1,3-diethynylallenes (DEAs): Enantioselective synthesis, absolute configuration, and chiral induction in 1,1,4,4-tetracyanobuta-1,3-dienes (TCBDs)

Article abstract of DOI:10.1002/chem.200801456

A study was conducted to demonstrate enantioselective synthesis, absolute configuration, and chiral induction in 1,1,4,4-tetracyanobuta-1,3-dienes. The study demonstrated that 4-N,N-dimethylanilino (DMA) donor-substituted optically active DEAs undergo photoisomerization, leading to racemization. It was found that these 1,1,4,4-tetracyanobuta-1,3-dienes react in a facile [2+2] cycloaddition with tetracyanoethene (TCNE), to form optically active and photostable 1,1,4,4-tetracyanobuta-1,3-diene (TCBD) derivatives. Chiral induction from the optically active allene moiety in the TCBD chromophore was observed in these compounds by circular dichromism (CD) spectroscopy. More investigations were also conducted to improve the yield and the enantioselectivity of the synthesis of optically active DEAs.

Full text of DOI:10.1002/chem.200801456

DOI: 10.1002/chem.200801456
1,3-Diethynylallenes (DEAs): Enantioselective Synthesis, Absolute
Configuration, and Chiral Induction in 1,1,4,4-Tetracyanobuta-1,3-dienes
(TCBDs)
Josꢀ Lorenzo Alonso-Gꢁmez, Patrick Schanen, Pablo Rivera-Fuentes, Paul Seiler, and
FranÅois Diederich*[a]
Dedicated to Professor Javier de Mendoza on the occasion of his 65th birthday
In 1875 vanꢀt Hoff predicted that in cumulenes with an
even number of double bonds the four substituents must be
arranged in two perpendicular planes.[1] Vanꢀt Hoff’s propos-
al implied that allenes must be chiral when appropriately
substituted.[2] The predictions were confirmed when the first
optically active allenes were described in 1935.[3] For 1,3-di-
methylallene, the activation enthalpy for rotational isomer-
ism leading to racemization was determined by Roth et al.
as DH° =45.07 kcalmolÀ1.[4]
In 1952, Celmer and Solomons recognized that optically
active allenes also occur in nature.[5] Since then, a number of
natural chiral allenes have been found. Today, allenes are
versatile starting materials and intermediates in organic syn-
thesis because their double bonds participate in all types of
SN2’-type cross-coupling of alkyne 2a with the optically pure
bispropargylic ester (S)-3.[8] The absolute configuration of
the allene was tentatively assigned as (P) on the basis of an
anti-SN2’-type addition of 2a to (S)-3, as previously reported
for enantioselective[11] and diastereoselective[12] Pd-mediated
SN2’-type cross-coupling reactions.
Here, we give X-ray crystallographic evidence that the
enantioselective Pd-mediated addition of alkynes 2 to (S)-3
actually proceeds under opposite stereocontrol, leading to
(M)-1, thereby providing the first example for a Pd-mediat-
ed enantioselective syn-SN2’-type cross-coupling reaction.
We show that 4-N,N-dimethylanilino (DMA) donor-substi-
tuted optically active DEAs undergo photoisomerization
leading to racemization. They also react in a facile [2+2] cy-
cloaddition with tetracyanoethene (TCNE)[13] to form, after
retrocycloaddition, optically active, photostable 1,1,4,4-tetra-
cyanobuta-1,3-diene (TCBD) derivatives. In these com-
pounds, chiral induction from the optically active allene
moiety in the TCBD chromophore is observed by circular
dichroism (CD) spectroscopy.
First, we undertook further studies to improve both the
yield and the enantioselectivity of the previously reported
synthesis of optically active DEAs.[8] Alkynes 2a,b with dif-
ferent protecting groups were used to enable selective de-
protection, providing subsequent access to oligomers in a
controlled manner (Scheme 1, Table 1). The e.r. of Me3Si-
protected DEA 1a was determined after derivatization with
the Mosher acid chloride[8] and the e.r. of 1b by recycling
HPLC on the chiral stationary phase (CSP) WHELK-O1
(hexane/0.25% iPrOH) after removal of the iPr3Si group
with nBu4NF/THF (see Supporting Information).
