Diastereomeric atropisomers from a chiral diyne by cobalt(I)-catalyzed cyclotrimerization

Article abstract of DOI:10.1002/ejoc.201200402

The reaction of new, chiral, proline-based naphthyl diynes with different nitriles through a key [2+2+2] cycloaddition reaction step catalyzed by Co ^I-olefin complexes under thermal and photochemical conditions gave diastereomeric atropisomers in good yield and nearly 1:1 ratios. Facile chromatographic separation of the naphthyl tetrahydroisoquinolines gave access to both pure and stable diastereomeric atropisomers. The deprotection and direct functionalization of the methyl-or methoxymethyl-protected 2-naphthyl position of the atropisomers were investigated. The configuration of the formed atropisomers was assigned from results of X-ray studies and circular dichroism spectroscopy.

Full text of DOI:10.1002/ejoc.201200402

Job/Unit: O20402
/KAP1
Date: 04-09-12 15:49:07
Pages: 12
FULL PAPER
DOI: 10.1002/ejoc.201200402
Diastereomeric Atropisomers from a Chiral Diyne by Cobalt(I)-Catalyzed
Cyclotrimerization
Fabian Fischer,[a] Phillip Jungk,[a] Nico Weding,[a] Anke Spannenberg,[a] Holger Ott,[b] and
Marko Hapke*[a]
Keywords: Homogeneous catalysis / Cobalt / Cycloaddition / Cyclotrimerization / Atropisomerism / Biaryls / Alkynes
The reaction of new, chiral, proline-based naphthyl diynes
with different nitriles through a key [2+2+2] cycloaddition re-
action step catalyzed by CoI–olefin complexes under thermal
and photochemical conditions gave diastereomeric atropiso-
mers in good yield and nearly 1:1 ratios. Facile chromato-
graphic separation of the naphthyl tetrahydroisoquinolines
gave access to both pure and stable diastereomeric atropiso-
mers. The deprotection and direct functionalization of the
methyl- or methoxymethyl-protected 2-naphthyl position of
the atropisomers were investigated. The configuration of the
formed atropisomers was assigned from results of X-ray stud-
ies and circular dichroism spectroscopy.
it might also be very interesting to gain access to biaryl
systems with more than one stereogenic element, that is to
introduce a different stereochemical element into the pre-
cursor that is not meant to act as an auxiliary and be
cleaved from the final product in a later step, but rather
stays in it. In this way one can gain access to a pair of
diastereomeric atropisomers with different properties and
that might even be easily separated. Classes of different dia-
stereomeric atropisomers have been described and their
properties towards asymmetric synthesis and stability of the
stereoisomers, as well as their use in chiral separations, have
been studied.[9] The approach presented herein was aimed
at the synthesis of diastereomeric aryl pyridines, containing
two different stereochemical elements, by different achiral
CoI–olefin catalysts, and their synthetic potential was inves-
tigated.
Introduction
The large body of experimental work on synthetic ap-
proaches to chiral biaryls highlights their importance in
many fields of organic chemistry and especially in catalysis
today.[1] Biaryls are a widespread structural element in nat-
ural products,[2] and recently their role in pharmacological
ingredients was also discussed.[3] Within the array of dif-
ferent methods, the [2+2+2] cycloaddition reaction has de-
veloped into a mature methodology for this purpose in re-
cent years.[4] The construction of heterocyclic ring systems
by cross-cyclotrimerization has also been established for the
synthesis of pyridine and related systems.[5] However, the
use of cobalt-catalyzed cycloaddition reactions as a key step
in the construction of natural products has been applied in
numerous examples.[6] A highly interesting example is the
preparation of Steganone analogues by Motherwell et al.,
notably because of the very interesting and intriguing struc-
ture of the molecule.[7] Beside the axis of a atropisomeric
biaryl moiety two more stereogenic elements are derived
from a trans-fused γ-lactone ring. The synthetic approach
featured the preparation of the chiral diyne and the final
elaboration of the second aromatic ring providing the biaryl
axis by application of a [2+2+2] cycloaddition reaction.
We are interested in the synthesis of chiral biaryl systems
containing pyridine fragments.[8] For potential applications,
for example, as ligands in stereoselective catalysis, however,
Results and Discussion
The use of a cheap and synthetically versatile chiral
group in diyne substrate 2 and the application of an achiral
CoI-catalyzed [2+2+2] cycloaddition with nitriles should re-
sult in the formation of both diastereomeric atropisomers,
which, after separation, should provide access to both dia-
stereomerically pure stereoisomers (1, Scheme 1).[10]
These diastereomeric atropisomers should be a highly
useful platform for further introduction of functionalities,
especially regarding the preparation of new ligand systems.
Before the start of the synthetic sequence with the chiral
diyne substrate, the choice of the chiral group was essential
(Scheme 2). It was required that it (a) provided a configura-
tionally stable chiral center and (b) could be incorporated
into the backbone of the diyne moiety in a synthetically
straightforward fashion. Initially, we considered proline (3)
[a] Leibniz-Institut für Katalyse e.V. (LIKAT) an der Universität
Rostock,
Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Fax: +49-381-1281-51213
E-mail: marko.hapke@catalysis.de
Homepage: www.catalysis.de
[b] Bruker AXS GmbH, Östliche Rheinbrückenstr. 49,
76187 Karlsruhe, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200402.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O20402
/KAP1
Date: 04-09-12 15:49:07
Pages: 12
M. Hapke et al.
FULL PAPER
Scheme 1. Approach for the synthesis of diastereomeric biaryls 1
containing two chiral elements.
and tartaric acid derived 2,3-O-isopropylidenethreitol (4) as
suitable chiral precursor compounds (Scheme 2). For the
latter, the preparation of alkynylated derivatives was not
very convenient and low yielding, making it an unattractive
approach.[11] Therefore, we chose (S)-proline [(S)-3] as the
chiral group.
Scheme 3. Synthesis of the alkynylated naphthalene derivatives 6
and 8 (TMS = trimethylsilyl, dba = dibenzylideneacetone, dppf =
1,1Ј-bis(diphenylphosphanyl)ferrocene).
presence of PPh3 and elemental iodine, turned out to be a
very smooth reaction with up to an excellent yield of 82%,
providing pure (S)-11 as a dark oil after chromatographic
purification.
Scheme 2. Chiral groups investigated and the retrosynthetic ap-
proach for the proline-based chiral diyne.
The convergent synthesis of the chiral diyne cycload-
dition substrate started with the preparation of the appro-
priate methoxy-protected naphthalene derivative 6 from 5
as well as the MOM-protected (MOM = –CH2OCH3)
Scheme 4. Synthesis of (S)-proline derivative (S)-11.
Finally, the complete chiral diyne precursors needed to
naphthalene 8 from 7 (Scheme 3).[12] While the methoxy be assembled (Scheme 5). After testing the reaction with
group proved to be very useful in cycloaddition reactions different additives, such as 1,3-dimethyl-3,4,5,6-tetrahydro-
with related naphthyl derivatives,[8] the use of the MOM 2(1H)-pyrimidinone (DMPU), the simple reaction of lithi-
group should be beneficial for the ease of cleavage to pro- ated acetylene 6 with (S)-11 under reflux was the best cou-
vide a free hydroxy group. The synthesis of compound 8 has pling protocol. However, the maximum isolated yield for
been described before,[13] but we used a modified procedure: (S)-12 was 60%, but some unreacted starting material could
deprotonation of 7 with NaH in DMF/THF and quenching be recovered from the reaction mixture after workup and
with MOMCl gave the protected naphthole, which was then purification. For the reaction with MOM-protected alkyne
subjected to a Sonogashira reaction and deprotection to 8, we initially applied Grignard reagents for the deproton-
give arylacetylene 8.
ation of the terminal alkyne to circumvent possible depro-
The synthesis of the required chiral proline coupling tonation in the 3-position of the naphthyl ring by the use
component, (S)-11, started from enantiomerically pure (S)- of nBuLi, which would possibly be alleviated by the MOM
proline [(S)-3] (Scheme 4). The one-pot esterification/prop- group. However, deprotonation seemed to proceed
argylation sequence gave ester (S)-9, which could easily be smoothly as expected, and subsequently, reaction with iod-
reduced to the corresponding alcohol (S)-10 by using ide (S)-11 occurred. Usual workup yielded a product that
1
LiAlH4 in ethyl ether, with good yields in both cases. The showed the expected resonances for (S)-13 in the H NMR
final iodination, involving a substitution reaction in the spectrum, comparable to the resonances of (S)-12 for iden-
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20402
/KAP1
Date: 04-09-12 15:49:07
Pages: 12
Diastereomeric Atropisomers from a Chiral Diyne
tical parts of the molecule. Unfortunately, a side reaction spectroscopy of the crude product or in the isolated
seemed to have occurred because additional signals were amounts of the products, regardless of whether THF or tol-
identified to indicate that the isolated coupling product was uene was used as the solvent. This observation was unsur-
not the expected product (S)-13.[14] For comparison, we prising because the chiral proline moiety was too far from
then utilized the same conditions with nBuLi as those used the reaction center to induce significant selectivity; there-
for the preparation of (S)-12. Coupling product (S)-13 was fore, both atropisomers could be concurrently constructed.
isolated in a yield of 58% (Scheme 5). The use of lithium This finding was complemented by the ease of separation
diisopropylamide (LDA) as the deprotonating base did not of both diastereomeric atropisomers, which could be sepa-
give any advantages.
rated by simple column chromatography on silica gel, yield-
ing the pure individual diastereomers (S)-(aS)-16 and (S)-
(aR)-16.
Scheme 5. Successful synthesis of the chiral diynes (S)-12 and (S)-
13.
Scheme 6. Cobalt-catalyzed [2+2+2] cycloaddition reaction of (S)-
12 with acetonitrile, using different catalysts systems, to provide the
diastereomeric atropisomers 16. The stereochemistry of (S)-(aS)-16
was determined by X-ray crystallography; see below.
