Synthesis of Naphthylpyridines from Unsymmetrical Naphthylheptadiynes and the Configurational Stability of the Biaryl Axis

Article abstract of DOI:10.1021/acs.joc.5b02190

A series of different unsymmetrically substituted naphthyl-based diynes were synthesized. These substrates formed the foundation for the assembly of novel biaryls containing pyridine moieties with differently substituted five-membered rings in the backbone of the newly formed heterobiaryl system. The key step for their efficient construction was the photo- and cobalt-catalyzed [2 + 2 + 2] cycloaddition reaction between the corresponding naphthyldiyne and aceto- or benzonitrile. The heterobiaryl products have been isolated and investigated with respect to the configurational stability of their biaryl axis using dynamic chiral HPLC; subtle effects of the substitution pattern on the stability of the axis were observed. For several compounds the activation barriers (ΔG^?) of racemization were determined. Suitable substitution of the five-membered ring backbone exemplarily allowed the Co-catalyzed enantioselective cyclization to yield the enantiomerically enriched heterobiaryl.

Full text of DOI:10.1021/acs.joc.5b02190

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Article
Synthesis of Naphthylpyridines from Unsymmetrical
Naphthylheptadiynes and the Configurational Stability of the Biaryl Axis
Fabian Fischer, Alexander F Siegle, Marek Checinski, Christine
Fischer, Karolin Kral, Richard Thede, Oliver Trapp, and Marko Hapke
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02190 • Publication Date (Web): 21 Mar 2016
Downloaded from http://pubs.acs.org on March 24, 2016
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Synthesis of Naphthylpyridines from Unsymmetrical Naphthylheptadiynes
and the Configurational Stability of the Biaryl Axis
†
ǁ
‡
†
†
Fabian Fischer, Alexander F. Siegle, Marek Checinski, Christine Fischer, Karolin Kral,
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§
ǁ
,
†
Richard Thede, Oliver Trapp and Marko Hapke*
†
LeibnizꢀInstitut für Katalyse e.V. an der Universität Rostock (LIKAT), AlbertꢀEinsteinꢀStr. 29a, Dꢀ
18059 Rostock, Germany; since November 1st, 2015 also: Johannes KeplerꢀUniversität Linz, Institut
für Katalyse, Altenberger Straße 69, Aꢀ4040 Linz, Austria
‡
CreativeQuantum GmbH (Adlershof), Wegedornstr. 36, Dꢀ12524 Berlin, Germany
(
http://www.creativeꢀquantum.eu)
§
Institut für Biochemie, Universität Greifswald, FelixꢀHausdorffꢀStraße 4, Dꢀ17487 Greifswald,
Germany
ǁ
OrganischꢀChemisches Institut, Universität Heidelberg, Im Neuenheimer Feld 270, Dꢀ69120
Heidelberg, Germany
Abstract: A series of different unsymmetrically substituted naphthylꢀbased diynes were
synthesized. These substrates formed the foundation for the assembly of novel biaryls
containing pyridine moieties with differently substituted fiveꢀmembered rings in the backbone
of the newly formed heterobiaryl system. The key step for their efficient construction was the
photoꢀ and cobaltꢀcatalyzed [2+2+2] cycloaddition reaction between the corresponding
naphthyldiyne and acetoꢀ or benzonitrile. The heterobiaryl products have been isolated and
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investigated with respect to their configurational stability around the biaryl axis using
dynamic chiral HPLC; subtle effects of the substitution pattern on the stability of the axis
ǂ
were observed. For several compounds the activation barriers (ꢀG ) of racemization were
determined.
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Introduction
The connecting axis between two aromatic ring systems, simply referred to the biaryl axis,
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belongs to the most fascinating structural and stereochemical features of biaryl compounds.
The biaryls comprise a steadily expanding class of compounds and represent a structural
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motif found in numerous natural products as well as in ligand systems used for catalysis.
Recently, atropisomers and the configurational stability of the chiral axes have gained
increasing attention in medicinal chemistry due to the fact that atropisomers can play a
4
significant structural role in drug potency, which might be an often overlooked phenomenon.
The development of efficient synthetic methodologies for the asymmetric assembly of biaryls
has become a flourishing area of synthetic organic chemistry over the last decade. In addition
to strategies utilizing chiral auxiliaries to induce stereoselectivity during formation of the
biaryl axis, direct asymmetric coupling methodologies of two aryl fragments or the
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stereoselective synthesis of one moiety in the atropisomers have found great interest. For the
direct asymmetric coupling methods, enantioselective oxidative coupling, as well as crossꢀ
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,7
coupling reactions such as enantioselective SuzukiꢀMiyaura reactions are worth mentioning.
Over the last decade de novo construction of chiral arene systems by cycloaddition
approaches has attained considerable interest and especially [2+2+2] cycloaddition reactions
have matured from the reports of single examples with preformed stereocenters into a
methodology using chiral transition metal complexes for the assembly of chiral biaryl
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frameworks from achiral substrates.
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We have investigated the use of chiral Co(I)ꢀcomplexes for the photochemical,
enantioselective [2+2+2] cycloaddition reaction of 1ꢀnaphthyldiynes with different nitriles,
providing enantioselective access to substituted biaryls possessing a tetrahydroisoquinoline
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fragment. During our studies it was established that the size of the spacer between the two
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alkyne bonds in the substrate, which later defines the size of the saturated backbone ring
annulated to the newly formed pyridine ring, obviously plays a significant role in both the
reactivity and selectivity of the cyclization reaction. Biaryls with newly formed sixꢀmembered
rings in the backbone of the pyridine were obtained in good yields and enantioselectivities,
while biaryls with fiveꢀmembered ring in the backbones were only obtained as racemates. At
first glance, the reason for the lack of selectivity might be assigned to obvious structural
parameters of the product, such as the size of the annulated fiveꢀmembered ring, providing
significantly less steric hindrance compared to a sixꢀmembered ring. Investigations published
so far on pyridineꢀcontaining heterobiaryls most often utilize isoquinoline moieties, leading to
rather stable heterobiaryls. For some of these systems, the free activation energy barrier has
1
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been determined with different methodologies.
We were interested in studying the configurational stability of the biaryl axis in molecules of
the general structure shown in Scheme 1 and how this stability can be influenced by
substituents on the fiveꢀmembered ring. In view of the large application of biaryl systems
such a systematic examination might also be generally interesting for the conceptual design of
new biaryl systems. In addition, such an investigation into the backbone modification offers a
higher degree of structural variability than functionalization of the pyridine Nꢀatom in the
orthoꢀposition, which is usually restricted to oxidation (Nꢀoxide) or alkylation. The dynamic
stereochemical behavior of such structures can be studied with a variety of chromatographic
methods, e.g. enantioselective dynamic HPLC or gas chromatography. These studies aim to
reveal the impact of small structural variations in the backbone ring on the stability of the
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biaryl axis under mild and accessible conditions. The selection of the 2ꢀmethoxynaphthalin
backbone resulted from our experience in previous studies and the easy access to key
intermediates for the synthesis of the required derivatives. In addition, the naphthyl moiety is
a very common component of numerous biaryl systems. We were also retaining the pyridine
core due to the obvious importance of the pyridine backbone substitution for the
configurational stability and therefore to elicit the impact of different structural changes for so
far unknown fiveꢀmembered ring derivatives in contrast to usually investigated isoquinoline
derivatives.
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Scheme 1. Effect of backbone substituents on the stability of the biaryl axis of
naphthylpyridines.
