at 100 oC for 40 h. After that, it was cooled down, and the solvent was evaporated (15 Torr).
The crude of the reaction and freshly recrystalized DDQ (0.091 g, 0.4 mmol) were dissolved in dry toluene (10.0
mL) in a pressure tube, and the reaction mixture was stirred at 80 oC for 20 h. After that, it was filtered through a
pad of celite with EtOAc (30 mL), and was evaporated (15 Torr). The residue was purified by column
chromatography (silica gel, hexane/EtOAc) to yield products 12a, 18a and ent-18a. Yields are given in Schemes
6 and 8. Physical, spectroscopic, and analytical data follow.
Dimethyl (3R)-2-(tert-butanesulfonyl)-3-phenethyl-1,2,3,4-tetrahydroisoquinoline-7,8-dicarboxylate (12a):
Orange wax; RF 0.36 (hexane/EtOAc 3:1); [α]20 +3.1 (c 0.74, CH2Cl2); IR (film) ν 2952, 2922, 2850, 1725,
D
1
1433, 1266, 1125, 1005, 735, 697 cm–1; H NMR (400 MHz, CDCl3) δ = 1.34 [9H, s, C(CH3)3], 1.73-1.98 (2H,
m, CH2), 2.69-2.71 (2H, m, CH2), 2.81 (1H, d, J = 17.2 Hz, CHH), 3.33 (1H, dd, J = 17.0, 6.1 Hz, CHH), 3.88
(3H, s, CH3), 3.95 (3H, s, CH3), 4.21-4.26 (1H, m, NCH), 4.32 (1H, d, J = 17.6 Hz, CHH), 4.70 (1H, d, J = 17.7
Hz, CHH), 7.11-7.20 (4H, m, ArH), 7.23-7.27 (2H, m, ArH), 7.83 (1H, d, J = 8.1 Hz, ArH); 13C NMR (100 MHz,
CDCl3) δ = 24.6 (CH3), 29.8 (CH2), 33.0 (CH2), 33.6 (CH2), 41.9 (CH2), 52.1 (CH), 52.7 (CH3), 53.0 (CH3), 61.7
(C), 126.3 (CH), 126.4 (C), 128.4 (CH), 128.6 (2 CH), 129.4 (CH), 129.9 (C), 131.3 (CH), 135.2 (CH), 136.6
(C), 138.1 (C), 141.0 (C), 166.1 (C), 168.7 (C); LRMS (EI) m/z 473 (M+, 0.10%), 352 (35), 321 (25), 320 (100),
248 (29), 235 (11), 216 (47), 91 (15), 57 (31); HRMS (ESI-TOF) Calcd for C24H28NO5S [M+ - OCH3] 442.1695,
found 416.1688.
Dimethyl (3R)-2-(tert-butanesulfonyl)-3-phenethyl-1,2,3,4-tetrahydroisoquinoline-5,6-dicarboxylate (18a):
Orange solid; mp 36-37 oC (hexane/CH2Cl2); RF 0.33 (hexane/EtOAc 3:1); 4.0:96.0 er [HPLC (Chiralpak AD-H
column, hexane/i-PrOH = 90/10, 1.0 mL/min, 220 nm): tminor = 19.70 min, tmajor = 37.62 min]; [α]20 +23.5 (c
D
0.92, CH2Cl2); IR (film) ν 3061, 2994, 2946, 1726, 1439, 1265, 732, 700 cm–1; 1H NMR (300 MHz, CDCl3) δ =
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901590
European Journal of Organic Chemistry
25
1.35 [9H, s, C(CH3)3], 1.69-1.97 (2H, m, CH2), 2.66-2.71 (2H, m, CH2), 2.77 (1H, d, J = 17.9 Hz, CHH), 3.18
(1H, dd, J = 16.6, 6.3 Hz, CHH), 3.90 (3H, s, CH3), 3.96 (3H, s, CH3), 4.18-4.25 (1H, m, NCH), 4.43 (1H, d, J =
17.9 Hz, CHH), 4.74 (1H, d, J = 17.7 Hz, CHH), 7.12-7.26 (6H, m, ArH), 7.85 (1H, d, J = 7.8 Hz, ArH); 13C
NMR (100 MHz, CDCl3) δ = 24.5 (CH3), 29.8 (CH2), 33.0 (CH2), 33.7 (CH2), 44.7 (CH2), 52.3 (CH), 52.7 (CH3),
52.9 (CH3), 61.7 (C), 126.1 (CH), 126.2 (CH), 127.1 (CH), 127.9 (CH), 128.4 (CH), 128.5 (CH), 128.6 (CH),
130.0 (C), 134.5 (C), 136.8 (C), 137.6 (C), 141.1 (C), 165.9 (C), 169.4 (C); LRMS (EI) m/z 473 (M+, 0.20%),
352 (26), 320 (21), 248 (18), 230 (19), 217 (17), 216 (100), 57 (28); HRMS (ESI-TOF) Calcd for C25H31NO6S
[M+] 473.1872, found 473.1858.
Dimethyl (3S)-2-(tert-butanesulfonyl)-3-phenethyl-1,2,3,4-tetrahydroisoquinoline-5,6-dicarboxylate (ent-
18a): Physical and spectroscopic data were found to be same than for 18a. 98:7 er [HPLC (Chiralcel OD-H
column, hexane/i-PrOH = 90/10, 1.0 mL/min, 220 nm): tmajor = 19.33 min, tminor = 1.3 min]; [α]D20 = −16.5 (c =
0.37, CH2Cl2).
1
Supporting Information (see footnote on the first page of this article): Copies of H, 13C NMR and DEPT
spectra for new compounds 1e, 2d, 2e, 3d, 3e, 4, 5, 7, 8a-10a, 12a, 14a-18a. Copies of chiral HPLC
chromatograms for compounds 7d, ent-7d, 18a and ent-18a.
Acknowledgements
We thank the continued financial support from the Ministerio de Economía y Competitividad (MINECO; project
CTQ2014-53695-P, CTQ2014-51912-REDC, CTQ2016-81797-REDC, CTQ2017-85093-P), Ministerio de
Ciencia, Innovación
y
Universidades (RED2018-102387-T), FEDER, the Generalitat Valenciana
(PROMETEOII/2014/017), ant the University of Alicante.
__________________
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Table of Contents
3,6,7-Trisubstituted 1,2,3,4-tetrahydroisoquinolines were prepared through a [2+2+2] cyclotrimerization
of chiral 4-azaocta-1,7-dienys promoted by Wilkinson catalyst. Regioisomeric 5,6- and 7,8-disubstituted
tetrahydroisoquinolines were synthesized by [4+2] cycloaddition of dimethyl acetylenedicarboxylate
and chiral cyclic dienes.
Key Topic: Synthesis of Tetrahydroisoquinolines by Cyclotrimerization of 4-Azaocta-1,7-diynes
and Alkynes, and by [4+2] Cycloaddition of Alkynes and Cyclic 1,3-Dienes Resulting from Ring
Closing Metathesis of 4-Azaocta-1,7-enynes
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