A mild and efficient CH2-extrusion reaction for the enantiospecific synthesis of highly configurationally stable tr?ger bases

Article abstract of DOI:10.1002/anie.201500435

A novel CH₂-extrusion reaction leading to the transformation of ethano-Tr?ger bases into disubstituted methano derivatives is reported (yields up to 93%). Under mild and metal-free oxidative conditions, a loss of CH₂ and a ring contraction are provoked. Despite two bond cleavages at stereogenic nitrogen and carbon centers and a temporary rupture of the bicyclic structure, a very high enantiospecificity (es≥98%) is observed for this unusual reaction. Against all odds: Simple treatment of ethano-Tr?ger bases with DDQ in wet nitromethane provokes a novel CH₂-extrusion reaction. Disubstituted methano-derivatives are formed in high yield and enantiospecificity despite undergoing two bond cleavages at stereogenic nitrogen and carbon centers, and a temporary rupture of the bicyclic structure. DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

Full text of DOI:10.1002/anie.201500435

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International Edition: DOI: 10.1002/anie.201500435
German Edition: DOI: 10.1002/ange.201500435
Asymmetric Synthesis
A Mild and Efficient CH2-Extrusion Reaction for the Enantiospecific
Synthesis of Highly Configurationally Stable Trçger Bases**
Sandip A. Pujari, CØline Besnard, Thomas Bürgi, and JØrôme Lacour*
Dedicated to Professor Volker Schurig on the occasion of his 75th birthday
Abstract: A novel CH2-extrusion reaction leading to the
transformation of ethano-Trçger bases into disubstituted
methano derivatives is reported (yields up to 93%). Under
mild and metal-free oxidative conditions, a loss of CH2 and
a ring contraction are provoked. Despite two bond cleavages at
stereogenic nitrogen and carbon centers and a temporary
rupture of the bicyclic structure, a very high enantiospecificity
(es ꢀ 98%) is observed for this unusual reaction.
E
xtrusion reactions, which are formally the reverse of
insertion processes, are characterized by the removal of an
atom or a group of atoms from a given combination of
functional groups and by the reformation of a bond between
the atoms to which the departing moiety was attached.[1] Such
processes are relatively common in organometallic and
chalcogen chemistry.[2,3] With more classical organic sub-
strates, only few CH2 extrusions are reported using metal-free
conditions and activated benzylamines and a-hydroxy car-
bonyl compounds as substrates.[4] Herein, in the context of
nitrogen stereochemistry and Trçger base (TB) derivatives in
particular, we report a novel methylene extrusion which sees
the enantiospecific transformation of the ethano-TB 1 into
the disubstituted methano-TB 2 (Scheme 1, top). Under mild
oxidative conditions, the loss of CH2 occurs with yields of up
to 93%. Importantly, a very high enantiospecificity (es ꢀ
98%) is obtained in this reaction which proceeds with
retention of configuration through a ring opening and two
bond cleavages at stereogenic nitrogen and carbon centers.
Recently, it was shown that Trçger bases of type 3
(Scheme 1, bottom),[5] which are classical chiral molecules as
À
À
Scheme 1. Extrusion of CH2 group by concomitant C C and C N
À
bond-cleavage reactions (top). Insertion of carbene into a C N bond
(bottom). DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
a result of the presence of stereogenic nitrogen atoms, react in
a single step with metal carbenes to afford ethano-Trçger
bases of type 1.[6] With donor-acceptor diazo reagents as
precursors, the enantiospecificity of the ring expansion is
excellent (es 97–99%).[7] The compounds 1,[8] which are 1,2-
diamines, do not racemize under Brønsted- (pH < 1) or
Lewis-acidic conditions, which are known to promote the loss
of enantiomeric purity of 3.[9] These ethano-adducts 1 are
essentially unknown. We wondered about their global reac-
tivity and decided to use them as substrates in various
reactions, including nitrene insertion reactions.[10]
The compound 1a (R = R1 = Me, Ar= Ph) was thus
treated with PhI NTs under rhodium(II) and copper(II)
=
catalysis. To our surprise, instead of obtaining a product with
a higher molecular weight of 169, the derivative 2a with a loss
of a mass of 14 was isolated in good yield (Table 1, entries 1
and 2). This data indicated a probable loss of a CH2 group, and
was confirmed by 1H and 13C spectroscopic analyses. Only an
interesting methano-Trçger base structure with two substitu-
ents on the aminal carbon atom was consistent with the data,
and the motif was ascertained later by X-ray diffraction
analysis (see Table 2).[11] Starting with (+)-1a (ee 99%), 2a
was furthermore obtained with an interesting enantiomeric
purity of 47 and 69% (Table 1, entries 1 and 2), thus denoting
a rather effective transfer of chirality in this unusual extrusion
reaction.[12] Trying to obtain some clues on the reaction
mechanism and improve the results, (+)-1a was treated
[*] Dr. S. A. Pujari, Prof. J. Lacour
Department of Organic Chemistry, University of Geneva
Quai Ernest Ansermet 30, 1211 Geneva 4 (Switzerland)
E-mail: jerome.lacour@unige.ch
Dr. C. Besnard
Laboratory of Crystallography, University of Geneva
Quai Ernest Ansermet 24, 1211 Geneva 4 (Switzerland)
Prof. T. Bürgi
Department of Physical Chemistry, University of Geneva
Quai Ernest Ansermet 30, 1211 Geneva 4 (Switzerland)
[**] We thank the University of Geneva and the Swiss National Science
Foundation for financial support. We are also grateful to Dr. Alain
de Mesmaeker (Syngenta) and Dr. ThØo Berclaz (Geneva) for
fruitful discussions. We also acknowledge the contributions of the
Sciences Mass Spectrometry (SMS) platform at the Faculty of
Sciences, University of Geneva.