The influence of substitution in the backbone of the pyridine ring on the configurational
stability of the biaryl axis can generally be envisioned in different ways (Scheme 1). These
substitution effects, however, should be clearly distinguishable. Certainly, the
functionalization of the orthoꢀposition (A in Scheme 1) has the most essential steric, and
potentially electronic, impact on the stability of the biaryl axis, as it is already textbook
knowledge. Even smaller substituents here should have an observable effect on the stability.
Position B should be much less important for administering stability to the chiral axis. Finally,
the introduction of substituents in position C will obviously have no steric influence due to its
remote position in the backbone, but potentially have a possible electronic factor.
In the present study we set out to investigate the steric effect of substitution in the A position,
neighboring the pyridine ring as well as an exemplarily look into an electronic effect of
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different groups in the C position. This synthetic endeavor requires the efficient assembly of a
range of differently functionalized diynes for the first time. These diynes will be substrates for
the synthesis of the corresponding heterobiaryls by applying [2+2+2] cycloadditions as the
key reaction step. Subsequent studies regarding the stereochemical features of the biaryl axis
will provide the required information about the configurational stability.
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Results and Discussion
Synthesis of the substituted unsymmetrical diynes: To study the steric effects of potential
substituents, an array of differently and unsymmetrically substituted diynes as precursor
molecules for the cyclization reaction were prepared. The preparation of arylalkynes is a
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highly efficient synthetic methodology, usually following the Sonogashira protocol.
Unfortunately, when it comes to the coupling of aryl halides with diynes, selectivity issues
begin to have an effect on the reaction outcome, usually leading to both monoꢀ and
bisarylation. The coupling of unsymmetrical terminal diynes also faces potential selectivity
issues due to the fact that in the Sonogashira reaction more electronꢀrich alkyne groups are
usually coupled preferentially. Therefore, the synthetic pathways for unsymmetrical diynes
follow a stepwise construction approach, to allow the incorporation of a variety of various
functionalities like methyl, carbonyl, malonyl or alkenyl groups which later constitute the A
position substituent.
Common synthethic starting materials for our purposes are 1ꢀiodoꢀ2ꢀmethoxynaphthalene (1)
9b
or the derived 1ꢀethinylꢀ2ꢀmethoxynaphthalene (2). The direct synthesis of monoꢀarylated
diynes using symmetrical terminal diyne precursor molecules and aromatic halides like 1
generally uses the Sonogashira protocol. The monoarylation reaction of 1 with 2,4,6ꢀ
trimethylꢀN,Nꢀdi(propꢀ2ꢀynyl)aniline (3) or 1,3ꢀdiethynyltetramethyldisiloxane (5) is
exemplified in Scheme 2.
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Compared to often highꢀyielding Sonogashira reactions without selectivity issues, the isolated
yields for biaryls 4 and 6 are rather low, resulting from the significant formation of the
diarylated products (not shown). This problem can generally be circumvented by a
protection−crossꢀcoupling−deprotection approach, as it has been demonstrated for other
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symmetrical diynes.
Scheme 2. Synthesis of the monoarylated diynes 4 and 6 by Sonogashira reaction of 1 with
diynes 3 (Mes = 2,4,6ꢀtrimethylphenyl) or 5. The isolated yields are shown.
The synthesis of diynes with unsymmetrical backbones pose greater synthetic challenges
caused by the need to construct the diyne backbone stepwise. Initial investigations into the
possibility of the selective Sonogashira coupling of 1 with unsymmetrically substituted diynes
1
3
did not prove to be a useful route to obtain products with the envisioned substitution pattern.
The preparative procedures for the unsymmetrical diynes 8, 9, 11, 12, 14, 18, 22 and 25 are
detailed in Scheme 3. The synthesis of diynylester 8 was found to be feasible either from
alkyne 2 or carboxylic acid 7. Thus using 2 as a starting material, lithiation followed by
quenching with propargyl chloroformate yielded ester 8 in 76% yield. The preparation of 8
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from 7 and propargyl alcohol was possible under standard coupling conditions using DMAP
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and DCC, however, resulting in lower yield (67%). Applying identical conditions as the
latter for the preparation of amide 9 from 7 and NꢀmethyꢀNꢀpropargylamine also gave the
desired compound. Unfortunately the complete separation from the resulting coupling
reaction byproducts proved to be very difficult. Alternatively, the synthesis of amide 9 was
conducted by the reaction of the lithiated naphthylacetylene 2 with methyl(propꢀ2ꢀ
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1
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ynyl)carbamic chloride. Furthermore, preparation of the bisꢀpropargylated amines 11 and 12
started with the Sonogashira coupling of 2ꢀmethylbutꢀ3ꢀynꢀ2ꢀamine with iodide 1, providing
10 in excellent yield. The subsequent derivatization with propargyl bromide provided the
desired secondary amine 11 in 55% yield, as well as the bisꢀpropargylated tertiary amine as
minor byproduct. Isolated 11 was submitted to subsequent alkylation with methyl iodide,
furnishing 12 in modest yield. The more straight forward synthesis of the Nꢀtosylated diyne
14 initially involved crossꢀcoupling of the tosylated 2ꢀmethylbutꢀ3ꢀynꢀ2ꢀamine with iodide 1
1
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to deliver product 13 in 83% yield. Subsequent propargylation of this intermediate building
block proceeded in an excellent yield of 93%, allowing the isolation of the desired diyne 14.
Preparation of ketodiyne 18 started with the conversion of 4ꢀpropynꢀ1ꢀol (15) to the
corresponding aldehyde 16 by Swern oxidation. Reaction of 16 with lithiated 2 gave the
hydroxylated diyne 17, from which 18 was easily accessible via oxidation under convenient
17
conditions with DessꢀMartin periodinane.
The synthesis of enediyne 22 was initially attempted by olefination from 18 using Wittig or
Tebbe reagents. Unfortunately, the reaction mostly gave a mixture 18 and 22, which were
difficult to separate. A new approach was then initiated with the double hydroiodination of
1,5ꢀhexadiyne (19) affording bisolefin 20. Interestingly, we were only able to isolate 20
despite various attempts to change the amount of hydroiodination reagent in order to obtain
the corresponding monohydroiodination product.
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Scheme 3. Synthesis of the diynes 8, 9, 11, 12, 13, 14, 18, 22 and 25 with unsymmetrical
backbones by stepwise construction. The given yields are isolated yields.
O
O
R
Me
O
N
a1
from 2
b
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6%
from 2
OMe
OMe
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from 7
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OMe
6
7%
2
7
(R = H)
(R = COOH)
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Me
MeH
Me Me
Me
NH2
Me
N
Me
N
c1
c2
c3
OMe
OMe
OMe
9
7%
55%
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I
1
0
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12
OMe
Me
MeTs
Me
N
Me
NHTs
1
c4
83%
c5
OMe
OMe
93%
1
3
14
HO
O
OH
O
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1%
d2
79%
d3
74%
7
OMe
OMe
1
5
16
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18
I
e1
e2
44%
e3
I
I
43%
81%
OMe
OMe
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9
20
21
22
O
OH
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f2
O
7
7%
93%
OMe
OMe
Br
23
24
25
Conditions and reagents: (a1) Alkyne 2, n-BuLi, 78 °C, 0 °C, then 78 °C, addition of propargyl
chloroformate, 0 °C to rt. (a2) Propargyl alcohol, DMAP (4-dimethylaminopyridine), DCC (N,N'-
dicyclohexylcarbodiimide), CH2Cl2, 0 °C, then rt. (b) n-BuLi, THF, 78 °C, then rt for 30 min, then 78 °C,
methyl(prop-2-ynyl)carbamic chloride, rt. (c1) 2-Methylbut-3-yn-2-amine, Pd(PPh3)4 (2 mol%), CuI (6 mol%),
Et3N, 55 °C, 14 h. (c2) K2CO3, DMF, propargyl bromide, 100 °C, 18 h. (c3) K2CO3, DMF, MeI, 80 °C, 24 h.