With chiral diynes (S)-12 and (S)-13 in hand, we set out
to investigate the CoI-catalyzed [2+2+2] cycloaddition reac-
tion with nitriles as the key step.[15] The cycloaddition reac-
tion with substrates possessing a methoxy group in the 2-
To gain insight into the stability of the diastereomers (S)-
position of the naphthalene system, such as (S)-12, was (aS)-16 and (S)-(aR)-16, we heated solutions of the biaryls
known to be more successful than that of substrates with in [D8]toluene in Young NMR tubes and monitored the
other groups; therefore, we first investigated this substrate.[8] appearance and disappearance of significant resonances
Two different CoI catalyst systems were evaluated towards such as the methoxy group of the respective diastereomers
their usefulness in the assembly of the chiral diyne sub- by 1H NMR spectroscopy. The experiments showed that
strates (S)-12 and (S)-13. The complex [CpCo(cod)] (14; the half-life time was about 7.5 h at 100 °C for both dia-
cod = 1,5-cyclooctadiene, Cp = cyclopentadiene) is a well- stereomers, which were converted into the opposite stereo-
known catalyst with a long history as a catalyst in cyclo- isomer. Finally, 1:1 mixtures of both diastereomers were ob-
trimerization reactions.[4] Whereas this complex requires tained after heating for 15 h. Therefore, it can be concluded
rather high temperatures under thermal reaction conditions, that the formation of neither of the investigated dia-
significantly milder conditions are possible with a photo- stereomers were thermodynamically favored over the other.
chemical setup, which is especially useful for reactions with
Having isolated each diastereomeric atropisomer as a
chiral substrates.[16] Recently, we reported the synthesis and pure solid, we decided to determine the absolute configura-
catalytic features of the new CoI complex, [CpCo- tion of the biaryl axis. CD spectroscopic investigation of
(H2C=CHSiMe3)2] (15), which showed extraordinary reac- the diastereomers clearly showed the opposite configuration
tivity in cycloaddition reactions, even at low tempera- of the chromophore.[19] We were able to obtain single crys-
tures.[17] Even though both precatalyst complexes deliver tals of (S)-(aS)-16 suitable for X-ray analysis, and thus,
the “CpCo”-fragment as a catalytically active species,[18] the were able to assign the (aS)-configuration to the biaryl moi-
reactivity differences should be investigated.
The results for the cycloaddition reaction of (S)-12 with tion was assigned for the second atropisomer.
acetonitrile and either 14 or 15 as the catalysts nicely dis- We also investigated the reaction with aromatic nitriles,
ety (Figure 1).[20] As a result, the opposite (aR)-configura-
play the excellent reactivity of precatalyst 15 (Scheme 6). specifically benzonitrile and 2-fluorobenzonitrile, to evalu-
Although in both cases the products 16 were formed, the ate the versatility of the method (Scheme 7). The fluori-
overall yield for catalyst 15 (69%) is significantly higher nated nitrile should later provide the potential opportunity
than the yield observed for the use of 14 (49%). In both for further functionalization by nucleophilic aromatic sub-
cases, no large selectivity effects were observed by 1H NMR stitution.[21] For the reaction with benzonitrile using [Cp-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O20402
/KAP1
Date: 04-09-12 15:49:07
Pages: 12
M. Hapke et al.
FULL PAPER
We were able to determine the absolute configuration of
one of the diastereomers of 18 by obtaining a single crystal
that was suitable for X-ray analysis (Figure 2).[22,23] It
turned out that the atropisomer isolated second by column
chromatography had an (aR)-configured biaryl axis. There-
fore, the dr value was determined from the isolated products
to be slightly in excess for (S)-(aS)-18. However, both atrop-
isomers are accessible.
Figure 1. ORTEP plot of the molecular structure of (S)-(aS)-16
(the naphthyl ring points in the opposite direction than that shown
in Figure 2). Ellipsoids are drawn at the 30% probability level.
Co(cod)] (14) under photochemical conditions, again a
much lower total yield (38%) of 17 was obtained. The esti-
mation of the diastereomeric ratio (dr) from the crude
NMR spectrum was 1.22:1; a slight excess of the first dia-
stereomer was collected by column chromatography. The
application of optimized conditions with catalyst 15 pro-
vided much higher total yields (66%) and also with a
slightly higher dr (1.75:1) for the isolated atropisomers 17.
The use of 2-fluorobenzonitrile for cycloaddition with (S)-
12 using 15 as the catalyst led to the isolation of the two
atropisomers 18 in a total yield of 44%.
Figure 2. ORTEP plot of the molecular structure of (S)-(aR)-18
(the naphthyl ring points in the opposite direction than that shown
in Figure 1). Ellipsoids are drawn at the 30% probability level.
The atropisomers 16 appeared to be a useful chiral plat-
form for the preparation of chiral derivatives and potential
ligands. While the methyl group at the pyridine moiety and
the methoxy group in the 2-position of the naphthyl ring
can be regarded as potential targets for further functionali-
zation, the substitution of the methoxy group for a PPh2
group is well documented for the synthesis for P,N li-
gands.[24] Interestingly, our experiments with conventional
systems for the demethylation of the methoxy group showed
that the methyl group of 16 was very difficult to cleave and
largely resisted most conditions investigated. All attempts
to cleave the methoxy functional group by using standard
strong Lewis acid reagents, such as BBr3, BBr3·SMe2, or
Me3SiI, did not provide the OH-unprotected biaryl in use-
ful amounts.[25] It should be noted that 16 could be easily
protonated by HCl and became soluble in the aqueous
phase, from which it could be extracted with organic sol-
vents upon the addition of base.
We sought to investigate other direct functionalization
possibilities for the methoxy group in 16. For example, we
examined the nickel-catalyzed methylation of the methoxy
group, which has emerged as a new and highly interesting
arene functionalization methodology only very recently.[26]
We expected this substitution to proceed without any epi-
merization concerning the biaryl axis; this would immedi-
ately be seen by the formation of two diastereomeric atrop-
isomers, which could therefore act as a chemical probe for
epimerization. Initial experiments provided the information
Scheme 7. Cobalt-catalyzed [2+2+2] cycloaddition reactions of (S)-
12 with benzonitrile and 2-fluorobenzonitrile [the stereochemistry
of (S)-(aR)-18 was determined by X-ray crystallography; see be-
low].
that [NiCl2(PCy3)2] (Cy
= cyclohexyl) together with
MeMgBr was the most suitable methylation system and the
reaction proceeded smoothly at 90 °C in toluene. Both
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20402
/KAP1
Date: 04-09-12 15:49:07
Pages: 12
Diastereomeric Atropisomers from a Chiral Diyne
atropisomers (S)-(aS)-16 and (S)-(aR)-16 can be reacted here the photochemically activated catalyst system was su-
under these conditions, which is exemplified in Scheme 8 perior to catalyst 15, where in addition slightly higher tem-
for the methylation of (S)-(aS)-16, providing (S)-(aR)-19 in peratures were applied. The reason is certainly the presence
63% yield. Although the absolute configuration of the axial of the larger group in the 2-position, leading to a lower
bond is the same, the stereochemical assignment changes reaction rate and catalyst deactivation over time. The
due to interchanged priority of the substituents, according stereochemistry of the products could be assigned by
to Cahn–Ingold–Prelog (CIP) nomenclature. No epimeri- comparison of the CD spectra with those measured for
zation was observed, demonstrating the stability of the chi- 16.[19]
ral axis of this heterobiaryl for transition-metal-catalyzed
With the diastereomers of 20 in hand, we investigated the
substitution reactions in the ortho position. The introduc- functionalization of the 2-naphthyl position again. In the
tion of the methyl group in the ortho position seems to con- first step, and in contrast to 2-methoxy-substituted 16, the
tribute to a higher stability of the biaryl axis, as can be MOM group of 20 could easily be cleaved off with HCl in
concluded in the light of the epimerization experiments dis- good yields (Scheme 10). Further transformation into a P,N
cussed above.
ligand was investigated for the pure 2-naphthol derivative
(S)-(aR)-21. The biaryl was converted into the triflate by
using Tf2O in the presence of amine under standard reac-
tion conditions, yielding (S)-(aR)-22. Finally, nickel-cata-
lyzed coupling with HPPh2 was attempted for the prepara-
tion of the P,N ligand (S)-(aR)-23, following a reported pro-
cedure for related P,N ligands.[24d] This method is advan-
tageous to other methods, applying the oxide HP(O)Ph2 as
coupling partner, but requires subsequent reduction of the
resulting phosphane oxide. Unfortunately, after purification
by column chromatography, only traces of product were
identified by NMR spectroscopy and MS.[27] We turned our
attention to another functionalization, using compound
(S)-(aR)-21 directly for the preparation of a chiral phos-
phite with 1,1Ј-bi-2,2Ј-naphthol (BINOL), as reported by
Brown et al.[28] However, also in this case, the conditions
provided in the literature were largely unsuccessful to pro-
vide the expected product in preparative yields. No further
optimization of reaction conditions was attempted, but
compounds 19, 21, and 22 are certainly interesting starting
materials for further derivatization studies.
Scheme 8. Nickel-catalyzed coupling reaction with (S)-(aS)-16,
leading to the methylated product (S)-(aR)-19.
The problematic demethylation step for 16 turned our
attention again to the use of a different protecting group,
which is easier to cleave, allowing further functionalization.
However, the 2-position of the naphthyl system was found
to have a significant influence on the outcome of the cobalt-
catalyzed cycloaddition reaction under photochemical con-
ditions.[8] We therefore investigated the use of (S)-13 for our
purpose because of the ease of cleavage of the MOM group
under mild acidic conditions. Application of the cycload-
dition conditions used for the cyclization of (S)-12 with ace-
tonitrile gave both diastereomers of 20, although lower
overall yields were encountered (Scheme 9). Interestingly,
Scheme 9. Cobalt-catalyzed [2+2+2] cycloaddition reaction of (S)-
13 with acetonitrile, using different catalyst systems, to provide the
diastereomeric atropisomers 20 [the stereochemistry of (S)-(aS)-20
and (S)-(aR)-20 was assigned by CD spectroscopy].
Scheme 10. Conversion of MOM-protected biaryls 20 into the OH-
free compounds and attempted transformation into the P,N ligand
23.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20402
/KAP1
Date: 04-09-12 15:49:07
Pages: 12
M. Hapke et al.
FULL PAPER
(7.0 mL, 95.6 mmol) was added dropwise. The reaction mixture was
heated for 1 h under reflux and allowed to cool to room temp. All
volatile compounds were removed in vacuo through a cool trap.