Increasing the amount of base from 0.4 to 2.1 equiv was
essential to improve the yield considerably without affecting
the enantioselectivity (entries 1 and 2, Table 1). When the
acetonide-protected acetylene 2b was used, a lower reactivi-
ty was observed. Raising the temperature from 30 to 508C
À
addition processes, their terminal, acidic C H bonds are
easily replaced by functional groups, and their axial chirality
is increasingly exploited in stereoselective synthesis.[6]
We have been involved in the preparation of ethynylated
allenes[7a–c] as building blocks for the construction of linear[8]
and macrocyclic[7d,9] carbon-rich scaffolds through oxidative
acetylenic coupling. Following the synthesis of a first series
of stable 1,3-diethynylallenes (DEAs), we proceeded with
the preparation of shape-persistent macrocycles with alle-
noacetylenic carbon backbones.[7d] Although DEAs are ax-
ially chiral, racemic mixtures were previously used in our
group for acetylenic scaffolding. Recently, we reported the
synthesis of optically enriched DEA 1a in 25% yield and
with an enantiomer ratio (e.r.)[10] of 89:11 by Pd-mediated
[a] Dr. J. L. Alonso-Gꢁmez, Dr. P. Schanen, P. Rivera-Fuentes, P. Seiler,
Prof. Dr. F. Diederich
Laboratorium fꢂr Organische Chemie, ETH Zurich
Hçnggerberg, HCI, 8093 Zurich (Switzerland)
Fax : (+41)44-632-1109
E-mail: diederich@org.chem.ethz.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801456.
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COMMUNICATION
Scheme 2. Synthesis of (M,M)-5. A diastereomeric ratio (d.r.) of 90.25
((M,M)-5):9.5 ((M,P)-5):0.25 ((P,P)-5) is expected for an unselective
homo-coupling reaction of 4a (e.r. 95:5). TMEDA=N,N,N’,N’-tetrame-
thylethylenediamine. (M)-4a (e.r. 95:5) was obtained by deprotection of
(M)-1a (e.r. 95:5) with K2CO3, THF/MeOH 1:1 as previously reported.[8]
Scheme 1. Enantioselective synthesis of DEAs (M)-1a/b starting from
optically pure (S)-3.[8] For reaction conditions, see Table 1.
Table 1. Enantioselective synthesis of DEAs by Pd-mediated syn-SN2’
substitution of 2a/b to (S)-3 or (R)-3.
cross-coupling reaction.[11,12] As
a note, Molander and
Entry
PG
Base
T [8C]/t [h]
Yield [%]/e.r. M:P
Sommers recently reported a syn-carbometallation/syn-elim-
ination of propargyl substrates to form allenes using chiral
cationic CrIII catalysts.[13]
1[a,b][8]
20/24
30/5
30/96
50/72
25/89:11[e]
61/90:10[f]
69/96:4[g]
93/74:26[g]
Me3Si
CMe2OH
2[a,b]
Cy2NMe
3[a,b]
4[a,b]
5[a,c]
6[c,d]
7[c,d]
8[b,d]
9[b,d]
20/14
20/20
20/96
30/16
50/6
53/6:94[f]
90/5:95[e]
49/7:93[g]
70/71:29[g]
86/69:31[g]
Me3Si
iPr2NH
CMe2OH
[a] Solvent: toluene. [b] Starting material (S)-3 was used. [c] Starting ma-
terial (R)-3 was used. [d] Solvent: (ClCH2)2. [e] The enantiomeric ratio
(e.r.) was determined by derivatization with the Mosher acid chloride as
previously reported.[8] [f] The e.r. was estimated from the optical rotation.
[g] The e.r. was determined by recycling HPLC on the CSP WHELK-O1
(hexane/0.25% iPrOH) after removal of the iPr3Si group with nBu4NF/
THF. In general, 2.1 equiv of base were used in the reaction, except for
entry 1 where only 0.4 equiv were used. Cy=cyclohexyl.
Figure 1. ORTEP plot of (M,M)-5 with vibrational ellipsoids shown at
the 30% probability level. T=160 K. Arbitrary numbering (see Support-
ing Information). Flack parameter: 0.03(18).
increased the yield but a loss in stereoselectivity occurred
(entries 3 and 4, Table 1). The enantioselectivity was very
sensitive to the nature of the base used. With iPr2NH, the
e.r. was improved for 1a, but the yield was only moderate
(entry 5, Table 1). When the solvent was changed from tolu-
ene to 1,2-dichloroethane, the yield became excellent with-
out any loss in enantioselectivity (entry 6, Table 1). Under
the same conditions, the acetonide-protected DEA 1b was
obtained in moderate yield and with good e.r. The yield was
increased when the temperature was changed to 30 or 508C,
however, at the cost of stereoselectivity (entries 7–9,
Table 1). Enantiopure (M)-4b and (P)-4b were obtained by
resolution of (Æ)-4b, using recycling HPLC on the CSP
WHELK-O1 (hexane/0.25% iPrOH; see Supporting Infor-
mation).