(c4) 4-Methyl-N-(2-methylbut-3-yn-2-yl)benzenesulfonamide, Pd(PPh3)4 (5 mol%), ZnCl2 (20 mol%), I2 (cat.),
piperidine, 65 °C, 20 h. (c5) NaH, DMF, rt, 1h, then propargyl bromide, rt, 16 h, 18 h. (d1) Et3N, DMSO,
(
COCl)2, 78 °C, then rt. (d2) Alkyne 2, n-BuLi, 78 °C, 0 °C, then 78 °C, addition of 16, rt. (d3) Dess-Martin
periodinane, CH2Cl2, rt. (e1) NaI, CH3CN, TMSCl, H2O, rt, 15 min; 1,5-hexadiyne, CH3CN, rt, 16 h.
e2) Pd(PPh3)4 (4.8 mol%), CuI (4.9 mol%), alkyne 2, i-Pr2NH, rt, 4 h. (e3) DMF, 0 °C, then NaHMDS
(
soln. (0.6 M), 10 min. (f1) Alkyne 2, PdCl2(PPh3)2 (3.8 mol%), CuI (7.6 mol%), Et3N, 50 °C, 36 h.
(f2) Trimethylsilylacetylene, n-BuLi, 78 °C, rt for 75 min, then 78 °C, addition of 24, 78 °C to rt,
work-up; then MeOH/THF (1:1), KF (6 equiv.), rt, 16 h.
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In the following step, a Sonogashira coupling under slow addition of 2 to the reaction solution
furnished 21 with 44% yield. Finally, the elimination reaction applying NaHMDS in DMF
solution proceeded smoothly to give the desired enediyne 22 in high yield. The synthesis of
diyne 25 possessing an annulated phenyl ring in the A and B position (Scheme 1) was
envisioned to provide a compound with a large steric hindrance between these two positions.
Several synthetic approaches for related diynes were investigated but the one presented
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starting from 2ꢀbromobenzaldehyd (23) was identified as the most efficient and reliable.
Starting from 23 the Sonogashira reaction with 2 delivered 24 in good yield (77%).
Subsequent reaction with in situꢀprepared lithium trimethylsilylacetylide followed by
desilylation of the crude product delivered the intended precursor diyne 25. Having this
selection of differently substituted diynes in sufficient amounts, we were then able to
investigate the Co(I)ꢀcatalyzed [2+2+2] cycloaddition reactions and subsequently, the
configurational stability of the atropisomers’ chiral axes.
[2+2+2] Cycloaddition reactions of the diynes with nitriles: The [2+2+2] cycloaddition
under photochemical conditions using [CpCo(COD)] (COD = 1,5ꢀcyclooctadiene) has proven
to be an excellent method for the cyclization of acetylenes or diynes with nitriles, resulting in,
for example, the formation of heterobiaryls with fiveꢀ and sixꢀmembered rings annulated to
9
the newly formed pyridine. Consequently, we applied [CpCo(COD)] for most syntheses of
racemic mixtures of the heterobiaryls for subsequent analysis by dynamic chromatography
methods. The cycloaddition reactions were performed in a photoreactor usually at
temperatures between 0ꢀ25 °C, using either benzonitrile or in a single case acetonitrile in
9
excess amounts. The cycloaddition reactions furnished the desired heterobiaryls in moderate
to good yields (Table 1).
In several cases (Entries 4, 8 and 11) the cyclization was additionally performed under
thermal or microwave conditions using the novel airꢀstable catalyst [CpCo(transꢀ
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2 2 3
MeO CHC=CHCO Me){P(OEt) }], leading to the desired products in moderate to good
1
9
yields. However, in the case of lactone 29, a minor yield was observed under microwave
conditions (21%), which can be attributed to the decomposition of the ester moiety under
these reaction conditions. The products could easily be isolated by column chromatography
and in some cases unreacted diyne was recovered and recycled. The use of MeCN instead of
PhCN led to the formation of the methylated pyridine 28 in significantly higher yield (Table
0
1
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1
, heterobiaryls 27 and 28, entries 2 and 3). While most compounds are stable solids after
isolation, the mesitylꢀsubstituted amine 24, as well as the disiloxaneꢀderived compounds 27
and 28 were isolated as oils. Cyclization of 14 with PhCN under microwave conditions
furnished 33 in 71% yield. The cyclization of enediyne 22 indeed gave the expected product
35, containing the exocyclic double bond and only very minor amounts of the internal
isomerization product with an endocyclic double bond.
In the case of naphthyldiynol 25 the reaction delivered a mixture of products with both
conventional heating or under microwave conditions. Diastereomers of the expected benzylic
alcohol 36 and unexpected ketone 37 were formed. Formation of 37 is easy recognizable from
the intense yellow color of the compound. This unusual direct oxidation under cycloaddition
conditions was also observed when Oꢀacetylated diynol 25 was subjected to the cycloaddition
reaction under photochemical conditions.
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Table 1. Synthesis of the heterobiaryls by photoꢀ and Coꢀcatalyzed [2+2+2] cycloaddition
reaction of diynes with nitriles.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
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45
46
47
48
49
50
51
52
53
54
55
56
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[a]
Entry
Diyne
Nitrile
Biaryl
Conditions
Yield
1
4
PhCN
Cat: [CpCo(COD)]
43%
THF, h·ν, 0 °C
Cat: [CpCo(COD)]
2
3
6
6
PhCN
44%
93%
THF, h·ν, 0 °C
Cat: [CpCo(COD)]
MeCN
THF, h·ν, 0 °C
Ph
O
Cat: [CpCo(COD)]
[b]
4
5
8
9
PhCN
PhCN
N
39% (21%
)
O
29
OMe
THF, h·ν, 25 °C
Cat: [CpCo(COD)]
42%
THF, h·ν, 25 °C
Cat: [CpCo(COD)]
6
7
8
9
11
12
14
18
PhCN
PhCN
PhCN
PhCN
62%
35%
THF, h·ν, 25 °C
Cat: [CpCo(COD)]
THF, h·ν, 25 °C
Cat:
[b]
71%
2 2 3
[CpCo(transꢀMeO CHC=CHCO Me){P(OEt) }]
Toluene, MW, 140 °C
Cat: [CpCo(COD)]
70%
THF, h·ν, 25 °C
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[b]
Cat:
[c]
1
0
1
22
25
PhCN
PhCN
56%
[CpCo(transꢀMeO
2
CHC=CHCO
CHC=CHCO
2
Me){P(OEt)
3
}]
}]
Toluene, 100 °C
[
b]
Cat
CpCo(transꢀMeO
Toluene, MW, 140 °C
:
1
14% (36);
[
2
2
Me){P(OEt)
3
[
b,d]
4
3% (37)
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0
[a] Isolated yields. [b] The cycloaddition was performed under microwave conditions at 140 °C in
toluene with [CpCo(transꢀMeO CHC=CHCO Me){P(OEt) }] as catalyst. [c] The cycloaddition was
performed at 100 °C in toluene with [CpCo(transꢀMeO CHC=CHCO Me){P(OEt) }] as catalyst. The
product contained ca. 20% of the compound with the endoꢀisomerized double bond. [d] After workꢀup
of the reaction mixture, purification by chromatography on silica gel yielded the expected 36 and
ketone 37.