=
separately with an excess of Cu(OTf)2 and PhI NTs. Impor-
tantly, ring-contracted (+)-2a was isolated again (entries 3
and 4) and this indicated an oxidative nature for the
transformation.[13] Manganese(III) and manganese(IV) com-
plexes, in combination or without Cu(OTf)2, were tested
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201500435.
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Table 1: Optimization.[a]
Table 2: Substrate scope.[a]
Entry Oxidant
Solvent
t [h] 2a
Yield ee
[%][e] [%][f]
1
2
3
4
5
6
PhINTs/[Rh2(esp)2]
PhINTs/Cu(OTf)2
Cu(OTf)2
CH2Cl2
CH3CN
CH3CN
CH3CN
24
24
4
48
6
48
48
16
6
30
24
8
62
75
30
79
47
69
83
46
70
–
PhINTs
Mn(OAc)3·2H2O/Cu(OTf)2 CH3CN
Mn(OAc)3·2H2O
MnO2
Iodine
NBS
DDQ
DDQ
DDQ
56
CH3CN
CH2Cl2
THF
CH3CN
CH3CN
CH3NO2
CH3NO2
trace
trace
77
84
77
7[b]
8[c]
9[c]
10[c]
11[c]
12[c]
–
70
83
98
98
98
81
85
[d]
[a] Reaction conditions: the ethano Trçger base (+)-1a (1 equiv), oxidant
(2 equiv), solvent (0.05m). [b] 10 equiv of MnO2 was used. [c] 1.2 equiv
of oxidant was used. [d] Nitromethane containing 1.3% of H2O. [e] Yield
of isolated product. [f] Determined by HPLC using a chiral stationary
phase. esp=a,a,a’,a’-tetramethyl-1,3-benzenedipropionate, NBS=N-
bromosuccinimide, Tf = trifluoromethanesulfonyl, THF=tetrahydro-
furan, Ts = 4-toluenesulfonyl.
(entries 5–7).[14] Reactions either did not occur or proceeded
with only moderate enantioselectivity (70% ee). Metal-free
conditions were attempted. While iodine and NBS provided
(+)-2a in good yields and interesting levels of chirality
transfer (ee 70 and 83% respectively), DDQ (entries 10–12)
offered the best results, particularly in wet nitromethane
(1.3% H2O).[15] Under these reaction conditions, at 208C,
(+)-2a was obtained in 85% yield and with 98% ee. These
optimized reaction conditions were used throughout the
study.
The generality of the extrusion reaction was established
by using a series of ethano-TB derivatives (1a–q). Electron-
rich and electron-poor substituents were introduced para to
the bridgehead nitrogen atoms (Me, OMe and CO2Et). Care
was also taken to prepare substrates with electron-donating
and electron-withdrawing substituents on the aromatic group
carried by the stereogenic carbon center. Most of these
compounds were synthesized in both racemic and enantioen-
riched forms (96 to > 99% ee; see Table S1 in the Supporting
Information).[6a] To our satisfaction, in the 2,8-dimethyl series
(1a–i) the methylene extrusion proceeded well. Not too
surprisingly, reactions were slightly faster with electron-rich
substituents on the aromatic ring (e.g., OMe; 1c). Sterics did
not significantly influence the reactivity and stereoselectivity
(e.g., 2 f and 2g).[16] Changing the ester functional group, from
methyl to benzyl and allyl, did not affect the outcome of the
reaction either. Very similar results were obtained with 2,8-
dimethoxy-substituted 1j–p. The reactions were faster thanks
to the electron-donating p-MeO substituents (max. 4 h). On
the contrary, a seven-day reaction was necessary with 1q to
afford 2q in moderate yield (51%).[17] For mechanistic
purposes, the benzoyl 1r and its reduced alcohol derivative
1s were also tested.[8c] While a slow but effective extrusion
occurred with the first derivative, no trace of ring contraction
could be detected with 1s. The necessity of an electron-
[a] Reaction conditions: the substrate 1 (1 equiv), DDQ (1.2 equiv),
CH3NO2/H2O (1.3%) (0.05m), 208C. Yield is that for product isolated
after chromatography. The ee value was determined by CSP-HPLC. Used
4 equiv of DDQ in the case of 2q and 2r. Structures of substrates 1 are
indicated in the Supporting Information.