The enantioselective synthesis of DEAs opens access to
novel chromophores with interesting optical properties. Re-
cently, we introduced a new class of intramolecular charge
transfer (CT) chromophores, DMA donor-substituted
TCBDs, accessible in excellent yields in an atom-economic
synthesis by [2+2] cycloadditions between tetracyanoethy-
lene (TCNE) and DMA-substituted alkynes, followed by
electrocyclic ring-opening of the initially formed cyclobu-
tenes.[14] We were interested in exploring whether the stereo-
genic allene moiety in compounds such as (M)-6 (Figure 2)
would induce conformational preferences and a sense of
chirality in the adjacent, nonplanar donor-substituted TCBD
moieties.[15]
Starting from (M)-4a (e.r. 95:5), Sonogashira cross-cou-
pling with 4-iodo-N,N-dimethylaniline gave DEA (M)-7 in
In order to assign the absolute configuration of the
DEAs, the dimer (M,M)-5 was synthesized from (M)-4a
(e.r. 95:5) (Scheme 2).[8]
Suitable single crystals of (M,M)-5 were grown for X-ray
crystallographic analysis. The presence of the silicon heavy
atoms enabled the unambiguous assignment of the absolute
configuration of the allene moieties as (M), disproving the
previously proposed assignment (Figure 1).[8] These results
suggest that a syn-SN2’-type substitution of 2a,b to ester (S)-
3 had taken place. To the best of our knowledge this is the
first reported enantioselective Pd-mediated syn-SN2’-type
Figure 2. Bis-TCBD-substituted allene (M)-6.
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10565

F. Diederich et al.
71% yield. Deprotection with nBu4NF in THF to give (M)-
8, followed by another Sonogashira cross-coupling, afforded
(M)-9 in good yield along with the side product (M,M)-10
resulting from homo-coupling (Scheme 3). The e.r. of (M)-7,
(M)-8 and (M)-9 was determined to be ꢀ91:9 based on the
e.r. measured for (M)-6 (see Scheme 4) by HPLC on the
CSP WHELK-O1 (hexane/ethanol/methanol 65:30:5). The
d.r. of (M,M)-10 was determined to be ꢀ78 ((M,M)-10):20
((M,P)-10):2 ((P,P)-10) based on the d.r. measured for
(M,M)-11 (see Scheme 4) by recycling HPLC on the CSP
WHELK-O1 (hexane/55% CH2Cl2).
Since we had previously observed that DEAs attached to
electron-rich chromophores undergo photoisomerization,[7d]
(M)-9 and analogously obtained (P)-9 were synthesized and
characterized in the dark. This way reproducible mirror-
image CD spectra of both enantiomers with consistent
molar ellipticities were obtained (Figure 3).
Figure 3. CD spectra of (M)-9 (gray line) and (P)-9 (black line) recorded
in hexane at 298 K. The e.r. was determined to be ꢀ91:9 based on the
e.r. measured for (M)-6 (see Scheme 4) by HPLC on the CSP WHELK-
O1 (hexane/ethanol/methanol 65:30:5).
Photoracemization was con-
firmed when (M)-9 was exposed
to daylight and CD spectra
were recorded at given time in-
tervals (Figure 4).
A similar photoisomerization
was observed for (P,P)-10 (see
Supporting Information). Ac-
cordingly, the “click-type” syn-
thesis of the TCBD derivatives
(M)-6 and (M,M)-11 by TCNE
addition to (M)-9 and (M,M)-
10, respectively, followed by
retro-electrocyclization was car-
ried out in the absence of light
(Scheme 4).
The conversions were per-
formed in CDCl3 to allow moni-
toring of the reaction progress
Scheme 3. Synthesis of (M)-9 (e.r. determined to be ꢀ91:9 based on the e.r. measured for (M)-6)) and (M,M)-
10 (e.r. was determined to be ꢀ78 ((M,M)-10):20 ((M,P)-10):2 ((P,P)-10) based on the e.r. measured for
(M,M)-11 (see Scheme 4)).
by 1H NMR spectroscopy. For-
tunately, these new charge-
transfer chromophores showed
no photoisomerization.
Enantiomerically pure (M)-6
and (P)-6 were obtained by res-
olution of (Æ)-6, using HPLC
on the CSP WHELK-O1
(hexane/ethanol/methanol
65:30:5; see Supporting Infor-
mation) as well as enantiopure
(M,M)-11 and (P,P)-11 by recy-
cling HPLC on the same CSP
(hexane/55% CH2Cl2; see Sup-
porting Information). Single
crystal X-ray crystallographic
analysis of (Æ)-6 and (M,M)-11
showed that in the solid state,
the bulky tert-butyl groups on
the allene moieties force the
Scheme 4. Synthesis of (M)-6 (e.r. determined as 91:9 by HPLC on the CSP WHELK-O1 (hexane/ethanol/
methanol 65:30:5)) and (M,M)-11 (d.r. determined as 78 ((M,M)-11):20 ((M,P)-11):2 ((P,P)-11) by recycling
HPLC on the CSP WHELK-O1 (hexane/55% CH2Cl2)).