2
2
3
2
2
3
Alcohol 36 was formed as a mixture of diastereomeric atropisomers due to the presence of the
stereogenic carbon atom carrying the hydroxyl group. Accordingly, further functional group
conversions were executed to eliminate this additional racemic stereo center to gain access to
either ketone 37 or the reduced compound 38. Because we had the alcohol 36 already in our
hand, the derivative 38 containing a methylene group was targeted (Scheme 4). Therefore, 36
was initially transformed into the tosylate ester with tosyl chloride. The subsequent reduction
4
with LiAlH , however, did not work in our case to finally afford 38. An alternative approach
starting from ketone 37 via WolffꢀKishner reduction under microwave (MW) conditions
initially proved to be troublesome after the successful formation of the hydrazide intermediate
and subsequent reaction with aqueous KOH solution. Under the chosen conditions, a possible
decomposition to undesired sideꢀproducts was a major process. An alternative approach
applying an excess of hydrazine hydrate without added base at 180 °C in diglyme under
microwave conditions was finally successful and furnished the desired compound 38 in 83%
2
1
yield. As indicated in Scheme 4, compound 38 slowly reoxidizes in solution to ketone 37,
which might also explain the favored isolation of 38 from the cyclotrimerization reaction (see
22
Table 1). From these transformations we were able to obtain two heterobiaryls (37 and 38)
possessing an annulated phenyl group in the backbone of the newly formed biaryl system and,
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in addition, exhibiting two electronically different substituents in the C position (compare
Scheme 1), whose influence on the biaryl axis stability should be possible to study.
Scheme 4. Transformation of primary cyclization product 36 into the oxidized ketoꢀform 37
and the reduced methyleneꢀcontaining heterobiaryl 38.
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22
23
24
25
26
27
28
29
30
31
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34
35
36
37
38
39
40
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HO
O
Ph
Ph
Ph
N
N
N
a)
b)
3%
OMe
OMe
OMe
8
36
38
37
slowreoxidation
Reaction conditions: a) TsCl, NEt , CH Cl , 0 °C - rt; then LiAlH , Et O, 0 °C - rt.
3
2
2
4
2
2 4 2
b) N H •H O, diglyme, MW, 180 °C, 4h (MW = microwave).
We were able to corroborate the molecular structure of compound 37 by xꢀray structure
analysis of suitable crystals which were obtained by recrystallization from THF (Figure 1).
The structure displays the nearly perpendicular torsion of the planar naphthyl and pyridine
moieties.
Figure 1. Molecular structure of racemic biaryl 37 (hydrogens omitted for clarity, ellipsoids
with 30% probability).
Investigation of configurational stabilities of the heterobiaryl axes: Investigation of the
rotational barriers of atropisomerization in biaryls can be performed using spectroscopic (e.g.
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dynamic NMR), chiroptical (e.g. polarimetry, circular dichroism) or chromatographic
1,23
methods (enantioselective dynamic HPLC or GC).
In the case of stable isolable
enantiomers, the individual stereoisomer can be heated at certain temperatures and the
conversion into the opposite enantiomer is easily determined by HPLC or GC using chiral
phases. From the obtained data, the halfꢀlife time and rotational barriers can be derived, as it
was exemplified early on for 1,1’ꢀbinaphthyl and 1,1’ꢀbinaphthylꢀ2,2’ꢀdiol (BINOL) and later
0
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4
corroborated by theoretical calculations. Especially the configurational stability of BINOL,
ǂ
ꢀ1
possessing a high barrier of rotation of up to ꢀG = 158 kJ mol , deriving from the tetraꢀ
orthoꢀsubstituted biaryl system has made it one of the most frequently utilized axially chiral
2
5
structure elements for synthetic and catalytic purposes.
The successful synthesis of heterobiaryls 26ꢀ35, 37 and 38 (Table 1) gave us the opportunity
to investigate these formally triꢀorthoꢀsubstituted naphthylpyridines. Initial assessment of the
activation barrier of interconversion of the compound containing the pure carbocyclic,
ǂ
unsubstituted ring (see Scheme 1, A, B, C = CH and compound 39 in Figure 1) gave a ꢀG =
2
ꢀ1
9b, 29a
8
9 kJ mol (20 °C) from numerical approximation of the HPLC data.
This value
corroborates that the component is configurationally labile at room temperature, according to
ǂ
ꢀ1
a general estimate of ꢀG = 96 kJ mol necessary for biaryl configurational stability at this
2
6
temperature. It was expected that when introducing stabilizing structural changes in the
molecule’s backbone, these should be visible through corresponding changes in energetics for
the biaryl axis activation barrier for racemization. The convenient tool we applied here was
enantioselective dynamic HPLC analysis to determine the rate constants of interconversion k,
ǂ
ǂ
ǂ
the interconversion barriers ꢀG and the activation parameters ꢀH and ꢀS from temperatureꢀ
2
7,28,29
dependent measurements.
Initial attempts to separate the Nꢀmesitylꢀsubstituted heterobiaryl 26 via HPLC on different
chiral phases unfortunately did not lead to a successful separation of atropisomers, possibly
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pointing to a molecule with low configurational stability leading to peak coalescence or due to
lack of enantioselectivity of the chiral stationary phases. Therefore, no stabilization compared
to the completely unsubstituted fiveꢀmembered carbocycle 39 could be accounted for.
Investigations of the compounds 27 and 28 with the symmetrically substituted disiloxane
backbone were more successful and a stabilizing effect of the tetramethylꢀsubstituted
disiloxane moiety was clearly visible. While in 39, already at 20 °C, the formation of a
plateau between the signals shows the increase in the number of molecules with unhindered
rotation around the biaryl axis, a similar observation for 27 and 28 requires temperatures of up
to 40 °C. Loss of configurational stability of the heterobiaryl’s chiral axis was observed at
60 °C (Figure 2). In addition, and in accordance with the observations from 27 and 28, a
potential electronic or steric influence of the substituent on the nitrile cyclization component
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(either Me or Ph) for the configurational stability of the naphthylpyridine was found to be
ǂ
negligible. It was again possible to determine the free energy activation barrier ꢀG for 27 and
29a
ǂ
28 from the obtained data as exemplified for 39. The estimated values for 27 (ꢀG = 93 kJ
ꢀ1
ǂ
ꢀ1
mol at 22 °C) and 28 (ꢀG = 97 kJ mol at 40 °C) correspond to a slightly higher activation
barrier for the interconversion of the enantiomers compared to 39. Significant racemization
occurs already at rather low temperature and the halfꢀlife time of 27 was estimated to be
around 13 minutes at 25 °C. However, when comparing these data to those discussed in the
next paragraph for the carbonyl groupꢀcontaining heterobiaryls (Figure 3, 29, 30 and 34),
these values appear to be too high in terms of the HPLC elution profiles observed (Figure 2
and 3). The latter compounds even at 80 °C do not show peak coalescence, which would
indicate free rotation around the biaryl axis, while this is the case for 27 and 28.
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5
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5
5
5
5
6
Figure 2. Effects of substituents on configurational stability of the biaryl axis in the fiveꢀ
membered backbone ring: reference compound 39 and the heterobiaryls 27 and 28 with
[#]
tetramethyldisiloxane backbones.