Conclusions
We demonstrated the use of two chiral diynes for the
concurrent preparation of diastereomeric atropisomers con- The residue together with Et3N (26.7 mL, 191.2 mmol), toluene
(100 mL), and propargyl bromide (11.2 mL, 100.4 mmol) were
heated to 60 °C for 18 h. After cooling, the reaction mixture was
treated with a saturated aqueous solution of NaHCO3 and the
aqueous phase was extracted with toluene after separation. The
combined phases were washed with H2O twice (50 mL each) and
brine (50 mL) and dried with Na2SO4. After evaporation of the
solvent, the oily residue was purified by column chromatography
on silica gel with n-hexane/ethyl acetate, 4:1 (v/v + 1% Et3N) as
the eluent and compound (S)-9 was obtained as colorless oil
(10.63 g, 74%). Further purification could be executed by bulb-to-
taining two different stereochemical elements. The study
was initiated to make both stereoisomers accessible in one
step combined with an easy chromatographic separation
procedure. The key step is the [2+2+2] cycloaddition reac-
tion between the chiral diyne and nitriles, catalyzed by achi-
ral cobalt(I) complexes. The choice of the reaction condi-
tions was crucial for the [2+2+2] cycloaddition between the
chiral diyne and nitriles and the highly reactive precatalyst
complex [CpCo(H2C=CHSiMe3)2] (15) was superior to the
application of [CpCo(cod)] (14) under photochemical con- bulb (Kugelrohr) distillation (50–60 °C/ 5ϫ10–3 mbar). [α]2D2
=
1
–148.7 (c = 1.168, CHCl3). H NMR (400 MHz, CDCl3): δ = 3.67
(s, 3 H), 3.54 (t, J = 2.5 Hz, 2 H), 3.38 (dd, J = 9.0, 6.6 Hz, 1 H),
2.99 (ddd, J = 8.7, 7.8, 2.7 Hz, 1 H), 2.66 (td, J = 9.0, 7.6 Hz, 1
H), 2.16 (t, J = 2.4 Hz, 1 H), 2.12–2.05 (m, 1 H), 1.97–1.71 (m, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.9, 78.2, 73.2, 62.3,
52.1, 51.8, 41.1, 29.5, 23.2 ppm. MS (ESI+): m/z (%) = 168 (100)
[M + H]+, 108 (69). HRMS (ESI): calcd. for C9H14NO2 [M + H]+
168.1019; found 168.1020.
ditions for small groups in the 2-naphthyl position of the
biaryl. In all cases, nearly equal amounts (dr ca. 1:1–1:2) of
both pure diastereomeric atropisomers were isolated after
facile separation by column chromatography. The stereo-
chemistry of the biaryl atropisomers was elucidated by X-
ray analysis and CD spectroscopy. The use of the MOM
group in the 2-naphthol position was superior to the methyl
group for subsequent cleavage to supply the OH-free com-
pound. This strategy provides access to both diastereomeric
atropisomers without the need for chiral catalysts, offering
a chiral platform for further manipulations towards ligands
and chiral backbones for synthetic purposes.
(S)-[1-(Prop-2-ynyl)pyrrolidin-2-yl]methanol [(S)-10]:[32] Lithium
aluminum hydride (100 mL, 100 mmol, 1 m in Et2O) was diluted
with dry Et2O (200 mL) in a 500 mL flask fitted with a dropping
funnel and argon inlet. The ester (S)-9 (8.3 g, 50 mmol) was added
dropwise over about 2.5 h and the reaction mixture was stirred for
additional 4 h. TLC control [eluent: n-hexane/ethyl acetate, 1:1
(v/v) + 1% Et3N] indicated complete conversion and the reaction
was quenched with a mixture of NH4Cl/aq. NH3 in water, the solu-
tion was buffered to pH 8 and a saturated aqueous solution of
Na2SO4 was added to enhance precipitation of the metal salts. The
suspension was filtered through Celite and the solid residue was
washed with ethyl ether. The filtrate was separated from the aque-
ous phase and dried with Na2SO4. After removal of the solvent in
vacuo, the crude product was purified by Kugelrohr distillation
(80–90 °C/ 5ϫ10–3 mbar). The pure product was obtained in 79%
yield (5.44 g). [α]2D3 = –47.0 (c = 0.961, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 3.61 (dd, J = 11.1, 3.6 Hz, 1 H), 3.55–3.38
(m, 2 H), 3.41 (dd, J = 11.1, 2.9 Hz, 1 H), 3.04–2.97 (m, 1 H),
2.86–2.78 (m, 1 H), 2.65 (q, J = 8.5 Hz, 2 H), 2.18 (t, J = 2.4 Hz,
1 H), 1.92–1.82 (m, 1 H), 1.79–1.69 (m, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 79.4, 72.7, 62.3, 61.9, 53.4, 41.1, 27.8,
23.5 ppm. MS (ESI+): m/z (%) = 140 (100) [M + H]+. HRMS (ESI):
calcd. for C8H14NO [M + H]+ 140.1070; found 140.1074.
Experimental Section
General Methods: NMR spectra were, in general, recorded at 298 K
and the individual measurement conditions are given with the data.
Chemical shifts are reported in ppm relative to the 1H and 13C
residual signals of the deuterated solvent (deuteriochloroform: δ =
7.26 ppm for 1H and δ = 77.16 ppm for 13C). Mass spectra were
obtained 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. In all
cases, the enantiomeric excesses of pyridines were analyzed by
HPLC using appropriate chiral columns. For photochemistry, two
metal halogen lamps (460 W each) were used for irradiation of
thermostated Schlenk-type reaction vessels.
All reactions including transition metal catalysts were carried out
in an argon atmosphere, using standard techniques in dry, oxygen-
free solvents. All liquid reagents were distilled under argon prior
to use. The liquid starting materials were dried with and distilled
from molecular sieves under argon before use. Chromatographic
purifications were done with 240–400 mesh silica gel or an auto-
mated flash chromatography system (Biotage SP1). THF used as
eluent for chromatographic separations was distilled before use to
remove the added stabilizer (BHT) or unstabilized THF was used.
1-Iodo-2-methoxynaphthalene (5),[29] 1-iodonaphthalen-2-ol (7),[29]
[CpCo(cod)] (14),[30] [CpCo(H2C=CHSiMe3)2] (15),[17] and
[NiCl2(PCy3)2],[31] were synthesized according to known pro-
cedures. A modified procedure was applied for 1-ethynyl-2-(meth-
oxymethoxy) naphthalene (8) and is given in the Supporting Infor-
mation. All other compounds and reagents not referenced were
commercially available and have been purchased.
(S)-2-(Iodomethyl)-1-(prop-2-ynyl)pyrrolidine [(S)-11]: A solution of
imidazole (1.95 g, 28.7 mmol) and PPh3 (5.64 g, 21.45 mmol) in
Et2O (40 mL) was cooled to 0 °C and iodine (5.44 g, 21.45 mmol)
was added in three portions within 30 min. The mixture was
warmed to room temp. and stirred for an additional 10 min, fol-
lowed by the addition of a solution of alcohol (S)-10 in CH2Cl2
(30 mL), and the precipitation of a white solid was observed. After
stirring for 15 h, a thick suspension was obtained. The suspension
was filtered and the solids were washed with n-hexane. The precipi-
tation of more white solid (PPh3) was observed with increasing
amounts of n-hexane and when the filtrate was evaporated. The
precipitate was removed by additional filtration. After evaporation,
the product was isolated from the residue by column chromatog-
raphy (n-hexane/ethyl acetate, 1:1 v/v + 1% Et3N) and obtained as
a dark oil (2.92 g, 82%). [α]2D2 = +34.3 (c = 1.047, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 4.29–4.19 (m, 1 H), 3.31 (dd, J =
2.4, 0.9 Hz, 2 H), 3.09 (d, J = 11.0 Hz, 1 H), 2.79 (dd, J = 11.0,
(S)-Methyl 1-(Prop-2-ynyl)pyrrolidine-2-carboxylate [(S)-9]:[32] (S)-
Proline [(S)-3, 10.0 g, 86.9 mmol] was suspended in dry methanol
(100 mL) under argon and cooled to 0 °C, afterwards SOCl2
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20402
/KAP1
Date: 04-09-12 15:49:07
Pages: 12
Diastereomeric Atropisomers from a Chiral Diyne
4.0 Hz, 1 H), 2.65 (dd, J = 11.0, 4.0 Hz, 1 H), 2.34 (ddd, J = 11.0,
9.9, 3.8 Hz, 1 H), 2.25 (t, J = 2.4 Hz, 1 H), 2.22–2.15 (m, 1 H),
1.89–1.79 (m, 1 H), 1.74–1.61 (m, 2 H) ppm. 13C NMR (75 MHz,
2.68 (m, 1 H), 2.65 (dd, J = –16.7, 5.0 Hz, 1 H), 2.23 (t, J = 2.4 Hz,
1 H), 2.21–2.11 (m, 1 H), 1.95–1.76 (m, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 156.7, 134.8, 129.5, 129.3, 128.1, 127.1,
CDCl3): δ = 78.4, 73.6, 62.5, 51.7, 46.7, 37.0, 27.2, 26.1 ppm. MS 125.8, 124.7, 116.8, 109.3, 97.7, 95.7, 79.5, 75.8, 72.7, 60.4, 56.5,
(ESI+): m/z (%) = 250 (100) [M + H]+. HRMS (ESI): calcd. for
53.4, 41.2, 31.4, 25.9, 22.6 ppm. MS (ESI+): m/z (%) = 334 (100)
[M + H]+. HRMS (ESI): calcd. for C22H24NO2 [M + H]+ 334.1802;
found 334.1804.
C8H13IN [M + H]+ 250.0087; found 250.0088.
(S)-2-[3-(2-Methoxynaphthalen-1-yl)prop-2-ynyl]-1-(prop-2-ynyl)pyr-
rolidine [(S)-12]: Compound 6 (2.72 g, 14.9 mmol) was dissolved
in THF (ca. 150 mL) and cooled to –78 °C. Then nBuLi (9.8 mL,
15.6 mmol, 1.6M) was added dropwise and after complete addition
the reaction mixture was stirred for a further 30 min at 0 °C, re-
sulting in the formation of a beige suspension. Subsequently, a
solution of iodide (S)-11 (3.37 g, 13.5 mmol) in THF (30 mL) was
added and the reaction mixture heated under reflux for 16 h, re-
sulting in the formation of a dark-brown solution and TLC control
predominantly showed consumption of 11. After cooling, the reac-
tion was quenched with water and Et2O was added. The aqueous
phase was separated and repeatedly extracted with Et2O. The com-
bined organic phases were washed with brine and dried with
Na2SO4. After evaporation of the solvent, a black oily crude prod-
uct was obtained and purified by flash chromatography on silica
gel, using n-hexane/ethyl acetate (2:1 v/v) as the eluent. In addition
to the recovery of unreacted 6 (900 mg, 33% recovered), the prod-
uct (S)-12 was isolated as a dark viscous oil [2.25 g, 60% with re-
spect to (S)-11]. The product was stored under argon in the fridge
(4 °C). [α]2D2 = –69.6 (c = 1.250, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 8.28 (dd, J = 8.5, 1.0 Hz, 1 H), 7.77 (d, J = 9.1 Hz, 1
H), 7.76 (d, J = 8.2 Hz, 1 H), 7.52 (ddd, J = 8.5, 6.8, 1.3 Hz, 1 H),
7.36 (ddd, J = 8.2, 6.8, 1.2 Hz, 1 H), 7.23 (d, J = 9.1 Hz, 1 H), 4.01
(s, 3 H), 3.66 (t, J = 2.4 Hz, 2 H), 3.13–3.00 (m, 2 H), 2.88 (dd, J
= –16.7, 4.9 Hz, 1 H), 2.73–2.69 (m, 1 H), 2.65 (dd, J = –16.7,
7.6 Hz, 1 H), 2.13 (t, J = 2.4 Hz, 1 H), 1.95–1.74 (m, 4 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 158.8, 135.0, 129.5, 128.7, 128.1,
127.2, 125.6, 124.2, 112.8, 107.1, 97.8, 79.5, 75.8, 72.7, 60.5, 56.7,
53.4, 41.3, 31.4, 25.9, 22.6 ppm. MS (ESI+): m/z (%) = 304 (100)
[M + H]+. HRMS (ESI): calcd. for C21H22NO [M + H]+ 304.1700;
found 304.1700. C21H21NO (303.40): calcd. C 83.13, H 6.98, N
4.62; found C 83.41, H 7.20, N 4.25.