withdrawing group on the ethano-bridge was confirmed by
using 1t,[8a] which was found to be unreactive.
Importantly, in all examples performed with enantioen-
riched substrates, an efficient chirality transfer was observed
as enantiospecificity values higher than or equal to 98% were
constantly obtained. To our surprise, the enantiospecificity
was high even under Lewis-acidic conditions which are known
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to promote the racemization of 3 (e.g. Cu(OTf)2, es 84%;
Table 1, entry 3). The configurational stability of the 13,13’-
disubstituted derivatives was thus tested. Solutions in DMF
(N,N-dimethylformamide) of (+)- and (À)-2a were treated
with camphorsulfonic acid (2 equiv) for 2 hours at 1008C. To
our satisfaction, these samples retained their enantiomeric
purity (97–98% ee)[18] while, under the same reaction con-
ditions, a complete racemization was observed with the
Trçger base (+)-3 (R = Me, Scheme 1). Also, for these
reactions that proceed through bond cleavages at stereogenic
nitrogen and carbon atoms, care was taken to determine the
absolute configuration of the products 2 with certainty.[19] This
configuration was established by vibrational circular dichro-
ism (VCD) in view of the rigidity of the compounds 2.[20] IR
absorption and VCD spectra were measured for solutions
(CCl4) of both (+)- and (À)-2a and compared to the averaged
spectrum calculated for (5SN,11SN)-2a (Figure 1). Overall,
Scheme 2. Proposed reaction mechanism.
and the C C bond.[26] This through-bond-promoted fragmen-
À
tation creates the intermediate C, which is characterized by
the presence of an iminium ion and a radical stabilized by the
adjacent nitrogen lone pair (two-center three-electron “half-
bond”).[26] Then, rapid oxidation of the a-aminomethyl
radical forms the cationic intermediate D which is trapped
by a water molecule (!E). Intramolecular nucleophilic
attack of the tertiary nitrogen atom onto the iminium ion
leads to the ring closure (E!F). Hydrolysis of the carbinol-
ammonium group leading to the release of the methylene
group as formaldehyde and to the formation of the ring-
contracted products 2. Finally, it is essential to stress the
importance of the aryl and ester-substituted iminium moiety
(C!E) which is conformationally locked and forbids a relax-
ation of the azocine ring. This restraint leads to the high level
of enantiospecificity and retention of configuration.
In conclusion, a highly enantiospecific methylene extru-
sion reaction is reported and requires only mild oxidative
conditions. Interestingly, the products of ring contraction are
significantly more configurationally stable than regular
Trçger bases. Applications of these derivatives in asymmetric
synthesis and catalysis are looked for.
CCDC 1040107 (2b) contains the supplementary crystal-
lographic 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.
Figure 1. Calculated spectrum of (5SN, 11SN)-2a (green). Experimental
VCD spectra (CCl4, 298 K) of (+)-2a (red) and (À)-2a (blue). The
calculated spectrum represents a weighted average of the VCD spectra
of two conformers (see the Supporting Information for details).
a good agreement between the experimental and theoretical
spectra was observed, thus allowing the assignment of (+)-2a
as (5SN,11SN). These results clearly indicate that the methyl-
ene extrusion occurs with retention of configuration.[21]
At that stage, the fate of the extruded CH2 group was
determined. Careful 1H NMR monitoring of the oxidation
process was performed with a catalytic amount of DDQ
(10 mol%) and an excess of MnO2 (10 equiv).[22] It revealed
a significant amount of formaldehyde in the crude reaction
mixture [up to 15 mol%, Eq. (1)].[23] With that information in
hand, several mechanistic proposals can be considered, the
most likely being that detailed in Scheme 2.
Keywords: configuration determination · enantioselectivity ·
heterocycles · ring contraction · stereochemistry
How to cite: Angew. Chem. Int. Ed. 2015, 54, 7520–7523
Angew. Chem. 2015, 127, 7630–7633
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Received: January 16, 2015
Revised: March 11, 2015
Published online: May 8, 2015
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