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[#] THPLC is the temperature of the chiral column during the dynamic HPLC analysis.
The next set of molecules we investigated were compounds containing a carbonyl group in
the orthoꢀposition including 29, 30 and 34. The C=O group in the fiveꢀmembered ring is
assumed to be coplanar to the pyridine ring, thus representing a substituent which should be
able to efficiently hinder the rotation around the biaryl axis. These heterobiaryls display a
highly interesting behavior (Figure 3). The lactone 29 and ketone 34 display rather similar
HPLC elution profiles at different temperatures, characterized by pronounced plateau
formation, which indicates the enantiomerization by rotation around the biaryl axis. In
contrast, the lactam 30 shows no sign of enantiomerization even at 80 °C and therefore
appears to be significantly more stable than the related compounds 29 and 34. This can be
explained by the high degree of planarity of the –(C=O)–(NꢀMe)–CH – fragment due to the
2
partial “doubleꢀbond character” in the resonance structure between C and N, which obviously
imparts the higher configurational stability compared with the carbonyl congeners. A high
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substantial barrier to rotation has even been observed in the acyclic form of secondary amides
ǂ
ꢀ1 30
(
typically ꢀG = 62ꢀ84 kJ mol ).
Figure 3. Effects of different neighboring groups on the configurational stability of fiveꢀ
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26
27
28
29
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34
35
36
37
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ǂ
membered carbonylꢀcontaining backbone rings in heterobiaryls 29, 30 and 34 (
ꢀ
G at
[
#]
25 °C).
[
#] THPLC is the temperature of the chiral column during the dynamic HPLC analysis.
From the HPLC data measured at different temperatures between 35 °C and 80 °C, the free
ǂ
activation energy (
ꢀ
G ) values were determined from the rate constants of enantiomerization
ǂ
ǂ
and the activation parameters
ꢀ
H and
ꢀ
S were obtained from an Eyring plot by temperature
ǂ
dependent dynamic HPLC measurements. The
ꢀ
G values represent the differences in stability
for the various carbonyl compounds; for compound 30 a lower limit of the enantiomerization
barrier has been estimated because of negligible interconversion at 80 °C. While the energetic
ǂ
ꢀ1
difference between 29 and 34 is small (ꢀꢀG = 2.5 kJ mol ), the lactam 30 has an estimated
ǂ
ꢀ1
ꢀ
G value already over 100 kJ mol . However, all investigated heterobiaryls so far have
ǂ
ꢀ1
larger activation barrier compared to 1ꢀ(1’ꢀnaphthalenyl)isoquinoline (
ꢀ
G ~ 80 kJ mol at
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3
1
−20 °C). Comparable investigations with structurally related compounds have been
3
2
performed with atropisomeric analogues of DMAP (4ꢀdimethylaminopyridine).
We performed calculations for two model compounds, 5
Hꢀcyclopenta[c]pyridinꢀ7(6H)ꢀone
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(
40) and furo[3,4ꢀ ]pyridinꢀ3(1 )ꢀone (41), to evaluate the energetics of a possible deviation
c
H
of the annulated fiveꢀmembered ring, which could influence the interconversion also in 29
and 34 (Figure 4). The computed energies of the two compounds illustrate that the lactone
needs slightly more energy to distort from the planarity of the fiveꢀmembered ring compared
to the ketone. With increasing deviation from planarity, the required amount of energy rises
ꢀ1
significantly. At a deviation of 60° from planarity, about 18 kJ mol more energy was
required for the ester 41. This trend correlates well with the different free activation energies
derived from the dynamic HPLC experiments with 29 and 34 (Figure 3) and thus illustrates
the importance minor structural changes can have for the configurational stability of the biaryl
axis in closely related compounds.
Figure 4. Computed energy profiles for the ketone 40 and lactone 41.
A possible detour for the enantiomerization by enolization of ketone 29 was excluded by
treatment of the ketone under thermal conditions in deuterated solvents like CD
no incorporation of deuterium has been observed.
3
OD, where
2
Finally the other heterobiaryls were investigated, possessing either a –CMe – group in the A
position (compare Scheme 1) like compounds 31ꢀ33, an exocyclic double bond (compound
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35) or an annulated phenyl group in position A and B (compound 37 and 38). The
investigation of these compounds by dynamic HPLC evidenced rather large activation
barriers; as up to 80 °C column temperature no changes could be observed (Figure 5).
ǂ
ꢀ1
Therefore, the activation barriers for all these compounds are higher than ꢀG = 115 kJ mol
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34
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at 80 °C. We were able to determine the enantiomerization rate for the naphthylꢀ
tetrahydroisoquinoline compound 42, which can be synthesized with high enantioselectivity
applying the asymmetric [2+2+2] cycloaddition, by heating the solution of one enantiomer at
110 °C and subsequently analyzing the enantiomeric ratio by chiral HPLC. We found the
halfꢀlife time for racemization to be approximately 148 min corresonding to an activation
ǂ
ꢀ1
barrier ꢀG of approximately 114 kJ mol . For further comparison, the structurally very
similar 1ꢀ(2ꢀmethoxynaphthalenꢀ1ꢀyl)isoquinoline was found to possess an activation barrier
ǂ
ꢀ1
10b
of ꢀG = 117 kJ mol at 87 °C. These examples corroborate the assumption that adequate
substitution of the fiveꢀmembered ring backbone in the right position can lead to heterobiaryls
with comparable or even higher configurational stability compared to heterobiaryls possessing
sixꢀmembered backbone rings. The in A position dimethylated amines 31ꢀ33 are obviously
more rigid, independent from the substitution of the fiveꢀmembered ring nitrogen atom. This
is also obvious when comparing these with other compounds containing a dimethylated
carbon atom in the A position like the structurally related tetramethyldisiloxaneꢀsubstituted
heterobiaryls 27 and 28. The presence of a free NꢀH proton seems to have no effect on the
configurational stability as observed under HPLC conditions. The heterobiaryl 35 decorated
with an exocyclic olefin bond is structurally analogous to the ketone 34. The significantly
2
larger stability of 35 can therefore certainly be derived from the terminal CH group, which is
sterically significant larger compared to the carbonyl oxygen and leads to the observed
stabilization against free rotation around the biaryl axis. Finally, installation of an annulated
phenyl ring as for 37 and 38, which can be considered as embedding of the double bond in
position A in an aromatic system also provides significant stabilization, by increasing the
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rigidity of the newly formed fiveꢀmembered ring and increasing the steric size of the
backbone. A significant effect of the keto group in the position C of 37, which would be the
only plausible influence thinkable, was not observed.
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We isolated very small amounts of the heterobiaryls 33 and 37 from analytical chiral HPLC
separations and heated solutions of the samples at different temperatures to check the
stereochemical integrity. It was found that 37 could be heated for several hours at 120 °C
without significant racemization. Unfortunately decomposition was an interfering problem at
higher temperatures using NMP or toluene as solvent, preventing further studies.
Figure 5. Exemplary dynamic chiral HPLC diagram for 33 and activation barriers of
ǂ
investigated compounds 31ꢀ33, 35, 37 and 38 (
ꢀ
G at 80 °C) as well as compound 42 for
[#]
comparison.
[
#] THPLC is the temperature of the chiral column during the dynamic HPLC analysis.