General Procedures for the [2+2+2] Cycloaddition Reaction of (S)-8
with Nitriles under Photochemical Conditions (Catalyst 14) or under
Thermal Conditions (Catalyst 15): Note for the following examples
using acetonitrile as the substrate: During the separation process,
using the general solvent mixture THF/n-hexane as the eluent, the
first diastereomer (dia1) with Rf = 0.80 and the second dia-
stereomer (dia2) with Rf = 0.78 (Rf’s for the eluent THF/n-hexane,
6:1 v/v) were obtained. Investigation into the stereochemistry pro-
vided the information that dia1 could be assigned as (S)-(aS)-16
and dia2 as (S)-(aR)-16.
General Procedure 1: Photochemical Conditions (Catalyst 14) with
Acetonitrile: In a typical experiment, the chiral diyne (S)-12
(890 mg, 2.93 mmol) was secured in a Schlenk flask under argon
and dissolved in THF (20 mL). The yellow–brownish solution was
transferred to a secured and thermostated (25 °C) Schlenk reactor
containing 14 (69 mg, 0.294 mmol). Finally, acetonitrile (0.78 mL,
14.7 mmol, 5 equiv.) was added by syringe. The reactor was radi-
ated for 48 h, after which time the starting material had disap-
peared. After switching off the lamps, the reaction vessel was
opened to air, the reaction mixture was transferred to a round-
bottomed flask, and the reaction mixture was evaporated to dry-
ness. The residue was dissolved in a mixture of THF/Et2O (1:1)
and filtered through Celite. The solution was evaporated to dryness
and purified by column chromatography (eluent: THF/n-hexane,
6:1 v/v) on silica gel. The two diastereomers were obtained sepa-
rately; however, sometimes a second chromatography step was nec-
essary for complete separation. Isolation of the diastereomeric
atropisomers gave dia1 (243 mg, 24%) and dia2 (255 mg, 25%) in
a combined overall yield of 49%. The diastereomeric ratio was esti-
1
mated from the H NMR spectra: 1:1.05 (dia1:dia2).
General Procedure 2: Thermal Conditions (Catalyst 15) with Aceto-
nitrile in THF or Toluene: In a typical experiment, the diyne (S)-12
(380 mg, 1.25 mmol) was dissolved in THF or toluene and acetoni-
trile (0.33 mL, 6.32 mmol, 5 equiv.) was added by syringe. The solu-
tion was cooled to 0 °C and then a solution of 15[17] (0.063 mmol
in 0.57 mL Et2O) was added. The reaction mixture was warmed to
room temp. with stirring and TLC control showed complete con-
version after a couple of hours, while the reaction mixture became
dark. After the reaction was complete, the solvent was evaporated
and the dark residue was charged to silica gel and then purified by
repeated flash column chromatography (eluent: THF/n-hexane, 6:1,
v/v) or by using an automated chromatography system. Isolation
of the diastereomeric atropisomers gave dia1 (154 mg, 36%) and
dia2 (140 mg, 33%) in a combined overall yield of 69%. The dia-
(S)-2-{3-[2-(Methoxymethoxy)naphthalen-1-yl]prop-2-ynyl}-1-(prop-
2-ynyl)pyrrolidine [(S)-13]: Compound 8 (2.5 g, 11.8 mmol) was dis-
solved in THF (ca. 35 mL) and cooled to 0 °C. Then nBuLi
(7.3 mL, 12.4 mmol, 1.6M) was added dropwise and, after com-
plete addition, the reaction mixture was stirred for a further 60 min
at 0 °C, resulting in the formation of a beige suspension. Sub-
sequently, a solution of iodide (S)-11 (2.67 g, 10.7 mmol) in THF
(35 mL) was added and the reaction mixture was heated under re-
flux for 14 h, resulting in a dark-brown solution and TLC control
predominantly showed consumption of 11. After cooling, the reac-
tion was quenched with a saturated aqueous solution of NH4Cl
and Et2O was added. The aqueous phase was separated and repeat-
edly extracted with diethyl ether. The combined organic phases
were washed with water and brine and dried with Na2SO4. After
evaporation of the solvent, a black oily crude product was obtained
and purified by flash chromatography on silica gel, using n-hexane/
ethyl acetate (1:1 v/v) as the eluent. Unreacted 8 was recovered
(500 mg, 20% recovered) and the product (S)-13 was isolated as a
dark viscous oil [2.04 g, 58% with respect to (S)-11]. The product
was stored under argon in the fridge (4 °C). [α]2D2 = –63.1 (c = 0.809,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 8.30 (dd, J = 8.5,
1
stereomeric ratio was estimated from the crude H NMR spectra:
1.13:1 (dia1:dia2). The yields of optimized reactions using THF
were in the same range and differences in the ratio of isolated
atropisomers were due to the purification process.
(S)-(aS)-1-(2-Methoxynaphthalen-1-yl)-3-methyl-5,7,8,9,9a,10-hexa-
hydropyrrolo[1,2-b][2,6]naphthyridine [(S)-(aS)-16 (dia1)]: M.p. 105–
107 °C. [α]2D2 = +113.1 (c = 0.273, CHCl3). 1H NMR (400 MHz,
1.0 Hz, 1 H), 7.77 (d, J = 8.3 Hz, 1 H), 7.74 (d, J = 8.9 Hz, 1 H), 318 K, CDCl3): δ = 7.87 (d, J = 9.0 Hz, 1 H), 7.79–7.76 (m, 1 H),
7.53 (ddd, J = 8.4, 6.9, 1.4 Hz, 1 H), 7.42–7.36 (m, 1 H), 7.38 (d,
J = 8.9 Hz, 1 H), 5.36 (s, 2 H), 3.68 (t, J = 2.0 Hz, 2 H), 3.57 (s, 3
H), 3.14–2.99 (m, 2 H), 2.86 (dd, J = –16.7, 5.0 Hz, 1 H), 2.76–
7.33 (d, J = 9.0 Hz, 1 H), 7.30–7.24 (m, 2 H), 7.09 (br. d, J =
7.4 Hz, 1 H), 6.93 (s, 1 H), 4.16 (d, J = –15.5 Hz, 1 H), 3.83 (s, 3
H, -OCH3), 3.53 (br. d, J = –15.5 Hz, 1 H), 3.29–3.20 (m, 1 H),
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20402
/KAP1
Date: 04-09-12 15:49:07
Pages: 12
M. Hapke et al.
2.61–2.53 (m, 1 H), 2.56 (s, 3 H, -CH3), 2.44–2.24 (m, 2 H), 2.18– 13C NMR (100 MHz, CDCl3): δ = 156.0, 154.6, 154.5, 144.7, 139.9,
FULL PAPER
2.07 (m, 1 H), 1.94–1.71 (m, 3 H), 1.37–1.25 (m, 1 H) ppm. 13C
NMR (100 MHz, 318 K, CDCl3): δ = 155.5, 155.3, 153.8, 144.3,
133.3, 129.9, 129.6, 128.0, 127.9, 126.8, 124.9, 123.8, 123.6, 120.2,
114.1, 61.0, 57.0 (-OCH3), 55.3, 54.7, 32.1, 30.9, 24.3 (-CH3),
21.6 ppm. MS (ESI+): m/z (%) = 345 (100) [M + H]+. HRMS (ESI):
calcd. for C23H25N2O [M + H]+ 345.1961; found 345.1967.
C23H24N2O (344.45): calcd. C 80.20, H 7.02, N 8.13; found C
80.57, H 7.18, N 8.27.
133.4, 130.1, 130.0, 129.3, 128.6, 128.5, 128.1, 127.2, 126.7, 124.8,
123.6, 123.1, 117.5, 113.8, 60.9, 56.6, 55.7, 54.8, 32.4, 30.9,
21.6 ppm. MS (EI, GC–MS): m/z (%) = 406 (100) [M]+, 405 (77),
363 (15), 336 (20), 322 (86), 306 (33). HRMS (ESI): calcd. for
C28H27N2O [M + H]+ 407.2118; found 407.2116.
(S)-(aS)/(aR)-3-(2-Fluorophenyl)-1-(2-methylnaphthalen-1-yl)-
5,7,8,9,9a,10-hexahydro-pyrrolo[1,2-b][2,6]naphthyridine [(S)-(aS)-
18/(S)-(aR)-18]: The reaction of the chiral diyne (S)-12 with 2-fluo-
robenzonitrile was performed according to General Procedure 2.
Compound (S)-12 (600 mg, 1.98 mmol) and 2-fluorobenzonitrile
(1.07 mL, 10.89 mmol, 5.5 equiv.), together with THF (15 mL),
were cooled to 0 °C in a Schlenk flask and a solution of 15
(0.099 mmol in 0.6 mL Et2O, concentration of the catalyst stock
solution: 0.165 mmolmL–1) was added. The reaction mixture was
warmed to room temp. and stirring was continued for an additional
15 h. TLC control showed complete conversion. The dark reaction
mixture was then evaporated to dryness and chromatographic sepa-
ration (THF/n-hexane, 3:1 v/v) gave both diastereomeric atropiso-
mers (separated by chromatography column). Diastereomer 1 was
obtained in 26% (215 mg) yield and diastereomer 2 was obtained
in 18% (148 mg) yield, providing a total yield of 44% (363 mg).