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1,3-Diethynylallenes
COMMUNICATION
adjacent dicyanovinyl residues to adopt dihedral angles
around 908 (C49-C1-C2-C3 and C3-C4-C5-C21 in (Æ)-6 or
C2-C1-C44-C60 and C9-C10-C11-C27 in (M,M)-11,
Figure 5). In solution, this could also induce chirality in the
non-planar TCBD chromophores which feature central di-
hedral angles between 588 and 758.
UV/Vis spectroscopy studies of (P)-6 and (M)-6 revealed
two CT absorptions at 390 nm and 520 nm in CH2Cl2. The
absorptions in the region between 350 and 700 nm disap-
peared to a large extent upon acidification with CF3COOH
and were fully recovered after neutralization with Et3N (see
Supporting Information). The CD spectra show Cotton ef-
fects associated with the CT absorptions. This clearly indi-
cates chiral induction[15] from the allene into the TCBD moi-
eties (Figure 6).
Figure 4. Photoracemization of (M)-9 in hexane upon exposure to day-
light at 298 K, as monitored over time by CD spectroscopy. The e.r. at
the initial time was determined to be ꢀ91:9 based on the e.r. measured
for (M)-6 (see Scheme 4) by HPLC on the CSP WHELK-O1 (hexane/
ethanol/methanol 65:30:5).
Figure 6. CD spectra (top) of (M)-6 (e.r. 100:0, black line) and (P)-6 (e.r.
100:0, gray line) and UV/Vis spectra (bottom) recorded in CH2Cl2.
In conclusion, we performed the enantioselective synthe-
sis of differently protected (M) and (P)-DEAs 1a,b in good
to excellent yields with high enantioselectivity. Unambigu-
ous assignment of the absolute configuration by X-ray crys-
tallographic analysis led us to confirm the first enantioselec-
tive Pd-mediated syn-SN2’-type cross-coupling reaction. CD
spectroscopy revealed chiral induction in TCBDs when they
are directly attached to optically pure allenes. Further stud-
ies on chiral induction in TCBDs are currently under way,
using a combination of CD spectroscopy and theoretical cal-
culations. Furthermore, the availability of optically pure
DEAs opens the way to new chiral, non-racemic helical fol-
damers and allenoacetylenic macrocycles.
Figure 5. ORTEP plot of (Æ)-6 (top, T=170 K) and (M,M)-11 (bottom,
T=220 K) with vibrational ellipsoids shown at the 30% probability level.
Arbitrary numbering. Selected dihedral angles [8]: (Æ)-6: C3-C4-C5-C21
71.9(3), C3-C4-C5-C6 À106.0(2), C21-C5-C6-C7 58.4(3), C12-C6-C7-C8
8.7(4), C49-C1-C2-C3 65.8(3), C34-C1-C2-C3 À113.2(2), C49-C1-C34-C44
65.4(3), C35-C34-C44-C45 3.6(4); (M,M)-11: C2-C1-C44-C60 À77.6(12),
C2-C1-C44-C45 98.4(10), C60-C44-C45-C46 À70.2(14), C51-C45-C46-C49
À0.6(16), C9-C10-C11-C27 101.8(12), C9-C10-C11-C12 À74.1(11), C27-
C11-C12-C13 73.3(13), C18-C12-C13-C14 7.4(14) (see Supporting Infor-
mation).
Experimental Section
General procedure for the synthesis of 1: Two solutions A and B were
prepared. A) A solution of enantiomerically pure 3 and base (2.1 equiv)
in the corresponding solvent (0.05m); B) A solution of [PdCl2ACHTUNGTRENNUNG(PPh3)2]
(0.09 equiv) in the corresponding solvent (0.05m). Both solutions were
degassed with Ar. Acetylene 2a,b (2.05 equiv) was added to solution A,
CuI (0.10 equiv) to solution B and both were degassed again. Solution B
was added to A and the reaction stirred at the corresponding tempera-
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F. Diederich et al.
ture. Purification by FC on silica gel (hexane for 1a and hexane/10%
AcOEt for 1b) gave colorless oils.
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Acknowledgements
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This work was supported by the ETH Research Council and the German
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Keywords: allenes
·
chirality
·
circular dichroism
·
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Received: July 18, 2008
Published online: October 27, 2008
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Chem. Eur. J. 2008, 14, 10564 – 10568