For a better understanding of the experimental data from the dynamic HPLC investigations,
we calculated the energy profiles of the rotation around the biaryl axis for selected
3
3
molecules. A number of theoretical investigations on the rotational barriers of different
32
heterobiaryls have been reported. In our approach, we computed relative energies for a
complete 360° rotation around the biaryl axis, providing an energetic curve for model
heterobiaryls. The results corroborated a) the size of the backbone either of the naphthyl or
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the pyridine ring has a large impact of stability, b) substitution of the pyridine nitrogen for a
CꢀH group or methylation of the nitrogen significantly raises the activation barrier for the
rotation around the biaryl axis, and c) the substituent of the pyridine ring ortho to the ring
nitrogen atom (Ph or Me) plays no role for the activation barrier.
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42
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55
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58
59
60
Finally, we applied the conditions for the enantioselective photoꢀcatalyzed [2+2+2]
9
cycloaddition with the chiral Co(I)ꢀindenyl complex 43 to diyne 25 and benzonitrile, to prove
the higher configurational stability of the products’ biaryl axis under these reaction conditions
(
Scheme 5). As it was mentioned in the beginning this reaction failed to deliver compound 39
with any selectivity. We investigated several conditions, also at lower reaction temperatures
as low as 20 °C to maximize the enantioselectivity, however, at these low temperatures no
̵
reaction was observed. We then successfully performed the reaction at 0° under
photochemical conditions.
Scheme 5. Coꢀcyclotrimerization of diyne 25 with PhCN, yielding enantiomerically enriched
heterobiaryl product 37.
To our delight the expected heterobiaryl product 37 was formed, albeit with low yield, but
much more important with an enantiomeric ratio of 72:28, demonstrating exemplarily that
here the barrier of rotation was large enough to allow the enantioselective syntheses of 37,
possessing a substituted fiveꢀmembered backbone ring. This also substantiates the assumption
that the appropriate configuration of the backbone ring can result in a barrier of rotation large
enough to be useful for further enantioselective elaborations.
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6
Conclusion
The presented investigation details the systematic synthetic approach for a series of
heterobiaryls containing pyridines with annulated, differently substituted fiveꢀmembered ring
systems by Coꢀcatalyzed cyclotrimerization of unsymmetrical diynes with acetoꢀ or
benzonitrile reactions as the key step. Many of the unsymmetrically substituted diynes with
structurally diverse connections of the two alkyne moieties were synthesized for the first time.
The photochemical cycloaddition of the diynes and nitriles catalyzed by [CpCo(COD)] was
found as an efficient possibility for the construction of the heterobiaryls. Application of
0
1
2
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8
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[
2 2 3
CpCo(transꢀMeO CHC=CHCO Me){P(OEt) }] under thermal or microwave conditions
proved to be even superior for certain cases. The obtained heterobiaryl racemates were
investigated in terms of their configurational stability of the newly formed stereogenic biaryl
axis by dynamic HPLC on different chiral phases. Some of the compounds display
remarkable differences while increasing the column temperature, showing that small
structural differences can play a large role for the stabilization of the biaryl axis. From these
ǂ
HPLC investigations it was possible to determine the free energy activation barriers (
ꢀ
G ) for
the enantiomerization process. It was found that A) the heterobiaryls with a
tetramethyldisiloxane backbone (27 and 28) are configurationally more stable compared to
the compound with an unsubstituted fiveꢀmembered ring (39); B) introduction of a carbonyl
group as a member of the fiveꢀmembered ring and at the pyridine ring ortho to the biaryl axis
ǂ
ꢀ1
significantly raises the free energy activation barriers (ꢀG = 96.8 ꢀ ~103 kJ mol ), especially
depending on the group adjacent to the C=O group in the fiveꢀmembered ring (CH , O or
2
NMe). The fiveꢀmembered lactam ring provided the largest stabilization of the biaryl axis; C)
we found, that the introduction of a cyclic amine possessing a “CMe
2
” group ortho to the
ǂ
ꢀ1
biaryl axis significantly raises the activation barrier over
ꢀ
G = 115 kJ mol ; D) the same
effect was found for an exocyclic double bond ortho to the biaryl axis and also the connection
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of an annulated phenyl ring at the fiveꢀmembered ring backbone. Comparison with biaryl 42,
possessing a sixꢀmembered ring in the backbone, yielded comparable activation enthalpies.
This demonstrates the feasibility of stabilizing the configuration of the biaryl axis by
appropriate substitution of the fiveꢀmembered ring.
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40
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42
43
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48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 6. Summary on the observed effects of backbone substituents on biaryl axis
stabilization.
In summary, the investigations demonstrated that in addition to the novel synthetic access to
this class of increasingly important unsymmetrically substituted heterobiaryls, the suitable
substitution of fiveꢀmembered ring backbones can significantly support the configurational
stability of the biaryl axis of such systems (Scheme 6). As further evidence the
enantioselective photocatalyzed [2+2+2] cycloaddition of diyne 25 applying a chiral Co(I)ꢀ
catalyst enabled the formation of the corresponding heterobiaryl product 37 with an er of
72:28.
Experimental Section
The NMR spectra were in general recorded at 298 K and the individual measurement
1
13
conditions given with the data. Chemical shifts are reported in ppm relative to the H and C
1
residue signals of the deuterated solvent (deuterochloroform: δ 7.26 ppm for H and δ 77.16
13
ppm for C). Mass spectra were obtained with a mass spectrometer at an ionizing voltage of
70 eV for EI. Only characteristic fragments containing the isotopes of highest abundance are
listed. Relative intensities in percentages are given in parentheses. Highꢀresolution mass
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6
spectroscopy (HRMS) analyses were performed using electrospray ionization/ timeꢀofꢀflight
(ESIꢀTOF) mass spectrometry or electron ionization (EI) with a sector field mass analyzer.
Melting points were not corrected. In all cases the enantiomeric excesses of pyridines were
analyzed by HPLC using appropriate chiral columns. For the photochemistry two halogen
lamps (460 W each) have been used for irradiation of the thermostated Schlenkꢀtype reaction
vessel (pictures of the setꢀup are given in the Supporting Information). All reactions were
carried out in an argon atmosphere, using standard techniques in dry, oxygenꢀfree solvents.
The liquid reagents were distilled under argon prior to use. All solid compounds used for the
photoꢀcatalyzed reactions were recrystallized from degassed solvents and the liquid starting
materials were dissolved in the appropriate solvent and dried over and distilled from
molecular sieves under argon before use. For microwave experimentation we used a CEM
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3
4
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9
0
TM
Discover SP with glass tubes. Chromatographic purifications were done with 240ꢀ400 mesh
3
4
35
3 4
silica gel or on an automated flashꢀchromatography system. CpCo(COD), Pd(PPh ) ,
35
36
Pd
2
dba
3
•CHCl
3
,
1ꢀiodoꢀ2ꢀmethoxynaphthalene (1)
and 3ꢀ(2ꢀmethoxynaphthalenꢀ1ꢀ
14
yl)propiolic acid (7) were synthesized according to known procedures. 1ꢀEthynylꢀ2ꢀ
3
7
methoxynaphthalene (2) was prepared after either one of the published procedures. The
synthesis and catalytic properties of the airꢀstable precatalyst [CpCo(trans
ꢀ
1
9
2 2 3
MeO CHC=CHCO Me){P(OEt) }] has been reported by us recently. All other starting
materials and compounds were commercially available and have been purchased or were
prepared by procedures described below.