Later crystals of diastereomer 2 were obtained from evaporation of
a solution in CDCl3 and the absolute configuration of the biaryl
axis was determined to be (aR). Therefore, diastereomer 1 was de-
fined as (S)-(aS)-18 and diastereomer 2 was (S)-(aR)-18.
(S)-(aR)-1-(2-Methoxynaphthalen-1-yl)-3-methyl-5,7,8,9,9a,10-hexa-
hydropyrrolo[1,2-b][2,6]naphthyridine [(S)-(aR)-16 (dia2)]: M.p.
118–121 °C. [α]2D2
=
+150.4 (c = 0.195, CHCl3). 1H NMR
(300 MHz, 295 K, CDCl3): δ = 7.89 (d, J = 9.0 Hz, 1 H), 7.82–7.77
(m, 1 H), 7.33 (d, J = 9.0 Hz, 1 H), 7.33–7.27 (m, 2 H), 7.18–7.14
(m, 1 H), 6.92 (s, 1 H), 4.19 (d, J = –15.7 Hz, 1 H), 3.79 (s, 3 H,
-OCH3), 3.44 (d, J = –15.7 Hz, 1 H), 3.29 (ddd, J = 8.6, 8.5, 2.1 Hz,
1 H), 2.56 (s, 3 H, -CH3), 2.39–2.31 (m, 2 H), 2.24–2.13 (m, 2 H),
1.90–1.78 (m, 2 H), 1.77–1.68 (m, 1 H), 1.44–1.31 (m, 1 H) ppm.
13C NMR (75 MHz, 295 K, CDCl3): δ = 155.3, 155.0, 154.3, 144.5,
133.2, 129.8, 129.2, 128.2, 128.0, 126.7, 124.6, 123.5, 122.9, 120.0,
113.6, 60.9, 56.5 (-OCH3), 55.6, 54.8, 32.3, 30.8, 24.4 (-CH3),
21.5 ppm. MS (ESI+): m/z (%) = 345 (100) [M + H]+. HRMS
(ESI+): calcd. for C23H25N2O [M + H]+ 345.1961; found 348.1966.
C23H24N2O (344.45): calcd. C 80.20, H 7.02, N 8.13; found C
80.45, H 7.07, N 7.89.
(S)-(aS)/(aR)-3-Phenyl-1-(2-methylnaphthalen-1-yl)-5,7,8,9,9a,10-
hexahydro-pyrrolo[1,2-b][2,6]naphthyridine [(S)-(aS)-17/(S)-(aR)-
17]: The reaction of the chiral diyne (S)-12 with benzonitrile was
performed according to General Procedure 2. Compound (S)-12
(400 mg, 1.32 mmol) and benzonitrile (0.68 mL, 6.6 mmol,
5 equiv.), together with THF (10 mL), were cooled to 0 °C in a
Schlenk flask, then a solution of 15 (0.066 mmol in 0.4 mL Et2O,
concentration of the catalyst stock solution: 0.122 mmolmL–1) was
added. The reaction mixture was warmed to room temp. and stir-
ring was continued for an additional 15 h. TLC control showed
complete conversion. The dark reaction mixture was then evapo-
rated to dryness and chromatographic separation (THF/n-hexane,
3:1 v/v) gave both diastereomeric atropisomers (description in the
succession of their elution from the chromatography column). Dia-
stereomer 1 was obtained in 42% (223 mg) yield and diastereomer
2 was obtained in 24% (131 mg) yield, providing a total yield of
66% (354 mg).
(S)-(aS)-3-(2-Fluorophenyl)-1-(2-methylnaphthalen-1-yl)-5,7,8,9,
9a,10-hexahydropyrrolo[1,2-b][2,6]naphthyridine [(S)-(aS)-18]: M.p.
111–112 °C. [α]2D2 = –20.9 (c = 0.546, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.97–7.91 (m, 1 H), 7.93 (d, J = 9.0 Hz, 1 H), 7.84–
7.81 (m, 1 H), 7.60 (d, J = 2.1 Hz, 1 H), 7.38 (d, J = 9.0 Hz, 1 H),
7.34–7.27 (m, 3 H), 7.20–7.09 (m, 3 H), 4.30 (d, J = –15.6 Hz, 1
H), 3.87 (s, 3 H, -OCH3), 3.65 (d, J = –15.6 Hz, 1 H), 3.30 (t, J =
8.5 Hz, 1 H), 2.69 (dd, J = –16.4, 3.8 Hz, 1 H), 2.54–2.30 (m, 2 H),
2.21 (dd, J = –16.4, 10.4 Hz, 1 H), 2.02–1.74 (m, 3 H), 1.42–1.29
(m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 156.2, 153.7,
150.6, 144.2, 133.2, 131.7, 130.1 (d, J = 3.2 Hz), 130.0, 129.9, 129.4,
128.0, 126.9, 124.8, 124.5 (d, J = 3.7 Hz), 123.8, 123.2, 121.6 (d, J
= 8.5 Hz), 116.2, 115.9, 113.8, 60.8, 56.9, 55.5, 54.7, 32.3, 30.9,
21.6 ppm (not all carbon resonances detected). 19F NMR
(282 MHz, CDCl3): δ = –116.7 ppm. MS (EI, GC–MS): m/z (%) =
424 (100) [M]+, 423 (89), 381 (22), 354 (23), 340 (83), 324 (33).
HRMS (ESI): calcd. for C28H26FN2O [M + H]+ 425.2024; found
425.2029.
Diastereomer 1: M.p. 135–137 °C. [α]2D3 = –26.2 (c = 1.324, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 8.02–7.97 (m, 2 H), 7.94 (d, J =
9.0 Hz, 1 H), 7.84 (dd, J = 7.0, 2.0 Hz, 1 H), 7.53 (s, 1 H), 7.45–
7.29 (m, 6 H), 7.20 (d, J = 7.7 Hz, 1 H), 4.31 (d, J = –15.6 Hz, 1
H), 3.88 (s, 3 H, -OCH3), 3.60 (d, J = –15.6 Hz, 1 H), 3.37–3.28
(m, 1 H), 2.68 (dd, J = –16.4 Hz, 1 H, 3.6 Hz), 2.45–2.13 (m, 3 H),
2.01–1.74 (m, 3 H), 1.42–1.27 (m, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 156.1, 154.8, 153.7, 144.8, 139.9, 133.2, 129.9, 129.8,
129.4, 128.6, 128.5, 127.9, 127.2, 126.8, 124.9, 123.8, 123.6, 117.7,
114.0, 60.8, 57.0, 55.8, 54.7, 32.5, 30.9, 21.5 ppm. MS (EI, GC–
MS): m/z (%) = 406 (100) [M]+, 405 (81), 363 (17), 336 (23), 322
(87), 306 (32). HRMS (ESI): calcd. for C28H27N2O [M + H]+
407.2118; found 407.2123.
(S)-(aR)-3-(2-Fluorophenyl)-1-(2-methylnaphthalen-1-yl)-5,7,8,9,
9a,10-hexahydro-pyrrolo[1,2-b][2,6]naphthyridine [(S)-(aR)-18]: M.p.
117–118 °C. [α]2D4
=
+161.0 (c = 0.436, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.95 (dd, J = 8.0, 2.1 Hz, 1 H), 7.93 (d, J
= 9.1 Hz, 1 H), 7.86–7.81 (m, 1 H), 7.58 (d, J = 1.8 Hz, 1 H), 7.37
(d, J = 9.1 Hz, 1 H), 7.37–7.27 (m, 4 H), 7.18–7.09 (m, 2 H), 4.33
(d, J = –15.7 Hz, 1 H), 3.83 (s, 3 H, -OCH3), 3.59 (d, J = –15.7 Hz,
1 H), 3.33 (t, J = 7.6 Hz, 1 H), 2.59–2.19 (m, 4 H), 1.98–1.74 (m,
3 H), 1.53–1.37 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
156.0, 154.4, 150.3, 133.2, 131.9, 131.6 (d, J = 3.0 Hz), 130.4, 130.0,
129.8 (d, J = 8.7 Hz), 129.2, 128.0, 126.7, 124.6, 124.4 (d, J =
3.2 Hz), 123.6, 122.7, 121.4, 121.3 (d, J = 8.5 Hz), 116.1, 115.8,
113.6, 60.7, 56.5, 55.5, 54.7, 32.2, 30.7, 21.5 ppm. 19F NMR
(282 MHz, CDCl3): δ = –116.9 ppm. MS (EI, GC–MS): m/z (%) =
424 (100) [M]+, 423 (85), 381 (20), 354 (23), 340 (80), 324 (33).
HRMS (ESI): calcd. for C28H26FN2O [M + H]+ 425.2024; found
425.2029.
Diastereomer 2: M.p. 99–102 °C. [α]2D3 = +162.8 (c = 0.458, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.94–7.90 (m, 2 H), 7.87 (d, J =
9.0 Hz, 1 H), 7.80–7.76 (m, 1 H), 7.43 (s, 1 H), 7.36–7.24 (m, 6 H),
7.31 (d, J = 9.0 Hz, 1 H), 4.26 (d, J = –15.6 Hz, 1 H), 3.76 (s, 3
H, -OCH3), 3.51 (d, J = –15.6 Hz, 1 H), 3.30–3.24 (m, 1 H), 2.44
(dd, J = –16.5, 10.8 Hz, 1 H), 2.34 (dd, J = –16.5, 3.6 Hz, 1 H),
2.26–2.14 (m, 2 H), 1.89–1.66 (m, 3 H), 1.43–1.32 (m, 1 H) ppm.
(S)-(aS)-3-Methyl-1-(2-methylnaphthalen-1-yl)-5,7,8,9,9a,10-hexa-
hydropyrrolo[1,2-b][2,6]naphthyridine [(S)-(aS)-19]: Compound (S)-
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20402
/KAP1
Date: 04-09-12 15:49:07
Pages: 12
Diastereomeric Atropisomers from a Chiral Diyne
(aS)-(16) (100 mg, 0.29 mmol) and [NiCl2(PCy3)2] (20 mg, [α]2D2 = +18.3 (c = 1.093, CHCl3). H NMR (300 MHz, CDCl3): δ
1
0.029 mmol, 10 mol-%) were weighed into a secured Schlenk flask,
then the air was evacuated and back-filled with argon three times.
Afterwards toluene (10 mL) was added and finally a solution of
methylmagnesium bromide (0.85 mL, 1.19 mmol, 1.4 m, toluene/
THF, 3:1 v/v) was added by syringe. The reaction mixture became
dark brown–red and was stirred for 19 h at 90 °C. After cooling to
room temp., the mixture was quenched with a saturated aqueous
solution of Na2CO3 and extracted several times with CH2Cl2. The
combined organic phases were washed with water and brine and
dried with Na2SO4. After removal of the solvent and all volatile
compounds, the residue was purified by column chromatography
on silica gel, using THF/n-hexane (3:1 v/v) as the eluent. One main
fraction was obtained, yielding product (S)-(aS)-18 (60 mg, 63%)
as an oily solid. [α]2D3 = +48.2 (c = 0.437, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.84–7.78 (m, 1 H), 7.80 (d, J = 8.4 Hz, 1
H), 7.41 (d, J = 8.4 Hz, 1 H), 7.38 (ddd, J = 8.1, 6.8, 1.3 Hz, 1 H),
7.29 (ddd, J = 8.4, 6.8, 1.4 Hz, 1 H), 7.14 (d, J = 8.3 Hz, 1 H), 6.99
(br. s, 1 H), 4.24 (d, J = –15.7 Hz, 1 H), 3.57 (d, J = –15.7 Hz, 1
H), 3.35–3.25 (m, 1 H), 2.58 (s, 3 H, -CH3), 2.48–2.37 (m, 2 H),
2.25–2.16 (m, 2 H), 2.17 (s, 3 H, -CH3), 1.96–1.74 (m, 3 H), 1.38–
1.26 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 157.7, 155.7,
151.4, 144.1, 135.8, 129.1, 128.7, 128.2, 128.0, 127.9, 126.8, 126.4,
125.3, 125.0, 120.1, 60.1, 55.1, 54.6, 31.0, 30.6, 24.3 (-CH3), 21.5,
20.1 (-CH3) ppm. MS (EI, GC–MS): m/z (%) = 328, (97) [M]+, 327
(100) [M+ – H], 285 (35), 258 (40), 244 (52). HRMS (ESI): calcd.
for C23H25N2 [M + H]+ 329.2012; found 329.2008.
= 7.87 (d, J = 9.0 Hz, 1 H), 7.81 (dd, J = 7.8, 1.6 Hz, 1 H), 7.46
(d, J = 9.0 Hz, 1 H), 7.36–7.24 (m, 2 H), 7.11 (br. d, J = 8.2 Hz, 1
H), 6.96 (s, 1 H), 5.22 (d, J = 6.7 Hz, 1 H, -OCH2-), 5.10 (d, J =
6.7 Hz, 1 H, -OCH2-), 4.21 (d, J = –15.7 Hz, 1 H), 3.49 (br. d, J =
–15.7 Hz, 1 H), 3.34 (s, 3 H, -OCH3), 3.32–3.24 (m, 1 H), 2.66–
2.57 (m, 1 H), 2.56 (s, 3 H, -CH3), 2.37–2.07 (m, 3 H), 1.97–1.69
(m, 3 H), 1.39–1.24 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 155.4, 155.3, 151.3, 144.0, 133.0, 130.1, 129.9, 128.0, 127.7, 126.9,
125.0, 124.6, 124.4, 120.3, 116.9, 95.4 (-OCH2-), 60.9, 56.4
(-OCH3), 56.2, 54.7, 32.2, 30.8, 24.3 (-CH3), 21.6 ppm. MS (EI,
GC–MS): m/z (%) = 374 (61) [M]+, 329 (100), 260 (31), 45 (25).
HRMS (EI): calcd. for C24H26N2O2 [M]+ 374.1989; found
374.1986.
(S)-(aR)-1-(2-Methoxymethoxynaphthalen-1-yl)-3-methyl-5,7,8,9,
9a,10-hexahydropyrrolo[1,2-b][2,6]naphthyridine [(S)-(aR)-20
(dia2)]: [α]2D4 = +76.7 (c = 0.952, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.86 (d, J = 9.0 Hz, 1 H), 7.84–7.79 (m, 1 H), 7.50 (d,
J = 9.0 Hz, 1 H), 7.37–7.28 (m, 2 H), 7.19–7.15 (m, 1 H), 6.94 (s,
1 H), 5.10 (s, 2 H, -OCH2-), 4.21 (d, J = –15.7 Hz, 1 H), 3.47 (d,
J = –15.7 Hz, 1 H), 3.33 (s, 3 H, -OCH3), 3.31–3.25 (m, 1 H), 2.56
(s, 3 H, -CH3), 2.50–2.32 (m, 2 H), 2.31–2.14 (m, 2 H), 1.94–1.70
(m, 3 H), 1.46–1.31 (m, 1 H) ppm. 13C NMR (75 MHz, 295 K,
CDCl3): δ = 155.1, 154.9, 152.3, 144.4, 133.1, 130.1, 129.8, 128.2,
128.0, 126.6, 124.8, 124.7, 124.1, 120.0, 117.1, 95.5 (-OCH2-), 60.9,
56.2 (-OCH3), 55.5, 54.8, 32.3, 30.9, 24.3 (-CH3), 21.5 ppm. MS
(EI, GC–MS): m/z (%) = 374 (61) [M]+, 329 (100), 260 (32), 45
(25). HRMS (EI): calcd. for C24H26N2O2 [M]+ 374.1989; found
374.1985.
(S)-(aS)/(aR)-1-(2-Methoxymethoxynaphthalen-1-yl)-3-methyl-
5,7,8,9,9a,10-hexahydropyrrolo[1,2-b][2,6]naphthyridine [(S)-(aS)-20
(dia1)/(S)-(aR)-20 (dia2)]. Thermal Conditions: The reaction of the
chiral diyne (S)-13 with acetonitrile was performed according to
General Procedure 2. Compound (S)-13 (1.0 g, 2.99 mmol) and
acetonitrile (0.79 mL, 15.0 mmol, 5 equiv.), together with THF
(20 mL), were cooled to 0 °C in a Schlenk flask and a solution of
15 (0.15 mmol in 1 mL Et2O, concentration of the catalyst stock
solution: 0.153 mmolmL–1) was added. The reaction mixture was
warmed to room temp. and stirring was continued for a further 2 h
at room temp. and then for 14 h at 45 °C. Then the reaction mixture
was allowed to cool to room temp. and additional catalyst 15
(0.06 mmol in 0.4 mL Et2O) was added. After 2 h at room temp.,
TLC control showed complete disappearance of (S)-13. The dark
reaction mixture was then evaporated to dryness and chromato-
graphic separation (THF/n-hexane, 3:1 v/v) gave both dia-
stereomeric atropisomers (separated by chromatography column).
The dia1 was obtained in 19% (192 mg) yield and dia2 was ob-
tained in 18 % (190 mg) yield, providing a total yield of 37 %
(382 mg).
(S)-(aS)-1-(3-Methyl-5,7,8,9,9a,10-hexahydropyrrolo[1,2-b][2,6]-
naphthyridin-1-yl)naphthalen-2-ol [(S)-(aS)-21]: For hydrolysis of
the MOM groups, compound (S)-(aS)-20 (110 mg, 0.29 mmol) was
dissolved in THF (40 mL) and methanol (40 mL) and finally conc.
HCl (3.7 mL) was added by pipette. The reaction mixture was
stirred at room temp. for 16 h and then quenched with a saturated
aqueous solution of NaHCO3 until the aqueous phase was slightly
basic. The mixture was extracted with CH2Cl2 several times and
the combined organic phases were dried with Na2SO4. After evapo-
ration of the solvent, the residue was purified by column
chromatography on silica gel (eluent: THF/n-hexane, 3:1 v/v), yield-
ing the product as an oily solid (66 mg, 69%). Additionally, a small
amount of starting material was recovered (10 mg, 9%). [α]2D2
=
+296.4 (c = 0.938, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.74–
7.70 (m, 1 H), 7.42 (d, J = 8.8 Hz, 1 H), 7.31–7.21 (m, 2 H, H),
7.04 (br. d, J = 7.4 Hz, 1 H), 6.88 (s, 1 H), 6.53 (d, J = 8.8 Hz, 1
H), 4.21 (d, J = –16.1 Hz, 1 H), 3.43 (d, J = –16.1 Hz, 1 H), 3.27
(ddd, J = 9.6, 8.5, 2.1 Hz, 1 H), 2.54 (m, 1 H), 2.31 (s, 3 H, -CH3),
2.25–2.09 (m, 3 H), 1.90–1.66 (m, 3 H), 1.35–1.22, (m, 1, H) (OH
resonance was not observed) ppm. 13C NMR (75 MHz, CDCl3): δ
= 155.1, 154.3, 152.0, 146.4, 132.5, 130.0, 129.3, 128.9, 127.9, 126.3,
124.3, 123.1, 120.5, 120.3, 119.7, 60.8, 55.7, 54.8, 32.7, 30.7, 23.1
(-CH3), 21.5 ppm. MS (EI, GC–MS): m/z (%) = 330 (72) [M]+,
315 (40), 287 (49), 260 (100), 232 (44). HRMS (ESI): calcd. for
C22H23N2O [M + H]+ 331.1805; found 331.1806.
Photochemical Conditions: The photochemical reaction was per-
formed according to General Procedure 1 by reacting the chiral
diyne (S)-13 (500 mg, 1.50 mmol) and acetonitrile (0.4 mL,
7.45 mmol, 5 equiv.) together with 14 (17.4 mg, 0.074 mmol) in a
thermostated (25 °C) Schlenk reactor. The reactor was radiated for
17 h, after which time the starting material has disappeared. Usual
workup and separation by chromatography under the conditions
mentioned before (eluent: THF/n-hexane, 3:1 v/v) yielded dia1
(127 mg, 23%) and dia2 (135 mg, 24%) in a combined overall yield
of 47%.
(S)-(aR)-1-(3-Methyl-5,7,8,9,9a,10-hexahydropyrrolo[1,2-b][2,6]-
naphthyridin-1-yl)naphthalen-2-ol [(S)-(aR)-21]: Diastereomer (S)-
(aR)-20 was deprotected as described before: compound (S)-(aR)-
20 (85 mg, 0.23 mmol) was dissolved in THF (40 mL) and meth-
anol (40 mL) and finally conc. HCl (3.0 mL) was added by pipette.
The reaction time and workup were identical to those described for
The configuration of the diastereomers could be assigned by com-
parison of the CD spectra with those of compound 16. Therefore,
dia1 was identified to be (S)-(aS)-20 and dia2 was identified as (S)-
(aR)-20.
(S)-(aS)-1-(2-Methoxymethoxynaphthalen-1-yl)-3-methyl-5,7,8,9, (S)-(as)-20. The oily product was obtained in 60% yield (45 mg).