Preparation of cyclization substrate molecules
Nꢀ(3ꢀ(2ꢀmethoxynaphthalenꢀ1ꢀyl)propꢀ2ꢀynyl)ꢀ2,4,6ꢀtrimethylꢀNꢀ(propꢀ2ꢀynyl)aniline (9)
2,4,6-Trimethyl-N,N-di(prop-2-ynyl)aniline (3)
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The synthetic procedure for 2,4,6ꢀtrimethylꢀN,Nꢀdi(propꢀ2ꢀynyl)aniline (3) was derived
3
8
according to published work. In a 3ꢀnecked flask equipped with reflux condenser anhydrous
CO (21.9 g, 159.8 mmol) was suspended in DMF (135 mL). Afterwards, the 2,4,6ꢀ
K
2
3
trimethylaniline as well as the propargyl bromide (18 mL, 159.8 mmol, 80% soln. in toluene)
were added and the reaction mixture stirred at 100 °C for 18 h. Then additional propargyl
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28
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60
bromide and K
continued for another 2 h. After cooling, the reaction was quenched with water and then
extracted with ethyl acetate. After drying over MgSO and evaporation of the solvent, the oily
2 3
CO (one fifth of the original amounts each) were added and heating at 100 °C
4
ꢀ2
residue can be purified either by bulb to bulb distillation (ca. 4·10 mbar, 100 °C) in high
vacuum or column chromatography on silica gel with petrol ether/ethyl acetate (10:1, v/v) as
the eluent. The known product was obtained as a slightly yellow liquid (yield: 10.7 g, 76%).
1
H NMR (300 MHz, CDCl
3
):
δ = 6.87 (s, 2H), 3.98 (d, J = 2.3 Hz, 4H), 2.35 (s, 6H), 2.29 (s,
1
3
3
1
9
H), 2.25 (t,
J
= 2.3 Hz, 2H) ppm. C NMR (75 MHz, CDCl
3
):
δ
= 144.3, 137.5, 135.4,
+
29.5, 81.3, 71.8, 41.4, 20.9, 19.5. ppm. MS (EI, 70 EV): 211 (69) [M] , 172 (71), 157 (100),
1 (28), 77 (20), 39 (32).
N-(3-(2-Methoxynaphthalen-1-yl)prop-2-ynyl)-2,4,6-trimethyl-N-(prop-2-ynyl)aniline (4)
The best results were obtained utilizing the Sonogashira reaction according to the following
procedure: 1ꢀIodoꢀ2ꢀmethoxynaphthalene (1, 1.83 g, 6.44 mmol), Pd(PPh
mmol, 5 molꢀ%), CuI (182 mg, 0.96 mmol, 15 molꢀ%) were secured in a Schlenk flask under
argon. Et N (80 mL), the 2,4,6ꢀtrimethylꢀN,Nꢀdi(propꢀ2ꢀynyl)aniline (3, 4.08 g, 19.3 mmol)
3 4
) (370 mg, 0.32
3
and finally THF (20 mL) were added subsequently and the reaction mixture heated to 50 °C.
After 60 min a thick precipitate already formed and the reaction was stopped after 15 h, when
TLC showed complete consumption of iodide. The reaction mixture was quenched with sat.
4
NH Cl soln. and stirred for 15 min. The phases were separated and the aqueous phase was
extracted several times with ether and the combined organic phases washed with sat. NaHCO
3
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2 4
soln. and brine. After drying over Na SO and removal of the solvent, the dark oily residue
containing large amounts of unreacted amine was charged to silica gel and purified by
chromatography, using petrol ether/ethyl acetate (3:1, v/v) as the eluent. It turned out to be
beneficial to remove excessive diyne 3 by bulb to bulb distillation before the chromatographic
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purification. The pure product is a yellow solid (1.07 g, 45%). For further purification the
1
product can be recrystallized from Et
MHz, CDCl ): = 7.98 (d, = 8.4 Hz, 1H), 7.79 (d,
= 8.4, 6.8, 1.3 Hz, 1H), 7.37 (ddd, = 8.0, 6.9, 1.2 Hz, 1H), 7.23 (d,
H), 6.90 (s, 2H), 4.42 (s, 2H), 4.11 (d, = 2.4 Hz, 2H), 4.01 (s, 3H), 2.42 (s, 6H), 2.31 (s,
= 2.4 Hz, 1H) ppm. C NMR (100 MHz, CDCl ): = 158.9, 144.4, 137.8,
2
O/
n
ꢀpentane (2:1, v/v). Mp. 106ꢀ108 °C. H NMR (400
3
δ
J
J
= 9.1 Hz, 1H), 7.77 (d,
J
= 8.0 Hz, 1H),
= 9.1 Hz,
7
1
3
1
7
.45 (ddd,
J
J
J
J
13
H), 2.28 (t,
J
3
δ
35.3, 134.8, 129.7, 129.6, 128.6, 128.0, 127.2, 125.6, 124.2, 112.9, 106.7, 96.5, 81.7, 78.3,
+
1.8, 56.7, 42.9, 41.9, 21.0, 19.6 ppm. MS (ESI): 366 (18) [MH] , 195 (100). Anal. calcd for
26
C H25NO (367.48): C 84.98, H 6.86, N 3.81. Found: C 84.71, H 6.88, N 3.51.
3ꢀ(2ꢀMethoxynaphthalenꢀ1ꢀyl)ethynꢀ2ꢀynyl)ꢀtetramethyldisiloxane (6)
2 3 3
In a 250 mL Schlenk flask, Pd dba •CHCl (437 mg, 0.42 mmol, 6 mol%), CuI (402 mg, 2.11
mmol, 15 mol%) and dppf (505 mg, 0.92 mmol, 6.5 mol%) were evacuated and backfilled
with argon three times. THF (15 mL) was added and the mixture stirred for a short period (ca.
20 min) at rt. In another Schlenk flask 1 (4.0 g, 14.1 mmol) was set up as above and dissolved
in THF (9 mL). To the catalyst solution Et N (120 mL) as well as 1,3ꢀ
3
diethynyltetramethyldisiloxane (5, 5.14 g, 28.2 mmol) were added. The solution of the
naphthyliodide 1 was then charged to a 10 mL syringe, connected to the reaction flask via a
Teflon tubing and a needle and afterwards the syringe was clamped into a syringe pump. The
reaction mixture was heated to 45 °C and the addition of the diyne started with 1 mL of the
solution immediately and then with an addition rate of 2.5 mL/h. After stirring for a total time
of 22 h, the reaction was allowed to cool down and subsequently quenched with sat. NH
4
Cl
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soln. under argon. The aqueous phase was extracted with ethyl acetate (3x), the combined
organic phases washed with water and brine and dried over Na SO . After evaporation of the
2
4
solvent, a darkꢀbrown oily residue remained and the excessive diyne was removed in high
vacuum. The crude product was charged to silica gel and purified by flashꢀchromatography
10
11
12
13
14
15
16
17
18
19
20
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23
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60
with nꢀheptane and ethyl acetate, yielding two main fractions: diarylated byproduct (903 mg,
13%) and the monoarylated product 6 (oil, 2.28 g, 48%). We later developed a modified
procedure, preventing the formation of the diarylated product, however, the overall yields are
1
2
1
lower. Characterization data for compound 6: H NMR (300 MHz, CDCl
3
):
= 8.3, 6.9, 1.4 Hz,
= 9.1 Hz, 1H), 4.03 (s, 3H), 2.46 (s, 1H),
): = 159.8, 134.8, 130.6, 128.4,
δ = 8.32 (d, J =
8
.3 Hz, 1H), 7.83 (d, = 9.1 Hz, 1H), 7.79 (d, = 8.1 Hz, 1H), 7.56 (ddd, J
J
J
1H), 7.40 (ddd,
J
= 8.1, 6.9, 1.2 Hz, 1H), 7.23 (d, J
13
0
.48 (s, 6H), 0.41 (s, 6H) ppm. C NMR (75 MHz, CDCl
3
δ
29
1
28.0, 127.4, 125.3, 124.2, 112.7, 105.8, 103.1, 98.7, 92.2, 89.4, 56.5, 2.4, 2.0 ppm. Si
+
NMR (79 MHz, CDCl3):
δ
= −16.5, −16.7 ppm. MS (EI, 70 eV), m/z (%): 338 (61) [M ], 323
23 2 2
(95), 308 (57), 293 (100), 283 (70), 189 (28), 165 (26). HRMS (pos. ESI) for C19H O Si
+
[
MH ]: calcd 339.1231, found 339.1234.