9a,10-hexahydropyrrolo[1,2-b][2,6]naphthyridine [(S)-(aS)-20 (dia1)]: Additionally, a small amount of starting material was recovered
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O20402
/KAP1
Date: 04-09-12 15:49:07
Pages: 12
M. Hapke et al.
FULL PAPER
(17 mg, 20%). [α]2D2 = +43.5 (c = 0.896, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.74 (dd, J = 6.2, 3.3 Hz, 1 H), 7.45 (d, J
= 8.8 Hz, 1 H), 7.32–7.25 (m, 2 H), 7.10–7.03 (m, 1 H), 6.83 (s, 1
H), 6.44 (d, J = 8.8 Hz, 1 H), 4.15 (d, J = –15.9 Hz, 1 H), 3.41 (d,
J = –15.9 Hz, 1 H), 3.26 (ddd, J = 9.5, 8.6, 2.2 Hz, 1 H), 2.51–2.30
(m, 2 H), 2.26 (s, 3 H, -CH3), 2.21–2.11 (m, 2 H), 1.89–1.65 (m, 3
[3]
[4]
a) J. Clayden, W. J. Moran, P. J. Edwards, S. R. LaPlante, An-
gew. Chem. 2009, 121, 6516–6520; Angew. Chem. Int. Ed. 2009,
48, 6398–6401; b) S. R. LaPlante, P. J. Edwards, L. D. Fader,
A. Jakalian, O. Hucke, ChemMedChem 2011, 6, 505–513; c)
S. R. LaPlante, L. D. Fader, K. R. Fandrick, D. R. Fandrick,
O. Hucke, R. Kemper, S. P. F. Miller, P. J. Edwards, J. Med.
Chem. 2011, 54, 7005–7022.
H), 1.43–1.29 (m, 1 H) (OH resonance was not observed) ppm. 13
C
For recent general reviews, see: a) Y. Yamamoto, Curr. Org.
Chem. 2005, 9, 503–519; b) S. Kotha, E. Brahmachary, K.
Lahiri, Eur. J. Org. Chem. 2005, 4741–4767; c) V. Gandon, C.
Aubert, M. Malacria, Curr. Org. Chem. 2005, 9, 1699–1712; d)
V. Gandon, C. Aubert, M. Malacria, Chem. Commun. 2006,
2209–2217; e) P. R. Chopade, J. Louie, Adv. Synth. Catal. 2006,
348, 2307–2327; f) K. Tanaka, Synlett 2007, 1977–1993; g) N.
Agenet, O. Busine, F. Slowinski, V. Gandon, C. Aubert, M.
Malacria, Org. React. 2007, 68, 1–302; h) T. Shibata, K. Tsu-
chikama, Org. Biomol. Chem. 2008, 6, 1317–1323; i) R. Sanz,
Org. Prep. Proced. Int. 2008, 40, 215–291; j) W. Hess, J. Treutw-
ein, G. Hilt, Synthesis 2008, 3537–3562; k) C. J. Scheuerm-
ann neé Taylor, B. D. Ward, New J. Chem. 2008, 32, 1850–1880;
l) K. Tanaka, Chem. Asian J. 2009, 4, 508–518; m) B. R. Galan,
T. Rovis, Angew. Chem. 2009, 121, 2870–2874; Angew. Chem.
Int. Ed. 2009, 48, 2830–2834; n) S. Perreault, T. Rovis, Chem.
Soc. Rev. 2009, 38, 3149–3159; o) L. Zhou, S. Li, K. Kanno,
T. Takahashi, Heterocycles 2010, 80, 725–738; p) P. A. Inglesby,
P. A. Evans, Chem. Soc. Rev. 2010, 39, 2791–2805; q) A. Pla-
Quintana, A. Roglans, Molecules 2010, 15, 9230–9251; r) M. R.
Shaaban, R. El-Sayed, A. H. M. Elwahy, Tetrahedron 2011, 67,
6095–6130; s) R. Hua, M. V. A. Abrenica, P. Wang, Curr. Org.
Chem. 2011, 15, 712–729; t) G. Domínguez, J. Pérez-Castells,
Chem. Soc. Rev. 2011, 40, 3430–3444; u) N. Weding, M. Hapke,
Chem. Soc. Rev. 2011, 40, 4525–4538; v) Y. Shibata, K. Tanaka,
Synthesis 2012, 44, 323–350.
NMR (75 MHz, CDCl3): δ = 154.6, 154.3, 152.5, 146.0, 132.9,
129.9, 129.4, 129.0, 127.9, 126.3, 124.0, 123.0, 120.6, 120.4, 120.1,
60.8, 55.5, 54.8, 31.7, 30.7, 23.1 (-CH3), 21.4 ppm. MS (EI, GC–
MS): m/z (%) = 330 (73) [M]+, 315 (42), 287 (50), 260 (100), 232
(44). HRMS (ESI+): calcd. for C22H23N2O [M + H]+ 331.1805;
found 331.1805.
(S)-(aX)-1-(3-Methyl-5,7,8,9,9a,10-hexahydropyrrolo[1,2-b][2,6]-
naphthyridin-1-yl)naphthalen-2-yl trifluoromethanesulfonate [(S)-
(aR)-22]: Diastereomer (S)-(aR)-21 (130 mg, 0.39 mmol) was se-
cured in a Schlenk flask and dissolved in CH2Cl2 (4.5 mL) and
Et3N (0.54 mL, 3.9 mmol). The solution was cooled to –20 °C and
trifluromethanesulfonic anhydride (0.11 mL, 0.59 mmol) was
added by syringe. The reaction mixture was stirred for 15 min at
–20 °C and then for 1 h at 0 °C. Afterwards the mixture was
warmed to room temp. and then quenched by the addition of a
saturated aqueous solution of NH4Cl and extracted with CH2Cl2
several times. The combined organic phases were dried with
Na2SO4 and the solvent was evaporated. Column chromatography
on silica gel (eluent: THF/ethyl acetate, 3:1 v/v + 1% Et3N) gave
the pure product as a viscous oil (87 mg, 48% yield). [α]2D4 = +12.0
(c = 0.915, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.97 (d, J =
9.0 Hz, 1 H), 7.93 (d, J = 8.2 Hz, 1 H), 7.54 (ddd, J = 8.2, 6.8,
1.3 Hz, 1 H), 7.50 (d, J = 9.0 Hz, 1 H), 7.47 (ddd, J = 8.6, 6.8,
1.4 Hz, 1 H), 7.38 (d, J = 8.6 Hz, 1 H), 7.01 (s, 1 H), 4.23 (d, J =
–15.9 Hz, 1 H), 3.47 (d, J = –15.9 Hz, 1 H), 3.28 (dd, J = 8.4,
2.1 Hz, 1 H), 2.57 (s, 3 H, -CH3), 2.36–2.31 (m, 2 H), 2.26–2.18
(m, 2 H), 1.92–1.80 (m, 2 H), 1.78–1.69 (m, 1 H), 1.41–1.32 (m, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.7, 151.4, 145.5,
144.9, 132.7, 132.4, 130.7, 130.4, 128.4, 128.2, 127.9, 127.1, 126.0,
121.2, 119.8, 118.4 (CF3, JC,F = 320 Hz), 60.6, 55.5, 54.7, 32.2,
30.7, 24.0 (-CH3), 21.4 ppm. 19F NMR (280 MHz, CDCl3): δ =
–73.9 ppm. MS (ESI+): m/z (%) = 462 (21) [M]+, 329 (100), 260
(34), 243 (19). HRMS (ESI+): calcd. for C23H22F3N2O3S [M +
H]+ 463.1298; found 463.1297.
[5]
[6]
a) B. Heller, M. Hapke, Chem. Soc. Rev. 2007, 36, 1085–1094;
b) J. A. Varela, C. Saá, Synlett 2008, 2571–2578.
For recent examples, see: a) U. Groth, T. Huhn, C. Ke-
senheimer, A. Kalogerakis, Synlett 2005, 1758–1760; b) C. Ke-
senheimer, U. Groth, Org. Lett. 2006, 8, 2507–2510; c) A.
McIver, D. D. Young, A. Deiters, Chem. Commun. 2008, 4750–
4752; d) N. Nicolaus, S. Strauss, J.-M. Neudörfl, A. Prokop,
H.-G. Schmalz, Org. Lett. 2009, 11, 341–344; e) A. L. McIver,
A. Deiters, Org. Lett. 2010, 12, 1288–1291; f) C. Kesenheimer,
A. Kalogerakis, A. Meißner, U. Groth, Chem. Eur. J. 2010, 16,
8805–8821; g) C. Yuan, C.-T. Chang, A. Axelrod, D. Siegel, J.
Am. Chem. Soc. 2010, 132, 5924–5925.
[7]
[8]
[9]
A. Bradley, W. B. Motherwell, F. Ujjainwalla, Chem. Commun.
1999, 917–918.
M. Hapke, K. Kral, C. Fischer, A. Spannenberg, A. Gutnov,
Supporting Information (see footnote on the first page of this arti-
cle): Synthesis and characterization of 8, copies of 1H and 13C spec-
tra of all relevant compounds, and CD spectra of 16 and 20.
D. Redkin, B. Heller, J. Org. Chem. 2010, 75, 3993–4003.
For selected publications, see: a) T. Kitamura, K. Harano, T.
Hisano, Chem. Pharm. Bull. 1992, 40, 2255–2261; b) O. Kita-
gawa, M. Fujita, M. Kohriyama, H. Hasegawa, T. Taguchi,
Tetrahedron Lett. 2000, 41, 8539–8544; c) K. R. Gibson, L.
Hitzel, R. J. Mortishire-Smith, U. Gerhard, R. A. Jelley, A. J.
Reeve, M. Rowley, A. Nadin, A. P. Owens, J. Org. Chem. 2002,
67, 9354–9360; d) U. S. M. Maharoof, G. A. Sulikowski, Tetra-
hedron Lett. 2003, 44, 9021–9023; e) A. Bracegirdle, J. Clayden,
L. W. Lai, Beilstein J. Org. Chem. 2008, 4, no. 47; f) S. B.
Luesse, C. M. Counceller, J. C. Wilt, B. R. Perkins, J. N. John-
ston, Org. Lett. 2008, 10, 2445–2447; g) C. Zhu, Y. Shi, M.-H.
Xu, G.-Q. Lin, Org. Lett. 2008, 10, 1243–1246; h) J. Clayden,
S. P. Fletcher, J. J. W. McDouall, S. J. M. Rowbottom, J. Am.
Chem. Soc. 2009, 131, 5331–5343; i) J. Clayden, S. P. Fletcher,
S. J. M. Rowbottom, M. Helliwell, Org. Lett. 2009, 11, 2313–
2316; j) D. B. Guthrie, S. J. Geib, D. P. Curran, J. Am. Chem.