Propꢀ2ꢀynyl 3ꢀ(2ꢀmethoxynaphthalenꢀ1ꢀyl)propiolate (8)
In a 50 ml Schlenk tube 1ꢀethynylꢀ2ꢀmethoxynaphthalene (2, 770 mg, 4.23 mmol) was
evacuated and backfilled with argon three times. Then THF (20 mL) was added and the
resulting solution was cooled to –78 °C, following by the addition of
n
ꢀBuLi (1.5M, 3.0 ml,
.44 mmol) at this temperature. After 10 min the reaction mixture was allowed to warm to
°C and stirred for additional 20 min. Afterwards the mixture was cooled again down
4
0
to ꢀ78 °C and propargyl chloroformate (526 mg, 0.44 mL, 4.44 mmol) was added via syringe
slowly. The reaction solution was stirred for further 15 min, then stirred in an iceꢀbath for 3 h
4
and finally allowed to warm to rt. The brown reaction mixture was quenched with sat. NH Cl
soln. and extracted with Et O (2x). The combined organic layers were washed with washed
2
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6
2 4
with water (3x) and brine und dried over Na SO . The crude product charged to silica gel and
purified by chromatography with petrol ether and ethyl acetate (4:1 v/v), yielding 8 as slightly
yellowish solid (845 mg, 76%).
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Alternative approach for 8: 3ꢀ(2ꢀMethoxynaphthalenꢀ1ꢀyl)propiolic acid (7, 500 mg, 2.21
mmol) and 4ꢀdimethylaminopyridine (DMAP) (26.9 mg, 0.22 mmol) were evacuated in a 25
ml Schlenk tube and backfilled with argon three times. Afterwards CH
alcohol were added and the reaction mixture cooled to 0 °C. 'ꢀDicyclohexylcarbodiimide
DCC) (912 mg, 4.42 mmol) was added in portions under inert conditions and the reaction
2 2
Cl and propargyl
N,N
(
mixture stirred for 16 h. TLC control showed complete conversion and a new spot. Finally,
the reaction mixture was quenched with HCl (0.25M), the aqueous phase extracted with
2 2
CH Cl several times and then washed again with HCl (0.25M). Afterwards, the organic
phase was washed with sat. NaHCO soln., water and brine and dried over Na SO . The crude
3
2
4
product was charged to silica gel and purified by chromatography with
n
ꢀhexane and ethyl
1
acetate (4:1, v/v), yielding 8 as a whiteꢀyellow solid (386 mg, 67%). Mp. 98ꢀ99 °C. H NMR
(300 MHz, CDCl
H), 7.59 (ddd,
Hz, 1H), 4.88 (d,
MHz, CDCl ):
3
):
δ = 8.22 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.79 (d, J = 8.2 Hz,
1
J
= 8.5, 6.8, 1.3 Hz, 1H), 7.41 (ddd,
J
= 8.2, 6.8, 1.2 Hz, 1H), 7.24 (d, J = 9.2
13
J
= 2.5 Hz, 2H), 4.04 (s, 3H), 2.56 (t,
J
= 2.5 Hz, 1H) ppm. C NMR (75
3
δ = 162.1, 153.6, 135.1, 133.5, 128.5 (2x), 128.3, 124.9, 124.8, 112.3, 102.1,
89.3, 83.7, 75.7, 56.7, 53.2 ppm (one C could not be detected, presumably due signal
+
overlap). MS (EI, 70 eV), m/z (%): 264 (48) [M ], 220 (65), 205 (25), 191 (25), 182 (78), 163
(
32), 152 (100), 139 (75). HRMS (EI) for C H O : calcd 264.0781, found 264.0781.
17 12 3
3ꢀ(2ꢀMethoxynaphthalenꢀ1ꢀyl)ꢀNꢀmethylꢀNꢀ(propꢀ2ꢀynyl)propiolamide (16)
Methyl(prop-2-ynyl)carbamic chloride
15
The general preparation for this class of compounds was reported.
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Page 29 of 53
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
In a 250 mL Schlenk flask triphosgene (2.95 g, 9.95 mmol) was dissolved in CH
2
Cl
ꢀmethylpropꢀ2ꢀ
2
(20 mL) were added slowly, while adjusting the
2
(30 mL)
and cooled to –78 °C. Dry pyridine (0.25 mL, 3.0 mmol) and a solution of
ynꢀ1ꢀamine (2.5 mL, 28.0 mmol) in CH Cl
N
2
pressure to the atmospheric pressure. Afterwards the reaction mixture was allowed to warm to
rt, continuing stirring for another 68 h. After evaporation of the solvent the crude product was
distilled in vacuum at 80 °C oilꢀbath temperature. Methyl(propꢀ2ꢀynyl)carbamic chloride is a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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26
27
28
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48
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51
52
53
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55
56
57
58
59
60
yellowish oily liquid, which becomes dark brown after storage for several weeks in fridge
1
(
yield: 2.22 g, 60%). H NMR (300 MHz, CDCl
3
):
δ
= 4.23 (d,
= 2.4 Hz, 0.38H), 2.33 (t,
= 149.8/148.7, 76.7/76.6, 73.7, 42.4/39.7,
J
= 2.4 Hz, 0.8H), 4.14 (d,
J =
2
0
3
.5 Hz, 1.2H), 3.15 (s, 1.8 H), 3.05 (s, 1.2H), 2.36 (t,
J
J
= 2.5 Hz,
1
3
.62H) ppm. C NMR (75 MHz, CDCl
3
):
δ
13
7.5/36.1 ppm (there are too many C signal, due to the formation of rotamers; accordingly,
these signals are separated with „/“).
3-(2-Methoxynaphthalen-1-yl)-N-methyl-N-(prop-2-ynyl)propiolamide (9)
In a 250 ml Schlenk tube 1ꢀethynylꢀ2ꢀmethoxynaphthalene (2, 640 mg, 3.51 mmol) was
evacuated and backfilled with argon three times. Then THF (20 mL) was added and the
resulting solution was cooled to –78 °C, following by the addition of nꢀBuLi (1.6M, 2.3 ml,
3.7 mmol) at this temperature. After 10 min the reaction mixture was allowed to warm to
roomꢀtemperature and stirred for additional 30 min. Afterwards the mixture was cooled again
down to –78 °C and methyl(propꢀ2ꢀynyl) carbamic chloride (466 mg, 3.51 mmol) was added
via syringe slowly. The reaction solution was then allowed to warm to rt over night. The
mixture was quenched with water and extracted with CH
2
Cl
2
(3x 20 mL each). The combined
. The crude product charged to
organic layers were washed with brine und dried over Na
2
SO
4
silica gel and purified by chromatography with nꢀhexane and ethyl acetate (1:1 v/v + 2%
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