Soc. 2010, 132, 115–122; k) M. Hapke, A. Gutnov, N. Weding,
A. Spannenberg, C. Fischer, C. Benkhäuser-Schunk, B. Heller,
Eur. J. Org. Chem. 2010, 509–514; l) P. Przybylski, M. Kwit, K.
Pyta, R. Pankiewicz, G. Schroeder, J. Gawron´ski, B. Brzezinski,
Tetrahedron: Asymmetry 2010, 21, 973–981; m) P. Nareddy, L.
Acknowledgments
This work was supported by the Leibniz-Institut für Katalyse (LI-
KAT). We thank Prof. Uwe Rosenthal for his support and helpful
comments. We thank Dr. Thomas Schareina for the measurement
of CD spectra and Dipl.-Ing. Andreas Koch for recording the
NMR spectra.
[1] a) G. Bringmann, T. Gulder, T. A. M. Gulder, M. Breuning,
Chem. Rev. 2010, 111, 563–639; b) G. Bringmann, A. J.
Price Mortimer, P. A. Keller, M. J. Gresser, J. Garner, M.
Breuning, Angew. Chem. 2005, 117, 5518–5563; Angew. Chem.
Int. Ed. 2005, 44, 5384–5427.
[2] G. Bringmann, C. Günther, M. Ochse, O. Schupp, S. Tasler, in:
Progress in the Chemistry of Organic Natural Products (Eds.:
W. Herz, H. Falk, G. W. Kirby, R. E. Moore), Springer, Vi-
enna, 2001, vol. 82, p. 1–293.
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20402
/KAP1
Date: 04-09-12 15:49:07
Pages: 12
Diastereomeric Atropisomers from a Chiral Diyne
Mantilli, L. Guénée, C. Mazet, Angew. Chem. 2012, 124, 3892–
3897; Angew. Chem. Int. Ed. 2012, 51, 3826–3831.
[10] For an investigation on intramolecular cyclotrimerizations with
chiral triynes, see: P. Sehnal, Z. Krausová, F. Teplý, I. G. Stará,
I. Starý, L. Rulísˇek, D. Saman, I. Císarˇová, J. Org. Chem. 2008,
73, 2074–2082.
[11] The bisalkynylated derivative of 4 was mentioned, but no de-
tailed synthetic procedure was described: K. Tamao, K. Kobay-
ashi, Y. Ito, J. Am. Chem. Soc. 1989, 111, 6478–6480. Our own
experiments with bismesylated (S,S)-4 and reactions with nu-
cleophilic alkyne reagents never yielded the products in promis-
ing yields.
[12] For the synthesis of 6 by a Sonogashira approach, see: a) P.
Wessig, G. Müller, Chem. Commun. 2006, 4524–4526; b) G.
Nishida, K. Noguchi, M. Hirano, K. Tanaka, Angew. Chem.
2007, 119, 4025–4028; Angew. Chem. Int. Ed. 2007, 46, 3951–
3954; for a different approach, see: c) B. Heller, A. Gutnov, C.
Fischer, H.-J. Drexler, A. Spannenberg, D. Redkin, C. Sun-
dermann, B. Sundermann, Chem. Eur. J. 2007, 13, 1117–1128.
[13] K. Tanaka, A. Kamisawa, T. Suda, K. Noguchi, M. Hirano, J.
Am. Chem. Soc. 2007, 129, 12078–12079.
[20]
CCDC-847945 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
For a recent overview, see: H. Amii, K. Uneyama, Chem. Rev.
2009, 109, 2119–2183.
CCDC-847944 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
The crystal for X-ray analysis and determination of the config-
uration was obtained from the slow evaporation of the solvent
from a sample of (S)-(aR)-18 prepared in CDCl3 for NMR
spectroscopy.
For selected references, see: a) J. M. Brown, D. I. Hulmes, T. P.
Layzell, J. Chem. Soc., Chem. Commun. 1993, 1673–1674; b)
J.-M. Valk, T. D. W. Claridge, J. M. Brown, D. Hibbs, M. B.
Hursthouse, Tetrahedron: Asymmetry 1995, 6, 2597–2610; c) P.
Guiry, C. Saunders, Adv. Synth. Catal. 2004, 346, 497–537; d)
T. F. Knöpfel, P. Aschwanden, T. Ichikawa, T. Watanabe, E. M.
Carreira, Angew. Chem. 2004, 116, 6097–6099; Angew. Chem.
Int. Ed. 2004, 43, 5971–5973.
BBr3 and BBr3·SMe2 (2–4 equiv.) were used in CH2Cl2 at room
temp. and under reflux or in ClCH2CH2Cl at 70 °C; Me3SiI
(3 equiv.) was used in CHCl3 at 60 °C for reaction times up to
49 h. The application of AlCl3 (12 equiv.) in ClCH2CH2Cl at
70 °C gave clear decomposition. While 1H NMR spectra
showed the unselective formation of several undefined com-
pounds, GC–MS proved the formation of OH-free 21, which
was always companied by unreacted 16. Column chromatog-
raphy never yielded pure product.
[21]
[22]
[23]
[24]
[14] NMR spectroscopic analysis showed that resonances for two
different MOM groups were observed in the main product,
pointing towards an unexpected side reaction. However, we
have not further investigated the structure of this unwanted
product.
[25]
[15] For comparable cycloaddition reactions with nitriles, see: a) Y.
Yamamoto, K. Kinpara, R. Ogawa, H. Nishiyama, K. Itoh,
Chem. Eur. J. 2006, 12, 5618–5631; b) Y. Zhou, J. A. Porco,
J. K. Snyder, Org. Lett. 2007, 9, 393–396; c) H.-T. Chang, M.
Jeganmohan, C.-H. Cheng, Org. Lett. 2007, 9, 505–508; d)
B. L. Gray, X. Wang, W. C. Brown, L. Kuai, S. L. Schreiber,
Org. Lett. 2008, 10, 2621–2624; e) J.-C. Hsieh, C.-H. Cheng,
Chem. Commun. 2008, 2992–2994; f) L. Sripada, J. A. Teske,
A. Deiters, Org. Biomol. Chem. 2008, 6, 263–265; g) A. Gos-
wami, K. Ohtaki, K. Kase, T. Ito, S. Okamoto, Adv. Synth.
Catal. 2008, 350, 143–152; h) A. Kadlkova, M. Kotora, Mole-
cules 2009, 14, 2918–2926; i) C. Yuan, C.-T. Chang, A. Axel-
rod, D. Siegel, J. Am. Chem. Soc. 2010, 132, 5924–5925; j) C.
Wang, X. Li, F. Wu, B. Wan, Angew. Chem. 2011, 123, 7300–
7304; Angew. Chem. Int. Ed. 2011, 50, 7162–7166.
[26]
For reviews, see: a) B. M. Rosen, K. W. Quasdorf, D. A. Wil-
son, N. Zhang, A.-M. Resmerita, N. K. Garg, V. Percec, Chem.
Rev. 2011, 111, 1346–1416; b) B.-J. Li, D.-G. Yu, C.-L. Sun,
Z.-J. Shi, Chem. Eur. J. 2011, 17, 1728–1759.
[27] We checked our reaction conditions at two different reaction
temperatures (100 and 130 °C) by reacting 2-naphthyl triflate
as the test substrate with diphenylphosphane, successfully
yielding 2-diphenylphosphanyl naphthalene in 61 (at 100 °C)
and 64% (at 130 °C) isolated yield. Clearly, substrate (S)-(aR)-
22 was problematic for the successful introduction of the phos-
phanyl group by this applied Ni-catalyzed methodology.
[28] A. Korostylev, I. Gridnev, J. M. Brown, J. Organomet. Chem.
2003, 680, 329–334.
[29] For examples, see: a) J. Iskra, S. Stavber, M. Zupan, Synthesis
2004, 1869–1873; b) K. S. K. Reddy, N. Narender, C. N. Rohi-
tha, S. J. Kulkarni, Synth. Commun. 2008, 38, 3894–3902.
[30] H. Bönnemann, B. Bogdanovicˇ, R. Brinkmann, B. Spliethoff,
D.-W. He, J. Organomet. Chem. 1993, 451, 23–31.
[31] L. Brandsma, S. F. Vasilevsky, H. D. Verkruijsse, Application of
Transition Metal Catalysts in Organic Synthesis, Springer,
Berlin, 1999.
[16] a) B. Heller, B. Sundermann, H. Buschmann, H.-J. Drexler, J.
You, U. Holzgrabe, E. Heller, G. Oehme, J. Org. Chem. 2002,
67, 4414–4422; b) B. Heller, B. Sundermann, C. Fischer, J. You,
W. Chen, H.-J. Drexler, P. Knochel, W. Bonrath, A. Gutnov, J.
Org. Chem. 2003, 68, 9221–9225; c) B. Heller, D. Redkin, A.
Gutnov, C. Fischer, W. Bonrath, R. Karge, M. Hapke, Synthe-
sis 2008, 69–74.
[17] M. Hapke, N. Weding, A. Spannenberg, Organometallics 2010,
29, 4298–4304.
[18] The initial substitution reactions for entry to the catalytic cycle
have been investigated by computational methods, see, for ex-
ample: V. Gandon, N. Agenet, K. P. C. Vollhardt, M. Malacria,
C. Aubert, J. Am. Chem. Soc. 2006, 128, 8509–8520, and refer-
ences cited therein.
[19] The CD spectra of (S)-(aS)-16 and (S)-(aR)-16 as well as those
of the MOM-protected congeners (S)-(aS)-20 and (S)-(aR)-20
can be found in the Supporting Information
[32] J. Montgomery, M. V. Chevliakov, H. L. Brielmann, Tetrahe-
dron 1997, 53, 16449–16462.
Received: March 29, 2012
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O20402
/KAP1
Date: 04-09-12 15:49:07
Pages: 12
M. Hapke et al.
FULL PAPER
[2+2+2] Cyclotrimerization
F. Fischer, P. Jungk, N. Weding,
A. Spannenberg, H. Ott,
M. Hapke* ...................................... 1–12
Diastereomeric Atropisomers from a Chi-
ral Diyne by Cobalt(I)-Catalyzed Cyclo-
trimerization
The cobalt-catalyzed [2+2+2] cycload-
dition of chiral diynes with different nitriles
under very mild conditions led to the for-
mation of pairs of diastereomeric biaryl
atropisomers in one step. These diastereo-
mers can easily be separated by column
chromatography to provide the pure single
atropisomers. The 2-position of the naphth-
yl ring can further be functionalized.
Keywords: Homogeneous catalysis / Co-
balt / Cycloaddition / Cyclotrimerization /
Atropisomerism / Biaryls / Alkynes
12
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0